Imaging of diffuse fibroepithelial polyps on surgical free flap in oral cancer patients: two case reports.

Fibroepithelial polyp (FEP) is a common benign tumor occurring in the skin and genitourinary tract, and there are no reports of multiple FEPs occurring on the myocutaneous flap. We report two cases of FEPs occurring diffusely on the skin tissue of the free anterolateral thigh flap after surgical reconstruction for oral squamous cell carcinoma. Clinically, multiple papillary nodules on the myocutaneous flap gradually increased. CT and MRI showed multiple papillary nodules on an enhanced layer covering the entire myocutaneous flap. PET/CT showed high uptake. One case was diagnosed with FEPs by surgery, the other by biopsy. The tumor-limited localization on the myocutaneous flap, characteristic morphology showing multiple papillary projection with an enhanced layer, and MRI signal showing patchy mild elevation of the apparent diffusion coefficient value may help in differential diagnosis from tumor recurrence or secondary carcinoma of the myocutaneous flap on diagnostic imaging.

Ceramide/sphingomyelin cycle involvement in gentamicin-induced cochlear hair cell death.

Ceramide, a sphingolipid metabolite, regulates diverse cellular processes including apoptosis, cell senescence, the cell cycle, and cellular differentiation. Exogenously administered ceramide reportedly increased cochlear hair cell death due to gentamicin-induced ototoxicity. Ceramide is mainly generated via a ceramide/sphingomyelin cycle by sphingomyelinase and sphingomyelin synthase or via de novo synthesis by serine palmitoyltransferase and ceramide synthase. This study was designed to investigate the possible involvement of neutral sphingomyelinase, sphingomyelin synthase, or serine palmitoyltransferase in hair cell death due to gentamicin. The basal turns of the organ of Corti of Sprague-Dawley rats were dissected on postnatal days 3-5. Cochlear cultures were exposed to media containing 35 µM gentamicin for 48 h to assess the effects of GW4869 (a neutral sphingomyelinase inhibitor), 2-hydroxyoleic acid (a sphingomyelin synthase activator), and myriocin (a serine palmitoyltransferase inhibitor). Hair cell loss was significantly decreased in the presence of GW4869 or 2-hydroxyoleic acid. Myriocin had no significant effects against gentamicin-induced hair cell loss. In addition, neutral sphingomyelinase was activated by gentamicin exposure. The present findings strongly suggest that the ceramide/sphingomyelin cycle plays an important role in the protection of hair cells against gentamicin-induced ototoxicity.

Inflammation-Based Score (Combination of Platelet Count and Neutrophil-to-Lymphocyte Ratio) Predicts Pharyngocutaneous Fistula After Total Laryngectomy.

OBJECTIVES/HYPOTHESIS: Postoperative complications may depend on the systemic inflammatory response. We evaluated the predictive potential of the combination of platelet count and neutrophil-to-lymphocyte ratio (COP-NLR) for the incidence of pharyngocutaneous fistula (PCF) in patients who have undergone total laryngectomy. STUDY DESIGN: Retrospective cohort study. METHODS: Patients who underwent total laryngectomy between 2000 and 2020 were recruited from four hospitals. The correlations between the incidence of PCF and several risk factors, including the COP-NLR, were examined. Patients with both elevated platelet count and elevated neutrophil-to-lymphocyte ratio (NLR) were categorized as COP-NLR 2, and patients with either one or no abnormal values of both parameters were assigned as COP-NLR 1 and COP-NLR 0, respectively. RESULTS: A total of 235 patients were identified. The overall incidence of PCF was 12.3%. The cut-off value for NLR before surgery was set at 3.95 (sensitivity = 58.6%, specificity = 69.4%, area under the curve [AUC] = 0.635), and the platelet count was set at 320 × 109 /L (sensitivity = 27.6%, specificity = 87.9%, AUC = 0.571). Multivariate analysis revealed that COP-NLR was an independent risk factor for PCF (COP-NLR 1 vs. COP-NLR 0: odds ratio [OR], 4.17; 95% confidence interval [CI], 1.64 to 10.59; and COP-NLR 2 vs. COP-NLR 0: OR, 5.33; 95% CI, 1.38 to 20.56). CONCLUSIONS: COP-NLR is a novel predictive factor for the development of PCF in patients undergoing total laryngectomy. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1582-1587, 2022.

Efficacy of the pretreatment geriatric nutritional risk index for predicting severe adverse events in patients with head and neck cancer treated with chemoradiotherapy.

OBJECTIVE: The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established nutritional assessment tool. Although concurrent chemoradiotherapy (CCRT), particularly cisplatin-based CCRT, is a standard treatment for locoregional advanced head and neck squamous cell carcinoma (HNSCC), the predictive factors of adverse events related to CCRT remain to be elucidated. The present study aimed to determine the association between GNRI and CCRT-related adverse events in patients of all ages with head and neck cancer (HNC) who underwent CCRT. METHODS: We retrospectively analyzed and compared the clinical characteristics and adverse events of 82 patients with HNC treated with CCRT according to their GNRI at the Department of Otolaryngology, Head and Neck Surgery, University of Tsukuba Hospital, between May 2014 and November 2019. The GNRI was calculated according to the equation: 1.489 × serum albumin (g/L) + 41.7 × (body weight/ideal body weight). We compared two groups: low GNRI (GNRI < 98) and normal GNRI (GNRI ≥ 98) groups. RESULTS: Eighty-two patients were enrolled in this study. There were 61 (76%) and 21 (26%) patients in the normal GNRI group and low GNRI group, respectively. There were significant differences in the incidence of grade ≥ 3 radiation mucositis, radiation dermatitis, and leukopenia between the low GNRI group and the normal GNRI groups. CONCLUSIONS: Patients with low GNRI scores were more likely to have severe adverse events. Pretreatment GNRI predicted severe CCRT-related adverse events in patients of all ages with HNC undergoing CCRT.

Protective role of Nrf2 in age-related hearing loss and gentamicin ototoxicity.

Expression of antioxidant enzymes is regulated by transcription factor NF-E2-related factor (Nrf2) and induced by oxidative stress. Reactive oxygen species contribute to the formation of several types of cochlear injuries, including age-related hearing loss and gentamicin ototoxicity. In this study, we examined the roles of Nrf2 in age-related hearing loss and gentamicin ototoxicity by measuring auditory brainstem response thresholds in Nrf2-knockout mice. Although Nrf2-knockout mice maintained normal auditory thresholds at 3 months of age, their hearing ability was significantly more impaired than that of age-matched wild-type mice at 6 and 11 months of age. Additionally, the numbers of hair cells and spiral ganglion cells were remarkably reduced in Nrf2-knockout mice at 11 months of age. To examine the importance of Nrf2 in protecting against gentamicin-induced ototoxicity, 3-day-old mouse organ of Corti explants were cultured with gentamicin. Hair cell loss caused by gentamicin treatment was enhanced in the Nrf2-deficient tissues. Furthermore, the expressions of some Nrf2-target genes were activated by gentamicin treatment in wild-type mice but not in Nrf2-knockout mice. The present findings indicate that Nrf2 protects the inner ear against age-related hearing injuries and gentamicin ototoxicity by up-regulating antioxidant enzymes and detoxifying proteins.

The Geriatric Nutritional Risk Index as a Prognostic Factor in Patients with Advanced Head and Neck Cancer.

OBJECTIVE: The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established nutritional assessment tool and is a significant prognostic factor in various cancers. However, the role of the GNRI in predicting clinical outcomes in patients with advanced head and neck cancer (AHNC) has not been investigated. The aim of the present study was to examine the association between the GNRI and prognosis in patients with AHNC. STUDY DESIGN: Retrospective cohort study. METHODS: Data collected between 2002 and 2013 from Tsukuba University Hospital were reviewed. The GNRI was calculated according to the equation, 1.489 × serum albumin (g/l) + 41.7 × (body weight/ideal body weight). Characteristics and prognosis were compared among three risk groups: high (GNRI <82); intermediate (GNRI 82-98); and normal (GNRI >98). The primary endpoint was overall survival. RESULTS: A total of 248 AHNC patients were enrolled, among whom 134 (54%) exhibited no nutritional risk, 53 (21%) had an intermediate risk for malnutrition, and 61 (25%) exhibited a high risk for malnutrition. Three-year survival rates according to the three-group GNRI scores for normal, intermediate, and high risk were 76.6%, 56.3%, and 19.5%, respectively. As the three-group GNRI score increased, the risk for mortality significantly increased (adjusted hazard ratio [HR] for intermediate to normal, 1.73 [95% CI, 1.02-2.92]; adjusted HR for high to normal, 4.31 [95% CI, 2.71-6.84]). CONCLUSIONS: The GNRI could be considered a useful prognostic factor in patients with AHNC. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E151-E156, 2021.

Case Report: Complete Response of Recurrent and Metastatic Cystadenocarcinoma of the Parotid Gland With a Single Course of Combined Nivolumab and Ipilimumab Therapy.

Although cystadenocarcinoma is classified as a low-grade histological subtype of salivary gland carcinoma (SGC), recurrence and metastases sometimes develop. However, standard treatments for advanced cases have not yet been established. Here, we present a case of unresectable local recurrence and cervical lymph node metastases of cystadenocarcinoma of the parotid gland with multiple lung nodules, all of which showed complete response with only a single course of combined nivolumab and ipilimumab therapy. The patient's medical history of metastatic melanoma roused our suspicions that the multiple lung nodules were cystadenocarcinoma metastases or malignant melanoma. Combination therapy was used based on our suspected diagnosis of lung metastases of melanoma although histological examination of the lung nodules could not be performed. While various chemotherapies are used for advanced SGCs including cystadenocarcinoma, overall, the results are unsatisfactory. In contrast, there have not yet been any reports of advanced cystadenocarcinoma of the salivary gland treated with immune checkpoint inhibitors (ICIs). Given that, in our case, a single course of combined ICI therapy induced a complete response in the unresectable and lymph node metastases from the cystadenocarcinoma and the multiple lung nodules, ICIs, including combined therapy, could be a promising treatment for advanced cystadenocarcinoma.

Epiglottic cyst in an infant.

Epiglottic cyst is a rare cause of stridor and respiratory distress in newborns and infants. A 2-year-old girl was referred to our department for the treatment of an epiglottic cyst causing inspiratory stridor. Flexible fiberoptic laryngoscopy and a computed tomography (CT) scan revealed a cystic lesion on the lingual surface of the epiglottis. Frequent episodes of sleep apnea accompanied by desaturation had been observed during her sleep. Endoscopic deroofing was performed under general anesthesia. After the operation, stridor and sleep apnea disappeared.

Modified combination of platelet count and neutrophil "to" lymphocyte ratio as a prognostic factor in patients with advanced head and neck cancer.

BACKGROUND: We evaluated the prognostic potential of the combination of platelet count and neutrophil to lymphocyte ratio (COP-NLR) in patients with advanced head and neck cancer. METHODS: We proposed a modified COP-NLR scoring system defined as follows: score 0 (platelet count level <300 × 109 /L and NLR <3); score 1 (platelet count level ≥300 × 109 /L and NLR <3); and score 2 (NLR ≥3). We assessed whether the modified scoring system had better performance as an indicator of prognosis than the existing COP-NLR scoring system (original and 4-group scores). RESULTS: A total of 248 patients were enrolled. The Akaike Information Criterion value with the modified COP-NLR score was the smallest among the 3 models. The 3-year survival rates according to the modified COP-NLR scores of 0, 1, and 2 were 80.6%, 59.9%, and 23.8%, respectively. CONCLUSION: The modified COP-NLR score is a useful prognostic marker in patients with advanced head and neck cancer.

The influence of sphingosine-1-phosphate receptor antagonists on gentamicin-induced hair cell loss of the rat cochlea.

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates various critical biological processes, such as cell proliferation, survival, migration, and angiogenesis. The action of S1P is exerted by its binding to 5 specific G protein-coupled S1P receptors (S1PR), S1PR1-S1PR5. Aminoglycoside antibiotics including gentamicin induce cochlear hair cell loss and sensorineural hearing loss. Apoptotic cell death is considered to play a key role in this type of cochlear injury. S1P acts as a cochlear protectant against gentamicin ototoxicity. In the present study, expression of S1PRs in the cochlea was examined. In addition, the effects of S1PR antagonists on gentamicin ototoxicity were investigated using tissue culture techniques. Cochleas were dissected from Sprague-Dawley rats on postnatal days 3-5. Basal turn organ of Corti explants were exposed to 35 µM gentamicin for 48 h with or without S1PR antagonists. S1PR(1-3) were expressed in the organ of Corti and spiral ganglion. The S1PR2 antagonist increased gentamicin-induced hair cell loss, while the S1PR1 and S1PR3 antagonists did not affect gentamicin ototoxicity. These results indicate the possibility that S1P act as a cochlear protectant against gentamicin ototoxicity via activation of S1PR2.

The effects of A1 and A2A adenosine receptor agonists on kainic acid excitotoxicity in the guinea pig cochlea.

The present study aimed to clarify the protective effect of adenosine receptors against the excitotoxicity of cochlear afferent dendrites. The effects of 2-chloro-N6-cyclopentyladenosine (CCPA), an A1 adenosine receptor agonist, and 5'-N-cyclopropyl-carboxamidoadenosine (CPCA), an A2A adenosine receptor agonist, on cochlear excitotoxicity induced by kainic acid (KA) were examined using guinea pigs. KA was applied to the round window membrane at a concentration of 10mM for 30 min. CCPA or CPCA was given at the onset of KA application. KA morphologically induced the swelling of cochlear afferent dendrites and significantly elevated the threshold of the compound action potential (CAP) of the cochlea. CCPA inhibited the KA-induced CAP threshold shift and swelling of the cochlear afferent dendrites. However, CPCA did not affect cochlear excitotoxicity induced by KA. The results suggest that adenosine A1 receptor activation could prevent the excitotoxicity of cochlear afferent dendrites.

Effects of neuroactive steroids on cochlear hair cell death induced by gentamicin.

As neuroactive steroids, sex steroid hormones have non-reproductive effects. We previously reported that 17ß-estradiol (ßE2) had protective effects against gentamicin (GM) ototoxicity in the cochlea. In the present study, we examined whether the protective action of ßE2 on GM ototoxicity is mediated by the estrogen receptor (ER) and whether other estrogens (17α-estradiol (αE2), estrone (E1), and estriol (E3)) and other neuroactive steroids, dehydroepiandrosterone (DHEA) and progesterone (P), have similar protective effects. The basal turn of the organ of Corti was dissected from Sprague-Dawley rats and cultured in a medium containing 100 µM GM for 48h. The effects of ßE2 and ICI 182,780, a selective ER antagonist, were examined. In addition, the effects of other estrogens, DHEA and P were tested using this culture system. Loss of outer hair cells induced by GM exposure was compared among groups. ßE2 exhibited a protective effect against GM ototoxicity, but its protective effect was antagonized by ICI 182,780. αE2, E1, and E3 also protected hair cells against gentamicin ototoxicity. DHEA showed a protective effect; however, the addition of ICI 182,780 did not affect hair cell loss. P did not have any effect on GM-induced outer hair cell death. The present findings suggest that estrogens and DHEA are protective agents against GM ototoxicity. The results of the ER antagonist study also suggest that the protective action of ßE2 is mediated via ER but that of DHEA is not related to its conversion to estrogen and binding to ER. Further studies on neuroactive steroids may lead to new insights regarding cochlear protection.

Protective effects of corticosteroids and neurosteroids on cochlear injury.

Dysfunction of the cochlea causes sensorineural hearing loss. Glucocorticoids have been clinically applied for sensorineural hearing loss of sudden onset, including idiopathic sudden sensorineural hearing loss, acoustic injury, Meniere's disease, and immune-mediated hearing loss. However, clinical studies on sudden sensorineural hearing loss have revealed conflicting results regarding the efficacy of glucocorticoids. The findings obtained from animal experiments have demonstrated that glucocorticoids exhibited protective effects on some types of cochlear injury, but there were limitations regarding glucocorticoid therapy. Recently, the actions of neurosteroids in the cochlea have drawn much attention from auditory researchers. Clinical and experimental studies of the auditory system have indicated that estrogens affect auditory perception. Furthermore, estrogens and dehydroepiandrosterone (DHEA) exhibit protective effects on cochlear injury. This article was aimed to give an overview of steroid treatment for protection of the inner ear against various cochlear injuries. Findings obtained from animal studies are focused on.

Early detection of nasopharyngeal carcinoma.

Nasopharyngeal carcinoma (NPC) is a unique disease with a clinical presentation, epidemiology, and histopathology differing from other squamous cell carcinomas of the head and neck. NPC is an Epstein-Barr virus-associated malignancy with a marked racial and geographic distribution. Specifically, it is highly prevalent in southern China, Southeast Asia, and the Middle East. To date, most NPC patients have been diagnosed in the advanced stage, but the treatment results for advanced NPC are not satisfactory. This paper provides a brief overview regarding NPC, with the focus on the early detection of initial and recurrent NPC lesions.

Age-related hearing loss and expression of antioxidant enzymes in BDF1 mice.

CONCLUSION: Our data suggest that the changes in expression of antioxidant enzymes may cause age-related hearing loss (AHL). OBJECTIVES: AHL is an aging process of the inner ear, and oxidant stressors are considered to be one of the leading causes. We investigated the hearing level and expression profile of antioxidant enzymes in aged mice. METHODS: Mice aged 3, 6, and 11 months were used. Hearing levels of the mice were examined using the auditory brainstem response (ABR). After measuring the ABR threshold, cochleae were dissected. RNA was isolated from the cochleae, and cDNA was synthesized using the retro-transcription enzyme. Expression of the antioxidant enzymes was measured by quantitative real-time PCR. RESULTS: The ABR thresholds of the BDF1 mice were elevated by 6 months of age. The expression of superoxide dismutase 1 (SOD1) and heme oxygenase 1 (HO1) at 11 months of age significantly decreased compared with that of those at 6 months of age. In contrast, a decrease in the expression level was not observed regarding NAD(P)H-quinone oxidoreductase 1 (NQO1).

The influences of sphingolipid metabolites on gentamicin-induced hair cell loss of the rat cochlea.

Sphingolipid metabolites inducing ceramide, sphingosine, and sphingosine-1-phosphate (S1P) play important roles in the regulation of cell proliferation, survival, and death. Aminoglycoside antibiotics including gentamicin induce inner ear hair cell loss and sensorineural hearing loss. Apoptotic cell death is considered to play a key role in this injury. The present study was designed to investigate the possible involvement of ceramide and S1P in hair cell death due to gentamicin. In addition, the effects of other metabolites of ceramide, gangliosides GM1 (GM1) and GM3 (GM3), on gentamicin ototoxicity were also investigated. Basal turn organ of Corti explants from p3 to p5 rats were maintained in tissue culture and exposed to 20 or 35µM gentamicin for 48h. The effects of ceramide, S1P, GM1, and GM3 on gentamicin-induced hair cell loss were examined. Gentamicin-induced hair cell loss was increased by ceramide but was decreased by S1P. GM1 and GM3 exhibited protective effects against gentamicin-induced hair cell death at the limited concentrations. These results indicate that ceramide enhances gentamicin ototoxicity by promoting apoptotic hair cell death, and that S1P, GM1, and GM3 act as cochlear protectants. In conclusion, sphingolipid metabolites influence the apoptotic reaction of hair cells to gentamicin ototoxicity.

Ischemia-reperfusion injury of the cochlea: pharmacological strategies for cochlear protection and implications of glutamate and reactive oxygen species.

A large amount of energy produced by active aerobic metabolism is necessary for the cochlea to maintain its function. This makes the cochlea vulnerable to blockade of cochlear blood flow and interruption of the oxygen supply. Although certain forms of human idiopathic sudden sensorineural hearing loss reportedly arise from ischemic injury, the pathological mechanism of cochlear ischemia-reperfusion injury has not been fully elucidated. Recent animal studies have shed light on the mechanisms of cochlear ischemia-reperfusion injury. It will help in the understanding of the pathology of cochlear ischemia-reperfusion injury to classify this injury into ischemic injury and reperfusion injury. Excitotoxicity, mainly observed during the ischemic period, aggravates the injury of primary auditory neurons. On the other hand, oxidative damage induced by hydroxyl radicals and nitric oxide enhances cochlear reperfusion injury. This article briefly summarizes the generation mechanisms of cochlear ischemia-reperfusion injury and potential therapeutic targets that could be developed for the effective management of this injury type.

Estradiol protects the cochlea against gentamicin ototoxicity through inhibition of the JNK pathway.

Gentamicin induces outer hair cell death through the apoptotic pathway. It has been reported that this death pathway of outer hair cells is mediated by specific apoptotic enzymes including c-jun N-terminal kinase (JNK) and caspases. 17beta-Estradiol (E2), the most potent estrogen, is known to function as an antiapoptotic agent to prevent the death of various cell types. The purpose of the present study was to examine the effects of E2 on gentamicin-induced apoptotic cell death in outer hair cells. The basal turn organ of Corti explants from p3 or p4 rats were maintained in a tissue culture and exposed to 100muM gentamicin for 48h. The effects of E2 on gentamicin-induced outer hair cell loss, JNK activation, and staining for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick-end labeling (TUNEL) were examined. E2 significantly decreased gentamicin-induced outer hair cell loss in a dose-dependent manner. JNK activation and TUNEL staining were observed in organ of Corti explants exposed to gentamicin, and staining levels were significantly decreased by E2 treatment. The results indicate that, through the inhibition of JNK and subsequent apoptotic reactions, E2 decreases outer hair cell loss induced by gentamicin ototoxicity.

Involvement of poly(ADP-ribose) synthetase in acoustic trauma of the cochlea.

We investigated effects of poly(ADP-ribose) synthetase (PARS) inhibitors on acoustic trauma. Albino guinea pigs were intravenously given 3-aminobenzamide, nicotinamide or 3-aminobenzoic acid (an inactive analog of 3-aminobenzamide) just prior to exposure to a 2 kHz pure tone of 120 dB sound pressure level (SPL) for 10 minutes. The threshold of the compound action potential (CAP) and the amplitude of distortion-product otoacoustic emissions (DPOAEs) were measured before and 4 hours after the acoustic overexposure. Statistically significant decreases in the CAP threshold shifts and significant increases in the DPOAE amplitudes were observed 4 hours after the acoustic overexposure in the animals treated with 3-aminobenzamide or nicotinamide, whereas 3-aminobenzoic acid did not exert any protective effect. These results strongly suggest that excessive activation of PARS is involved in generation of the acoustic trauma.