Diffuse midline glioma H3 K27M-mutant treatment

Diffuse midline glioma H3 K27M-mutant treatment

Stereotactic biopsy is being performed in some centers, and may become routine when therapies specifically targeted to these mutations become available.

Diffuse midline glioma H3 K27M-mutant have no effective treatment, and their location and diffuse nature render them inoperable. Radiation therapy remains the only standard of care for this devastating disease.

Until recently biopsies were considered not informative enough and therefore not recommended.

Systemic administration of chemotherapeutic agents is often hindered by the blood brain barrier (BBB), and even drugs that successfully cross the barrier may suffer from unpredictable distributions. The challenge in treating this deadly disease relies on effective delivery of a therapeutic agent to the bulk tumor as well as infiltrating cells. Therefore, methods that can enhance drug delivery to the brain are of great interest. Convection-enhanced delivery (CED) is a strategy that bypasses the BBB entirely and enhances drug distribution by applying hydraulic pressure to deliver agents directly and evenly into a target region. This technique reliably distributes infusate homogenously through the interstitial space of the target region and achieves high local drug concentrations in the brain. Moreover, recent studies have also shown that continuous delivery of drug over an extended period of time is safe, feasible, and more efficacious than standard single session CED. Therefore, CED represents a promising technique for treating midline tumors with the H3K27M mutation 1).

Based on the molecular heterogeneity observed in this tumor type, personalized treatment is considered to substantially improve therapeutic options. Therefore, clinical evidence for therapy, guided by comprehensive molecular profiling, is urgently required. In this study, we analyzed feasibility and clinical outcomes in a cohort of 12 H3K27M glioma cases treated at two centers. Patients were subjected to personalized treatment either at primary diagnosis or disease progression and received backbone therapy including focal irradiation. Molecular analyses included whole-exome sequencing of tumor and germline DNA, RNA-sequencing, and transcriptomic profiling. Patients were monitored with regular clinical as well as radiological follow-up. In one case, liquid biopsy of cerebrospinal fluid (CSF) was used. Analyses could be completed in 83% (10/12) and subsequent personalized treatment for one or more additional pharmacological therapies could be recommended in 90% (9/10). Personalized treatment included inhibition of the PI3K/AKT/mTOR pathway (3/9), MAPK signaling (2/9), immunotherapy (2/9), receptor tyrosine kinase inhibition (2/9), and retinoic receptor agonist (1/9). The overall response rate within the cohort was 78% (7/9) including one complete remission, three partial responses, and three stable diseases. Sustained responses lasting for 28 to 150 weeks were observed for cases with PIK3CA mutations treated with either miltefosine or everolimus and additional treatment with trametinib/dabrafenib in a case with BRAFV600E mutation. Immune checkpoint inhibitor treatment of a case with increased tumor mutational burden (TMB) resulted in complete remission lasting 40 weeks. Median time to progression was 29 weeks. Median overall survival (OS) in the personalized treatment cohort was 16.5 months. Last, we compared OS to a control cohort (n = 9) showing a median OS of 17.5 months. No significant difference between the cohorts could be detected, but long-term survivors (>2 years) were only present in the personalized treatment cohort. Taken together, we present the first evidence of clinical efficacy and an improved patient outcome through a personalized approach at least in selected cases of H3K27M glioma 2).

Although GD2CAR T-cells demonstrated significant anti-tumor activity against Diffuse midline glioma H3 K27M-mutant in vivo, a multimodal approach may be needed to more effectively treat patients. de Billy et al. investigated GD2 expression in DMG/DIPG and other pediatric high-grade gliomas (pHGG) and sought to identify chemical compounds that would enhance GD2-CAR T-cell anti-tumor efficacy.

Immunohistochemistry in tumor tissue samples and immunofluorescence in primary patient-derived cell lines were performed to study GD2 expression. We developed a high-throughput cell-based assay to screen 42 kinase inhibitors in combination with GD2-CAR T-cells. Cell viability, western blots, flow-cytometry, real time PCR experiments, DIPG 3D culture models and orthotopic xenograft model were applied to investigate the effect of selected compounds on DIPG cell death and CAR T-cell function.

GD2 was heterogeneously, but widely, expressed in the tissue tested, while its expression was homogeneous and restricted to DMG/DIPG H3K27M-mutant cell lines. We identified dual Insulin-like growth factor 1 receptor( IGF1R/IR) antagonists, BMS-754807 and linsitinib, able to inhibit tumor cell viability at concentrations that do not affect CAR T-cells. Linsitinib, but not BMS-754807, decreases activation/exhaustion of GD2-CAR T-cells and increases their central memory profile. The enhanced anti-tumor activity of linsitinib/GD2-CAR T-cell combination was confirmed in DIPG models in vitro, ex vivo and in vivo.

The study supports the development of IGF1R/IR inhibitors to be used in combination with GD2-CAR T-cells for Diffuse midline glioma H3 K27M-mutant treatment and, potentially, by pHGG 3).

Findings suggest that targeting PLK1 with small-molecule inhibitors, in combination with radiation therapy, will hold a novel strategy in the treatment of Diffuse intrinsic pontine glioma (DIPG) that warrants further investigation 4).


Himes BT, Zhang L, Daniels DJ. Treatment Strategies in Diffuse Midline Gliomas With the H3K27M Mutation: The Role of Convection-Enhanced Delivery in Overcoming Anatomic Challenges. Front Oncol. 2019 Feb 8;9:31. doi: 10.3389/fonc.2019.00031. PMID: 30800634; PMCID: PMC6375835.

Gojo J, Pavelka Z, Zapletalova D, Schmook MT, Mayr L, Madlener S, Kyr M, Vejmelkova K, Smrcka M, Czech T, Dorfer C, Skotakova J, Azizi AA, Chocholous M, Reisinger D, Lastovicka D, Valik D, Haberler C, Peyrl A, Noskova H, Pál K, Jezova M, Veselska R, Kozakova S, Slaby O, Slavc I, Sterba J. Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities. Front Oncol. 2020 Jan 10;9:1436. doi: 10.3389/fonc.2019.01436. PMID: 31998633; PMCID: PMC6965319.

de Billy E, Pellegrino M, Orlando D, Pericoli G, Ferretti R, Businaro P, Ajmone-Cat MA, Rossi S, Petrilli LL, Maestro N, Diomedi-Camassei F, Pezzullo M, De Stefanis C, Bencivenga P, Palma A, Rota R, Del Bufalo F, Massimi L, Weber G, Jones C, Carai A, Caruso S, De Angelis B, Caruana I, Quintarelli C, Mastronuzzi A, Locatelli F, Vinci M. Dual IGF1R/IR inhibitors in combination with GD2-CAR T-cells display a potent anti-tumor activity in diffuse midline glioma H3K27M-mutant. Neuro Oncol. 2021 Dec 29:noab300. doi: 10.1093/neuonc/noab300. Epub ahead of print. PMID: 34964902.

Amani V, Prince EW, Alimova I, Balakrishnan I, Birks D, Donson AM, Harris P, Levy JM, Handler M, Foreman NK, Venkataraman S, Vibhakar R. Polo-like Kinase 1 as a potential therapeutic target in Diffuse Intrinsic Pontine Glioma. BMC Cancer. 2016 Aug 18;16:647. doi: 10.1186/s12885-016-2690-6. PubMed PMID: 27538997.

Cervical Cage Subsidence

Cervical Cage Subsidence

Cage subsidence was defined as the sum subsidence of the superior and inferior part of the cage into the vertebral body. Mild and major cage subsidence was defined as ≤2 mm and >2 mm, respectively. The extent of cage subsidence was greater after ACDF with cage alone. Cage subsidence occurred more often when the end plate was removed. Additional anterior plate fixation is recommended when the end plate is removed 1).

Subsidence in ACDF with cages occurs in 21% of patients. The risk for subsidence seems lower using PEEK or titanium cages or adding screws 2).

Zero profile anchored spacer (ROI-C) use resulted in a higher subsidence rate than conventional cage and plate construct (CPC) use in multi-segment ACDF procedures. The male sex, the use of ROI-C, operation in multiple segments, and over-distraction were the most significant factors associated with an increase in the risk of cage subsidence 3).

The greater the cage height, the greater the risk of cage subsidence in ACDF. Polyetheretherketone cages are superior to titanium cages for the maintenance of intervertebral height in cases where cage height is >5.5 mm 4)

Subsidence irrespective of the measurement technique or definition does not appear to have an impact on successful fusion and/or clinical outcomes. A validated definition and standard measurement technique for subsidence is needed to determine the actual incidence of subsidence and its impact on radiographic and clinical outcomes 5).

PEEK cages showed a high rate of secondary subsidence (32%) 6).

Titanium Wing cage-augmented ACDF was associated with comparatively good long-term results. Subsidence was present but did not cause clinical complications. Furthermore, radiological studies demonstrated that the physiological alignment of the cervical spine was preserved and a solid bone arthrodesis was present at 2 years after surgery 7).

There is evidence documenting relatively frequent complications in stand-alone cage assisted ACDF, such as cage subsidence and cervical kyphosis 8).

Subsidence irrespective of the measurement technique or definition does not appear to have an impact on successful fusion and/or clinical outcomes. A validated definition and standard measurement technique for subsidence is needed to determine the actual incidence of subsidence and its impact on radiographic and clinical outcomes 9).

Findings suggest that the value of ratio of anterior endplate more than 1.18, alignment of titanium mesh cage (TMC) and poor bone mineral density are the risk factors for subsidence. TMC subsidence does not negatively affect the clinical outcomes after operation. Avoiding over expansion of intervertebral height, optimizing placing of TMC and initiation of anti-osteoporosis treatments 6 months prior to surgery might help surgeons to reduce subsidence after ACCF 10).

Lee et al. from Yangsan retrospectively reviewed the medical records of 40 patients who underwent stand-alone single-level ACDF using a polyetheretherketone (PEEKcage between January 2012 and December 2018. The study population comprised 19 male and 21 female patients aged 24-70 years. The minimum follow-up period was 1 year. Twenty-seven patients had preoperative bone mineral density (BMD) data on dual-energy X-ray absorptiometry. Clinical parameters included sex, age, body mass indexsmoking history, and prior medical history. Radiologic parameters included the C2-7 cobb angle, segmental angle, sagittal vertical axis, disc height, and total intervertebral height (TIH) at the preoperative and postoperative periods. Cage decrement was defined as the reduction in TIH at the 6-month follow-up compared to preoperative TIH. To evaluate the bone quality, Hounsfield unit (HU) value was calculated in the axial and sagittal images of conventional computed tomography.

Lumbar BMD values and cervical HU values were significantly correlated (r=0.733, p<0.001). They divided the patients into two groups based on cage decrement, and 47.5% of the total patients were regarded as cage decrement. There were statistically significant differences in the parameters of measuring the HU value of the vertebra and intraoperative distraction between the two groups. Using these identified factors, we performed a receiver operating characteristic (ROC) curve analysis. Based on the ROC curve, the cut-off point was 530 at the HU value of the upper cortical and cancellous vertebrae (p=0.014; area under the curve [AUC], 0.727; sensitivity, 94.7%; specificity, 42.9%) and 22.41 at intraoperative distraction (p=0.017; AUC, 0.722; sensitivity, 85.7%; specificity, 57.9%). Using this value, they converted these parameters into a bifurcated variable and assessed the multinomial regression analysis to evaluate the risk factors for cage decrement in ACDF. Intraoperative distraction and HU value of the upper vertebral body were independent factors of postoperative subsidence.

Insufficient intraoperative distraction and low Hounsfield unit (HU) value showed a strong relationship with postoperative intervertebral height reduction following single stand-alone PEEK cage ACDF 11).

Mende et al. performed a retrospective analysis of ACDF patients from 2004 to 2010. Numeric analog scale (NAS) score pre-op and post-op, Oswestry Disability Index (ODI) on x-rays, endplate (EP) and cage dimensions, implant position, lordotic/kyphotic subsidence patterns (>5°), and cervical alignment were recorded. Subsidence was defined as height loss >40%. Patients were grouped into single segment (SS), double segment (DS), and plated procedures. We included 214 patients. Prevalence of subsidence was 44.9% overall, 40.9% for SS, and 54.8% for DS. Subsidence presented mostly for dorsal (40.7%) and mid-endplate position (46.3%, p < 0.01); dorsal placement resulted in kyphotic (73.7%) and central placement in balanced implant migration (53.3%, p < 0.01). Larger cages (>65% EP) showed less subsidence (64.6 vs. 35.4%, p < 0.01). There was no impact of subsidence on ODI or alignment. NAS was better for subsided implants in SS (p = 0.06). Cages should be placed at the anterior endplate rim in order to reduce the risk of subsidence. Spacers should be adequately sized for the respective segment measuring at least 65% of the segment dimensions. The cage frame should not rest on the vulnerable central endplate. For multilevel surgery, ventral plating may be beneficial regarding construct stability. The reduction of micro-instability or over-distraction may explain lower NAS for subsided implants 12).

a retrospective observational cohort study to test the hypothesis that radiographic subsidence of cervical cages is not associated with adverse clinical outcomes. 33 cervical segments were treated surgically by ACDF with stand-alone cage in 17 patients (11 female, 6 male), mean age 56 years (33-82 years), and re-examined after eight and twenty-six months (mean) by means of radiology and score assessment (Medical Outcomes Study Short Form (MOS-SF 36), Oswestry Neck Disability Index (ONDI), painDETECT questionnaire and the visual analogue scale (VAS)).

Results: Subsidence was observed in 50.5% of segments (18/33) and 70.6% of patients (12/17). 36.3% of cases of subsidence (12/33) were observed after eight months during mean time of follow-up 1. After 26 months during mean time of follow-up 2, full radiographic fusion was seen in 100%. MOS-SF 36, ONDI and VAS did not show any significant difference between cases with and without subsidence in the two-sample t-test. Only in one type of scoring (painDETECT questionnaire) did a statistically significant difference in t-Test emerge between the two groups (p = 0.03; α = 0.05). However, preoperative painDETECT score differ significantly between patients with subsidence (13.3 falling to 12.6) and patients without subsidence (7.8 dropped to 6.3).

Conclusions: The radiological findings indicated 100% healing after stand-alone treatment with ACDF. Subsidence occurred in 50% of the segments treated. No impact on the clinical results was detected in the medium-term study period 13).


Pinder EM, Sharp DJ. Cage subsidence after anterior cervical discectomy and fusion using a cage alone or combined with anterior plate fixation. J Orthop Surg (Hong Kong). 2016 Apr;24(1):97-100. doi: 10.1177/230949901602400122. PMID: 27122522.

Noordhoek I, Koning MT, Jacobs WCH, Vleggeert-Lankamp CLA. Incidence and clinical relevance of cage subsidence in anterior cervical discectomy and fusion: a systematic review. Acta Neurochir (Wien). 2018 Apr;160(4):873-880. doi: 10.1007/s00701-018-3490-3. Epub 2018 Feb 21. PMID: 29468440; PMCID: PMC5859059.

Jin ZY, Teng Y, Wang HZ, Yang HL, Lu YJ, Gan MF. Comparative Analysis of Cage Subsidence in Anterior Cervical Decompression and Fusion: Zero Profile Anchored Spacer (ROI-C) vs. Conventional Cage and Plate Construct. Front Surg. 2021 Oct 27;8:736680. doi: 10.3389/fsurg.2021.736680. PMID: 34778358; PMCID: PMC8579909.

Igarashi H, Hoshino M, Omori K, Matsuzaki H, Nemoto Y, Tsuruta T, Yamasaki K. Factors Influencing Interbody Cage Subsidence Following Anterior Cervical Discectomy and Fusion. Clin Spine Surg. 2019 Aug;32(7):297-302. doi: 10.1097/BSD.0000000000000843. PMID: 31169615.
5) , 9)

Karikari IO, Jain D, Owens TR, Gottfried O, Hodges TR, Nimjee SM, Bagley CA. Impact of Subsidence on Clinical Outcomes and Radiographic Fusion Rates in Anterior Cervical Discectomy and Fusion: A Systematic Review. J Spinal Disord Tech. 2014 Feb;27(1):1-10. PubMed PMID: 24441059.

König SA, Spetzger U. Distractable titanium cages versus PEEK cages versus iliac crest bone grafts for the replacement of cervical vertebrae. Minim Invasive Ther Allied Technol. 2013 Nov 29. [Epub ahead of print] PubMed PMID: 24289173.

Schmieder K, Wolzik-Grossmann M, Pechlivanis I, Engelhardt M, Scholz M, Harders A. Subsidence of the wing titanium cage after anterior cervical interbody fusion: 2-year follow-up study. J Neurosurg Spine. 2006 Jun;4(6):447-53. PubMed PMID: 16776355.

Cloward RB: The anterior approach for removal of ruptured cervical disks. 1958. J Neurosurg Spine 6:496-511, 2007

Ji C, Yu S, Yan N, Wang J, Hou F, Hou T, Cai W. Risk factors for subsidence of titanium mesh cage following single-level anterior cervical corpectomy and fusion. BMC Musculoskelet Disord. 2020 Jan 14;21(1):32. doi: 10.1186/s12891-019-3036-8. PMID: 31937288; PMCID: PMC6961320.

Lee JS, Son DW, Lee SH, Ki SS, Lee SW, Song GS, Woo JB, Kim YH. The Effect of Hounsfield Unit Value with Conventional Computed Tomography and Intraoperative Distraction on Postoperative Intervertebral Height Reduction in Patients Following Stand-Alone Anterior Cervical Discectomy and Fusion. J Korean Neurosurg Soc. 2021 Dec 29. doi: 10.3340/jkns.2021.0131. Epub ahead of print. PMID: 34963207.

Mende KC, Eicker SO, Weber F. Cage deviation in the subaxial cervical spine in relation to implant position in the sagittal plane. Neurosurg Rev. 2017 Apr 4. doi: 10.1007/s10143-017-0850-z. [Epub ahead of print] PubMed PMID: 28374128.

Zajonz D, Franke AC, von der Höh N, Voelker A, Moche M, Gulow J, Heyde CE. Is the radiographic subsidence of stand-alone cages associated with adverse clinical outcomes after cervical spine fusion? An observational cohort study with 2-year follow-up outcome scoring. Patient Saf Surg. 2014 Nov 7;8(1):43. doi: 10.1186/s13037-014-0043-4. PMID: 25408710; PMCID: PMC4234826.

Vestibular schwannoma natural history

Vestibular schwannoma natural history

see also Vestibular schwannoma conservative treatment.

Spontaneous involution of acoustic tumors does occur. Long-term follow-up is necessary to determine this potential 1).

Three-dimensional volumetric assessment of VS provides a more sensitive measure of tumor growth when compared with linear diameter assessment. Through volumetric analysis, a study revealed that a significant proportion of VSs demonstrate growth during observation 2).

An extensive MEDLINE search was performed to cull studies on VS growth according to sequential imaging. The percentages of growing and regressing tumors and lesions requiring treatment during follow-up periods were calculated. Factors associated with differences among studies were identified. Twenty-six studies including 1340 patients met all inclusion criteria. The overall frequency of VS growth during a mean follow-up period of 38 months was 46% (95% confidence interval [CI] 43-48%) and that of regression was 8% (95% CI 6-10%). The mean annual tumor growth rate was 1.2 mm/year. Furthermore, the percentage of cases requiring treatment during follow up was 18% (95% CI 16-21%). According to results of a sensitivity analysis, evaluation by serial MR imaging (39%, 95% CI 35-43%) and a prospective study design (29%, 95% CI 21-37%) were associated with less frequent reported tumor growth.

Conclusions: Although their applicability may be limited to relatively elderly patients with small tumors, data revealing a limited frequency of VS enlargement and an infrequent necessity for eventual therapy should assist decision-making in the treatment of small VSs causing minimal symptoms 3)

Volumetric tumor measurements from 3,505 serial MRI studies were analyzed from unselected consecutive patients undergoing wait-and-scan management at three tertiary referral centers between 1998 and 2018. Volumetric tumor growth was defined as a change in volume ≥20%.

Among 952 patients undergoing observation, 622 experienced tumor growth with initial growth-free survival rates (95% CI) at 1, 3, and 5 years following diagnosis of 66% (63-69), 30% (27-34), and 20% (17-24). Among 405 patients who continued to be observed despite demonstrating initial growth, 210 experienced subsequent tumor growth with subsequent growth-free survival rates at 1, 3, and 5 years following initial growth of 77% (72-81), 37% (31-43), and 24% (18-31). Larger tumor volume at initial growth (HR 1.13, p=0.02) and increasing tumor growth rate (HR 1.31; p<0.001) were significantly associated with an increased likelihood of subsequent growth, whereas a longer duration of time between diagnosis and detection of initial growth was protective (HR 0.69; p<0.001).

While most vestibular schwannomas exhibit an overall propensity for volumetric growth following diagnosis, prior tumor growth does not perfectly predict future growth. Tumors can subsequently grow faster, slower, or demonstrate quiescence and stability. Larger tumor size and increasing tumor growth rate portend a higher likelihood of continued growth. These findings can inform timing of intervention: whether upfront at initial diagnosis, after detection of initial growth, or only after continued growth is observed 4).

Of the 1,818 consecutive patients, diagnosed with VS during the period from 1975 to 2005, 729 patients were allocated to observation by repetitive magnetic resonance imaging. At least two scans had been performed in 552 patients at the time of data analysis. Two hundred thirty patients had a tumor confined to the internal acoustic meatus, whereas 322 patients had a tumor with an extrameatal extension. Growth to extrameatal extension was the definition for growth in intrameatal tumors, whereas a largest diameter change of more than 2 mm was the criteria for growth/shrinkage of extrameatal tumors. The mean observation time was 3.6 years (range, 1-15 yr).

Seventeen percent of the intrameatal tumors grew, whereas significantly more of the extrameatal tumors displayed growth during the period (28.9%). Growth occurred within the first 5 years after diagnosis. No correlation could be demonstrated between tumor growth rate, sex, or age.

VS growth occurs within the first 5 years after diagnosis in a limited number of tumors, primarily in tumors with an extrameatal extension. They found no relation between tumor growth and sex or age. These findings justify primary observation of small tumors. A treatment strategy is proposed for this disease, focusing on the patient group allocated to observation 5).

The natural history of Vestibular Schwannomas (VS) is yet not totally known, but most of them have the tendency to slow growth, sometimes without any kind of symptoms during the individuals entire time. About 69% of diagnosed VS do not grow at all and 16% of these can even regress. Considering tumors that grow, about 70% have grown less than 2mm an year. Advanced radiological diagnosis, especially magnetic resonance imaging with gadolinium helps us diagnose small and less symptomatic tumors. Treatment of choice still is complete tumor resection. Surgical approaches have improved considerably and have helped preserve facial nerve function and hearing. Considering VSs natural history, there is a possibility for conservative treatment for these tumors, because their growth in the first year after diagnosis predicts tumor growth behavior in the next years. Surgery should be done in cases of tumor growth, patients desire or symptoms worsening. Moreover, in terms of postoperative sequelae, there is no difference between patients who underwent surgery immediately after diagnosis and those who underwent initial conservative treatment for these tumors 6).


Luetje CM. Spontaneous involution of acoustic tumors. Am J Otol. 2000 May;21(3):393-8. PubMed PMID: 10821554.

Lees KA, Tombers NM, Link MJ, Driscoll CL, Neff BA, Van Gompel JJ, Lane JI, Lohse CM, Carlson ML. Natural History of Sporadic Vestibular Schwannoma: A Volumetric Study of Tumor Growth. Otolaryngol Head Neck Surg. 2018 Sep;159(3):535-542. doi: 10.1177/0194599818770413. Epub 2018 Apr 24. PMID: 29685084.

Yoshimoto Y. Systematic review of the natural history of vestibular schwannoma. J Neurosurg. 2005 Jul;103(1):59-63. doi: 10.3171/jns.2005.103.1.0059. PMID: 16121974.

Marinelli JP, Schnurman Z, Killeen DE, Nassiri AM, Hunter JB, Lees KA, Lohse CM, Roland JT, Golfinos JG, Kondziolka D, Link MJ, Carlson ML. Long-term Natural History and Patterns of Sporadic Vestibular Schwannoma Growth: A Multi-institutional Volumetric Analysis of 952 Patients. Neuro Oncol. 2021 Dec 29:noab303. doi: 10.1093/neuonc/noab303. Epub ahead of print. PMID: 34964894.

Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. The natural history of vestibular schwannoma. Otol Neurotol. 2006 Jun;27(4):547-52. doi: 10.1097/01.mao.0000217356.73463.e7. PMID: 16791048.

Oliveira Penido N, Tangerina RP, Macoto Kosugi E, Cesário de Abreu CE, Brandão Vasco M. Vestibular Schwannoma: spontaneous tumor involution. Braz J Otorhinolaryngol. 2007 Nov-Dec;73(6):867-871. doi: 10.1016/S1808-8694(15)31189-7. PubMed PMID: 18278239.
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