Conductive Hearing Loss with Present Acoustic Reflex: A Case Report

Acoustic reflex is a sensitive indicator of middle ear lesions when the tympanic membrane is in-tact and tympanometry is normal. Acoustic reflex is not usually observed in conductive hearing loss caused by disruption of the ossicular chain including ossicular discontinuity and fixation. Ossicular disruption can show at least partially intact acoustic reflex under a certain condition. Moreover, ossicular discontinuity with a nearly intact acoustic reflex is quite rare and there have been few reports published to date. We here present a rare case of conductive hearing loss with a nearly intact acoustic reflex, and the patient was surgically confirmed to have ossicular discontinuity.

Frequent Copy Gain of the <i>MET</i>Gene in Hypopharyngeal and Laryngeal Cancer in the Japanese Population

Molecular targeting therapy to specific genetic alterations has not been established in head and neck squamous cell carcinoma (HNSCC) except for cetuximab treatment. To characterize alterations of actionable oncogenes in HNSCC, we examined the gain of copy and mutation of the MET gene in 54 Japanese HNSCC. Copy gain of the MET was analyzed by droplet digital PCR (ddPCR) and quantitative real time PCR (qPCR) using 2 distinct fragments of the gene, and mutation was examined in exons 14 - 19 of MET by Sanger sequencing. Both ddPCR and qPCR showed significantly correlated results in copy number at two distinct fragments of the MET gene (R = 0.96 and R = 0.78), although ddPCR gave more significant and sensitive results. Copy gain of the MET was detected in 10 of 54 (19%) HNSCCs and more frequently observed in tumors of the hypopharynx (4 of 12;33%) or larynx (5 of 13;38%) than those of the oral cavity (1 of 21;4%) or oropharynx (0 of 8;0%), suggesting the existence of site-specific features in the oncogenic mechanisms of HNSCCs. Copy gain of the MET was also observed preferentially in older patients, although no correlation in other parameters, including clinical stages and overall or recurrence-free survival, was observed. On the other hand, of the two HNSCCs in which nucleotide substitution was detected, one was R1040Q in exon 15 with unknown function, and the other was a silent mutation in exon16. These results suggest that copy gain of the MET can provide an indicator for treatment with tyrosine kinase inhibitors for MET in a subset of hypopharyngeal or laryngeal cancer.

High Incidence of Null-Type Mutations of the <i>TP</i>53 Gene in Japanese Patients with Head and Neck Squamous Cell Carcinoma

Objective: Molecular targeting therapy has not been generally established in head and neck squamous cell carcinoma (HNSCC) except for cetuximab treatment for targeting epidermal growth factor receptor (EGFR). We analyzed alterations of the TP53, KRAS2, and EGFR genes in Japanese HNSCC to identify subpopulations of tumors potentially susceptible or not susceptible to specific therapy based on their genetic alterations. Materials and Methods: A total of 56 Japanese subjects were included in this study. Genomic DNA of exons 5 - 9 of the TP53, exons 1 and 2 of the KRAS2, exons 19 - 22 of the EGFR, and their flanking sequences were amplified by polymerase chain reaction (PCR) followed by direct sequencing. Splicing variants of EGFR were examined by reverse transcription (RT)-PCR. Results: Mutations of the TP53 and KRAS genes were detected in 25 (45%) and 2 (4%) of 56 HNSCC cases, respectively, while neither mutation nor splicing variant of EGFR was observed. The TP53 mutation did not correlate with clinical stages or primary sites of the tumors. The patterns of nucleotide substitutions specific to HNSCC were not observed. However, the incidence of null-type mutations of the TP53, which cannot be detected as abnormal by conventional immunohistochemical (IHC) studies, was significantly higher (10/25;40%) than that of HNSCC reported in other countries. Conclusion: Frequent TP53 mutations, especially null-type mutations, but infrequent or no alterations of the KRAS and EGFR suggest that the sequencing analysis of theTP53 mutation rather than IHC analysis of p53 provides a potentially useful marker to predict the response of HNSCC to chemotherapy or radiotherapy.