Abraham Jacob

Nerve of Origin, Tumor Size, Hearing Preservation, and Facial Nerve Outcomes in 359 Vestibular Schwannoma Resections at a Tertiary Care Academic Center

Objective: To determine nerve of origin, tumor size, hearing preservation rates, and facial nerve outcomes in a retrospective cohort study of patients undergoing translabyrinthine (TL), middle cranial fossa (MCF), and retrosigmoid/suboccipital (SO) approaches to vestibular schwannomas (VS).

Consensus Recommendations for Current Treatments and Accelerating Clinical Trials for Patients with Neurofibromatosis Type 2

Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome characterized by bilateral vestibular schwannomas (VS) which often result in deafness despite aggressive management. Meningiomas, ependymomas, and other cranial nerve and peripheral schwannomas are also commonly found in NF2 and collectively lead to major neurologic morbidity and mortality. Traditionally, the overall survival rate in patients with NF2 is estimated to be 38% at 20 years from diagnosis. Hence, there is a desperate need for new, effective therapies. Recent progress in understanding the molecular basis of NF2 related tumors has aided in the identification of potential therapeutic targets and emerging clinical therapies. In June 2010, representatives of the international NF2 research and clinical community convened under the leadership of Drs. D. Gareth Evans (University of Manchester) and Marco Giovannini (House Research Institute) to review the state of NF2 treatment and clinical trials. This manuscript summarizes the expert opinions about current treatments for NF2 associated tumors and recommendations for advancing therapies emerging from that meeting. The development of effective therapies for NF2 associated tumors has the potential for significant clinical advancement not only for patients with NF2 but for thousands of neuro‐oncology patients afflicted with these tumors.

Consensus Recommendations to Accelerate Clinical Trials for Neurofibromatosis Type 2

Purpose: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves. Significant morbidity can result from surgical treatment of these tumors. Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2. The lack of effective treatments for NF2 marks an unmet medical need. Experimental Design: Here, we provide recommendations from a workshop, cochaired by Drs. D. Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials. Results: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials. Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2. Conclusions: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials. The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics. (Clin Cancer Res 2009;15(16):5032–9)

Growth Inhibitory and Anti-Tumour Activities of OSU-03012, a Novel PDK-1 Inhibitor, on Vestibular Schwannoma and Malignant Schwannoma Cells

BACKGROUND Vestibular schwannomas (VS) frequently express high levels of activated AKT. Small-molecule inhibitors of AKT signalling may have therapeutic potential in suppressing the growth of benign VS and malignant schwannomas. METHOD Primary VS and Schwann cells, human malignant schwannoma HMS-97 cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared to investigate the growth inhibitory and anti-tumour activities of OSU-03012, a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent kinase-1. Cell proliferation assays, apoptosis, Western blot, in vivo xenograft analysis using SCID mice and immunohistochemistry were performed. RESULTS OSU-03012 inhibited cell proliferation more effectively in both VS and HMS-97 cells than in normal human Schwann cells. The IC5) of OSU-03012 at 48h was approximately 3.1 microM for VS cells and 2.6 microM for HMS-97 cells, compared with the IC(50) of greater than 12 microM for human Schwann cells. Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann cells and mouse schwannoma cells established from transgenic mice carrying the NF2 promoter-driven SV40 T-antigen gene. Like VS cells, malignant schwannoma HMS-97 cells expressed high levels of activated AKT. OSU-03012 induced apoptosis in both VS and HMS-97 cells and caused a marked reduction of AKT phosphorylation at both the Ser-308 and Thr-473 sites in a dose-dependent manner. In vivo xenograft analysis showed that OSU-03012 was well tolerated and inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks of oral treatment. The anti-tumour activity correlated with reduced AKT phosphorylation. CONCLUSION OSU-03012 is a potential chemotherapeutic agent for VS and malignant schwannomas.

Use of Mimix hydroxyapatite bone cement for difficult ossicular reconstruction.

OBJECTIVE: To describe the advantages of using MimixTM hydroxyapatite (HA) bone cement in reconstructing a variety of ossicular chain abnormalities. STUDY DESIGN AND SETTING: Case series at a tertiary medical center. RESULTS: Twenty-five cases of HA reconstruction are included in this series (ages 23-74; mean, 47 years). The examples presented include (1) HA as the sole reconstructive material for incus erosion, (2) HA for securing a total or partial ossicular replacement prosthesis, (3) incus augmentation after crimping for revision stapedotomy with incus erosion, (4) HA in primary stapedotomy to fix the crimped prosthesis to an intact incus, and (5) other unique situations. Preoperative and postoperative audiograms were evaluated for 4-tone pure tone average (PTA), speech reception thresholds, word recognition scores, and air-bone gaps (AB gaps). Mean follow-up was 11 months (range 2 to 22 months). The mean PTA improved from 57 dB to 37 dB, whereas the mean AB gaps decreased from 33 dB to 16 dB. There were no cases of infection or extrusion. CONCLUSIONS: Hydroxyapatite bone cement is an excellent adjunct or alternative to ossiculoplasty with preformed prostheses. Easily malleable, rapidly setting, and rapidly hardening, Mimix is particularly well suited for middle ear work. SIGNIFICANCE: Definitive fixation with bone cements during difficult ossicular chain reconstruction may ensure a more enduring successful outcome. (Otolaryngol Head Neck Surg 2005; 132:727-34.)

Phosphatidylinositol 3-kinase/AKT pathway activation in human vestibular schwannoma.

Hypothesis: The neurofibromatosis 2 gene, which encodes the tumor suppressor protein merlin, is frequently mutated in vestibular schwannomas (VS). Merlin can inhibit phosphatidylinositol 3 kinase (PI3 kinase) by binding to PI3 kinase enhancer long isoform. Therefore, we hypothesized that the PI3 kinase/AKT pathway is activated in VS. Background: Despite advances in diagnosis and treatment, VS continue to cause patient morbidity. A more thorough understanding of the signaling pathways deregulated in VS will aid in the development of novel medical therapeutics. Activation of the PI3 kinase/AKT pathway increases cell survival and cell proliferation and has been observed in a variety of human cancers. However, whether the PI3 kinase/AKT pathway is activated in human VS has not been reported. Methods: Complementary deoxyribonucleic acid microarrays were performed using cultured Schwann cells, 4 VS specimens, and 2 paired normal vestibular nerves. Immunohistochemical analysis using antibodies to activated phosphorylated-AKT was performed on 14 VS tissue sections. Western blots using various antibodies to components of the PI3 kinase/AKT pathways were conducted. Results: Microarray analysis demonstrated that total AKT gene expression was upregulated in VS, compared with normal vestibular nerves. Immunohistochemical analysis of 14 VS tissue sections detected positive staining for activated AKT phosphorylated at both serine-473 and threonine-308 in all tumors. Western blots comparing VS specimens with normal vestibular nerves showed that the AKT pathway was activated in VS but not in normal nerve. Total AKT, phosphorylated-AKT, PI3-kinase, phosphorylated-phosphatase and tensin homologue deleted on chromosome 10, phosphorylated-phosphoinositide-dependent protein kinase 1, phosphorylated-forkhead box O, phosphorylated-glycogen synthase kinase 3&bgr;, and phosphorylated-mammalian target of rapamycin were upregulated in VS. Conclusion: The PI3 kinase/AKT pathway is activated in VS. Using our recently reported quantifiable VS xenograft model, novel inhibitors of the PI3 kinase/AKT pathway may be tested for VS growth inhibition in vivo.

Preclinical validation of AR42, a novel histone deacetylase inhibitor, as treatment for vestibular schwannomas.

Recent studies indicate that vestibular schwannomas (VSs) rely on phosphatidylinositol 3‐kinase/AKT activation to promote cell proliferation and survival; therefore, targeting AKT may provide new therapeutic options. We have previously shown that AR42, a novel histone deacetylase inhibitor, potently suppresses VS growth in vitro at doses correlating with AKT inactivation. The objectives of the current study were translational: 1) to examine the end biologic effects of AR42 on tumor growth in vivo, 2) to validate AKT as its in vivo molecular target, 3) to determine whether AR42 penetrates the blood‐brain barrier (BBB), and 4) to study the pharmacotoxicity profile of AR42.

Histone Deacetylase Inhibitor AR-42 Differentially Affects Cell-cycle Transit in Meningeal and Meningioma Cells, Potently Inhibiting NF2-Deficient Meningioma Growth

Meningiomas constitute about 34% of primary intracranial tumors and are associated with increased mortality in patients with neurofibromatosis type 2 (NF2). To evaluate potential medical therapies for these tumors, we have established a quantifiable orthotopic model for NF2-deficient meningiomas. We showed that telomerase-immortalized Ben-Men-1 benign meningioma cells harbored a single nucleotide deletion in NF2 exon 7 and did not express the NF2 protein, merlin. We also showed that AR-42, a pan-histone deacetylase inhibitor, inhibited proliferation of both Ben-Men-1 and normal meningeal cells by increasing expression of p16(INK4A), p21(CIP1/WAF1), and p27(KIP1). In addition, AR-42 increased proapoptotic Bim expression and decreased anti-apoptotic Bcl(XL) levels. However, AR-42 predominantly arrested Ben-Men-1 cells at G(2)-M whereas it induced cell-cycle arrest at G(1) in meningeal cells. Consistently, AR-42 substantially decreased the levels of cyclin D1, E, and A, and proliferating cell nuclear antigen in meningeal cells while significantly reducing the expression of cyclin B, important for progression through G(2), in Ben-Men-1 cells. In addition, AR-42 decreased Aurora A and B expression. To compare the in vivo efficacies of AR-42 and AR-12, a PDK1 inhibitor, we generated and used luciferase-expressing Ben-Men-1-LucB cells to establish intracranial xenografts that grew over time. While AR-12 treatment moderately slowed tumor growth, AR-42 caused regression of Ben-Men-1-LucB tumors. Importantly, AR-42-treated tumors showed minimal regrowth when xenograft-bearing mice were switched to normal diet. Together, these results suggest that AR-42 is a potential therapy for meningiomas. The differential effect of AR-42 on cell-cycle progression of normal meningeal and meningioma cells may have implications for why AR-42 is well-tolerated while it potently inhibits tumor growth.

Round window perfusion dynamics: implications for intracochlear therapy.

Purpose of reviewThe treatments for inner ear diseases are evolving as the systemic administration of medication is replaced by novel intratympanic and intracochlear drug delivery. The current review explores the background and recent developments in this field. Recent findingsAlthough still in various stages of clinical development, novel drug delivery techniques such as the Silverstein MicroWick, the round window microcatheter, biodegradable hydrogels, biopolymers, nanoparticles, newly designed cochlear implant arrays, osmotic mini/micro pumps, and reciprocating perfusion systems hold significant promise. Animal data suggest that sustained delivery systems have more reliable inner ear pharmacokinetics than both systemic administration and intratympanic injections. SummaryAs research scientists advance technologies for treating inner ear diseases, drug delivery techniques must keep pace. Viable treatment options for sensorineural hearing loss, tinnitus, and vestibular disorders are on the horizon and may usher in a new golden age for otology.

Survey anatomy of the paranasal sinuses in the normal mouse.

Objective: To provide researchers with a survey atlas of normal paranasal sinus anatomy in the mouse as well as to standardize the reporting of data within the murine nose and sinuses.