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Purpose Radiation dermatitis is one of the most common acute toxicities induced by chemoradiation therapy (CRT) for head and neck cancer (HNC). The benefit of topical steroids in the management of radiation dermatitis is still unclear. This phase 3, multi-institutional, randomized, double-blind, placebo-controlled trial evaluated the efficacy and safety of topical steroids for radiation dermatitis in patients with locally advanced HNC receiving CRT. Methods and Materials Eligible patients were scheduled to receive bilateral neck irradiation (≥66 Gy) with concurrent cisplatin (≥200 mg/m2) as definitive or postoperative CRT. Patients were randomly assigned to receive either topical steroid or placebo when grade 1radiation dermatitis was observed or the total radiation dose reached 30 Gy. Basic skin care including gentle washing and moistening in the head and neck region was performed in both groups. The primary endpoint was the frequency of grade ≥2 radiation dermatitis, in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Grading of radiation dermatitis was performed by independent central review using photographs taken weekly. Results A total of 211 patients were enrolled (intention to treat: steroid 101 and placebo 102). The frequency of grade ≥2 radiation dermatitis was not significantly reduced with the steroid (73.3%; 95% confidence interval, 64.6%-81.9%) compared with the placebo (80.4%; 95% confidence interval, 72.7%-88.1%; P = .23), whereas the steroid significantly reduced the frequency of grade ≥3 radiation dermatitis (13.9% vs 25.5%; P = .034). No significant differences in adverse events, including local infection or compliance with CRT, were observed between the groups. Conclusions Topical steroid may reduce the severity of radiation dermatitis in patients with HNC and thus may become an important therapeutic tool in the management of radiation dermatitis.

Radical surgery with free flap reconstruction for locally advanced head and neck cancer (HNC) is quite challenging for older adults. This retrospective study aimed to elucidate the usefulness of the geriatric-8 (G8) screening tool for predicting postoperative complications in older adults with HNC. A retrospective review of 37 older adults with HNC who underwent radical surgery with free flap reconstruction and were assessed by the G8 screening tool was performed. Postoperative complications during hospitalization were classified according to the Clavien–Dindo classification, and possible contributing factors, including the G8 score, for major and minor complications were subjected to univariate and multivariate analyses. The appropriate G8 cut-off value for both major and minor complications was 12 (area under the curve 0.56 and 0.55, respectively). Multivariate logistic regression analysis showed that both smoking and lower G8 score (≤ 12) were independently associated with the severity of complications (p = 0.043, p = 0.034, respectively). The G8 was a possible predictor of major and minor complications in older adults with HNC who underwent radical surgery with free flap reconstruction.

The present case study reports contrast-enhanced magnetic resonance findings in three patients with histopathologically proven IgG4-related chronic sclerosing sialadenitis of the submandibular gland. All three patients presented with painless swelling of the submandibular region. The contrast-enhanced T1-weighted images showed reticular enhancement of the swollen submandibular gland. Radiological–pathological correlation revealed that the characteristic reticular enhancement corresponded to fibrosis and to inflammatory cell infiltration in the interlobular septa and in the periductal region of the submandibular gland.

Here we present a patient with a parotid secretory carcinoma (SC) with high-grade transformation. A 65-year-old female was referred to our hospital due to a gradually growing right parotid tumor discovered initially about 4 years earlier. MRI imaging detected a right parotid tumor 50 mm in the longer axis. Fine needle aspiration cytology indicated a class III tumor. Nine months after her initial visit, she revisited our department because of pain, trismus and facial paralysis. MRI detected a tumor 69 mm in the longer axis and 64 mm in the shorter axis and a biopsy specimen revealed parotid cancer. Furthermore, positron emission tomography revealed a synchronous small cell lung cancer (SCLC). Chemoradiotherapy for the SCLC was performed followed by an extended total parotidectomy for the parotid SC. Histological findings and ETV6-FISH analysis confirmed a parotid SC with high-grade transformation. Two months after the surgery, CT revealed a loco-regional recurrence and proton beam therapy (70.2 GyE/26 Fr) was performed. Three months after the proton beam therapy, CT indicated pleural effusion and lung metastasis, and fine needle aspiration cytology revealed the metastatic SC. Eight months after the surgery, the patient died due to the lung metastasis of SC.

Squamous cell carcinoma of the head and neck is characterized by an immunosuppressive environment and evades immune responses through multiple resistance mechanisms. A breakthrough in cancer immunotherapy employing immune checkpoint inhibitors has evolved into a number of clinical trials with antibodies against programmed cell death 1 (PD-1), its ligand PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) for patients with squamous cell carcinoma of the head and neck. CheckMate141 and KEYNOTE-048 were practice-changing randomized phase 3 trials for patients with platinum-refractory and platinum-sensitive recurrent or metastatic squamous cell carcinoma of the head and neck, respectively. Furthermore, many combination therapies using anti-CTLA-4 inhibitors, tyrosine kinase inhibitors and immune accelerators are currently under investigation. Thus, the treatment strategy of recurrent or metastatic squamous cell carcinoma of the head and neck is becoming more heterogeneous and complicated in the new era of individualized medicine. Ongoing trials are investigating immunotherapeutic approaches in the curative setting for locoregionally advanced disease. This review article summarizes knowledge of the role of the immune system in the development and progression of squamous cell carcinoma of the head and neck, and provides a comprehensive overview on the development of immunotherapeutic approaches in both recurrent/metastatic and locoregionally advanced diseases.

Background Adenoid cystic carcinoma is a rare malignant tumor arising from exocrine glands such as the major and minor salivary glands of the paranasal sinuses or the external auditory canal. Although multiple retrospective clinical studies of ACC have been reported to date, clinical questions, such as 1) long-term prognosis beyond 20 years, 2) usefulness and suitability for treatment of therapeutic interventions, 3) therapeutic goal to aim for, and 4) prognosis by recurrence sites, are still unclear. Methods To improve understanding and management of adenoid cystic carcinoma of the head and neck (ACC), a retrospective study with 58 new ACC cases between 1991 and 2016 was performed. The median observation period was 66.8 months (range 3–316 months). The overall clinical stages were as follows: I, 6.9%; II, 25.9%; III, 19.0%; and IV, 48.2%. Histology was cribriform/tubular type (C-T type) in 62.0% and solid type in 27.5%. The main treatment strategy was definitive surgery, which was performed in 75.2% of cases. Results Overall 10-year, 20-year, and 25-year survivals were 63.7, 27.3, and 20.0%, respectively. Similarly, disease-specific survival (DSSs) was 65.7, 51.2, and 38.4%, respectively, and disease-free survival was 25.2, 9.4, and 9.4%, respectively. Conducting surgery (HR: 0.19, 95% CI: 0.06–0.61, p = 0.005) and C-T type (HR: 0.32, 95% CI: 0.11–0.93, p = 0.036) were independent prognostic predictors of DSS. DSS was significantly prolonged after salvage surgery for both locoregional recurrence (p = 0.004) and lung metastatic recurrence (p = 0.012, vs best supportive care). Conclusions In ACC cases, both initial surgical treatment and repetitive surgical resection of resectable recurrent lesions, including both locoregional and lung metastases, resulted in longer survival. The major goal of treatment for ACC may be long-term survival including cancer-bearing survival, resulting in either natural death or intercurrent-disease death, since judging cure of ACC is almost impossible. Trial registration Retrospectively registered.

To clarify the correlations among symptoms, swallowing functions, and ingestion status and to validate a method of swallowing evaluation during chemoradiotherapy (CRT) for head and neck cancer. Oropharyngeal and hypopharyngeal cancer patients who were to receive definitive CRT as initial treatment were included in this prospective, single-center, observational study. The Functional Oral Intake Scale (FOIS) for ingestion status and grades of symptoms (dryness, dysgeusia, mucositis, and the analgesic ladder); the Yale Pharyngeal Residue Severity Rating Scale on fiberoptic endoscopic evaluation of swallowing (FEES) and the Penetration-Aspiration Scale (PAS) on videofluoroscopic (VF) evaluation for swallowing functions; and the 10-item Eating Assessment Tool (EAT-10) questionnaire were assessed at 5 time points unless the participant refused. The FEES and VF evaluation findings at each point were also compared. There were 38 participants. Dysgeusia, mucositis, and pain grade, as well as the FOIS score, were the worst at 70 Gy and then improved after treatment. The improvements of pharyngeal residue and the PAS after treatment were limited. The EAT-10 and the pain ladder were highly correlated with the FOIS changes at many time points. The VF evaluation rate dropped after 40 Gy, whereas the FEES rate remained high. There were good correlations between pharyngeal residue and the PAS at 0 Gy, 70 Gy, and 3 months. The EAT-10 and pain reflected the FOIS score changes well, while two swallowing evaluations did not. To avoid aspiration, VF evaluation may not be necessary during CRT because of high correlations with pharyngeal residue on FEES.

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic–polycytidylic acid (Poly (I:C)) generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1(hi) TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor specific CD8(+) T cells. Overall, the CD8(+)/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).

Oral rehabilitation with prosthodontic treatment considerably influences the well-being and quality of life of patients after ablative oral tumor surgery. This study evaluated the effects of implant-supported prostheses (ISPs) on oral health-related quality of life (OHRQoL) and chewing ability in 10 patients who requested ISPs after mandibular oral tumor resection. OHRQoL was assessed using the Japanese version of the Oral Health Impact Profile (OHIP-49) before and one year after ISP placement. Chewing ability, including self-assessed masticatory ability and occlusal force, was examined at one year after ISP placement. The initial mean total OHIP-49 score of 65.3 ± 9.79 decreased to 46.0 ± 8.14 at one year after ISP placement. Mean OHIP-49 score decreased in all domains, whereas self-assessed masticatory ability increased within one year of ISP placement. There were no significant differences between prosthesis types with respect to the mean OHIP-49 score or self-assessed masticatory ability. In conclusion, ISP placement improves OHRQoL and the self-assessed masticatory ability. Moreover, the prosthesis type might not significantly affect OHRQoL.

Background This study aimed to reveal the influence of the invasion site of external auditory canal (EAC) cancer by analyzing the outcome of patients with advanced tumor. Methods A total of 111 patients with T4 EAC cancer were enrolled in this study. Of these patients, 79 underwent chemoradiotherapy and 32 underwent surgery under curative intent. Univariate and multivariate analyses and the Kaplan-Meier method were used to focus on the tumor invasion sites and overall survival of the patients. Results The 3-year overall survival rate of all patients was 55.0%. In multivariate analysis, the only significant invasion site for overall survival was the facial nerve, with the dura mater being the next most influential site. When Kaplan-Meier survival curve was calculated, facial nerve and dura mater were the significant factors resulting in poor patient outcomes. Conclusion The facial nerve and dura mater are crucial sites of EAC cancer for patient outcomes.

Objectives The efficacy of intratympanic steroid (ITS) injection for intractable Meniere's disease has been reported; however, its differences in responsiveness are not fully understood. This study investigated the clinical characteristics of patients who responded to ITS injection treatment. Methods This retrospective study included 32 patients with Meniere's disease who were unable to control frequent vertigo attacks despite conservative treatment for at least 3 months. They received an intratympanic injection of dexamethasone (3.3 mg/mL) in the affected side at least three times. We measured hearing threshold, subjective symptom scores, cervical and ocular vestibular evoked myogenic potential (cVEMP and oVEMP), and performed glycerol and bithermal caloric tests. Results Satisfactory control of vertigo for 1 year after the first round of injection was found in 18 patients (56.3%; the response group). However, the injections failed to control vertigo in the other 14 patients (43.8%; the non-response group), and they were then treated with middle ear micropressure therapy. The response group showed improvement in low-frequency hearing, whereas hearing acuity did not change in the non-response group. Significantly reduced amplitude of cVEMP on the affected side was found in 62.5% of patients in the response group; however, no patients in the non-response group showed reduced amplitude of cVEMP. Conclusions ITS injection significantly improved the subjective symptoms for intractable Meniere's disease; however, the long-term effects were heterogeneous. Our results suggest that reduced amplitude in cVEMP is associated with the effectiveness of ITS injection treatment.

In order to maximize the benefit of induction chemotherapy, practice based on a comprehensive interpretation of a large number of clinical trials, as in this review, is essential. The standard treatment for locally advanced squamous cell carcinoma of the head and neck is surgery or chemoradiation. However, induction chemotherapy followed by (chemo) radiotherapy may be used in some circumstances. Although many clinical trials of induction chemotherapy have been conducted, a rationale other than to preserve the larynx is still controversial. Selection of this modality should therefore be made with care. The current standard regimen for induction chemotherapy is docetaxel, cisplatin and 5-FU, but concerns remain about toxicity, cost and the duration of treatment. Regarding treatment after induction chemotherapy, it is also unclear whether radiation alone or chemoradiation is the better option. Furthermore, there is no answer as to what drugs should be used in combination with radiation therapy after induction chemotherapy. Several new induction chemotherapy treatment developments are currently underway, and future developments are expected. This review article summarizes the current position of induction chemotherapy for head and neck squamous cell carcinoma, based on the evidence produced to date, and discusses the future prospects for this treatment.

To clarify the usefulness of geriatric assessment screening tools for predicting prognosis and complications in older adults with head and neck cancer (HNC).The geriatric-8 (G8) screening tool was administered to 78 older adults with HNC at their first visit to the hospital before any treatments. The ability of the G8 to predict survival was evaluated by receiver operating characteristic (ROC) curve analysis and determining the cut-off value using Youden's Index. The G8 and other factors related to prognosis (age, performance status (PS), Charlson comorbidity index, number of oral medicines (polypharmacy), the controlling nutritional status (CONUT) score for biological nutrition status, and treatment intent (curative or palliative)) were validated by Cox proportional hazards regression analysis. The survival analysis was validated in a propensity score-weighting cohort to correct for confounding factors. Correlations between these factors and complications were examined using Fishers exact test.The G8 cut-off value for overall survival was 10.5 (area under the curve (AUC) 0.69; 95% confidence interval (CI) 0.56-0.82). In the propensity score-weighted cohort, on Cox proportional hazards regression analysis, the hazard ratio of an abnormal G8 (11) was 3.70 [1.59-8.61 (p = 0.002)], and the hazard ratio of PS-abnormal (≥2) was 0.85 [0.09-7.60 (p = 0.88)]. Thirty-day mortality and all-complication rates were significantly higher in the G8-abnormal group. Neither major complications nor transfer to other institutions was correlated with an abnormal G8.The G8 was a strong prognostic factor and a possible predictor of complications in older adults with HNC.

Background The latency of the swallowing reflex is an important factor causing dysphagia in head and neck cancer patients. Although there are many reports comparing voluntary swallowing function before and after treatment, few studies have focused on the latency of the swallowing reflex, which is a risk factor for pneumonia due to silent aspiration. The aim of this retrospective study was to clarify the changes in the latency of the swallowing reflex before and after treatment. Methods The latency of the swallowing reflex was quantified using the time from the injection of 1 ml of distilled water into the pharynx through a nasal catheter to the onset of swallowing. Results The latency time of the swallowing reflex was significantly decreased 3 months after treatment compared to before treatment. A significant reduction was also observed in patients with pharyngeal cancer who underwent chemoradiation therapy. Conclusions This retrospective study showed that a delayed swallowing reflex improved with treatment in advanced head and neck cancer patients. Trial registration The Institutional Review Board of Tohoku University Hospital (Number 2014–1-274).

Objective Surgery for locally advanced oral cancer often requires wide resections of multiple subsites of the oral cavity, including the oral tongue, floor of the mouth, and lower gingiva, and it causes chewing and swallowing disorders. The aim of this prospective, observational study was to determine which subsites have a greater impact on chewing and swallowing disorders after surgery. Methods A prospective, observational study was conducted involving 52 patients who underwent surgery for locally advanced oral cancer with free flap reconstruction. The patients' Functional Oral Intake Scale scores were measured before surgery and 1 and 3 months after surgery. Possible predictors of chewing and swallowing disorders were subjected to univariate analysis and multivariate logistic regression analysis. Age, sex, preoperative body mass index, clinical stage, extent of mandibular bone resection, floor of the mouth resection, total or subtotal glossectomy, laryngeal suspension, bilateral neck dissection, and postoperative radiation therapy were the variables evaluated. Results Multivariate logistic regression analysis showed that both anterior or extensive mandibular bone resection and postoperative radiation therapy were independently associated with poor oral intake after surgery. Conclusions The identified predictors will be helpful for better management of patients identified as being at high risk of chewing and swallowing disorders.

To identify precipitating factors responsible for enteral nutrition (EN) dependency after concomitant chemoradiotherapy (CCRT) of head and neck cancers and to examine their statistical correlations. Factors related to feeding condition, nutritional status, disease, and treatment of 26 oropharyngeal and hypopharyngeal cancer patients who received definitive CCRT were retrospectively investigated by examining their medical records. The days of no oral intake (NOI) during hospitalization and the months using enteral nutrition after CCRT were counted as representing the feeding condition, and the changes in body weight (BW) were examined as reflecting nutritional status. The factors related to EN dependency after CCRT were analyzed. Long duration of total NOI (≥ 30 days) and maximum NOI ≥ 14 days were significant predictors of EN dependency. Decreased BW (≥ 7.5 kg) was the next predictor identified, but it was not significant. Multivariate analysis showed that the total duration of NOI was more correlated with EN dependency than changes in BW. A long duration of NOI was more strongly related to EN dependency than nutritional factors.

Pheochromocytomas and paragangliomas are neuroendocrine tumors which arise from adrenal medulla, and sympathetic or parasympathetic nerves, respectively. Hereditary cases afflicted by both or either pheochromocytomas and paragangliomas have been reported: these are called hereditary pheochromocytoma/paraganglioma syndromes (HPPS). Many cases of HPPS are caused by mutations of one of the succinate dehydrogenase (SDH) genes; mainly SDHB and SDHD that encode subunits for the mitochondrial respiratory chain complex II. In this study, we investigated mutations of SDH genes in six HPPS patients from four Japanese pedigrees using peripheral blood lymphocytes (from one patient with pheochromocytoma and five patients with neck paraganglioma) and tumor tissues (from two patients with paraganglioma). Results showed that all of these pedigrees harbor germline mutations in one of the SDH genes. In two pedigrees, a novel IVS2-2A>C mutation in SDHB, at the acceptor-site in intron 2, was found, and the tumor RNA of the patient clearly showed frameshift caused by exon skipping. Each of the remaining two pedigrees harbors a reported missense mutation, R242H in SDHB or G106D in SDHD. Importantly, all these mutations are heterozygous in constitutional DNAs, and two-hit mutations were evident in tumor DNAs. We thus conclude that the newly identified IVS2-2A>C mutation in SDHB is responsible for HPPS. The novel mutation revealed by our study may contribute to improvement of clinical management for patients with HPPS.

Objective Concurrent chemoradiotherapy (CCRT) with three-weekly high-dose cisplatin (100 mg/m2) is a standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC), but compliance with cisplatin is often poor due to various adverse events. The aim of this prospective, observational study was to determine the predictors of achievement of full-dose cisplatin. Methods A prospective, observational study was conducted involving 60 patients who received CCRT with three-weekly high-dose cisplatin (100 mg/m2) for locally advanced HNSCC. Possible predictors affecting compliance with cisplatin were subjected to univariate and multivariate logistic regression analyses. Age, sex, primary site, clinical stage, treatment intent, history of hypertension, diabetes mellitus, smoking and drinking habits, body mass index, creatinine clearance, serum albumin, controlling nutrition status, trace elements (Fe, Zn, Cu, Se), acute kidney injury, white blood cell count decrease, neutrophilia, and weight loss were the variables evaluated. Results Twenty-seven patients achieved full-dose cisplatin (300 mg/m2), and the other 33 patients did not. Multivariate logistic regression analysis showed that both mild renal dysfunction and selenium deficiency before treatment independently had negative impacts on achievement of full-dose cisplatin. Conclusions As well as renal function, selenium deficiency is a potential therapeutic target for CCRT with high-dose cisplatin in HNSCC patients.

Parapharyngeal neuroglial heterotopia is a rare entity, and the specific radiographical findings are unclear. We present a case of parapharyngeal neuroglial heterotopia examined with proton magnetic resonance spectroscopy (1H-MRS) and 18F-fluorodesoxyglucose positron emission tomography (18F-FDG PET). Our neonate patient presented with neck mass and polyhydramnios during gestation. Computed tomography and magnetic resonance imaging demonstrated the morphological characteristics, but failed to establish the diagnosis. 1H-MRS showed a non-malignant pattern, but 18F-FDG PET demonstrated high glucose metabolism. Complete resection was achieved and the histopathological diagnosis was neuroglial heterotopia. Assessment of biological activity may be useful for both preoperative diagnosis and postoperative evaluation of residual lesions.

Background The usefulness of apparent diffusion coefficient (ADC) and diffusion-weighted magnetic resonance imaging (DWI) in the detection of malignant tumors has been reported. The purpose of this study is to clarify the role of ADC and DWI for diagnosis of skull base tumors. Methods A total of 27 patients with head and neck tumors with skull base invasions undergoing skull base surgery were enrolled in this study. Pathological findings of dural invasion and bone invasion were compared with the diagnostic imaging. Results Advanced magnetic resonance imaging techniques revealed that ADC values in regions of pathological bone and dural invasions were significantly lower than in regions of no invasion. The area under the curve of ADC in bone invasions and dural invasions were 0.957 and 0.894, respectively. Conclusions Our findings indicate that ADC and DWI are useful tools for the diagnosis of head and neck tumors with skull base invasion.

Background Induction chemotherapy (IC) in locally advanced squamous cell carcinoma of the head and neck (LA‐SCCHN) often compromises compliance with subsequent chemoradiotherapy (CRT), which negatively affects outcomes. Here, we assessed the combination of paclitaxel (PTX), carboplatin (CBDCA), and cetuximab (Cmab) as IC for unresectable LA‐SCCHN. Methods Induction chemotherapy consisted of weekly CBDCA area under the plasma concentration‐time curve = 1.5, PTX 80 mg/m2 and Cmab with an initial dose of 400 mg/m2 followed by 250 mg/m2 for 8 weeks. Following IC, CDDP (20 mg/m2, 4 days × 3 cycles) and concurrent radiotherapy (70 Gy/35 fr) were started. Primary endpoint was the proportion of CRT completion (%CRT completion). PCE was planned to be deemed effective if the Bayesian posterior probability (PP), defined as the probability that %CRT completion was larger than the threshold value of 65%, exceeded 84%. Results Thirty‐five patients were enrolled. Cases were hypopharynx/oropharynx/larynx in 17/17/1 patients, all at Stage IV. Of 35 patients, 34 (97%) completed IC and 32 received CRT and met the criteria of full analysis set (FAS). In FAS, the %CRT completion was 96.9%, and PP was 99.9%, exceeding the prespecified boundary of 84%. Mean cumulative dose and relative to dose intensity of CDDP in CRT was 232.5 mg/m2 and 100%, respectively. Response rate was 88.6% by IC and 93.8% in the CRT phase. Three year overall survival was 83.5%. Main grade 3 toxicities included neutropenia (11.4%) and skin rash (5.7%) during IC; and oral mucositis (31.3%) and neutropenia (12.5%) during CRT. No grade 4 toxicity or treatment‐related death was seen. Conclusions PCE as IC was feasible, with promising efficacy and no effect on compliance with subsequent CRT in unresectable LA‐SCCHN., The combination of PCE as induction chemotherapy was feasible and had no effect on compliance with subsequent chemoradiotherapy (CRT) with CDDP, and provided encouraging efficacy in high‐risk unresectable locally advanced squamous cell carcinoma of the head and neck (LA‐SCCHN). The regimen is a favorable alternative to TPF for LA‐SCCHN patients who required more aggressive treatment, herein sequential CRT.

OBJECTIVES This study aimed to evaluate the efficacy of chemoradiotherapy (CRT) for patients with advanced cancer of the external auditory canal (EAC) by analyzing the outcome of the patients. METHODS This is a multi-institutional retrospective survey, and we reviewed the medical records of the subjects. A total of 181 patients with tumor (T)3 or T4 tumor in 17 institutions were enrolled. Further analysis was performed for 74 patients who underwent CRT under curative intent. RESULTS Overall 5-year survival rates of the patients who underwent CRT (n = 74) were 54.6%. Those of the patients who underwent CRT with modified TPF (docetaxel, cisplatin [CDDP], and 5-fluorouracil) regimen (n = 50) and CRT with CDDP regimens (n = 24) were 64.4% and 36.7%, respectively. Significant differences were observed between these two groups. CONCLUSION Given the tendency that head and neck surgeons prefer CRT for advanced larger cancer of the EAC, CRT for advanced EAC cancer using the modified TPF regimen showed good clinical outcomes. LEVEL OF EVIDENCE 4 Laryngoscope, 131:E870-E874, 2021.

Melanotic neuroectodermal tumor of infancy (MNTI) is an extremely rare, pigmented neoplastic entity of neural crest origin. Histological and immunohistochemical profiles indicate the presence of two components, small rounded neuroblast-like cellular areas and areas with large melanin-containing cells which consist of combination of neural, melanocytic, and epithelial cell types. Here we present two interesting cases of infants with MNTI which have different clinicopathological features. The first case is a 3-month-old female with rapidly growing MNTI involving the lacrimal sac and inferior wall of the orbital cavity, treated with total maxillectomy without orbital exenteration followed by chemotherapy. The second case is a 7-month-old male with slow-growing maxillary MNTI treated with complete surgical excision. In the female patient, histological findings revealed a predominance of neuroblast-like cellular areas and a high Ki67 index indicating rapid cellular proliferation. In the male patient however, large melanin-containing cells were dominant in this slow-growing tumor. These findings support the presence of two different types of MNTI, rapid-growing and slow-growing types, determined by the component of neuroblast-like cellular areas.

6502 Background: The standard treatment for post-operative high-risk patients (pts) with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is chemoradiotherapy with 3-weekly cisplatin (CDDP) (100 mg/m2, q3wk, 66 Gy/33Fr; 3-weekly CDDP+RT). However, one concern with 3-weekly CDDP+RT is insufficient CDDP compliance due to high-dose-related toxicities. Weekly CDDP+RT (40 mg/m2, qwk, 66 Gy/33Fr; weekly CDDP+RT) is an alternative regimen with better compliance. Here, we conducted a phase II/III trial of weekly CDDP+RT in post-operative high-risk LA-SCCHN. Methods: This is a multi-institutional randomized phase II/III trial to confirm the non-inferiority of weekly CDDP+RT (Arm B) compared with 3-weekly CDDP+RT (Arm A). The trial enrolled pts aged 20-75 years with post-operative high-risk features (microscopically positive margin and/or extranodal extension) and ECOG-PS 0-1. Pts were randomized in a 1:1 ratio to Arm A or Arm B. Primary endpoint of phase II was the proportion of treatment completion and that of phase III was overall survival (OS). A non-inferiority margin of hazard ratio (HR) was set at 1.32. Results: Between Oct 2012 and Dec 2018, 261 pts were enrolled (Arm A 132 pts, Arm B 129 pts). At the planned second interim analysis in phase III with 76/161 events, the Data and Safety Monitoring Committee recommended terminating the trial and publishing the results because the statistical boundary for OS non-inferiority had met the pre-specified stop criteria. With a median follow-up of 2.2 years in all randomized pts, 3-year OS was 59.1% in Arm A and 71.6% in Arm B with a HR of 0.69 (99.1% CI, 0.374-1.273 [ < 1.32], one-sided p for non-inferiority = 0.00272 < 0.00433). 3-year RFS was 53.0% in Arm A and 64.5% in Arm B with a HR of 0.71 (95% CI, 0.48-1.06). Regarding acute adverse events, neutropenia (≥ grade 3), increased creatinine (≥ grade 2), hearing impairment (≥ grade 2) and mucositis (≥ grade 2) occurred in 48.8%, 8.5%, 7.8% and 55.0% in Arm A and 35.3%, 5.7%, 2.5% and 59.0% in Arm B, respectively. For compliance, median total dose of CDDP was 280 mg/m2 (IQR, 250-299) in Arm A and 239 mg/m2 (IQR, 199-277) in Arm B. Total radiation dose was 66 Gy (IQR, 66-66) in both arms. Proportion of treatment completion was 93.2% in Arm A and 86.8% in Arm B. Conclusions: Weekly CDDP+RT is non-inferior to 3-weekly CDDP+RT for post-operative high-risk LA-SCCHN pts and has a favorable toxicity profile. Weekly CDDP+RT should be considered the new standard treatment option for these pts. Clinical trial information: 000009125 .

A number of major modifications were made to the classification of head and neck carcinomas in the eighth edition of the American Joint Committee on Cancer, Cancer Staging Manual and Union for International Cancer Control TNM classification of Malignant Tumors. These modifications were aimed at improving the prognosis prediction accuracy of the system. In this article, we review the new edition of the TNM classification system. Among the several changes in the new system, a separate algorithm for p16-positive oropharyngeal carcinoma was included, as were new chapters on ‘Head and Neck Skin Carcinoma’ and ‘Unknown Primary Carcinoma—Cervical Nodes.’ Changes to Tumor (T) classification were made by introducing the depth of invasion of oral carcinoma, whereas changes to Node (N) classification were made by adding extra-nodal extension. It is believed that these changes will help improve the accuracy of the system in the prediction of prognosis. However, it is necessary to verify their validity through further clinical research.

Background: Extensive resection and free-flap reconstruction surgery has become the standard treatment for locally advanced head and neck cancer. Surgical site infection (SSI) is one of the serious complications of this treatment. This study aimed to investigate the risk factor for onset of SSI, particularly focusing on whether preoperative professional oral health care in cooperation with general dental clinics is effective in reducing the occurrence of SSI. Methods: From March 2003 to August 2011, 183 patients who underwent head and neck free-flap reconstructive surgery by the same plastic surgeon at Miyagi Cancer Center for Head and Neck Surgery were investigated retrospectively. Results: Of the 183 patients, 135 and 48 were men and women, respectively, with a mean age of 62 (range, 29-82) years. The tumor was located in the oral cavity (n = 76), hypopharynx (n = 55), oropharynx (n = 28), and others (n = 24). Clinical stages were stage I/II in 18, stage III/IV in 164 patients, and benign tumor in one patient, based on UICC classification. SSI occurred in 66 patients (36.1%). Based on multivariate analysis, professional oral health care [P = 0.0076, odds ratio (OR) = 0.39] and radiation therapy history (P = 0.0214, OR = 2.820) were shown as factors that are significantly related to SSI. Conclusion: This study identified history of radiation therapy as a significant risk factor for SSI from univariate and multivariate analysis and revealed that patients receiving preoperative professional oral health care at general dental clinics reduce the risk of SSI. Preoperative professional oral health care in cooperation with general dental clinics has been shown to reduce SSI of head and neck free-flap reconstructive surgery.

Objectives This article aims to clarify the long-term outcomes of patients with squamous cell carcinoma of the temporal bone who underwent concomitant chemoradiotherapy (CCRT). Design and Setting The study design was a retrospective chart review. Patients and Methods From December 2001 to June 2014, 23 patients with cancer of the temporal bone who were treated by CCRT at the Tohoku University Hospital and the Iwate Medical University Hospital were enrolled in this study. For advanced cancer of the temporal bone, a modified docetaxel, cisplatin, and 5-fluorouracil (TPF) regimen was used for CCRT. The long-term outcomes, including prognoses and late complications, were analyzed after CCRT of patients with cancers of the temporal bone. Results The main long-term complications were stenosis of the external auditory canal and conductive hearing loss. No harmful late complications were observed in these patients. Disease-specific survival rates were 84.9% for all patients, 100% for patients of stage I, II, and III (n = 10), and 75.5% for patients of stage IV (n = 13) at 5 years. Conclusions Our study showed that CCRT is an effective treatment choice for squamous cell carcinoma of the temporal bone. Furthermore, CCRT using the TPF regimen is a safe and effective initial treatment for patients with advanced cancers of the temporal bone.

In this article, a simple, new laryngeal suspension procedure is described. The effect of hyoid bone suspension by suturing the digastric muscle to the periosteum of the mandible is analyzed.To elucidate the effect of hyoid bone suspension, CT scans of 26 patients who underwent ipsilateral neck dissection with primary resection of tongue cancer were retrospectively reviewed, and the distance between the hyoid bone and the mandible was measured on the operated and unoperated sides of the neck. A total of 14 patients who underwent suturing of the digastric muscle to the mandible (digastric muscle-sutured group) and the 12 patients who did not (control group) were compared.In the digastric muscle-sutured group, the average distance between the hyoid bone and the mandible was significantly smaller on the operated side (17.8 ± 0.57 mm) than on the unoperated side (19.8 ± 0.93 mm; p 0.05). In the control group, there was no significant difference between the operated side (21.0 ± 1.42 mm) and the unoperated side (19.7 ± 1.39 mm). The difference in the distance between the operated and unoperated sides was significantly larger in the digastric muscle-sutured group (1.97 ± 0.79 mm) than in the control group (-1.32 ± 0.61; p 0.05).It was shown for the first time that suturing of the digastric muscle to the periosteum of the mandible in neck dissection with primary resection of tongue cancer resulted in hyoid bone suspension. This simple procedure can be useful for laryngeal suspension.

Background Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). Methods Patients aged 20–75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. Results From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. Conclusions The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. Trial registration ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014). Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3295-4) contains supplementary material, which is available to authorized users.

Background and Aim Dysphagia caused by pharyngo-upper esophageal stricture is a complication of treatment for head and neck cancer. Endoscopic balloon dilation (EBD) is in widespread use as an effective and safe treatment for stricture in many areas of the gastrointestinal tract. In the present study, we investigated the efficacy and safety of EBD for pharyngo-upper esophageal strictures that developed after treatment for head and neck cancer. Methods From January 2010 to December 2013, the medical records and endoscopic findings of 19 consecutive patients with pharyngo-upper esophageal strictures occurring after surgery and/or chemoradiotherapy for head and neck cancer were retrospectively examined. Results Mean number of EBD sessions per patient was 6.6 (1–30), and mean maximum diameter of dilation was 15.8 (11–20) mm. Technical success was achieved in 16 of 19 (84.2%) patients, and only two major complications (bleeding and pha ryngeal edema) occurred in a total of 125 dilatation sessions (1.6%). Regarding the influence of chemoradiotherapy on the outcome of EBD, patients who had undergone chemoradiotherapy plus surgery experienced significantly more restenosis during the follow-up period compared to those who had undergone surgery alone (50% vs 0%, P

The purpose of this study was to clarify the diagnostic value of capsule-like rim enhancement (CLRE) on magnetic resonance imaging (MRI) for distinguishing malignant from benign tumours of the parotid gland. We retrospectively evaluated contrast-enhanced T1-weighted images of 100 patients with malignant and benign parotid tumours for the presence, completeness, and irregularity of CLRE and its maximum thickness. We investigated any correlation of imaging and histopathological findings for 51 cases showing CLRE with available histology. The presence and completeness of CLRE did not differ significantly between benign and malignant tumours. Malignant tumours had more irregular CLRE than benign tumours (P

Summary Objective A standardized assay to determine the HPV status of head and neck squamous cell carcinoma (HNSCC) specimens has not yet been established, particularly for cytologic samples. The goal of this study was to determine whether the hybrid capture-2 (HC-2) assay, already widely used for the detection of high risk HPV in cervical brushings, is applicable to cytologic specimens obtained from patients with suspected HNSCCs. Materials and methods Fine needle aspirates (FNA) of cervical lymph nodes were pre-operatively obtained from patients with suspected HNSCCs and evaluated for the presence of HPV using the HC-2 assay. HPV analysis was performed on the corresponding resected tissue specimens using p16 immunohistochemistry (IHC) and HR-HPV in situ hybridization (ISH). A cost analysis was performed using the Center for Medicare & Medicaid Services. Results HPV status of the cervical lymph node metastases was correctly classified using the HC-2 assay in 84% (21/25) of cases. Accuracy was improved to 100% when cytologic evaluation confirmed the presence of cancer cells in the test samples. The estimated cost savings to CMS using the HC-2 assay ranged from $113.74 to $364.63 per patient. Conclusions HC-2 is a reliable method for determining the HPV status of HNSCCs. Its application to HNSCCs may reduce costs by helping to localize the primary site during the diagnostic work-up as well as decrease the interval time of determining the HPV status which would be relevant for providing prognostic information to the patient as well as determining eligibility for clinical trials targeting this unique patient population.

Summary Objectives For patients with tobacco-related head and neck squamous cell carcinoma (HNSCC), the occurrence of a second primary tumor (SPT) is an ominous development that is attributed to a field cancerization effect and portends a poor clinical outcome. The goal of this study was to determine whether patients with human papillomavirus (HPV)-related index tonsillar carcinomas can also develop SPTs in the contralateral tonsil, and to discern the molecular etiology of HPV-related tumor multifocality. Materials and methods The surgical pathology archives of The Johns Hopkins Hospital were searched for all patients with primary HPV-related tonsillar squamous cell carcinoma who developed a synchronous or metachronous carcinoma in the contralateral tonsil. The HPV-16 E6 exon was sequenced from each independent cancer site to determine whether the tumor pairs harbored the same or a different HPV-16 variant. Results Four patients with bilateral HPV-related tonsillar carcinomas were identified. In every case, the HPV DNA sequences derived from the index tumor and corresponding SPT were 100% concordant, indicating that the index and SPTs were caused by the same HPV-16 variant. Conclusion For the small subset of patients with tonsillar carcinomas who develop SPTs in the contralateral tonsil, the index case and the SPT consistently harbored the same HPV variant. This finding suggests that HPV-related tumor multi-focality can be attributed either to independent inoculation events by the same virus, or by migration of HPV-infected cells from a single inoculation site to other regions of Waldeyer’s ring.

Sinonasal papilloma is a common benign epithelial tumor of the sinonasal tract and accounts for 0.5% to 4% of all nasal tumors. The etiology of sinonasal papilloma remains unclear, although human papilloma virus has been proposed as a major risk factor. Other etiological factors, such as anatomical variations of the nasal cavity, may be related to the pathogenesis of sinonasal papilloma, because deviated nasal septum is seen in patients with chronic rhinosinusitis. We, therefore, investigated the involvement of deviated nasal septum in the development of sinonasal papilloma. Preoperative computed tomography or magnetic resonance imaging findings of 83 patients with sinonasal papilloma were evaluated retrospectively. The side of papilloma and the direction of septal deviation showed a significant correlation. Septum deviated to the intact side in 51 of 83 patients (61.4%) and to the affected side in 18 of 83 patients (21.7%). Straight or S-shaped septum was observed in 14 of 83 patients (16.9%). Even after excluding 27 patients who underwent revision surgery and 15 patients in whom the papilloma touched the concave portion of the nasal septum, the concave side of septal deviation was associated with the development of sinonasal papilloma (p = 0.040). The high incidence of sinonasal papilloma in the concave side may reflect the consequences of the traumatic effects caused by wall shear stress of the high-velocity airflow and the increased chance of inhaling viruses and pollutants. The present study supports the causative role of human papilloma virus and toxic chemicals in the occurrence of sinonasal papilloma.

Here we present an extremely rare case of giant infantile hemangiopericytoma (HPC) of the tongue diagnosed prenatally by fetal ultrasonography and MR imaging. Due to airway stenosis, the patient was delivered by the ex utero intrapartum treatment (EXIT) procedure at 36 weeks of pregnancy. Initial diagnosis was infantile hemangioma based on physical examination, diagnostic imaging and the high incidence of hemangioma. The tumor was resistant to conservative treatments. Due to severe tumor hemorrhage, the nutrient vessel was embolized by endovascular treatment on the 73th day after birth. Two days after embolization, a hemiglossectomy was performed. Histological analysis after surgery diagnosed infantile HPC with microscopically positive stumps. After receiving adjuvant chemotherapy, the patient has had no recurrence after 53 months with normal speech and swallowing function resulting in normal growth. Our findings support that infantile HPC is one of the differential diagnosis of infantile hemangioma. The EXIT procedure could be effective for infants with upper respiratory stenosis by head and neck tumor diagnosed prenatally. Though complete resection is required for infantile HPC, our report suggests that a conservative surgical approach followed by adjuvant chemotherapy should be used for giant head and neck infantile HPC.

The aim of this study was to compare the therapeutic outcomes of total pharyngolaryngectomy with those of concomitant chemoradiotherapy in advanced hypopharyngeal cancer. This is a retrospective multi-institutional study. The medical records of 979 patients with hypopharyngeal cancer, who were initially treated between 2006 and 2008, were reviewed. In this study, we matched a group of total pharyngolaryngectomy patients with a second group of chemoradiotherapy patients, according to age, gender, subsite, arytenoid fixation, cartilage invasion, and N classification, and analyzed overall survival, disease-specific survival, and locoregional control rates. The matched-pair analysis included 254 patients. The 5-year overall survival, disease-specific survival, and locoregional control rates were 58.5% and 53.5% (P = 0.30), 68.9% and 68.0% (P = 0.80), and 82.2% and 63.6% (P

For the purpose of analyzing mechanisms related to the cis‐diamminedichloroplatinum resistance in head and neck squamous cell carcinoma, we analyzed RPMI2650 and its derived previously established cis‐diamminedichloroplatinum resistant cell line RPMI2650CR. To identify resistant phenotype‐related microRNAs, we compared microRNA expressions between RPMI2650CR and RPMI2650 by microarray. One of the microRNAs as downregulated, miR‐34a, was further investigated. Decreased expression of miR‐34a in RPMI2650CR was confirmed by quantitative reverse transcription‐polymerase chain reaction, but introduction of the miR‐34a precursor into RPMI2650CR or the inhibitor of miR‐34a into RPMI2650 did not change cis‐diamminedichloroplatinum sensitivities. However, 24 patients with sinonasal squamous cell carcinomas treated with intra‐arterial infusion of cis‐diamminedichloroplatinum showed a significant association between decreased expression of miR‐34a and poor disease specific survival (P = 0.0015), poor disease free survival (P = 0.0019), and poor local control rates (P = 0.017) (median follow‐up period: 53 months). Furthermore, multivariate analyses demonstrated significant associations between miR‐34a expression and the hazard ratios of disease free survival at 0.005 (95% confidence interval [CI] 0.00–0.29, P = 0.011) and local control rate at 0.008 (95% CI 0.00–0.44, P = 0.019), although other parameters such as age, gender, treatment method, T and N stages did not show any similar association. These results strongly suggest that miR‐34a expression can be an independent prognostic biomarker in patients with sinonasal squamous cell carcinoma who are undergoing treatment with cis‐diamminedichloroplatinum.

For patients with head and neck squamous cell carcinoma (HNSqCC), the development of squamous cell carcinoma (SqCC) in the lung may signal a new primary or the onset of metastatic dissemination. Although the distinction influences prognosis and therapy, it may not be straightforward on histologic or clinical grounds. The human papillomavirus (HPV) is an etiologic agent for SqCCs arising from the oropharynx but not for SqCCs arising from other head and neck sites. For patients with HNSqCC who develop a lung SqCC, HPV analysis could be useful in establishing tumor relationships. High-risk HPV in situ hybridization was performed on 54 lung SqCCs from patients with a previously diagnosed HNSqCC and on 166 primary lung carcinomas from patients without a prior HNSqCC. HPV was detected in 11 of 220 (5%) cases. All HPV-positive cases were from patients with a prior oropharyngeal SqCC. For the paired oropharyngeal and lung SqCCs, HPV status was concordant in 95% of cases. Time from treatment of HPV-positive oropharyngeal carcinomas to detection of lung carcinoma ranged from 1 to 97 months (mean, 36 mo). Two HPV-positive cancers were detected in the lung 8 years after treatment of the oropharyngeal primary. Despite the long interval, E6 sequencing analysis of 1 of these paired samples confirmed that the tumors harbored the same HPV-16 variant. HPV does not seem to play a role in the development of primary lung cancer. For patients with oropharyngeal SqCC who develop lung SqCC, HPV analysis may be helpful in clarifying tumor relationships. These relationships may not be obvious on clinical grounds, as HPV-related HNSqCC may metastasize long after treatment of the primary tumor.