Intratympanic steroid therapy for refractory sudden sensory hearing loss: a 12-year experience with the Silverstein catheter

Background: Sudden sensorineural hearing loss (SSNHL) is commonly encountered in clinical practice.

Aim/Objective: Determine if local administration of corticosteroids to the inner ear can improve hearing and speech intelligibility after the failure of conventional treatment for SSNHL loss when administered for 10 days after the onset of the hearing loss in a large cohort of 77 patients.

Materials and methods: A Silverstein MicroWick? was placed under local anesthesia and endoscopic control in the round window niche, allowing self-administration of methylprednisolone twice daily for four weeks.

Results: An improvement of the pure tone average was shown in 31% of patients. Speech intelligibility improved significantly in 55% of the total cohort and in 34% of the population with a stable pure tone average. Among the 77 patients, 22% used a hearing aid. Only 14% of the patients were hearing-aid users in the group with an improvement in speech intelligibility as opposed to 31% in the failure group.

Conclusion and significance: Local administration of steroids to the inner ear through the round window route improves hearing and speech intelligibility in patients after failure of conventional therapy. The use of a hearing aid was reduced by 50% when speech intelligibility was improved.     

Dexamethasone inhibits the HSV-<Emphasis Type="Italic">tk</Emphasis>/ ganciclovir bystander effect in malignant glioma cells

Background  

HSV-tk/ganciclovir (GCV) gene therapy has been extensively studied in the setting of brain tumors and largely relies on the bystander effect. Large studies have however failed to demonstrate any significant benefit of this strategy in the treatment of human brain tumors. Since dexamethasone is a frequently used symptomatic treatment for malignant gliomas, its interaction with the bystander effect and the overall efficacy of HSV-TK gene therapy ought to be assessed.     

Adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling

Background

Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. We previously demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors.

Method

In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs.

Results

We demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself. In vitro migration bio-assays highlighted that human U87MG GSCs isolated from the SVZs (U87MG-SVZ) display stronger migratory abilities in response to recombinant CXCL12 and/or SVZ-conditioned medium (SVZ-CM) compared with cancer cells isolated from the tumor mass (U87MG-TM). Moreover, in vitro inhibition of the CXCR4 signaling significantly decreased the U87MG-SVZ cell migration in response to the SVZ-CM. Very interestingly, treating U87MG-xenografted mice with daily doses of AMD3100, a specific CXCR4 antagonist, prevented the specific invasion of the SVZ. Another in vivo experiment, using CXCR4-invalidated GBM cells, displayed similar results.

Conclusion

Taken together, these data demonstrate the significant role of the CXCL12/CXCR4 signaling in this original model of brain cancer invasion.     

Transforming growth factor β as a neuronoglial signal during peripheral nervous system response to injury

In contrast to the central nervous system (CNS), the peripheral nervous system (PNS) displays an important regenerative ability which is dependent, at least in part, on Schwann cell properties. The mechanisms which stimulate Schwann cells to adapt their behavior after a lesion to generate adequate conditions for PNS regeneration remain unknown. In this work, we report that adult rat dorsal root ganglion (DRG) neurons are able, after a lesion performed in vivo or when they are dissociated and cultured in vitro, to synthesize transforming growth factor β (TGFβ), a pleiotropic growth factor implicated in wound healing processes and in carcinogenesis. This TGFβ is tentatively identified as the β-1 isoform. Adult rat DRG neurons release a biologically active form of TGFβ which is able to elicit multiple Schwann cell responses including a stimulation to proliferate. Moreover, purified TGFβ-1 produces a Schwann cell morphology alteration and decreases the secretion of tissue-type plasminogen activator (tPA) and enhances the secretion of plasminogen activator inhibitor (PAI) by Schwann cells. This generates conditions which are thought to favor a successful neuritic regrowth. Furthermore, purified TGFβ-1 stimulates type IV collagen mRNA expression in Schwann cells. This subtype of collagen is associated with the process of myelinization. Finally, TGFβ-1 decreases nerve growth factor (NGF) mRNA expression by Schwann cells, an effect which could participate in the maintenance of a distoproximal NGF gradient during nerve regeneration. We propose that neuronal TGFβ plays an essential role as a neuronoglial signal that modulates the response of Schwann cells to injury and participates in the successful regeneration processes observed in the PNS. © 1993 Wiley-Liss, Inc.     

In vitro kinetics of a newborn rat astroglia-derived neuronotoxic activity

A low-molecular weight astrocyte-derived neuronotoxic activity (ANTA) was detected, using a colorimetric bioassay of cell survival, by its effect on cultured granule cells. This neuronotoxic activity was found to be released rapidly from newborn rat astrocytes in culture upon incubation in 50 mM K+-containing growth medium. The release by astrocytes could be induced repetitively by successive incubations in high-K+ medium alternating with incubations in normal medium. Astrocytes were also found to inactivate rapidly isobutanol-extracted ANTA in normal K+-containing growth medium. Kinetic studies showed that ANTA induces a slow (greater than 12 h) degeneration of cultured granule cells. ANTA is shown here to be an intermediate of normal astrocyte metabolism and to display appropriate kinetic characteristics compatible with its proposed role in inducing part of the delayed neuronal loss that occurs after a brain injury (secondary neuronal death).     

Brain basic fibroblast growth factor stimulates the release of plasminogen activators by newborn rat cultured astroglial cells

Basic fibroblast growth factor (bFGF), a growth factor for many cell types including newborn rat astroglial cells, stimulates in a dose-dependent fashion the release of plasminogen activators (PAs) by these cells as measured by the fibrin-overlay method or the Coleman and Green's colorimetric assay. This effect of bFGF on PAs secretion (about 4.5-fold increase at 40 ng/ml bFGF) does not result from an aspecific stimulation of protein secretion by astrocytes and is only partly correlated with the mitogenic activity of bFGF. bFGF was also tested on two clonal glioma cell lines (C6 and LN18). Only one of those cell types (LN18) showed a stimulated PA release in the presence of bFGF. These data are discussed with respect to the putative roles of plasminogen activators in the developing nervous system.     

Grafts of syngenic cultured, adult dorsal root ganglion-derived Schwann cells to the injured spinal cord of adult rats: preliminary morphological studies.

Highly enriched cultures of Schwann cells were obtained from adult rat dorsal root ganglia and implanted (5 x 10(5) -9 x 10(5) cells) in the spinal cord of syngenic adult rats at the site of an acute compression lesion produced by a subdural inflatable microballoon. These autografts survived and invaded the host tissue, reducing central cavitation and astrocytic gliosis. They dramatically promoted ingrowth of axons, the majority of which appeared to come from the dorsal roots as judged by their neuropeptide content. Invasion of the transplants by descending, e.g. aminergic fibers, was negligible at survival times of up to 4 months. Nonetheless, autologous Schwann cells, which are readily available in the host, represent a promising material for grafts into the injured spinal cord.