Prospective observational study of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

A Case of Maxillary Arteriovenous Fistula Rupture Treated by Vascular Interventional Radiology.

A 64-year-old woman with neurofibromatosis type 1 was admitted because of a sudden hematoma in her right neck and throat. To prevent an airway obstruction, tracheostomy was performed, but bleeding into the trachea persisted and was difficult to stop. Bleeding arose from a vessel lesion in the right parapharyngeal space, passed through the paratracheal space, and finally reached the tracheostomy wound. An arteriovenous fistula (AVF) in the maxillary artery was revealed by angiography. We diagnosed rupture of the varix resulting from venous high pressure caused by the AVF. The patient was treated by vascular interventional radiology (IVR). A large number of platinum coils were inserted and N-butyl-2-cyanoacrylate (NBCA) was embolized in the AVF and varix. Although innovative vascular IVR was better than surgery to treat AVF of the head and neck lesion, some problems were encountered. The cost for the provided medical services was high, and NBCA was not approved by the pharmaceutical affairs law in Japan.

[Sequential Chemoradiotherapy for Advanced Head and Neck Cancer: A Clinical Study with 33 Cases].

A total of 33 patients with advanced head and neck cancer (AHNC) treated with sequential chemoradiotherapy (SCRT) were retrospectively evaluated at Gunma University Hospital between 2009 and 2011. The regimen of SCRT was docetaxel, cisplatin, and fluorouracil (TPF)-based induction chemotherapy (ICT), accompanied by docetaxel and cisplatin-based concurrent chemoradiotherapy (CCRT), and oral administration of TS-1 after that. The response rate was 61%, the 3-year overall survival rate was 42%, the non-tumor-bearing survival rate was 27%, and the tumor-bearing survival rate was 15%. Fourteen of 33 patients were tumor-free, and their 3-year overall survival rate was surprisingly 86%. On the other hand, 3-year overall survival rate in the remaining 19 patients was significantly low. To select good response cases for ICT was important. In such cases, TPF should be applied repeatedly, which achieved a 61% response rate even in AHNC. A long-term TS-1 oral medication suppressed cancer regrowth and contributed to long-term survival.

[Prediction of Post-operative Lymph Node Metastasis with a Molecular Biological Test in Head and Neck Cancer].

We assessed herein the post-operative lymph node metastasis in head and neck cancer, using the One-step nucleotide amplification (OSNA) method targeting matrix metalloproteinase 7 (MMP-7). Compared with the pathological test, the molecular biological test revealed more lymph node metastasis, resulting in poor prognosis. Six cases, of which the number of lymph node metastasis was the same between pathological and molecular biological test, survived. On the other hand, three of four cases, in which number of lymph node metastasis in the molecular biological test were larger than the pathological test, died from metastasis. We concluded that the pathological test underestimated metastasis, and OSNA with MMP-7 was useful for the prediction of post-operative lymph node metastasis.

Alteration of cancer stem cell-like phenotype by histone deacetylase inhibitors in squamous cell carcinoma of the head and neck.

Recent progression in the understanding of stem cell biology has greatly facilitated the identification and characterization of cancer stem cells (CSCs). Moreover, evidence has accumulated indicating that conventional cancer treatments are potentially ineffective against CSCs. Histone deacetylase inhibitors (HDACi) have multiple biologic effects consequent to alterations in the patterns of acetylation of histones and are a promising new group of anticancer agents. In this study, we investigated the effects of two HDACi, suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA), on two CD44+ cancer stem-like cell lines from squamous cell carcinoma of the head and neck (SCCHN) cultured in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. Histone deacetylase inhibitors inhibited the growth of SCCHN cell lines in a dose-dependent manner as measured by MTS assays. Moreover, HDACi induced cell cycle arrest and apoptosis in these SCCHN cell lines. Interestingly, the expression of cancer stem cell markers, CD44 and ABCG2, on SCCHN cell lines was decreased by HDACi treatment. In addition, HDACi decreased mRNA expression levels of stemness-related genes and suppressed the epithelial-mesencymal transition phenotype of CSCs. As expected, the combination of HDACi and chemotherapeutic agents, including cisplatin and docetaxel, had a synergistic effect on SCCHN cell lines. Taken together, our data indicate that HDACi not only inhibit the growth of SCCHN cell lines by inducing apoptosis and cell cycle arrest, but also alter the cancer stem cell phenotype in SCCHN, raising the possibility that HDACi may have therapeutic potential for cancer stem cells of SCCHN.

Immunosuppressive activity of CD14+ HLA-DR- cells in squamous cell carcinoma of the head and neck.

Myeloid-derived suppressor cells (MDSC) represent a heterogeneous population and have the potential to suppress immune responses via diverse mechanisms. In recent studies, a new subset of MDSC was identified by the markers CD14(+) and HLA-DR(-) in the peripheral blood from cancer patients. In this study, we investigated the proportions and characteristics of CD14(+) HLA-DR(-) cells in patients with squamous cell carcinoma of the head and neck (SCCHN). As expected, the percentage of CD14(+) HLA-DR(-) cells was significantly elevated in patients relative to healthy donors and the sorted CD14(+) HLA-DR(-) cells were able to suppress effectively both the proliferation and IFN-γ production of anti-CD3/anti-CD28 stimulated T cells, suggesting that CD14(+) HLA-DR(-) cells in patients with SCCHN contribute to the immune suppressive status. Furthermore, CD14(+) HLA-DR(-) cells revealed a higher level of CD86 and PD-L1 expression and transforming growth factor (TGF)-ß production than CD14(+) HLA-DR(+) cells. Addition of anti-CD86 mAb, anti-PD-L1 mAb and anti-TGF-ß mAb partially restored T-cell proliferation and IFN-γ production, respectively, indicating that the suppressive effects of CD14(+) HLA-DR(-) cells appear to be mediated by various molecules, including coinhibitory molecules and cytokines. Our data suggest that CD14(+) HLA-DR(-) cells act as potent immunosuppressive cells and particularly contribute to tumor escape from the host immune system in patients with SCCHN.

Intraoperative molecular assessment for lymph node metastasis in head and neck squamous cell carcinoma using one-step nucleic acid amplification (OSNA) assay.

BACKGROUND: Conventional intraoperative pathological examination for Sentinel node navigation surgery (SNNS) has been controversial. We evaluated the efficacy of one-step nucleic acid amplification (OSNA) assay for intraoperative diagnosis of cervical lymph node (CLN) metastasis compared with histopathological examination in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 175 CLNs dissected from 56 patients with HNSCC who underwent surgery at Aichi Cancer Center, Kyorin University, Gunma University or Fukushima Medical University, between April 2008 and December 2011 were enrolled. CLN samples were sectioned into four equal pieces, with two of each used for OSNA assay and other histopathological examinations. The diagnostic value of OSNA assay in HNSCC patients in predicting the results of histopathological diagnosis was evaluated using the area under the receiver operating characteristic (AUROC) curve. RESULTS: OSNA assay showed acceptable efficacy in the detection of pathological CLN metastasis (AUROC 0.918, 95 % confidence interval [CI] 0.852-0.984). Regarding the CK19mRNA cutoff value, the optimum cutoff point in HNSCC patients was 131 copies/µl (sensitivity: 82.4, 95 % CI 65.5-93.2; specificity: 99.3, 95 % CI 96.1-100.0; positive likelihood ratio 116.1; negative likelihood ratio 0.2]. CONCLUSIONS: We demonstrated that OSNA assay is useful in intraoperative diagnosis for CLN metastasis in patients with HNSCC. OSNA assay could be applied for SNNS in HNSCC patients.

A 14-year nationwide epidemiological analysis of delayed endolymphatic hydrops in Japan.

BACKGROUND: Delayed endolymphatic hydrops (DEH) is an inner ear disease that causes recurrent vertigo in the ipsilateral ear or fluctuating hearing in the contralateral ear due to endolymphatic hydrops secondary to preceding deafness. There are few reports of large, multicentre studies investigating the clinical-epidemiological characteristics of DEH. OBJECTIVE: This study aimed to clarify the characteristics of DEH in Japan. METHODS: Clinical data on 662 patients with DEH were analysed by nationwide, multicentre surveys conducted by the Peripheral Vestibular Disorders Research Group of Japan. RESULTS: The proportion of ipsilateral DEH (IDEH) was slightly higher than that of contralateral DEH (CDEH) at 55.4%. The time delay between onset of precedent deafness and onset of DEH was significantly longer for CDEH than for IDEH. The most common cause of precedent deafness was a disease of unknown cause with onset in early childhood (33.1%). Epidemiological characteristics were not significantly different between CDEH with and without vertigo. CONCLUSION: DEH appearing to be caused by viral labyrinthitis has a high rate of onset within 40 years of precedent deafness. Clinical and epidemiological characteristics of IDEH, CDEH with vertigo, and CDEH without vertigo were very similar. SIGNIFICANCE: The clinical-epidemiological characteristics of DEH in Japan were clarified.

Angiotensin II receptor blocker-induced angioedema in the oral floor and epiglottis.

We report the rare case of angioedema (also known as Quincke edema), which was induced by valsartan, an angiotensin II receptor blocker (ARB). ARBs are a new class of antihypertensive agent that is developed to exclude the adverse effects of angiotensin-converting enzyme inhibitors. In theory, ARBs do not contribute to the occurrence of angioedema because they do not increase the serum level of bradykinin, the responsible substance for angioedema. However, some reports of ARB-induced angioedema have recently been published. In this study, we present the forth case and the first Asian case of angioedema due to valsartan, which is one of the ARBs. Otolaryngologist should be wary of the prescribing ARB and discontinue ARBs treatment soon, if angioedema is recognized.

Does the middle temporal area carry vestibular signals related to self-motion?

Recent studies have described vestibular responses in the dorsal medial superior temporal area (MSTd), a region of extrastriate visual cortex thought to be involved in self-motion perception. The pathways by which vestibular signals are conveyed to area MSTd are currently unclear, and one possibility is that vestibular signals are already present in areas that are known to provide visual inputs to MSTd. Thus, we examined whether selective vestibular responses are exhibited by single neurons in the middle temporal area (MT), a visual motion-sensitive region that projects heavily to area MSTd. We compared responses in MT and MSTd to three-dimensional rotational and translational stimuli that were either presented using a motion platform (vestibular condition) or simulated using optic flow (visual condition). When monkeys fixated a visual target generated by a projector, half of MT cells (and most MSTd neurons) showed significant tuning during the vestibular rotation condition. However, when the fixation target was generated by a laser in a dark room, most MT neurons lost their vestibular tuning whereas most MSTd neurons retained their selectivity. Similar results were obtained for free viewing in darkness. Our findings indicate that MT neurons do not show genuine vestibular responses to self-motion; rather, their tuning in the vestibular rotation condition can be explained by retinal slip due to a residual vestibulo-ocular reflex. Thus, the robust vestibular signals observed in area MSTd do not arise through inputs from area MT.

Enhanced methamphetamine-induced conditioned place preference in risk-taking rats.

Patients with psychiatric disorders, such as gambling and substance use, tend to exhibit maladaptive decision-making. In this study, we assessed individual differences in risk-taking behaviors using a rat gambling task (GT) and investigated the relationship between risk-taking behaviors and vulnerability to drug dependence using methamphetamine (METH)-induced conditioned place preference (CPP). In the GT using a radial arm maze, male Long-Evans rats were trained to choose one of three choice arms (a low-risk/low reward (L-L), a high-risk/high reward (H-H), and an empty arm) in 16 trials per day for 14 days. METH-induced CPP consisted of 6 sessions: habituation, conditioning, preference test (Test I), extinction, extinction test (Test II), and reinstatement test (Test III). Results demonstrated that the percentage of choosing the H-H arm was significantly positively correlated with the percentage of time spent in the METH-paired compartment in the preference test, but not with the extinction and reinstatement tests, suggesting that risk-taking rats are more vulnerable to drug dependence.

Carbon-ion radiotherapy combined with chemotherapy for head and neck mucosal melanoma: Prospective observational study.

This study aimed to evaluate the efficacy of carbon-ion radiotherapy in combination with chemotherapy using dacarbazine, nimustine, and vincristine (DAV therapy) in mucosal melanoma. Twenty-one patients with clinically localized mucosal melanoma of the head and neck were enrolled. The primary endpoint was 3-year overall survival (OS). Secondary endpoints included local control, progression-free survival (PFS), and adverse event occurrence. Carbon-ion radiotherapy with a dose of 57.6-64.0 Gy (relative biological effectiveness) in 16 fractions was delivered concurrently with DAV therapy, and 2 cycles of adjuvant DAV therapy were administered every 6 weeks. The median follow-up periods were 15.5 months for all patients, and 31.2 months for 12 surviving patients. All patients had locally advanced T4a or T4b disease in the rhino-sinus area. In 16 patients (76.2%), 3 cycles of planned DAV therapy were completed. The 3-year OS and PFS rates were 49.2% and 37.0% respectively. The 3-year local control rate was 92.3%. Eleven patients (52%) developed distant metastasis, which was the most frequent pattern of the first failure. Commonly presenting acute grade 2-3 toxicities associated with radiotherapy and chemotherapy were mucositis (11 patients [53%]) and leukopenia (9 patients [43%]), which improved with conservative therapy. None of the patients developed grade 3 or greater late toxicities. Carbon-ion radiotherapy in combination with DAV therapy led to excellent local control for advanced mucosal melanoma within acceptable toxicities. The efficacy of additional DAV therapy in improving survival was weaker than expected as distant metastases still occurred frequently. Trial registration no. UMIN000007939.

Multimodal coding of three-dimensional rotation and translation in area MSTd: comparison of visual and vestibular selectivity.

Recent studies have shown that most neurons in the dorsal medial superior temporal area (MSTd) signal the direction of self-translation (i.e., heading) in response to both optic flow and inertial motion. Much less is currently known about the response properties of MSTd neurons during self-rotation. We have characterized the three-dimensional tuning of MSTd neurons while monkeys passively fixated a central, head-fixed target. Rotational stimuli were either presented using a motion platform or simulated visually using optic flow. Nearly all MSTd cells were significantly tuned for the direction of rotation in the absence of optic flow, with more neurons preferring roll than pitch or yaw rotations. The preferred rotation axis in response to optic flow was generally the opposite of that during physical rotation. This result differs sharply from our findings for translational motion, where approximately half of MSTd neurons have congruent visual and vestibular preferences. By testing a subset of neurons with combined visual and vestibular stimulation, we also show that the contributions of visual and vestibular cues to MSTd responses depend on the relative reliabilities of the two stimulus modalities. Previous studies of MSTd responses to motion in darkness have assumed a vestibular origin for the activity observed. We have directly verified this assumption by recording from MSTd neurons after bilateral labyrinthectomy. Selectivity for physical rotation and translation stimuli was eliminated after labyrinthectomy, whereas selectivity to optic flow was unaffected. Overall, the lack of MSTd neurons with congruent rotation tuning for visual and vestibular stimuli suggests that MSTd does not integrate these signals to produce a robust perception of self-rotation. Vestibular rotation signals in MSTd may instead be used to compensate for the confounding effects of rotatory head movements on optic flow.

Preparation of C60-based active esters and coupling of C60 moiety to amines or alcohols.

We report the syntheses of C(60)-based active esters and the coupling of their C(60) moiety to various amines or alcohols. Methano[60]fullerene carboxylic acid was activated by esterification with N-hydroxysuccinimide (NHS) or pentafluorophenol (PFP) and the active esters were isolated. Reactions of the active esters with amines or alcohols proceeded easily to give a variety of compounds having the C(60) moiety.

A case of squamous cell carcinoma of the head and neck producing granulocyte-colony stimulating factor with marked leukocytosis.

In squamous cell carcinoma of the head and neck (SCCHN), tumor cells have been shown to secrete detectable amounts of various cytokines, such as interleukin (IL)-6, IL-10, and transforming growth factor (TGF)-beta. These tumor-derived factors might be responsible for promoting malignancy. Here, we describe a SCCHN patient with tumor produced G-CSF and characterized by marked leukocytosis. In this 45-year-old man, severe leukocytosis developed in parallel with aggressive tumor growth. G-CSF production by the tumor was confirmed by immunohistochemistry (IHC). Serum G-CSF levels were elevated. The leukocyte counts and the blood G-CSF level decreased following a course of radiotherapy. Tumor cells were also positive for G-CSF receptor, suggesting autocrine growth regulation by G-CSF. Moreover, the tumor cells were also investigated by IHC with anti-p53, anti-P-glycoprotein (P-gp), anti-thymidylate synthase (TS), and anti-dihydropyrimidine dehydrogenase (DPD), which molecules are thought to contribute the acquisition of therapeutic resistance. The tumor cells were positively stained for TS and DPD, but neither p53 nor P-gp. These results suggest that a variety of molecules may be responsible for acquisition of high malignancy.

Concurrent chemoradiotherapy with conventional fractionated radiotherapy and low-dose daily cisplatin plus weekly docetaxel for T2N0 glottic cancer.

BACKGROUND: To assess the efficacy of concurrent chemoradiotherapy (CCRT) with daily low-dose cisplatin (CDDP) plus weekly docetaxel (DTX) for patients with T2N0 glottic cancer. METHODS: Between January 2004 and December 2013, 62 treatment-naive patients with histologically proven T2N0 glottic cancer were treated with concurrent chemoradiotherapy. Radiation therapy (RT; 2 Gy daily fractions up to a total dose of 66 Gy) was administered in combination with daily low-dose CDDP (6 mg/m2, five times a week), plus weekly DTX (10 mg/m2) for up to 4 weeks from the commencement of RT. RESULTS: Median duration of follow-up was 70 months. The actuarial 3-year and 5-year overall survival rates were 95% and 93%. The 3-year and 5-year cause-specific survival rates were both 100%. The actuarial 3-year and 5-year local control rates were 94% and 94%, respectively. Hematologic toxicity (neutoropenia of severity ≥ Grade 3) was observed in 8% of the patients, and non-hematologic toxicity (radiation mucositis of severity ≥ Grade 3) developed in one patient (2%). Radiation dermatitis of severity ≥ Grade 3 and laryngeal necrosis developed in one patient. CONCLUSION: CCRT with weekly DTX and low-dose CDDP appears to be a practical and safe modality and is expected to improve local control. TRIAL REGISTRATION: UMIN000025046 . Registered 1 October 2015, retrospectively registered.

Temporal bone histopathologic abnormalities associated with mitochondrial mutation T7511C.

OBJECTIVES: We previously reported a mitochondrial T7511C mutation in the tRNA gene in a Japanese family with nonsyndromic hearing loss (HL). However, the temporal bone histopathology associated with T7511C has not been reported. The aim of the present study is to report histopathologic findings of a temporal bone from a patient in the Japanese family with this mutation. STUDY DESIGN: Single case study. METHODS: A temporal bone was obtained from the right ear of a male subject with progressive HL from 5 years of age and who died at 60 years of age from cerebral infarction. The bone was embedded, sectioned, and stained with hematoxylin-eosin for light microscopic study. Graphic reconstruction of the cochlea was performed using the method described by Schuknecht to determine loss of the stria vascularis and neurosensory elements including hair cells and spiral ganglion neurons. RESULTS: The most significant histopathologic finding was severe loss of spiral ganglion cells in all turns of the cochlea. Severe loss of neuronal filaments in Rosenthal's canal was also observed. The organ of Corti showed scattered loss of inner and outer hair cells in the basal turn. Partial atrophy of the stria vascularis was observed in all turns of the cochlea. CONCLUSION: Our results suggest that severe loss of spiral ganglion cells was the main cause of sensorineural HL associated with the T7511C mutation.

Expression of ER stress markers (GRP78/BiP and PERK) in adenoid cystic carcinoma.

CONCLUSION: A high GRP78/BiP expression was proved to be a significant marker for predicting poor outcome after surgery. GRP78/BiP may be a promising molecular target for treatment of ACC. BACKGROUND: The glucose-regulated protein GRP78/BiP plays a crucial role in the endoplasmic reticulum (ER) stress. The level of GRP78 is highly elevated in various human cancers, but the clinicopathological significance of GRP78/BiP remains controversial in patients with adenoid cystic carcinoma (ACC). METHODS: A total of 26 ACC patients were analyzed, and tumor specimens were stained by immunohistochemistry for GRP78/BiP, PERK, Ki-67, and microvessel density (MVD) determined by CD34. RESULTS: GRP78/BiP and PERK were highly expressed in 58% (15/26) and 35% (9/26), respectively. The high expression of GRP78/BiP was significantly associated with PERK, cell proliferation and angiogenesis.

Clinical Outcomes of Definitive and Postoperative Radiotherapy for Stage I-IVB Hypopharyngeal Cancer.

BACKGROUND: Hypopharyngeal cancer is relatively rare disease and continues to have a poor prognosis. This study analyzed the efficacy and safety of radiotherapy for stage I-IVB hypopharyngeal cancer. PATIENTS AND METHODS: Between 2000 and 2015, 72 patients were treated with definitive radiotherapy and 29 patients with stage IVA were treated with postoperative radiotherapy. RESULTS: With definitive radiotherapy, the 3-year locoregional control rates for stage I-II, III, IVA, and IVB disease were 89%, 74%, 51% and 0%, respectively. The 3-year overall survival rates for patients with stage I-II, III, IVA and IVB disease were 84%, 89%, 55% and 15%, respectively. In patients with stage IVA disease treated with postoperative radiotherapy, 3-year locoregional control and overall survival rates were 83% and 75%, respectively, which were significantly better than those treated with definitive radiotherapy. CONCLUSION: Definitive radiotherapy was effective for stage I-III disease. Surgery and postoperative radiotherapy improved the survival rate of patients with stage IVA hypopharyngeal cancer.

Infiltration of dendritic cells and NK cells into the sentinel lymph node in oral cavity cancer.

The sentinel lymph node (SLN) is regarded as the first tumor-draining lymph node, which may be the initial site activated by tumor antigens. To clarify the immunological functions of SLNs, a total of 89 tumor-free regional lymph nodes (41 SLNs and 48 non-SLNs) were obtained from 12 patients with oral cavity cancer, and infiltration of both DCs and NK cells was determined by immunohistochemistry. S-100+ and CD1a+ DCs infiltrated significantly into SLNs compared to non-SLNs. Analysis in each of the pN0 and pN+ patients showed that all the DC markers in pN0 patients and only S-100+ in pN+ patients were significantly more abundant in SLNs. Moreover, infiltration of CD83+ DCs was less in pN+ patients than in pN0 patients. These results suggest that more significant immune responses against cancer occur in SLNs than in non-SLNs. However the progression of disease including nodal disease may cause systemic immunosuppression.