Functional Outcomes and Temporal Profile of Recovery in Patients with Intradural Extramedullary Spinal Cord Tumors with Poor Nurick Grade.

BACKGROUND: Patients with spinal intradural extramedullary (IDEM) tumors usually have a good functional outcome after tumor excision. However, the literature is sparse on the functional outcome in patients with poor Nurick grade (NG 4 and 5). METHODS: A retrospective review of 81 patients with IDEM tumors presenting with a poor NG was performed to determine postoperative functional outcome and the temporal pattern of recovery. The following risk factors were analyzed: preoperative NG, duration of symptoms, tumor location, peritumoral edema, presence of syrinx, and tumor type. RESULTS: Neurologic function started recovering soon after surgery, with >80% of the patients improving by ≥1 grade at the end of 1 week after surgery. Of the 66 patients available for follow-up of >6 months after surgery, 63 (95.5%) improved to NG 0-2 and 51 (77.2%) became asymptomatic (NG 0 or 1). Three patients had a poor functional outcome on follow-up of >31 months; 2 had improved from NG 5 to NG 4, whereas 1 patient continued to be in NG 4. Factors associated with a poor outcome were an upper thoracic location (P = 0.025) and presence of a syrinx (P = 0.004). None of the patients had bladder dysfunction at follow-up of >6 months. CONCLUSIONS: After excision of spinal IDEM tumors, in patients who present with a poor neurologic function (NG 4 and 5), good functional outcome (NG 0-2) can be expected in >95% of patients. No recovery can be anticipated beyond 1 year after surgery.

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.

Neurofibromatosis tipos 1 y 2 / Neurofibromatosis type 1 and 2

La neurofibromatosis (NF) comprende un grupo de enfermedades genéticas de herencia autosómica dominante, que se clasifican de la siguiente manera: neurofibromatosis tipo 1 (NF1), neurofibromatosis tipo 2 (NF2) y schwannomatosis (también conocida como neurofibromatosis tipo 3). Esta última es una enfermedad muy infrecuente, con una prevalencia aproximada de 1/126 000 personas, por lo que solo profundizaremos las dos primeras. La NF1, también conocida como la enfermedad de Von Recklinghausen, es la más frecuente de las tres y afecta principalmente la piel y el sistema nervioso periférico. Se caracteriza por la presencia de máculas "café con leche", pecas axilares o inguinales, nódulos de Lisch (hamartomas en el iris) y neurofibromas (tumores de la vaina de nervios periféricos). Otras manifestaciones menos frecuentes, aunque de mayor gravedad, incluyen gliomas del nervio óptico, meningiomas, neurofibromas malignos, escoliosis y displasia de la tibia. Su diagnóstico se suele realizar al nacimiento o durante los primeros años de vida, y se estima que un 50% de quienes la padecen presenta dificultades cognitivas. No hay datos concluyentes sobre la mortalidad en los pacientes con NF1, aunque se sabe que la expectativa de vida es menor que en la población general. La NF2 tiene una prevalencia considerablemente menor que la NF1 y su inicio es más tardío, afectando principalmente a adultos jóvenes. La presentación clínica típica se caracteriza por acúfenos, hipoacusia y ataxia en contexto de la presencia de schwannomas vestibulares bilaterales. Otros hallazgos menos frecuentes incluyen schwannomas de nervios periféricos, meningiomas, ependimomas o astrocitomas. La esperanza de vida es de unos 36 años, con una supervivencia media desde el momento del diagnóstico de 15 años. (AU)

Neurofibromatosis (NF) includes a group of genetic diseases with an autosomal-dominant inheritance pattern, and they are classified as follows: Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2) and Schwannomatosis (also known as neurofibromatosis type 3). This last one is a very rare disease, with an approximate prevalence of 1/126000, so we will only deepen in the first two. NF1, also known as von Recklinghausen disease, is the most frequent, and mainly affects the skin and peripheral nervous system. Its typical manifestations are the presence of café-au-lait macules, axillary or inguinal freckles, Lisch nodules (hamartomas in the iris) and neurofibromas (peripheral nerve sheath tumors). Less frequent manifestations, although more serious, include optic nerve gliomas, meningiomas, malignant neurofibromas, scoliosis and tibial dysplasia. The diagnosis is usually made at birth or during the first years of life, and approximately 50% of patients present cognitive difficulties. There is no conclusive data on mortality in patients with NF1, although it is known that life expectancy is lower than in general population. NF2 has a considerably lower prevalence than NF1, and its onset is later in life, mainly affecting young adults. Its typical clinical presentation is characterized by tinnitus, hearing loss and ataxia in the context in the presence of bilateral vestibular schwannomas. Less frequent findings include peripheral nerve schwannomas, meningiomas, ependymomas or astrocytomas. Life expectancy is about 36 years old, with a median survival from the moment of diagnosis of 15 years. (AU)

Surgical treatment of giant benign sacral neurogenic tumors using the posterior-only approach.

OBJECTIVE: Few studies have reported on the effects of surgery on giant benign sacral neurogenic tumors since these tumors represent a major challenge for surgical oncologists. In the present study, we retrospectively reviewed our experiences in performing resections of giant benign sacral neurogenic tumors using the posterior-only approach via "fishing" method, and assessed the outcomes of patients after this procedure. PATIENTS AND METHODS: We retrospectively reviewed and analyzed the records of 155 consecutive patients with giant benign sacral neurogenic tumors who underwent resection by a posterior-only approach in our center from Feb 2008 to Feb 2018. RESULTS: Operations lasted for a mean of 183 ±â€¯37 min (range, 125-230 min). The mean estimated blood loss during the surgery was 1098 ±â€¯889 ml (range, 600-4100 ml). The mean follow-up time was 65 ±â€¯39 months (range, 12-118 months). By the last follow-up, the local recurrence rate was 7.1% (11/155), the combined overall symptom resolution and remission rate was 91.1% (123/135), and the total complication rate was 17.4% (27/155). CONCLUSION: The posterior-only approach is safe and effective in patients with giant benign sacral neurogenic tumors.

Cellular Origin, Tumor Progression, and Pathogenic Mechanisms of Cutaneous Neurofibromas Revealed by Mice with Nf1 Knockout in Boundary Cap Cells.

Patients carrying an inactive NF1 allele develop tumors of Schwann cell origin called neurofibromas (NF). Genetically engineered mouse models have significantly enriched our understanding of plexiform forms of NFs (pNF). However, this has not been the case for cutaneous neurofibromas (cNF), observed in all NF1 patients, as no previous model recapitulates their development. Here, we show that conditional Nf1 inactivation in Prss56-positive boundary cap cells leads to bona fide pNFs and cNFs. This work identifies subepidermal glia as a likely candidate for the cellular origin of cNFs and provides insights on disease mechanisms, revealing a long, multistep pathologic process in which inflammation-related signals play a pivotal role. This new mouse model is an important asset for future clinical and therapeutic investigations of NF1-associated neurofibromas. SIGNIFICANCE: Patients affected by NF1 develop numerous cNFs. We present a mouse model that faithfully recapitulates cNFs, identify a candidate cell type at their origin, analyze the steps involved in their formation, and show that their development is dramatically accelerated by skin injury. These findings have important clinical/therapeutic implications.This article is highlighted in the In This Issue feature, p. 1.

Spatiotemporal Loss of NF1 in Schwann Cell Lineage Leads to Different Types of Cutaneous Neurofibroma Susceptible to Modification by the Hippo Pathway.

Neurofibromatosis type 1 (NF1) is a cancer predisposition disorder that results from inactivation of the tumor suppressor neurofibromin, a negative regulator of RAS signaling. Patients with NF1 present with a wide range of clinical manifestations, and the tumor with highest prevalence is cutaneous neurofibroma (cNF). Most patients harboring cNF suffer greatly from the burden of those tumors, which have no effective medical treatment. Ironically, none of the numerous NF1 mouse models developed so far recapitulate cNF. Here, we discovered that HOXB7 serves as a lineage marker to trace the developmental origin of cNF neoplastic cells. Ablating Nf1 in the HOXB7 lineage faithfully recapitulates both human cutaneous and plexiform neurofibroma. In addition, we discovered that modulation of the Hippo pathway acts as a "modifier" for neurofibroma tumorigenesis. This mouse model opens the doors for deciphering the evolution of cNF to identify effective therapies, where none exist today. SIGNIFICANCE: This study provides insights into the developmental origin of cNF, the most common tumor in NF1, and generates the first mouse model that faithfully recapitulates both human cutaneous and plexiform neurofibroma. The study also demonstrates that the Hippo pathway can modify neurofibromagenesis, suggesting that dampening the Hippo pathway could be an attractive therapeutic target.This article is highlighted in the In This Issue feature, p. 1.

The biology of cutaneous neurofibromas: Consensus recommendations for setting research priorities.

OBJECTIVE: A group of experts in dermatology, genetics, neuroscience, and regenerative medicine collaborated to summarize current knowledge on the defined factors contributing to cutaneous neurofibroma (cNF) development and to provide consensus recommendations for future research priorities to gain an improved understanding of the biology of cNF. METHODS: The group members reviewed published and unpublished data on cNF and related diseases via literature search, defined a set of key topic areas deemed critical in cNF pathogenesis, and developed recommendations in a series of consensus meetings. RESULTS: Five specific topic areas were identified as being relevant to providing an enhanced understanding of the biology of cNF: (1) defining the human cells of origin; (2) understanding the role of the microenvironment, focusing on neurons, mast cells, and fibroblasts; (3) defining the genetic and molecular differences between the cNFs, focusing on size and number; (4) understanding if sex hormones are critical for cNF development or progression; and (5) identifying challenges in establishing in vitro and in vivo models representing human cNF. CONCLUSIONS: The complexity of cNF biology stems from its heterogeneity at multiple levels including genetic, spatial involvement, temporal development, and cellular composition. We propose a unified working model for cNF that builds a framework to address the key questions about cNF that, when answered, will provide the necessary understanding of cNF biology to allow meaningful development of therapies.

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.

Improved patient quality of life following intradural extramedullary spinal tumor resection.

OBJECTIVE Resection significantly improves the clinical symptoms and functional outcomes of patients with intradural extramedullary tumors. However, patient quality of life following resection has not been adequately investigated. The aim in this retrospective analysis of prospectively collected quality of life outcomes is to analyze the efficacy of resection of intradural extramedullary spinal tumors in terms of quality of life markers. METHODS A retrospective review of a single institutional neurosurgical administrative database was conducted to analyze clinical data. The Oswestry Disability Index (ODI), visual analog scale (VAS) for pain, and the EQ-5D-3 L descriptive system were used to analyze quality of life preoperatively, less than 1 month postoperatively, 1-3 months postoperatively, 3-12 months postoperatively, and more than 12 months postoperatively. RESULTS The ODI scores increased perioperatively at the < 1-month follow-up from 36 preoperatively to 47. Relative to preoperative values, the ODI score decreased significantly at 1-3, 3-12, and > 12 months to 23, 17, and 20, respectively. VAS scores significantly decreased from 6.1 to 3.5, 2.4, 2.0, and 2.9 at the < 1-month, 1- to 3-, 3- to 12-, and > 12-month follow-ups, respectively. EQ-5D mobility significantly worsened at the < 1-month follow-up but improved at the 3- to 12-and > 12-month follow-ups. EQ-5D self-care significantly worsened at the < 1-month follow-up but significantly improved by the 3- to 12-month follow-up. EQ-5D usual activities improved at the 1- to 3-, 3- to 12-, and > 12-month follow-ups. EQ-5D pain and discomfort significantly improved at all follow-up points. EQ-5D anxiety and depression significantly improved at 1- to 3-month and 3- to 12-month follow-ups. CONCLUSIONS Resection of intradural extramedullary spine tumors appears to significantly improve patient quality of life by decreasing patient disability and pain and by improving each of the EQ-5D domains.

Massive Soft Tissue Neurofibroma (Elephantiasis Neuromatosa): Case Report and Review of Literature.

The authors review the literature on massive soft tissue neurofibroma. The methods included a review of 71 reports (PubMed search 1929-2012) with a total of 91 massive soft tissue neurofibroma patients and illustration of clinical and radiological progression of massive soft tissue neurofibroma on a patient with neurofibromatosis type 1. The mean age at initial examination was 21 years. Tumor onset was mostly in childhood years. The commonest affected body segment was the lower extremity (46%), followed by head/neck (30%). Surgical management was pursued in the majority of cases (79%). Bleeding was a common complication (25%). Recurrence was described in 12%; multiple resections cases were described. Malignant transformation occurred in 5%. Although massive soft tissue neurofibroma may be present early in life, massive tumor overgrowth may take years. Predicting disease progression and/or benefit of surgical intervention early in the disease course is challenging. Recurrence and malignant transformation are possible. Massive soft tissue neurofibroma does not respond to chemotherapy or radiotherapy and is associated with life-threatening surgical complications.

Epigenetic induction of the Ink4a/Arf locus prevents Schwann cell overproliferation during nerve regeneration and after tumorigenic challenge.

The number of Schwann cells is fitted to axonal length in peripheral nerves. This relationship is lost when tumorigenic stimuli induce uncontrolled Schwann cell proliferation, generating tumours such us neurofibromas and schwannomas. Schwann cells also re-enter the cell cycle following nerve injury during the process of Wallerian degeneration. In both cases proliferation is finally arrested. We show that in neurofibroma, the induction of Jmjd3 (jumonji domain containing 3, histone lysine demethylase) removes trimethyl groups on lysine-27 of histone-H3 and epigenetically activates the Ink4a/Arf-locus, forcing Schwann cells towards replicative senescence. Remarkably, blocking this mechanism allows unrestricted proliferation, inducing malignant transformation of neurofibromas. Interestingly, our data suggest that in injured nerves, Schwann cells epigenetically activate the same locus to switch off proliferation and enter the senescence programme. Indeed, when this pathway is genetically blocked, Schwann cells fail to drop out of the cell cycle and continue to proliferate. We postulate that the Ink4a/Arf-locus is expressed as part of a physiological response that prevents uncontrolled proliferation of the de-differentiated Schwann cell generated during nerve regeneration, a response that is also activated to avoid overproliferation after tumorigenic stimuli in the peripheral nervous system.

Potential role of 18fluorodeoxyglucose-positron emission tomography/computed tomography in differentiating benign neurofibroma from malignant peripheral nerve sheath tumor associated with neurofibromatosis 1.

OBJECTIVE: Benign plexiform neurofibromas (PNfib), especially those occurring in patients with neurofibromatosis type 1, are at a significant risk of progressing to a malignant peripheral nerve sheath tumor (MPNST). Early diagnosis, followed by radical surgery and adjuvant radiation to maintain local tumor control, is of critical importance to prevent metastasis and subsequent mortality from MPNSTs. However, early diagnosis is hampered by the sensitivity of current imaging modalities such as computed tomography (CT) or magnetic resonance imaging to reliably detect this malignant transformation, which can occur heterogeneously in a PNfib to a MPNST. 18Fluorodeoxyglucose (18FDG)-positron emission tomography (PET) is linked to metabolism and proliferation of tissues and has been widely used in oncology including PNSTs. 18FDG-PET/CT has the added advantage of fusing metabolic and anatomic imaging data sets. METHODS: In this prospective study, 9 neurofibromatosis type 1-associated PNfibs suspected to have undergone transformation to an MPNST were preoperatively evaluated by 18FDG-PET/CT and magnetic resonance imaging. A detailed histological evaluation correlated the average and regional standard uptake value (SUV) from the 18FDG-PET/CT to grade of malignancy of the suspected MPNST. RESULTS: Imaging from 18FDG-PET/CT and associated SUV of the suspected MPNSTs demonstrated either a homogeneous or a heterogeneous pattern. Stratification of the maximal SUV to low (<4.0), intermediate (4.0-7.0), or high (>7.0) correlated to the proliferative index (Ki-67) and grade of MPNST. A maximal SUV of more than 7.0 was closely correlated to a focus of malignant transformation. CONCLUSION: This study, on a limited number of cases, demonstrates the potential use of 18FDG-PET/CT to augment management of PNfibs, especially in the context of neurofibromatosis type 1, which is characterized by multiple tumors. The addition of CT anatomic imaging to 18FGD-PET can facilitate targeting biopsies to metabolic hot spots, to further augment diagnostic sensitivity. Much larger numbers of MPNSTs, which can only be accrued in a collaborative manner among institutions, are required to further assess the specificity and sensitivity of 18FDG-PET/CT in the diagnosis of MPNSTs.

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.

Influence of hormones and hormone metabolites on the growth of Schwann cells derived from embryonic stem cells and on tumor cell lines expressing variable levels of neurofibromin.

Loss of neurofibromin, the protein product of the tumor suppressor gene neurofibromatosis type 1 (NF1), is associated with neurofibromas, composed largely of Schwann cells. The number and size of neurofibromas in NF1 patients have been shown to increase during pregnancy. A mouse embryonic stem cell (mESC) model was used, in which mESCs with varying levels of neurofibromin were differentiated into Schwann-like cells. NF1 cell lines derived from a malignant and a benign human tumor were used to study proliferation in response to hormones. Estrogen and androgen receptors were not expressed or expressed at very low levels in the NF1+/+ cells, at low levels in NF1+/-cells, and robust levels in NF1-/-cells. A 17beta-estradiol (E2) metabolite, 2-methoxy estradiol (2ME2) is cytotoxic to the NF1-/- malignant tumor cell line, and inhibits proliferation in the other cell lines. 2ME2 or its derivatives could provide new treatment avenues for NF1 hormone-sensitive tumors at times of greatest hormonal influence.

Combined manifestation of a neurofibroma and a nerve sheath ganglion in the ulnar nerve after radiotherapy in early childhood.

Occurrence of clinically symptomatic benign neurofibromas of peripheral nerves after radiotherapy is a rarity. We saw a 55-year-old female who developed progressive failure of the ulnar nerve 55 years after 20Gy (226)Ra brachytherapy of a haemangioma of the left elbow at the age of 3 months. Nerve compression at the sulcus segment was caused by the intraneural growth of a neurofibroma and the formation of a nerve sheath ganglion. The rapidly progressive symptoms required operative treatment. Due to the infiltrating tumour growth we decided to resect this segment of the ulnar nerve and reconstruct it with an interfascicular nerve graft. This case demonstrates a rare possible consequence of radiotherapy in which the co-existence of two benign lesions required surgical intervention. Radiotherapy-induced malignant tumours and tissue scarring are well known as complications. The present case suggests further possible late effects of radiotherapy to consider.

Phase II trial of pirfenidone in adults with neurofibromatosis type 1.

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.

Our experience with surgical treatment of the tumours of peripheral nerves in extremities and brachial plexus.

OUTLINE: The paper presents the results of 33 microsurgical removal of 33 tumours of brachial plexus and of peripheral nerves in extremities performed on 31 patients during the period of 11 years, from 1990 to 2001. PATIENT GROUP AND METHODS: The patient group included 26 patients treated for removal of 28 tumours of peripheral nerves in extremities and 5 patients treated for removal of 5 tumours of brachial plexus. Three of these brachial plexus tumours showed intraspinal spread. 32 tumours of neural sheath included 20 schwannomas and 12 neurofibromas. 6 of these 12 neurofibromas were observed in 4 patients suffering from Reklinghausen disease (VRD). One patient had a tumour of non-neural elements--lipoma. We did not encounter any malign tumours of neural sheaths or other neural sheath-derived tumours (benign or metastatic malign ones) that would compress or invade the nerves or plexus. The results were evaluated according to Donner classification of motor and sensory functions. RESULTS: Motor functions improved or remained unchanged in 18 (90%) patients with schwannoma. 5 patients (83.3%) with pain in the distribution of the affected nerve reported complete or partial improvement of the symptoms. Regarding neurofibroma patients, 3 exhibited either an improvement or unchanged motor functions, and all of them reported partial or complete retreat of pain symptoms. 4 patients with VRD were subjected to the removal of 6 tumours of peripheral nerves in extremities; all of them exhibited improved or stabilised motor functions and partial or complete retreat of pain symptoms. The outcome of treatments was generally better in smaller tumours of neural sheaths with more distal localisation. CONCLUSION: Patients should be treated in the early stage of tumour development when the size remains smaller and neurological deficits are absent.

Aberrant G protein signaling in nervous system tumors.

OBJECT: Guanosine triphosphate (GTP)-binding proteins, also known as G proteins, play important roles in the regulation of cell growth and differentiation by transmitting intracellular signals from cell surface receptors. In this paper, the authors review G protein signaling in general and its aberrations in four human nervous system tumors. METHODS: In the nervous system, four tumor types have been associated with aberrant G protein signaling. The first tumor type includes astrocytomas, which have increased levels of the activated form of the small G protein, p21-ras, without primary oncogenic p21-ras mutations. The likely source for increased p21-ras activity in sporadically occurring astrocytomas is overexpressed or constitutively activated growth factor receptors, whereas in neurofibromatosis Type 1 (NF1)-associated astrocytomas, the source is a loss of expression of neurofibromin, a major inactivator of p21-ras (ras-GTPase activating protein [GAP]). The second type of tumor associated with aberrant G protein signaling includes sporadic and NF1-associated neurofibromas and malignant peripheral nerve sheath tumors, which also have increased p21-ras activity due to a loss of neurofibromin expression. The third tumor type includes subependymal giant cell astrocytomas as part of the tuberous sclerosis complex (TSC). These tumors display a loss of tuberin expression due to germline mutations in the TSC2 gene. Tuberin functions as an inactivator of the small G protein rap1B (rap1-GAP) and, hence, loss of its expression could lead to increased rap1B activity. In addition to TSC-associated tumors, the authors demonstrate that the majority of sporadically occurring astrocytomas display either loss of tuberin or overexpression of rap1B. This suggests that increased rap1B activity, which can augment p21-ras-mediated signals, also contributes to G protein-mediated aberrant signaling in sporadically occurring astrocytomas. The fourth tumor type includes a significant subset of pituitary adenomas that show constitutive activation of the G alpha subunit of the large heterotrimeric G s protein, which is involved in hormone receptor signaling. The net result of this aberrant activation is increased cyclic adenosine monophosphate and mitogenic tumor-promoting signals. CONCLUSIONS: The authors' review of G protein signaling and aberrations in this process is made with the long-term view that increased understanding of relevant signaling pathways will eventually lead to novel biological targeted therapies against these tumors.