Bevacizumab Treatment for Patients with NF2-Related Schwannomatosis: A Single Center Experience.

(1) Background: NF2-related schwannomatosis, characterized by the development of bilateral vestibular schwannomas, often necessitates varied treatment approaches. Bevacizumab, though widely utilized, demonstrates variable effectiveness on hearing and tumor growth. At the same time, (serious) adverse events have been frequently reported. (2) Methods: A single center retrospective study was conducted, on NF2-related schwannomatosis patients treated with bevacizumab from 2013 to 2023, with the aim to assess treatment-related and clinical outcomes. Outcomes of interest comprised hearing, radiologic response, symptoms, and adverse events. (3) Results: Seventeen patients received 7.5 mg/kg bevacizumab for 7.1 months. Following treatment, 40% of the patients experienced hearing improvement, 53%, stable hearing, and 7%, hearing loss. Vestibular schwannoma regression occurred in 31%, and 69% remained stable. Further symptomatic improvement was reported by 41%, stable symptoms by 47%, and worsened symptoms by 12%. Treatment discontinuation due to adverse events was observed in 29% of cases. Hypertension (82%) and fatigue (29%) were most frequently reported, with no occurrences of grade 4/5 toxicities. (4) Conclusion: Supporting previous studies, bevacizumab demonstrated positive effects on hearing, tumor control, and symptoms in NF2-related schwannomatosis, albeit with common adverse events. Therefore, careful consideration of an appropriate management strategy is warranted.

SDHAF2-Linked Metastatic Paraganglioma: A Case Report with Implications for Counseling and Follow-Up of Pathogenic SDHAF2 Variant Carriers.

Head and neck paragangliomas are slow growing and highly vascular neuroendocrine tumors. It is currently assumed that SDHAF2 variants exclusively cause benign and often multicentric head and neck paragangliomas. Here, we present a patient diagnosed with multiple SDHAF2-linked head and neck paragangliomas who in addition developed paraganglioma metastases to the lung and spine and a primary or metastatic paraganglioma in the head of the pancreas. During the course of the disease, a range of management strategies were deployed for the different head and neck tumors, including total resections, partial resections, and active surveillance. After identification of the paraganglioma metastases, the patient was treated with lanreotide after which the disease remained stable during the 27 months of follow-up.

The effect of intratympanic gentamicin as a prehabilitation strategy for objective and subjective vestibular function in patients undergoing microsurgery for a unilateral vestibular schwannoma.

OBJECTIVE: To review the literature on intratympanic gentamicin treatment as prehabilitation for patients undergoing surgery for a unilateral vestibular schwannoma. DATA SOURCES: A systematic literature search was conducted up to March 2023 in Pubmed, Embase, Cochrane, Web of Science, Academic Search Premier, Google Scholar and Emcare databases. REVIEW METHODS: Articles on the effect of intratympanic gentamicin followed by vestibular schwannoma surgery were reviewed. Data on objective vestibular function and subjective outcomes were compiled in tables for analysis. Relevance and methodological quality were assessed with the methodological index for non-randomized tool. RESULTS: A total of 281 articles were identified. After screening and exclusion of duplicates, 13 studies were reviewed for eligibility, of which 4 studies could be included in the review. The posturography test, the subjective visual horizontal test, and the optokinetic nystagmus test showed decreased vestibular function in the group of patients who received intratympanic gentamicin before microsurgery compared to the group of patients without gentamicin. Other objective tests did not show significant differences between patient groups. Subjective vestibular outcomes, as evaluated by questionnaires on quality of life and/or dizziness, did not seem to improve from intratympanic gentamicin pretreatment. CONCLUSION: Vestibular schwannoma patients who received intratympanic gentamicin before surgical resection of the tumor performed better in the posturography test, subjective visual horizontal test, and the optokinetic nystagmus test afterwards. However, studies that also evaluated subjective outcomes such as dizziness, anxiety, depression, and balance self-confidence did not show a positive effect of intratympanic gentamicin on the vestibular complaints and symptoms.

Automated 2-Dimensional Measurement of Vestibular Schwannoma: Validity and Accuracy of an Artificial Intelligence Algorithm.

OBJECTIVE: Validation of automated 2-dimensional (2D) diameter measurements of vestibular schwannomas on magnetic resonance imaging (MRI). STUDY DESIGN: Retrospective validation study using 2 data sets containing MRIs of vestibular schwannoma patients. SETTING: University Hospital in The Netherlands. METHODS: Two data sets were used, 1 containing 1 scan per patient (n = 134) and the other containing at least 3 consecutive MRIs of 51 patients, all with contrast-enhanced T1 or high-resolution T2 sequences. 2D measurements of the maximal extrameatal diameters in the axial plane were automatically derived from a 3D-convolutional neural network compared to manual measurements by 2 human observers. Intra- and interobserver variabilities were calculated using the intraclass correlation coefficient (ICC), agreement on tumor progression using Cohen's kappa. RESULTS: The human intra- and interobserver variability showed a high correlation (ICC: 0.98-0.99) and limits of agreement of 1.7 to 2.1 mm. Comparing the automated to human measurements resulted in ICC of 0.98 (95% confidence interval [CI]: 0.974; 0.987) and 0.97 (95% CI: 0.968; 0.984), with limits of agreement of 2.2 and 2.1 mm for diameters parallel and perpendicular to the posterior side of the temporal bone, respectively. There was satisfactory agreement on tumor progression between automated measurements and human observers (Cohen's κ = 0.77), better than the agreement between the human observers (Cohen's κ = 0.74). CONCLUSION: Automated 2D diameter measurements and growth detection of vestibular schwannomas are at least as accurate as human 2D measurements. In clinical practice, measurements of the maximal extrameatal tumor (2D) diameters of vestibular schwannomas provide important complementary information to total tumor volume (3D) measurements. Combining both in an automated measurement algorithm facilitates clinical adoption.

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants.

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

The Course of Hearing Loss in Patients With a Progressive Vestibular Schwannoma.

OBJECTIVE: This study evaluates the natural course of hearing loss (HL) prior to treatment in patients with progressive tumors and an indication for active intervention. Evaluating this patient group specifically can put hearing outcomes after vestibular schwannoma therapy into an adequate context. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral center. METHODS: Inclusion criteria comprised unilateral vestibular schwannomas prior to active treatment, with ≥2 mm extracanalicular (EC) tumor growth and ≥2 audiograms. We performed a comprehensive assessment of hearing using multiple outcome parameters including (the annual decrease in) pure-tone averages (PTAs; an average of 0.5, 1, 2, and 3 kHz). Predictors for HL were evaluated (patient age, tumor size/progression, follow-up duration, baseline hearing). RESULTS: At presentation, 86% of patients suffered from sensorineural HL on the affected side (≥20 dB PTA) with a median of 39 dB (interquartile rate [IQR]: 27-51 dB). The median follow-up duration was 21 months (IQR: 13-34 months), after which 58% (187/322) of patients experienced progressive HL (≥10 dB), with a median increase of 6.4 dB/year. At the last follow-up, the median PTA was 56 dB (IQR: 37-73). Median speech discrimination scores deteriorated from 90% (IQR: 70%-100%) to 65% (IQR: 35%-100%). Tumor progression (maximal EC diameter) was significantly correlated to the progression of sensorineural HL, corrected for follow-up (F(2,228) = 10.4, p < .001, R2 = 8%). CONCLUSION: The majority of patients (58%) with radiologically confirmed progressive vestibular schwannomas experience progressive sensorineural HL during observation. Tumor progression rate, EC tumor extension, and longer follow-up are factors associated with more sensorineural HL.

Proton Radiotherapy for Vestibular Schwannomas in Patients with NF2-Related Schwannomatosis: A Case Series.

(1) Background: This study aimed to evaluate the efficacy and treatment-related toxicity of proton radiotherapy (PRT) for vestibular schwannoma (VS) in patients with neurofibromatosis type 2-related schwannomatosis (NF2). (2) Methods: Consecutive NF2 patients treated with PRT for VS between 2004 and 2016 were retrospectively evaluated, focusing on tumor volume, facial and trigeminal nerve function, hearing, tinnitus, vestibular symptoms, and the need for salvage therapy after PRT. (3) Results: Eight patients were included (median age 36 years, 50% female). Median follow-up was 71 months. Five (63%) patients received fractionated PRT and three (38%) received PRT radiosurgery for VS. Six patients (75%) received prior VS surgery; three also received bevacizumab. Six patients (75%) did not require salvage therapy after PRT. Two patients (25%) with residual hearing lost it after PRT, and six had already lost ipsilateral hearing prior to PRT. Tumor and treatment-related morbidity could be evaluated in six patients. Following PRT, conditions that occurred or worsened were: facial paresis in five (83%), trigeminal hypoesthesia in two (33%), tinnitus in two (33%), and vestibular symptoms in four patients (67%). (4) Conclusion: After PRT for VS, the majority of the NF2 patients in the cohort did not require additional therapy. Tumor and/or treatment-related cranial nerve deficits were common. This is at least partly explained by the use of PRT as a salvage treatment after surgery or bevacizumab, in the majority of cases. There remains the further opportunity to elucidate the efficacy and toxicity of proton radiotherapy as a primary treatment.

Vestibular Complaints Impact on the Long-Term Quality of Life of Vestibular Schwannoma Patients.

OBJECTIVE: To analyze the effect of dizziness-related symptoms on the long-term quality of life (QoL) of patients with unilateral vestibular schwannoma. METHODS: In this cross-sectional study, patients with a unilateral vestibular schwannoma diagnosed between 2004 and 2013 completed a disease-specific QoL questionnaire (Penn Acoustic Neuroma Quality of Life [PANQOL]) and the Dizziness Handicap Inventory (DHI) in 2020. Linear regression was performed to assess the correlation between QoL and the DHI total score, and the scores of the DHI functional, emotional, and physical subdomains. Potential confounders such as age, sex, tumor size at baseline, and treatment modality (active surveillance, surgery, or radiotherapy) were included in the model. RESULTS: In total, 287 of 479 patients (59%) experienced dizziness with a median follow-up of 10 years. The DHI total score was significantly associated with the PANQOL total score. On average, we found a reduction of 0.7 points on the PANQOL for each additional point on the DHI. The DHI emotional subdomain was the most prominent determinant of poorer QoL. Each point on the DHI emotional subscale was associated with a reduction of 1.3 on the PANQOL score. Treatment modality did not have a clinically relevant effect on dizziness-related QoL. CONCLUSIONS: Even mild dizziness can have a significant and clinically relevant effect on the QoL of patients with unilateral vestibular schwannoma in the long term. This holds true for all treatment modalities. Addressing the vestibular problems may improve QoL in vestibular schwannoma patients, and DHI subscale analysis may help tailor the optimal vestibular intervention.

SDHB variant type impacts phenotype and malignancy in pheochromocytoma-paraganglioma.

BACKGROUND: Traditional genotype-phenotype correlations for the succinate dehydrogenase-complex II (SDH) genes link SDHB variants to thoracic-abdominal pheochromocytoma-paraganglioma (PPGL) and SDHD variants to head and neck paraganglioma (HNPGL). However, in a recent study we found strong and specific genotype-phenotype associations for SDHD variants. In the present study we zoom in on the genotype-phenotype associations of SDHB gene variants, considering the impact of individual gene variants on disease risk and risk of malignancy. METHODS: We analysed two large independent data sets, including a total of 448 patients with PPGL and HNPGL, and studied the association of missense or truncating SDHB variants with tumour incidence, age of onset and malignancy risk using binomial testing and Kaplan-Meier analysis. RESULTS: Compared with missense variants, truncating SDHB variants were significantly and consistently more common in patients with PPGL, by a 20 percentage point margin. Malignancy was also significantly more common in truncating versus missense variant carriers. No overall differences in age of PPGL onset were noted between carriers of the two variant types, although some individual variants may differ in certain cases. Missense variants were marginally over-represented among patients with HNPGL, but the difference was not statistically significant. CONCLUSION: SDHB truncating variants convey an elevated risk for development of both PPGL and malignancy compared with missense variants. These results further support earlier robust associations between truncating variants and PPGL, and also suggest that the two variant types differ in their impact on complex II function, with PPGL/HNPGL tissues displaying differing sensitivities to changes in complex II function.

Long-Term Quality of Life of Vestibular Schwannoma Patients: A Longitudinal Analysis.

OBJECTIVE: Vestibular schwannoma management aims to maintain optimal quality of life (QoL) while preventing severe sequelae of the tumor or its treatment. This study assessed long-term QoL of patients with vestibular schwannoma in relation to treatment modality and decisional regret. STUDY DESIGN: A longitudinal study, in which clinical and QoL data were used that were cross-sectionally acquired in 2014 and again in 2020 from the same patient group. SETTING: A tertiary expert center for vestibular schwannoma care in the Netherlands. METHODS: QoL was measured by the Penn Acoustic Quality of Life (PANQOL) scale. Changes in time were assed using a linear mixed model. In addition, the Decision Regret Scale was analyzed. RESULTS: Of 867 patients, 536 responded (62%), with a median follow-up of 11 years. All PANQOL subdomain scores remained stable over time and did not exceed minimal clinically important difference (MCID) levels. Time since treatment did not affect QoL. Patients had comparable average QoL scores and proportions of patients with changing QoL scores (ie, exceeding the MCID) over time, irrespective of the received initial treatment. Female patients and those who required salvage therapy (either by radiotherapy or surgery) reported a lower QoL. The latter patient group reported the highest decisional regret. CONCLUSION: On average, the long-term QoL of patients with vestibular schwannoma is comparable for patients under active surveillance and those who have received active treatment, and it remains stable over time. This suggests that, on average, preservation of QoL of patients with vestibular schwannoma is feasible when adequately managed.

Long-term in vitro 2D-culture of SDHB and SDHD-related human paragangliomas and pheochromocytomas.

The neuroendocrine tumours paraganglioma and pheochromocytoma (PPGLs) are commonly associated with succinate dehydrogenase (SDH) gene variants, but no human SDH-related PPGL-derived cell line has been developed to date. The aim of this study was to systematically explore practical issues related to the classical 2D-culture of SDH-related human paragangliomas and pheochromocytomas, with the ultimate goal of identifying a viable tumour-derived cell line. PPGL tumour tissue/cells (chromaffin cells) were cultured in a variety of media formulations and supplements. Tumour explants and dissociated primary tumour cells were cultured and stained with a range of antibodies to identify markers suitable for use in human PPGL culture. We cultured 62 PPGLs, including tumours with confirmed SDHB, SDHC and SDHD variants, as well as several metastatic tumours. Testing a wide range of basic cell culture media and supplements, we noted a marked decline in chromaffin cell numbers over a 4-8 week period but the persistence of small numbers of synaptophysin/tyrosine hydroxylase-positive chromaffin cells for up to 99 weeks. In cell culture, immunohistochemical staining for chromogranin A and neuron-specific enolase was generally negative in chromaffin cells, while staining for synaptophysin and tyrosine hydroxylase was generally positive. GFAP showed the most consistent staining of type II sustentacular cells. Of the media tested, low serum or serum-free media best sustained relative chromaffin cell numbers, while lactate enhanced the survival of synaptophysin-positive cells. Synaptophysin-positive PPGL tumour cells persist in culture for long periods but show little evidence of proliferation. Synaptophysin was the most consistent cell marker for chromaffin cells and GFAP the best marker for sustentacular cells in human PPGL cultures.

Fully Automated 3D Vestibular Schwannoma Segmentation with and without Gadolinium-based Contrast Material: A Multicenter, Multivendor Study.

Purpose: To develop automated vestibular schwannoma measurements on contrast-enhanced T1- and T2-weighted MRI scans. Materials and Methods: MRI data from 214 patients in 37 different centers were retrospectively analyzed between 2020 and 2021. Patients with hearing loss (134 positive for vestibular schwannoma [mean age ± SD, 54 years ± 12;64 men] and 80 negative for vestibular schwannoma) were randomly assigned to a training and validation set and to an independent test set. A convolutional neural network (CNN) was trained using fivefold cross-validation for two models (T1 and T2). Quantitative analysis, including Dice index, Hausdorff distance, surface-to-surface distance (S2S), and relative volume error, was used to compare the computer and the human delineations. An observer study was performed in which two experienced physicians evaluated both delineations. Results: The T1-weighted model showed state-of-the-art performance, with a mean S2S distance of less than 0.6 mm for the whole tumor and the intrameatal and extrameatal tumor parts. The whole tumor Dice index and Hausdorff distance were 0.92 and 2.1 mm in the independent test set, respectively. T2-weighted images had a mean S2S distance less than 0.6 mm for the whole tumor and the intrameatal and extrameatal tumor parts. The whole tumor Dice index and Hausdorff distance were 0.87 and 1.5 mm in the independent test set. The observer study indicated that the tool was similar to human delineations in 85%-92% of cases. Conclusion: The CNN model detected and delineated vestibular schwannomas accurately on contrast-enhanced T1- and T2-weighted MRI scans and distinguished the clinically relevant difference between intrameatal and extrameatal tumor parts.Keywords: MRI, Ear, Nose, and Throat, Skull Base, Segmentation, Convolutional Neural Network (CNN), Deep Learning Algorithms, Machine Learning Algorithms Supplemental material is available for this article. © RSNA, 2022.

Evaluation of subclasses for T4-classified squamous cell carcinoma of the external auditory canal.

BACKGROUND: T4-classified squamous cell carcinoma (SCC) of external auditory canal (EAC) can potentially involve different anatomical structures, which could translate into different treatment strategies and survival outcomes within one classification. Our aim is to evaluate the clinical added value of T4-subclasses proposed by Lavieille and by Zanoletti. METHODS: Retrospective data, including patients with primary operated cT4-classified EAC SCC, was obtained from 12 international hospitals. We subclassified according to the T4-subclasses. The treatment strategies, disease-free survival (DFS) and overall survival per subclass were calculated. RESULTS: A total of 130 T4-classified EAC SCC were included. We found commonly used treatment strategies per subclass according to Lavieille and the DFS seems also to differ per subclass. Subclass according to Zanoletti showed comparable treatment strategies and survival outcomes per subclass. CONCLUSION: Our study suggests that the subclass according Lavieille might have added value in clinical practice to improve care of T4-classified EAC SCC.

A prediction model for recurrence after translabyrinthine surgery for vestibular schwannoma: toward personalized postoperative surveillance.

PURPOSE: The aim of this study is to compute and validate a statistical predictive model for the risk of recurrence, defined as regrowth of tumor necessitating salvage treatment, after translabyrinthine removal of vestibular schwannomas to individualize postoperative surveillance. METHODS: The multivariable predictive model for risk of recurrence was based on retrospectively collected patient data between 1995 and 2017 at a tertiary referral center. To assess for internal validity of the prediction model tenfold cross-validation was performed. A 'low' calculated risk of recurrence in this study was set at < 1%, based on clinical criteria and expert opinion. RESULTS: A total of 596 patients with 33 recurrences (5.5%) were included for analysis. The final prediction model consisted of the predictors 'age at time of surgery', 'preoperative tumor growth' and 'first postoperative MRI outcome'. The area under the receiver operating curve of the prediction model was 89%, with a C-index of 0.686 (95% CI 0.614-0.796) after cross-validation. The predicted probability for risk of recurrence was low (< 1%) in 373 patients (63%). The earliest recurrence in these low-risk patients was detected at 46 months after surgery. CONCLUSION: This study presents a well-performing prediction model for the risk of recurrence after translabyrinthine surgery for vestibular schwannoma. The prediction model can be used to tailor the postoperative surveillance to the estimated risk of recurrence of individual patients. It seems that especially in patients with an estimated low risk of recurrence, the interval between the first and second postoperative MRI can be safely prolonged.

Multidimensional assessment of voice quality after injection augmentation of the vocal fold with autologous adipose tissue or calcium hydroxylapatite.

PURPOSE: The purpose of this study was to evaluate short- and long-term outcome of injection augmentation with autologous adipose tissue (AAT) and calcium hydroxylapatite injection (CAHA) in patients with a unilateral vocal fold paralysis (UVFP). DESIGN/METHODS: A retrospective cohort study was performed in patients diagnosed with UVFP, who had received injection augmentation with AAT or CAHA. Multidimensional voice analysis was performed before, 3 and 12 months after injection. This analysis included patient self-assessment (Voice Handicap Index-30), perceptual (overall dysphonia grade according to the GRBAS scale), aerodynamic (MPT, s/z ratio) and acoustic (fundamental frequency, dynamic range) parameters. Effects were assessed using a linear mixed model analysis. RESULTS: Forty-six patients were available for evaluation, with a total of 53 injection augmentations (AAT n = 39; CAHA n = 14). We found significant improvement of patient self-assessment and perceptive voice outcome at 3 months, which were maintained at 12 months. In the CAHA group, s/z ratio and dynamic range of extreme frequencies also improved significantly over time. No statistically significant differences were found between the two treatments (AAT vs. CAHA). No major complications were reported. CONCLUSION: This study, using a guide-line recommended panel of outcome parameters, shows a high success rate of injection augmentation with AAT or CAHA for patients with UVFP at 12 months with significant improvement in most voice outcome parameters, although voices do not completely normalize. There is no significant difference in outcome between the two materials.

Long-term voice outcomes of laryngeal framework surgery for unilateral vocal fold paralysis.

OBJECTIVE: To evaluate the short- and long-term voice outcomes after unilateral medialization thyroplasty (MT) and unilateral medialization thyroplasty with arytenoid adduction (MT + AA) in patients with unilateral vocal fold paralysis. METHODS: Voice outcomes were assessed preoperatively, and postoperatively at 3 and 12 months according to a standardized protocol. Voice assessment was performed using Voice Handicap Index (VHI), GRBAS Grade, Maximum Phonation Time (MPT), s/z-ratio and subjective numeric rating scales on voice quality, effort, performance and influence on life. RESULTS: Sixty-one patients were included (34 MT and 27 MT + AA). Significant pre- to postoperative improvements were seen in all voice outcome parameters. No significant differences in post-operative values were identified between the groups. CONCLUSION: Based on our findings, we conclude that patients with unilateral vocal fold paralysis who undergo MT and MT + AA achieve comparable and significant long time voice improvement, although voices do not completely normalize. We also conclude that this does not mean that AA is a superfluous procedure, but can indicate the accurate identification of patients in need of the additional AA procedure based on clinical parameters.

Prognostic Factors for the Outcome of Translabyrinthine Surgery for Vestibular Schwannomas.

OBJECTIVE: To identify predictors of tumor recurrence and postoperative facial nerve function after translabyrinthine surgery for unilateral vestibular schwannomas. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center. PATIENTS: Between 1996 and 2017 a total of 596 patients with unilateral vestibular schwannoma underwent translabyrinthine surgery. Pre- and postoperative clinical status, radiological, and surgical findings were evaluated. INTERVENTIONS: Translabyrinthine surgery. MAIN OUTCOME MEASURES: Potential predictors for tumor recurrence and facial nerve outcome were analyzed using Cox regression and ordinal logistic regression, respectively. RESULTS: The extent of tumor removal was total in 32%, near-total in 58%, and subtotal in 10%. In 5.5% (33/596) of patients the tumor recurred. Subtotal tumor resection (p = 0.004, hazard ratios [HR] = 10.66), a young age (p = 0.008, HR = 0.96), and tumor progression preoperatively (p = 0.042, HR = 2.32) significantly increased the risk of recurrence, whereas tumor size or histologic composition did not. A good postoperative facial nerve function (House-Brackmann grade 1-2) was achieved in 85%. The risk of postoperative facial nerve paresis or paralysis increased with tumor size (p < 0.001, OR = 1.52), but was not associated with the extent of tumor removal, histologic composition, or patient demographics. CONCLUSIONS: Translabyrinthine surgery is an effective treatment for vestibular schwannoma, with a good local control rate and facial nerve outcome. The extent of tumor removal is a clinically relevant predictor for tumor recurrence, as are young patient age and preoperative tumor progression. A large preoperative tumor size is associated with a higher risk of postoperative facial nerve paresis or paralysis.

Germline DLST Variants Promote Epigenetic Modifications in Pheochromocytoma-Paraganglioma.

CONTEXT: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors in which altered central metabolism appears to be a major driver of tumorigenesis, and many PPGL genes encode proteins involved in the tricarboxylic acid (TCA) cycle. OBJECTIVE/DESIGN: While about 40% of PPGL cases carry a variant in a known gene, many cases remain unexplained. In patients with unexplained PPGL showing clear evidence of a familial burden or multiple tumors, we aimed to identify causative factors using genetic analysis of patient DNA and functional analyses of identified DNA variants in patient tumor material and engineered cell lines. PATIENTS AND SETTING: Patients with a likely familial cancer burden of pheochromocytomas and/or paragangliomas and under investigation in a clinical genetic and clinical research setting in university hospitals. RESULTS: While investigating unexplained PPGL cases, we identified a novel variant, c.1151C>T, p.(Pro384Leu), in exon 14 of the gene encoding dihydrolipoamide S-succinyltransferase (DLST), a component of the multi-enzyme complex 2-oxoglutarate dehydrogenase. Targeted sequence analysis of further unexplained cases identified a patient carrying a tumor with compound heterozygous variants in DLST, consisting of a germline variant, c.1121G>A, p.(Gly374Glu), together with a somatic missense variant identified in tumor DNA, c.1147A>G, p.(Thr383Ala), both located in exon 14. Using a range of in silico and functional assays we show that these variants are predicted to be pathogenic, profoundly impact enzyme activity, and result in DNA hypermethylation. CONCLUSIONS: The identification and functional analysis of these DLST variants further validates DLST as an additional PPGL gene involved in the TCA cycle.

Evaluation of the modified Pittsburgh classification for predicting the disease-free survival outcome of squamous cell carcinoma of the external auditory canal.

BACKGROUND: Squamous cell carcinoma (SCC) of the external auditory canal (EAC) is a rare disease, which is commonly classified with the modified Pittsburgh classification. Our aim was to evaluate the predictive performance of this classification in relation to disease-free survival (DFS). METHODS: We examined retrospective data from a nationwide Dutch cohort study including patients with primary EAC SCC. These data were combined with individual patient data from the literature. Using the combined data, the predictive performances were calculated using the c-index. RESULTS: A total of 381 patients were included, 294 for clinical and 281 for the pathological classification analyses. The c-indices of the clinical and the pathological modified Pittsburgh classification predicting DFS were 0.725 (0.668-0.782) and 0.729 (0.672-0.786), respectively. CONCLUSION: The predictive performance of the modified Pittsburgh classification system as such appears to be acceptable to predict the DFS of EAC SCC. Other factors need to be added to a future model to improve the predicted performance.