Role of follow-up gallium scintigraphy in the evaluation of malignant external otitis (skull base osteomyelitis): A case report.

Malignant otitis externa (skull base osteomyelitis) can be fatal and long-term antibiotic therapy is recommended. Despite being potentially fatal, this infection causes minor changes in inflammatory biomarkers (white blood cell count and C-reactive protein levels) upon blood testing. Computed tomography and magnetic resonance imaging changes persist over a long period. Therefore, it is difficult to determine the optimal time for the discontinuation of antibiotics. We present a 77-year-old male whose medical history included type 2 diabetes mellitus who suffered from chronic otitis media with Pseudomonas aeruginosa infection. His condition did not improve with proper treatment, and imaging revealed malignant otitis media. Intravenous cefepime treatment was administered. Antibiotic treatment was de-escalated to oral levofloxacin treatment after Gallium-67 scintigraphy showed less accumulation after 6 weeks of Cefepime administration; accumulation almost disappeared after 1 year. In this report, we describe the usefulness of gallium scintigraphy in the evaluation of malignant otitis externa.

Ricolinostat enhances adavosertib­induced mitotic catastrophe in TP53­mutated head and neck squamous cell carcinoma cells.

TP53 mutation is one of the most frequent gene mutations in head and neck squamous cell carcinoma (HNSCC) and could be a potential therapeutic target. Recently, the WEE1 G2 checkpoint kinase (WEE1) inhibitor adavosertib (Adv) has attracted attention because of its selective cytotoxicity against TP53­mutated cells and has shown promising activity in early phase clinical trials. In the present study, it was demonstrated that combined treatment with Adv and a selective histone deacetylase 6 (HDAC6) inhibitor, ricolinostat (RCS), synergistically enhanced cell death induction in four out of five HNSCC cell lines with TP53 mutation (CAL27, SAS, HSC­3, and OSC­19), one HNSCC cell line with impaired TP53 function by HPV­infection (UPCI­SCC154), and TP53­knockout human lung cancer cell line (A549 TP53­KO), but not in TP53 wild­type A549 cells. Time­lapse imaging showed that RCS enhanced the Adv­induced mitotic catastrophe. Consistent with this, RCS treatment suppressed checkpoint kinase 1 (Chk1) (Ser345) phosphorylation and co­administration of RCS with Adv suppressed cyclin­dependent kinase 1 (Tyr15) phosphorylation along with increased expression of γ­H2A.X, a marker of DNA double­strand breaks in CAL27 cells. These data showed that RCS enhanced Adv­induced premature mitotic entry and cell death induction in the mitotic phase. However, although HDAC6 knockdown enhanced Adv­induced cell death with γ­H2A.X elevation, HDAC6 knockdown did not repress Chk1 phosphorylation in CAL27 cells. Our data demonstrated that the co­administration of RCS with Adv in HNSCC cells resulted in the suppression of Chk1 activity, leading to synergistically enhanced apoptosis via mitotic catastrophe in a p53­dependent manner. This enhanced cell death appeared to be partially mediated by the inhibition of HDAC6 activity by RCS.

Induction of synergistic non-apoptotic cell death by simultaneously targeting proteasomes with bortezomib and histone deacetylase 6 with ricolinostat in head and neck tumor cells.

Following surgery and chemoradiation, ~50% of patients with locally advanced head and neck tumors experience relapse within the first two years, with a poor prognosis. Therefore, a novel therapeutic approach is required. The aim of the present study was to investigate the effect of combination treatment with the proteasome inhibitor bortezomib (BTZ), and ricolinostat (RCS), a specific inhibitor of histone deacetylase 6 (HDAC6), on CAL27 and Detroit562 head and neck cancer cells. BTZ and RCS exhibited cytotoxicity in a dose- and time-dependent manner. Simultaneous treatment with BTZ and RCS resulted in the synergistic enhancement of non-apoptotic cell death and autophagy. The receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor, necrostatin, but not the autophagy inhibitor, 3-methyladenine, attenuated the cytotoxicity of combined BTZ and RCS treatment. Thus, necroptosis [type-III programmed cell death (PCD)], but not autophagic cell death (type-II PCD), appeared to contribute to the pronounced cytotoxicity. However, no phosphorylation of RIPK1 or mixed lineage kinase domain-like protein was detectable in response to BTZ or RCS. Furthermore, RCS induced α-tubulin acetylation and inhibited BTZ-induced aggresome formation along with endoplasmic reticulum stress loading. Combined treatment with BTZ and RCS enhanced the production of reactive oxygen species (ROS). The ROS scavenger, N-acetyl cysteine, abrogated the increase in cytotoxicity. These results suggest the potential therapeutic value of the dual targeting of the proteasome and HDCA6 for head and neck cancers through the induction of necroptosis-like cell death along with ROS generation.

Efficacy and Safety of Paclitaxel Combined With Cetuximab for Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: For recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN), popular regimens containing platinum-based anticancer agents and immune checkpoint inhibitors are impractical for platinum-intolerant patients. Herein, the efficacy and safety of paclitaxel and cetuximab combination therapy in R/M SCCHN were evaluated. PATIENTS AND METHODS: In this retrospective study, paclitaxel (80 mg/m2) and cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 weekly) were administered in 28-day cycles on days 1, 8, and 15. RESULTS: Thirty-eight patients were treated. The overall response and disease control rates of first-line therapy were 43% and 79%, respectively, while those of second-line and later therapies were 20% and 90%, respectively. The median progression-free and overall survival were 5.3 and 12.5 months, respectively. All adverse events were manageable, including grade 3/4 neutropenia and anaemia affecting 8-13% of patients. CONCLUSION: Paclitaxel and cetuximab combination therapy may be suitable for treating R/M SCCHN.

Cochlear implantation in a patient with a POU4F3 mutation.

Cochlear implants (CIs) are generally considered useful in the treatment of hereditary hearing loss with progressive deafness. Early CI can be beneficial for maintaining social activities in POU4F3 mutation patients.

Neck dissection prolongs survival in patient with stage IVC hypopharyngeal carcinoma with mixed responses to nivolumab.

Surgical intervention aids in maintaining quality of life in patients with recurrent metastatic head and neck carcinoma with mixed responses to nivolumab treatment. However, the mechanisms involved in these mixed responses remain unclear. Systemic chemotherapy using the EXTREME regimen was administered to the patient with hypopharyngeal carcinoma and liver metastases as well as cervical lymph node metastases. The patient was subsequently treated with nivolumab after developing signs of progressive disease. Although the hypopharyngeal tumors and liver metastases were well-controlled, cervical lymph node dissection was performed because of the enlargement of some of the lymph node metastases. Postoperative nivolumab administration was resumed, and this patient is presently alive and disease-free. Immediately after neck dissection, the LNs that responded and those that did not respond to nivolumab were separated and evaluated. The LNs that responded well to nivolumab presented with prominent interstitial fibrosis. Conversely, in LNs that enlarged after nivolumab, significant proliferation of the viable tumor cells and almost no degeneration or necrosis was observed. Additionally, we performed immunohistological assessments on pathologic samples of multiple lesions with differing responses to treatment. Targeted surgical intervention appears to be a valuable adjunct to treatment with nivolumab.

Simultaneous metastasized primary unknown signet ring cell carcinoma of the cervical lymph node and mucoepidermoid carcinoma of the parotid gland as double cancers.

Lymph node metastasis from signet ring cellcarcinoma (SRCC) primary unknown is extremely rare. We here report a case of primary-unknown SRCC that metastasized to the cervical lymph nodes, co-existing with mucoepidermoid carcinoma (MEC) of the parotid gland as a simultaneous double cancer. A 68-year-old female patient with right swollen cervical lymph nodes consulted our medical center. A diagnosis of bilateral cervical lymph node metastasis and a right parotid tumor was made. After bilateral neck dissection and right parotidectomy, the pathological diagnosis was SRCC of primary unknown with metastasis to the cervical lymph node and MEC of the parotid gland. Examination of the CRTC1/3-MAML2 fusion gene showed no relation between SRCC of primary unknown with metastasis to the cervical lymph node and MEC of the parotid gland. Ten months after the first treatment, there was recurrence in the left neck lymph node, and left neck dissection was performed. Fourteen months after the first treatment, the patient is alive and cancer-free. This case is the fourth report of SRCC with lymph node metastasis, and highlights the value of fusion gene detection to determine relatedness between simultaneous cancers. Moreover, such cases should be closely monitored for the subsequent appearance of distant metastases.