Micro cell aggregates such as circulating tumor cell clusters or micro metastases of head and neck squamous cell carcinoma putatively cause later recurrence or metastasis. For this study, cancer spheroids were obtained from a human oropharyngeal cancer cell line, T3M-1, through 3D culture to analyze resistance against chemo-radiotherapy in an in vitro model of micro cancer cell aggregates. Observations demonstrated that T3M-1 spheroids have resistance against cisplatin, paclitaxel, and radiation. The monolayer cell line T3M-1SMO was established with single cells separated from T3M-1 spheroids. T3M-1SMO was proven to lose resistance, suggesting that resistance of the spheroid is not irreversible. PCR array analysis was used to investigate the alteration of mRNA expression between monolayer culture and spheroids of T3M-1. The results demonstrated that the expression of CD82 and CXCR2 was increased in spheroids. Real-time PCR analyses confirmed that the expression of CD82 and CXCR2 was increased only in spheroids and not in T3M-1SMO cells. CD82 and CXCR2 can play important roles in spheroid formation. They are promising targets for overcoming the chemo-radio resistance of micro cancer cell aggregates in head and neck cancers.

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Biphenotypic sinonasal sarcoma （BSNS） is a double-phenotype sarcoma showing nervous and muscular system differentiation. BSNSs have recently been added to the 4th edition of the World Health Organization Classification of Head and Neck Tumors. We report two cases of BSNSs confirmed based on recent pathologic analyses. Case 1 was a 67-year-old female in whom the tumor occurred mainly in the right ethmoid sinus. The biopsy revealed a low-grade malignant tumor. We performed a radical resection; however, a definitive diagnosis could not be established. She had no evidence of a recurrence for ＞10 years following the radical resection. Case 2 was a 25-year-old male in whom the tumor occurred mainly in the right maxillary sinus and grew rapidly. The biopsy showed a high-grade malignant tumor. We performed surgical resection; however, a definitive diagnosis could not be made. He has been free of a recurrence for ＞5 years following the surgical resection, post-operative radiotherapy, and systemic chemotherapy.
BSNS has been reported to be a tumor of relatively low malignant potential with rare distant metastases. Complete excision of the tumor is important in the treatment of BSNS.

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We treated two cases of oral polypoidal malignant melanoma （PMM） with marked exophytic growth. We noted changes in levels of serum 5-S-cysteinyldopa （5-S-CD）, a tumor marker. Case 1 was a 51-year-old man. A brownish polypoidal mass of 55×40×40mm was found in the right mandibular gingiva, and was identified by biopsy to be malignant melanoma. 5-S-CD decreased from 12.5nmol/l before surgery to 3.9nmol/l after surgery. The 5-S-CD 3 years after operation is within the reference value range, and currently the course is good with no recurrence. Case 2 was an 81-year-old woman. A black polypoidal mass of 50×40×25mm was found in the right maxillary gingiva, and was identified by biopsy to be malignant melanoma. 5-S-CD decreased from 26.9nmol/l before surgery to 4.3nmol/l after surgery. The oral primary PMM was considered to be rare in these two cases. In addition, serum 5-S-CD could be useful in the oral cavity region.

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The recent increase in the incidence of oropharyngeal cancer in the USA and northern Europe has been attributed to human papillomavirus （HPV） infection. Because the carcinogenic mechanism of HPV related oropharyngeal cancer （OPC） is different from that of other OPC, biological malignancy and treatment effects are considered to be different between the two groups. We performed a prospective study in the Japanese cooperative study group for basic research in head and neck cancer （JCSG-BRHNC） to compare the effects of first-line treatment between HPV positive or negative stage Ⅲ and Ⅳ OPC.
From May 2014 to March 2016, 92 patients were enrolled by 18 institutions in the whole country. Sixty-five patients （71％） were HPV-positive in the PCR. We examined the effects of primary treatment in a prognosis investigation conducted one year after registration. The results showed that 60 of the 65 HPV-positive cases successfully achieved complete response （CR）, and the primary treatment success ratio was 92.3％ as the ratio of CR cases without recurrence or metastasis within one year. In comparison, 15 cases （57.7％） of 26 HPV-negative patients successfully achieved CR. The effect of chemoradiotherapy was high, and even cetuximab combination radiotherapy （BRT） showed enough effects for HPV-positive cases. Also, induction chemotherapy （IC） was successful and all cases achieved CR in RT singularity cases. These results will provide a useful reference when examining clinical trials that lower the intensity of treatment for HPV-positive cases.

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Adenoid cystic carcinoma that occurs in the head and neck is a rare malignant tumor. The tongue base is an important part of the swallowing function and the articulation function, and tumor removal at this site may cause postoperative dysphagia and dysarthria. Here, we experienced a relatively large adenoid cystic cancer case that occurred at the base of the tongue. The approach to the tumor was performed in the mandible midline transection, and was reconstructed with the rectus abdominis muscle flap, and because postoperative dysphagia was expected, laryngeal elevation and cricopharyngeal muscle amputation were performed at the same time. A postoperative jelly meal can be taken orally and daily conversation without the need for writing is possible, but some speech is intelligible. In this case, this procedure was useful for maintaining QOL.

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Portal venous gas （PVG） is sometimes seen in severe diseases such as intestinal necrosis and is a symptom indicating poor prognosis. Pneumatosis intestinalis （PI） is a morphological finding wherein multiple small gas cysts are seen in the intestinal wall, and it is also seen in intestinal necrosis and other intestinal injuries. We report a case of PI and PVG which occurred after chemoradiotherapy （CRT） for the treatment of hypopharyngeal cancer. A 79-year-old man was referred to us due to swelling of the left neck and we diagnosed hypopharyngeal cancer （T2N2bM0）. CRT （CBDCA＋5-FU×2 courses, RT: 70Gy/35fr） was performed after left neck dissection. He experienced dysphagia for more than one month after CRT, so we performed percutaneous endoscopic gastrostomy （PEG）. However, the next day he developed peritonitis, which progressed to a pelvic abscess in several days. Because his condition was improved by conservative therapy such as antibiotics and drainage, we provided him with tube feeding. Eight days later （the 25th day after PEG）, he suddenly developed severe abdominal pain and vomiting. Contrast-enhanced abdominal computed tomography （CT） showed PI and widespread PVG. We performed conservative therapy again and he recovered without PI and PVG. Although such cases may be rare, it is important to consider the possibility of PI and PVG as complications of CRT.

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We retrospectively analyzed 65 patients with StageⅡ-ⅣB hypopharyngeal squamous cell carcinoma who underwent platinum-based concurrent chemoradiotherapy using 3D conformal radiation therapy at our hospital between July 2009 and January 2016. The numbers of clinical stage Ⅱ/Ⅲ/ⅣA/ⅣB were 24/14/26/1, respectively. The median dose to the primary tumor and the nodes was 66Gy/33 fractions. Twelve patients underwent neck dissection preceding chemoradiotherapy.
The median follow-up time was 43 months （range 9-91 months）.
The assessment of initial response in three months was as follows: CR/PR/PD 61/2/2. Two cases received salvage surgery. Among the CR cases, 14 cases developed treatment failures in the irradiated fields and 8 cases received salvage surgery.
The three-year overall survival, larynx preservation survival and progression-free survival rates were 75.0％, 85.8％ and 74.0％, respectively.
Our clinical result of platinum-based concurrent chemoradiotherapy using 3D conformal radiation therapy is satisfactory. Because we actively perform neck dissection preceding chemoradiotherapy for patients with advanced-stage cancer, the rate of larynx preservation is improved.

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Objective: Parotid gland carcinoma （PGC） and submandibular gland carcinoma （SMGC） are relatively rare. The aim of this retrospective study was to compare the clinical outcomes of PGC and SMGC.
Patients: Our study included 260 patients （195 with PGC and 65 with SMGC） who underwent initial surgical treatment at Kyoto University and its affiliated hospitals between 2006 and 2015.
Results: A total of 44％ of the PGCs and 58％ of the SMGCs were classified as high-grade malignancies. The sensitivity of fine-needle aspiration cytology was 50％ for PGC and 75％ for SMGC. At a mean follow-up time of 3.6 years, the 3-year overall survival, disease-specific survival （DSS）, locoregional control, and no distant metastasis （NDM） rates for PGC were 85％, 89％, 85％, and 87％, respectively, while those for SMGC were 74％, 74％, 90％, and 65％, respectively. Furthermore, the DSS and NDM rates for SMGC were statistically significantly lower than those for PGC.
Conclusions: In comparison to PGC, SMGC has a higher risk of distant metastasis and a poorer DSS rate.

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When treating advanced thyroid cancer cases with Lenvatinib, most of these patients are old and we sometimes hesitate to administer the drug to elderly cases. We have experienced administering low-dose Lenvatinib to aging patients who were over 80 years old. The first case was a 92-year-old man. He was administered 10mg of Lenvatinib at the outpatient clinic, could continue the treatment without serious side effects, and maintained PR for one year. The second case was an 86-year-old female. She had an obstructed airway due to tumor invasion. Due to her poor general condition, we decided to start with 4mg of Lenvatinib. The trachea-invading tumor shrank, and she was able to stay at home, but eventually died when the tumor progressed.
Low-dose Lenvatinib administration was shown to be tolerated and to reduce side effects even in the elderly. This treatment, however, may have insufficient antitumor effects. The organ function, social status, and living environment of older adults are varied, so we should decide the administration dose and method according to the condition of each case.

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Differentiated thyroid cancer is a disease with a good prognosis and can be treated by surgical excision, but cases that are locally advanced or have distally metastasized can be difficult to control. Recently, molecular-targeting therapeutic agents are recommended for such uncontrolled cases, and lenvatinib is used as the first choice in view of its effectiveness.
We report the effectiveness and adverse events of lenvatinib from our experience with four differentiated thyroid cancer patients refractory to radioactive iodine treatment. Of the four patients, treatment of one was discontinued because of adverse events of fatigue and Grade 3 hand-foot syndrome. Three cases had adverse events such as hypertension, proteinuria, thrombocytopenia and fatigue but were controllable by antihypertensive medications and a withdrawal period of 7 days, thus being able to continue the treatment. Excluding the discontinued case, one patient achieved partial response, and two cases had stable disease.
High-grade cases in which the patients’ quality of life is likely to be impaired are potential indications for lenvatinib, however, the adverse events and patients’ social background should also be carefully considered.

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The purpose of this study was to analyze the risk factors for osteoradionecrosis （ORN） of the mandible after radiotherapy for treatment of oral or oropharyngeal cancers. Sixty patients with oral or oropharyngeal cancers who had undergone external radiotherapy from January 2011 to December 2016 were retrospectively reviewed. Seven patients （12%） had ORN, and the median time to the development of ORN was 15 months （range, 1-53 months）. In the analysis of the whole mandible, univariate analysis revealed that tooth extractions within one month before radiotherapy （p<0.001）, the mean dose of radiotherapy to the mandible （p=0.04）, and the volume of mandible receiving doses of 40Gy （p=0.02） and 50Gy （p=0.04） were significant risk factors for ORN. In the analyses of the right and left sides of the mandible, the mean dose of radiotherapy to the mandible and the volume of mandible receiving a dose of 40Gy were significant risk factors （p=0.04 for each）. In the multivariate analysis, tooth extractions in the analysis of the whole mandible was the only significant risk factor for ORN （p<0.01）. Incorporation of both mean dose constraints to the mandible in addition to maximal dose constraints might be needed to reduce the occurrence rate of ORN.

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We describe our experience with three cases of external auditory canal cholesteatoma in patients after radiotherapy. The first patient in her 80s developed cholesteatoma 2 years and 7 months after postoperative radiotherapy （50Gy in 25 fractions） to the ipsilateral neck from the tumor bed to the base of the skull for right parotid adenoid cystic carcinoma. The second patient, who had received chemotherapy and radiotherapy after anterior skull base surgery for olfactory neuroblastoma, presented bilateral cervical lymph node metastases 7 years later and received salvage lymph node dissection and postoperative radiotherapy （60Gy in 30 fractions）; she developed cholesteatoma 3 years and 7 months later while in her 40s. The last patient in her 70s developed cholesteatoma 2 years and 8 months after postoperative radiotherapy （66Gy in 33 fractions） to the ipsilateral neck from the tumor bed to the base of the skull for tongue base adenoid cystic carcinoma with marked perineural invasion, which was confirmed by pathological analysis of surgery in the preoperative diagnosis of pleomorphic adenoma. We must be alert to the possible development of external auditory canal cholesteatoma, if the external auditory canal was included in the radiation field.

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S-1 is widely used as adjuvant chemotherapy for head and neck cancer. The recommended regimen of four-week administration followed by a two-week rest with drug withdrawal frequently causes toxic events. From 2012 to 2015, we performed adjuvant chemotherapy with S-1 on alternate days for head and neck squamous cell carcinoma in 22 patients with stage Ⅲ/Ⅳ carcinomas in the maxillary sinus, oral cavity, mesopharynx, hypopharynx and larynx with no evidence of distant metastases. We examined the adverse events, the rate of compliance and the survival rate. Nineteen patients （86.3％） received S-1 for more than 1 year. None of the 22 patients developed grade 3 or worse adverse events. The 5-year progression-free survival rate was 81.8％. Alternate-day treatment with S-1 has a high rate of compliance and may cause milder adverse events without compromising the therapeutic effectiveness.

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The detection of pharyngocutaneous fistula by videofluoroscopic examination of swallowing is sometimes difficult. We report two cases of pharyngocutaneous fistula after total laryngectomy detected by computed tomography （CT） with oral contrast. We put the gauze with X-ray contrast thread around the pharyngeal fistula on the neck of the patient as a sign if the patient had no drainage tube. Further, we examined non-contrast neck CT immediately after the patient had swallowed nonionic iodinated contrast medium. We identified the pharyngeal fistula on the neck by detecting the leak of the contrast medium. We made a skin incision just above the pharyngeal fistula and reopened the wound. This method could be effective for identifying pharyngeal fistulas.

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There have been a limited number of studies about clinical symptoms in patients in the terminal phase of head and neck cancers. The aim of this prospective multi-institutional study （11 institutes） was to assess the prevalence of symptoms and functional status among patients with advanced head and neck cancer. Of the 100 patients who met the inclusion criteria, 72 patients were observed until their death. Neck dressing treatment was needed for skin-infiltration symptoms, such as bleeding, infection, and exudation in 30.6% of patients at study entry and in 36.1% just before death. Severe bleeding causing death was observed in 6.9% of patients and the lethal rupture of the carotid artery was seen in only one case （1.4%）. At the time of study entry, 75% of patients maintained enteral nutrition, and 61.1% still received enteral nutrition just before death. Laryngeal phonation ability was not maintained in 44.4% of patients at the time of study entry and 50% just before death. Edema in the head and neck region was observed in 23.6% of patients at entry and 36.1% at the time of death. Since the above-mentioned symptoms in patients in the terminal phase were not mild, these symptoms sometimes cause uneasiness in head and neck patients, their families, and the medical staff.
To relieve the anxiety of patients, families, and the medical staff, further large-scale prospective studies are needed to establish care management of head and neck cancer patients in the terminal phase and bring them a better quality of life in the terminal phase.

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