Repeat Gamma Knife surgery for vestibular schwannomas.

BACKGROUND: Gamma Knife (GK) surgery is a recognized treatment option for the management of small to medium-sized vestibular schwannoma (VS) associated with high-tumor control and low morbidity. When a radiosurgical treatment fails to stop tumor growth, repeat GK surgery can be proposed in selected cases. METHODS: A series of 27 GK retreatments was performed in 25 patients with VS; 2 patients underwent three procedures. The median time interval between GK treatments was 45 months. The median margin dose used for the first, second, and third GK treatments was 12 Gy, 12 Gy, and 14 Gy, respectively. Six patients (4 patients for the second irradiation and 2 patients for the third irradiation) with partial tumor regrowth were treated only on the growing part of the tumor using a median margin dose of 13 Gy. The median tumor volume was 0.9, 2.3, and 0.7 cc for the first, second, and third treatments, respectively. Stereotactic positron emission tomography (PET) guidance was used for dose planning in 6 cases. RESULTS: Mean follow-up duration was 46 months (range 24-110). At the last follow-up, 85% of schwannomas were controlled. The tumor volume decreased, remained unchanged, or increased after retreatment in 15, 8, and 4 cases, respectively. Four patients had PET during follow-up, and all showed a significant metabolic decrease of the tumor. Hearing was not preserved after retreatment in any patients. New facial or trigeminal palsy did not occur after retreatment. CONCLUSIONS: Our results support the long-term efficacy and low morbidity of repeat GK treatment for selected patients with tumor growth after initial treatment.

Dosimetric and clinical analysis of spatial distribution of the radiation dose in gamma knife radiosurgery for vestibular schwannoma.

OBJECTIVES: We investigated variations in the distribution of radiation dose inside (dose inhomogeneity) and outside (dose falloff) the target volume during Gamma Knife (GK) irradiation of vestibular schwannoma (VS). We analyzed the relationship between some parameters of dose distribution and the clinical and radiological outcome of patients. METHODS AND MATERIALS: Data from dose plans of 203 patients treated for a vestibular schwannoma by GK C using same prescription dose (12 Gy at the 50% isodose) were collected. Four different dosimetric indexes were defined and calculated retrospectively in all plannings on the basis of dose-volume histograms: Paddick conformity index (PI), gradient index (GI), homogeneity index (HI), and unit isocenter (UI). The different measures related to distribution of the radiation dose were compared with hearing and tumor outcome of 203 patients with clinical and radiological follow-up of minimum 2 years. RESULTS: Mean, median, SD, and ranges of the four indexes of dose distribution analyzed were calculated; large variations were found between dose plans. We found a high correlation between the target volume and PI, GI, and UI. No significant association was found between the indexes of dose distribution calculated in this study and tumor control, tumor volume shrinkage, hearing worsening, loss of functional hearing, or complete hearing loss at last follow-up. CONCLUSIONS: Parameters of distribution of the radiation dose during GK radiosurgery for VS can be highly variable between dose plans. The tumor and hearing outcome of patients treated is not significantly related to these global indexes of dose distribution inside and around target volume. In GK radiosurgery for VS, the outcome seems more to be influenced by local radiation dose delivered to specific structures or volumes than by global dose gradients.

Gamma knife radiosurgery for intralabyrinthine schwannomas.

OBJECT: To analyze indications and technical specificities of treatment of intralabyrinthine schwannoma (ILS) by Gamma Knife radiosurgery. METHODS: Six patients were treated by Gamma Knife irradiation for a schwannoma arising from the cochleo-vestibular structures. Patients presented hearing worsening at different stages, tinnitus, imbalance and/or vertigo. RESULTS: ILS was intravestibular/intracochlear/intravestibulocochlear/ transmacular in respectively 2/1/2/1 patients. We cover the entire tumor volume with a margin prescription dose of 12-Gy. The tumor volume remained unchanged at last follow-up in all cases; for 4 patients with functional hearing still present before treatment, the audiological status remained stable in 2 patients, worsened moderately in 1 patientand worsened to cophosis in 1 patient. No patient experienced worsening of tinnitus, imbalance or vertigo after irradiation. CONCLUSIONS: Gamma Knife treatment of ILS is technically feasible without risk thanks to the precision of current robotized Gamma Knife devices. Patients treated radiosurgically avoid some of the risks of microsurgery, could in some cases maintain useful hearing and prevent further symptoms worsening.

Irradiation of cochlear structures during vestibular schwannoma radiosurgery and associated hearing outcome.

OBJECT: The purpose of this study was to measure the dose of radiation delivered to the cochlea during a Gamma knife surgery (GKS) procedure for treatment of patients with vestibular schwannomas (VSs), and to analyze the relationship between cochlear irradiation and the hearing outcome of these patients. METHODS: Eighty-two patients with VSs were treated with GKS using a marginal dose of 12 Gy. No patient had neurofibromatosis Type 2 disease, and all had a Gardner-Robertson hearing class of I to IV before treatment, and a radiological and audiological follow-up of at least 1-year after GKS. The dosimetric data of the volume of the cochlea were retrospectively analyzed and were correlated with the auditory outcome of patients. RESULTS: The mean radiation dose delivered to the cochlear volume ranged from 1.30 to 10.00 Gy (median 4.15 Gy). The cochlea received significantly higher radiation doses in patients with worsening of hearing after GKS. A highly significant association between the cochlear and the intracanalicular dose of radiation delivered during GKS was found. CONCLUSIONS: During GKS for VSs, relatively high doses of radiation can be delivered to the cochlea. Worsening of hearing after GKS can be the consequence of either radiation injury to the cochlea or the irradiation dose delivered into the auditory canal, or both.

Animal model for cholesteatoma induced in the gerbil: will the profiles of differentiation/growth-regulatory markers be similar to the clinical situation?

INTRODUCTION: Cholesteatoma is a benign tumor of the middle ear characterized by an aggressive and invasive potential. The only current treatment being surgery, it is important to have access to a reliable animal model to study and better understand cholesteatoma pathogenesis. Our study aimed to examine the biological validity of the most common experimental model of cholesteatoma: the Mongolian gerbil. MATERIAL AND METHODS: We have induced cholesteatoma by surgical ligature of the gerbil's external auditory duct. Quantitative comparison of eight biological markers involved in inflammation (macrophage migration inhibitory factor [MIF]), cell differentiation (retinoic acid receptors-alpha, -beta, and -gamma), and cell adhesion/apoptosis (galectins-1, -3, -7, and -8). The immunohistochemical staining was quantified by computer-assisted microscopy. RESULTS: Two immunohistochemical parameters were determined in sections. The labeling index (LI) represents the percentage of tissue area specifically stained, and the mean optical density (MOD) denotes the staining intensity index. The LI reveals statistically significant differences for each marker tested. The MOD also shows statistically significant differences except for MIF (P = .259). CONCLUSION: From the panel of markers, the majority of staining parameters was statistically significantly different between sections of the animal model and clinical specimen. These data do not support the concept of complete validity of the popular animal model.

Role of intracanalicular volumetric and dosimetric parameters on hearing preservation after vestibular schwannoma radiosurgery.

PURPOSE: To analyze the relationship between hearing preservation after gamma knife radiosurgery (GKR) for vestibular schwannoma (VS) and some volumetric and dosimetric parameters of the intracanalicular components of VS. METHODS AND MATERIALS: This study included 82 patients with a VS treated by GKR; all patients had no NF2 disease, a Gardner-Robertson hearing class 1-4 before treatment, a marginal dose of 12 Gy, and a radiologic and audiologic follow-up > or =1 year post-GKR. The volume of both the entire tumor and the intracanalicular part of the tumor and the mean and integrated dose of these two volumes were correlated to the auditory outcomes of patients. RESULTS: At last hearing follow-up, 52 patients had no hearing worsening, and 30 patients had an increase of > or =1 class on Gardner-Robertson classification. We found that hearing preservation after GKR is significantly correlated with the intracanalicular tumor volume, as well as with the integrated dose delivered to the intracanalicular tumor volume. CONCLUSIONS: Some volumetric and dosimetric parameters of the intracanalicular part of the tumor influence hearing preservation after GKR of VS. Consequently, we advise the direct treatment of patients with preserved functional hearing and a VS including a small intracanalicular volume.

Budesonide-dependent modulation of expression of macrophage migration inhibitory factor in a polyposis model: evidence for differential regulation in surface and glandular epithelia.

Macrophage migration inhibitory factor (MIF) is a counterregulatory lymphokine for glucocorticoid action within the immune system. To provide further insights into the way expression of pleiotropically acting MIF is modulated by glucocorticoids, we investigated the influence of the glucocorticoid budesonide on the level of expression of MIF in a model of human nasal polyposis by quantitative immunohistochemical analysis. Ten nasal polyps obtained from surgical resection were maintained for 24 hours in the presence of 3 budesonide concentrations: 10, 50, and 250 ng/mL. As quantitatively demonstrated by computer-assisted microscopy, 50 ng/mL induced an increase in MIF expression in the surface epithelium and a decrease in MIF expression in the glandular epithelium. At the 250 ng/mL dose, the inverse effect was induced. Evidently, surface and glandular epithelia react nonuniformly to the glucocorticoid regarding MIF presence, adding dependence on the cell type to the regulatory network.

Respiratory epithelial adenomatoid hamartoma associated with nasal polyposis.

Hamartoma is a rare, non-neoplastic tumor characterized by an abnormal mixture of tissues, which are indigenous to the region. They are rare in the nasal cavity. We report a 79-year-old woman with an adenomatoid hamartoma in the left nasal cavity associated with nasal polyposis. This association supports the hypothesis that inflammation is one of the factors that induce the development of a hamartoma. Functional endoscopic sinus surgery was performed to completely remove it, and this lesion was found to have arisen from the lateral nasal wall. It is an unusual localization because the most common site in the nasal cavity is the nasal septum, particularly the posterior aspect. Limited but complete surgical resection is the treatment of choice. Although adenomatoid hamartoma arising from the sinonasal tract is very rare, head and neck surgeons should be aware of this pathological entity as a differential diagnosis for inverted papilloma and adenocarcinoma. Misinterpretation of these lesions as a true neoplasm may result in unnecessarily aggressive surgery for this benign lesion.

Expression patterns of galectin-1 and galectin-3 in nasal polyps and middle and inferior turbinates in relation to growth regulation and immunosuppression.

BACKGROUND: The term nasal polyposis describes benign growth processes in the nasal and sinus mucosa, which are mainly located in the middle meatus and never in the inferior meatus. As a step to define the biochemical determinants relevant for growth regulation, we focused on endogenous lectins known for anti-apoptotic (galectin-3) and immunomodulatory (galectin-1) activities. DESIGN: Using computer-assisted microscopy, we performed an immunohistochemical investigation defining the quantitative parameters of expression of galectin-1 and galectin-3 in 10 nasal polyps, 10 middle turbinates, and 10 inferior turbinates, all of which were obtained from surgical resection. RESULTS: Our data show that galectin-3 expression is markedly (P<.001) higher in nasal polyps than in turbinates. No relation to the allergic status was discovered. Galectin-1 expression is higher in nasal polyps than in middle turbinates (P<.001) in nonallergic patients compared with allergic ones (in glandular epithelium, P =.009; in connective tissue, P =.006). The lowest galectin-1 expression was observed in the middle turbinate. CONCLUSIONS: These data are in line with a positive influence of galectin-3 on growth and an immunoregulatory role of galectin-1, mimicking an increased expression dependent on glucocorticoid.

Glucocorticoid-induced differential expression of the sialylated and nonsialylated Lewis(a) epitopes and respective binding sites in human nasal polyps maintained under ex vivo tissue culture conditions.

We characterized the anti-inflammatory effects of budesonide on the expression of adhesion molecules involving Lewis(a) (Le(a)) epitope, its sialylated derivative (sLe(a)), and their respective binding sites in human nasal polyposis. By computer-assisted microscopy, we quantitatively characterized the level of histochemical expression of L- and P-selectins, sialylated and nonsialylated Le(a) epitopes, and their respective binding sites in both surface epithelium and glandular epithelium of human nasal polyps obtained from surgical resection, maintained under ex vivo tissue culture conditions for 24 hours, and treated or not with budesonide. Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) were chosen as methodological controls, because data already published in the literature clearly indicated budesonide-mediated effects on ICAM-1 and VCAM-1 levels of expression. The present data show that budesonide significantly modified the levels of expression of ICAM-1 and VCAM-1, and to a lesser extent that of P-selectin, in the surface and glandular epithelia. Budesonide markedly decreased the levels of expression of the binding sites for both Le(a) and sLe(a), while those of Le(a) and sLe(a) remained globally unchanged. In conclusion, the present study documents that glucocorticoid-induced effects can encompass receptors for Le(a) epitopes different from E- and P-selectins on epithelial cells of human nasal polyps.

Galectin-1 is overexpressed in nasal polyps under budesonide and inhibits eosinophil migration.

Because of the importance of galectins for various cellular activities, the influence of the glucocorticoid budesonide on the level of expression of galectins-1 and -3 was investigated in human nasal polyposis. Ten nasal polyps obtained from surgical resection were maintained for 24 hours in the presence of various concentrations of budesonide. As quantitatively demonstrated by means of computer-assisted microscopy, 250 ng/ml (the highest dose tested) induced a pronounced increase of galectin-1 expression. This feature was observed in nasal polyps from allergic patients but not in those from nonallergic patients. Since eosinophils represent the main inflammatory cell population in nasal polyps, we investigated the effect of galectin-1 on their migration levels by means of quantitative phase-contrast computer-assisted videomicroscopy. Our results show that galectin-1 (coated on plastic supports) markedly reduced the migration levels of eosinophils in comparison to P-selectin. On the cellular level, marked modifications in the polymerization/depolymerization dynamics of the actin cytoskeleton (as revealed by means of computer-assisted fluorescence microscopy) and, to a much lesser extent, an increase in the adhesiveness of eosinophils to tested substrata were detectable. The present study therefore reveals a new galectin-1-mediated mechanism of action for glucocorticoid-mediated anti-inflammatory effects.