Selective vulnerability of the primitive meningeal layer to prenatal Smo activation for skull base meningothelial meningioma formation.

Somatic activating mutations of smoothened (SMO), a component of the embryonic sonic hedgehog (SHH) signaling pathway, are found in 3-5% of grade I meningiomas, most of them corresponding to meningothelial meningiomas located at the anterior skull base. By generating different developmental stage-specific conditional activations in mice, we define a restricted developmental window during which conditional activation of Smo in Prostaglandin D2-synthase-positive mesoderm-derived meningeal layer of the skull base results in meningothelial meningioma formation. We show a selective vulnerability of the arachnoid from the skull base to Smo activation to initiate tumor development. This prenatal period and specific topography are correlated to the timing and location of SHH signaling involvement in the formation of craniofacial and meninges patterning, strongly corroborating the hypothesis of a developmental origin for Smo-activated meningiomas. Finally, we provide preclinical in vitro evidence of the efficacy of the SMO-inhibitor Sonidegib, supporting further preclinical and clinical evaluation of targeted treatment for refractory SMO-mutant meningiomas.

Denosumab treatment for progressive skull base giant cell tumor of bone in a 14 year old female - a case report and literature review.

BACKGROUND: Giant cell tumor of bone (GCT) is a rare primary bone tumor, which can metastasize and undergo malignant transformation. The standard treatment of GCT is surgery. In patients with unresectable or metastatic disease, additional therapeutic options are available. These include blocking of the receptor activator of NF-kappa B ligand (RANKL) signaling pathway, which plays a role in the pathogenesis of GCT of bone, via the anti-RANKL monoclonal antibody denosumab. CASE PRESENTATION: Herein we report on a female teenager who presented in a very poor clinical condition (cachexia, diplopia, strabismus, dysphonia with palsy of cranial nerves V, VI, VIII, IX, X, XI and XII) due to progressive disease, after incomplete resection and adjuvant radiotherapy, of a GCT which affected the cervical spine (C1 and C2) as well as the skull base; and who had an impressive clinical response to denosumab therapy. To the best of our knowledge, this is the youngest patient ever reported with a skull base tumor treated with denosumab. CONCLUSION: In situations when surgery can be postponed and local aggressiveness of the tumor does not urge for acute surgical intervention, upfront use of denosumab in order to reduce the tumor size might be considered. Principally, the goal of denosumab therapy is to reduce tumor size as much as possible, with the ultimate goal to make local surgery (or as in our case re-surgery) amenable. However, improvement in quality of life, as demonstrated in our patient, is also an important aspect of such targeted therapies.

In vitro regulation of proliferation and differentiation within a postnatal growth plate of the cranial base by parathyroid hormone-related peptide (PTHrP).

Parathyroid hormone-related peptide (PTHrP) is known to be an important regulator of chondrocyte differentiation in embryonic growth plates, but little is known of its role in postnatal growth plates. The present study explores the role of PTHrP in regulating postnatal chondrocyte differentiation using a novel in vitro organ culture model based on the ethmoidal growth plate of the cranial base taken from the postnatal day 10 mouse. In vitro the ethmoidal growth plate continued to mineralize and the chondrocytes progressed to hypertrophy, as observed in vivo, but the proliferative zone was not maintained. Treatment with PTHrP inhibited mineralization and reduced alkaline phosphatase (ALP) activity in the hypertrophic zone in the ethmoidal growth plates grown ex vivo, and also increased the proliferation of non-hypertrophic chondrocytes. In addition, exogenous PTHrP reduced the expression of genes associated with terminal differentiation: type X collagen, Runx2, and ALP, as well as the PTH/PTHrP receptor (PPR). Activation of the protein kinase A pathway using 8-Br-cAMP mimicked some of these pro-proliferative/anti-differentiative effects of PTHrP. PTHrP and PPR were found to be expressed within the ethmoidal growth plate using semi-quantitative PCR, and in other cranial growth plates such as the spheno-occipital and pre-sphenoidal synchondroses. These results provide the first functional evidence that PTHrP regulates proliferation and differentiation within the postnatal, cranial growth plate. J. Cell. Physiol. 219: 688-697, 2009. (c) 2009 Wiley-Liss, Inc.

Bisphosphonate-related osteonecrosis of the skull base.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is reported in up to 18.6% of patients treated with intravenous bisphosphonates and can result in significant morbidity. Most cases are managed by oral surgeons with only a handful of reports appearing in the otolaryngology literature. We present a unique case of extensive BRONJ involving the maxilla, sinuses, and skull base, complicated by sinusitis and an intracranial abscess. This is the first description of BRONJ involving the skull base. The pathogenesis and management of this process are reviewed.

Analysis of prognostic factors in 146 patients with anterior skull base sarcoma: an international collaborative study.

BACKGROUND: Single-institutional studies lack sufficient power to assess the role of surgery and radiotherapy in the management of sarcomas involving the anterior skull base. For this study, an international collaborative study group analyzed a large cohort of patients who underwent surgery for the treatment of skull base tumors. METHODS: A subset of 146 patients who had a histologic diagnosis of skull base sarcoma (SBS) formed the basis of this report. Most patients were aged > or =21 years (77%) and had stage IV disease (56%). Adjuvant radiotherapy was received by 35% of patients, and chemotherapy was received by 10% of patients. RESULTS: Orbital involvement was encountered in 53% of patients, involvement of the orbital wall was encountered in 46% of patients, and intracranial extension was encountered in 28% of patients. Positive microscopic margins were reported in 43% of patients (51 of 118 patients). Treatment-related complications were reported in 27% of patients, and postoperative mortality was reported in 1.4% of patients. With a median follow-up of 34 months, the 5-year overall, disease-specific, and recurrence-free survival rates were 62%, 64%, and 57%, respectively. Tumor grade and adjuvant radiotherapy were not significant predictors of survival. Prior radiotherapy, intraorbital extension, positive margins, and postoperative complications were significant predictors of reduced disease-specific survival on univariate analysis. The presence of positive/close margins, however, was the only independent predictor of poor overall, recurrence-free, and disease-specific survival on multivariate analysis (relative risk, 2.4; P = .006). The 5-year disease-specific survival rate was 77%, 43%, and 36% for patients with negative, close, and positive margins, respectively. CONCLUSIONS: The current results indicated that wide craniofacial resection with negative margins is an independent prognostic predictor of better outcome. Patients with positive margins have a high risk for tumor recurrence independent of tumor grade.

[Invasive aspergillosis of the skull base with orbit infiltration]. / Invasive Aspergillose der Schädelbasis mit Orbitaspitzensyndrom.

BACKGROUND: [corrected] Aspergillosis of the paranasal sinuses is subdivided into noninvasive and invasive types, depending on invasion of the tissue. The invasive form often occurs in immunodeficient patients and can be divided further into granulomatous, chronic invasive, and acute fulminating forms. CASE REPORT: We report the clinical course of an immunosuppressed 64-year-old male with invasive aspergillosis originating from the sphenoid sinus with infiltration of the orbit and intracranial extension into the cavernous sinus. The patient was referred to our hospital with loss of vision, ptosis, and ophthalmoplegia of 3-month duration. Additionally he suffered from diabetes mellitus II and kidney failure after kidney transplantation. After CT scanning, endonasal sinus debridement and decompression of the orbit were carried out immediately. Histology revealed invasive aspergillosis. Postoperatively, both systemic and local antimycotic therapy and antibiotic treatment were performed. According to recommendations of the Undersea and Hyperbaric Medicine Society, cerebral abscess is a certain indication of hyperbaric oxygenation. We decided to attempt therapy for that as well. The patient died 3 weeks after surgical intervention due to carotid dissection. CONCLUSION: Invasive aspergillosis of the paranasal sinuses and the skull base of immunsuppressed patients is usually lethal because of intracranial complications. Therefore, fast diagnosis using CT and MRI and surgical and antimycotic therapy are necessary.

Craniofacial skeletal deviations following in utero exposure to the anticonvulsant phenytoin: monotherapy and polytherapy.

OBJECTIVE: To identify and quantify the craniofacial effects from prenatal exposure to phenytoin monotherapy and polytherapy using cephalometric, hand-wrist, and panoramic radiographs and to determine if such deviations persist with age. DESIGN: Craniofacial structures of 28 anticonvulsant-exposed individuals were evaluated using 20 landmarks in lateral cephalometric radiographs and 19 landmarks in frontal cephalometric radiographs. Skeletal maturity was assessed using hand-wrist radiographs. Dental maturity and the presence of dental anomalies were evaluated using panoramic radiographs. Eleven individuals were re-evaluated 7 years later, on average, to determine the persistence of any measured deviations. SETTING AND SAMPLE POPULATION: Department of Growth and Development, Harvard School of Dental Medicine and Massachusetts General Hospital. Patients were recruited from several sources. OUTCOME MEASURE: The evaluated dimensions included linear, angular, and proportional measures. RESULTS: The most common deviations were decreased height and length of the maxilla, decreased length of the posterior cranial base, length of the mandible, cranial width and level of the cribriform plate, and a decrease in the Wits Appraisal assessment. The deviations were more significant in the polytherapy-exposed individuals than in the monotherapyexposed individuals. These deviations, especially in the maxilla, persisted with age as revealed in a re-evaluation of 11 individuals. CONCLUSION: The craniofacial skeletal findings among individuals exposed in utero to phenytoin monotherapy or phenytoin polytherapy, when considered in aggregate, suggest a mild pattern of maxillary hypoplasia that becomes more pronounced with age.

The effect of growth hormone therapy on mandibular and cranial base development in children treated with total body irradiation.

The aim of the present investigation was to study craniomandibular development during growth hormone (GH) therapy in nine girls and one boy, aged between 7.3 and 16 years, who exhibited pronounced growth reduction after total body irradiation (TBI) and bone marrow transplantation (BMT). Age- and sex-matched healthy children with normal dentofacial development constituted the control material. The investigation data were based on measurements made on lateral skull radiographs taken at the start and, on average, 6 months after cessation of GH treatment. The control group comprised similar longitudinal cephalographic records. The results showed that GH therapy in patients who exhibited growth retardation after TBI and BMT had only a minor effect on cranial base dimensions, probably due to the fact that the development of this area is completed at a relatively early age. The effect of GH treatment on mandibular growth was very obvious. The dimensional increase of the mandibular variables in the patients was equivalent to, or in some cases even exceeded, that of the controls. In relation to basion, the mandibular condyles were displaced in a backward/upward direction in the patient group. Displacement in the opposite direction was recorded in the controls. It seems likely that the development seen in the patients is a reflection of a normalization of the condyle-fossa relationship made possible by enhanced condylar growth. This change should be advantageous for the function of the craniomandibular complex.