Auditory brainstem implant outcomes and MAP parameters: Report of experiences in adults and children

The auditory brainstem implant (ABI) was first developed to help neurofibromatosis type 2 patients. Recently, its use has been recently extended to adults with non-tumor etiologies and children with profound hearing loss who were not candidates for a cochlear implant (Cl). Although the results has been extensively reported, the stimulation parameters involved behind the outcomes have received less attention. Objective: The aim of this study is to describe the audiologic outcomes and the MAP parameters in ABI adults and children at our center. Methods: Retrospective chart review. Five adults and four children were implanted with the ABI24M from September 2005 to June 2009. In the adult patients, four had Neurofibromatosis type 2, and one had postmeningitic deafness with complete ossification of both cochleae. Three of the children had cochlear malformation or dysplasia, and one had complete ossified cochlea due to meningitis. Map parameters as well as the intraoperative electrical auditory brainstem responses were collected. Evaluation was performed with at least six months of device use and included free-field hearing thresholds, speech perception tests in the adult patients and for the children, the Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) and (ESP) were used to evaluate the development of auditory skills, besides the MUSS to evaluate. Results: The number of active electrodes that did not cause any non-auditory sensation varied from three to nineteen. All of them were programmed with SPEAK strategy, and the pulse widths varied from 100 to 300 mu s. Free-field thresholds with warble tones varied from very soft auditory sensation of 70 dBHL at 250 Hz to a pure tone average of 45 dBHL. Speech perception varied from none to 60% open-set recognition of sentences in silence in the adult population and from no auditory sensation at all to a slight improvement in the IT-MAIS/MAIS scores. Conclusion: We observed that ABI may be a good option for offering some hearing attention to both adults and children. In children, the results might not be enough to ensure oral language development. Programming the speech processor in children demands higher care to the audiologist. (C) 2011 Elsevier Ireland Ltd. All rights reserved.

Manifestazioni Cranio-facciali delle Neurofibromatosi

The term neurofibromatosis (NF) subsumes at least seven different genetic disorders associated by the presence of neurofibromas located in the skin, oral cavity, visceral and skeletal level. As NF1 (Von Recklinghausen disease), one of the most common genetic diseases, can have oral manifestations, dentists have to be aware about pathognomonic features. The thesis’ target is the literature’s review on the NF1 manifestations either systemic or cefalic area and these features’ research in a specimen of 30 patients NF1 affected. NF1 is manifested in the cefalic area locating either in the jaws (isolated neurofibromas, ipoplasia or bone structures absence) or soft tissues (fibromas and neurofibromas located in: cheeck, lips, oral mucosa, tongue, mouth’s floor, gingiva and palate). Frequently, NF1 patients are affected by dental anomalies of position, number and eruption, that determinates the possibility of orthopaedic-orthodontic problems. An increased prevalence of the caries risk and a possible pulpar involvement of neurofibromas is reported. Clinical and radiographical typical signs of the disease and specific indications for the differential diagnosis with other oral pathologies are described (cysts and odontogenic tumors, periapical lesions of endodontic origin and severe parodontitis). The importance of screening programs and periodical follow-ups (biannual dental visits from the age of four years, annual X-ray checks from the age of six) is supported by the high frequency of manifestations at hard and soft tissues level of the cefalic area and by the documented risk of malignant transformation.

Plexiform hybrid granular cell tumor/perineurioma: a novel variant of benign peripheral nerve sheath tumor with divergent differentiation

The descriptive term hybrid peripheral nerve sheath tumor refers to any neoplasm of the neurilemmal apparatus composed of more than one pathologically defined tumoral equivalent derived from its constituent cells. Within this uncommon nosological category, participation of granular cell tumor - a neoplasm of modified Schwann cells - has been reported only exceptionally. We describe a hitherto not documented variant composed of an organoid mixture of granular cell tumor and perineurioma with plexiform growth. A solitary subcutaneous nodule of 1.5 cm diameter was excised from the right ring finger of a 19-year-old female with no antecedents of neurofibromatosis or relevant trauma. Histology revealed a monotonous, yet cytologically dimorphic proliferation of classical granular cells intermingled with flattened, inconspicuous perineurial cells. Immunohistochemical double labeling detected expression of S100 protein in the former and of EMA and GLUT-1 in the latter. While the respective staining patterns for S100 protein and EMA or GLUT-1 tended to be mutually exclusive, a minority of cells exhibited transitional granular cell/perineurial immunophenotype. Electron microscopy permitted direct visualization of a plethora of lysosomes in the granular cell moiety, and of pinocytotic vesicles and tight junctions in perineurial cells. Intratumoral axons were not detected. Expanding intraneurally, the lesion showed discrete encapsulation by the local perineurium, and resulted in plexiform growth. The MIB-1 labeling index averaged 1%. We interpret our findings as supporting evidence for the dual cell lineage to have arisen through metaplasia, with the tumor's dynamics probably having been driven by the granular cell component.

An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis

BACKGROUND: Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. METHODS: Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. FINDINGS: SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively. INTERPRETATION: Phaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma-paraganglioma syndrome. FUNDING: The Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and a PHRC grant COMETE 3 for the COMETE network.

Factors affecting postoperative cerebrospinal fluid leaks after retrosigmoidal craniotomy for vestibular schwannomas

OBJECT: The aim of this study was to identify patients likely to develop CSF leaks after vestibular schwannoma surgery using a retrospective analysis for the identification of risk factors. METHODS: Between January 2001 and December 2006, 420 patients underwent retrosigmoidal microsurgical tumor removal in a standardized procedure. Of these 420 patients, 363 underwent treatment for the first time, and 27 suffered from recurrent tumors. Twenty-six patients had bilateral tumors due to neurofibromatosis Type 2, and 4 patients had previously undergone radiosurgical treatment. An analysis was performed to examine the incidence of postoperative CSF fistulas in all 4 groups. RESULTS: The incidence of CSF leakage was higher in the tumor recurrence group (11.1%) than in patients undergoing surgery for the first time (4.4%). There were no CSF fistulas in the neurofibromatosis Type 2 group or in patients with preoperative radiosurgical treatment. Tumor size was identified as a possible risk factor in a previous study. CONCLUSIONS: Surgery for recurrent tumors is a significant risk factor for the development of CSF leaks.

The ROAM/EORTC-1308 trial: Radiation versus Observation following surgical resection of Atypical Meningioma: study protocol for a randomised controlled trial.

BACKGROUND Atypical meningiomas are an intermediate grade brain tumour with a recurrence rate of 39-58 %. It is not known whether early adjuvant radiotherapy reduces the risk of tumour recurrence and whether the potential side-effects are justified. An alternative management strategy is to perform active monitoring with magnetic resonance imaging (MRI) and to treat at recurrence. There are no randomised controlled trials comparing these two approaches. METHODS/DESIGN A total of 190 patients will be recruited from neurosurgical/neuro-oncology centres across the United Kingdom, Ireland and mainland Europe. Adult patients undergoing gross total resection of intracranial atypical meningioma are eligible. Patients with multiple meningioma, optic nerve sheath meningioma, previous intracranial tumour, previous cranial radiotherapy and neurofibromatosis will be excluded. Informed consent will be obtained from patients. This is a two-stage trial (both stages will run in parallel): Stage 1 (qualitative study) is designed to maximise patient and clinician acceptability, thereby optimising recruitment and retention. Patients wishing to continue will proceed to randomisation. Stage 2 (randomisation) patients will be randomised to receive either early adjuvant radiotherapy for 6 weeks (60 Gy in 30 fractions) or active monitoring. The primary outcome measure is time to MRI evidence of tumour recurrence (progression-free survival (PFS)). Secondary outcome measures include assessing the toxicity of the radiotherapy, the quality of life, neurocognitive function, time to second line treatment, time to death (overall survival (OS)) and incremental cost per quality-adjusted life year (QALY) gained. DISCUSSION ROAM/EORTC-1308 is the first multi-centre randomised controlled trial designed to determine whether early adjuvant radiotherapy reduces the risk of tumour recurrence following complete surgical resection of atypical meningioma. The results of this study will be used to inform current neurosurgery and neuro-oncology practice worldwide. TRIAL REGISTRATION ISRCTN71502099 on 19 May 2014.

Genetic epidemiology of childhood brain tumors

A rare familial cancer syndrome involving childhood brain tumors (CBT), breast cancer, sarcomas and an array of other tumors has been described (Li and Fraumeni 1969, 1975, 1982, 1987). A survey of CBT identified through the Connnecticut Tumor Registry in 1984 revealed a high frequency of CBT, leukemia and other childhood cancer in siblings of CBT patients (Farwell and Flannery, 1984). Other syndromes such as neurofibromatosis and nevoid basal cell carcinoma syndrome have also been associated with CBT; however, no systematic family studies have been conducted to determine the extent to which cancer aggregates in family members of CBT patients. This family study was designed to determine the frequency of cancer aggregation overall or at specific sites, to determine the frequency of known or potentially hereditary syndromes in families of CBT patients, and to determine a genetic model to characterize familial cancer syndromes and to identify specific kindreds to which such a model(s) might apply. This study includes 244 confirmed CBT patients referred to the University of Texas M. D. Anderson Cancer Center between the years 1944 and 1983, diagnosed under the age of 15 years and resident in the U.S. or Canada. Family histories were obtained on the proband's first (parents, siblings and offspring) and second degree (proband's aunts, uncles and grandparents) relatives following sequential sampling scheme rules. To determine if cancer aggregates in families, we compared the cancer experience in the population to that expected in the general population using Connecticut Tumor Registry calendar year, age, race and sex-specific rates. The standardized incidence ratio (SIR) for cancer overall was 0.91 (41 observed (O) and 44.94 expected (E); 95% Confidence Interval (CI) = 0.65-1.24). We observed a significant excess of colon cancer among the proband's first degree relatives (O/E = 5/1.64; 95% CI = 1.01-7.65), in particular those under age 45 year. Segregation analysis showed evidence for multifactorial inheritance in the small percentage (N = 5) of the families. ^

Targeting Histone deacetylases (HDAC) for the treatment of soft tissue sarcoma

Targeting Histone deacetylases (HDAC) for the treatment of genetically complex soft tissue sarcoma Histone deactylase inhibitors (HDACi) are a new class of anticancer therapeutics; however, little is known about HDACi or the individual contribution of HDAC isoform activity in soft tissue sarcoma (STS). We investigated the potential efficacy of HDACi as monotherapy and in combination with chemotherapy in a panel of genetically complex STS. We found that HDACi combined with chemotherapy significantly induced anti-STS effects in vitro and in vivo. We then focused our study of HDACi in malignant peripheral nerve sheath tumor (MPNST), a subtype of highly aggressive, therapeutically resistant, and commonly fatal malignancies that occur in patients with neurofibromatosis type-1 (NF1) or sporadically. The therapeutic efficacy of HDACi was investigated in a panel of NF1-associated and sporadic MPNST cell lines. Our results demonstrate the NF1-assocaited cohort to be highly sensitive to HDACi while sporadic cell lines exhibited resistance. HDACi-induced productive autophagy was found to be a mode of resistance and inhibiting HDACi-induced autophagy significantly induced pro-apoptotic effects of HDACi in vitro and in vivo. HDACs are not a single enzyme consisting of 11 currently known isoforms. HDACis used in these studies inhibit a variety of these isoforms, namely class I HDACs which include HDAC1, 2, 3, and 8. Recently, HDAC8-specific inhibitors (HDAC8i) have been created and tested in various cancer cell lines. Lastly, the potential therapeutic efficacy of HDAC8i was investigated in human (NF1-associated and sporadic) and NF1-associated murine-derived MPNST. HDAC8i abrogated cell growth in human and murine-derived MPNST cells. Similar to the pattern noticed with pan-HDACis NF1-associated cells, especially murine-derived, were more sensitive to HDAC8i compared to human sporadic MPNST cell lines. S-phase arrest was observed in human and murine MPNST cells, independent of p53 mutational and NF1 status. HDAC8i induced apoptosis is all cell lines tested, with a more pronounced effects in human and murine-derived NF1-associated cells. Most importantly, HDAC8i abrogated murine-derived MPNST xenograft growth in vivo. Taken together, these findings support the evaluation of pan-HDACi and isoform-specific inhibitors as a novel therapy to treat MPNST, including in combination with autophagy blocking combination regimens in particular for patients with sporadic MPNST.

Rasopatias : mutações germinativas na via de sinalização Ras/MAPK e associação ao desenvolvimento de patologia neoplásica

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014

The scaffold protein KSR1, a novel therapeutic target for the treatment of Merlin-deficient tumors

Merlin has broad tumor-suppressor functions as its mutations have been identified in multiple benign tumors and malignant cancers. In all schwannomas, the majority of meningiomas and 1/3 of ependymomas Merlin loss is causative. In neurofibromatosis type 2, a dominantly inherited tumor disease because of the loss of Merlin, patients suffer from multiple nervous system tumors and die on average around age 40. Chemotherapy is not effective and tumor localization and multiplicity make surgery and radiosurgery challenging and morbidity is often considerable. Thus, a new therapeutic approach is needed for these tumors. Using a primary human in vitro model for Merlin-deficient tumors, we report that the Ras/Raf/mitogen-activated protein, extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) scaffold, kinase suppressor of Ras 1 (KSR1), has a vital role in promoting schwannomas development. We show that KSR1 overexpression is involved in many pathological phenotypes caused by Merlin loss, namely multipolar morphology, enhanced cell-matrix adhesion, focal adhesion and, most importantly, increased proliferation and survival. Our data demonstrate that KSR1 has a wider role than MEK1/2 in the development of schwannomas because adhesion is more dependent on KSR1 than MEK1/2. Immunoprecipitation analysis reveals that KSR1 is a novel binding partner of Merlin, which suppresses KSR1's function by inhibiting the binding between KSR1 and c-Raf. Our proteomic analysis also demonstrates that KSR1 interacts with several Merlin downstream effectors, including E3 ubiquitin ligase CRL4DCAF1. Further functional studies suggests that KSR1 and DCAF1 may co-operate to regulate schwannomas formation. Taken together, these findings suggest that KSR1 serves as a potential therapeutic target for Merlin-deficient tumors.

The potential role of environmental exposures and genomic signaling in development of central nervous system tumors

The etiology of central nervous system tumors (CNSTs) is mainly unknown. Aside from extremely rare genetic conditions, such as neurofibromatosis and tuberous sclerosis, the only unequivocally identified risk factor is exposure to ionizing radiation, and this explains only a very small fraction of cases. Using meta-analysis, gene networking and bioinformatics methods, this dissertation explored the hypothesis that environmental exposures produce genetic and epigenetic alterations that may be involved in the etiology of CNSTs. A meta-analysis of epidemiological studies of pesticides and pediatric brain tumors revealed a significantly increased risk of brain tumors among children whose mothers had farm-related exposures during pregnancy. A dose response was recognized when this risk estimate was compared to those for risk of brain tumors from maternal exposure to non-agricultural pesticides during pregnancy, and risk of brain tumors among children exposed to agricultural activities. Through meta-analysis of several microarray studies which compared normal tissue to astrocytomas, we were able to identify a list of 554 genes which were differentially expressed in the majority of astrocytomas. Many of these genes have in fact been implicated in development of astrocytoma, including EGFR, HIF-1α, c-Myc, WNT5A, and IDH3A. Reverse engineering of these 554 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme (GBM) were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. Lastly, bioinformatics analysis of environmental databases and curated published results on GBM was able to identify numerous potential pathways and geneenvironment interactions that may play key roles in astrocytoma development. Findings from this research have strong potential to advance our understanding of the etiology and susceptibility to CNSTs. Validation of our ‘key genes’ and pathways could potentially lead to useful tools for early detection and novel therapeutic options for these tumors.

Retrocaval mass in patient with von Recklinghausen disease. Case report

Type I Neurofibromatosis (NF1) is an autosomal-dominant inheritable disorder, with an incidence of 1:3,000, and a prevalence of 1:4,000 to 5,000. Pathogenesis is based on mutations of the NF1 gene, a tumor suppressor gene encoding a cytoplasmic protein named neurofibromin that controls cellular proliferation. Patients affected by NF1 typically present with cutaneous neurofibromas, cafè au lait spots and eye involvement, but they can also be affected by various visceral tumors, such as neurofibromas (nodular or plexiform type), gastrointestinal stromal tumors or endocrine tumors, such as pheochromocytomas. Visceral neurofibromas are often asymptomatic but when growing in size they may present with pain, palpable abdominal mass, symptoms secondary to bowel obstruction or main vessels compression, and even gastrointestinal bleeding when mucosa or submucosa are involved. In these cases surgery becomes mandatory in order to remove all neoplastic tissue. The Authors describe a case of a young man affected by NF1 with associated retrocaval abdominal mass with compression and displacement of the inferior vena cava, thus requiring a complex surgical procedure.

Vacuum-assisted closure treatment of leg skin necrosis after angiographic embolization of a giant plexiform neurofibroma

Type 1 neurofibromatosis is a relatively common inherited disease of the nervous system, with a frequency of almost 1 in 3000. It is associated with neurofibromas of various sites. Our case report is about the surgical management of a giant neurofibroma of the right gluteal fold in a 46-year-old male with NF1. The patient presented with increasing edema and accelerated growth of the mass; he underwent percutaneous embolization of lesion vessels that induced necrosis of the neurofibroma. The patient was taken to the operating room, where surgical resection of the bulk of the lesion was undertaken. The postoperative course was complicated by delayed wound closure managed with antibiotics and vacuum-assisted wound closure. Giant neurofibromas similar to this tumor require complex preoperative, intraoperative and postoperative management strategies. Surgical debulk is best managed with preoperative percutaneous embolization that help to avoid surgical bleeding. Postoperative delayed wound closure was managed with the application of negative pressure in a closed environment that triggers granulation and tissue formation.

Tumores malignos de la vaina nerviosa periférica como origen de dolor orofacial

Los tumores malignos de la vaina nerviosa periférica (TMVNP), también llamados neurofribrosarcomas o schwannomas malignos, representan el 10% de todos los sarcomas de tejidos blandos. El tumor usualmente se encuentra en las extremidades inferiores, y solo del 10 al 20% de las lesiones ocurren en la región de cabeza y cuello, convirtiéndolas en una entidad rara. Los neurofibromas son tumores de la vaina nerviosa que aparecen comúnmente en la neurofibromatosis 1 o enfermedad de Von Recklinghausen. Se ha reportado que los individuos con antecedentes familiares de neurofibromatosis 1 tienen un riesgo incrementado de desarrollar TMVNP en el transcurso de sus vidas, sin embargo, esta asociación no se ha confirmado en TMVNP a nivel de los nervios craneales. En este artículo los autores analizaron la literatura actual con respecto a los TMVNP del nervio trigémino, así como la inclusión de un caso inusual que involucra las 3 ramas de dicho nervio.