Chordoma: the entity.

Chordomas are malignant tumors of the axial skeleton, characterized by their locally invasive and slow but aggressive growth. These neoplasms are presumed to be derived from notochordal remnants with a molecular alteration preceding their malignant transformation. As these tumors are most frequently observed on the skull base and sacrum, patients suffering from a chordoma present with debilitating neurological disease, and have an overall 5-year survival rate of 65%. Surgical resection with adjuvant radiotherapy is the first-choice treatment modality in these patients, since chordomas are resistant to conventional chemotherapy. Even so, management of chordomas can be challenging, as chordoma patients often present with recurrent disease. Recent advances in the understanding of the molecular events that contribute to the development of chordomas are promising; the most novel finding being the identification of brachyury in the disease process. Here we present an overview of the current paradigms and summarize relevant research findings.

Electrical stimulation of the motor cortex enhances progenitor cell migration in the adult rat brain.

Clinical and preclinical investigations suggest that epidural stimulation of the motor cortex (MC) can improve stroke-induced neurological deficits. The mechanisms involved in stimulation-induced recovery are not well understood and might involve neurogenesis-related processes. Here, we addressed the question whether MC stimulation influences processes of migration and differentiation of neuronal progenitor cells in vivo. Epidural stimulation electrodes were implanted at the level of the MC in rats, and electrical current was applied for a period of 1 month. Increased cell proliferation was observed in the subventricular zone (SVZ). We also found evidences for enhanced cell migration toward the source of current, a process known as electrotaxis. Some of these cells expressed the neuronal marker, NeuN. In addition, our results indicate that MC stimulation enhances neuronal activity of the dorsal raphe nucleus, leading to an increase in the expression of 5-hydroxytryptamine in the SVZ. It is known that such an increase can promote formation of new cells in the SVZ. Our findings suggest that epidural MC stimulation influences neurogenesis-related processes in animal models.

Intraoperative MRI-guided resection of glioblastoma multiforme: a systematic review.

We did a systematic review to address the added value of intraoperative MRI (iMRI)-guided resection of glioblastoma multiforme compared with conventional neuronavigation-guided resection, with respect to extent of tumour resection (EOTR), quality of life, and survival. 12 non-randomised cohort studies matched all selection criteria and were used for qualitative synthesis. Most of the studies included descriptive statistics of patient populations of mixed pathology, and iMRI systems of varying field strengths between 0·15 and 1·5 Tesla. Most studies provided information on EOTR, but did not always mention how iMRI affected the surgical strategy. Only a few studies included information on quality of life or survival for subpopulations with glioblastoma multiforme or high-grade glioma. Several limitations and sources of bias were apparent, which affected the conclusions drawn and might have led to overestimation of the added value of iMRI-guided surgery for resection of glioblastoma multiforme. Based on the available literature, there is, at best, level 2 evidence that iMRI-guided surgery is more effective than conventional neuronavigation-guided surgery in increasing EOTR, enhancing quality of life, or prolonging survival after resection of glioblastoma multiforme.

Quality of life after gamma knife radiosurgery treatment in patients with a vestibular schwannoma: the patient's perspective.

This study evaluates the impact of gamma knife radiosurgery (GKRS) on the quality of life (QOL) of patients with a sporadic vestibular schwannoma (VS). This study pertains to 108 VS patients who had GKRS in the years 2003 through 2007. Two different QOL questionnaires were used: medical outcome study short form 36 (SF36) and Glasgow benefit inventory (GBI). Radiosurgery was performed using a Leksell 4C gamma knife. The results of the QOL questionnaires in relation to prospectively and retrospectively gathered data of the VS patients treated by GKRS. Eventually, 97 patients could be included in the study. Their mean tumor size was 17 mm (range 6-39 mm); the mean maximum dose on the tumor was 19.9 Gy (range 16-25.5 Gy) and the mean marginal dose on the tumor was 11.1 (range 9.3-12.5 Gy). SF36 scores showed results comparable to those for a normal Dutch population. GBI showed a marginal decline in QOL. No correlation was found between QOL and gender, age, tumor size, or radiation dose. Increased audiovestibular symptoms after GKRS were correlated with a decreased GBI score, and decreased symptoms were correlated with a higher QOL post-GKRS. In this study shows that GKRS for VS has little impact on the general QOL of the VS patient. However, there is a wide range in individual QOL results. Individual QOL was influenced by the audiovestibular symptoms. No predictive patient, tumor, or treatment factors for QOL outcome after GKRS could be determined. Comparison with microsurgery is difficult because of intra group variability.

State-of-the-Art Imaging in Human Chordoma of the Skull Base.

PURPOSE OF REVIEW: Chordoma are rare tumours of the axial skeleton which occur most often at the base of the skull and in the sacrum. Although chordoma are generally slow-growing lesions, the recurrence rate is high and the location makes it often difficult to treat. Both computed tomography (CT) and magnetic resonance imaging (MRI) are crucial in the initial diagnosis, treatment planning and post-treatment follow-up. RECENT FINDINGS: Basic MRI and CT characteristics of chordoma were described in the late 1980s and early 1990s. Since then, imaging techniques have evolved with increased resolution and new molecular imaging tools are rapidly evolving. New imaging tools have been developed not only to study anatomy, but also physiologic changes and characterization of tissue and assessment of tumour biology. Recent studies show the uptake of multiple PET tracers in chordoma, which may become an important aspect in the diagnosis, follow-up and personalized therapy. SUMMARY: This review gives an overview of skull base chordoma histopathology, classic imaging characteristics, radiomics and state-of-the-art imaging techniques that are now emerging in diagnosis, treatment planning and disease monitoring of skull base chordoma.

Oncogenic Viruses in Skull Base Chordomas.

BACKGROUND: Chordomas are rare tumors assumed to derive from notochordal remnants. We believe that a molecular switch is responsible for their malignant behavior. The involvement of oncogenic viruses has not been studied, however. Thus, in the present study, we investigated the presence of oncogenic viruses in chordomas. METHODS: DNA and RNA from snap-frozen chordoma (n = 18) and chondrosarcoma (n = 15) specimens were isolated. Real-time PCR or RT-PCR was performed to assess the presence of multiple oncogenic viruses, including herpesviridea (herpes simplex virus [HSV]-1, HSV-2, Epstein-Barr virus [EBV], cytomegalovirus, human herpesvirus [HHV]- 6, HHV-7, and Kaposi's sarcoma-associated herpesvirus), polyomaviridea (parvovirus B19 [PVB19], BK virus, JC virus, Simian virus 40, Merkel cell polyomavirus, human polyomavirus [HPyV]-6, and HPyV-7), papillomaviridae, and respiratory viruses. Immunohistochemistry (IHC) and in situ hybridization (ISH) were used to validate the positive results. RESULTS: PVB19 DNA was detected in 4 of 18 chordomas (22%) and in 1 of 15 chondrosarcomas (7%). IHC recognizing the VP2 capsid protein of PVB19 showed a positive cytoplasmic staining in 44% of the cases (14 of 32). HHV7 DNA was present in 6 of the 18 chordomas (33%). Genomic DNA of EBV was found in 22% of the samples; however, no positive results were found on ISH. None of the chordoma cases showed any presence of DNA from the remaining viruses. CONCLUSIONS: Viral involvement in the etiology of chordomas is likely, with PVB19 the most distinguishing.

Gamma Knife radiosurgery for intracranial meningiomas: Do we need to treat the dural tail? A single-center retrospective analysis and an overview of the literature.

BACKGROUND: The dural tail (DT) has been described as a common feature in meningiomas. There is a great variation of tumor invasion and extent of tumor cells in the DT. Therefore, the necessity to include the whole DT in Gamma Knife radiosurgery is not clear, since inclusion increases the target volume and therefore increases the risk of complications. In this analysis, we evaluated whether the complete tail should be included as part of the target in Gamma Knife radiosurgery for meningiomas. METHODS: Between June 2002 and December 2010, Gamma Knife radiosurgery was performed in 160 patients with 203 meningiomas with a DT. In 105 tumors, the diagnosis was based on magnetic resonance imaging (MRI) characteristics, and in 98 tumors, the diagnosis was confirmed by histopathologic examination after surgery. The median volume of the tumors was 3.55 cc. All tumors were treated with Gamma Knife radiosurgery with a median prescribed dose of 13 Gy (range 11-15), resulting in a median marginal dose of 11 Gy (range 10-15). Only the part of the DT closely related to the tumor mass was included in the target. The median follow-up period was 41 months (range 12-123). RESULTS: In image-based meningiomas, the overall local control rate was 96.2% with 2- and 5-year control rates of 98.0% and 95.1%, respectively. In WHO grade I tumors, the overall local control rate was 85.9% with 2- and 5-year control rates of 94.5% and 88.0%, respectively. The overall local control rate in World Health Organization (WHO) grade II tumors was 70.6% with control rates of 83.4% and 64.4% after 2 and 5 years, respectively. The growth of all new tumors was found in the radiation target area. No tumor growth was observed in the part of the DT that had been excluded from the target volume. CONCLUSION: We found in this study that routinely excluding the DT from the target does not lead to out-of-field tumor progression. Given the possibility that the DT is infiltrated with tumor cells, regular follow-up is needed.

A comparison of cell-cycle markers in skull base and sacral chordomas.

OBJECTIVE: Despite refinement of surgical techniques and adjuvant radiotherapy, the prognosis for patients with a chordoma remains poor. Identification of prognostic factors related to tumor biology might improve this assessment and result in molecular markers for targeted therapy. Limited studies have been performed to unravel the impact of cell-cycle markers in chordoma, and those performed have shown inconclusive results. In the current study, we aimed to discover the impact of cyclin-dependent kinase 4 (CDK4) expression and its relation to prognosis and other cell-cycle markers in chordoma. METHODS: Twenty-five human formalin-fixed, paraffin-embedded chordoma specimens were examined by immunohistochemistry for the expression of CDK4, protein 53 (p53), and murine double minute 2 (MDM2). The MIB-1 labeling index and mitotic index were used for the examination of proliferation. We collected detailed demographic and clinical data. RESULTS: Overexpression of CDK4, p53, and MDM2 was found in five (20%), seven (28%), and 14 (56%) of the cases, respectively. All three cell-cycle markers showed a significant correlation with MIB1 labeling index. Expression of CDK4 (P = 0.02) and p53 (P < 0.01) were both significantly correlated with poor overall survival. Also, histologically observed necrosis (P < 0.05) and a dedifferentiated tumor subtype (P < 0.01) were related to adverse patient outcome. CONCLUSION: Our results show that the expression of CDK4 and p53 are related to cell proliferation capacity and worse outcome in patients with chordoma.

Intraoperative magnetic resonance imaging versus standard neuronavigation for the neurosurgical treatment of glioblastoma: A randomized controlled trial.

BACKGROUND: Although the added value of increasing extent of glioblastoma resection is still debated, multiple technologies can assist neurosurgeons in attempting to achieve this goal. Intraoperative magnetic resonance imaging (iMRI) might be helpful in this context, but to date only one randomized trial exists. METHODS: We included 14 adults with a supratentorial tumor suspect for glioblastoma and an indication for gross total resection in this randomized controlled trial of which the interim analysis is presented here. Participants were assigned to either ultra-low-field strength iMRI-guided surgery (0.15 Tesla) or to conventional neuronavigation-guided surgery (cNN). Primary endpoint was residual tumor volume (RTV) percentage. Secondary endpoints were clinical performance, health-related quality of life (HRQOL) and survival. RESULTS: Median RTV in the cNN group is 6.5% with an interquartile range of 2.5-14.75%. Median RTV in the iMRI group is 13% with an interquartile range of 3.75-27.75%. A Mann-Whitney test showed no statistically significant difference between these groups (P =0.28). Median survival in the cNN group is 472 days, with an interquartile range of 244-619 days. Median survival in the iMRI group is 396 days, with an interquartile range of 191-599 days (P =0.81). Clinical performance did not differ either. For HRQOL only descriptive statistics were applied due to a limited sample size. CONCLUSION: This interim analysis of a randomized trial on iMRI-guided glioblastoma resection compared with cNN-guided glioblastoma resection does not show an advantage with respect to extent of resection, clinical performance, and survival for the iMRI group. Ultra-low-field strength iMRI does not seem to be cost-effective compared with cNN, although the lack of a valid endpoint for neurosurgical studies evaluating extent of glioblastoma resection is a limitation of our study and previous volumetry-based studies on this topic.

Radiation therapy for vestibular schwannomas.

PURPOSE OF REVIEW: Recently, new information on the natural course and on the results of radiation therapy of vestibular schwannomas has been published. The aim of this study is to summarize the most recent literature on the contemporary insights on the natural course and the results of the latest strategies of radiotherapy for vestibular schwannomas. RECENT FINDINGS: After diagnosis only about one-third of all vestibular schwannomas will progress. Many patients do well with a 'wait and see' policy and, when necessary, radiation treatment has the advantage that tumor control rates are high (95%) and treatment-related side effects are very low. Different approaches to radiotherapy continue to evolve. Up till now stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) yield comparable results both in terms of tumor control and cranial nerve preservation. With new data available on hearing preservation after radiotherapy, a watchful waiting policy is a renewed matter of debate. SUMMARY: When a vestibular schwannoma grows, radiotherapy (SRS or FSRT) may be a valuable treatment modality. Future clinical research (properly designed randomized trials) should focus on when and when not to treat, even if a vestibular schwannoma is not growing and on potential differences in long-term effects between SRS and fractionated radiotherapy.

Correlation between contrast enhancement on intraoperative magnetic resonance imaging and histopathology in glioblastoma.

OBJECT: Glioblastoma is a highly malignant brain tumor, for which standard treatment consists of surgery, radiotherapy, and chemotherapy. Increasing extent of tumor resection (EOTR) is associated with prolonged survival. Intraoperative magnetic resonance imaging (iMRI) is used to increase EOTR, based on contrast enhanced MR images. The correlation between intraoperative contrast enhancement and tumor has not been studied systematically. METHODS: For this prospective cohort study, we recruited 10 patients with a supratentorial brain tumor suspect for a glioblastoma. After initial resection, a 0.15 Tesla iMRI scan was made and neuronavigation-guided biopsies were taken from the border of the resection cavity. Scores for gadolinium-based contrast enhancement on iMRI and for tissue characteristics in histological slides of the biopsies were used to calculate correlations (expressed in Kendall's tau). RESULTS: A total of 39 biopsy samples was available for further analysis. Contrast enhancement was significantly correlated with World Health Organization (WHO) grade (tau 0.50), vascular changes (tau 0.53), necrosis (tau 0.49), and increased cellularity (tau 0.26). Specificity of enhancement patterns scored as "thick linear" and "tumor-like" for detection of (high grade) tumor was 1, but decreased to circa 0.75 if "thin linear" enhancement was included. Sensitivity for both enhancement patterns varied around 0.39-0.48 and 0.61-0.70, respectively. CONCLUSIONS: Presence of intraoperative contrast enhancement is a good predictor for presence of tumor, but absence of contrast enhancement is a bad predictor for absence of tumor. The use of gadolinium-based contrast enhancement on iMRI to maximize glioblastoma resection should be evaluated against other methods to increase resection, like new contrast agents, other imaging modalities, and "functional neurooncology" - an approach to achieve surgical resection guided by functional rather than oncological-anatomical boundaries.

Neuromodulation in psychiatric disorders.

Psychiatric disorders are worldwide a common cause of severe and long-term disability and socioeconomic burden. The management of patients with psychiatric disorders consists of drug therapy and/or psychotherapy. However, in some patients, these treatment modalities do not produce sufficient therapeutic effects or induce intolerable side effects. For these patients, neuromodulation has been suggested as a potential treatment modality. Neuromodulation includes deep brain stimulation, vagal nerve stimulation, and transcranial magnetic and electrical stimulation. The rationale for neuromodulation is derived from the research identifying neurobiologically localized substrates for refractory psychiatric symptoms. Here, we review the clinical data on neuromodulation in the major psychiatric disorders. Relevant data from animal models will also be discussed to explain the neurobiological basis of the therapy.

Management of large vestibular schwannoma. Part I. Planned subtotal resection followed by Gamma Knife surgery: radiological and clinical aspects.

OBJECT: In large vestibular schwannoma (VS), microsurgery is the main treatment option, and complete resection is considered the primary goal. However, previous studies have documented suboptimal facial nerve outcomes in patients who undergo complete resection of large VSs. Subtotal resection is likely to reduce the risk of facial nerve injury but increases the risk of lesion regrowth. Gamma Knife surgery (GKS) can be performed to achieve long-term growth control of residual VS after incomplete resection. In this study the authors report on the results in patients treated using planned subtotal resection followed by GKS with special attention to volumetric growth, control rate, and symptoms. METHODS: Fifty consecutive patients who underwent the combined treatment strategy of subtotal microsurgical removal and GKS for large VSs between 2002 and 2009 were retrospectively analyzed. Patients with neurofibromatosis Type 2 were excluded. Patient charts were reviewed for clinical symptoms. Audiograms were evaluated to classify hearing pre- and postoperatively. Preoperative and follow-up contrast-enhanced T1-weighted MR images were analyzed using volume-measuring software. RESULTS: Surgery was performed via a translabyrinthine (25 patients) or retrosigmoid (25 patients) approach. The median follow-up was 33.8 months. Clinical control was achieved in 92% of the cases and radiological control in 90%. One year after radiosurgery, facial nerve function was good (House-Brackmann Grade I or II) in 94% of the patients. One of the two patients who underwent surgery to preserve hearing maintained serviceable hearing after resection followed by GKS. CONCLUSIONS: Considering the good tumor growth control and facial nerve function preservation as well as the possibility of preserving serviceable hearing and the low number of complications, subtotal resection followed by GKS can be the treatment option of choice for large VSs.

Surgical treatment of sphenoorbital meningiomas.

AIM: To evaluate the outcome of surgery and radiotherapy in the treatment of sphenoorbital meningioma (SOM). METHOD: A retrospective study of 66 consecutive cases treated with surgery for SOM with a minimum follow-up of 4 years. Clinical and radiological information were compared before and after the following surgical approaches: frontotemporal craniotomy, frontotemporal craniotomy combined with orbitozygomatic resection and extended lateral orbitotomy alone. RESULTS: The median age at presentation was 46 years (range, 26-68 years) and the median follow-up after surgery was 102 months (range, 48-288 months). In total, 48 (73%) patients showed preoperative visual deterioration, with visual field defects. All patients had proptosis at presentation (mean ± SD=6.4 ± 3.0 mm). Surgery for patients with SOM arrested visual deterioration in 61% and improved vision in 30% of cases. Furthermore, a substantial reduction of proptosis was achieved in 85% of patients. The proptosis in this group was reduced by 2.6 ± 2.6 mm. There was no correlation between surgical approach and proptosis reduction (p = 0.125). The recurrence rate was 17%. Only 1 out of 15 patients who underwent radiotherapy showed signs of recurrence. CONCLUSIONS: The surgical aims in the treatment of SOM should be the restoration of visual acuity and reduction of proptosis, rather than complete tumour removal. The surgical approach can be tailored to individual cases. The authors recommend radiotherapy in cases of subtotally removed SOM.

Management of large vestibular schwannoma. Part II. Primary Gamma Knife surgery: radiological and clinical aspects.

OBJECT: In large vestibular schwannomas (VSs), microsurgery is the main treatment option. A wait-and-scan policy or radiosurgery are generally not recommended given concerns of further lesion growth or increased mass effect due to transient swelling. Note, however, that some patients do not present with symptomatic mass effect or may still have serviceable hearing. Moreover, others may be old, suffer from severe comorbidity, or refuse any surgery. In this study the authors report the results in patients with large, growing VSs primarily treated with Gamma Knife surgery (GKS), with special attention to volumetric growth, control rate, and symptoms. METHODS: The authors retrospectively analyzed 33 consecutive patients who underwent GKS for large, growing VSs, which were defined as > 6 cm(3) and at least indenting the brainstem. Patients with neurofibromatosis Type 2 were excluded from analysis, as were patients who had undergone previous treatment. Volume measurements were performed on contrast-enhanced T1-weighted MR images at the time of GKS and during follow-up. Medical charts were analyzed for clinical symptoms. RESULTS: Radiological growth control was achieved in 88% of cases, clinical control (that is, no need for further treatment) in 79% of cases. The median follow-up was 30 months, and the mean VS volume was 8.8 cm(3) (range 6.1-17.7 cm(3)). No major complications occurred, although ventriculoperitoneal shunts were placed in 2 patients. The preservation of serviceable hearing and facial and trigeminal nerve function was achieved in 58%, 91%, and 86% of patients, respectively, with any facial and trigeminal neuropathy being transient. In 92% of the patients presenting with trigeminal hypesthesia before GKS, the condition resolved during follow-up. No patient- or VS-related feature was correlated with growth. CONCLUSIONS: Primary GKS for large VSs leads to acceptable radiological growth rates and clinical control rates, with the chance of hearing preservation. Although a higher incidence of clinical control failure and postradiosurgical morbidity is noted, as compared with that for smaller VSs, primary radiosurgery is suitable for a selected group of patients. The absence of symptomatology due to mass effect on the brainstem or cerebellum is essential, as are close clinical and radiological follow-ups, because there is little reserve for growth or swelling.

Intraobserver and interobserver agreement in volumetric assessment of glioblastoma multiforme resection.

BACKGROUND: The role of extent of tumor resection in improving outcome for patients with glioblastoma multiforme (GBM) is still under debate. OBJECTIVE: To analyze intraobserver and interobserver agreement of manual segmentation as a method for volumetric assessment of GBM resection. METHODS: Three observers performed volumetric assessment of preoperative tumor volume (PreTV) and postoperative tumor volume (PostTV) by manual segmentation on contrast-enhanced T1-weighted MRI data sets of 8 patients. Measurements were repeated after a minimum interval of 2 weeks. Intraobserver and interobserver agreement for PreTV, PostTV, and residual tumor volume (RTV) percentage were expressed in intraclass correlation coefficients (ICCs). RESULTS: Intraobserver agreement is high for PreTV (ICC = 0.99), PostTV (ICC = 0.73-0.94), and RTV (ICC = 0.89-0.94). Interobserver agreement is high for PreTV (ICC = 0.97), but low for PostTV (ICC = 0.54) and RTV (ICC = 0.52). CONCLUSION: Postoperative assessment of GBM volume seems to offer high intraobserver agreement, but low interobserver agreement. Using absolute RTV values to relate extent of tumor resection with survival may be unreliable. More research is needed before this method can be used as a valid end point for clinical studies. Computer-assisted tumor volume calculation may increase interobserver agreement in the future.

Gamma knife radiosurgery for vestibular schwannomas: results of hearing preservation in relation to the cochlear radiation dose.

OBJECTIVES/HYPOTHESIS: This study was designed to evaluate hearing preservation after gamma knife radiosurgery (GKRS) and to determine the relation between hearing preservation and cochlear radiation dose in patients with a sporadic vestibular schwannoma (VS). METHODS: Prospective study involving patients suffering from VS who received GKRS from June 2003 until November 2007. Pure tone and speech audiometry were conducted before and after GKRS. The thresholds at pure tone audiometry were taken as a measure of hearing. Pure tone average (PTA) was defined as the mean threshold at 0.5 kHz, 1.0 kHz, 2.0 kHz, and 4.0 kHz. Hearing was classified according to the 2003 consensus meeting in Tokyo. Stereotactic surgery was performed using a Leksell 4C Gamma Knife (Elekta, Stockholm, Sweden). RESULTS: A total of 69 patients were included in the study. Mean tumor size was 17 mm. Mean marginal dose at the tumor was 11.0 Gy (range, 9.3 Gy-12.3 Gy), mean maximal dose was 19.7 Gy (range, 16 Gy-25.5 Gy). Mean maximal dose at the cochlea was 10.27 Gy (range, 3.1 Gy-16.1 Gy), and mean minimal dose at the cochlea was 2.6 Gy (range, 0.9 Gy-7.4 Gy). Mean PTA before GKRS was 43 dB (standard deviation [SD] 20 dB), mean PTA after GKRS was 63 dB (SD 30 dB). Mean interval between pre-GKRS audiometry and GKRS was 8.0 months. Between GKRS and post-GKRS audiometry, mean interval was 14.2 months. Hearing was considered to be preserved (max +1 class, Tokyo classification) in 52 (75%) of 69 patients. However, only 32 patients had class A, B, or C (serviceable hearing) before GKRS. Within this group, only 13 patients (41%) had a hearing class A, B, or C after GKRS. A significant relation was found between the maximal cochlear dose and the difference in PTA before and after GKRS. CONCLUSIONS: Hearing preservation is correlated to the maximal radiation dose at the cochlea. The purpose of developing GKRS techniques was to avoid collateral damage in healthy tissues. This study emphasizes the need for exact radiation planning to reduce the cochlear radiation dose if the hearing is to be preserved. Laryngoscope, 2009.