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Purpose Depending on its histological subtype, salivary gland carcinoma (SGC) may have a poor prognosis. Due to the scarcity of preclinical experimental models, its molecular biology has so far remained largely unknown, hampering the development of new treatment modalities for patients with these malignancies. The aim of this study was to generate experimental human SGC models of multiple histological subtypes using patient-derived xenograft (PDX) and organoid culture techniques. Methods Tumor specimens from surgically resected SGCs were processed for the preparation of PDXs and patient-derived organoids (PDOs). Specimens from SGC PDXs were also processed for PDX-derived organoid (PDXO) generation. In vivo tumorigenicity was assessed using orthotopic transplantation of SGC organoids. The pathological characteristics of each model were compared to those of the original tumors using immunohistochemistry. RNA-seq was used to analyze the genetic traits of our models. Results Three series of PDOs, PDXs and PDXOs of salivary duct carcinomas, one series of PDOs, PDXs and PDXOs of mucoepidermoid carcinomas and PDXs of myoepithelial carcinomas were successfully generated. We found that PDXs and orthotopic transplants from PDOs/PDXOs showed similar histological features as the original tumors. Our models also retained their genetic traits, i.e., transcription profiles, genomic variants and fusion genes of the corresponding histological subtypes. Conclusion We report the generation of SGC PDOs, PDXs and PDXOs of multiple histological subtypes, recapitulating the histological and genetical characteristics of the original tumors. These experimental SGC models may serve as a useful resource for the development of novel therapeutic strategies and for investigating the molecular mechanisms underlying the development of these malignancies.

This Japanese single-center retrospective cohort study aimed to evaluate the real-world therapeutic outcomes of pembrolizumab or pembrolizumab plus chemotherapy (pembrolizumab regimen) as first-line therapy for patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).Thirty-two Japanese patients with R/M SCCHN treated with the pembrolizumab regimen between January 2020 and January 2022 were analyzed. The primary endpoint of the study was overall survival.The median follow-up duration was 9.8 months (range=1.6-25.1 months). Fourteen patients received pembrolizumab alone, whereas the others received pembrolizumab with chemotherapy. The 1-year overall and progression-free survival rates were 64.5% (95% CI=38.9-81.6) and 54.9% (95% CI=33.9-71.8), respectively. The objective response rate was 56.2%. The Kaplan-Meier analysis showed that patients with favorable objective responses and an Eastern Cooperative Oncology Group performance status of 0 had longer survival. Immune-related adverse events (irAEs) occurred in 16 out of 32 patients (50.0%) during treatment; however, there were no irAEs greater than grade 4.The observed therapeutic efficacy and safety of pembrolizumab in real-world clinical practice was consistent with the data of the KEYNOTE-048 trial.

We previously identified hypopharyngeal cancer as an independent risk factor for the incidence of newly diagnosed secondary cancers after the treatment of early-stage laryngeal, oropharyngeal, and hypopharyngeal cancers. We subsequently used a different patient cohort to validate the usefulness of this factor during the follow-up period in these patients. Patients who underwent transoral surgery (TOS) as a definitive treatment between April 1, 2016, and September 30, 2020, were included. The incidence of secondary cancer was evaluated in hypopharyngeal and other cancers. Overall survival (OS), recurrence-free survival (RFS), and disease-free survival (DFS) outcomes were evaluated. Statistical analyses based on the risk factors were also performed. Incidence of new secondary cancer was 30% in hypopharyngeal cancer patients as compared to 11% in other cancer patients, and the risk was 3.60-fold (95% confidence interval 1.07–12.10) higher after definitive treatment for initial head and neck cancers. The 3-year OS, RFS, and DFS rates were 98%, 86%, and 67%, respectively. Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, who were initially treated with TOS, hypopharyngeal cancer patients had a higher risk of newly diagnosed secondary cancers as observed during the follow-up period.

Our prospective study of patients with early T-stage head and neck cancer indicated a high incidence of newly diagnosed secondary malignancies during the follow-up period. We aimed to determine the incidence rate and risk factors of secondary malignancies in early-stage head and neck cancer patients. We sub-analyzed the patient data of a previous study focusing on secondary cancer incidence. The endpoints were statistical analyses of risk factors and survival and incidence rates. The incidence rate of secondary cancer was 37%, the crude incidence of second primary cancers was 10.6 per 100 person-years, and the 5 year secondary cancer-free survival rate was 63%. The hypopharynx as the primary site was an independent significant predictive factor (odds ratio 3.96, 95% confidence interval 1.07–14.6, p = 0.039). Early stages of laryngeal, oropharyngeal, and hypopharyngeal cancer had a risk of secondary cancer, especially hypopharyngeal cancer. Attention to the secondary cancer has to be paid during the follow-up period after controlling the early-stage disease. These findings highlight the need for awareness of the incidence of secondary cancer in cases of early-stage primary head and neck cancer.

In this study, we examine the relationship between developmental insufficiency of mastoid air cells and abnormal morphology of the paranasal sinuses in patients with chronic otitis media (COM) and acquired middle ear cholesteatoma (AMEC) using precise image assessment, in order to evaluate whether the anatomical features of paranasal sinuses has any impact on the pathogenesis in COM and AMEC.A total of 127 patients, including 45 COM patients and 82 AMEC patients, were enrolled for this study. The existence of nasal septal deviation, the existence of paranasal sinus opacification, the modified Lund-Mackay score, the diameters of the paranasal sinuses, the Vidic classification, mastoid development, and cranial size were assessed by CT examination. A further 76 adult patients who underwent high-resolution CT imaging of their skull bone for other diseases were enrolled as the control.The AMEC group showed a significantly shorter sphenoid length (P 0.01) and lower Vidic classification score (P 0.01) compared to the control group in this study. In addition, we observed that patients with AMEC had less pneumatization of the mastoid air cells compared to the control individuals, and that the sphenoid length of the poor MC score group was significantly shorter than that of the good MC score group.Our results suggested that the developmental deficiency in sphenoid length caused by long-standing pediatric rhinosinusitis might indicate the potential of chronic middle ear inflammation in childhood and impact the pneumatization of mastoid air cells. Therefore, chronic rhinosinusitis during the childhood and adolescence might play a role in the pathophysiology of AMEC.

To evaluate the feasibility of narrow-field supracricoid partial laryngectomy with cricohyoidoepiglottopexy (NF-SCPL-CHEP).Between 2019 and 2020, five patients with glottic cancers underwent NF-SCPL-CHEP. The mean durations of surgical drains, tracheostomy canula, and nasogastric tube use were evaluated. Length of stay following NF-SCPL-CHEP was compared with that of our open SCPL historical controls. A case summary is provided for the first patients, with detailed information about postoperative management and function.All five patients achieved uneventful postoperative recoveries without major complications. The average time for surgical drains, tracheostomy canula, and nasogastric tube use were 2, 15, and 46 days, respectively. The mean overall hospitalization period was 36 days for NF-SCPL-CHEP patients. The mean period of hospitalization based on our early experiences between 1997 and 2005 with classical open SCPL was 72 days. All patients were fully functional and local recurrences or distant metastases were not encountered during a mean observation period of 39 months.NF-SCPL-CHEP with 6 cm cervical access appeared technically feasible and oncologically sound in this initial clinical experience. An extra 2 cm incision, which enabled lateral neck dissection, was not felt to detract from the overall minimally invasive basis of NF-SCPL-CHEP. The clinical results were encouraging with limited complications and predictable postoperative recovery. The length of stay for patients undergoing NF-SCPL was half that of open SCPL historical controls. Less damages to local circulation may associate with the positive influences. Further study with a large patient sample across multiple institutions are needed to carefully evaluate long-term functional and oncological outcomes.

Purpose: Salivary gland carcinoma (SGC) has poor prognosis depending on the histological subtype. However, due to the scarcity of preclinical experimental models, its molecular biology remains largely unknown, hampering the development of new treatment modalities for patients with these malignancies. The aim of this study is to generate human SGC experimental models for multiple histological subtypes using patient-derived xenograft (PDX) and organoid culture techniques. Methods: Tumor specimens from surgically resected SGC were proceeded for the preparation of PDX and patient-derived organoid (PDO). Specimens from SGC PDX were also proceeded for PDX-derived organoid (PDXO). in vivo tumorigenicity was assessed by orthotopic transplantation of SGC organoids. The pathological characteristics of each model were compared to those of the original tumor by Immunohistochemistry analysis. The genetic traits of PDO samples were analyzed by RNA-seq. Results: A series of SGC PDOs, PDX and PDXO models using human SGC tumor section for salivary duct carcinoma, mucoepidermoid carcinoma, and myoepithelial carcinoma were successfully generated. Through passaging, each model was confirmed to almost maintain the pathological characteristics of the original tumor and the genetic traits including transcription profiles, genomic variation and the presence of fusion genes of corresponding histological subtypes. Conclusion: We here described success in the generation of in vitro and in vivo SGC models of multiple histological subtypes using organoid culture and PDX, recapitulating the histological and genetical characteristics of original tumor. Thus, our experimental models of SGC could be a powerful resource for the development of novel therapeutic agents and investigating the molecular biology of these malignancies.

Background/aim This Japanese multiple-center retrospective study aimed to examine the real-world treatment outcomes of the EXTREME regimen as a first-line therapy for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Patients and methods A total of 100 R/M SCCHN patients treated with the EXTREME regimen as first-line therapy were analyzed. The treatment outcomes were evaluated to compare patient and treatment characteristics with overall survival. Results Patients treated with carboplatin-based EXTREME regimen showed similar overall survival with less adverse effects compared to that of patients using cisplatin. The post-progression survival was significantly longer in patients treated with second-line treatment following the EXTREME regimen than in those without second-line treatment. Conclusion The carboplatin-based EXTREME regimen was more feasible with similar treatment outcomes compared to cisplatin-based EXTREME regimen. In addition, subsequent lines of therapy contributed to improvement of survival for R/M SCCHN patients.

Background Transoral surgery (TOS) has been widely applied for early T‐stage head and neck cancer (HNC). The resection is performed with a minimum safety margin for function preservation under a limited surgical field; therefore, it is difficult to have a strong conviction about the complete resection. This study aims to evaluate the completeness of the initial TOS procedure; possibility of primary control by TOS alone; and predictive factors in patients with early T‐stage laryngeal, oropharyngeal, and hypopharyngeal cancer. Methods Patients were treated by TOS at the primary site with or without neck dissection. The patients were divided into two groups based on the pathological evaluation of their surgical specimens: the control (observation) group, in that the resection was considered complete and the intervention (second‐look procedure) group, in that incomplete tumor resection was suspected. The predictive factors for the possibility and/or limitations of complete resection by TOS were then analyzed. Results The study enrolled 26 and 25 patients in the control and intervention group, respectively. The success rate for single resection was 66% and the predictive factor was tumor depth obtained by enhanced computed tomography (CT) examination (odds ratio, 7.870, P = .0243). The success rate for definitive therapy by TOS alone was 83% and the predictive factor was poor differentiation observed on pathological examination (odds ratio, 6.800, P = .0248). Conclusions TOS has the potential for both definitive resection and function preservation with minimal invasiveness. Identification of the risk factors for TOS is advantageous for accurate treatment selection in patients with early T‐stage HNC., Transoral surgery has the potential for both definitive resection and function preservation with minimal invasiveness. Identification of the risk factors for transoral surgery, such as tumor depth obtained by enhanced CT examination and poor differentiation observed on pathological examination, is advantageous for accurate treatment selection in patients with early T‐stage head and neck cancer.

Salivary gland carcinoma (SGC) has poor prognosis depending on the histological subtype. However, due to the scarcity of preclinical experimental models, its pathogenesis remains largely unknown, hampering the development of new treatment modalities for patients with these malignancies. Here, we first report the establishment of a large collection of human SGC experimental models for multiple histological subtypes using patient-derived xenograft (PDX) and organoid culture techniques with our previously optimized method. Additionally, we successfully generated organoids by culturing established PDXs (PDX-derived organoids). Through passaging, each pre-clinical model was confirmed to maintain the pathological characteristics of the original tumor and the genetic traits of corresponding histological subtypes. Finally, we confirmed that these organoids were available for pharmacologic studies. Thus, our comprehensive models of SGC could be a powerful resource for the development of novel therapeutic agents and investigating the pathogenesis of these malignancies.

We had previously identified the following risk factors for insufficient control of early T-stage head and neck cancer by transoral surgery (TOS): (1) tumor thickness 7 mm on enhanced computed tomography (CT), and (2) poor differentiation in pathological examination. We subsequently used a different patient cohort to validate the usefulness of these factors in determining the need for adaptation of TOS.A prospective observational study METHODS: Patients who received TOS as a definitive treatment between April 1, 2016 and September 30, 2020 were included. Primary control rates (by single TOS and TOS alone) in relation to the above-mentioned risk factors were calculated. Overall (O), recurrence-free (RF), and disease-free (DF) survival (S) outcomes were evaluated. A combination analysis based on the number of risk factors was also performed.Patients with tumor thickness 7 mm had a 2.88-fold [95% confidence interval (CI) 1.01-8.51] higher risk of incomplete primary resection by single TOS, while patients who showed poor differentiation on pathological assessments had a 13.14-fold (95% CI 3.66-47.14) higher risk of insufficient primary control by TOS alone. The 3 year OS, RFS, and DFS rates were 99%, 83%, and 63%, respectively. Patients with both risk factors had a 93.00-fold (95% CI 4.99-1732.00) higher risk of incomplete primary control by TOS alone.Among patients with early-stage laryngeal, oropharyngeal, and hypopharyngeal squamous cell carcinoma, primary control by TOS alone may not be achieved in patients with both risk factors, that is, tumor thickness 7 mm as measured by enhanced CT and poor differentiation on pathological examination.

To generate a reliable preclinical model system exhibiting the molecular features of salivary adenoid cystic carcinoma (ACC) whose biology is still unclear due to the paucity of stable cell cultures. To develop new in vitro and in vivo models of ACC, the techniques of organoid culture and patient-derived tumor xenograft (PDX), which have attracted attention in other malignancies in recent years, were applied. Tumor specimens from surgically resected salivary ACC were proceeded for the preparation of PDX and organoid culture. The orthotopic transplantation of patient-derived or PDX-derived organoids was demonstrated into submandibular glands of NSG mice and those histology was evaluated. PDX-derived organoid cells were evaluated for the presence of MYB-mediated fusion genes and proceeded for in vitro drug sensitivity assay. Human ACC-derived organoids were successfully generated in three-dimensional culture and confirmed the ability of these cells to form tumors by orthotopic injection. Short-term organoid cell cultures from two individual ACC PDX tumors were also established that maintain the characteristic MYBL1 translocation and histological features of the original parent and PDX tumors. Finally, the establishment of drug sensitivity tests on these short-term cultured cells was confirmed using three different agents. This is the first to report an approach for the generation of human ACC-derived organoids as in vitro and in vivo cancer models, providing insights into understanding of the ACC biology and creating personalized therapy design for patients with ACC.

Objective The purpose of this study is to validate the applicability of new TNM classification for human papillomavirus (HPV)-related oropharyngeal cancer (OPC) in the 8th edition of the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) TNM staging system in Japan. Methods A total of 91 OPC patients treated with radiation-based therapy between November 2001 and July 2015 were analyzed retrospectively in this study. HPV infection status was evaluated using tumor p16 expression. Results 40 OPC patients (44.0%) had HPV-positive disease in this study. The distribution of disease stage of HPV-positive OPC patients dramatically changed from the 7th edition to the 8th edition of AJCC/UICC TNM classification. However, neither the 8th edition nor the 7th edition of the AJCC/UICC TNM staging system could adequately predict outcomes of HPV-positive OPC patients in our patient series. On the other hand, our multivariate analysis indicated that matted nodes and age ≥63 were independent prognostic factors for progression-free survival. In addition, HPV-positive OPC patients with stage I without matted nodes showed significantly better overall and progression-free survival compared with those with stage I with matted nodes and stages II and III in the 8th edition of the AJCC/UICC TNM staging system (P = 0.008, and P = 0.043, respectively). Conclusion Our results suggested that matted nodes of HPV-positive OPC patients might be additionally examined to apply the 8th edition of AJCC/UICC TNM classification for more adequate predicting outcomes of HPV-positive OPC patients.

Objective/Hypothesis We previously reported that the metabolic tumor volume (MTV) of a primary tumor was an independent prognostic factor for survival in laryngeal carcinoma treated by radiotherapy (RT)-based protocol. The purpose of this study was to evaluate the difference in survival outcomes between surgery-based and RT-based treatment in patients with a MTV laryngeal cancer. Study Design An individual retrospective cohort study. Methods We reviewed the records of 63 patients with laryngeal cancer showing a primary tumor with a high MTV value (≥ 4.9 mL). The patients were separated into two groups by primary treatment strategy: 22 patients were included in the surgery group, and 41 patients were included in the RT group. Clinical factors and treatment modalities were analyzed for their association with survival. Results Multivariate analysis, including age, sex, subsite, T classification, nodal metastasis, and treatment modality, showed that the subsite (hazard ratio [HR] 2.55, P = 0.043) and treatment modality (HR 3.98, P = 0.019) were independent predictors for survival. The Kaplan-Meier curves for 2-year relapse-free survival rates and overall survival rates for patients in the surgery and RT groups were 74.2% versus 38.8% (P = 0.025) and 80.1% versus 66.7% (P = 0.078). Conclusions Patients with a high metabolic volume laryngeal cancer treated by a surgery-based protocol showed better relapse-free survival and overall survival than did those undergoing RT-based treatment. Pretreatment MTV assessment could be useful in planning the treatment strategy for patients with a laryngeal cancer. Level of Evidence 2b. Laryngoscope, 2016

Background The purpose of this study was to elucidate the prognostic significance of the pretreatment metabolic tumor volume (MTV) in patients with piriform sinus carcinoma treated by radiation-based therapy. Methods This retrospective study included 100 patients with piriform sinus carcinomas who had received treatment by radiation-based therapy. The MTV values were obtained from pretreatment positron emission tomography (PET). The association between clinical factors, including the MTV, and survival was analyzed. Results Kaplan–Meier estimates revealed the 5-year disease-free survival (DFS) rates were significantly poorer for patients with a high MTV compared to those with a low MTV. In the multivariate analysis, MTV (p < .001), nodal metastasis (p = .011), and applied chemotherapy regimen (p = .004) were found to be independent prognostic factors for DFS. Conclusion The locoregional MTV is a prognostic factor for DFS in patients with piriform sinus carcinoma treated by radiation-based therapy. © 2016 Wiley Periodicals, Inc. Head Neck, 2016

BACKGROUND We confirmed the safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel in a small number of patients with cis-platinum–intolerant core high-risk head and neck cancer. OBJECTIVE To assess treatment efficacy, we planned a phase 2 study of postoperative bio-chemoradiotherapy for patients with cis-platinum–intolerant core high-risk head and neck cancer and will compare the results to those of previously collected radiotherapy data. METHODS Patients who underwent definitive surgery for oral cavity, laryngeal, oropharyngeal, or hypopharyngeal advanced cancer, whose postoperative pathological results indicated core high risk for recurrence (eg, positive margin in the primary site or extranodal extension) and who were cis-platinum–intolerant, will undergo postoperative bio-chemoradiotherapy. The primary end point is 2-year disease-free survival. RESULTS The expected 2-year disease-free survival is set at 55%, and the calculated sample size is 35 patients, according to a statistical analysis based on previous reports. CONCLUSIONS This treatment method is expected to improve the survival rate of patients with severe head and neck cancer. CLINICALTRIAL UMIN Clinical Trials Registry UMIN000031835; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000036355 (Archived by WebCite at http://www.webcitation.org/71fejVjMr)

Definitive chemoradiotherapy (CRT) is used to treat lymph node metastatic head and neck cancer patients. Regional control of the neck disease is important to improve the prognosis, and the accuracy of the method used to evaluate the metastatic lymph node(s) after CRT is crucial to the decision-making process for any following salvage surgery. Patients undergoing CRT were divided in two groups of patients of those showing complete clinical response (CR) and those showing clinical non-response (non-CR), as assessed by computed tomography (CT) and/or magnetic resonance imaging (MRI), ultrasonography, fluorodeoxyglucose-positron emission tomography (FDG-PET), and fine needle aspiration cytology. The responses (CR vs. non-CR) were compared with the actual clinical outcomes. For the interim analysis, the study period was broken down into two periods, namely, the exploratory phase (patients treated between January 2002 and April 2012) and the validating phase (patients treated between May 2012 and January 2014). The sensitivity, specificity, and accuracy were as follows: CT and/or MRI, 66.7, 73.8, and 72.8 %, respectively, in the exploratory phase; ultrasonography, 91.7, 70.6, and 73.4 %, respectively, in the exploratory phase and 80.0, 82.8, and 82.4 %, respectively, in the validating phase; FDG-PET, 50.0, 97.5, and 91.3 %, respectively, in the exploratory phase and 60.0, 100, and 94.1 %, respectively, in the validating phase; cytology, 68.4, 95.9, and 90.3 %, respectively, in the exploratory phase and 66.7, 100, and 85.7 %, respectively, in the validating phase. Based on our results, CT and/or MRI appear to be inadequate methods for the evaluation of the response of lymph node(s) to CRT. In contrast, ultrasonography appears to be a highly sensitive and useful tool for positive screening at 6–8 weeks after CRT, and FDG-PET appears to be a highly specific and useful tool for negative screening at 8–12 weeks after CRT.

Chemoradiotherapy (CRT) is used to treat cervical lymph node(s) metastatic head and neck cancer patients. Evaluation and treatment of lymph node(s) after CRT is important to improve the prognosis. Prior to CRT, we determined the TNM stage by visual and imaging examinations. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were calculated from the results of fluorodeoxyglucose-positron emission tomography (FDG-PET). After CRT, the patients were divided in two groups—complete response (CR) and non-CR—and their responses were compared with the clinical characteristics. T4, N2b, N2c and TLG2.5 ≥18.8 were statistically significant predictive indices before CRT. The odds ratio, 95 % confidence interval and p value were, respectively—T4: 2.73, 1.15–6.51, 0.0230; N2b: 6.96, 1.50–32.3, 0.0132; N2c: 11.80, 2.37–58.50, 0.00258; and TLG2.5 ≥18.8: 6.25, 2.17–18.00, 0.000672. TLG was found to be a good predictive factor for metastatic lymph node(s) prior to CRT treatment. After CRT treatment, FDG-PET was found to be highly specific and useful for negative screening.

It is known that cochlear implantation for deaf patients with eosinophilic otitis media (EOM) is safe and can provide good speech perception. However, the best timing of implant surgery in patients with EOM is not yet known. The aim of this case report is to suggest the appropriate timing of the surgery in EOM patients with deaf. Cochlear implantation was indicated in two patients with EOM. One underwent cochlear implantation in the absence of any ear discharge. In the other case, implant surgery was delayed for three years due to persistent ear discharge. No complications related to implant device or skin flap were observed in either case. The speech recognition score after implantation was good in the first case and poor in the second case. Perioperative complications were manageable even in the patient with persistent ear discharge. However, the delay in implant surgery due to the persistent ear discharge resulted in a poor speech recognition score. Early implantation should be considered even in EOM patients with ear discharge, although the presence of active middle ear inflammation is regarded as one of the contraindications for implantation according to the current Japanese guidelines.

The Hyodo scoring system during the endoscopic procedure has been proposed as a new tool for evaluating oral intake feasibility. However, the effectiveness of the information obtained from this procedure in predicting aspiration is not fully elucidated. The aim of this study was to assess the significance of clinical factors, including Hyodo scores, for predicting the risk of aspiration.Five hundred and twenty-eight endoscopic swallowing examinations were performed. Clinical factors, including age, sex, disease type, history of aspiration pneumonia, cognitive function, presence of tracheostomy, presence of vocal cord paralysis, consciousness level on the Japan Coma Scale, ECOG Performance Status, serum albumin level and Hyodo score, were obtained for each examination. The relationship between each of these factors and the presence of aspiration during endoscopic procedure was evaluated.Three hundred and thirty-two patients (62.9%) were scored less than 5, 153 (29.0%) were scored between 5 and 8, and 43 (8.1%) were scored above 8. The number of patients with aspiration was 133 (25.2%). ROC analysis revealed that a cut-off point of 6 for Hyodo score was effective for predicting aspiration, with a sensitivity of 0.65 and a specificity of 0.86. History of aspiration pneumonia (OR 1.87, P0.001), vocal cord paralysis (OR 2.23, P0.001), PS≥3 (OR 2.47, P0.001) and Hyodo score6 (OR 9.08, P0.001) were found to be independent predictive factors for aspiration.The Hyodo scoring method was easy for otolaryngologists to perform and the scores were useful for predicting aspiration with moderate sensitivity and high specificity. Hyodo score6, history of aspiration pneumonia, vocal cord paralysis, and PS≥3 were independent predictive factors for aspiration and that a Hyodo score above 6 was the statistically strongest predictor for aspiration.

The preservation of residual hearing after conventional cochlear implantation (CI) is frequently observed when atraumatic soft surgery is adopted. The purpose of this study was to elucidate the predictive factors for residual hearing preservation after atraumatic CI.This study included 46 patients who underwent CI based on an atraumatic technique using a standard-length flexible electrode implant through a round window approach.Cochlear volume was measured using magnetic resonance imaging (MRI). Cochlear duct length (CDL) was taken as the length of the scala media measured using computed tomography (CT). The association between residual hearing preservation and cochlear volume/CDL was then examined.Cochlear volume and CDL were significantly larger in patients with complete hearing preservation than in those with hearing loss. Multivariate logistic regression analysis revealed that cochlear volume was a significant predictive factor for residual hearing preservation.Residual hearing preservation after conventional CI was observed in patients with a larger cochlear volume and longer CDL. Cochlear volume could be a predictive factor for residual hearing preservation after conventional CI.

The purpose of this study is to validate the concept of lymph node ratio (LNR) in head and neck squamous cell carcinoma (HNSCC).A total of 63 patients with HNSCC who underwent resection of the primary tumor combined with neck dissection in our institution were analyzed in this study. LNR was defined as the number of positive lymph nodes divided by the total number of lymph nodes excised. LNR was categorized into two groups (0.068 and ≥0.068) according to the results of receiver-operating characteristic plots for determination of the cut-off value.LNR≥0.068 was associated with poor overall survival (OS), progression-free survival (PFS) and locoregional recurrence-free survival (LRFS) after resection of the primary tumor combined with neck dissection in patients with HNSCC. Univariate and multivariate data analysis showed that LNR≥0.068 was an independent prognostic factor for OS, PFS and LRFS. Both pathological T stage status (pT3 or 4) and ≥3 positive LNs were also an independent prognostic factors for PFS in patients with HNSCC in our univariate and multivariate analysis.These results suggested that LNR could be useful tools in identifying HNSCC patients with poor outcomes.

BACKGROUND Transoral videolaryngoscopic surgery (TOVS) has been widely applied for early T stage head and neck cancer. The resection is performed with a minimum safety margin for function preservation under a limited surgical field of view, making it difficult to be certain of complete resection. OBJECTIVE Our aim is the evaluation of the completeness of resection by initial TOVS resection, and the possibility of primary control by TOVS alone, allowing for repeat procedures for function preserving treatment in early T stage laryngeal, oropharyngeal, and hypopharyngeal cancer patients. METHODS Patients are treated by TOVS for the primary site with or without neck dissection. Patients are divided in two groups based on the results of the pathological evaluation of the surgical specimen; the control group in which the resection is considered to be complete, and the intervention (second-look procedure) group in which incomplete tumor resection is suspected. The predictive factors for the possibility of complete resection by TOVS will then be analyzed. RESULTS Patient enrollment started on January 1, 2014, and closed on March 31, 2016, with 54 patients. The control group consists of 27 patients, the intervention group is 21 patients, and 6 patients were excluded. There were no clinical differences between the control and intervention groups. The observation period will end on December 31, 2018. CONCLUSIONS TOVS has potential for both definitive resection and function preservation with minimal invasiveness. Identifying the limitations of TOVS is beneficial to ensure accurate treatment selection in early T stage head and neck cancer patients. CLINICALTRIAL UMIN Clinical Trials Registry: UMIN000012485; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi? recptno=R000014472 (Archived by WebCite at http://www.webcitation.org/6v1b741Iw)

To confirm the efficacy and safety of cetuximab and docetaxel in postoperative radiotherapy for high-risk head and neck cancer patients who cannot to be administered high-dose cisplatin. The eligibility criteria required stage III–IVB head and neck cancer patients who had undergone total resection, and for whom pathological evaluation revealed positive or close margins in the primary site and/or extracapsular nodal extension and/or two or more nodal metastases. In each case, the patients general condition prevented the use of high-dose cisplatin. Instead, they received cetuximab and docetaxel every week during a 66.6 Gy course of postoperative radiotherapy. Eleven patients were enrolled; the median follow-up period was 22 months, and the 1- and 2-year disease free survival rates were 91 and 55%, respectively. Grade 3 adverse events included oral mucositis, radiation dermatitis, reduced white blood cell and neutrophil counts, lung infection, aspiration, and hyponatremia; however, no grade 4 adverse events were observed. Administration of cetuximab and docetaxel during postoperative radiotherapy for high-risk poor condition head and neck cancer patients in poor general condition was both feasible and tolerable. With the safety of this treatment confirmed, we propose a phase trail to further clarify the efficacy of cetuximab and docetaxel use for high-risk cisplatin-intolerant patients.

The purpose of the study is to review our experience with concurrent chemoradiotherapy (CCRT) for patients with advanced resectable squamous cell carcinoma (SCC) of the hypopharynx and to evaluate the factors affecting survival and larynx preservation. Retrospective study. The records of 102 patients with Stage III or IV resectable SCC of the hypopharynx treated with CCRT between January 1998 and August 2010 were reviewed. Of the 102 patients, 62 were treated with high-dose regimens including cisplatin, 5-fluorouracil, methotrexate, leucovorin or docetaxel, cisplatin, and 5-fluorouracil. The remaining 40 were treated with low-dose regimens including carboplatin and uracil-tegafur, weekly docetaxel, or S-1. Radiotherapy was delivered 5 days a week using a single daily fraction of 1.8–2.0 Gray (Gy), to a total dose of 64.8–70.2 Gy. Overall survival (OS), disease-specific survival (DSS), and DSS with larynx preservation were estimated using Kaplan–Meier methods. The log-rank test and Cox proportional hazards regression were used to identify significant prognostic factors for OS, DSS, and DSS with larynx preservation. The 5-year OS and DSS for all patients treated with CCRT were 51.3 and 64.3 %, respectively. The 5-year DSS with larynx preservation was 55.5 %. On multivariate analysis, the content of chemotherapy was a significant predictor of OS and DSS for patients undergoing CCRT; N stage was a significant prognostic factor for DSS and larynx preservation. The treatment method including the indication for CCRT may be determined by the contents of the chemotherapy and the N stages of SCC of the hypopharynx.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is used to treat advanced head and neck cancer. The accuracy of evaluating lymph nodes metastases following CCRT is important for subsequent therapy. PATIENTS AND METHODS: Patients were divided into two groups according to the nodal status, the complete response (CR) and the non-CR groups, as determined by imaging and fine-needle aspiration cytology (FNAC) performed 4-8 weeks after the CCRT, and the findings were compared with the status 6 months after the treatment completion. RESULTS: The sensitivity, the specificity, positive predictive value, negative predictive value and accuracy of each evaluation method were as follows: 66.7%, 73.5%, 26.7%, 93.8% and 72.5%, respectively, for computer tomography (CT) and magnetic resonance imaging (MRI); 91.7%, 69.9%, 30.6%, 98.3% and 72.6% for ultrasonography (US) ; 50.0%, 96.4%, 66.7%, 93.0% and 90.5% for fluorodeoxyglucose-positron emission tomography (FDG-PET) or PET-CT; and 68.4%, 96.1%, 81.3%, 92.5% and 90.6% for FNAC. CONCLUSION: To evaluate the response of lymph node(s) treated by CCRT, US is useful as a positive screening tool and FDG-PET and PET-CT as negative screening tools. FNAC is useful in evaluating suspicious lymph nodes in both positive and negative cases.

Background Radioresistance remains a critical issue in the use of radiotherapy for the treatment of head and neck squamous cell carcinoma (HNSCC). This study evaluated the efficacy of combination treatment with OBP-301, a telomerase-specific replication-selective adenovirus, and radiotherapy in overcoming radioresistance by examining its effect on radiation-resistant HNSCC cells. Methods Radiation-resistant HNSCC cells were treated with OBP-301 and radiation in vitro and in an orthotopic nude mouse model in vivo and synergism was assessed. Apoptosis and expression of MRN complex, which plays a key role in DNA repair machinery, were also analyzed. Results Infection with OBP-301 was found to enhance the antitumor efficacy of radiation both in vitro and in vivo by inhibiting MRN complex expression and increasing apoptosis induction. Conclusion Combined OBP-301 and radiation therapy seems to overcome radioresistance in HNSCC cells by inhibiting DNA repair machinery, and may thus be a novel therapeutic strategy for treating HNSCC. © 2013 Wiley Periodicals, Inc. Head Neck 36: 411–418, 2014

This is a case report of a 58-year-old woman with advanced small-cell undifferentiated (neuroendocrine) carcinoma of the nasal cavity treated with concurrent chemoradiotherapy (CCRT) with irinotecan and cisplatin. No recurrence has been observed more than 5 years after treatment. CCRT with irinotecan and cisplatin is regarded as effective for neuroendocrine small-cell carcinoma of the nasal cavity.

We previously reported that the metabolic tumor volume (MTV) of a primary tumor was an independent prognostic factor for survival in laryngeal carcinoma treated by radiotherapy (RT)-based protocol. The purpose of this study was to evaluate the difference in survival outcomes between surgery-based and RT-based treatment in patients with a MTV laryngeal cancer.An individual retrospective cohort study.We reviewed the records of 63 patients with laryngeal cancer showing a primary tumor with a high MTV value (≥ 4.9 mL). The patients were separated into two groups by primary treatment strategy: 22 patients were included in the surgery group, and 41 patients were included in the RT group. Clinical factors and treatment modalities were analyzed for their association with survival.Multivariate analysis, including age, sex, subsite, T classification, nodal metastasis, and treatment modality, showed that the subsite (hazard ratio [HR] 2.55, P = 0.043) and treatment modality (HR 3.98, P = 0.019) were independent predictors for survival. The Kaplan-Meier curves for 2-year relapse-free survival rates and overall survival rates for patients in the surgery and RT groups were 74.2% versus 38.8% (P = 0.025) and 80.1% versus 66.7% (P = 0.078).Patients with a high metabolic volume laryngeal cancer treated by a surgery-based protocol showed better relapse-free survival and overall survival than did those undergoing RT-based treatment. Pretreatment MTV assessment could be useful in planning the treatment strategy for patients with a laryngeal cancer.2b. Laryngoscope, 127:862-867, 2017.

Objective This study evaluates the utility of fluorodeoxyglucose-positron emission tomography (FDG-PET) in patients with head and neck squamous cell carcinoma (HNSCC) who received concurrent chemoradiotherapy (CCRT). Methods Sixty-five patients were recruited for this study between November 2002 and April 2007. The FDG-PET scan was performed before treatment and 4–6 weeks after treatment. Results The mean of maximum standardized uptake value (SUVmax) before treatment at the primary tumor site was 8.1 (range, 2–22). The sensitivity of FDG-PET for the diagnosis of primary tumor site was 98%. The mean of SUVmax after treatment was 2.6 (range, 2–5). The sensitivity, specificity, and accuracy of FDG-PET for the diagnosis of primary tumor site after treatment were 100%, 40%, and 46%, respectively. The mean of SUVmax before treatment at the nodal site was 4.7 (range, 2–16). The mean of SUVmax after treatment was 2.0 (range, 2–6.7). The pre-treatment SUVmax of T2, T3, and T4 stages were significantly higher than that of the T1 stage. The N stage had no correlation in terms of the pre-treatment nodal site SUVmax. Conclusion Our results indicate that FDG-PET is a useful imaging method for evaluating the response of CCRT in patients with HNSCC. However, performing FDG-PET 4–6 weeks after treatment may be too early as it may give false-positive results due to fibrosis and scarring.

We assessed the sensitivity of positron emission tomography (PET) for detecting synchronous multiple primary cancers, particularly synchronous esophageal cancers in head and neck cancer patients. We retrospectively reviewed 230 head and neck cancer patients. All the patients routinely underwent the following examinations: urinalysis, occult blood, tumor marker detection [squamous cell carcinoma (SCC), cytokeratin fragment (CYFRA), and carcinoembryonic antigen (CEA)], esophagogastroduodenoscopy, colonoscopy (when CEA was high or occult blood was positive), abdominal ultrasonography, plain chest computed tomography (CT), and PET. Bronchoscopy was performed when CT revealed lung shadow of central region. Synchronous multiple primary cancers were detected in 42 (18.2%) patients. The diagnostic sensitivity of PET for synchronous primary cancers was as follows: esophagus, 7.6% (1/13); stomach, 25.0% (2/8); lung, 66.7% (4/6); head and neck, 75.0% (3/4); colon, 0% (0/1); kidney, 0% (0/1); and subcutaneous, 100% (1/1). The sensitivity of PET for detecting synchronous esophageal cancers is low because these are early-stage cancers (almost stage 0–I). Therefore, it is necessary to perform esophagogastroduodenoscopy for detecting synchronous esophageal cancers. PET is an important additional tool for detecting synchronous multiple primary cancers because the diagnostic sensitivity of PET in synchronous head and neck cancer and lung cancer is high. But PET has the limitation of sensitivity for synchronous multiple primary cancers because the diagnostic sensitivity of PET in synchronous esophageal cancer is very low.

Cetuximab is a chimeric IgG1 monoclonal antibody that targets epidermal growth factor receptor (EGFR). Cetuximab binds to EGFR and prevents phosphorylation of EGFR. Moreover, preclinical results have shown the ability of cetuximab to induce either complement-mediated tumor cell killing (CDC) or antibody-dependent cell-mediated-cytotoxicity (ADCC). We previously reported mutation in EGFR regarding head and neck squamous cell carcinoma (HNSCC) cell lines. In the present study, we analyzed the same 16 HNSCC cell lines for mutations in KRAS, PIK3CA, BRAF and PTEN. Furthermore, we evaluated cetuximab-mediated biological activities (antiproliferative effect by the MTT assay and ADCC) regarding these cell lines. Mutations in PIK3CA and PTEN were observed in two cell lines (2/16, 12.5%), but no mutation was observed in KRAS and BRAF. The antiproliferative effect of cetuximab by the MTT assay was not strong, and no correlation was observed between the antiproliferative effect of cetuximab and mutations in EGFR, KRAS, PIK3CA, BRAF and PTEN in these cell lines. Therefore, the mutation status of EGFR and downstream molecules were not useful for predicting the antitumor effects of cetuximab on HNSCC. Cetuximab-mediated ADCC was observed in these cell lines and might have been influenced by the expression of EGFR. Therefore, cetuximab-mediated ADCC seems to be an important part of the antitumor mechanisms of cetuximab and the expression levels of EGFR might influence the antitumor activity of cetuximab. Therefore, besides the antiproliferative effect of cetuximab by the MTT assay, it appeared important to evaluate cetuximab-mediated ADCC as well as EGFR expression in HNSCC cells.

The aim of this study was to evaluate the feasibility and toxicity of concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP) and 5-fluorouracil (5-FU) (TPF regimen) or with CDDP, 5-FU, methotrexate and leucovorin (PFML regimen) in previously untreated patients with advanced oropharyngeal squamous cell carcinoma (SCC).Fifty-six eligible patients with stage III or IV oropharyngeal SCC were treated with CCRT. Forty-four patients were men and 12 were women, and the average age of the patients was 58.8 years (range, 37-72 years). In the TPF group, patients received CCRT with the TPF regimen [docetaxel (50 mg/m(2), day 1), CDDP (60 mg/m(2), day 4) and a continuous 5-FU infusion (600 mg/m(2)/day, days 1-5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m(2), day 4), a continuous 5-FU infusion (600 mg/m(2)/day, days 1-5), methotrexate (30 mg/m(2), day 1) and leucovorin (10 mg/m(2)/day, days 1-5)]. The total radiation dose was between 66.6 and 70.2 Gy.The overall 5-year survival rate was 64.6% in all patients, 68.6% in the resectable group and 47.4% in the unresectable group. The 5-year disease-specific survival rate was 72.2% in all patients, 78.1% in the resectable group and 47.7% in the unresectable group. Regarding clinical stage, the 5-year disease-specific survival rates were 91% in stage III, 72% in stage IVa and 44% in stage IVb.CCRT with TPF or PFML regimen for advanced oropharyngeal SCC is tolerable and effective, especially in patients with resectable disease.

The aim of this study was to verify the effectiveness of positron emission tomography (PET) in detecting primary sites in carcinoma of unknown primary (CUP) patients. In this study, CUP represented a group of heterogeneous tumors that shared the clinical manifestation of metastatic carcinoma with no obvious primary site at the time of first diagnosis, which included clinical investigations, computed tomography, magnetic resonance imaging and panendoscopy. We reviewed the records of 24 patients with CUP between January 1995 and December 2009. The patients who demonstrated additional tracer uptake sites other than previously known metastatic lesions by PET scan were done direct biopsies for the sites of accumulation. Patients who had a negative PET scan or for whom the primary site could not be identified by direct biopsies underwent examination under anesthesia of the at-risk occult tumor sites. PET scan demonstrated focal accumulation suspicious for primary tumor in 12 (50.0%) of 24 patients: tonsil 5, nasopharynx 3, hypopharynx 1, tongue 1, larynx 1, and maxillary sinus 1. A subsequent biopsy of these sites revealed primary cancer in 9 (37.5%) of 24 patients: tonsil 5, nasopharynx 1, hypopharynx 1, tongue 1, and maxillary sinus 1. In the remaining three patients, no malignant cells were found by the biopsy of the accumulated area: nasopharynx 2, larynx 1. PET scans increase the yield of primary tumor by 37.5%. The sensitivity, specificity for PET scan were 80.8, 76.9%, respectively. PET scanning is useful in detecting primary cancer of CUP patients.

Background: We confirmed the safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel in a small number of patients with cis-platinum–intolerant core high-risk head and neck cancer. Objective: To assess treatment efficacy, we planned a phase 2 study of postoperative bio-chemoradiotherapy for patients with cis-platinum–intolerant core high-risk head and neck cancer and will compare the results to those of previously collected radiotherapy data. Methods: Patients who underwent definitive surgery for oral cavity, laryngeal, oropharyngeal, or hypopharyngeal advanced cancer, whose postoperative pathological results indicated core high risk for recurrence (eg, positive margin in the primary site or extranodal extension) and who were cis-platinum–intolerant, will undergo postoperative bio-chemoradiotherapy. The primary end point is 2-year disease-free survival. Results: The expected 2-year disease-free survival is set at 55%, and the calculated sample size is 35 patients, according to a statistical analysis based on previous reports. Conclusions: This treatment method is expected to improve the survival rate of patients with severe head and neck cancer. Trial Registration: UMIN Clinical Trials Registry UMIN000031835; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000036355 (Archived by WebCite at http://www.webcitation.org/71fejVjMr)

喉頭・下咽頭癌症例に対するconcurrent chemoradiotherapy (CCRT) により温存された喉頭の機能評価を行った。1998年10月から2003年9月までの期間に切除可能な喉頭・下咽頭扁平上皮癌病期II～IV期で一次治療としてCCRTを施行した32症例を対象とした。この32例中，すべての調査・検査に参加可能であったのは20例であった。喉頭機能の評価方法としては，アンケート調査，GRBAS尺度，最長発声持続時間，声域・話声位の測定，嚥下機能評価基準の栄養摂取方法，および気管切開孔の有無に関して検討した。喉頭・下咽頭癌のCCRT後は，大多数の症例で種々の程度の嗄声が認められ，また声域が狭まる症例があるが最長発声持続時間は75％の症例で正常範囲内であった。一方，1例を除くすべての症例 (97％) で，誤嚥性肺炎の既往なく経口摂取が可能となっていた。喉頭癌症例中2例で気管切開孔が閉鎖できなかったが，大多数の症例で喉頭の呼吸機能は温存されていると考えられた。

We compared concurrent chemoradiotherapy (CCRT) with docetaxel, cisplatin (CDDP), and 5-fluorouracil (5-FU) (TPF) with CCRT with CDDP, 5-FU, methotrexate and leucovorin (PFML) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) in terms of safety and efficacy on survival. A total of 100 patients were enrolled. The TPF group received CCRT with the TPF regimen [docetaxel (50 mg/m(2): day 1), CDDP (60 mg/m(2): day 4), and continuous 5-FU infusion (600 mg/m(2)/day: days 1-5)]. In the PFML group, patients received CCRT with the PFML regimen [CDDP (60 mg/m(2): day 4)], continuous 5-FU infusion (600 mg/m(2)/day: days 1-5), methotrexate (30 mg/m(2): day 1) and leucovorin (20 mg/m(2)/day: days 1-5)]. Both groups received 2 cycles of chemotherapy during definitive radiotherapy. The total radiation dose was between 66.6 and 70.2 Gray. The overall response rates after CCRT were 98 with 90% of a pathologically complete response (pCR) in the TPF group and 94 with 77% in the PFML group. For grade 3/4 adverse events, mucositis was more frequent in the PMFL group, and the TPF group showed a higher incidence of hematological toxicity. CCRT with TPF or PMFL for advanced SCCHN was tolerable and produced excellent survival rates.