Immunosuppressive property of submandibular lymph nodes in patients with head and neck tumors: differential distribution of regulatory T cells.

OBJECTIVE: Different sensitizations and immune responses are thought to be induced in response to antigens at different mucosal sites between the oral floor and nose. The aim of this study was to investigate differences in the distributions of lymphocyte subsets in the submandibular (SM) and upper jugular (UJ) lymph nodes (LNs), which are supposed to be regional LNs of the oral floor and nasal mucosa, respectively. SMLNs and UJLNs were collected from patients with head and neck tumors who underwent surgical resection. The populations of T cells, Natural Killer (NK) cells, Natural Killer T (NKT) cells, regulatory T cells (Tregs) and dendritic cells (DCs) in LNs without metastasis were analyzed by flow cytometry. The high-affinity IgE receptor (FcεRI) expression of LN cells were also evaluated. RESULTS: The proportions of CD4+CD25+Foxp3+ Tregs, CD4+CD45RA-Foxp3high effector Tregs and FcεRIα+CD33+CD11c+ DCs were significantly larger in SMLNs compared with UJLNs, while those of CD3+ T cells, CD3-CD56+ NK cells, CD3+Vα24+Vß11+ NKT cells, and CD123+CD303+ DCs did not show any significant differences between SMLNs and UJLNs. The differential distributions of CD4+CD25+Foxp3+ Tregs were observed regardless of tumor region, LN metastasis and clinical staging. These data indicate that SMLNs may have immunosuppressive properties compared with UJLNs.

Prognostic and histogenetic roles of gene alteration and the expression of key potentially actionable targets in salivary duct carcinomas.

The molecular characteristics of therapeutically-relevant targets and their clinicopathological implications in salivary duct carcinomas (SDCs) are poorly understood. We investigated the gene alterations and the immunoexpression of crucial oncogenic molecules in 151 SDCs. The mutation rates that were identified, in order of frequency, were as follows: TP53, 68%; PIK3CA, 18%; H-RAS, 16%; BRAF, 4%; and AKT1, 1.5%. PIK3CA/H-RAS/BRAF mutations were more common in de novo SDC than in SDC ex-pleomorphic adenoma. Furthermore, these mutations were mutually exclusive for HER2 overexpression/amplification. TP53 mutations were frequently detected in cases with the aberrant p53 expression, and TP53 missense and truncating mutations were associated with p53-extreme positivity and negativity, respectively. DISH analysis revealed no cases of EGFR amplification. The rates of PI3K, p-Akt, and p-mTOR positivity were 34%, 22%, and 66%, respectively; PTEN loss was observed in 47% of the cases. These expressions were correlated according to the signaling axis. Cases with PI3K negativity and PTEN loss appeared to show a lower expression of androgen receptor. In the multivariate analysis, patients with SDC harboring TP53 truncating mutations showed shorter progression-free survival. Conversely, p-Akt positivity was associated with a favorable outcome. This study might provide information that leads to advances in personized therapy for SDC.

Endoscopic contralateral transmaxillary approach for pterygoid process osteotomy in total maxillectomy: A technical case report.

An approach for total maxillectomy with endoscopic transection of the pterygoid process via the contralateral maxillary sinus is described. In total maxillectomy, the resection of the pterygoid process of the sphenoid is a key step for successful resection. However, a conventional craniofacial approach requires extensive incision in the face, elevation of the lateral cheek flap. Even after elevation of the lateral cheek flap, visualization of this region is not good. An endoscopic approach through the contralateral maxillary sinus improved visualization of the pterygoid process, and osteotomy using a diamond-drilling bar was successfully performed. This technique has the potential to widen the indication for total maxillectomy in malignant neoplasms of the maxillary sinus.

Biomarker immunoprofile in salivary duct carcinomas: clinicopathological and prognostic implications with evaluation of the revised classification.

Salivary duct carcinoma (SDC) is an uncommon, aggressive malignant neoplasm histologically resembling high-grade mammary ductal carcinoma. SDC can arise de novo or ex pleomorphic adenoma. To clarify the correlation of biomarker immunoprofile with clinicopathological findings and clinical outcome of SDC, we conducted immunohistochemistry for EGFR, HER2, HER3, AR, CK5/6, p53, and Ki-67, along with HER2 fluorescence in situ hybridization in 151 SDCs. SDCs ex pleomorphic adenoma more commonly overexpressed EGFR, HER2, HER3, and Ki-67 than de novo SDCs (P = 0.015, < 0.001, 0.045, and 0.02, respectively). In multivariate analysis, AR- and CK5/6+ were associated with shorter progression-free survival (P = 0.027 and 0.004, respectively). Moreover, patients with p53-extreme negative/positive demonstrated poorer overall survival (P = 0.007). On assessing the revised classification by the combination of biomarker expression, the percentages of each subtype were as follows: 'apocrine A' (AR+/HER2-/Ki-67-low) (24%), 'apocrine B' (AR+/HER2-/Ki-67-high) (18%), 'apocrine HER2' (AR+/HER2+) (35%), 'HER2-enriched' (AR-/HER2+) (12%), and 'double negative' (AR-/HER2-) (11%). 'Double negative' was further subclassified into 'basal-like' (EGFR and/or CK5/6+) (7%) and 'unclassified' (3%). Consequently, patients with 'apocrine A' showed a better progression-free survival than those with any other subtypes. Our revised immunoprofiling classification was valuable for predicting the survival and might be useful in personalized therapy for patients with SDC.

Clinical Outcomes and Prognostic Factors for Salivary Duct Carcinoma: A Multi-Institutional Analysis of 141 Patients.

BACKGROUND: Among salivary gland malignancies, the prognosis of salivary duct carcinoma (SDC) is assumed to be the poorest. However, because of its low incidence, reliable survival estimates and prognostic factors based on a large number of patients remain to be elucidated, thereby making it impossible to standardize the optimal treatment for SDC. METHODS: We performed this multi-institutional, retrospective analysis by collecting the clinical information of 141 patients with SDC without distant metastasis who underwent curative surgery as the initial treatment to elucidate overall survival (OS) and disease-free survival (DFS) along with their prognostic factors. RESULTS: The 3-year OS and DFS rates were 70.5 and 38.2 %, respectively. Multivariate analysis revealed that age ≥65 years (p < 0.001) and N1 and N2 (p = 0.047 and <0.001, respectively) were independent prognostic factors for OS, whereas the primary site of the minor salivary and sublingual gland (p < 0.001) and N2 (p < 0.001) were those for DFS. The most common treatment failure was distant metastasis (55 patients, 39.0 %). For early parotid SDC, neither total parotidectomy in the patients with early T stage nor nerve resection in the patients without facial nerve palsy showed survival benefits. CONCLUSIONS: Advanced N stage independently affects both OS and DFS. Partial parotidectomy with facial nerve preservation could be a less invasive standard surgical procedure for parotid gland SDC in the early T stage without facial nerve palsy. Effective systemic therapy is imperative to improve DFS of SDC.

Initial experience of radiotherapy plus cetuximab for Japanese head and neck cancer patients.

In Japan, cetuximab with concurrent bioradiotherapy (BRT) for squamous cell carcinoma of head and neck (SCCHN) was approved in December 2012. We herein report our initial experience of BRT, with special emphasis on acute toxicities of this combination therapy. Thirty-one non-metastatic SCCHN patients who underwent BRT using cetuximab between July 2013 and June 2014 were retrospectively evaluated. All patients received cetuximab with a loading dose of 400 mg/m(2) one week before the start of radiotherapy, followed by 250 mg/m(2) per week during radiotherapy. The median cycle of cetuximab was seven cycles and the median dose of radiotherapy was 70 Gy. Twenty-five patients (80.6%) accomplished planned radiotherapy and six cycles or more cetuximab administration. Six patients (19.4%) discontinued cetuximab. Grade 3 dermatitis, mucositis and infusion reaction occurred in 19.4%, 48.3% and 3.2%, respectively. One patient experienced Grade 3 gastrointestinal bleeding caused by diverticular hemorrhage during BRT. Grade 3 drug-induced pneumonitis occurred in two patients. The response rate was 74%, including 55% with a complete response. BRT using cetuximab for Japanese patients with SCCHN was feasible as an alternative for cisplatin-based concurrent chemoradiation, although longer follow-up is necessary to evaluate late toxicities.

Adamantinoma-like Ewing family tumor of soft tissue associated with the vagus nerve: a case report and review of the literature.

Adamantinoma-like Ewing family tumor (EFT) is a rare subset of EFTs showing mixed features of Ewing sarcoma and adamantinoma of the long bones. All currently reported cases of the adamantinoma-like type have been associated with bone. Recently, a unique type of EFT was reported showing complex epithelial differentiation associated with the vagus nerve. Here we describe another unique type of EFT arising in the soft tissue of the neck associated with the vagus nerve. An 11-year-old girl presented to our hospital with a neck tumor on her right side. Surgical resection was performed, and histopathologic examination demonstrated a high-grade malignant neoplasm. The tumor was composed of sheets of small round proliferating cells, basaloid tumor nests with marked squamous differentiation, biphasic growth pattern with epithelioid tumor nests, and spindle cell proliferation. Immunohistochemically, the tumor cells showed diffuse expression of CD99 and FLI-1. In addition, small round cells and basaloid/squamoid components were immunoreactive for AE1/AE3, CAM5.2, cytokeratin 5/6, high-molecular weight keratin, p63, and p40 (ΔNp63). Reverse transcription polymerase chain reaction and direct sequencing analysis revealed that the tumor harbored a t(11;22) translocation, involving EWSR1 and FLI-1, which are characteristic of EFTs. According to these findings, our case has characteristics of both a subset of adamantinoma-like EFT and EFT with complex epithelial differentiation. We suggest that EFT with complex epithelial differentiation is in a common spectrum with the adamantinoma-like type and that adamantinoma-like EFTs can arise in soft tissue, leading to difficulty in differential diagnosis with malignant epithelial tumors.

[Eight cases of calcific retropharyngeal tendinitis/retropharyngeal calcific tendinitis].

Calcific retropharyngeal tendinitis/retropharyngeal calcific tendinitis is an inflammation of the longus colli muscle caused by calcium hydroxyapatite crystal depositon in the longus colli muscle tendon. The three major symptoms are neck pain, limitations of neck movement, and swallowing pain. We treated 8 cases of calcific retropharyngeal tendinitis/ retropharyngeal calcific tendinitis. Each patient complained of neck pain, limitations of neck movement, and swallowing pain. The only local finding was the smooth swelling of the posterior pharyngeal wall. CT imaging showed calcification of the tendon of the longus colli muscle and a low density area in the retropharyngeal space without ring enhancement, suggesting a retropharyngeal abscess. MR imaging showed the smooth swelling of the retropharyngeal space and an increased signal intensity on T2-weighted MR imaging. Calcific retropharyngeal tendinitis heals spontaneously, and treatment is not usually required. However, the clinical outcomes are similar and can be confused with retropharyngeal abscess and pyogenic spondylitis, so antibiotics are administrated in many cases. In our report, 7 patients were hospitalized and were treated with the intravenous administration of antibiotics, while 1 patient who refused hospitalization was treated with an oral antibiotic. Steroids were administrated in 2 cases. The 7 patients who were hospitalized were cured within 6 to 10 days.

Effects of aging on the natural history of seasonal allergic rhinitis in middle-aged subjects in South chiba, Japan.

BACKGROUND: The natural history of allergic rhinitis has been examined in a few longitudinal studies. The purpose of the study was to investigate the course, development and remission of seasonal allergic rhinitis (SAR) over 10 successive years in middle-aged subjects. METHODS: An annual questionnaire survey on allergic rhinitis symptoms combined with an examination of specific IgE has been undertaken in a rural town in south Chiba since 1995. The analyzed subjects were 703 residents who underwent every examination in 1995, 2004 and 2005. In the last 15 years, the annual pollen count in Chiba was highest in 2005. RESULTS: The sensitization rates to cedar pollen decreased with age in the same subject groups over 10 years, but the prevalence of SAR was higher in 2005 compared with 1995. Of the 52 subjects with SAR in 1995, the symptoms had disappeared in 10 subjects in 2005. Specific IgE had converted to negative or borderline in 4 of these patients, had decreased but was still positive in 4 and was increased or unchanged in 2. During the 10-year period, 22 subjects developed SAR, of whom 12 had increased specific IgE and 10 had similar or decreased specific IgE in 2005. CONCLUSION: SAR induced by cedar pollen takes a chronic course in the majority of middle-aged patients in south Chiba, Japan. The prevalence of SAR increased over 10 years due to a high level of pollen exposure. Changes in specific IgE were not directly associated with the development or remission of SAR.

The influence of environmental exposure to formaldehyde in nasal mucosa of medical students during cadaver dissection.

BACKGROUND: Environmental exposure to formaldehyde is commonly associated with clinical symptoms such as mucosal irritation and olfactory disorders. However, the impact of such exposure on the development of mucosal inflammation and its outcome has not been carefully evaluated. METHODS: The observational non-comparative study was planned. The study population consisted of group of 41 medical students who had signed up for a cadaver dissection course as part of their gross anatomy teaching at the school of medicine Chiba University in Japan. During such dissection course, the students are exposed to variable levels of environmental formaldehyde routinely employed for the preservation the cadavers. The subjects were evaluated by a detailed medical examination. We measured their serum IgE levels. In addition, an olfaction test and nasal mucosal sensitivity to histamine was serially determined, immediately before and after the course and 6 months after the completion of the course. RESULTS: Olfactory abnormalities were observed in 13/41 (32%) subjects and increased nasal mucosal hypersensitivity to histamine was observed in 17/41 (41%) during and immediately after completion of the course. These subjects had evidence of preexisting allergic rhinitis. 6/41 (15%) other students with no prior evidence of allergic rhinitis also exhibited formaldehyde associated clinical symptoms during the dissecting course. However, the symptoms disappeared upon completion of the course in all subjects studied. CONCLUSIONS: Temporary abnormalities in the olfaction test and increased nasal mucosal hypersensitivity to histamine were observed in a few students with preexisting allergic rhinitis after environmental exposure of high concentrations of formaldehyde. These effects appeared to be transient.

Reevaluation of pollen quantitation by an automatic pollen counter.

Accurate and detailed pollen monitoring is useful for selection of medication and for allergen avoidance in patients with allergic rhinitis. Burkard and Durham pollen samplers are commonly used, but are labor and time intensive. In contrast, automatic pollen counters allow simple real-time pollen counting; however, these instruments have difficulty in distinguishing pollen from small nonpollen airborne particles. Misidentification and underestimation rates for an automatic pollen counter were examined to improve the accuracy of the pollen count. The characteristics of the automatic pollen counter were determined in a chamber study with exposure to cedar pollens or soil grains. The cedar pollen counts were monitored in 2006 and 2007, and compared with those from a Durham sampler. The pollen counts from the automatic counter showed a good correlation (r > 0.7) with those from the Durham sampler when pollen dispersal was high, but a poor correlation (r < 0.5) when pollen dispersal was low. The new correction method, which took into account the misidentification and underestimation, improved this correlation to r > 0.7 during the pollen season. The accuracy of automatic pollen counting can be improved using a correction to include rates of underestimation and misidentification in a particular geographical area.

Effects of daily intake of Lactobacillus paracasei strain KW3110 on Japanese cedar pollinosis.

Japanese cedar pollinosis is an important contributor to allergic rhinitis in Japan. Lactobacillus may be useful as an immunomodulator and is used widely as a foodstuff. The purpose of the study was to examine the effects of daily intake of the Lactobacillus paracasei strain KW3110 in patients with cedar pollinosis. The effects of daily intake of KW3110 in patients with cedar pollinosis were investigated in 126 patients who received KW3110 or a placebo in a double-blind study. The study began 1 month before the start of the pollen season and lasted for 3 months. A significant reduction of nasal symptoms and the serum level of eosinophil cationic protein and improvement of quality of life scores occurred in the patients who received KW3110 when pollen scattering was low. However, the effects were limited during the peak period of pollen scattering. Intake of KW3110 may reduce allergic inflammation, but the effect is limited.

Cedar and cypress pollinosis and allergic rhinitis: quality of life effects of early intervention with leukotriene receptor antagonists.

BACKGROUND: Allergic rhinitis involves inflammation of the nasal passages. The use of nasal steroids is generally very effective in providing significant symptom relief. However, compliance for their use is sometimes poor. METHODS: To examine the efficacy of early intervention (before pollen dispersal) with oral cysteinyl leukotriene receptor antagonists (LTRA) on pollinosis in patients with allergy to cedar and Japanese cypress pollens, groups of subjects were treated with LTRA or a placebo for 4 weeks at the beginning of the cedar pollen dispersal season. Subsequently, all patients received nasal steroid therapy concomitantly with LTRA throughout the remaining period of the pollen dispersal season. The effects of such early treatment with LTRA on pollinosis were investigated using symptom scores from an allergy diary and quality of life (QOL) scores. RESULTS: Sneezing and nasal congestion scores were significantly lower in the LTRA-pretreated subjects than observed in the placebo-pretreated patients between weeks 4 and 6 and weeks 3 and 5, respectively. QOL scores improved significantly in all domains after concomitant therapy with nasal steroids. The percent improvement in the nasal congestion score after the concomitant therapy was significantly higher in the LTRA group (69%) than in the placebo group (41%). CONCLUSION: Significant differences observed in symptoms and in QOL effects between LTRA- and placebo-pretreated patients and the absence of major adverse effects noted in these studies suggest that early intervention with LTRA is beneficial and safe and should be considered in the management of pollinosis-associated allergic rhinitis.

Identification of a novel therapeutic target for head and neck squamous cell carcinomas: a role for the neurotensin-neurotensin receptor 1 oncogenic signaling pathway.

Distant metastasis is a major factor associated with poor prognosis in head and neck squamous cell carcinomas (HNSCC), but little is known of its molecular mechanisms. New markers that predict clinical outcome, in particular the ability of primary tumors to develop metastatic tumors, are urgently needed. Based on a genome-wide gene expression analysis using clinical specimens of HNSCC, we narrowed our focus to the analysis of the neurotensin (NTS) and neurotensin receptor 1 (NTSR1) oncogenic signal pathways. Kaplan-Meier curves and log rank tests revealed that high mRNA expression levels of NTS and NTSR1 had a significant adverse effect on metastasis-free survival rate, suggesting a contribution of this pathway in HNSCC cancer progression. In HNSCC cells, which expressed NTSR1, a NTS agonist promoted cellular invasion, migration and induction of several mRNAs, such as interleukin 8 and matrix metalloproteinase 1 transcripts. In addition, knock down of NTSR1 expression with small interfering RNAs resulted in reduction of cellular invasion and migration in HNSCC cell lines. Our findings suggest a critical role for the NTS and NTSR1 oncogenic pathways in invasion and migration of HNSCC cells during the metastatic process. Our study raises the possibility that NTS and NTSR1 could be a useful predictive marker of poor prognosis in patients with HNSCC and a molecular therapeutic target in antimetastatic strategies for HNSCCs.

Migration of tumor antigen-pulsed dendritic cells after mucosal administration in the human upper respiratory tract.

Tumor-specific peptide-pulsed dendritic cells (DC) were administered via different routes to a group of patients with head and neck cancers. The migration and homing patterns of such antigen-stimulated cells was carefully studied employing single photon emission computed tomography (SPECT). The DC administered directly into the nasal submucosa quickly migrated very rapidly to the regional neck lymph nodes in the neck. However, after inoculation of the cells into the palatine tonsils, the DCs remained close to the site of administration and did not migrate to the regional lymph nodes or to other mucosal regions. After nasal submucosal administration of the DC, tumor-antigen-specific cytotoxic T cells were detected in the ipsilaterals but not in the contra lateral lymph nodes. These results suggest that after antigen processing, the regional lymph nodes serve as inductive sites for development of mucosal immune responses and for induction of memory cells during the local immunological responses in the nasopharyngeal-associated lymphoid tissue in man.

Identification of Warthin tumor: magnetic resonance imaging versus salivary scintigraphy with technetium-99m pertechnetate.

OBJECTIVE: The aim of this study was to evaluate the accuracy of technetium-99m (Tc-99m) pertechnetate scintigraphy and magnetic resonance (MR) imaging in the diagnosis of Warthin tumor. METHODS: Sixteen cases of Warthin tumor and 17 cases of non-Warthin tumor were examined by Tc-99m pertechnetate scintigraphy with lemon juice stimulation and MR imaging, including T1-weighted, T2-weighted, short inversion time inversion recovery, diffusion-weighted, and contrast-enhanced dynamic images. We used the receiver operating characteristic (ROC) curve to evaluate diagnostic accuracy. RESULTS: The mean area under the ROC curves of MR imaging in the diagnosis of Warthin tumor (0.97) was higher than that of Tc-99m pertechnetate scintigraphy (0.88). CONCLUSION: Magnetic resonance imaging is more useful in the evaluation of Warthin tumor than Tc-99m pertechnetate scintigraphy.

Carotid artery resection: preoperative temporary occlusion is not always an accurate predictor of collateral blood flow.

CONCLUSION: The morbidity predicted by means of preoperative PET studies does not always correlate with the morbidity experienced after permanent carotid artery occlusion. A pre-resection extracranial-intracranial bypass may be necessary to reduce the risk of neurologic morbidity, in particular when carotid artery resection is planned for tumors involving the skull base. OBJECTIVES: Carotid artery resection is generally considered the only curative treatment for patients with advanced head and neck carcinoma involving the carotid artery. PET can be used during temporary occlusion of the internal carotid artery to assess the safety of the procedure. The aims of this paper were to clarify the risk of carotid artery resection and the benefit of extracranial-intracranial bypass. MATERIAL AND METHODS: Twelve patients diagnosed with head and neck cancer adherent to the carotid artery and in proximity to the skull base who had shown good hemispheric collateral blood flow by means of PET underwent carotid artery resection without preoperative bypass. RESULTS: Of the 12 patients who underwent carotid artery resection without reconstruction, 10 suffered no serious neurologic complications; however, 2 suffered cerebral infarctions intraoperatively.

Expression of membrane-bound CD23 in nasal mucosal B cells from patients with perennial allergic rhinitis.

BACKGROUND: CD23 is the low-affinity receptor for IgE on B cells and is thought to play an important role in regulation of IgE production. OBJECTIVE: To measure the expression of membrane-bound CD23 in nasal B cells and examine its correlation with CD4 subtypes or serum IgE levels in patients with perennial allergic rhinitis. METHOD: We used flow cytometric analysis with double, direct immunofluorescence staining of the mucosal-infiltrating lymphocytes to examine the expression of CD23 in nasal mucosal B cells of patients with perennial allergic rhinitis. The expression of CD23 in nasal B cells of patients with nonatopic rhinosinusitis served as a control. RESULT: The ratio of CD23+ B cells to total B cells in patients with perennial allergic rhinitis was significantly higher than in nonatopic controls, whereas that of B cells to total lymphocytes was unchanged. The ratio of CCR4+ CD4 cells to total CD4 cells in allergic patients was significantly higher than in nonatopic controls, whereas the ratio of CXCR3+ CD4 cells to total CD4 cells was unchanged. There was no significant correlation between the percentages of CD23+ B cells and CCR4+ CD4 cells. In addition, the percentage of CD23+ B cells did not correlate with the total IgE level or with the specific IgE level. CONCLUSIONS: Our results indicate that nasal mucosal CD23-bearing B cells, as well as T(H)2 cells, increase in patients with perennial allergic rhinitis. However, the expression of CD23 did not directly correlate with the number of T(H)2 cells in the nasal mucosa.

Extracranial-intracranial bypass for reconstruction of internal carotid artery in the management of head and neck cancer.

Extracranial-intracranial bypass surgery was performed prior to carotid resection in eight patients with head and neck carcinoma that involved the carotid artery near the skull base. Four patients underwent the standard one-stage extracranial-intracranial bypass procedure. A two-stage procedure was performed in the remaining four patients. The procedure first involved an anastomosis between the M3 segment of the middle cerebral artery and the superficial temporal artery, followed by a bypass between the M2 segment of the middle cerebral artery and the internal carotid artery. One of the patients who underwent the standard one-stage extracranial-intracranial bypass procedure suffered an intraoperative infarction. Despite even longer occlusion times of the M2 segment, none of the patients who underwent the two-stage bypass suffered from any serious neurologic consequences. Three of seven patients who underwent the curative operations, survived more than 4 years, however, the remaining patients died within 1 year from recurrence. Our results show that carotid artery resection yields an opportunity for cure. In extracranial-intracranial bypass surgery, the temporary occlusion of the middle cerebral artery may also induce serious ischemia; however, the two-stage extracranial-intracranial bypass procedure appears to minimize the risk.