Predicting lymph node recurrence in cT1-2N0 tongue squamous cell carcinoma: collaboration between artificial intelligence and pathologists.

Researchers have attempted to identify the factors involved in lymph node recurrence in cT1-2N0 tongue squamous cell carcinoma (SCC). However, studies combining histopathological and clinicopathological information in prediction models are limited. We aimed to develop a highly accurate lymph node recurrence prediction model for clinical stage T1-2, N0 (cT1-2N0) tongue SCC by integrating histopathological artificial intelligence (AI) with clinicopathological information. A dataset from 148 patients with cT1-2N0 tongue SCC was divided into training and test sets. The prediction models were constructed using AI-extracted information from whole slide images (WSIs), human-assessed clinicopathological information, and both combined. Weakly supervised learning and machine learning algorithms were used for WSIs and clinicopathological information, respectively. The combination model utilised both algorithms. Highly predictive patches from the model were analysed for histopathological features. In the test set, the areas under the receiver operating characteristic (ROC) curve for the model using WSI, clinicopathological information, and both combined were 0.826, 0.835, and 0.991, respectively. The highest area under the ROC curve was achieved with the model combining WSI and clinicopathological factors. Histopathological feature analysis showed that highly predicted patches extracted from recurrence cases exhibited significantly more tumour cells, inflammatory cells, and muscle content compared with non-recurrence cases. Moreover, patches with mixed inflammatory cells, tumour cells, and muscle were significantly more prevalent in recurrence versus non-recurrence cases. The model integrating AI-extracted histopathological and human-assessed clinicopathological information demonstrated high accuracy in predicting lymph node recurrence in patients with cT1-2N0 tongue SCC.

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.

Development of Monoclonal Antibodies Specific to Either CD300AR111 or CD300AQ111 or Both.

CD300A is a member of the CD300 immunoglobulin (Ig)-like receptor family consisting of eight molecules in humans, all of which contain one Ig-like domain in the extracellular portion. Upon binding its ligand phosphatidylserine or phosphatidylethanolamine, CD300A mediates an inhibitory signal through the immunoreceptor tyrosine-based inhibitory motif in the cytoplasmic portion. The CD300 family molecules are highly homologous to each other. In addition, CD300A has a single nucleotide polymorphism (rs2272111), which is a nonsense mutation encoding glutamine (CD300AQ111) instead of arginine (CD300AR111) at residue 111 in the Ig-like domain of CD300A. In this study, we successfully generated monoclonal antibodies (mAbs) specific to either CD300AR111 or CD300AQ111 or both. These mAbs are useful for the analysis of CD300A genotype by flow cytometry and the development of an antibody drug for the treatment of various diseases.

Loss of synaptic ribbons is an early cause in ROS-induced acquired sensorineural hearing loss.

Considerable evidence of reactive oxygen species (ROS) involvement in cochlear hair cell (HC) loss, leading to acquired sensorineural hearing loss (SNHL), were reported. Cochlear synaptopathy between HCs and spiral ganglion neurons has been gathering attention as a cochlear HC loss precursor not detectable by normal auditory evaluation. However, the molecular mechanisms linking ROS with HC loss, as well as the relationship between ROS and cochlear synaptopathy have not been elucidated. Here, we examined these linkages using NOX4-TG mice, which constitutively produce ROS without stimulation. mRNA levels of Piccolo 1, a major component of the synaptic ribbon (a specialized structure surrounded by synaptic vesicles in HCs), were decreased in postnatal day 6 NOX4-TG mice cochleae compared to those in WT mice; they were also decreased by noise exposure in 2-week-old WT cochleae. As noise exposure induces ROS production, this suggests that the synaptic ribbon is a target of ROS. The level of CtBP2, another synaptic ribbon component, was significantly lower in NOX4-TG cochleae of 1-month-old and 4-month-old mice compared to that in WT mice, although no significant differences were noted at 1.5- and 2-months. The decrease in CtBP2 plateaued in 4-month-old NOX4-TG, while it gradually decreased from 1 to 6 months in WT mice. Furthermore, CtBP2 level in 2-month-old NOX4-TG mice decreased significantly after exposure to cisplatin and noise compared to that in WT mice. These findings suggest that ROS lead to developmental delays and early degeneration of synaptic ribbons, which could be potential targets for novel therapeutics for ROS-induced SNHL.

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.

Effect of Average Relative Humidity on Epistaxis.

Background Epistaxis is a very common symptom. The occurrence of epistaxis may be affected by dry environments, but there are some differences among previous reports and this view is controversial. Objective We investigated the relationship between the number of epistaxes and daily average relative humidity. Methods Data on patients with epistaxis between March 2011 and February 2021 were collected from two hospitals. The daily average relative humidity was examined, and the change in the number of patients with epistaxis due to humidity was investigated using a generalized linear mixed model. Results A total of 4184 cases of epistaxis were identified. The number of epistaxis cases per day was significantly associated with the daily average relative humidity (p < 0.001). One percent increment in average relative humidity decreases the number of epistaxis cases per day by 1.1%. Conclusion A negative correlation was found to exist between daily average relative humidity and occurrences of epistaxis.

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.

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.

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.

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.

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.

Cost-effectiveness analyses of monovalent mumps vaccination programs for Japanese children.

BACKGROUND: The most common preventative measure against mumps is vaccination with mumps vaccine. Over 122 countries have implemented mumps vaccine routine immunization programs, mostly via Measles-Mumps-Rubella (MMR) vaccine. In Japan, the unexpectedly high incidence of aseptic meningitis caused by mumps vaccine led to the discontinuation of the MMR national vaccination program in 1993, inadvertently resulting in the re-emergence of mumps. Plans of introducing monovalent mumps vaccine into routine vaccination schedule have become one of the emerging topics in health policy that has warranted the need in evaluating its value for money. METHODS: We conducted cost-effectiveness analyses with Markov model and calculated incremental cost-effectiveness ratios (ICERs) of two different vaccination programs (a single-dose program at one-year-old, a two-dose program with second dose uptakes at five) compared to status quo from both payers' and societal perspectives. Transition probabilities and utility weights in estimating quality-adjusted life-year (QALY), and disease treatment costs were either estimated or obtained from literature. Costs per vaccination were assumed at ¥6140 (US$58;1US$ = ¥106). RESULTS: Both programs reduce disease treatment costs compared to status quo, while the reduction cannot offset vaccination cost. ICER of either program is found to be under ¥5,000,000 (US$47,170)/QALY willingness-to-pay (WTP) threshold from either perspective. Results of probabilistic sensitivity analyses expressed by net monetary benefit indicated that at the WTP threshold, the acceptability is at 92.6% for two-dose vaccination program, 0% for single-dose vaccination program, and 7.4% for current no vaccination program. Two-dose program was optimal among the alternatives. One-way sensitivity analyses revealed that proportion of mumps-related hearing loss among mumps cases and vaccine effectiveness (VE) were key variables in changing the ICERs. CONCLUSION: Routine vaccination program of single- and two-dose programs were cost-effective from both payers' and societal perspectives. Between the two, the two-dose vaccination program was observed to be more favorable.

A New Health Promotion Program That Includes Wadaiko Rhythm Exercise to Maintain the Health of Persons Excluded from Receiving Specific Health Guidance.

This study examined the effectiveness of a new health promotion program, which is a collective intervention program aimed at improving lifestyle habits. It was designed as a one-year prospective cohort study. This program targeted non-obese persons at risk of developing lifestyle-related diseases and participants with hypertension, dyslipidemia, or hyperglycemia who were not included in the specific health guidance system in Japan. The Wadaiko rhythm exercise, which is a traditional performing art, is incorporated into this intervention as an enjoyable routine that can help participants continue the program, preventing them from dropping out. After a one-year follow-up, the effectiveness of the health promotion program was evaluated in 18 participants (2 males, 16 females; mean age 65.2 ± 3.4 years) and 92 controls. The results showed that triglyceride in the intervention group significantly decreased (−24.5 mg/dL; p = 0.02; 95% confidence interval [CI], −44.73 to −4.27) and high-density lipoprotein cholesterol significantly increased (+6.1 mg/dL; p < 0.01; 95% CI, 2.46 to 9.65), although levels in the control group did not change. These results suggest that the health promotion program could contribute to lifestyle habit improvements in those who are excluded from receiving specific health guidance.

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.

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.

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.