Left Cochlea Research Articles

Automated Machine-Learning Radiation Therapy Treatment Planning for Pediatric and Adult Brain Tumors

To evaluate the feasibility of using a machine-learning (ML) treatment planning method to automatically generate treatment plans for pediatric and adult brain tumor cases, and compare ML-generated treatment plans with human-generated plans used clinically. The application of a ML radiation treatment planning method [1] was investigated using a training set of adults (n = 25) and pediatric (n = 91) brain tumor patients treated from December 2007 to March 2018 with dose prescription of 54 Gy in 30 fractions using IMRT/VMAT. Our ML model predicts the optimal dose to targets and normal tissues based on learned relationships between image features and dose distributions of anatomically similar patients. Predicted dose plans are converted to clinically deliverable single-arc VMAT plans using optimization algorithms that enforce technical beam delivery constraints. Ten children and three adults with centrally-located primary brain tumors clinically treated with 54 Gy, not previously used for model training, were re-planned with this ML model. Dosimetry to targets and organs-at-risk (OAR) were compared between ML and manual clinical plans. Comparable target coverage was observed in both ML and manual plans. At least 95% of PTV received >51.3 Gy (95% of prescription) in 11 ML vs 12 manual plans. Similar maximum doses to OARs including optic nerves, chiasm and cord were observed. Maximum dose to optic nerves was <54 Gy in all ML and manual plans; maximum chiasm dose was <54 Gy in 12 ML vs 13 manual plans; maximum cord dose was <54 Gy in 12 ML vs 11 manual plans. Maximum brainstem dose was >54 Gy in 11 out of 13 ML (85%) and 7 manual (54%) plans, because 81% of the training cases with centrally located tumors had brainstem doses >54 Gy. The median differences in mean dose to left and right cochleae were 3 Gy and 0.3 Gy higher in ML than manual plans, respectively, whereas mean doses to left and right temporal lobes were 2.5 Gy and 2.8 Gy lower in ML plans than manual plans, respectively. Average time for ML plan generation was 27 minutes (range, 17-34). We demonstrate the feasibility of rapidly generating clinically-deliverable ML plans with consistent plan quality, similar target coverage and OAR sparing as compared to manual clinical plans. A similar proportion of cases with maximum brainstem doses >54 Gy was observed in both ML plans and historical training cases which illustrates the importance of continuous quality improvement in ML models.

Enhanced optimization of volumetric modulated arc therapy plans using Monte Carlo generated beamlets.

A treatment planning system (TPS) produces volumetric modulated arc therapy (VMAT) plans by applying an optimization process to an objective function, followed by an accurate calculation of the final, deliverable dose. However, during the optimization step, a rapid dose calculation algorithm is required, which reduces its accuracy and its representation of the objective function space. Monte Carlo (MC) routines, considered the gold standard in accuracy, are currently too slow for practical comprehensive VMAT optimization. Therefore, we propose a novel approach called enhanced optimization (EO), which employs the TPS VMAT plan as a starting point, and applies small perturbations to nudge the solution closer to a true objective minimum. The perturbations consist of beamlet dose matrices, calculated using MC routines on a distributed-computing framework. DICOM files for clinical VMAT plans files are exported from the TPS and used to generate input files for the EGSnrc MC toolkit. Beamlet doses are calculated using the MC routines, each corresponding to a single multileaf collimator leaf from a single control point traveling 0.5cm in or out of the field. A typical VMAT plan requires 5000 to 10000 beamlets, which may be calculated overnight. This results in a ternary-valued objective function, which may use the same clinical objectives as the original VMAT plan. A simple greedy search algorithm is applied to minimize this function and determine the optimal set of ternary variables. The resulting modified control point parameters are imported into the TPS to calculate the final, deliverable dose, and to compare the EO plan with the original. EO was evaluated retrospectively on seven VMAT plans (two adult brain, one pediatric brain, two head and neck, and two prostate). Additionally, the use of stricter objectives was investigated for two of the cases: the left cochlea planning organ at risk (OAR) volume objective for the pediatric brain case, and the rectum objective for a prostate case. EO produced improved objective scores (by 6% to 60%) and dose-volume histograms (DVH) for the brain plans and the head and neck plans. For each of these plans, the target dose minimum and homogeneity were preserved, while one or more of the OAR DVH's was reduced. Although EO also reduced the objective scores for the prostate plans (by 46% and 79%), their absolute score and DVH improvements were not substantial. The stricter objective on the pediatric brain case resulted in lower dose to the OAR without compromising the target dose. However, the rectum dose in the prostate case could not be improved without reducing dose homogeneity to the planning target volume, suggesting that VMAT prostate cases may already be highly optimized by the TPS. We have developed a novel approach to improving the dose distribution of VMAT plans, which relies on MC calculations to provide small modifications to the control points. This method may be particularly useful for complex treatments in which a certain OAR is of concern and it is difficult for the treatment planner to obtain an acceptable solution with the TPS. Further development will reduce the beamlet computation time and result in more sophisticated EO treatment planning methods.

Effect of myricetin on the gene expressions of NOX3, TGF-β1, prestin, and HSP-70 and anti-oxidant activity in the cochlea of noise-exposed rats.

Objective(s):Noise-induced hearing loss is one of the most common occupational diseases in industrialized countries and can be affected by various environmental and genetic factors. This study was designed to examine the effect of myricetin in preventing this disorder.Materials and Methods:Twenty-one Wistar rats were randomly divided into five groups: Non-exposed, noise exposure only, noise exposure with vehicle, noise exposure with myricetin 5 mg/Kg, and noise exposure with myricetin 10 mg/kg. All animals were sacrificed after last noise exposure. The left cochlea was dissected from each rat. It was used for mRNA expression analysis (NOX3, TGF-β1, prestin, and HSP-70). Blood samples were collected to assess superoxide dismutase (SOD) activity, 1, 1 diphenyl picrylhydrazyl (DPPH), and malondialdehyde (MDA) measurements.Results:Real time-PCR assay revealed that noise decreased NOX3 and increased TGF-β1, prestin, and HSP-70 gene expressions. Administration of myricetin at the dose of 5 mg/kg, but not at 10 mg/kg, significantly reversed these changes. Noise also increased MDA levels and decreased SOD and DPPH scavenging activities. Myricetin at the doses of 5 and 10 mg/kg also reversed these changes. Conclusion:The findings of this study showed that myricetin at the dose of 5 mg/Kg was able to reverse noise-induced abnormalities in gene expression and oxidant/anti-oxidant balance. It is a possibility that myricetin via enhancement of anti-oxidant activity induced these effects.

Otopathology in CHARGE syndrome.

Postmortem temporal bone computed tomography (CT) and histopathologic findings in an infant with CHARGE syndrome revealed bilateral cochleovestibular hypoplasia, including cochlear pathology relevant to cochlear implant candidacy. Both ears had absence of the superior semicircular canals (SCCs), severely hypoplastic posterior SCCs, and hypoplastic (right ear) or absent (left ear) lateral SCCs seen on CT and histopathology. Histopathology further revealed the absence of all SCC ampullae except the right lateral SCC ampulla and atrophic vestibular neuroepithelium in the saccule and utricle bilaterally. The right cochlea consisted of a basal turn with patent round window, and malformed middle turn (type IV cochlear hypoplasia), with a small internal auditory canal (IAC) but near normal cochlear nerve aperture (fossette). Quantification of spiral ganglion neurons (SGNs) on histologic sections revealed a reduced SGN population (35% of normal for age), but this ear would still have likely achieved benefit from a cochlear implant based on this population. The left cochlea consisted of only a basal turn with patent round window (type III cochlear hypoplasia) with a small IAC and very small cochlear nerve aperture. Notably, histology revealed that there were no SGNs in the cochlea, and therefore, this ear would not have been a good candidate for cochlear implantation. Level of evidence: IV.

The study of AAV9 expression in cochleae of mice at different ages

Objective: To determine the extent of transfection and expression of adeno-associated virus (AAV) serotype 9 (AAV9) in the cochleae of mice at different ages. Methods: AAV9-green fluorescent protein (GFP) was inoculated into the cochlea of mice via the round window membrane (RWM) or through cochleostomy at different ages. Four groups were divided according to ages and injection sites: P1SM group, AAV9-GFP was delivered to the scala media by cochleostomy at postnatal day 1; P1RW group, AAV9-GFP was delivered to the scala tympani via RWM at postnatal day 1; P9RW group: AAV9-GFP was injected through RWM at postnatal day 9; and P30RW group, adult mice (P30) were injected through RWM. GFP expression in cochlear whole mount was analyzed and auditory brainstem response (ABR) tests were conducted one month after virus injection (for each animal, only left cochlea was injected and the right side was used as a control). GraphPad Prism 5 statistical software was used for data analysis. Results: All of inner hair cells (IHCs) and most of outer hair cells (OHCs) were transfected via two approaches at P1 injection. There was no significant difference in ABR threshold between injected ears and untreated ears (P>0.05). All of the IHCs and parts of OHCs (69% in apical turn) were transfected via RWM at P9. The strongest GFP expression was observed near the apical turn. Cochlear inoculation via RWM at P30 led to transgene expression in only IHCs. The ABR threshold of injected ears in P9RW group and P30RW group was significantly higher than that of contralateral ears (P<0.01). Conclusions: AAV9 can be highly expressed in the inner and outer hair cells of the cochlea and hearing sensitivity can be preserved if virus injections are performed in neonatal mice. After AAV9 is transfected into the inner ear of adult mice, it is only expressed in the inner hair cells, which leads to the increase of the ABR response threshold of mice. Transfection efficiency is significant higher in neonate mice than in P9 and adult mice.

Organs at Risk Delineation for Brain Tumor Radiation Planning in Patients with Glioblastoma Using Deep Learning

Our standalone software, using deep learning technology, performs fully automatic organs at risk (OAR) segmentation within the brain in 2 minutes for brain radiation planning in patients with glioblastoma (GBM). The aim of the present study is to evaluate, if fully automated segmentation of the OAR within the brain in GBM patients is non-inferior to human rater segmentation for radiation planning. We included post-OP T1w, T1c, T2w and FLAIR MRI datasets of 23 patients with newly diagnosed, surgically resected and histologically confirmed GBM. Manual segmentations of the brain OAR (brainstem, cochleae, eyes, hippocampus, lacrimal glands, lenses, optic chiasm, optic nerves, pituitary gland and retinae) according to Scoccianti et al. (Scoccianti 2015) were performed by 3 experienced radiation oncologists on the T1c MRI sequence. For fully automatic segmentation, we developed an OAR segmentation method. The MRI data was co-registered for automatic segmentation. Manual delineations were utilized for training the deep learning system based on the U-Net architecture. We evaluated the segmentation method on the results of a 6-fold cross-validation considering the imaging data of all patients in terms of dice-coefficient (DC) (volumetric overlap) and volume similarity (VS) using the Kruskal-Wallis test. Median DC and interquartile range (IQR) of the different pairings of expert raters (reported as tuples) were (0.74, 0.19), (0.67, 0.28) and (0.72, 0.20) for all OAR structures combined. The results of the automatic segmentation compared to the three different raters were (0.63, 0.39), (0.65, 0.36) and (0.63, 0.41). Large distribution of DC and VS were observed for small OAR like the left cochlea between the raters [(0.78, 0.12), (0.43, 0.13), (0.49, 0.12); Kruskal-Wallis test: chi-square=43.80, p=0.001)] and the automatic method: [(0.00, 0.23), (0.00, 0.26), (0.00, 0.18; Kruskal-Wallis test: chi-square=81.29, p=0.001)]. The cochlea was missed completely by the automatic method in 9 patients. For larger OAR, such as the brainstem, no statistical difference was detected between measured volumes among raters (Kruskal-Wallis test: chi-square=4.6, p=0.098) [(0.91, 0.02), (0.91, 0.02), (0.89, 0.02)], and compared to the automatic segmentation: [(0.91, 0.02), (0.91, 0.01), (0.90, 0.02)]. The performance of the proposed system is highly dependent on the raters agreement. The higher the agreement among raters, the better predicts the prototype the OAR within the brain. With this proof of concept study, we generate first promising results, and plan next steps to improve results.

Symptom: Deafness After Stapedectomy

Symptom: Deafness After Stapedectomy

Hearing differences in Hartley guinea pig stocks from two breeders

Across the world, dozens of outbred Hartley guinea pig stocks are used for auditory experiments. The genetic makeup of these different stocks will differ due to differences in breeding protocols, history and genetic drift. In fact, outbred breeding protocols are not intended to produce genetically identical animals, neither across breeders, nor across time. For this reason, it is unclear how reproducible experimental results are likely to be using animals from different stocks. We evaluated the consistency of cochlear function using both clicks and tones in Hartley guinea pigs as a function of breeder (Kuiper and Charles River) and sex using archival Auditory Brain Stem Response (ABR) data and tissue from our own laboratory. Sound levels required to reach baseline threshold for click-induced ABRs were similar between male Charles River and male Kuiper guinea pig stocks. However, the median and average thresholds after exposure to high level noise were larger in the Kuiper population than in the Charles River population with corresponding threshold shifts higher in the Kuiper than in the Charles River animals. We evaluated the relationship between pure-tone thresholds and sex, age, breeder stock, left or right cochleas, weight and 5 test frequencies before and after noise exposure using a linear mixed statistical model. Across all frequencies, the effect of breeder on baseline threshold is statistically significant, with effect sizes most pronounced at the lower frequencies before exposure to noise. After noise exposure, the differences are minimal in the model, indicating that differences in threshold shift are chiefly due to differences in initial baseline hearing. However, a contingency calculation comparing response/no response at the highest speaker output at 32 kHz gave a statistically significant difference between the stocks: 28% of Kuiper cochleas responded to the highest output of the speaker as compared with 71.4% of Charles River cochleas, indicating that noise exposure induced a larger threshold shift in a greater proportion of Kuiper animals. Using our archival cochlear tissue from these studies, we confirmed the sex of each animal by PCR, then compared males and females of the Kuiper stock. Across all baseline frequencies, the effect of sex on threshold is statistically significant, with no noticeable difference after exposure. The effect sizes for baseline thresholds are most pronounced at lower frequencies. These data demonstrate that Hartley guinea pig stocks from different breeders are not uniform in their auditory characteristics, and that due to these differences, results and conclusions can differ among laboratories. Moreover, within a single stock, males and females can provide different data, confirming that male and female animals must be individually evaluated in any auditory protocol.

Neural Plastic Changes in the Subcortical Auditory Neural Pathway after Single-Sided Deafness in Adult Mice: A MEMRI Study.

Single-sided deafness (SSD) induces cortical neural plastic changes according to duration of deafness. However, it is still unclear how the auditory cortical changes accompany the subcortical neural changes. The present study aimed to find the neural plastic changes in the cortical and subcortical auditory system following adult-onset single-sided deafness (SSD) using Mn-enhanced magnetic resonance imaging (MEMRI). B57BL/6 mice (postnatal 8-week-old) were divided into three groups: the SSD-4-week group (postnatal 12-week-old, n = 11), the SSD-8-week group (postnatal 16-week-old, n = 11), and a normal-hearing control group (postnatal 8-week-old, n = 9). The left cochlea was ablated in the SSD groups. White Gaussian noise was delivered for 24 h before MEMRI acquisition. T1-weighted MRI data were analyzed from the cochlear nucleus (CN), superior olivary complex (SOC), lateral lemniscus (LL), inferior colliculus (IC), medial geniculate body (MG), and auditory cortex (AC). The differences in relative Mn2+-enhanced signal intensities (Mn2+SI) and laterality were analyzed between the groups. Four weeks after the SSD procedure, the ipsilateral side of the SSD showed significantly lower Mn2+SI in the CN than the control group. On the other hand, the contralateral side of the SSD demonstrated significantly lower Mn2+SI in the SOC, LL, and IC. These decreased Mn2+SI values were partially recovered at 8 weeks after the SSD procedure. The interaural Mn2+SI differences representing the interaural dominance were highest in CN and then became less prominently higher in the auditory neural system. The SSD-8-week group still showed interaural differences in the CN, LL, and IC. In contrast, the MG and AC did not show any significant intergroup or interaural differences in Mn2+SI. In conclusion, subcortical auditory neural activities were decreased after SSD, and the interaural differences were diluted in the higher auditory nervous system. These findings were attenuated with time. Subcortical auditory neural changes after SSD may contribute to the change in tinnitus severity and the outcomes of cochlear implantation in SSD patients.

A Pilot Study of MR-Guided Mid-Treatment Adaptive Proton Therapy for Pediatric Low-Grade Gliomas

Intensity-modulated proton therapy (IMPT) is associated with reduced integral brain dose compared to photon therapy in the treatment of pediatric low-grade gliomas (pLGG). Mid-treatment imaging and response evaluation may allow for further reductions in dose to organs at risk (OAR) and improvement of the therapeutic ratio. This study investigates potential dosimetry advantages to MRI-guided mid-treatment adaptive planning for patients treated using IMPT. From 2006 to 2017, patients less than 21 years of age with intact pLGGs were treated with definitive radiotherapy and underwent mid-treatment MRI. Clinically delivered regimens were 54Gy/30 fractions (n=26) or 52.2GyRBE/29 fractions (n=2). Simulated initial IMPT plans were created with prescribed dose of 52.2GyRBE/29 fractions. Target volumes and OARs were retrospectively contoured on mid-treatment MRI. Tumors with mid-treatment response (>20% reduction in GTV) were replanned using the response-based contours. Coverage, dose constraints, and robust optimization parameters were identical for the initial and adapted plans. The initial and adapted plans were compared for OAR sparing. Mid-treatment imaging response was observed in 6/28 (21%) patients: five were located in the diencephalon/optic pathway region and one in the brainstem. Mean (± SD) GTV reduction was 32%±8%. Mean reduction in the volume of the brainstem receiving 40 GyRBE (V40GyRBE), V45GyRBE and V50GyRBE was 9.3%±4.1%, 8.2%±3.8%, and 5.5±5.1% respectively. Four of six adapted plans showed reductions in right and left cochlea V25GyRBE (right cochlea mean reduction: 29.6%±15.6%, left cochlea mean reduction: 20.9%±21.8%). Two of six adapted plans showed reductions in optic chiasm V50GyRBE (mean reduction: 9.8%±5.4%). Based on mid-treatment response to IMPT, MRI-guided adaptive planning may allow for reductions in brainstem V40GyRBE-V50GyRBE. Select patients may benefit from reductions in optic chiasm V50GyRBE and cochlea V25GyRBE. Prospective evaluation of adaptive therapy in pLGG is warranted to avoid late brainstem and optic nerve toxicities.

Temporal Bone Histopathology of X-linked Inherited Alport Syndrome.

ObjectiveTo describe the histopathologic findings within the human cochlea in X‐linked Alport syndrome.Study DesignHistopathologic analysis of cellular elements within the human cochlea by light microscopy.Materials and MethodsA right and a left cochleae of a man with genetically confirmed X‐linked Alport syndrome was studied post‐mortem. The temporal bones underwent standard processing for histologic examination. The slides were examined by light microscopy. Graphic reconstruction of the cochlea was performed to quantify hair cells, pathologic changes of the stria vascularis, and loss of cochlear neuronal cells.ResultsThere was severe loss of inner hair cells and all three rows of outer hair cells in the apical two turns of the cochlea. The stria vascularis and spiral ligament showed areas of marked loss which became more prominent from base to apex in each ear. The spiral ganglion cell count in the Rosenthal's canal exhibited loss of 20% to 45% compared to matched historical controls. There was a zone of separation between the organ of Corti and the basilar membrane extending along the basal surface of Deiters cells, Hensen cells, Claudius cells and external sulcus cells. The tunnel of Corti and the space of Nuel were filled with cellular elements along the cochlea.ConclusionThe histopathologic findings of cochlear involvement in Alport's syndrome are basement membrane separation from the cells of the organ of Corti, outer and inner hair cell loss, and cellular infilling of the tunnel and extracellular spaces of the organ of Corti. These observations contribute to our understanding of the mechanism of sensorineural hearing loss in these patients.Level of Evidence

Bilateral tympanokeratomas (cholesteatomas) with bilateral otitis media, unilateral otitis interna and acoustic neuritis in a dog

BackgroundAn aural cholesteatoma, more appropriately named tympanokeratoma, is an epidermoid cyst of the middle ear described in several species, including dogs, humans and Mongolian gerbils. The cyst lining consists of stratified, keratinizing squamous epithelium with central accumulation of a keratin debris. This case report describes vestibular ganglioneuritis and perineuritis in a dog with chronic otitis, bilateral tympanokeratomas and presumed extension of otic infection to the central nervous system.Case presentationAn 11-year-old intact male Dalmatian dog with chronic bilateral otitis externa and sudden development of symptoms of vestibular disease was examined. Due to the dog’s old age the owner opted for euthanasia without any further examination or treatment and the dog was submitted for necropsy. Transection of the ears revealed grey soft material in the external ear canals and pearly white, dry material consistent with keratin in the tympanic bullae bilaterally. The brain and meninges were grossly unremarkable. Microscopical findings included bilateral otitis externa and media, unilateral otitis interna, ganglioneuritis and perineuritis of the spiral ganglion of the vestibulocochlear nerve and multifocal to coalescing, purulent meningitis. A keratinizing squamous epithelial layer continuous with the external acoustic meatus lined the middle ear compartments, consistent with bilateral tympanokeratomas. Focal bony erosion of the petrous portion of the temporal bone and squamous epithelium and Gram-positive bacterial cocci were evident in the left cochlea. The findings suggest that meningitis developed secondary to erosion of the temporal bone and ganglioneuritis and/or perineuritis of the vestibulocochlear nerve.ConclusionsMiddle ear tympanokeratoma is an important and potentially life-threatening otic condition in the dog. Once a tympanokeratoma has developed expansion of the cyst can lead to erosion of bone and extension of otic infection to the inner ear, vestibulocochlear ganglion and nerve potentially leading to bacterial infection of the central nervous system.

Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation.

Neuron–glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron–glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

Feasibility of tomotherapy to reduce cochlea radiation dose in patients with locally advanced nasopharyngeal cancer.

To evaluate the effectiveness of tomotherapy-based image-guided radiotherapy (IGRT) on the radiation dose to the cochlea in patients with nasopharyngeal cancer. A retrospective review of five patients undergoing concurrent chemoradiation with tomotherapy for locally advanced nasopharyngeal cancer was performed. The mean dose to the right and left cochlea was 25 Gy and 35.3 Gy respectively, while the dose to the gross tumor ranged from 70 to 75 Gy. All patients had excellent clinical response to the treatment at a median follow-up of five months. IGRT for head and neck cancer delivered by tomotherapy can significantly decrease the radiation dose to the cochlea without sacrificing target volume coverage.

Comparison of calculated dose distributions reported as dose-to-water and dose-to-medium for intensity-modulated radiotherapy of nasopharyngeal cancer patients

Advanced dose calculation algorithms for radiation therapy treatment planning can report external beam photon dose 2-sided, in terms of dose-to-medium (Dm) and dose-to-water (Dw). The purpose of our study was to determinate the effect of Dw and Dm reporting modes built in Elekta Monaco treatment planning system on intensity-modulated radiotherapy dose distributions for patients with nasopharyngeal cancer. For 13 patients involved in this retrospective study, 2 plans were created: 1 using Dw and another according to Dm reporting mode. Treatment plans were normalized such that 100% planning target volume should be covered by 95% of prescribed dose. Dose-volume constraints were assigned according to international standards. The comparison between dose distributions was performed evaluating quantities important for respective volumes of interest. For target volumes, heterogeneity index and conformity index methodology were used along with the maximum dose concept. Also, for the comparisons over particular organ at risk, maximum dose or mean dose as well as dose-volume concepts were used. For all target volumes and majority of organs at risk, the differences between 2 reporting modes are statistically insignificant, but this is not the case for bony structured organs at risks: mandible and cochlea. It was observed that Dw is higher than Dm with mean difference of 9.91% (p = 0.000009) of the mandible volume covered with 70 Gy. The same trend was observed for left and right cochlea with difference in mean dose of 8.74% (p = 0.037) and 6.87% (p = 0.029), respectively. The comparative analysis of dosimetric parameters in this study shows that the selection of reporting modes in Monaco treatment planning system can produce dose differences up to 15% in high-density volumes such as mandible and cochlea, which might have clinical consequences.

A dosimetric comparison between three-dimensional conformal radiation therapy and intensity-modulated radiation therapy in the treatment of posterior fossa boost in medulloblastoma.

To compare three-dimensional conformal radiation therapy (3DCRT) and intensity-modulated radiation therapy (IMRT) in posterior fossa (PF) boost in children with medulloblastoma (MB); dosimetrically evaluating and comparing both techniques with regard to target coverage and doses to organs at risk. Structured. Seven previously irradiated patients of MB were retrieved and re-planned with both 3DCRT and IMRT techniques. Dosimetric comparison was done by performing two plans for the PF boost for the same patient. Prescription dose and normal tissue constraints were identical for both plans. SPSS, version 19, statistical software package was used. For quantitative data, paired t-test was applied to calculate the difference between two means. Mean values of planning target volume (PTV); PTV95% and PTV5% in IMRT were 97.19% and 106.07% and for 3DCRT were 96.57% and 106.33%, respectively. The dose homogeneity was better in IMRT (1.091) as compared to 3DCRT (1.100), but was not statistically significant (P = 0.341). Conformity index was comparable in both the plans, i.e., 3DCRT (0.979) and IMRT (0.976) with P = 0.819. IMRT plan provided reduced mean dose to cochlea relative to the 3DCRT plans with P = 0.032 for the right cochlea and 0.020 for the left cochlea. IMRT showed no advantage over 3DCRT in sparing the anterior cranial structures where mean doses to the right and left lens were 0.61 Gy and 0.56 Gy for IMRT and 0.16 Gy and 0.09 Gy for 3DCRT, respectively. IMRT technique was able to improve homogeneity index, spare the cochleae, but 3DCRT plans were superior in sparing anterior cranial structures without compromising the dose to PF.

Effects of Memantine on Aminoglycoside-Induced Apoptosis of Spiral Ganglion Cells in Guinea Pigs.

To explore whether memantine, an N-methyl-D-aspartate receptor antagonist, exerts a neuroprotective effect against apoptosis of spiral ganglion cells (SGCs) induced by gentamicin. An animal experiment. Dong-A University College of Medicine, Busan, Korea. Gentamicin was injected into the left cochleae of guinea pigs to induce apoptosis of SGCs; the contralateral cochleae served as controls. Memantine was intraperitoneally injected 12 hours and 1 hour prior to gentamicin injection. At 1 week after gentamicin and/or memantine injection, the cochleae were removed and stained with hematoxylin and eosin to evaluate morphologic changes and apoptosis. Western blotting was performed to measure FasL expression and the extent of caspase activation in SGCs. SGC numbers remained stable after memantine treatment. Western blotting showed that FasL expression and activation of caspases 3, 8, and 9 were reduced in SGCs after memantine treatment. Memantine attenuated the gentamicin-induced apoptosis of SGCs in guinea pigs. Moreover, memantine may affect Fas-FasL signaling in the receptor-mediated apoptotic pathway and caspase activation involved in the receptor-mediated and mitochondrial apoptotic pathways.

Curvature measurement of human bilateral cochleae.

This study aimed to characterise the geometry of the human bilateral spiral cochlea by measuring curvature and length. Eight subjects were recruited in this study. Magnetic resonance imaging was used to visualise the right and left cochlea. Visualisation of the cochlear spiral was enhanced by T2 weighting and further processing of the raw images. The spirals were divided into three segments: the basal turn, the middle turn and the apex turn. The length and curvature of each segment were non-invasively measured. The mean left and right cochlear lengths were 3.11 cm and 3.95 cm, respectively. The measured lengths of the cochlear spiral are consistent with data in the literature derived from anatomical dissections. Overall, the apex turn segment of the cochlea had the greatest degree of curvature (p < 0.05). The mean apex turn segment curvatures for left and right cochleae were 9.65 cm(-1) and 10.09 cm(-1), respectively. A detailed description of the cochlear spiral is provided, using measurements of curvature and length. These data will provide a valuable reference in the development of cochlear implantation procedures for minimising the potential damage during implantation.

Delayed loss of hearing after hearing preservation cochlear implantation: Human temporal bone pathology and implications for etiology

After initially successful preservation of residual hearing with cochlear implantation, some patients experience subsequent delayed hearing loss. The etiology of such delayed hearing loss is unknown. Human temporal bone pathology is critically important in investigating the etiology, and directing future efforts to maximize long term hearing preservation in cochlear implant patients. Here we present the temporal bone pathology from a patient implanted during life with an Iowa/Nucleus Hybrid S8 implant, with initially preserved residual hearing and subsequent hearing loss. Both temporal bones were removed for histologic processing and evaluated. Complete clinical and audiologic records were available. He had bilateral symmetric high frequency severe to profound hearing loss prior to implantation. Since he was implanted unilaterally, the unimplanted ear was presumed to be representative of the pre-implantation pathology related to his hearing loss. The implanted and contralateral unimplanted temporal bones both showed complete degeneration of inner hair cells and outer hair cells in the basal half of the cochleae, and only mild patchy loss of inner hair cells and outer hair cells in the apical half. The total spiral ganglion neuron counts were similar in both ears: 15,138 (56% of normal for age) in the unimplanted right ear and 13,722 (51% of normal for age) in the implanted left ear. In the basal turn of the implanted left cochlea, loose fibrous tissue and new bone formation filled the scala tympani, and part of the scala vestibuli. Delayed loss of initially preserved hearing after cochlear implantation was not explained by additional post-implantation degeneration of hair cells or spiral ganglion neurons in this patient. Decreased compliance at the round window and increased damping in the scala tympani due to intracochlear fibrosis and new bone formation might explain part of the post-implantation hearing loss. Reduction of the inflammatory and immune response to cochlear implantation may lead to better long term hearing preservation post-implantation.

Local delivery of brain-derived neurotrophic factor on the perforated round window membrane in Guinea pigs: a possible clinical application.

Local delivery of neurotrophic factors on the intact round window membrane (RWM) of hair cell-deprived cochleas reduces degeneration of the cochlear nerve. In an animal model of profound hearing loss, we investigated whether this otoprotective effect could be enhanced by perforation of the RWM. Such method could be highly relevant for future clinical applications. Guinea pigs were deafened by coadministration of kanamycin and furosemide. Two weeks after deafening, Gelfoam cubes infiltrated with brain-derived neurotrophic factor (BDNF) were deposited onto the RWM of the right cochlea. In the experimental condition, the RWM was perforated. Electrically evoked auditory brainstem responses (eABRs) were recorded weekly. Two or four weeks after Gelfoam placement, both left (untreated) and right (BDNF-treated) cochleas were processed for histology. In BDNF-treated cochleas, both with and without perforation, neural survival in the basal turn of the cochlea was significantly larger than in untreated cochleas. Amplitudes of electrically evoked auditory brainstem responses were larger in BDNF-treated cochleas with an RWM perforation than in those without a perforation and comparable to those of normal-hearing controls. Perforation did not lead to collateral cochlear damage. When considering clinical applications of neuroprotective agents such as BDNF, delivery on a perforated RWM seems to be a safe and effective option.