Faculty Bibliography

Object The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM. Methods From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involved-field radiation therapy and concomitant temozolomide (75 mg/m(2) daily for 42 days) along with bevacizumab (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m(2) on Days 1-7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle. Results The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 patients (19.6%). No treatment-related deaths were observed. Asymptomatic intracranial bleeding was noted in 5 patients. Conclusions The addition of bevacizumab to conventional therapy in newly diagnosed GBM appears to improve both PFS and OS in patients with newly diagnosed GBM, with acceptable morbidity. A shift toward diffuse relapse was noted in a significant number of patients. Ongoing Phase III clinical trials will show the true benefit of this antiangiogenic approach.

The developmental plasticity of excitatory synapses is well established, particularly as a function of age. If similar principles apply to inhibitory synapses, then we would expect manipulations during juvenile development to produce a greater effect and experience-dependent changes to persist into adulthood. In this study, we first characterized the maturation of cortical inhibitory synapse function from just before the onset of hearing through adulthood. We then examined the long-term effects of developmental conductive hearing loss (CHL). Whole cell recordings from gerbil thalamocortical brain slices revealed a significant decrease in the decay time of inhibitory currents during the first 3 mo of normal development. When assessed in adults, developmental CHL led to an enduring decrease of inhibitory synaptic strength, whereas the maturation of synaptic decay time was only delayed. Early CHL also depressed the maximum discharge rate of fast-spiking, but not low-threshold-spiking, inhibitory interneurons. We then asked whether adult onset CHL had a similar effect, but neither inhibitory current amplitude nor decay time was altered. Thus inhibitory synapse function displays a protracted development during which deficits can be induced by juvenile, but not adult, hearing loss. These long-lasting changes to inhibitory function may contribute to the auditory processing deficits associated with early hearing loss.

Implantation of the ossified and dysplastic cochlea presents many unique challenges to both the surgeon and programming team. Altered embryology and physiology of these labyrinthine dysplasias may result in forms and functions unfamiliar to those casually involved with cochlear implants. Remarkable developments in diagnosis, surgical technique, electrode design, processing strategies, and programming have all contributed to the ability to successfully implant patient populations previously excluded from this life-changing intervention

Cochlear implants have become a viable treatment option for individuals who present with severe to profound hearing loss. While there are several parameters that affect the successful use of this technology, quality programming of the cochlear implant system is crucial. This review chapter focuses on general device programming techniques, programming techniques specific to children, objective programming techniques, a brief overview of programming parameters of the currently commercially available multichannel systems, and managing patient complaints and device failures. The chapter also provides what the authors believe the future may hold for new programming techniques

PURPOSE: Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy. The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG. The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy. METHODS AND MATERIALS: A total of 162 consecutive patients with HGG, either newly diagnosed (n = 58) or with recurrent disease (n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression. The pattern of recurrence and interval to progression were the primary aims of the present study. Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline. RESULTS: At a median follow-up of 7 months (range, 1-37), 105 patients had recurrence, and 79 patients ultimately developed DIR. The interval to progression was similar in the DIR and local recurrence groups (6.5 and 6.3 months, p = .296). The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R(2) = 0.957). The duration of bevacizumab therapy increased the interval to recurrence (p < .0001) and improved overall survival (p < .0001). However, the pattern of relapse did not affect overall survival (p = .253). CONCLUSION: Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients. The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials

Recent studies highlight the importance of BRAF alterations resulting in mitogen activated protein kinase (MAK/ERK) pathway activation in low-grade CNS tumors. We studied 106 low-grade CNS neoplasms in a cohort of primarily pediatric patients to identify the prevalence and clinicopathologic significance of these alterations. Polymerase chain reaction testing identified KIAA1549:BRAF fusions in 51 (48%) tumors overall, including 42 (60%) pilocytic astrocytomas, 4 (17%) unclassifiable low-grade gliomas, 4 (36%) low-grade glioneuronal/neuroepithelial tumors, 0 (of 5) pleomorphic xanthoastrocytomas, 0 (of 4) diffuse astrocytomas (World Health Organization grade II), and 1 (of 3, 33%) pilomyxoid astrocytoma. KIAA1549:BRAF gene fusions confirmed by sequencing included the previously reported ones involving exons 1-16/9-18 (49%), 1-15/9-18 (35%), and 1-16/11-18 (8%) and 2 fusions with novel breakpoints: 1-15/11-18 (6%) and 1-17/10-18 (1%). DNA sequencing identified BRAF mutations in 8% of tumors. BRAF mutations were absent. KIAA1549:BRAF fusions were significantly more frequent in infratentorial (57%) and optic pathway (59%) tumors versus supratentorial (19%) tumors (p = 0.001). We did not identify significantly improved progression-free survival in tumors with fusions. In summary, KIAA1549:BRAF fusions predominate in pilocytic astrocytomas but are also present in some low-grade unclassifiable gliomas and glioneuronal tumors. The prognostic and therapeutic significance of this alteration is unclear and merits further study.

The oral mucosa's accessibility, excellent blood supply, by-pass of hepatic first-pass metabolism, rapid repair and permeability profile make it an attractive site for local and systemic drug delivery. Technological advances in mucoadhesives, sustained drug release, permeability enhancers and drug delivery vectors are increasing the efficient delivery of drugs to treat oral and systemic diseases. When treating oral diseases, these advances result in enhanced therapeutic efficacy, reduced drug wastage and the prospect of using biological agents such as genes, peptides and antibodies. These technologies are also increasing the repertoire of drugs that can be delivered across the oral mucosa to treat systemic diseases. Trans-mucosal delivery is now a favoured route for non-parenteral administration of emergency drugs and agents where a rapid onset of action is required. Furthermore, advances in drug delivery technology are bringing forward the likelihood of transmucosal systemic delivery of biological agents.

Reconstruction of maxillectomy with extensive orbital rim and floor excision defects is a challenging problem. The goal of reconstruction here is to provide adequate orbital support to prevent enophthalmos and diplopia as well as obturation of the palatal defect. The existing methods of the reconstruction fail to simultaneously address these 2 goals of reconstruction. A new method of reconstruction of these defects using tensor fascia lata-iliac crest flap was used in 7 cases of cancers of the maxilla, which necessitated extensive resection of the orbital floor along with the maxillectomy. The flap was raised as a muscle and bone flap in 5 cases and in 2, a skin paddle was included. The immediate and delayed outcome at 6-month follow-up was analyzed. The functional outcome with regards to the ocular position and function, palatal obturation, speech, and swallowing were recorded. The bone viability at 6 months was assessed by computed tomography scan. The flap was successful in all the 7 cases. The delayed outcome assessment showed that the orbital support was excellent with no diplopia in all the cases. The palatal defect could be covered successfully in all the cases, resulting in normal speech and swallowing. The computed tomography scan showed excellent integration of the bone. The free tensor fascia lata-iliac crest flap is a reliable and safe method of reconstruction of the orbitomaxillary defects, addressing the issues of both orbital support and palatal obturation.

OBJECTIVES: To determine the efficacy of cochlear implantation (CI) in prelingually deafened adolescent children and to evaluate predictive variables for successful outcomes. DESIGN: Retrospective medical record review. PARTICIPANTS: Children aged 10 to 17 years with prelingual hearing loss (mean length of deafness, 11.5 years) who received a unilateral CI (mean age at CI, 12.9 years). Intervention Unilateral CI. MAIN OUTCOME MEASURES: Standard speech perception testing (Consonant-Nucleus-Consonant [CNC] monosyllabic word test and Hearing in Noise [HINT] sentence test) was performed preoperatively, 1 year postoperatively (year 1), and at the last follow-up/end of the study (EOS). RESULTS: There was a highly significant improvement in speech perception scores for both HINT sentence and CNC word testing from the preoperative testing to year 1 (mean change score, 51.10% and 32.23%, respectively; P < .001) and from the preoperative testing to EOS (mean change score, 60.02% and 38.73%, respectively; P < .001), with a significantly greater increase during the first year (P < .001). In addition, there was a highly significant correlation between improvements in performance scores on the CNC word and HINT sentence speech perception tests and both age at CI and length of deafness at the year 1 testing (P </=.009) but not from the year 1 testing to EOS testing. Adolescents with progressive deafness and those using oral communication before CI performed significantly better than age-matched peers. CONCLUSIONS: Adolescents with prelingual deafness undergoing unilateral CI show significant improvement in objective hearing outcome measures. Patients with shorter lengths of deafness and earlier age at CI tend to outperform their peers. In addition, patients with progressive deafness and those using oral communication have significantly better objective outcomes than their peers