Sensorineural Hearing Loss After Adoptive Cell Immunotherapy for Melanoma Using MART-1 Specific T Cells: A Case Report and Its Pathophysiology.

OBJECTIVE: To illustrate a case of sensorineural hearing loss (SNHL) after immunotherapy based on T cell receptor (TCR) gene therapy using modified T cells recognizing melanoma antigen recognized by T cells 1 for disseminated melanoma. PATIENT: We present a 59-year-old woman with profound subacute bilateral SNHL including unilateral deafness after immunotherapy based on TCR gene therapy using modified T cells recognizing melanoma antigen recognized by T cells 1 for disseminated melanoma. Ten days after treatment, the patient developed hearing loss of 57 dB hearing loss air conduction at pure-tone average 0.5-1-2-4 kHz in the right ear, and >100 dB hearing loss air conduction at pure-tone average 0.5-1-2-4 in the left ear. The right ear recovered partially, while the left ear remained deaf, despite oral prednisolone (1.0 mg/kg) and salvage treatment with three transtympanic injections of 0.5 ml dexamethasone (4.0 mg/ml). CONCLUSION: Based on our presented case and a vast amount of literature there is circumstantial evidence that TCR gene therapy for melanoma targets the perivascular macrophage-like melanocytes in the stria vascularis, resulting in SNHL. We suggest that SNHL after TCR gene therapy may be caused by a disruption of the blood-labyrinth-barrier and the endolymphatic potential and/or a sterile inflammation of the stria vascularis. In severe cases like our subject, we posit that endolymphatic hydrops or hair cell loss may cause irreversible and asymmetrical deafness. Steroid prophylaxis via transtympanic application is debatable.

A unique anomaly of the ear: Oculo-auriculo-vertebral spectrum or an isolated disruption?

We present a rare case of a neonate with an isolated congenital condition of his right ear involving the outer ear, middle ear, eustachian tube, and the facial nerve, with an external opening into the skull that connects to the oropharynx. Taking this bizarre aspect of the exterior lesion and the oropharyngeal communication into account, we consider the condition presented here, which to our knowledge is the first of its kind to have resulted from a vascular disruption. Laryngoscope, 1927-1931, 2018.

Prediction of Hearing Loss Due to Cisplatin Chemoradiotherapy.

IMPORTANCE: Patients with head and neck cancer may experience chemoradiotherapy-induced hearing loss, but the weighing of involved variables has been subjective. Identification of patient and treatment characteristics to predict the absolute posttreatment hearing level is important for effective counseling of patients undergoing chemoradiotherapy. OBJECTIVE: To predict treatment-induced hearing loss among patients with head and neck cancer. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was performed at The Netherlands Cancer Institute. One hundred and fifty-six patients with head and neck cancer treated with concomitant chemoradiotherapy as the primary treatment modality from January 1, 1997, through December 31, 2011, were enrolled. Follow-up was complete on March 1, 2012, and data were analyzed from April 1, 2011, through November 5, 2013. INTERVENTIONS: High-dose intravenously administered cisplatin-based concomitant chemoradiotherapy. Cisplatin, 100 mg/m2, was administered in 3 courses on days 1, 22, and 43 during 7 weeks of radiotherapy (total radiation dose, 70 Gy in 35 fractions). MAIN OUTCOMES AND MEASURES: Posttreatment bone conduction hearing threshold at pure-tone average frequencies of 1, 2, and 4 kHz, based on pure-tone audiometry after completion of treatment. Predictors included baseline hearing levels, radiation dose to the cochlea, and cisplatin dose. A multilevel mixed-effects linear regression model for predicting whether or not posttreatment hearing was at least 35 dB was established, and cross-validated sensitivity and specificity were obtained. RESULTS: Of 156 patients who received high-dose concomitant chemoradiotherapy, 15 were missing the exact radiation dose to the cochlea and 41 had no data on posttreatment pure-tone audiometry. Nineteen patients had a hearing level of at least 35 dB for at least 1 ear before the treatment. The remaining 81 patients (162 ears) had a total cumulative cisplatin dose ranging from 315 to 600 (median, 546) mg. The radiation dose to the cochlea ranged from 1.1 to 70.9 (median, 13.6) Gy. Based on data from the 81 patients (162 ears), the area under the receiver operating characteristic curve was 0.68, with a sensitivity of 29% (95% CI, 13%-51%) and a specificity of 97% (95% CI, 88%-100%), resulting in a positive predictive value of 78%. CONCLUSIONS AND RELEVANCE: Patient and treatment characteristics can be used to predict hearing level after concomitant chemoradiotherapy for head and neck cancer. This step may constitute the first in evidence-based individual counseling for treatment-induced hearing loss.

Sensorineural hearing loss in patients with head and neck cancer after chemoradiotherapy and radiotherapy: a systematic review of the literature.

BACKGROUND: Both radiotherapy (RT) and cisplatin-based chemoradiotherapy (CRT) in patients with head and neck cancer may cause sensorineural hearing loss (SNHL). The purpose of this review was to provide more insight into SNHL because of CRT compared to RT. METHODS: Comprehensive search of Medline and Embase with the terms "radiotherapy" combined with "ototoxicity," "head and neck squamous cell carcinoma," and synonyms. RESULTS: Of the 2507 studies found, 21 were included in this study. Pooled analysis could not be committed because of heterogeneity. Incidence rates of SNHL after RT and CRT varied considerably, with percentages ranging from 0% to 43% and 17% to 88%, respectively. Factors that influenced the risk of SNHL were radiation dose to the cochlea, follow-up time, age, baseline hearing level, and cisplatin dose. CONCLUSION: The wide range of SNHL incidence rates makes it impossible to draw any conclusions on the severity of RT- and CRT-induced ototoxicity. To allow for future comparison of study outcomes, development of uniform criteria is of utmost importance.

Cochlea sparing effects of intensity modulated radiation therapy in head and neck cancers patients: a long-term follow-up study.

BACKGROUND: Radiation to the inner ear may lead to (irreversible) sensorineural hearing loss. The purpose of this study was to evaluate the long-term effect of radiotherapy on hearing in patients treated with Intensity Modulated Radiation Therapy (IMRT), sparing the inner ear from high radiation dose as much as possible. METHODS: Between 2003 and 2006, 101 patients with head and neck cancer were treated with IMRT. Audiometry was performed before, short-term, and long-term after treatment. Data were compared to normal hearing levels according to the International Organisation for Standardization (ISO). Statistical analysis was done using repeated measurements. None of the patients received chemotherapy. RESULTS: In 36 patients an audiogram at long-term follow-up (median 7.6 years) was available. The mean dose to the cochlea was 17.8 Gy (1.0-66.6 Gy). A hearing deterioration of 1.8 dB at Pure Tone Average (PTA) 0.5-1-2 kHz (p = 0.11), 2.3 dB at PTA 1-2-4 kHz (p = 0.02), and 4.4 dB at PTA 8-10-12.5 kHz (p = 0.01) was found. According to the ISO, the expected age-related hearing loss was 2.7, 4.8, and 8.8 dB at PTA 0.5-1-2 kHz, 1-2-4 kHz, and 8-10-12.5 kHz, respectively. CONCLUSIONS: After IMRT with radiation dose constraint to the cochlea, potential long-term adverse effects of IMRT remained subclinical. The progressive hearing loss over time was mild and could be attributed to the natural effects of ageing. Therefore, we recommend that a dose constraint to the cochlea should be incorporated in the head and neck radiotherapy protocols.

Long-term hearing loss after chemoradiation in patients with head and neck cancer.

OBJECTIVES/HYPOTHESIS: The purpose of this study was to determine whether concomitant chemoradiation (CCRT)-induced hearing loss is progressive over time or not. STUDY DESIGN: Long-term (LT) follow-up study. METHODS: Between 1999 and 2004, 158 patients with head and neck cancer were treated with intravenous (IV) CCRT (n = 80) or intraarterial CCRT (n = 78). Audiometry was performed before, short-term (ST), and LT posttreatment. Differences in hearing were assessed with a multivariable linear regression analysis, incorporating the effect of aging. RESULTS: Long-term audiometry (median 4.5 years) was available in 67 patients (42%). At ST follow-up, a deterioration of 21.6 decibel was seen compared to baseline at pure-tone averages (PTA) 8-10-12.5 kHz. At LT follow-up, this deterioration further increased with 5 decibel (P = 0.005). Only in CCRT-IV patients was a significant progressive treatment-induced hearing loss seen, at PTA 8-10-12.5 kHz (P = 0.005), PTA 1-2-4 kHz air conduction (P = 0.014), and PTA 0.5-1-2 kHz bone conduction (P = 0.045). CONCLUSION: CCRT-induced hearing impairment was progressive over time, especially in higher frequencies and only in CCRT-IV patients, with a modest deterioration of 5 decibel 4.5 years post-treatment. LEVEL OF EVIDENCE: 4.

A new grading system for ototoxicity in adults.

OBJECTIVE: This study aimed to propose an ototoxicity grading system sensitive to the effect of ototoxicity on specific daily life situations like speech intelligibility and the perception of ultra-high sounds and to test its feasibility compared to current criteria. METHODS: Pure tone averages (PTAs) for speech perception (1-2-4 kHz) and ultra-high frequencies (8-10-12.5 kHz) were incorporated. Threshold shift and hearing level posttreatment were taken into account. Criteria were tested on head and neck cancer patients treated with (chemo-)radiotherapy ([C]RT) and compared with the Common Terminology Criteria for Adverse Events version 4 (CTCAEv4) and the American Speech-Language-Hearing Association criteria (ASHA). RESULTS: Grades 1 and 2 were based on threshold shifts from baseline (in dB) and subjective complaints. Grades 3 and 4 were defined as treatment-induced hearing loss of ≥ 35 dB at PTA 1-2-4 kHz and ≥ 70 dB at PTA 1-2-4 kHz, respectively. In high-dose cisplatin CRT incidences by the new criteria, CTCAEv4 and ASHA were comparable (78%-88%). In RT and low-dose cisplatin CRT, incidences were 36% to 39% in the new criteria versus 22% to 53% in CTCAEv4 and ASHA. CONCLUSION: The new criteria show an increased sensitivity to ototoxicity compared to CTCAEv4 and ASHA and provide insight into the effect of hearing loss on certain daily life situations. The new grading system seems feasible for clinic and research purposes.

Predictive factors for pharyngocutaneous fistulization after total laryngectomy.

OBJECTIVES: Postoperative complications, especially pharyngocutaneous fistulization (PCF), are more frequent after total laryngectomy (TL) performed for salvage after (chemo)radiotherapy than after primary TL. The aim of this study was to identify the incidence of PCF, predictive factors for PCF, and the relationship of PCF to survival. METHODS: We performed a retrospective chart review of 217 consecutive patients treated with TL between 2000 and 2010. Univariate and multivariable analysis with logistic regression was used to identify factors associated with PCF. We used a Kaplan-Meier survival analysis. RESULTS: The overall incidence of PCF was 26.3% (57 of 217 cases). The incidence of PCF after primary TL was 17.1% (12 of 70), that after salvage TL was 25.5% (25 of 98), that after TLE for a second primary was 37.5% (9 of 24), and that after TL for a dysfunctional larynx was 44.0% (11 of 25). The predictive factors for PCF were hypopharynx cancer (odds ratio [OR], 3.67; 95% confidence interval [CI], 1.74 to 7.71; P = .001), an albumin level of less than 40 g/L (OR, 2.20; 95% CI, 1.12 to 4.33; P = .022), previous chemoradiotherapy (OR, 3.38; 95% CI, 1.34 to 8.52; P = .010), more-extended pharyngeal resection (P = .001), and pharynx reconstruction (P = .002). The median duration of survival was 30 months (95% CI, 17.5 to 42.5); the 2-year overall survival rate was 54%. The median duration of survival of patients with PCF was 23 months (95% CI, 9.4 to 36.6), and that of those without PCF was 31 months (95% CI, 15.0 to 47.0; P = .421). The 2-year overall survival rate was 48% in patients with PCF and 57% in those without PCF (P = .290). CONCLUSIONS: Incidence of PCF after TL is significantly higher in patients with hypopharynx cancer, previous chemoradiotherapy, a low albumin level, more-extended pharyngeal resection, or pharynx reconstruction. The occurrence of PCF does not influence the rate of survival.

Total laryngectomy for a dysfunctional larynx after (chemo)radiotherapy.

OBJECTIVE: To evaluate the functional outcomes after total laryngectomy (TLE) for a dysfunctional larynx in patients with head and neck cancer that is in complete remission after (chemo)radiotherapy. DESIGN: Retrospective cohort study. SETTING: Tertiary comprehensive cancer center. PATIENTS: The study included 25 patients from a cohort of 217 consecutive patients with TLE who were treated between January 2000 and July 2010. The inclusion criteria for this subgroup analysis were complete remission and functional problems for which TLE was considered to be the only resolution. Quality of life assessment was carried out using the European Organization for Research and Treatment of Cancer Quality of Life C30 and Head and Neck Module 35 questionnaires and an additional study-specific questionnaire covering functional aspects, such as swallowing and dyspnea, in more detail. INTERVENTION: Total laryngectomy. MAIN OUTCOME MEASURES: Morbidity, mortality, and functional outcomes. RESULTS The indication for TLE was chronic aspiration with or without recurrent pneumonia (n = 15 [60%]), debilitating dyspnea (n = 8 [32%]), and persistent profuse hemorrhage (radiation ulcer) (n = 2 [8%]). After TLE, 14 of the 25 patients (56%) had 20 major postoperative complications, including 11 pharyngocutaneous fistulas, requiring additional treatment. Tube feeding and recurrent pneumonia incidence had decreased from 80% and 28% to 29% and 0%, respectively, 2 years after surgery. Prosthetic voice rehabilitation was possible in 19 patients (76%). Two years after surgery, 10 of 14 patients (71%) still reported TLE-related pulmonary problems despite the consistent use of a heat and moisture exchanger. The 5-year overall survival rate was 35%. CONCLUSIONS: Total laryngectomy for a dysfunctional larynx tends to have a high complication rate. However, in this study, the initial functional problems (aspiration, recurrent pneumonia, and dyspnea) did not recur. Tube feeding was significantly reduced, and the quality of life of the surviving patients appeared to be reasonable.