Cochlear-optimized treatment planning in photon and proton radiosurgery for vestibular schwannoma patients.

Objective: To investigate the potential to reduce the cochlear dose with robotic photon radiosurgery or intensity-modulated proton therapy planning for vestibular schwannomas. Materials and Methods: Clinically delivered photon radiosurgery treatment plans were compared to five cochlear-optimized plans: one photon and four proton plans (total of 120). A 1x12 Gy dose was prescribed. Photon plans were generated with Precision (Cyberknife, Accuray) with no PTV margin for set-up errors. Proton plans were generated using an in-house automated multi-criterial planning system with three or nine-beam arrangements, and applying 0 or 3 mm robustness for set-up errors during plan optimization and evaluation (and 3 % range robustness). The sample size was calculated based on a reduction of cochlear Dmean > 1.5 Gy(RBE) from the clinical plans, and resulted in 24 patients. Results: Compared to the clinical photon plans, a reduction of cochlear Dmean > 1.5 Gy(RBE) could be achieved in 11/24 cochlear-optimized photon plans, 4/24 and 6/24 cochlear-optimized proton plans without set-up robustness for three and nine-beam arrangement, respectively, and in 0/24 proton plans with set-up robustness. The cochlea could best be spared in cases with a distance between tumor and cochlea. Using nine proton beams resulted in a reduced dose to most organs at risk. Conclusion: Cochlear dose reduction is possible in vestibular schwannoma radiosurgery while maintaining tumor coverage, especially when the tumor is not adjacent to the cochlea. With current set-up robustness, proton therapy is capable of providing lower dose to organs at risk located distant to the tumor, but not for organs adjacent to it. Consequently, photon plans provided better cochlear sparing than proton plans.

A retrospective analysis of hearing after cholesteatoma surgery: the bony obliteration tympanoplasty versus canal wall up and canal wall down without mastoid obliteration.

OBJECTIVE: To evaluate and compare the hearing outcome after the bony obliteration tympanoplasty (BOT), canal wall up (CWU) without mastoid obliteration and canal wall down (CWD) without mastoid obliteration in a large patient cohort. As the aeration of the middle ear is associated with hearing outcome, we hypothesized that the post-operative hearing after the BOT may be better compared to CWU and CWD without obliteration. METHODS: This is a retrospective cohort study on all adult patients who underwent the BOT, CWU without obliteration or CWD without obliteration for primary or revision cholesteatoma between January 2003 and March 2019 with audiological follow-up at our institution. Pre-operative, short-term post-operative and long-term post-operative hearing tests were analyzed and potential factors influencing post-operative hearing were assessed. RESULTS: 626 ears were included. We found no significant differences between the short-term and long-term post-operative audiometry. The pre-operative air-bone gap (ABG) was the factor with the largest effect size on change in air-bone gap (ABG) between pre- and post-operative. When stratifying for this factor along with the type of ossicular chain reconstruction to account for differences at baseline, no significant differences in post-operative ABG were found between BOT and non-obliteration CWU and CWD. CONCLUSION: In this large retrospective cohort study, we found no significant differences in post-operative ABG between the BOT and the non-obliteration CWU and CWD. A solid comparison of hearing between groups remains very challenging as hearing outcome seems to be dependent on many different factors. Hearing outcome seems to be no additional argument to choose for BOT over non-obliteration surgery.

Revision surgery for chronically discharging mastoid cavities: mastoid obliteration with canal wall reconstruction versus non-obliteration surgery.

PURPOSE: To evaluate the surgical results of revision canal wall down (CWD) surgery for chronically discharging mastoid cavities and to compare the non-obliteration approach to mastoid obliteration with canal wall reconstruction. METHODS: This is a retrospective cohort study. All adult patients (≥ 18 years) who underwent revision surgery for chronically draining mastoid cavities between January 2013 and January 2020 were included. Primary outcome measures included the dry ear rate, complications and postoperative hearing. RESULTS: 79 ears were included; 56 ears received revision CWD with mastoid obliteration and posterior canal wall reconstruction and 23 ears received CWD without mastoid obliteration. The dry ear rate at the most recent outpatient clinic visit (median 28.0 months postoperative) was significantly higher in the obliteration group with 96.4% compared to 73.9% for the non-obliteration group (p = .002). There were no differences in audiological outcome and incidence of complications between the two techniques. CONCLUSION: We show that in our study population revision CWD surgery with mastoid obliteration and posterior canal wall reconstruction is superior to revision CWD surgery without mastoid obliteration in the management of chronically discharging mastoid cavities. In the obliteration group, a dry ear was achieved in 96.4% as this was 73.9% in the non-obliteration group. We found no differences in audiological outcome and in incidence of complications between the two techniques.

Treatment Outcome of the Bony Obliteration Tympanoplasty Versus Nonobliterative Techniques in Cholesteatoma Surgery: A Retrospective Analysis.

OBJECTIVE: In cholesteatoma surgery, obliteration of the mastoid and epitympanic space (bony obliteration tympanoplasty, BOT) is an increasingly used technique with low recurrent and residual cholesteatoma rates. While factors as the postoperative hearing level and infection rate are important for the patient as well, these outcome parameters are not frequently reported on in current literature. The objective of this study is to evaluate the recurrent and residual cholesteatoma rates of the BOT technique and nonobliterative canal wall up (CWU) and canal wall down (CWD) mastoidectomy in a large patient cohort. Secondary objectives were to evaluate the infection rate and hearing outcome for all three techniques. DESIGN: Retrospective cohort study. SETTING: Single-center study. PATIENTS: All 337 adult patients (≥18 yrs) who underwent primary or revision cholesteatoma surgery between January 2013 and March 2019 were included. MAIN OUTCOME AND MEASURES: Recurrent cholesteatoma rates, residual cholesteatoma rates, postoperative infections and other complications, hearing outcome. RESULTS: The estimated combined rate of recurrent and residual cholesteatoma at 5 years follow-up was 7.6% in the BOT group, 34.9% in the CWU group, and 17.9% in the CWD group. The postoperative infection rate in the different groups ranged from 4.3% to 4.9%. The median gain in AC threshold level varied from 0.0 dB in the BOT and CWD group to 3.8 dB in the CWU group. CONCLUSIONS: We show that cholesteatoma recurrence rates after the BOT technique in our clinic are significantly lower compared to CWU surgery. There were no differences in infection rate and no clinically relevant differences in postoperative hearing between the BOT, CWU, and CWD technique.

Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE.

OBJECTIVES: Inoperable or metastatic paragangliomas (PGLs) and malignant pheochromocytomas (PCCs) are rare tumours with limited options for systemic treatment. Aim of this study was to assess the safety and efficacy of the radiolabelled somatostatin analogue (177LutetiumDOTA0-Tyr3)octreotate (177Lu-DOTATATE) for the treatment of PGLs and PCCs. METHODS: Patients with histologically proven inoperable or malignant PGLs and PCCs treated with 177Lu-DOTATATE at our centre were retrospectively analysed. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gb per cycle. Response was assessed with use of RECIST 1.1. RESULTS: Thirty patients were included: 17 with parasympathetic, 10 with sympathetic PGLs and 3 with PCCs. Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. A reversible subacute adverse event due to cardiac failure following possible catecholamine release occurred in two patients. Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%), whereas 3 (10%) patients had progressive disease. In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs. CONCLUSION: This study suggests that PRRT with 177Lu-DOTATATE is a safe and effective treatment option for patients with inoperable or malignant PGL and PCC.

Hearing Loss Progresses Faster in Patients With Growing Intracanalicular Vestibular Schwannomas.

OBJECTIVE: To determine whether certain patient and tumor characteristics influence the progression of hearing loss in vestibular schwannoma (VS) patients. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center, Erasmus Medical Centre in Rotterdam, The Netherlands. PATIENTS: One hundred fifty-five patients referred from 2000 through 2010 with intracanalicular, small or medium sized, unilateral VS, managed without active treatment. INTERVENTION: Wait and scan protocol with sequential magnetic resonance imaging and audiometry. MAIN OUTCOME MEASURES: Hearing loss as pure-tone average (PTA) in dB and progression of hearing loss expressed as the annual change in PTA or annual hearing decreasing rate (AHDR) in dB/yr. RESULTS: At presentation the mean hearing loss was 47 dB and the mean asymmetry between the tumor ear and the contralateral ear was 28 dB. The mean AHDR in wait and scan patients was 3.5 dB/yr (sd 4.6). Tumor growth was associated with the AHDR in patients with intracanalicular tumors. In patients with tumors extending into the cerebellopontine angle, we found a negative association between the AHDR and the PTA of the contralateral side. The explained variance, however, was low. No association was found between the AHDR and patient age, PTA in the tumor ear, tumor size, speech discrimination score at diagnosis or hypo-intensity of the cochlear fluids on magnetic resonance imaging. CONCLUSION: There is no association between hearing deterioration and clinical characteristics in our 155 VS patients. Hearing loss is associated with tumor growth in intracanalicular tumors only.

What intervention is best practice for vestibular schwannomas? A systematic review of controlled studies.

OBJECTIVE: Largely, watchful waiting is the initial policy for patients with small-sized or medium-sized vestibular schwannoma, because of slow growth and relatively minor complaints, that do not improve by an intervention. If intervention (microsurgery, radiosurgery or fractionated radiotherapy) becomes necessary, the choice of intervention appears to be driven by the patient's or clinician's preference rather than by evidence based. This study addresses the existing evidence based on controlled studies of these interventions. DESIGN: A systematic Boolean search was performed focused on controlled intervention studies. The quality of the retrieved studies was assessed based on the Sign-50 criteria on cohort studies. DATA SOURCES: Pubmed/Medline, Embase, Cochrane Central Register of Controlled Trials and reference lists. STUDY SELECTION: Six eligibility criteria included a controlled intervention study on a newly diagnosed solitary, vestibular schwannoma reporting on clinical outcomes. Two prospective and four retrospective observational, controlled studies published before November 2011 were selected. DATA ANALYSIS: Two reviewers independently assessed the methodological quality of the studies and extracted the outcome data using predefined formats. RESULTS: Neither randomised studies, nor controlled studies on fractionated radiotherapy were retrieved. Six studies compared radiosurgery and microsurgery in a controlled way. All but one were confined to solitary tumours less than 30 mm in diameter and had no earlier interventions. Four studies qualified for trustworthy conclusions. Among all four, radiosurgery showed the best outcomes: there were no direct mortality, no surgical or anaesthesiological complications, but better facial nerve outcome, better preservation of useful hearing and better quality of life. CONCLUSIONS: The available evidence indicates radiosurgery to be the best practice for solitary vestibular schwannomas up to 30 mm in cisternal diameter.

An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis.

BACKGROUND: Phaeochromocytomas and paragangliomas are neuro-endocrine tumours that occur sporadically and in several hereditary tumour syndromes, including the phaeochromocytoma-paraganglioma syndrome. This syndrome is caused by germline mutations in succinate dehydrogenase B (SDHB), C (SDHC), or D (SDHD) genes. Clinically, the phaeochromocytoma-paraganglioma syndrome is often unrecognised, although 10-30% of apparently sporadic phaeochromocytomas and paragangliomas harbour germline SDH-gene mutations. Despite these figures, the screening of phaeochromocytomas and paragangliomas for mutations in the SDH genes to detect phaeochromocytoma-paraganglioma syndrome is rarely done because of time and financial constraints. We investigated whether SDHB immunohistochemistry could effectively discriminate between SDH-related and non-SDH-related phaeochromocytomas and paragangliomas in large retrospective and prospective tumour series. METHODS: Immunohistochemistry for SDHB was done on 220 tumours. Two retrospective series of 175 phaeochromocytomas and paragangliomas with known germline mutation status for phaeochromocytoma-susceptibility or paraganglioma-susceptibility genes were investigated. Additionally, a prospective series of 45 phaeochromocytomas and paragangliomas was investigated for SDHB immunostaining followed by SDHB, SDHC, and SDHD mutation testing. FINDINGS: SDHB protein expression was absent in all 102 phaeochromocytomas and paragangliomas with an SDHB, SDHC, or SDHD mutation, but was present in all 65 paraganglionic tumours related to multiple endocrine neoplasia type 2, von Hippel-Lindau disease, and neurofibromatosis type 1. 47 (89%) of the 53 phaeochromocytomas and paragangliomas with no syndromic germline mutation showed SDHB expression. The sensitivity and specificity of the SDHB immunohistochemistry to detect the presence of an SDH mutation in the prospective series were 100% (95% CI 87-100) and 84% (60-97), respectively. INTERPRETATION: Phaeochromocytoma-paraganglioma syndrome can be diagnosed reliably by an immunohistochemical procedure. SDHB, SDHC, and SDHD germline mutation testing is indicated only in patients with SDHB-negative tumours. SDHB immunohistochemistry on phaeochromocytomas and paragangliomas could improve the diagnosis of phaeochromocytoma-paraganglioma syndrome. FUNDING: The Netherlands Organisation for Scientific Research, Dutch Cancer Society, Vanderes Foundation, Association pour la Recherche contre le Cancer, Institut National de la Santé et de la Recherche Médicale, and a PHRC grant COMETE 3 for the COMETE network.