Visual Field Improvement and Electrode Extrusion Prevention by Extended Endaural Incision With Cavity Obliteration for Cochlear Implantation in Ears After Canal Wall-Down Mastoidectomy: Experience of Four Cases.

There is no global consensus on the surgical technique of cochlear implantation (CI) in ears with an open cavity after canal wall-down (CWD) mastoidectomy. Here, we report CI surgery with an endaural incision for the ears after CWD mastoidectomy. The endaural incision was extended upward to obliterate the open cavity of the temporal fascial flap. The endaural incision was extended downward to close the open cavity inlet. After inserting the implanted electrode, the open cavity was obliterated using a temporal fascial flap, and the cavity was closed at the inlet. We performed this type of CI surgery in four ears in three patients. This extended endaural incision provided an excellent view for pedicling the temporal fascial flap with the superficial temporal artery and for open cavity closure without any serious complications. This technique allowed us to opt for CI surgery of the ears after CWD mastoidectomy.

Extracting interpretable features for pathologists using weakly supervised learning to predict p16 expression in oropharyngeal cancer.

One drawback of existing artificial intelligence (AI)-based histopathological prediction models is the lack of interpretability. The objective of this study is to extract p16-positive oropharyngeal squamous cell carcinoma (OPSCC) features in a form that can be interpreted by pathologists using AI model. We constructed a model for predicting p16 expression using a dataset of whole-slide images from 114 OPSCC biopsy cases. We used the clustering-constrained attention-based multiple-instance learning (CLAM) model, a weakly supervised learning approach. To improve performance, we incorporated tumor annotation into the model (Annot-CLAM) and achieved the mean area under the receiver operating characteristic curve of 0.905. Utilizing the image patches on which the model focused, we examined the features of model interest via histopathologic morphological analysis and cycle-consistent adversarial network (CycleGAN) image translation. The histopathologic morphological analysis evaluated the histopathological characteristics of image patches, revealing significant differences in the numbers of nuclei, the perimeters of the nuclei, and the intercellular bridges between p16-negative and p16-positive image patches. By using the CycleGAN-converted images, we confirmed that the sizes and densities of nuclei are significantly converted. This novel approach improves interpretability in histopathological morphology-based AI models and contributes to the advancement of clinically valuable histopathological morphological features.

Proton beam therapy in multimodal treatment for locally advanced squamous cell carcinoma of the nasal cavity and paranasal sinus.

BACKGROUND: To evaluate proton beam therapy (PBT) in multimodal treatment for locally advanced squamous cell carcinoma of the nasal cavity and paranasal sinus (NPSCC). METHODS: The cases in this study included T3 and T4 NPSCC without distant metastases that were treated at our center using PBT between July 2003 and December 2020. These cases were classified into 3 groups based on resectability and treatment strategy: surgery followed by postoperative PBT (group A); those indicated to be resectable, but the patient refused surgery and received radical PBT (group B); and those declared unresectable based on the extent of the tumor and treated with radical PBT (group C). RESULTS: The study included 37 cases, with 10, 9 and 18 in groups A, B and C, respectively. The median follow-up period in surviving patients was 4.4 years (range 1.0-12.3 years). The 4-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 58%, 43% and 58% for all patients; 90%, 70% and 80% in group A, 89%, 78% and 89% in group B; and 24%, 11% and 24% in group C. There were significant differences in OS (p = 0.0028) and PFS (p = 0.009) between groups A and C; and in OS (p = 0.0027), PFS (p = 0.0045) and LC (p = 0.0075) between groups B and C. CONCLUSIONS: PBT gave favorable outcomes in multimodal treatment for resectable locally advanced NPSCC, including surgery followed by postoperative PBT and radical PBT with concurrent chemotherapy. The prognosis for unresectable NPSCC was extremely poor, and reconsideration of treatment strategies, such as more active use of induction chemotherapy, may improve outcomes.

Endoscopic observation of pharyngeal mucosal suture healing process after total laryngectomy: case series.

BACKGROUND: Pharyngocutaneous fistula (PCF), a major complication of total laryngectomy, is caused by pharyngeal repair failure. OBJECTIVE: Assess the usefulness of endoscopic observation of the pharyngeal suture's healing process for the early detection of PCF development. METHODS: Pharyngeal mucosal sutures were endoscopically observed postoperatively in patients who underwent total laryngectomy with primary closure. RESULTS: Postoperatively, a white coat adhered to the pharyngeal mucosal suture of all patients. In most cases, the white coat gradually receded, which was considered to be a normal healing process. Thickening of the white coat and/or dehiscence of surgical wound were interpreted as 'poor healing conditions'. Three cases were judged to have developed poor healing conditions of the pharyngeal mucosal suture and one patient developed PCF. The other two patients did not develop PCF, possibly due to early detection of 'poor healing condition' and conservative approach, such as discontinuation of oral intake. CONCLUSIONS: Postoperative poor healing conditions of the pharyngeal mucosal suture may be precursors to PCF development. Endoscopic observation enables early detection of these conditions and may enable the prevention of PCF.

Successful Treatment of Basaloid Squamous Cell Carcinoma of the Nasal Cavity With Brain Invasion.

Basaloid squamous cell carcinoma (BSCC) is a rare and aggressive subtype of squamous cell carcinoma (SCC). To date, no consensus on the treatment of BSCC has been established yet, especially in cases of invasion of the skull base. In addition, long-term prognosis has not been reported in T4b cases. Herein, we report the case of a 36-year-old Japanese man with locally advanced nasal BSCC that directly invaded the skull base and the brain. The patient was then treated with induction chemotherapy (IC). Owing to his good response to IC, we planned and performed en bloc resection followed by adjuvant proton beam therapy (PBT). Follow-up examinations five years after treatment showed no evidence of recurrence. This is the first report of IC followed by radical surgery and adjuvant PBT in a patient with T4b. IC has the potential to play an important role in treatment strategies.

Elevation of C-reactive protein during concurrent chemoradiotherapy is a poor predictive factor for head and neck cancer.

OBJECTIVE: The prognostic role of pretreatment C-reactive protein (CRP) has been reported for head and neck cancer. However, little is known about the relationship between the changes in CRP levels during treatment and prognosis. This study aimed to investigate the correlation between CRP elevation during concurrent chemoradiotherapy (CCRT) and survival outcomes. METHODS: The medical records of patients with oropharyngeal, hypopharyngeal, and laryngeal cancer treated with CCRT at the University of Tsukuba Hospital and National Hospital Organization Mito Medical Center from April 2014 to December 2019 were retrospectively reviewed. Patients were divided into normal (<0.3 mg/dl) and elevated (≥0.3 mg/dl) CRP groups according to the CRP level after the first cycle of cisplatin. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled, of whom 36 (49%) showed elevated CRP levels after the first cycle of cisplatin. The 3-year PFS was 83.3% and 61.0% in the normal and elevated CRP groups, respectively, showing significant differences between the two groups. CONCLUSION: Elevated CRP levels after the first cycle of cisplatin is an objective predictive marker for survival in patient with head and neck squamous cell carcinoma treated with CCRT.

Estradiol protects hair cells from cisplatin-induced ototoxicity via Nrf2 activation.

Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about the protective mechanisms of E2 against cisplatin-induced ototoxicity. In this study, we investigated the effect of E2 on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated hair cell protection using the organ of Corti isolated from mice. The organ of Corti collected from C57BL/6 mice at 3-5 postnatal days was used in all experiments. The organ of Corti was exposed to 20 µM cisplatin with/without 100 nM E2 to examine the effect of E2 on cisplatin-induced hair cell loss. The mRNA expression of Nrf2 and the phase II detoxification gene after E2 and cisplatin treatment was analyzed using quantitative real-time PCR. E2 significantly reduces cisplatin-induced cochlear hair cell death. In addition, 100 nM E2 increased the mRNA expression of Nrf2 and phase II detoxification genes in the organ of Corti under cisplatin treatment. Our results suggest that E2 activates Nrf2, phase II detoxification enzymes and exerts a protective effect against cisplatin-induced ototoxicity.

Vestibular schwannoma extending into the tympanic cavity and jugular fossa by invasion of the petrous bone.

Vestibular schwannomas usually originate in the internal acoustic meatus, and gradually extends into the cerebellopontine cistern. Invasive growth into the petrous bone is extremely rare. We describe a case of a vestibular schwannoma that aggressively extended into the petrous bone and extracranial space. This may have arisen because of an unusually peripheral site of origin on the vestibular nerve.

The area of residual tumor predicts esophageal squamous cell carcinoma prognosis following neoadjuvant chemotherapy.

PURPOSE: To clarify the utility of the area of residual tumor for patients with esophageal squamous cell cancer treated with neoadjuvant chemotherapy. METHODS: We enrolled 186 patients with esophageal squamous cell cancer who underwent surgical resection following neoadjuvant chemotherapy at our hospital. Using digital images, we measured the area of residual tumor at the maximum plane of the specimen and divided the patient into three groups as follows: 0 (area = 0 mm2), low (area = 0-40 mm2), and high (area ≥ 40 mm2). The clinicopathological factors and prognosis were compared among these groups. RESULTS: The median area of the residual tumor was 15.0 mm2　(range 0-1,448.8 mm2). Compared with the 0 and low group, the high group was significantly associated with poorer recurrence-free survival (all P < .001) and overall survival (P < .001 [vs. 0] and P = .017 [vs low]). The area of residual tumor, ypN, tumor regression grade, and lymphovascular invasion were independent predictors of recurrence-free survival. By dividing the patients using a combination of the area of residual tumor and lymphovascular invasion, the high and/or lymphovascular invasion ( +) group displayed significantly poor recurrence-free survival than the 0 group and low/lymphovascular invasion ( -) group. However, there was no significant difference in the recurrence-free survival between the 0 group and low/lymphovascular invasion ( -) group. CONCLUSION: The area of residual tumor is a promising histopathological prognostic factor for patients with esophageal squamous cell cancer treated with neoadjuvant chemotherapy. Moreover, it is a possible candidate histopathological factor for postoperative chemotherapy selection.

Glycoprotein NMB promotes tumor formation and malignant progression of laryngeal squamous cell carcinoma.

Laryngeal squamous cell carcinoma (LSCC), although one of the most common head and neck cancers, has a static or slightly decreased survival rate because of difficulties in early diagnosis, lack of effective molecular targeting therapy, and severe dysfunction after radical surgical treatments. Therefore, a novel therapeutic target is crucial to increase treatment efficacy and survival rates in these patients. Glycoprotein NMB (GPNMB), whose role in LSCC remains elusive, is a type 1 transmembrane protein involved in malignant progression of various cancers, and its high expression is thought to be a poor prognostic factor. In this study, we showed that GPNMB expression levels in LSCC samples are significantly higher than those in normal tissues, and GPNMB expression is observed mostly in growth-arrested cancer cells. Furthermore, knockdown of GPNMB reduces monolayer cellular proliferation, cellular migration, and tumorigenic growth, while GPNMB protein displays an inverse relationship with Ki-67 levels. Therefore, we conclude that GPNMB may be an attractive target for future LSCC therapy.

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.

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.

Objective evaluation of gustatory function after surgery for vestibular schwannoma: A pilot study.

OBJECTIVE: To evaluate the gustatory function before and after vestibular schwannoma (VS) surgery. METHODS: In this retrospective study, we evaluated the gustatory function of 12 patients who underwent VS surgery at Tsukuba University Hospital between 2012 and 2018. Gustatory function was examined using electrogustometry before VS surgery and 3 months, 6 months and 1 year after surgery. Electrogustometry was tested at the area mapped to the chorda tympani nerve, glossopharyngeal nerve and greater superficial petrosal nerve (GSPN). Intergroup mean comparisons of the threshold were performed using a one-way analysis of variance (ANOVA) followed by the Bonferroni post-hoc test. RESULTS: The gustatory function mapped to the chorda tympani nerve was significantly disturbed 6 months after the surgery as compared with the preoperative function (p = 0.033) and that the dysfunction recovered at 1 year. However, gustatory function mapped to the glossopharyngeal nerve and greater superficial petrosal nerve (GSPN) was not impaired. CONCLUSION: The gustatory function mapped to the chorda tympani nerve is impaired after surgery for VS. The dysfunction peaked at 6 months after surgery, and recovered within 1 year.

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.

Are Intraoral Stents Effective for Reducing the Severity of Oral Mucositis During Radiotherapy for Maxillary and Nasal Cavity Cancer?

PURPOSE: The intraoral stent (IOS) is an individualized mouth opening device that can be used during radiotherapy (RT) for head and neck cancer to prevent unnecessary irradiation to normal tissues. The purpose of the present study was to compare the severity of oral mucositis (OM) between patients using and not using an IOS during RT for maxillary and nasal cavity cancer. PATIENTS AND METHODS: We designed and implemented a retrospective cohort study. The study sample included patients with maxillary and nasal cavity cancer who had undergone RT. The primary predictor variable was IOS application, and the outcome variable was the grade of OM. RESULTS: The IOS group included 18 patients with an IOS and the control group, 16 patients without an IOS. The parameters of the dose-volume histogram included the median dosage covering 1 mL (D1mL) for the tongue and the mean dosage. The D1mL (36.2 vs 65.4 Gy) and mean dosage (4.9 Gy vs 25.9 Gy) were both significantly lower in the IOS group than in the control group (P < .005). The incidence of OM using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, were significantly different between the oral stomatitis grade and the use of an IOS (P = .028). A significant difference was found in opioid use between the IOS and control groups (P = .009). CONCLUSIONS: The use of an IOS decreased the radiation dosage to the tongue, the grade of OM, and opioid usage during RT.

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 role of peroxiredoxin I in cisplatin-induced ototoxicity.

OBJECTIVE: Peroxiredoxin (Prx) is a new family of antioxidative proteins. Prx I is ubiquitously expressed in various tissues and is important in the defense of tissues from increases in reactive oxygen species (ROS). The present study was designed to examine the expression of Prx subtypes in the mouse cochlea and to show the possible involvement of Prx I in protecting the cochlea against cisplatin ototoxicity. METHODS: Postnatal-day-3-to-5 wildtype mice and Prx I-deficient mice were used. Prx expression in the cochlea was assessed by real-time PCR assay. Prx I protein expression was examined by immunofluorescence staining. Cochlear explants were exposed to 2, 5, and 10-µM cisplatin for 48h, and the cochlear hair cell losses of the wildtype and Prx I-deficient mice were compared. In addition, the histologic features of the cochlear lateral wall were examined after cisplatin incubation. RESULTS: mRNAs of all Prx subtypes were expressed in the mouse cochlea. Prx I was one of the abundant subtypes and was upregulated after 48-h exposure to 5-µM cisplatin. Immunofluorescence staining showed the ubiquitous expression of Prx I in the cochlea. No difference in cochlear hair cell loss induced by cisplatin was found between the wildtype mice and the Prx I-deficient mice. However, spiral ligament fibrocytes of Prx I-deficient mice were significantly sensitive to cisplatin at 20-µM or lower. CONCLUSION: Prx I is important for protection of at least the spiral ligament fibrocytes of the cochlear lateral wall in cisplatin ototoxicity.

Hair Cell Loss Induced by Sphingosine and a Sphingosine Kinase Inhibitor in the Rat Cochlea.

Sphingolipid metabolites including ceramide, sphingosine (Sph), and sphingosine-1-phosphate (S1P) play important roles in the regulation of cell survival and death. Sphingosine kinase (Sk) phosphorylates Sph to S1P. Sk is reportedly overexpressed in various cancer cells, and Sk inhibitors are therefore a target of anti-tumor therapy. However, the effects of Sph and Sk inhibitors on cochlear hair cells were unknown. In the present study, expression of Sk isotypes in the cochlea was examined. In addition, the changes in Sk activity induced by cisplatin (CDDP) and the effects of an Sk inhibitor, Sph, and S1P on CDDP ototoxicity were investigated using tissue culture techniques. Cochleae were dissected from Sprague­Dawley rats on postnatal days 3­5. Organ of Corti explants were exposed to 5 lM CDDP for 48 h with or without the Sk inhibitor, Sph, or S1P. Both Sk1 and Sk2 were expressed in the normal cochlea. CDDP activated Sk. The Sk inhibitor itself caused hair cell loss at a high concentration, and at lower concentrations, it increased CDDP-induced hair cell loss. Sph itself also induced hair cell death and increased hair cell loss induced by CDDP. However, S1P decreased hair cell loss induced by CDDP. Sk inhibitor has the function by increasing ototoxic Sph and decreasing otoprotective S1P and therefore potentially causes ototoxicity. Consideration of the possibility of ototoxicity is required in the usage of Sk inhibitors.

Clinical utility of the modified Glasgow prognostic score in patients with advanced head and neck cancer.

BACKGROUND: The purpose of this study was to evaluate the prognostic potential of the modified Glasgow prognostic score (mGPS), known to reflect the degree of tumor-associated inflammation and cancer cachexia, in patients with advanced head and neck cancer. METHODS: Patients with advanced head and neck cancer treated at the University of Tsukuba Hospital between January 2002 and December 2011 were retrospectively evaluated. They were categorized by their mGPS. RESULTS: A total of 210 patients were enrolled in this study. Patients with an mGPS of 0 had better overall survival and disease-free survival than did those with an mGPS of 1 or 2. Multivariate analysis revealed that the mGPS was a significant risk factor for overall survival and disease-free survival. CONCLUSIONS: Our results suggest that the mGPS is useful for predicting outcome in patients with advanced head and neck cancer and should be included in their routine clinical assessment.