In Japan, cancer genome medicine started in 2018. The term “next-generation sequencer （NGS）,” which is the core component of this technology, is expected to become increasingly widespread. This paper illustrates what NGS is, what can be done using NGS, and how to use NGS to solve issues through plain images. In addition, strategies to identify the Achilles’ heel of cancer using NGS in combination with other advancing technologies is discussed through examples of head and neck cancer research.

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Pheochromocytoma （PCC） and paraganglioma （PGL） are derived from the neural crest: PCC is from the adrenal medulla and PGLs are from the extra-adrenal paraganglions. They have similar histologic features such as Zellballen pattern. PGLs are subdivided into head and neck parasympathetic PGLs （HNPGL） including carotid body tumor （60％）, middle ear PGL （30％）, vagal PGL （10％）, and sympathetic PGLs （S-PGL） in the abdominal, pelvic, and thoracic regions. PCCs and S-PGLs are catecholamine-producing tumors, however, HNPGLs are usually non-functioning tumors. Chromogranin A and dopamine-beta-hydroxylase are the most useful markers for PCC and S-PGLs, however, expression of these proteins is far less in HNPGLs than in PCCs and S-PGLs. In HNPGLs, 30％ are familial, 10-25％ are bilateral, 17-37％ are multiple, and 4-8％ are metastatic. In S-PGLs, the metastatic rate is about 30-40％, and the WHO Classification of Tumours of Endocrine Organs 4th edition （2017） defined that all PCCs and PGLs（PPGLs）have some metastatic potential, assigned them ICD-O3 （malignant tumor）, and deleted the term “benign PPGLs.„ To date, 20 susceptible genes for PPGLs have been detected and genotype-phenotype correlations have been clarified. Of these genes, mutations of succinate dehydrogenase complex, subunit SDHD, SDHAF2, SDHC and SDHB show high penetrance in HPGLs, and are especially important for hereditary, multiplicity and metastasis. Immunohistochemistry of SDHB shows negativity in PPGLs of SDH mutations, which is a useful tool for screening of such mutations. Pathologic diagnosis for predicting metastasis has been the most important issue for PPGLs. Grading of adrenal pheochromocytoma and paraganglioma （GAPP） scoring was made by the nationwide survey of Japanese study on PPGLs. It is recommended to make a diagnosis based on GAPP scoring, however, its application to HNPGLs may be difficult due to histologic damage by preoperative embolization. In conclusion, multicenter research is necessary to accumulate clinicopathologic data including metastasis, diagnostic tools, biologic and genomic studies, treatments, and patients' prognosis.

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There are two important things to consider when reconstructing swallowing function in cases of hypopharyngeal cancer and laryngeal cancer: that there is no defect in the structure that separates the airway and food, and that there are no obstacles in the flow path of food. Based on this idea, we developed a new surgery that can preserve laryngeal function in patients with advanced laryngeal cancer. All three patients have survived disease-free for more than 36 months after tumor resection, and laryngeal function is maintained. This surgery is routine and can be standardized, and future studies may show that it is a potential option for preserving the larynx in cases of advanced laryngeal cancer with vocal cord paralysis. We also examined 33 cases of hypopharyngeal cancer patients who underwent reconstruction by free tissue transplantation for partial hypopharyngeal laryngectomy. Regarding the morphology around the larynx after reconstruction, it was shown that it is important to secure a food channel outside the larynx.

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The tumor immune microenvironment is associated with disease progression and therapeutic resistance in various types of cancer including head and neck cancer. To quantitatively evaluate the tumor immune microenvironment, we have developed a practical and cost-effective 12-plex imaging platform based on sequential immunohistochemistry and image cytometry analysis （Tsujikawa et al., Cell Reports, 2017）. This novel imaging platform allows quantitative assessment of various immune cell lineages with preserved tissue architecture in a single tissue section, enabling exploration of immune-based biomarkers correlating with clinical outcome. Multiplex IHC/image cytometry could be further accelerated via tissue-geographical analysis, artificial intelligence-based image analysis, and integration with non-immune biomarkers, leading to the development of in-depth tissue-based predictive biomarkers and optimization of treatment selection in the field of head and neck oncology.

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Preclinical animal xenograft tumor models are widely used for modeling the growth and spread of disease in translational cancer research. In particular, orthotopic xenograft models of head and neck cancer, by implanting head and neck cancer cell lines into the tongue of the mouse, have advantages for their ability to mimic local tumor growth and recapitulate the pathways of cervical lymph node metastasis seen in human head and neck cancers. However, these animal models have limitations due to the issues related with using established cell lines, suggesting that it is difficult for these animal models to recapitulate tumor heterogeneity and microenvironment. This review summarizes the advantages and limitations of animal models for head and neck cancers and discusses the future directions of the role of animal models in translational cancer research.

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We performed only excision of the primary tumors for 40 cases of early-stage oral squamous cell carcinoma. Delayed metastases occurred in 9 of the 40 cases （22.5%）. In some Japanese facilities, the sentinel lymph nodes （SN） are identified using radioisotopes in clinical studies. In Europe and the United States, SN biopsy for early-stage head and neck cancers has been established as one of the standard treatment choices, whereas in Japan it has only been described in the Japanese Practice Guideline for Head and Neck Cancer （2018）. We developed a contrast-enhanced ultrasonography （CEUS）-guided SN-detection method, and predicted the SN metastatic status using a novel ultrasound technology, Superb Microvascular Imaging （SMI）, as a Phase I study. Establishing the CEUS-guided SN-detection method and criteria for the accurate diagnosis of SN metastases using SMI would be valuable, and the methods would safely and certainly support our decision-making for neck dissection in the routine outpatient clinical setting.

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Ten years have passed since Japanese board certification system for head and neck surgeons was established. Patients and operations have become more centralized at the board-certified facilities. The board certification system seems to have been welcomed by many Japanese head and neck surgeons. However, it was not found that human resources had become centralized and that surgeons could reduce their working hours. Additionally, there are many problems in provincial areas. We must continue to look for a more sustainable system in the future.

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Ten years have passed since the Japan Society for Head and Neck Surgery started to certify surgeons and institutes as board-certified specialists or special institutes in order to standardize and equalize head and neck treatment in Japan. This paper presents the current situation in Hyogo prefecture and in our hospital, Kobe City Medical Center General Hospital （KCGH）, as a representative municipal hospital. In Hyogo, there are 14 Cancer Base hospitals authorized by the national government, two of which do not employee full-time head and neck surgeons, especially in the northern part. We have five board-certified institutions in Hyogo, all of which are located in the southeastern part. According to DPC data in 2017, more than 60％ of head and neck patients were treated in these board-certified institutions. Our hospital, KCGH, is one of the board-certified institutions and we treated 308 head and neck patients and performed 288 head and neck operations in 2017. Because of the lack of beds in KCGH （13 beds are currently available for head and neck tumor treatment）, we need to minimize the period of hospitalization. In fact, the average period in our institution is the shortest among the five board-certified institutions （18.7 days）. This point may hinder the adoption of standardized treatment, especially in the field of chemoradiotherapy （CRT）. We use low-dose weekly CDDP, which is currently categorized as Category 2B in the NCCN guideline, as first-line concurrent chemotherapy, because this procedure can be started from the outpatient clinic. Another limitation is the lack of plastic surgeons for head and neck reconstruction, which sometimes requires us to use a pedicle flap even for reconstruction of oral cancer. Key words：Standardization of head and neck cancer treatment, Hyogo prefecture, Municipal hospital

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harged particle therapies including carbon-ion radiotherapy and proton beam therapy show superior dose distribution compared to X-ray therapy, resulting in safer and more effective treatments. Moreover, carbon-ion radiotherapy has the potential to overcome radio-resistance because of its higher linear energy transfer and relative biological effectiveness. Charged particle therapies have been recognized as an advanced medical technology since 2003 in Japan. However, the use of charged particles for treating malignant head and neck tumors has been covered by public medical insurance from April 2018 except for oral, laryngeal, and pharyngeal squamous cell carcinomas. This review describes the clinical indications of charged particle therapies for head and neck tumors.

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Imaging plays an important role in the management of patients with tongue cancer. In the updated eighth edition of the TNM category, there are critical changes to the oral cavity section, and the role of measurement of the depth of invasion （DOI） and diagnosis of ENE has been added to preoperative imaging of tongue cancer. There are several issues to be addressed, such as standardization of measurement methodologies in preoperative image diagnosis. In this article, these important factors in preoperative imaging for current tongue cancer are discussed from the radiologist’s viewpoint.

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In the 8th edition of AJCC, human papillomavirus （HPV） related oropharyngeal carcinoma became an independent clinical entity from oropharyngeal carcinoma, and p16 immunostaining is used to diagnose such carcinoma. Although HPV-related oropharyngeal carcinoma generally has a fair prognosis, there are still cases with recurrent lesions and poor prognosis. In the present study, 100 consecutive fresh cases with oropharyngeal carcinoma treated in our department from December 2006 to November 2014 were analyzed retrospectively. Of the 100 cases, there were 34 HPV-related oropharyngeal carcinomas, of which 4 patients had died by January 2019: 3 due to oropharyngeal carcinoma and 1 due to hypopharyngeal cancer later. According to the clinical staging of the 7th edition of AJCC, there was 1 case of stageⅢ and 3 cases of stageⅣ at the initial diagnosis, whereas according to the 8th edition, there was 1 case of stageⅡ and 3 cases of stageⅢ. This retrospective investigation demonstrated that smoking history, locoregional aggressive disease, high age and multiple cancers were related to poor prognosis in HPV-related oropharyngeal carcinoma. In addition, the cases of HPV-related oropharyngeal carcinoma tended to have long survival even after the locoregional recurrence and/or distant metastasis appeared. Therefore, additional treatment may be considered for these lesions if possible.

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It is often necessary to judge whether to use fine needle aspiration cytology （FNAC） on thyroid nodules ≤1cm at present. In our hospital, we have developed an original FNAC instrument for improving the diagnostic accuracy and safety of FNAC, and have been using this instrument since 2009. We have already reported on the usefulness of this instrument. In this study, we investigated the effects of FNAC using this instrument on thyroid nodules ≤1cm. A retrospective chart review was performed on 312 specimens of 265 patients who underwent FNAC on thyroid nodules ≤1cm between January 2014 and December 2015. We investigated the inappropriate rate of all specimens, operator, tumor site, presence or absence of calcification, and presence or absence of cysts. The inappropriate rate of all specimens was 8.3％; the investigated inappropriate rate did not differ among operators, site of tumor, or properties of tumor. The inappropriate rate of thyroid nodules ≤1 cm was improved by the original FNAC instrument and procedure.

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The modified Glasgow Prognostic Score （mGPS） was announced as a tool for the assessment of cancer cachexia by measuring serum levels of albumin and C-reactive protein （CRP）, which had been reported as risk factors for survival instead of cancer stage. In this study 74 patients with stage Ⅲ/ⅣA head and neck squamous cell cancers including 29 hypopharyngeal cancer patients, 24 laryngeal cancer patients and 21 oropharyngeal cancer patients, who had primarily undergone concurrent chemoradiotherapy （CCRT） at our hospital, were enrolled. Along with an evaluation of the relationship between cancer cachexia, hypoalbuminemia and survival, the scores were statistically analyzed at two points: at the first visit and at the time of post-CCRT. According to Miki’s classification the scores were classified into four groups: Group A with normal data （Alb≥3.5, CRP＜0.5）, Group B （Alb＜3.5, CRP＜0.5）, Group C （Alb≥3.5, CRP≥0.5）, and Group D with complete cancer cachexia （Alb＜3.5, CRP≥0.5）. To conclude, mGPS was clarified as a risk factor for survival for HNSCC patients, especially those with stage IVA hypopharyngeal cancer and oropharyngeal cancer. To obtain a better prognosis, cancer cachexia detected at the first visit should be treated immediately, and at the time of post-CCRT hypoalbuminemia also would be improved rapidly regardless of serum level of CRP.

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We studied 27 cases of metastatic carcinomas to the head and neck from the thoracoabdominal organs. Primary lesions were from the lung（12 cases）, thoracic esophagus（four cases）, kidney（three cases）, uterine cervix（two cases）, liver（one case）, pancreas（one case）, stomach（one case）, prostate（one case）, thymus（one case）, and pleura（one case）. Female gender was more common in the younger cases, whereas male gender was more common in the older cases, possibly due to differences in the morbidity of the primary lesion. The site of metastasis in the head and neck region of many cases was the inferior cervical region. However, metastasis to the superior cervical region or head and neck organs occurred in several cases, so the clinical detection of thoracoabdominal cancer was thought to be important in cases with cervical node metastasis. The 10 cases diagnosed as untreated neck masses on the first visit to our hospital showed a poor prognosis compared with the 17 cases that had been treated previously. The primary lesion in untreated cases was thought to progress rapidly and metastasize in the early period.

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Carboplatin（CBDCA）-based chemotherapy is considered for patients with recurrent/metastatic（RM）head and neck squamous cell carcinoma who are unsuitable for Cisplatin-based chemotherapy. In addition, efficacy of the combination of CBDCA and Paclitaxel（PTX）（TC therapy）has been reported in patients with RM head and neck non-squamous cell carcinoma. Efficacy and safety of TC therapy were retrospectively reviewed in patients with RM head and neck carcinoma at Nagoya City University Hospital from August 2014 to June 2018. CBDCA and PTX were given in a 21-day cycle（CBDCA, AUC6 and PTX, 175mg/m2 on day 1）. A total of 18 patients were enrolled in this study. Among them, 12 patients had squamous cell carcinoma（SCC）and 6 had non-squamous cell carcinoma（nonSCC）. Two patients（18.2％）achieved a partial response in the SCC group, and three patients（60.0％）achieved a partial response in the nonSCC group. As for complications, grade 3-4 toxicities included neutropenia（81.3％）and leukocytopenia（56.3％）. No treatment-related death was seen. This study indicated the efficacy and safety of TC therapy, especially for nonSCC patients. Although severe blood toxicities were observed, all of those were manageable using G-CSF formulations and preventative antibiotics. TC therapy is an effective option for patients with RM head and neck carcinoma who are unsuitable for Cisplatin-based chemotherapy.

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