ABSTRACT
A 16-year-old warmblood mare was referred with a progressive history of behavioral changes and left-sided blindness. Following neuroanatomical localization to the forebrain, magnetic resonance imaging of the head revealed a well-delineated, 4.5 cm in diameter, round pituitary mass causing marked compression of the midbrain and optic chiasm. Euthanasia was recommended but declined by the owners. Veterinary specialists and a human neurosurgeon collaboratively prepared for surgical case management. A novel navigated transmandibular lateral transsphenoidal approach was developed to access the region of the sella turcica and practiced on cadaver specimens. The horse was anesthetized and placed in sternal recumbency with the head above the heart line. Using a cone beam computed tomography (CBCT)-coupled navigation system, a navigated pin traversing the vertical ramus of the mandible and the lateral pterygoid muscle was placed in a direct trajectory to the predetermined osteotomy site of the basisphenoid bone. A safe corridor to the osteotomy site was established using sequential tubular dilators bypassing the guttural pouch, internal and external carotid arteries. Despite the use of microsurgical techniques, visualization of critical structures was limited by the long and narrow working channel. Whilst partial resection of the mass was achieved, iatrogenic trauma to the normal brain parenchyma was identified by intraoperative imaging. With consent of the owner the mare was euthanized under the same general anesthesia. Post-mortem magnetic resonance imaging and gross anatomical examination confirmed partial removal of a pituitary adenoma, but also iatrogenic damage to the surrounding brain parenchyma, including the thalamus.
Subject(s)
Adenoma , Horse Diseases , Pituitary Neoplasms , Horses , Humans , Female , Animals , Pituitary Neoplasms/surgery , Pituitary Neoplasms/veterinary , Adenoma/surgery , Adenoma/veterinary , Adenoma/pathology , Sella Turcica/pathology , Sella Turcica/surgery , Iatrogenic Disease/veterinary , Magnetic Resonance Imaging/veterinary , Horse Diseases/diagnostic imaging , Horse Diseases/surgery , Horse Diseases/pathologyABSTRACT
BACKGROUND: Intermediate nerve neuralgia is a rare type of cranial neuralgia that causes clinical, therapeutic, and diagnostic challenges. Studies have described pharmacological and surgical treatment options. Surgical treatment ranges from sectioning of neural structures to microvascular decompression. Given the rareness of the disease, there are no clear recommendations concerning treatment. OBSERVATIONS: Reported is the case of a patient with typical intermediate nerve neuralgia. In this particular case, decision-making toward surgical decompression in an earlier stage of the disease could have been beneficial. The authors found excellent results using only microvascular decompression without sectioning of neural structures. LESSONS: Knowledge of intermediate nerve anatomy is essential to understand this complex pain syndrome. This case illustrates that surgery should not only be regarded as a last resort in case of failure of conservative treatment but also should be considered early in the disease course, especially in the case of a clear neurovascular conflict. When no evident cause is found, surgery could be considered as an exploratory option to depict a neurovascular conflict intraoperatively. Microvascular decompression of the intermediate nerve without sectioning of neural structures can obtain excellent results. Since neural structures are saved, postoperative sequelae can be limited.
ABSTRACT
OBJECTIVE: Application of Medishield to the nerve root is common during spinal surgery to create a mechanical barrier from pain mediators and reduce scar formation. However, Medishield's signal characteristics on magnetic resonance imaging (MRI) have not yet been examined. METHODS: Microsurgical interlaminotomy was performed on 2 lower lumbar segments in 17 adult New Zealand white rabbits. After dural exposure, applications of 1 mL (autologous blood clot or Medishield) were randomized for each level. On postoperative days 1 through 3, various MRI sequences in 1.5T were performed including T1-weighted, T2-w, T1-gadolinium-weighted, susceptibility-weighted and turbo inversion recovery magnitude (TIRM) sequence. Signaling characteristics were analyzed by 3 blinded observers. Inter-rater agreement was calculated using Fleiss's kappa coefficient (κ). Positive and negative likelihood ratios in detecting Medishield by MRI were determined. RESULTS: Of 24 MRIs performed, TIRM sequence identified Medishield with the highest likelihood ratio. Medishield's positive likelihood ratio was highest (5.8) on postoperative day 1 with interobserver agreement of 93% (κ = 0.75); these rates declined to 2.5 and 1.4 on postoperative days 2 and 3 with interobserver agreements of 71% (κ = 0.43) and 83% (κ = 0.67), respectively. Medishield adherence was confirmed in each rabbit by histologic examinations. CONCLUSION: Understanding that radiologic detection of Medishield diminished over time as its signal characteristics became less distinguishable from a blood clot is essential in clinical practice. Medishield was detected on postoperative day 1 but not 2 days later after hemodynamic changes had occurred. These results may provide a guide for postoperative findings, such as differential diagnosis of hematoma.
Subject(s)
Laminectomy/methods , Lumbar Vertebrae/surgery , Microsurgery/methods , Organ Sparing Treatments/methods , Animals , Cicatrix/prevention & control , Disease Models, Animal , Female , Magnetic Resonance Imaging , Postoperative Period , Rabbits , Trauma, Nervous System/prevention & controlABSTRACT
OBJECTIVE: To study the rate of superficial temporal artery (STA) preservation and the effectiveness of STA reconstruction in patients undergoing a pterional craniotomy. METHODS: Included patients (n = 136) underwent either an emergency or an elective pterional craniotomy. In case of deliberate transection or accidental damage of the STA, it was repaired microsurgically at the end of the procedure. Postoperatively, the patency of the STA was assessed on CT angiography, MR angiography, or conventional angiography and complications related to wound healing were recorded. RESULTS: Of the 136 operated patients, the STA could be identified in 120 cases (88%). Of these 120 cases, the STA could be dissected and left undamaged in 60 patients (44%). In 52 patients (38%), 1 of the 2 branches of the STA had to be transsected to elevate the muscle-skin flap. Forty-six of the transected arteries could be anastomosed at the end of the procedure. All of these arteries were patent directly after repair. In the remaining 16 patients (12%), the STA was not identified during approach. All anastomosed arteries (n = 46) were patent. Two patients developed a postoperative infection. CONCLUSIONS: Preserving or reconstructing of the STA during pterional craniotomy is feasible in the majority of the patients with very high rate of anastomosis patency. STA hinders elevation of the skin/muscle flap in approximately 38% of the pterional approaches and without reconstruction afterwards, the STA would been occluded.
Subject(s)
Cerebral Revascularization/methods , Craniotomy/methods , Temporal Arteries/injuries , Temporal Arteries/surgery , Brain Neoplasms/surgery , Cerebral Angiography , Cerebral Revascularization/adverse effects , Craniotomy/adverse effects , Humans , Intracranial Aneurysm/etiology , Intracranial Aneurysm/surgery , Magnetic Resonance Angiography , Postoperative Complications , Surgical Instruments , Temporal Arteries/diagnostic imaging , Tomography, X-Ray ComputedABSTRACT
Myoepithelioma is a dimorphic neoplasm with contractile-epithelial phenotype, originally interpreted as deriving from, but not actually restricted to the salivary glands. As a novel addition to the list of exquisitely rare intracranial salivary gland-type tumors and tumor-like lesions, we report on an example of myoepithelioma encountered in the left cerebellopontine angle of a 32-year-old male. Clinically presenting with ataxia and dizziness, this extraaxial mass of 4 × 3.5 × 3 cm was surgically resected, and the patient is alive 6 years postoperatively. Histologically, the tumor exhibited a continuum ranging from compact fascicles of spindle cells to epithelial nests and trabeculae partitioned by hyalinized septa, while lacking tubular differentiation. Regardless of architectural variations, there was robust immunoexpression of S100 protein, smooth muscle actin, GFAP, cytokeratin, and vimentin. Cytologic atypia tended to be modest throughout, and the MIB1 labeling index averaged less than 1%. Fluorescent in situ hybridization indicated no rearrangement of the EWSR1 locus. We interpret these results to suggest that myoepithelioma of the posterior fossa - along with related salivary epithelial tumors in this ostensibly incongruous locale - may possibly represent analogous neoplasms to their orthotopic counterparts, ones arising within aberrant salivary anlagen. The presence of the latter lends itself to being mechanistically accounted for by either postulating placodal remnants in the wake of branchial arch development, or linking them to exocrine glandular nests within endodermal cysts. Alternatively, myoepithelioma at this site could be regarded as a non tissue-specific lesion similar to its relatives ubiquitously occurring in the soft parts.
Subject(s)
Cerebellar Neoplasms/pathology , Cerebellopontine Angle/pathology , Myoepithelioma/pathology , Adult , Biomarkers, Tumor/analysis , Cerebellar Neoplasms/metabolism , Cerebellar Neoplasms/surgery , Cerebellopontine Angle/metabolism , Cerebellopontine Angle/surgery , Humans , Immunohistochemistry , Male , Myoepithelioma/metabolism , Myoepithelioma/surgery , Skull/pathologyABSTRACT
QUESTIONS UNDER STUDY: Up to 88% of cavernous malformations (CMs) of the central nervous system can become symptomatic and cause long-term disability. The aim of this study was to document the characteristics of CMs in the catchment area of our institution. METHODS: We retrospectively analysed newly discovered CMs over a 20-year observation period, as well as the frequency of familial forms in the catchment area. RESULTS: In the period from 1985-2004, a total of 347 patients were investigated. The cohort included about 75% symptomatic CM cases. A total of 1.31 and 0.55 symptomatic and asymptomatic cases, respectively, were newly diagnosed per annum per 100'000 inhabitants. Symptomatic CMs were diagnosed on average at the age of 36 years (range: newborn to 79 years old). There were slightly more patients who presented with evidence of acute bleeding (28%) than those with seizures (26%). Most intracranial lesions were supratentorial in location (54%). Lesion size was predominately below 3 cm (range: 0.2 to 8 cm). Symptomatic CMs (average: 1.75 cm) were significantly larger (p <.0001) than asymptomatic ones (average 0.91 cm). When compared to medical literature, there was a relatively high frequency of multiple CMs (18.9%), which were more common in the familial form (62%). CONCLUSIONS: The observed frequency of CM, including multiple lesions in a single individual and the familial form of this pathological entity appears relatively high compared to medical literature.
Subject(s)
Hemangioma, Cavernous, Central Nervous System , Adolescent , Adult , Aged , Child , Child, Preschool , Cohort Studies , Female , Hemangioma, Cavernous, Central Nervous System/diagnosis , Hemangioma, Cavernous, Central Nervous System/epidemiology , Hemangioma, Cavernous, Central Nervous System/physiopathology , Humans , Infant , Infant, Newborn , Male , Middle Aged , Retrospective Studies , Switzerland/epidemiology , Young AdultABSTRACT
Temporal hollowing due to temporal muscle atrophy after standard skull base surgery is common. Various techniques have been previously described to correct the disfiguring defect. Most often reconstruction is performed using freehand molded polymethylmethacrylate cement. This method and material are insufficient in terms of aesthetic results and implant characteristics. We herein propose reconstruction of such defects with a polyetheretherketone (PEEK)-based patient-specific implant (PSI) including soft-tissue augmentation to preserve normal facial topography. We describe a patient who presented with a large temporo-orbital hemangioma that had been repaired with polymethylmethacrylate 25 years earlier. Because of a toxic skin atrophy fistula, followed by infection and meningitis, this initial implant had to be removed. The large, disfiguring temporo-orbital defect was reconstructed with a PEEK-based PSI. The lateral orbital wall and the temporal muscle atrophy were augmented with computer-aided design and surface modeling techniques. The operative procedure to implant and adopt the reconstructed PEEK-based PSI was simple, and an excellent cosmetic outcome was achieved. The postoperative clinical course was uneventful over a 5-year follow-up period. Polyetheretherketone-based combined bony and soft contour remodeling is a feasible and effective method for cranioplasty including combined bone and soft-tissue reconstruction of temporo-orbital defects. Manual reconstruction of this cosmetically delicate area carries an exceptional risk of disfiguring results. Augmentation surgery in this anatomic location needs accurate PSIs to achieve satisfactory cosmetic results. The cosmetic outcome achieved in this case is superior compared with previously reported techniques.
Subject(s)
Klebsiella Infections/surgery , Muscular Atrophy/surgery , Orbit/surgery , Plastic Surgery Procedures/methods , Prostheses and Implants , Soft Tissue Infections/surgery , Temporal Muscle/surgery , Aged , Anti-Bacterial Agents/therapeutic use , Benzophenones , Biocompatible Materials , Bone Cements , Esthetics , Female , Humans , Ketones , Klebsiella Infections/diagnosis , Klebsiella Infections/drug therapy , Polyethylene Glycols , Polymers , Soft Tissue Infections/diagnosis , Soft Tissue Infections/drug therapy , Surgical Flaps , Tomography, X-Ray ComputedABSTRACT
PURPOSE: The combination of ruptured aneurysms with acute subdural hematomas (aSDHs) is a rare presentation. Patients with aSDH associated with aneurysmal bleeding represent a subgroup within the spectrum of aneurysmatic hemorrhage. We summarize the clinical characteristics, diagnostic evaluation, and management of a series of cases presenting with aSDH associated with aneurysmal subarachnoid hemorrhage (SAH). METHODS: Medical records and surgical reports of 743 consecutive patients admitted to our institution with SAH from January 1995 to December 2007 were screened to detect cases of associated aSDH. Admission evaluations included the Glasgow Coma Scale (GCS) and the subarachnoid grade of the World Federation of Neurosurgical Societies (WFNS). Radiological assessment included computer tomography (CT) scan, CT angiography (CTA), and digital subtraction angiography (DSA). The presence and volume of SAH, intracerebral hemorrhage (ICH), and aSDH were documented. Outcome was measured in terms of Glasgow Outcome Scale (GOS) and modified Rankin Scale (mRS) at 4-8 months. RESULTS: A total of seven cases (0.9%) presenting with aSDH (mean width: 11.2 mm +/- 4.8 mm, range: 5-20 mm) attributable to SAH were documented. Three of these patients were admitted with a suspicion of trauma. Five patients presented with WFNS grade 5, one patient with WFNS grade 3, and one patient with WFNS grade 1. All patients underwent evacuation of the aSDH. In four patients, surgical obliteration of the aneurysm was achieved in the same procedure. Two patients underwent delayed occlusion of the aneurysm: one by coiling and one by clipping. Three of the seven patients recovered completely from their neurological deficits (GOS 5, mRS 0-1), three recovered with mild disability (GOS 4, mRS 2-3), and one died within 8 h after the decompressive procedure. CONCLUSIONS: The incidence of aSDH associated with SAH is low. Most of the patients with aSDH due to a ruptured aneurysm present in exceptionally poor neurological condition. Nevertheless, rapid surgical treatment of the hematoma and aneurysm obliteration can lead to a favorable outcome. Routine CTA should be performed in all patients presenting with an aSDH associated with SAH and no clear history of trauma.
Subject(s)
Hematoma, Subdural, Acute/epidemiology , Hematoma, Subdural, Acute/pathology , Intracranial Aneurysm/epidemiology , Intracranial Aneurysm/pathology , Adult , Aged , Angiography, Digital Subtraction , Comorbidity , Embolization, Therapeutic/instrumentation , Embolization, Therapeutic/methods , Emergency Medical Services/methods , Female , Glasgow Coma Scale , Hematoma, Subdural, Acute/diagnostic imaging , Humans , Incidence , Intracranial Aneurysm/diagnostic imaging , Male , Middle Aged , Neurosurgical Procedures/instrumentation , Neurosurgical Procedures/methods , Outcome Assessment, Health Care/methods , Predictive Value of Tests , Prognosis , Prosthesis Implantation/methods , Retrospective Studies , Severity of Illness Index , Surgical Instruments , Tomography, X-Ray Computed , Treatment Outcome , Vascular Surgical Procedures/instrumentation , Vascular Surgical Procedures/methodsABSTRACT
STUDY DESIGN: Case report and review of the literature. OBJECTIVE: We describe the first case of a synovial cyst arising from pseudarthrosis of a previous dens fracture. The literature is reviewed and etiological, diagnostic, and therapeutic options of atlantoaxial cysts are discussed. SUMMARY OF BACKGROUND DATA: Symptomatic synovial cysts of the atlantoaxial joint are rare. To the authors' knowledge only 24 cases have been reported.A 60-year-old patient presented with bilateral hand numbness, quadrihyperreflexia, and gait deterioration. Magnetic resonance imaging of the cervical spine disclosed a cystic mass located at the transverse ligament of dens axis causing bulbomedullary compression. METHODS: Surgery was performed via transoral image guided approach. The ventral atlas arch, dens, transverse ligament, tectorial membrane, and the compressing cyst were removed, followed by a C0-C3 fusion. RESULTS: Two months postsurgery the patient recovered completely from the cervical myelopathy with transient remnant dysparesthesia of the finger tips. CONCLUSION: Magnetic resonance imaging findings are not specific enough to establish a preoperative diagnosis. Radical resection via image-guided transoral route followed by posterior fusion allows complete resection of the cystic lesion and results in excellent long-term decompression.
Subject(s)
Atlanto-Axial Joint/surgery , Decompression, Surgical/methods , Neurosurgical Procedures/methods , Pseudarthrosis/surgery , Synovial Cyst/surgery , Atlanto-Axial Joint/diagnostic imaging , Atlanto-Axial Joint/pathology , Cervical Atlas/diagnostic imaging , Cervical Atlas/pathology , Female , Gait Disorders, Neurologic/etiology , Humans , Hypesthesia/etiology , Ligaments/diagnostic imaging , Ligaments/pathology , Magnetic Resonance Imaging , Middle Aged , Odontoid Process/diagnostic imaging , Odontoid Process/pathology , Pseudarthrosis/etiology , Pseudarthrosis/pathology , Radiography , Reflex, Abnormal/physiology , Spinal Cord Compression/diagnostic imaging , Spinal Cord Compression/etiology , Spinal Cord Compression/pathology , Spinal Fractures/complications , Spinal Fusion/methods , Surgery, Computer-Assisted/methods , Synovial Cyst/etiology , Synovial Cyst/pathology , Tectorial Membrane/surgery , Treatment OutcomeABSTRACT
The following is an analysis of the role of computer aided surgery by infralabyrinthine-subcochlear approach to the petrous apex for cholesterol granulomas with hearing preservation. In a retrospective case review from 1996 to 2008 six patients were analysed in our tertiary referral centre, otorhinolaryngology outpatient clinic. Excellent intraoperative localisation of the carotid artery, facial nerve and the entrance into the cholesterol cyst of the bone by means of the navigation system was seen. Additionally, the operation time decreased from an initial 4 h down to 2 h. The application of computer-aided surgery allows intraoperative monitoring of the position of the tip of the microsurgical instruments in case of a rare disease and in the delicate area of the petrous apex giving a high security level.
Subject(s)
Cholesterol/metabolism , Granuloma/surgery , Labyrinth Diseases/surgery , Petrous Bone/surgery , Surgery, Computer-Assisted/methods , Adult , Female , Follow-Up Studies , Granuloma/diagnosis , Humans , Labyrinth Diseases/diagnosis , Magnetic Resonance Imaging , Male , Middle Aged , Petrous Bone/pathology , Retrospective Studies , Risk Assessment , Sampling Studies , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
Intraoperative molding of polymethyl-methacrylate into complex three-dimensional shapes with correct thickness is often a time-consuming process and may lead to unsatisfying cosmetical results. This article describes an intraoperative technique to assemble a polymethyl-methacrylate implant as a replica of the patient's bone flap. This approach provides a fast and inexpensive alternative technique with good cosmetic outcome. The technique is feasible and can be applied in early and delayed cranioplasty procedures. In selected patients, immediate single-stage reconstruction avoids a second operation.
Subject(s)
Casts, Surgical , Craniotomy/methods , Intraoperative Care/methods , Adult , Brain Abscess/surgery , Casts, Surgical/economics , Cost-Benefit Analysis , Female , Humans , Meningioma/surgery , Middle Aged , Neuronavigation , Polymethyl Methacrylate , Surgical FlapsABSTRACT
Reconstruction of the anterior skull base and fronto-orbital framework following extensive tumor resection is both challenging and controversial. Dural defects are covered with multiple sheets of fascia lata that provide sufficient support and avoid herniation. Plating along the skull base is contraindicated. After resection of orbital walls, grafting is necessary if the periosteum or parts of the periorbital tissue had to be removed, to avoid enophthalmus or strabism. Free bone grafts exposed to the sinonasal or pharyngeal cavity are vulnerable to infection or necrosis: therefore, covering the grafts with vascularized tissue, such as the Bichat fat-pad or pedicled temporalis flaps, should reduce these complications. Alloplastic materials are indispensable in cranial defects, whereas microsurgical free tissue transfer is indicated in cases of orbital exenteration and skin defects. The authors review their experience and follow-up of 122 skull base reconstructions following extensive subcranial tumor resection. Most significant complications were pneumocranium in 4.9%, CSF leaks in 3.2%, and partial bone resorption in 8.1%.
ABSTRACT
We report on clinicopathological findings in two cases of rosette-forming glioneuronal tumor of the fourth ventricle (RGNT) occurring in females aged 16 years (Case 1) and 30 years (Case 2). Symptoms included vertigo, nausea, cerebellar ataxia, as well as headaches, and had been present for 4-months and 1 week, respectively. Magnetic resonance imaging (MRI) indicated a cerebellar-based tumor of 1.8 cm (Case 1) and 5 cm (Case 2) diameter each, bulging into the fourth ventricle. Case 2 involved a cyst-mural-nodule configuration. In both instances, the solid component appeared isointense on T(1) sequences, hyperintense in the T(2) mode, and enhanced moderately. Gross total resection was achieved via suboccipital craniotomy. However, functional recovery was disappointing in Case 1. On microscopy, both tumors comprised an admixture of low-grade astrocytoma interspersed with circular aggregates of synaptophysin-expressing round cells harboring oligodendrocyte-like nuclei. The astrocytic moiety in Case 1 was nondescript, and overtly pilocytic in Case 2. The architecture of neuronal elements variously consisted of neurocytic rosettes, of pseudorosettes centered on a capillary core, as well as of concentric ribbons along irregular lumina. Gangliocytic maturation, especially "floating neurons", or a corresponding immunoreactivity for neurofilament protein was absent. Neither of these populations exhibited atypia, mitotic activity, or a significant labeling for MIB-1. Cerebellar parenchyma included in the surgical specimen did not reveal any preexisting malformative anomaly. Despite sharing some overlapping histologic traits with dysembryoplastic neuroepithelial tumor (DNT), the presentation of RGNT with respect to both patient age and location is consistent enough for this lesion to be singled out as an autonomous entity.
Subject(s)
Cerebral Ventricle Neoplasms/pathology , Fourth Ventricle/pathology , Ganglioglioma/pathology , Adolescent , Adult , Cerebral Ventricle Neoplasms/physiopathology , Cerebral Ventricle Neoplasms/surgery , Diagnosis, Differential , Female , Fourth Ventricle/surgery , Ganglioglioma/physiopathology , Ganglioglioma/surgery , Glial Fibrillary Acidic Protein/metabolism , Humans , Immunohistochemistry , Magnetic Resonance Imaging , Neurosurgical Procedures , Synaptophysin/metabolismABSTRACT
The descriptive term papillary glioneuronal tumor (PGNT) has been repeatedly applied to a morphologic subset of low-grade mixed glial-neuronal neoplasia of juvenile and young adult patients. We report on a 13-year-old boy with PGNT of the left temporal lobe, who presented with headaches and a single generalized seizure. On magnetic resonance imaging, tumor was seen as a large, moderately enhancing paraventricular mass with cyst-mural nodule configuration and slight midline shift. Perifocal edema was virtually absent. Gross total resection could be performed, followed by an uneventful recovery. Histologically, the tumor exhibited similar, if not identical, features as reported previously. These comprised a patterned biphasic mixture of sheets of synaptophysin-expressing small round cells and pseudorosettes of GFAP-positive rudimentary astrocytes along vascular cores. Focally, the latter imprinted a pseudopapillary aspect on this otherwise solid lesion. Both cellular components expressed non-polysialylated neural cell adhesion molecule (NCAM)-L species, and several overlapping areas of synaptophysin and GFAP immunoreactivity were present. The mean MIB-1 labeling index remained below 1%. Signs of anaplasia, in particular mitotic figures, endothelial proliferation, or necrosis were consistently lacking. We perceive PGNT as a clinically and morphologically well-delineated subgroup of extraventricular neurocytic neoplasia, whose paradigmatic presentation may allow for consideration as an entity.
Subject(s)
Brain Neoplasms/pathology , Neurocytoma/pathology , Temporal Lobe , Adolescent , Diagnosis, Differential , Humans , Magnetic Resonance Imaging , Male , Neuroglia , Oligodendroglioma/pathologyABSTRACT
The pleiotropic cytokine interleukin-6 (IL-6) contributes to malignant progression and apoptosis resistance of various cancer types. Although IL-6 is elevated in malignant gliomas, and glioma cells respond to IL-6, its functional role in gliomagenesis is unclear. We have investigated this role of IL-6 in a mouse model of spontaneous astrocytoma by crossbreeding glial fibrillary acidic protein (GFAP)-viral src oncogene transgenic mice with IL-6-deficient mice. We show here that ablation of IL-6 prevents tumour formation in these predisposed animals, but did not affect preneoplastic astrogliosis. Moreover, we demonstrate phosphorylation and nuclear translocation of the transcription factor signal transducer and activator of transcription (STAT)3, a prerequisite for IL-6 signalling, in 51 human gliomas WHO grade II-IV and all experimental mouse tumours investigated. Together with the observation that STAT3 activation increases with malignancy, these findings indicate an important role for IL-6 in the development and malignant progression of astrocytomas.
Subject(s)
Glioma/etiology , Interleukin-6/physiology , Animals , DNA-Binding Proteins/analysis , DNA-Binding Proteins/physiology , Disease Models, Animal , Female , Glial Fibrillary Acidic Protein/analysis , Glial Fibrillary Acidic Protein/genetics , Glial Fibrillary Acidic Protein/physiology , Glioma/pathology , Humans , Interleukin-6/genetics , Male , Mice , Mice, Transgenic , Microglia/physiology , Precancerous Conditions/etiology , STAT3 Transcription Factor , Trans-Activators/analysis , Trans-Activators/physiology , Transgenes , src-Family Kinases/physiologyABSTRACT
Neuroinflammation induces a complex molecular cascade that leads to the proteolysis of cells. Matrix metalloproteinases (MMPs) attack all components of the extracellular matrix in a number of neuroinflammatory diseases and cause a delayed opening of the blood-brain barrier (BBB). Earlier, we showed that lipopolysaccharide (LPS) disrupted the BBB through the action of gelatinase B (MMP-9). In a study of cerebral ischemia, gelatinase A (MMP-2) was seen in astrocytic end-feet and stromelysin-1 (MMP-3) in microglia. Since other MMPs may be important in LPS-induced injury, we studied the gene transcription and cellular localization of several MMPs and an inflammatory mediator, tumor necrosis factor (TNF-alpha), using competitive polymerase chain reaction (PCR) and immunohistochemical methods. Significantly elevated levels of MMP-2 and -3 mRNA were observed in LPS-injected brains by 2 h after injection as compared to non-injected brain tissue (P<0.05). By 8 h post-LPS injection, gene expression of MMP-2 and -3 had declined in both saline- and LPS-injected tissue, while TNF-alpha mRNA levels rose significantly. Immunohistochemistry of control brains confirmed the earlier observation of MMP-2 immunoreactivity in processes abutting cerebral blood vessels, which increased after LPS injection. The expression of MMP-9 and MMP-3 was localized mainly to the cerebrovasculature in LPS-stimulated brain tissue, predominantly in the perivascular cells of the basal lamina near the site of injection. Both of these proteinases were present at the site of LPS injection at 8 h, but MMP-2 was absent. Our results show that MMP genes are up-regulated prior to the induction of cytokines such as TNF-alpha, and that MMP proteins are prominent around blood vessels in LPS-induced neuroinflammation.