Search

Aim: We evaluated the prognostic value of vasohibin-1 (VASH1) expression in head and neck squamous cell carcinoma. Materials and Methods: Immunohistochemistry for VASH1 and cluster of differentiation 34 (CD34) was performed on 61 head and neck squamous cell carcinoma specimens. The association between VASH1 expression in the tumour and clinical outcomes was analyzed statistically. Results: VASH1 staining in normal tissue adjacent to cancerous tissue was negative, whereas it was positive in tumour blood vessels and AE1/AE3 and Ki67-positive tumour cells. Therefore, we examined the association between VASH1 expression in the tumour and clinical outcomes. Patients with high VASH1 expression in tumour had significantly shorter disease-free survival and more frequently had lymph node recurrence than those with low VASH1 expression. Conclusion: These results suggest that VASH1 expression is associated with tumour progression and may be useful as a prognostic marker of head and neck squamous cell carcinoma.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic vasculitis in patients with bronchial asthma and eosinophilic rhinosinusitis. Serum IgG4 levels are markedly elevated in patients with active EGPA, a disease which has been closely associated with IgG4-related disease (IgG4RD). A 68-year-old male with a history of asthma and eosinophilic rhinosinusitis developed vasculitis and orbital symptoms. The results of a laboratory examination showed eosinophilia (4,067/μl; 39%), while image evaluations revealed hypertrophy of the rectus muscles, trigeminal nerve, lachrymal gland, and bilateral submandibular glands. Biopsy of the paranasal sinus showed the prominent infiltration of eosinophils and IgG4-positive plasma cells. The patient was diagnosed with EGPA concomitant with IgG4RD and treated with systemic steroids. Although concomitant cases of EGPA with IgG4RD are extremely rare, clinical manifestations associated with both diseases are sometimes mixed. Therefore, systemic scrutiny may be required for cases of EGPA with high serum IgG4 levels and pathognomonic symptoms or findings of IgG4RD

It has been described that tumor progression has many similarities to inflammation and wound healing in terms of the signaling processes involved. Among biological responses, angiogenesis, which is necessary for tumor progression and metastasis, is a common hallmark; therefore, tumor blood vessels have been considered as important therapeutic targets in anticancer therapy. We focused on pentraxin 3 (PTX3), which is a marker of cancer-related inflammation, but we found no reports on its expression and function in tumor blood vessels. Here we showed that PTX3 is expressed in mouse and human tumor blood vessels based on immunohistochemical analysis. We found that PTX3 is upregulated in primary mouse and human tumor endothelial cells compared to normal endothelial cells. We also showed that PTX3 plays an important role in the proliferation of the tumor endothelial cells. These results suggest that PTX3 is an important target for antiangiogenic therapy.

The complication of Fanconi anemia (FA) with acute leukemia is rare and challenging to treat because of high relapse rates, despite the improved outcome of hematopoietic stem cell transplantation with fludarabine-based conditioning for treating FA patients with hematological abnormalities. We added high-dose cytarabine to fludarabine-based conditioning to promote an enhanced antitumor effect and successfully subjected 4 patients with FA, including 3 with acute leukemia, to hematopoietic stem cell transplantation. All patients remain alive without treatment-related mortality or evidence of disease. Adding high-dose cytarabine to fludarabine-based conditioning may be tolerable and effective for treating FA patients with acute leukemia.

Odontogenic sinusitis (OS) is a disease commonly encountered by otolaryngologists and oral surgeons. There is currently no standard consensus for the management of the causative teeth of OS, and the therapeutic outcomes of endodontic surgery remain unclear. The authors herein report the outcomes of simultaneous surgery for OS, endoscopic sinus surgery (ESS) with endoscopic apicoectomy. Twenty-one OS patients who underwent ESS were included in the intent-to-treat population. Eleven patients who simultaneously underwent endoscopic apicoectomy were included as the study group, and another 10 patients who were subjected to the extraction of the causative teeth preceding or during surgery were included as the control group. The postoperative tooth course after surgery in the study group was assessed as the primary outcome by periodic radiographs. The postoperative sinus course was compared between the 2 groups as the secondary outcome. Seventeen teeth were subjected to endoscopic apicoectomy concurrently with ESS, and the treatment success rate for periapical lesions was 94.1% (16 out of 17 teeth), which was consistent with previously reported outcomes for endodontic microsurgery. Ten of 11 patients (90.9%) had good postoperative sinus courses, and the mean wound-healing period of the sinus mucosa was 6.9 ± 3.5 weeks. These results were not significantly different from those obtained for the control group (90% and 6.1 ± 3.2 weeks). This surgical procedure may contribute to the preservation of causative teeth without having an impact on the successful treatment of sinusitis. A comprehensive surgical approach by otolaryngologists and oral surgeons is desirable for the treatment of OS.

Wiskott–Aldrich syndrome is a rare X-linked recessive disease resulting from variations in the WAS gene. Wiskott–Aldrich syndrome is sometimes difficult to differentiate from immune thrombocytopenic purpura. A 2-month-old boy was admitted to our hospital for purpura and thrombocytopenia. His mean platelet volume was reported to be normal. Treatment with intravenous immunoglobulins failed to improve the patient’s platelet count. Subsequently, an acute cytomegalovirus infection was confirmed by serological testing and antigenemia. The patient was diagnosed with immune thrombocytopenic purpura secondary to a cytomegalovirus infection. However, based on the patient’s clinical course and the refractoriness of his condition, Wiskott–Aldrich syndrome was strongly suspected. Through direct sequencing of the genomic DNA of the Wiskott–Aldrich syndrome protein (WASP) gene, we identified a novel missense mutation in exon 3 of the patient’s WASP gene (c. 343 C>T, p. H115T), and the patient was diagnosed with Wiskott–Aldrich syndrome at 3 months after onset. Children with Wiskott–Aldrich syndrome are often initially diagnosed with immune thrombocytopenic purpura, which can lead to inappropriate treatment and delays to life-saving definitive therapy. Our findings imply that Wiskott–Aldrich syndrome should be considered as a differential diagnosis in cases of refractory immune thrombocytopenic purpura combined with a cytomegalovirus infection.

Tumor angiogenesis plays an important role in tumor progression and metastasis. Tumor endothelial cells (TECs) are a therapeutic target of antiangiogenic chemotherapy that was recently developed and is currently being investigated in the clinic with promising results. Low-dose chemotherapy, which is the long-term administration of relatively low doses of chemotherapeutic agents, has been proposed for targeting tumor angiogenesis in various types of cancers. Although the efficacy of low-dose chemotherapy has been confirmed in several clinical models, some studies show insufficient therapeutic effect for malignant cancers. As a possible mechanism of the treatment failure, it has been considered that tumor cells may acquire resistance to this therapy. However, drug resistance by TECs may also be due to another mechanism for resistance of tumor cells to low-dose chemotherapy. We reported elsewhere that TECs were resistant to the anticancer drug paclitaxel, which is a mitotic inhibitor, concomitant with P-glycoprotein up-regulation. Verapamil, a P-glycoprotein inhibitor, abrogated TEC resistance in vitro . Herein, we demonstrated that verapamil coadministration enhanced the effects of low-dose paclitaxel concomitant with inhibiting tumor angiogenesis in a preclinical in vivo mouse melanoma xenograft model. Furthermore, verapamil coadministration reduced lung metastasis. These results suggest that inhibiting P-glycoprotein in TECs may be a novel strategy for low-dose chemotherapy targeting TECs.

Kasabach–Merritt syndrome (KMS) is characterized by hemangioma associated with life-threatening thrombocytopenia, and is a consumptive coagulopathy. Although treatments available include corticosteroids, α-interferon, vincristine, and surgery, response may be unsatisfactory, and the mortality rate remains at approximately 30%. Although radiotherapy has been used effectively for KMS, it may cause growth retardation and secondary malignancy. We report a case of KMS in which hemangioma of the left thigh was successfully treated with low-dose radiotherapy (6 Gy in six fractions, weekly) after failure of corticosteroid therapy. No significant late effects due to the radiotherapy were noted at 5 year follow up. Thus, low-dose radiotherapy remains an important treatment method for KMS when patients fail to respond to other treatments.

The preservation or resection of the middle turbinate (MT) during endoscopic sinus surgery (ESS) currently remains a matter of debate. The present study aimed to investigate the effects of submucosal middle turbinectomy (SMT) in ESS for eosinophilic chronic rhinosinusitis (ECRS).The study included 38 ECRS patients (63 sides) who had undergone full-house ESS with SMT and 20 ECRS patients (40 sides) without SMT as a control group. Post-operative middle turbinate lateralization (MTL), synechia formation, and the patency grade of the olfactory cleft (OC) were assessed as the primary outcomes 3 months after surgery. CT scans and the TT test were performed on the SMT group 3 months after surgery and assessed as secondary outcomes.MTL and synechia formation rates were slightly higher in the control group than in the SMT group (20% vs. 7.9%, p=0.072, 17.5% vs. 9.5%, p=0.235), although neither reached statistically significance. The mean patency score of OC was significantly better in the SMT group than in the control group (0.5±0.6 vs. 1.3±0.7,0.001). CT findings and TT test scores showed good improvements after SMT combined with ESS. No major adverse events occurred due to SMT.We demonstrated the potential advantages of SMT for ECRS patients. This method may avoid physiological functional loss through its preservation of the mucosa and structure of the MT.

Objective Silver-containing carboxymethylcellulose fiber dressing (Aquacel ® -Ag) has been used to treat burns and ulcers with a large amount of exudate. The aim of this investigation was to confirm whether Aquacel ® -Ag has beneficial effects when it is used as nasal packing. Methods We included 44 patients who underwent bilateral endoscopic sinus surgery due to chronic rhino-sinusitis. Beschitin-F ® or Aquacel ® -Ag was packed postoperatively into the bilateral middle meatus. Patient's comfort was recorded using a VAS, as well as wound healing, postoperative bleeding and local infection. Postoperative-specific organisms were also evaluated from the removed packing materials located in the middle meatus when they were removed on the 4th day after surgery. Results The scores for nasal obstruction and pain were not statistically different in each group. Postoperative bacteriologic studies indicated marked differences. Coagulase-negative staphylococci were predominant and potential pathogens were recovered in a few cases in the Aquacel ® -Ag group. In contrast, potential pathogens, including Streptococcus pneumonia , Haemophilus influenza , and Gram-negative rods, were predominant in the Beschitin-F ® group. Conclusion The results indicate that Aquacel ® -Ag might contribute to hemostasis, wound healing, and patient comfort after endonasal surgery, similar to Beschitin-F ® . Additionally, it may have advantages concerning the prevention of postoperative infection.

Targeting tumor angiogenesis is an established strategy for cancer therapy. Because angiogenesis is not limited to pathological conditions such as cancer, molecular markers that can distinguish between physiological and pathological angiogenesis are required to develop more effective and safer approaches for cancer treatment. To identify such molecules, we determined the gene expression profiles of murine tumor endothelial cells (mTEC) and murine normal endothelial cells using DNA microarray analysis followed by quantitative reverse transcription-polymerase chain reaction analysis. We identified 131 genes that were differentially upregulated in mTEC. Functional analysis using siRNA-mediated gene silencing revealed five novel tumor endothelial cell markers that were involved in the proliferation or migration of mTEC. The expression of DEF6 and TMEM176B was upregulated in tumor vessels of human renal cell carcinoma specimens, suggesting that they are potential targets for antiangiogenic intervention for renal cell carcinoma. Comparative gene expression analysis revealed molecular differences between tumor endothelial cells and normal endothelial cells and identified novel tumor endothelial cell markers that may be exploited to target tumor angiogenesis for cancer treatment.

Tumor blood vessels play important roles in tumor progression and metastasis. Thus, targeting tumor blood vessels is an important strategy for cancer therapy. Tumor endothelial cells (TECs) are the main targets of anti‐angiogenic therapy. Although tumor blood vessels generally sprout from pre‐existing vessels and have been thought to be genetically normal, they display a markedly abnormal phenotype, including morphological changes. The degree of angiogenesis is determined by the balance between the positive and negative regulating molecules that are released by tumor and host cells in the microenvironment. Reportedly, tumor blood vessels are heterogeneous with TECs differing from normal endothelial cells (in contrast to the conventional view). We recently compared characteristics of different TECs isolated from highly and low metastatic tumors. We found TECs from highly metastatic tumors had more proangiogenic phenotypes than those from low metastatic tumors. Elucidating the variety of TEC phenotypes and identifying TEC molecular signatures should lead to more complete understanding of the mechanisms of tumor progression, discovery of new therapeutic targets, and development of biomarkers. This review considers current studies on TEC heterogeneity and discusses the therapeutic implications of these findings.

Intranasal corticosteroids are effective for allergic rhinitis and broadly used in daily clinical practice. Systemic oral corticosteroids are also known to be effective for treatment of allergic rhinitis. These topical and systemic corticosteroids are both effective formulations for allergic rhinitis, and both drugs have some side effects. When treatment formulations for allergic rhinitis are selected based on side effects, topical corticosteroids are more commonly selected than systemic steroids. Systemic corticosteroids, on the other hand, have traditionally been believed to have higher and more instantaneous therapeutic effects than those of topical corticosteroids. However, there have been few reports of direct comparisons between topical corticosteroid and systemic corticosteroid efficacy. The purpose of this study was to evaluate the subjective outcomes of nasal symptom management using topical intranasal corticosteroid therapy or systemic oral corticosteroid therapy in patients with seasonal allergic rhinitis. We compared the efficacy of mometasone furoate nasal spray (MFNS) to betamethasone oral tablets (BOT) for the treatment of patients with seasonal allergic rhinitis.In an open label study, patients with seasonal allergic rhinitis who had intermediate-to-severe symptoms and who visited the hospital without prior treatment were allocated to 1 of 3 treatment groups (noncorticosteroid group, topical corticosteroid group, and oral corticosteroid group). Evaluation was conducted using allergy diaries that consisted of patient questionnaires. The Japanese Rhinoconjunctivitis Quality of Life Questionnaire (JRQLQ) was used in this study.Compared to only loratazine nonsteroid therapy, both MFNS 200μg once daily and BOT 0.25mg twice daily significantly reduced the total and individual symptom scores for sneezing, nasal obstruction, watery nasal discharge, and nasal itching (P0.05). Scores for itching of the eyes were reduced slightly more in the MFNS group than in the noncorticosteriod treatment group, but the difference was not significant.MFNS and BOT have virtually equivalent effects on nasal symptoms in patients with seasonal allergies. Our study was the first direct comparison between an intranasal corticosteroid spray and a systemic oral corticosteroid for seasonal allergic rhinitis. No significant differences were found in the therapeutic effects of the topical and systemic corticosteroids tested, suggesting that topical corticosteroids are expected to sufficiently improve nasal symptoms without administration of oral corticosteroids. Treatment with intranasal corticosteroid spray is more strongly recommended than treatment with systemic corticoid steroids, due to the side effects associated with each treatment.

Tumor angiogenesis is necessary for tumor progression and metastasis; therefore, tumor blood vessels are potential therapeutic targets in anticancer therapy. We previously reported that tumor endothelial cells (TECs) exhibit different phenotypes compared with normal endothelial cells (NECs), and microarray analyses of mouse TECs and NECs have shown that several genes are upregulated in TECs compared with NECs. Among these genes, the expression levels of prostaglandin F receptor (PTGFR) mRNA, which encodes the prostaglandin F receptor (FP), were higher in TECs than in NECs. It has been reported that FP and its ligand, prostaglandin F(2α) , are involved in tumor angiogenesis. However, there have been no reports of the expression of PTGFR in the tumor vessels of renal cell carcinoma (RCC). Thus, we isolated human TECs (hTECs) from RCCs. The expression levels of PTGFR mRNA were also upregulated in hTECs. In addition, immunostaining showed that the PTGFR was expressed in human tumor blood vessels in vivo. These findings suggested that PTGFR is a novel TEC marker and that it may be a novel target for antiangiogenic therapy for RCC.

Objectives/Hypothesis: Pott's puffy tumor (PPT) is defined as one or more subperiosteal abscesses of the frontal bone based on osteomyelitis. PPT is observed predominantly in the adolescent age group and rarely in adults. Some parameters affecting prognosis and an appropriate surgical approach for antecedent frontal sinusitis have not been elucidated due to the rarity of patients with adult PPT. Study Design: Retrospective patient record and literature study. Methods: Five patients from our cohort and 27 patients identified in a literature search formed the study group. Results: The incidence rate of intracranial complications was lower than in previous reports at 29.0%. There was no correlation between the incidence rate of intracranial complications and each patient's parameters. It was indicated that the department first consulted by the patients was possibly related to the initial diagnosis and the incidence rate of intracranial complications. Conclusions: Although the incidence rate of major complications is lower than in children and later than in earlier published adult cases, patients are still at high risk of serious intracranial complications. Early diagnosis and adequate treatment may contribute to reducing the incidence rate. Laryngoscope, 2012

Objective Claudins are a family of membrane proteins which localize to tight junctions (TJs). Recent studies have shown that claudins can form pores for ions in the TJs and regulate the permeability of epithelial paracellular ion transport. The endolymphatic sac (ES) is a part of the inner ear, absorbing the endolymphatic fluid. ES dysfunction may result in endolymphatic hydrops. In this study, we focused on the paracellular transport and examined claudin mRNA expression in the ES epithelia. Materials and methods Total RNA was isolated from whole ES epithelia of rats by laser capture microdissection. RT-PCR was used to evaluate the expression of claudins. The expression of each claudin mRNA in the epithelial cells of rat ES was confirmed by in situ hybridization. Results RT-PCR indicated the expression of cldn2, cldn4, cldn6, cldn7, cldn9, cldn11, cldn12, and cldn14 . The expression of these claudin mRNAs in the epithelial cells of rat ES was confirmed by in situ hybridization. Conclusion We demonstrated mRNA expression of multiple claudins in the rat ES epithelia. These results in the ES epithelia were consistent with a role of claudins in paracellular ion transport.

The endolymphatic sac (ES) is a part of the membranous labyrinth that contains the cochlea, vestibular organs, an d semicircular canals, and is believed to absorb endolymphatic fluid. Na(+)-K(+)-2Cl(-) (NKCC) is a cotransporter that occurs as two isoforms (NKCC-1 and NKCC-2). Especially, NKCC-2 is suggested to participate in ES endolymph absorption. In the present study, the expression and cellular localization of NKCC-1 and NKCC-2 in the rat ES wer e examined by RT-PCR and in situ hybridization, respectively. The findings indicate that both NKCC-1 and NKCC-2 are expressed in the rat ES and suggest that NKCC is involved in ES homeostasis. NKCC-2 may be particularly involved in endolymph absorption. This is the first report confirming NKCC expression in the ES.

Nedaplatin and S-1 treatment with concurrent radiotherapy was effective, with acceptable toxicities. This regimen does not require extensive intravenous hydration and continuous infusion. Nedaplatin and S-1 may contribute to better clinical outcomes and improve quality of life for patients.We retrospectively analyzed the clinical efficacy and toxicity of concurrent chemoradiotherapy with nedaplatin and S-1 for head and neck squamous cell cancer.Forty-six patients with oropharyngeal, hypopharyngeal, and laryngeal cancer were treated with S-1 on days 1 through 14 and nedaplatin on day 1 every 4 weeks for two cycles of radiotherapy. Therapeutic responses and adverse events were assessed.Primary site tumors and neck lymph nodes exhibited complete response rates of 91% and 64.3%, respectively. The 4-year relapse-free survival and overall survival rates were 76.2% and 85.3%, respectively. The main grade 3 and 4 toxicities were mucositis (30%), leukopenia (30%), anorexia (22%), dermatitis (15%), and thrombocytopenia (9%).

Multi-drug resistance (MDR) of cancers to chemotherapy including doxorubicin (DOX) is mediated by several factors. To design an effective therapy for the treatment of chemotherapy-resistant cancers, it is essential to explore the elements responsible for mediating MDR. However, exploring these factors in detail in a wide range of tumor types is challenging as several critical analytical steps are involved. Here, we demonstrated the way of exploring the factors mediating MDR in the tumor types without performing the analysis at the molecular level of cells. The sensitivities of 15 different types of cancer cells to DOX were evaluated, and the role of P-glycoprotein (P-gp), one of the major efflux-pumps, was explored. A correlation curve was developed between the intracellular amounts of DOX and the sensitivities of cells, and, based on this correlation, the cells were classified in response to the involvement of P-gp that mediates MDR. P-gp plays an active role in mediating MDR of cancer cells where a correlation between the sensitivities of cells and the accumulated DOX exists. In contrast, in cells that show a resistance to DOX but whose sensitivities are independent of the amount of accumulated drug, it was reasonably presumed that mechanisms other than P-gp are likely to be involved in mediating MDR. Based on the correlation between the availability of a drug and cell sensitivity, it would be reasonable to explore the factors governing cancer MDR, which is essential in designing an effective therapeutic approach for treating chemotherapy-resistant cancers using chemotherapeutic drugs.

This study compared change of (18)F-fluorothymidine (FLT) uptake with that of (18)F-fluorodeoxyglucose (FDG) in head and neck squamous cell cancer (HNSCC) patients during and after treatment and evaluated the utility for early monitoring of response to chemoradiotherapy.Thirty patients with newly diagnosed HNSCCs treated with concurrent chemoradiotherapy underwent FLT and FDG PET in pre-treatment (PET1), mid-treatment (PET2) and post-treatment (PET3) stages. The PET images were evaluated quantitatively using maximum standardized uptake values (SUVs). Ratios between SUVs at PET2 and PET3 were also calculated.According to the SUVs, no significant differences were found with primary site location, cellular differentiation and T category in all PET scans. About a 78 % median decrease in FLT SUV was observed at the total dose (TD) of 30 Gy and no apparent change was observed thereafter. About a 40 % decrease in FDG SUV was observed at TD 30 Gy and significant decreases were then found at the 4- and 6-week time points after the therapy. FLT PET demonstrated no recurrence regions in patients with a PET3/PET2 ratio of1.5. In comparison, FLT SUVs in PET3 with recurrence were increased more than three times. However, no significant difference was found between the values with recurrence and those with no recurrence in FDG PET.FLT PET signal change preceded FDG PET change and the increase of FLT uptake after the therapy can imply recurrence or a residual tumor. FLT PET seems promising for early evaluation of chemoradiation effects in HNSCCs.

Tumour blood vessels are gateways for distant metastasis. Recent studies have revealed that tumour endothelial cells (TECs) demonstrate distinct phenotypes from their normal counterparts. We have demonstrated that features of TECs are different depending on tumour malignancy, suggesting that TECs communicate with surrounding tumour cells. However, the contribution of TECs to metastasis has not been elucidated. Here, we show that TECs actively promote tumour metastasis through a bidirectional interaction between tumour cells and TECs. Co-implantation of TECs isolated from highly metastatic tumours accelerated lung metastases of low metastatic tumours. Biglycan, a small leucine-rich repeat proteoglycan secreted from TECs, activated tumour cell migration via nuclear factor-κB and extracellular signal–regulated kinase 1/2. Biglycan expression was upregulated by DNA demethylation in TECs. Collectively, our results demonstrate that TECs are altered in their microenvironment and, in turn, instigate tumour cells to metastasize, which is a novel mechanism for tumour metastasis.

A 65-year-old man presented with right facial cellulitis and right blindness. Enhanced CT and MRI showed right facial cellulitis involved with pterigopalatine fossa. Additionally, orbital cellulitis, superior ophthalmic vein thrombosis, and pulmonary multiple nodules were observed. (18)F-FDG PET/CT supported these findings. He was diagnosed with septic superior ophthalmic vein thrombosis accompanied with Lemierre Syndrome variant and was treated mainly by the administration of intravenous antibiotics. His symptoms and image findings improved after a few days of treatment, but the right visual loss has not recovered. Since septic superior ophthalmic vein thrombosis and Lemierre Syndrome both have life-threatening potential, early diagnosis and appropriate treatment are important and may contribute to reduce the incidence of severe complications. Septic superior ophthalmic vein thrombosis accompanied with Lemierre Syndrome is exceeding rare, and this case is the first report of blindness in Lemierre Syndrome. A literature review and discussion of septic superior ophthalmic vein thrombosis and Lemierre Syndrome are included.

INTRODUCTION AND OBJECTIVES: The molecules which are highly expressed in tumor endothelial cell (TEC) are important for targeting TEC specifically to inhibit tumor angiogenesis. However, there are still a few reports about TEC marker, because it is difficult to isolate TEC. We found LOX gene was upregulated in TEC compared to normal endothelial cell (NEC) by DNA microarray analysis in three different types of human tumor xenografts in nude mouse including renal cell carcinoma (RCC). LOX is an enzyme which is reported to play a critical role in the metastatic potential of tumor, possibly promoting tumor cell trafficking into the premetastatic niche in various types of malignancies. However, the effect of LOX on TEC has not been reported. To investigate whether LOX might be a TEC-specific target in cancer therapy, we analyzed its expression in clinical sample and examined the function of LOX on TEC. METHODS: We successfully purified human TEC (hTEC) and NEC (hNEC) from surgically resected RCC and normal parenchyma from six patients, respectively. Using cultured hTEC and hNEC, competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed. LOX expression level was investigated using immunohistochemistry (IHC). To explore the role of LOX in TEC, mouse TEC (mTEC) and NEC (mNEC) were isolated from human tumor xenografts in nude mouse and the normal counterparts, respectively. To investigate the function of LOX, LOX was knock-downed using siRNA and TEC phenotypic changes were analyzed by migration assay and vascular tube formation assay. In addition, we investigated the effect of -aminopropionitrile (BAPN), an irreversible inhibitor of LOX, on tumor angiogenesis and metastatic colonization in vivo. RESULTS: LOX expression levels were higher in isolated TEC than NEC both in human (Tissues: clear cell carcinoma 6; Stage T1, 3; T3, 3; Grade 1, 1; Grade 2, 2; Grade 3, 3) and mouse by RT-PCR. In IHC, LOX was detected in blood vessels in human RCC, not in normal tissue. Cell migration and tube formation of mTEC were suppressed by LOX knock-down using siRNA with decrease in phosphorylation of focal adhesion kinase (Tyr397). Furthermore, BAPN specifically inhibited tumor angiogenesis and micrometastasis in vivo, via inhibition of LOX activity of TEC. CONCLUSIONS: Our findings suggest that LOX upregulated in TEC contributes in their proangiogenic phenotype and plays key roles in tumor metastasis. LOX might be a TEC-specific target and be useful for cancer therapeutic purposes.

A homeostasis of the electrochemical properties and volume of the endolymph in the inner ear is essential for hearing and equilibrium sensing and is maintained by ion-transport across an epithelial tissue, the endolymphatic sac. One of the key proteins in the maintenance is Na(+), K(+)-ATPase. Although we previously found that the Na(+), K(+)-ATPase in the sac plays a pivotal role in the control of the endolymphatic volume, the mechanism remains unclear. Therefore, in this study, we examined the expression of FXYD6, a functional modulator of the Na(+), K(+)-ATPase, in the epithelial cells of the endolymphatic sac using various approaches. Laser capture microdissection RT-PCR was used to identify FXYD6 mRNA in the endolymphatic sac. Immunolabeling with the specific antibody showed that FXYD6 was predominantly expressed in the intermediate portion of the endolymphatic sac, and it was colocalized with the Na(+), K(+)-ATPase. Because the Na(+), K(+)-ATPase in this region is known to exhibit a high level of activity, an interaction of FXYD6 with this transporter may be critically involved in the regulation of the characteristics of the endolymph.

Background Adenoid cystic carcinoma (ACC) is a malignant tumor commonly occurring in the major salivary glands. ACC of the nasal septum is exceeding rare. Methods The case of a 42-year-old woman with ACC of the nasal septum is presented. Her chief complaint was nasal obstruction and dysosmia for two month. CT and MRI demonstrated a massive mass occupying the nasal septum infiltrating the palate, vomeronasal, anterior skull base, and dura mater. Combined anterior cranial surgery, endoscopic intranasal surgery, and transpalatal surgery were selected due to the size and location of the tumor. A negative surgical margin was achieved without cosmetic deformity or functional disorder. Results She had postoperative radiotherapy with no recurrence or distant metastasis during the follow-up period. Conclusion The tumor location and the perineural spread pattern should be considered to determine the treatment plan for septum ACC. Post operative radiation is now generally recommended. ACC has a high incidence of local recurrence and distant metastasis rate; therefore, long-term follow-up is necessary.

Olfactory dysfunction is a frequent non-motor symptom in Parkinson’s disease (PD). This symptom is considered to be an early manifestation of the disease. The aim of this study was to establish the cortical basis of olfactory function in patients with PD. This study was conducted on ten healthy, normosmic subjects and seven patients with PD (one with subjective olfactory dysfunction and nine without subjective olfactory dysfunction). We employed a 22-channel near-infrared spectroscopy (NIRS) device with eight light-incident fibers and seven light-detector fibers, each with an inter-optode distance of 2.5 centimeters on the frontal head. Isovaleric acid was used as the odor stimulant. We measured the change in total hemoglobin concentrations (totalHb) from pre-baseline values and compared the results obtained for healthy normosmic subjects and patients with PD. In all healthy normosmic subjects and three patients with PD, isovaleric acid caused remarkable changes in (totalHb), especially in the lower areas of the frontal cortex. However, in four patients with PD, isovaleric acid caused no changes. This result indicates that subjective symptoms are different from objective test results in patients with PD. These activated areas may be related to the orbitofrontal cortex corresponding to the olfactory cortices. This study suggests that normosmic subjects with PD already have damage to their olfactory function.

Hemangiomas mostly arise from the soft tissues, and intraosseous hemangiomas are uncommon. They usually occur in the vertebra and skull bones, and intraosseous hemangioma of the nasal cavity is exceedingly rare. We describe a 56-year-old woman who was referred to our hospital with a tumor in her right nasal cavity, without subjective symptoms such as epistaxis. The tumor was located at the front end of the right middle turbinate. Enhanced computed tomography demonstrated a 3 cm×2cm expansive bony tumor replacing the bottom of the right middle turbinate with some partial enhancement effects. The characteristic honeycomb appearance was observed. The tumor and right middle turbinate were excised en bloc by the endoscopic endonasal approach. No complications or severe bleeding occurred during the peri-operative period. Histological examination showed endothelium-lined blood-filled vascular spaces within the bony trabeculae, which suggested the typical pattern of intraosseous cavernous hemangioma. To the best of our knowledge, this is the first case report of intraosseous cavernous hemangioma of the middle turbinate in the English literature.

Objective The normal value of nasal resistance in adults has been reported (0.25 Pa/cm 3 /s), but that in children has not. In this study, we measured nasal resistance in Japanese school children by employing rhinomanometry. Methods An otolaryngologist examined 939 Japanese school children with regard to the presence or absence of nasal diseases and tonsil size. Nasal resistance was measured by rhinomanometry employing the active anterior method in 892 children. A questionnaire concerning the condition during sleep, such as the presence or absence of snoring and sleep apnea syndrome, was performed. Results The mean nasal resistance was 0.43 ± 0.50 Pa/cm 3 /s: 0.46 ± 0.65 and 0.39 ± 0.22 Pa/cm 3 /s in boys and girls, respectively. Of the 892 children, Grade 3 and 4 tonsil hypertrophy was noted in 84 (9%), but the presence of tonsil hypertrophy did not influence nasal resistance. Nasal diseases were noted in 335 children (38%) and the nasal condition was normal (the normal group) in 557 (62%). Nasal resistance was 0.56 ± 0.75 Pa/cm 3 /s in the nasal disease group and 0.36 ± 0.21 Pa/cm 3 /s in the normal group, showing that the resistance was significantly higher in the nasal disease group. The resistance tended to decrease as the school grade increased. In the normal group, 290 children (33%) experienced no problem regarding the upper airway, such as snoring and sleep apnea syndrome, based on a questionnaire, and nasal resistance was 0.35 ± 0.17 Pa/cm 3 /s. Conclusion This normal nasal resistance value may be adopted for the objective evaluation of nasal obstruction and effects of treatment in pediatric nasal diseases.

Background: Interleukin-16 (IL-16) is a cytokine that induces selective migration of CD4+ cells and participates in inflammatory diseases including allergic rhinitis. Histamine and prostaglandin D2 are important chemical mediators of allergic inflammation, and antiallergic drugs are commonly used for the treatment of allergic rhinitis. It remains unknown whether treatment with the drugs affects IL-16. Objective: We evaluated the variability of IL-16 and the effects of the antiallergic drugs fexofenadine (40 mg/kg/day) and ramatroban (30 mg/kg/day) on IL-16 in an OVA-sensitized BALB/c murine experimental allergic rhinitis model. Methods: We measured the expression level of IL-16 protein in the mouse nasal septal mucosa by immunohistochemistry, and the serum level of IL-16 by ELISA. Several other parameters associated with allergic rhinitis (nasal symptoms, OVA-specific IgE, eosinophil and T cell infiltration) were also measured. Results: Local and systemic expressions of IL-16 were significantly increased in OVA-sensitized mice when compared to the nonsensitized group. Fexofenadine and ramatroban significantly inhibited the following OVA-induced allergic features when compared to the nontreated sensitized group: sneezing, nasal rubbing, eosinophil infiltration, IL-16 expressions in nasal tissue, and serum IL-16 level. Serum OVA-specific IgE and local T cell infiltration were reduced, but they did not reach significant values. Conclusions: These results suggest that IL-16 was both systemically and locally upregulated in the murine allergic rhinitis model and that IL-16 changed in parallel to allergic state by treatment with the drugs.

The endolymphatic sac (ES) is a part of the membranous labyrinth and is believed to absorb endolymph. It has been well-established that the endolymph absorption is dependent on several ion transporters in a manner similar to that in the kidney, and the ES is regulated by hormones such as aldosterone and vasopressin that also affect on the kidney. The thiazide-sensitive Na{sup +}, Cl{sup -} cotransporter (TSC) is an electroneutral cotransporter specific to the kidney that plays an important role in absorption of NaCl in renal tubules. In the inner ear, TSC expression has never been examined. The expression of TSC in the rat ES was examined by RT-PCR, in situ hybridization and immunohistochemistry. These analyses indicated that TSC genes and proteins were expressed in the rat ES. In contrast, it was not observed in the rat cochlea by RT-PCR. This is the first report confirming the expression of TSC in the ES.

Approximately one quarter of human astrocytomas show immunohistochemical positivity for p53 protein but lack p53 gene mutations, which could reflect either an accumulation of wild-type p53 protein or an inadequate sensitivity of mutation detection. Since wild-type p53 up-regulates p21 expression, increased p21 expression in those astrocytomas with p53 accumulation in the absence of mutations would argue that the protein was wild type in these tumors. We therefore compared p21 expression with p53 gene and protein status in 48 primary human astrocytomas. Single-strand conformation polymorphism analysis and direct sequencing of the p53 gene showed mutations in 11 tumors (22.9%), while immunohistochemistry revealed positive staining in 19 cases (39.6%). Those tumors with p53 immunopositivity in the absence of p53 mutation had significantly increased p21 expression when compared to either mutant p53 or p53-immunonegative cases. Neither p53 nor p21 status correlated with proliferation indices, as assessed by Ki-67 immunohistochemistry. These results support the hypotheses that functionally wild-type p53 accumulates in some astrocytomas, and that alternative cell cycle checkpoints (such as the p16 pathway) may be more important than p21 in regulating proliferation in astrocytomas.

Introduction and Objectives: The molecules which are highly expressed in tumor endothelial cell (TEC) are important to target TEC more specifically. We found LOX gene was upregulated in TEC compared to normal endothelial cell (NEC) by DNA microarray analysis in three different types of human tumor xenografts in nude mouse including renal cell carcinoma (RCC). LOX is an enzyme which is reported to play a critical role in the metastatic potential of tumor, possibly promoting tumor cell trafficking into the premetastatic niche in various types of malignancies. However, the effect of LOX on TEC has not been reported. To investigate whether LOX might be a TEC-specific target in cancer therapy, we analyzed its expression in clinical sample and examined the function of LOX on TEC. Methods: We successfully purified human TEC (hTEC) and NEC (hNEC) from surgically resected RCC and normal parenchyma from six patients, respectively. Using cultured hTEC and hNEC, competitive reverse transcription-polymerase chain reaction (RT-PCR) was performed. LOX expression level was investigated using immunohistochemistry (IHC). To explore the role of LOX in TEC, mouse TEC (mTEC) and NEC (mNEC) were isolated from human tumor xenografts in nude mouse and the normal counterparts, respectively. To investigate the function of LOX, LOX was knock-downed using siRNA and TEC phenotypic changes were analyzed by migration assay and vascular tube formation assay. In addition, we investigated the effect of α-aminopropionitrile (BAPN), an irreversible inhibitor of LOX, on tumor angiogenesis and metastatic colonization in vivo. Results: LOX expression levels were higher in isolated TEC than NEC both in human (Tissues: clear cell carcinoma 6; Stage T1, 3; T3, 3; Grade 1, 1; Grade 2, 2; Grade 3, 3) and mouse by RT-PCR. In IHC, LOX was detected in blood vessels in human RCC, not in normal tissue. Cell migration and tube formation of mTEC were suppressed by LOX knock-down using siRNA with decrease in phosphorylation of focal adhesion kinase (Tyr397). Furthermore, BAPN specifically inhibited tumor angiogenesis and micrometastasis in vivo, via inhibition of LOX activity of TEC. Conclusions: Our findings suggest that LOX upregulated in TEC contributes in their proangiogenic phenotype and plays key roles in tumor metastasis. LOX might be a TEC-specific target and be useful for cancer therapeutic purposes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4357. doi:1538-7445.AM2012-4357

Tumor angiogenesis is necessary for solid tumor progression and metastasis. Tumor blood vessels are morphologically different from their normal counterparts. We isolated tumor endothelial cells (TECs), demonstrated their abnormalities, compared gene expression profiles of TECs and normal endothelial cells (NECs) by microarray analysis and identified several genes upregulated in TECs. We focused on the gene encoding biglycan, a small leucine-rich repeat proteoglycan. Biglycan is overexpressed in inflammation and fibrosis. However, there has been no report about the expression or the function of biglycan in TEC. In this study, we investigated the expression and the role of biglycan in TECs. Real-time PCR, western blotting and immunocytochemistry revealed higher biglycan expression levels in TECs than in NECs. Furthermore, we confirmed that biglycan was secreted from TECs. Biglycan knockdown inhibited cell migration and tube formation in TECs. TLR2 and TLR4 are the biglycan receptors. TLR2 and TLR4 blocking antibodies suppressed biglycan mediated cell migration and tube formation. We isolated TECs from human renal cell carcinoma tissue and NECs from normal renal tissue in the same patients. TECs and NECs were obtained from six patients. Real-time RT-PCR revealed that the biglycan expression levels were significantly higher in four of the six TEC samples than in the corresponding NEC samples. Furthermore, immunostaining revealed strong biglycan expression in vivo in several human tumor vessels, as in mouse TECs. Biglycan was detected in the sera of cancer patients but was hardly detected in those of healthy volunteers. Biglycan is an autocrine angiogenic factor stimulating tumor endothelial cell migration and tube formation. These findings suggested that biglycan is a novel TEC marker and a target for anti-angiogenic therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5275. doi:1538-7445.AM2012-5275

It has been reported that the number of circulating endothelial cells (CECs) is higher in cancer patients compared to healthy controls. CECs may be acting as possible markers of vascular turnover or damage. Elevated level of CEC number has been reported to be correlated with tumor progression or response to anti-angiogenic therapy. Tumor endothelial cells (TECs) could be shed into circulation and being included in CECs. We have reported that primary cultured mouse TECs express reported TEC-specific markers, such as CD13, TEMs, Dickkopf-3 (Dkk-3) and others. In this study, we analyzed the expression of these TEC markers in CECs in lung cancer patients. Before and/or after dissecting tumor tissue, blood was collected and RNAs from peripheral blood mononuclear cells (PBMCs) were extracted from the patients. And mRNA expression of EC markers and several TEC markers, including both reported and novel candidate, were analyzed. We detected CD31 and CD105 expression in both lung cancer patients’ and healthy controls’ PBMCs. The expression levels of TEC markers and several novel TEC candidate genes were analyzed and compared with healthy controls. Expression levels of several TEC markers including novel TEC marker X and Y, which were expressed in human cultured TECs, were higher in cancer patients than in healthy controls. However, it was difficult for us to detect TEC marker gene expressions in PBMC from cancer patients’ blood since TECs are very small population in PBMC (0.2%). In order to obtain more concentrated TECs from lung cancer patients’ blood, we used blood from lung tumor specimen when lung cancer specimens were dissected under video-assisted thoracic surgery. This specimen (lung tumor specimen blood) contains pulmonary vein blood and it was thought to contain more TECs shed from lung tumor. So we isolated mononuclear cells form this specimen and analyzed TEC marker gene expressions. We sorted mononuclear cells by flow cytometry using anti-CD31 and anti-CD45. TECs are supposed to be included in CD31(+) CD45(−) (Q4) fraction. Novel TEC candidate marker gene X and Y expressions were detected, in crude mononuclear cells from the lung tumor specimen blood at high levels, but very low levels in CD31(−))CD45(+) (Q1) fraction or CD31(+)CD45(+) (Q2) fraction, leading a possibility that the gene X and Y were highly expressed in Q4 fraction. These results suggest that the lung tumor specimen blood can be one of useful materials to discover novel CTEC marker genes in lung cancer patients, and that these markers could be surrogate markers or predicted markers for anti-angiogenic therapy in lung cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 906. doi:10.1158/1538-7445.AM2011-906

Interaction between tumor endothelial cells (TECs) and tumor cells plays a key role in the early stage of hematogenous metastasis. TECs provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. We have reported TECs are different from normal endothelial cells (NECs) in various aspects, such as chromosomal abnormality and gene expression profiles. In this study, we isolated two types of TECs from different human tumor xenografts in nude mice to analyze interaction between TECs and tumor cells. One is HMTEC isolated from highly metastatic tumor and the other is LMTEC from low metastatic tumor. We also isolated NEC from dermis of normal nude mouse as normal control. HMTEC expressed higher levels of mRNA of angiogenesis-related genes than LMTEC or NEC. We hypothesized HMTECs may promote metastasis, in particular, intravasation at the primary site. We investigated the roles of TECs in tumor metastasis; 1) migration of tumor cells towards TECs, 2) adhesion to endothelial layer, 3) crossing the endothelium. Tumor cells migrated towards conditioned-media (CM) from HMTEC more than LMTEC-CM or NEC-CM in vitro. Tumor cells were more adhesive to HMTEC than to LMTEC or NEC. They migrated through the HMTEC-monolayer most among all ECs in transendothelial migration assay. These results suggested that HMTEC may help tumor cells to metastasize. Finally, we analyzed the effects of CM from highly metastatic tumor cells on NECs. Tumor CM induced mRNA expressions of several genes, such as CXCL12, VEGFA and extracellular matrix in NEC. Tumor cells more migrated towards tumor CM- treated NEC than non-treated NEC. Tumor cells adhered more to the tumor CM- treated NEC than to non-treated NEC. These results suggest that TECs “educated” in tumor microenvironment which have highly metastatic potential, may be collaborating with tumor cells for metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1509. doi:10.1158/1538-7445.AM2011-1509

Fourteen human bone and soft part tumor tissues were screened by Southern blot hybridization using five oncogene probes (c‐myc, c‐K‐ras, c‐fos, c‐raf‐l, and N‐myc). Amplification of c‐myc was found in two osteosarcomas and one malignant fibrous histiocytoma. One of these osteosarcomas had amplified c‐raf‐1 gene. Rearrangement of the amplified gene was not observed. This is the first report of c‐raf‐1 amplification in human cancer tissues.