Combined genetic polymorphisms of the GSTT1 and NRF2 genes increase susceptibility to cisplatin-induced ototoxicity: A preliminary study.

OBJECTIVE: The genotype-phenotype relationship in cisplatin-induced ototoxicity remains unclear. By assessing early shifts in distortion product otoacoustic emission (DPOAE) levels after initial cisplatin administration, we aimed to discriminate patients' susceptibility to cisplatin-induced ototoxicity and elucidate their genetic background. STUDY DESIGN: A prospective cross-sectional study. SETTING: Tertiary referral hospital in Japan. PATIENTS: Twenty-six patients with head and neck cancer were undergoing chemoradiotherapy with three cycles of 100 mg/m2 cisplatin. INTERVENTIONS: Repetitive pure-tone audiometry and DPOAE measurements, and blood sampling for DNA extraction were performed. Patients were grouped into early ototoxicity presence or absence based on whether DPOAE level shifts exceeded the corresponding reference limits of the 21-day test interval. MAIN OUTCOME MEASURES: Hearing thresholds after each cisplatin cycle, severity of other adverse events, and polymorphisms in cisplatin-induced ototoxicity-associated genes were compared. RESULTS: Early ototoxicity was present in 14 and absent in 12 patients. Ototoxicity presence on DPOAEs was associated with greater progression of hearing loss in frequencies ≥2 kHz throughout therapy and with higher ototoxicity grades compared with ototoxicity absence. Ototoxicity was further associated with grade ≥2 nausea. Ototoxicity presence was genetically associated with the GSTT1 null genotype and G-allele of NFE2L2 rs6721961, whereas ototoxicity absence was associated with the GSTM1 null genotype. Dose-dependent progression of hearing loss was the greatest in the combined genotype pattern of GSTT1 null and the T/G or G/G variants of rs6721961. CONCLUSION: Early DPOAE changes reflected genetic vulnerability to cisplatin-induced ototoxicity. Hereditary insufficiency of the antioxidant defense system causes severe cisplatin-induced hearing loss and nausea.

Management of the temporal bone defect after resection of external auditory canal cancer.

OBJECTIVE: To evaluate the surgical procedures used to treat external auditory canal cancer with respect to avoiding postoperative infection of the temporal bone defect. METHODS: Enrolled in the study were 52 patients with external auditory canal cancer surgically treated between July 2015 and October 2020 (38 lateral temporal bone resections, 12 subtotal temporal bone resections and 2 partial resections, accompanied by various combined procedures). Retrospective chart review was conducted taking into consideration postoperative infection, and univariate analysis of prognostic factors was performed. RESULTS: In cases managed with subtotal temporal bone resection, no postoperative infections occurred. Cases managed with subtotal temporal bone resection demonstrated increased use of free-flap reconstruction, and longer antibiotic infusion period. On the other hand, analysis of cases managed with lateral temporal bone resection revealed 10 out of 38 patients with postoperative infection (26.3%). However, we couldn't find out any factors that contributed significantly to the prevention of postoperative infection, including the surgical procedures used to manage the defected space, which included free-flap implantation, obliteration with fat tissue, muscular flap rotation, and leaving the space empty without obliteration or reconstruction. CONCLUSION: In cases managed with lateral temporal bone resection, leaving the resected space empty did not increase the risk of infection. On the other hand, in cases with subtotal temporal bone resection, filling the surgical defect with an autologous bulk, including the free-flap reconstruction and fat obliteration, seems to prevent the infection. Moreover, prolonged antibiotic infusion may suppress postoperative infection of the temporal bone defect.