Unmasking a new prognostic marker and therapeutic target from the GDNF-RET/PIT1/p14ARF/p53 pathway in acromegaly.

BACKGROUND: Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. METHODS: We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized' pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. FINDINGS: In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. INTERPRETATION: Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. FUND: This project was supported by national grants from Agencia Estatal de Investigación (AEI) and Instituto Investigación Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN). CVA is also supported from a grant of Medical Research Council UK MR/M018539/1.

Solitary fibrous tumour/haemangiopericytoma of the spinal cord. / Tumor fibroso solitario/hemangiopericitoma de la médula espinal.

Solitary fibrous tumours/haemangiopericytomas (SFT/HPC) are fibroblastic mesenchymal neoplasms that harbour a genetic fusion of NAB2/STAT6. There are few reported cases in the central nervous system (CNS), of which spinal tumours are minority. We present a case of a 63-year-old woman with progressive paraparesis and a sensory level of T6. On the MRI we detected an intradural extramedullary lesion on T9-T10. We performed a laminectomy with an intraoperative ultrasound study in which we observed a heterogeneous lesion with an infiltrating pattern affecting the medulla at several points, and resection of the lesion. Immunohistological findings revealed positivity for vimentin, CD34 and STAT6; Ki-67 was 2%. A final diagnosis of SFT/HPC with SFT phenotype was made. SFT/HPC of the CNS is a rare neoplasm that should be taken into account in the differential diagnosis of these kinds of lesions, as clinical and MRI findings often lead to errors in diagnostic approach. The support of intraoperative ultrasound can assist in surgical decision-making.

Spontaneous cerebrospinal fluid leaks in the anterior skull base secondary to idiopathic intracranial hypertension.

Spontaneous cerebrospinal fluid (CSF) leaks represent a clinical entity in which CSF rhinorrhea occurs in the absence of any inciting event. Spontaneous CSF leaks are associated with elevated intracranial pressure (ICP) or have underlying idiopathic intracranial hypertension (IIH). We report a cohort of patients who have undergone nasal endoscopic repair for spontaneous CSF leaks. We review our perioperative complications and the effectiveness of the nasal endoscopic approach to repair spontaneous CSF leaks. Also, we examine the evidence correlating spontaneous CSF leaks and IIH and the role of decreasing ICP in the treatment of nasal spontaneous CSF leaks. A retrospective analysis of patients with nasal spontaneous cerebrospinal fluid leaks was performed. Data on the nature of presentation, patient body mass index, defect location and size, ICP, clinical follow-up, and complications were collected. Thirty-five patients had nasal spontaneous cerebrospinal fluid leaks with evidence of IIH's symptoms. The most common sites were the cribriform plate, the ethmoid roof, and sphenoid lateral pterygoid recess. All patients underwent endonasal endoscopic surgery to repair the defect. Postoperatively, all patients underwent lumbar drainage and acetazolamide therapy. Nasal spontaneous cerebrospinal fluid leaks represent a surgical challenge because of their high recurrence rates. The most important factor for obtaining a successful repair in these patients is reducing their intracranial pressure through nutritional, medical, or surgical means.

[Cerebral infarction after pituitary apoplexy: Description of a case and review of the literature]. / Infarto cerebral tras apoplejía pituitaria: descripción de un caso y revisión de la literatura.

Pituitary apoplexy is usually the result of hemorrhagic infarction in a pituitary adenoma. The clinical presentation varies widely and includes asymptomatic cases, classical pituitary apoplexy and even sudden death. Cerebral ischemia due to pituitary apoplexy is very rare. It may be caused by vasospasm or direct compression of cerebral vessels by the tumor. We report a case of pituitary apoplexy associated with cerebral infarction and discuss the relationship between the two events.

[Bilateral chronic subdural haematoma: Analysis of a series of 190 patients]. / Hematoma subdural crónico bilateral: análisis de una serie de 190 pacientes.

OBJECTIVE: The aim of this study is to analyse the clinical findings and surgical results in a series of patients with bilateral chronic subdural haematoma (BCSDH), and compare the results with a series of patients treated for unilateral chronic subdural haematoma (UCSDH). PATIENTS AND METHODS: A retrospective study was performed on 1523 patients diagnosed and surgically treated for chronic subdural haematoma over a period of 30 years. Patients were divided into 2 groups: The study group consisting of 190 patients operated on for a BCSDH and the control group consisting of patients operated on for an UCSDH (1333 cases). RESULTS: The patient series included 126 males (66.3%) and 64 females (33.7%), with a mean age at diagnosis of 74.8±10.2. The control group consisted of 870 males (65.2%) and 463 women (34.8%), with a mean age of 73.2±12.1. The most common presenting symptoms was cognitive impairment in 63 patients (33.2%) with BCSDH and 416 (29.5%) with UCSDH. Recurrence rates were 9.4% (18 patients) and 5.7% (77 patients) in unilateral and bilateral haematomas, respectively. The mortality was 10 patients (5.2%) with BCSDH and 55(4%) with UCSDH. Factors significantly related to recurrence in the univariate analysis were being male (P=.040), anticoagulant/antiplatelet therapy (P=.032), and poor neurological status at admission (P=.039). CONCLUSIONS: This study indicates that BCSDH is more frequent in males, and the most common presentation is headache. The most important factors influencing recurrences are being male, intake of anticoagulant-antiaggregant drugs, and worse clinical status at admission.

[Imaging diagnosis of arachnoid cysts]. / Diagnóstico por imagen de los quistes aracnoideos.

Arachnoid cysts are malformed lesions that contain a fluid similar to the cerebrospinal fluid, and are usually located within the arachnoidal membrane. They represent 1% of all intracranial lesions, and in recent years, with the development of radiological techniques, the clinical detectability of arachnoid cysts seems to have increased. Although the majority of diagnosed arachnoid cysts are located in the cranial cavity and especially in the Sylvian fissure, a small number are located at spinal level and they can occur extra- or intra-spinally. An analysis is carried out, detailing the various tests used for the diagnosis of both intracranial and spinal arachnoids cysts, analysing the indications of each one depending on the location of the cysts and patient age.

[«De novo¼ development of a suprasellar arachnoid cyst]. / Desarrollo «de novo¼ de un quiste aracnoideo supraselar.

Intracranial arachnoid cysts are fluid-filled cavities that arise within the cranial arachnoid, representing approximately 1%-2% of all intracranial lesions among the paediatric population. We present the case of a 2-year-old boy who presented with instability and episodes of ocular deviation. A computed tomography scan (CT scan) and magnetic resonance imaging (MRI) of the brain revealed a suprasellar cyst and obstructive hydrocephalus. At birth a transfontanellar ultrasound was normal. The cyst underwent endoscopic fenestration with complete remission of symptoms. In the review of the literature, we found only 6 previous cases of an intracranial arachnoid cyst whose origin was not clearly congenital or traumatic, and ours is the second case of a suprasellar arachnoid cyst to arise de novo. The clinical features, imaging characteristics and treatment of the previously reported cases are discussed.

La fenestración endoscópica como tratamiento de los quistes aracnoideos intracraneales / Endoscopic fenestration to treat intracranial arachnoid cysts

Los quistes aracnoideos son lesiones quísticas con un contenido similar al líquido cefalorraquídeo. Representan alrededor del 1% de todas las lesiones expansivas intracraneales y son característicos de las dos primeras décadas de la vida, aunque en ocasiones se diagnostican en adultos. Presentamos una revisión sobre nuestra experiencia en el tratamiento quirúrgico de quistes aracnoideos intracraneales. Material y métodos: Realizamos una revisión de 103 niños menores de 16 años intervenidos quirúrgicamente por un quiste aracnoideo intracraneal en los que se empleó una derivación cistoperitoneal en 53 casos; una craneotomía con fenestración del quiste, en 44 niños, y 11 casos con fenestración por vía endoscópica. Resultados: En todos los pacientes se consiguió alivio de la sintomatología y reducción o desaparición del quiste. Se presentaron 21 complicaciones quirúrgicas: 12 en los pacientes tratados con válvula (22.6%) y 9 en los sometidos a craneotomía (20.4%). La mortalidad de la serie fue de dos casos (1.95%). Discusión y conclusiones: El tratamiento de los quistes aracnoideos intracraneales debe reservarse exclusivamente para los casos sintomáticos. La craneotomía con fenestración de las membranas y la derivación cistoperitoneal son buenas opciones de tratamiento, ya que consiguen un buen control, tanto del tamaño del quiste como en la resolución de la sintomatología. La mejor opción terapéutica es en la actualidad la fenestración endoscópica, ya que se trata de una técnica poco invasiva, que no requiere la implantación de materiales extraños y cuyo índice de complicaciones y recidivas es relativamente bajo...

Tension pneumocephalus as a result of endonasal surgery: an uncommon intracranial complication.

Tension pneumocephalus (TP) is a clinical entity characterized by continued build-up of air within the cranial cavity, leading to abnormal pressure exerted upon the brain and subsequent neurologic deterioration, due to development of a mass effect and potentially a herniation syndrome. Intracranial complications of endoscopic sinus surgery (ESS) and other endonasal procedures are fortunately very rare, occurring in less than 3% of cases. We report 4 cases of small bone defects (<3 mm) in the anterior cranial base accompanied by TP, caused by ESS and other endonasal procedures. The pathophysiology and management of this clinical entity is discussed with a pertinent literature. Four patients with small (<3 mm) skull base defects were identified. All patients presented with active cerebrospinal fluid leaks. CT scans showed intracranial tension pneumocephalus. Using image-guided endoscopic techniques, all defects were addressed with multi-layer repair. Closure was achieved in all patients on the first attempt, with an average follow-up of 36 months. Tension pneumocephalus is a rare event that can occur as a result of traumatic or iatrogenic violation of the dura and should be considered in all patients presenting with altered mental status after endoscopic sinus surgery or other surgical and diagnostic procedures that violate either the cranial or spinal dura. Because of the potential for rapid clinical deterioration and death, prompt brain imaging is warranted to rule out the diagnosis, and urgent neurosurgical consultation is indicated for definitive management.

[Congenital medulloblastoma associated with intracranial arachnoid cyst]. / Meduloblastoma congénito asociado a quiste aracnoideo intracraneal.

Arachnoid cysts are very common lesions in paediatric patients, with treatment depending on their location and symptomatology. They are usually solitary cysts but may be associated with other central nervous system diseases such as tumours and congenital deformities. We describe the case of a neonate diagnosed with an arachnoid cyst of the quadrigeminal cistern treated by endoscopy. After the operation, the child's condition worsened; a CT scan revealed a midline posterior fossa tumour not visible in the preoperative neuroradiological tests. The tumour, a medulloblastoma, was partially removed. Given the child's age and the poor prognosis, oncological treatment was not undertaken. The association between medulloblastoma and arachnoid cyst is very rare, and we could find only one such case in the literature.

[Chronic subdural hematoma in young patients]. / Hematoma subdural crónico en pacientes jóvenes.

OBJECTIVE: The objective of this study was to analyse demographic, clinical and radiological findings and surgical results in a series of chronic subdural haematomas (CSDH) in young adult patients. PATIENTS AND METHODS: This retrospective study included 42 patients under 40 years of age who were diagnosed and surgically treated for a CSDH during a 30-year period (1982-2011). RESULTS: Of the 42 cases analysed, 32 were males and 10 were females, and the mean age at diagnosis was 29.3±8.9 years (range: 4 to 39 years). The mean interval from trauma to appearance of clinical symptoms was 33.4±9.7 days (range: 19 to 95 days). The main symptoms were headache (59.5%) and seizures (21.4%), and the most frequent predisposing factors were ventriculoperitoneal shunting in 5 (11.9%) patients and haematological disorders in another 5 (11.9%) cases. CSDH was right-sided in 21 cases (50%), left-sided in 19 cases (45.3%) and bilateral in the remaining 2 patients (4.7%). Postoperative complications occurred in 2 patients (1 recurrence and 1 acute subdural haematoma). CONCLUSIONS: CSDH is a rare pathology during the first decades of life. It mainly affects males and headache is usually the first symptom. Prognosis is good in young patients, since postoperative complications and recurrences are less frequent at this age than in older populations.

[Primary prophylaxis of early seizures after surgery of cerebral supratentorial tumors: Group for the Study of Functional-Sterotactic Neurosurgery of The Spain Society of Neurosurgery recommendations]. / Control de las crisis epilépticas durante el postoperatorio inmediato de los tumores cerebrales supratentoriales: recomendaciones del Grupo de Neurocirugía Funcional y Estereotáctica de la Sociedad Española de Neurocirugía.

Our review of the literature is basically focused on the primary prophylaxis of early seizures after surgery of cerebral supratentorial tumors, with the aim of suggesting several recommendations in medical antiepileptic treatment to avoid this kind of seizures which occur immediately after surgery. In conclusion, it is recommended to provide criteria for prophylaxis of early seizures after surgery of cerebral supratentorial tumors. It́s recommended a one week treatment with antiepileptic drugs in patients who didnt have seizures jet, starting immediately after the surgical treatment. If seizures appear during progress of the disease, a large period treatment will be needed. Preferred antiepileptic treatment is intravenous and with a low interactions profile. Levetiracetam, followed by valproic acid seem to be most appropriated drugs due to their properties and protective effects, particularly for our patients requirements. These recommendations are considered a general proposal to effective clinical management of early seizures after surgery, not taking into account the single circumstances of our patients. Always, clinical features of the patients could modify even significantly these guides in the benefit of each patient.

Endovascular treatment of an acutely ruptured intracranial aneurysm in pregnancy: report of eight cases.

Treatment of acutely ruptured intracranial aneurysms in pregnancy represents a clinical challenge requiring a meticulously selected strategy. We report eight cases of ruptured cerebral aneurysms in eight pregnant patients treated safely and effectively via an endovascular approach.

Lumbar synovial cyst in an adolescent: case report.

BACKGROUND: Spinal extradural cysts are a rare cause of spinal cord or nerve root compression which tends to occur in the elderly but rarely reported in the under 20s. HISTORY: A 14-year-old girl with a 9-month history of left radicular pain was found to have an intraspinal cystic lesion causing radicular compression. MRI showed a 1.1-cm extradural cystic lesion with a low signal on T1 and high signal on T2-weighted images lying in the spinal canal at the L4 vertebral body level. The patient underwent an L4 hemi-laminectomy and excision of a synovial cyst, and the radicular pain completely regressed. DISCUSSION: We discuss the pathogenesis, radiological techniques, and management of synovial cyst in a pediatric patient. CONCLUSION: Intraspinal ganglion cysts are extremely rare in children and only two other cases have been reported previously. They are benign lesions, frequently presenting radiculopathy, and should be considered in the differential diagnosis, in patients with low back pain and radiculopathy.

Spinal extradural angiolipoma: report of two cases and review of the literature.

Spinal angiolipomas are benign uncommon neoplasm composed of mature lipocytes admixed with abnormal blood vessels. They account for only 0.04-1.2% of all spinal tumors. We report two cases of lumbar extradural angiolipoma and review previously reported cases. We found 118 cases of spinal epidural angiolipoma (70 females and 48 males; age range 1.5-85 years, mean 44.03) spanning from 1890 to 2006. Prior to diagnosis 40.6% of the patients had weakness of the lower limbs. The interval between the initial symptoms and tumor diagnosis ranged from 1 day to 17 years (mean 20.2 months). Except for four cases diagnosed at autopsy, 109 patients underwent surgery and gross-total resection was performed in 79 cases (72.4%). Spinal angiolipomas are tumors containing angiomatous and lipomatous tissue, predominantly located in the mid-thoracic region. All angiolipomas show iso- or hyperintensity on T1-weighted images and hyperintensity on T2-weighted images and most lesions enhance with gadolinium administration. The treatment for spinal extradural angiolipomas is total surgical resection and no adjuvant therapy should be administered.

Lumbar synovial cyst in a adolescence: case report.

BACKGROUND: Spinal extradural cysts are a rare cause of spinal cord or nerve root compression which tends to occur in the elderly but rarely reported in the under 20s. HISTORY: A 14-year-old girl with a 9-month history of left radicular pain was found to have an intraspinal cystic lesion causing radicular compression. Magnetic resonance imaging showed a 1.1-cm extradural cystic lesion with a low signal on T1-weighted images and high signal on T2-weighted images lying in the spinal canal at the L4 vertebral body level. The patient underwent an L4 hemilaminectomy and excision of a synovial cyst, and the radicular pain completely regressed. DISCUSSION: We discuss the pathogenesis, radiological techniques and management of synovial cyst in a paediatric patient CONCLUSION: Intraspinal ganglion cysts are extremely rare in children and only two other cases have been reported previously. They are benign lesions, frequently presenting radiculopathy, and should be considered in the differential diagnosis in patients with low back pain and radiculopathy.

Management of brain abscess in children.

AIM: Brain abscesses continue to pose a problem in paediatric neurosurgery because the associated morbidity and mortality have remained significant throughout the antibiotic and CT era. The objective of this paper is to report the treatment of 28 children with the diagnosis of brain abscess. METHODS: We report our experience with the surgical management of brain abscesses in 28 paediatric patients between 1981 and 2005. The following parameters were assessed: age, gender, clinical manifestations, physical examination, radiological data, aetiological agent, treatment and clinical evolution of the patients. RESULTS: Patients' age varied from 2 weeks to 16 years (mean 8.6 years); 17 were male. The most notable predisposing factor was contiguous infection in 11 cases, of which six were chronic otitis media. The abscess was supratentorial in 27 children with only one infratentorial case. In all patients, treatment consisted of a combination of surgical evacuation and antibiotics. In two children, the evacuation of pus was via transfontanelar puncture. Positive abscess cultures were obtained from 15 abscesses, and gram-negative were the main bacteria involved. Nine patients had neurological sequelae (seizure, cognitive impairment and paresis); two deaths occurred. CONCLUSIONS: Brain abscess in children continues to be associated with high rates of neurological impairment and death.

Preliminary experience with Leo self-expanding stent for the treatment of intracranial aneurysms.

We report initial experience with the use of a new intracranial stent, the Leo microstent in combination with detachable coils in treatment of patients with wide-necked cerebral aneurysms. The Leo stent represents a significant advance in the vascular treatment of intracranial aneurysm with high radial force and an easy delivery system. It is a feasible, secure, and effective system.

Chronic subdural haematoma: surgical treatment and outcome in 1000 cases.

Chronic subdural haematoma (CSDH) is one of the most common clinical entities in daily neurosurgical practice. To evaluate the clinical features, computed tomography findings, surgical results, and complications our series was statistically analysed to elucidate the factors affecting the post-operative outcome. A retrospective study (1980-2002) of the records of 1000 patients harbouring 1097 chronic subdural haematoma treated with burr-hole craniotomy with closed-system drainage was carried out. The series included 628 males and 372 females, age range 12-100 years, mean age 72.7+/-11.4 years. The mean interval from trauma to appearance of clinical symptoms was 49.1+/-7.4 days (15-751). The principal symptom was headache (29.7%) in the over 70s, and behavioural disturbance (33.8%) in the under 70s. The CSDH was right sided in 432 patients, left sided in 471, and bilateral in the remaining 97 cases. Post-operative complications occurred in 196 patients and 21 patients died in hospital. Poor prognosis was related to patient's age (>70) and clinical grade on admission (grades 0-2 versus grades 3-4).