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Fibroblasts, a rich source of chemokines, interact with eosinophils and play a key role in the pathogenesis of airway disease. RANTES is produced by fibroblasts to attract and activate eosinophils. LPS is known to induce RANTES and cause protein tyrosine phosphorylation. Nonreceptor protein tyrosine kinase Syk is widely expressed and an important role in intracellular signal transduction in hemopoietic cells. In the present study, we examined whether Syk was expressed in a number of primary human nasal polyp tissue-derived fibroblast lines and whether it played some role in cellular function. Syk proteins were expressed in human nasal fibroblasts, but the expression level varied. There were positive correlations between the level of Syk expression and RANTES production induced by LPS. Overexpression of wild-type Syk by gene transfer enhanced RANTES production from nasal fibroblasts stimulated with LPS. The decrease of Syk expression by the administration of Syk antisense inhibited RANTES production. These results suggest that Syk expression affects RANTES production in fibroblasts of nasal polyps.

G-CSFレセプター (G-CSFR) の発現は, 正常上皮, 肥厚上皮, 異形上皮, 扁平上皮癌の順に発現率が増加した。口腔・中咽頭扁平上皮癌においてG-CSFRを持つ癌細胞を認める癌患者は有意に予後が悪く, 独立した予後因子であった。頭頸部癌細胞株においてrG-CSF刺激は浸潤能を亢進させた。その機序は, JAK1のリン酸化に引き続くMT-MMPの発現増強とIV型コラゲナーゼ活性の亢進であった。これはG-CSFRの遺伝子導入によっても確認した。DNAアレーの解析よりp38MAP kinase 系を経た核内転写因子の増強による可能性が高いと推測された。頭頸部癌細胞株のおけるG-CSFRのアイソフォームに特色はなかったが, G-CSFRの細胞内ドメイン一部を欠損させた変異発現ベクターは, rG-CSF刺激によるMT-MMPの発現増強を抑制し, Dominant negative による遺伝子治療の可能性が示唆された。

Granulocyte colony-stimulating factor (G-CSF), a hematopoietic cytokine, regulates the proliferation and differentiation of granulocytic progenitor cells and functionally activated mature neutrophils. G-CSF also affects nonhematopoietic tumor cells through its binding to the specific receptor (G-CSFR) on the cells. The type IV collagenase [matrix metalloproteinase 2 (MMP-2)] is known to play a main role in the process of invasion and metastasis, but its regulation, for example, in expression or in activation, is not clearly understood. In this study, we investigated the role of G-CSF in the regulation of tumor cell invasion and the synthesis of MMP-2. G-CSFs producing the head and neck carcinoma cell line T3M-1 cells with metastatic ability and no G-CSF receptor (G-CSFR) expression were transfected with G-CSFR expression vector. In vitro treatment of G-CSFR-transfectant T3M-1 cells with recombinant G-CSF (rG-CSF) significantly augmented their invasive potential in a reconstituted basement membrane (Matrigel) system compared with that of parental cells. Moreover, MMP-2 activity of G-CSFR-transfectant T3M-1 cells was enhanced by the stimulation with rG-CSF, as assessed by gelatin zymography. These results identify G-CSF as a regulator of MMP-2 and cellular invasion.

Background Angiogenesis plays critical roles in various pathological mechanisms. It has been hypothesized that the vascularity in allergic nasal mucosa is different from that in normal mucosa, and that changes in the vascular network contributes the pathogenesis of allergic rhinitis. Objective To determine whether hypervascularity and overexpression of the platelet-derived endothelial cell growth factor (PD-ECGF), an angiogenic factor, are found in allergic nasal mucosa and whether these two factors are associated with the allergic reaction. Methods We investigated the expression of PD-ECGF and counted microvessels in 51 nasal mucosae (30 samples from patients with allergic rhinitis and 21 samples as control from normal subjects) using an immunohistochemical technique. Results PD-ECGF expression in allergic nasal mucosae was significantly higher than that in control mucosae at the interstitium of the lamina propria (P = 0.0024) and nasal gland (P = 0.024). PD-ECGF positive areas were coincident with areas of high vascularity in the sections. The microvessel count in the lamina propria of allergic mucosae was higher than that of control mucosae (P = 0.050). Regarding the correlation with various clinical factors, the total nasal symptom score was significantly associated with both the PD-ECGF expression in the interstitium of the lamina propria (P

Background: Apoptosis, which is regulated by both cell survival and death signals, is important for the swift clearance of unwanted cells. Objective: We sought to elucidate whether eosinophilic apoptosis is associated with tissue eosinophilia and to determine its resolution in allergic sinusitis (AS). Methods: Numbers of eosinophils, numbers of IL-5 + cells, and the apoptosis index of eosinophils were calculated in the submucosa (both superficial and deep layers) of patients with AS by using histochemical methods before and after prednisolone treatment. Patients without AS were used for control groups. Anti-EG2 antibody was used to identify eosinophils. IL-5, Fas, or Bax expression of eosinophils was evaluated to elucidate the role of the factors affecting eosinophilic apoptosis. Results: EG2 and IL-5 + cells were abundant in the submucosa of patients with AS, especially in the superficial layer. About 50% to 60% of the IL-5–producing cells were eosinophils. Apoptotic eosinophils were less numerous in the superficial layer than the deep layer in these diseases. After prednisolone treatment, an induction of eosinophilic apoptosis was accompanied by a significant decrease in the number of EG2 + and IL-5 + cells. No remarkable difference was observed in the Fas or Bax expression of eosinophils after prednisolone treatment. Conclusion: Autocrine secretion of IL-5 from eosinophils may be one reason why eosinophilic disease is difficult to manage. Induction of eosinophilic apoptosis is critical for reversing tissue eosinophilia in patients with AS. (J Allergy Clin Immunol 2000;106:551-8.)

Recently, epidemiologic and experimental studies have been reported that long-term macrolides are effective for the treatment of chronic airway inflammatory diseases including diffuse panbronchiolitis, chronic rhinosinusitis, and cystic fibrosis (Jaffe A, Francis J, Rosenthal M, et al. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet 351:420, 1998), and that macrolides can directly reduce the production of IL-8 by nasal epithelial cells (Suzuki H, Shimomura A, Ikeda K, et al. Inhibitory effect of macrolides on interleukin-8 secretion from cultured human nasal epithelial cells. Laryngoscope 107:1661–1666, 1997). In this study we administered macrolides with 14-membered rings to patients with nasal polyps due to chronic rhinosinusitis for at least 3 months and measured the IL-8 level in nasal lavage from those patients. The IL-8 levels in nasal lavage from patients with nasal polyps were reduced during macrolide treatment. There was significant correlation between decreased IL-8 levels in nasal lavage and the clinical effect of macrolides on the size of the nasal polyps. In the group whose polyps were reduced in size, the IL-8 levels dramatically decreased from 231.2 pg/mL to 44.0 pg/mL (p < 0.05), and were significantly higher before macrolide treatment than those in the group whose polyps showed no change (p < 0.005). This reduction in IL-8 may be an important aspect of the effect of macrolide treatment on nasal polyps in chronic rhinosinusitis.

SUMMARYThe pathogenesis of IgA nephropathy (IgAN) is unclear. We have previously shown glomerular deposition of Haemophilus parainfluenzae (HPI) antigens and the presence of IgA antibody against HPI antigens in patients with IgAN. We examined the immune response to HPI antigens in tonsillar lymphocytes from patients with IgAN. Lymphocytes isolated from the palatine tonsils of 13 IgAN patients and 16 patients with chronic tonsillitis but without renal disease were used as controls. We examined lymphocyte proliferation and production of IgA antibody against HPI antigens by measuring thymidine uptake and IgA antibody in culture supernatants after lymphocyte incubation with HPI antigens. Patients with IgAN showed a significantly higher stimulation index to HPI antigens (thymidine incorporation in tonsillar lymphocytes with HPI/thymidine incorporation in unstimulated tonsillar lymphocytes) than controls (P

Much evidence, both in vivo and in vitro, suggests that patients with IgA nephropathy (IgAN) have enhanced IgA production. We hypothesized that Haemophilus parainfluenzae (HP) in the tonsil plays an important role in the IgA production of IgAN patients. In this study, we focused on interferon-gamma (IFN-gamma) and IgA production by tonsillar mononuclear cells (TMC) in patients with IgAN. Tonsillectomies were performed in patients with IgAN and chronic tonsillitis (CT). The induction of IFN-gamma and IgA in vitro by TMC from IgAN patients was compared with that from CT patients. In addition, we investigated whether stimulation with the outer membranes of HP (OMHP) enhanced IFN-gamma and IgA induction by TMC from patients with IgAN. Spontaneous IFN-gamma production and spontaneous total IgA production by TMC were higher in IgAN patients than in those patients with CT (p < 0.05). IFN-gamma induction by OMHP stimulation was also higher in IgAN patients than in CT patients. The stimulation of OMHP enhanced HP-specific IgA in IgAN but had no influence on the production of IFN-gamma in patients with either IgAN or CT compared with spontaneous IFN-gamma production. IFN-gamma production was positively correlated with total IgA values in both IgAN and CT patients, but not with HP-specific IgA. These results suggest that increased IFN-gamma production in patients with IgAN is not associated with HP infection but may play a role in the pathogenesis of IgAN.

A DNA fraction purified from Mycobacterium bovis bacillus Calmette-Guérin (BCG) and designated MY-1 induced interferon (IFN)-gamma production by human peripheral blood mononuclear cells (PBMC). IFN-gamma is well known as a downregulator of IgE production. In this study we investigated whether MY-1 regulates IgE production by human PBMC in vitro. MY-1 inhibited IgE production in PBMC taken from normal donors and stimulated with interleukin (IL)-4 plus monoclonal anti-CD40 antibody, without affecting production of IgA. MY-1 enhanced production of IFN-gamma and IL-12 by PBMC. Inhibition by MY-1 of IgE production was mediated by both IFN-gamma and IL-12, since the MY-1-induced suppression was blocked by the addition of monoclonal anti-IFN-gamma antibody, monoclonal anti-IL-12 antibody or a monoclonal antibody (mAb) directed at the IL-12 receptor. MY-1 inhibited the induction of epsilon germ-line transcript by IL-4. Additionally, MY-1 inhibited spontaneous in vitro production of IgE by PBMC from atopic donors in the absence of IL-4 plus anti-CD40 mAb. These results suggest that exposure to MY-1 may be a novel strategy for the treatment of IgE-related allergic disease.

Modulation of apoptosis may potentiate the sensitivity of tumor cells to chemotherapeutic agents, thus improving the clinical outcome of cancer treatment. Bax, an apoptosis-promoting member of the bcl-2 family, may be a key factor influencing the chemosensitivity of tumor cells, however, its involvement in cellular sensitivity to anti-cancer drugs remains uncertain in squamous cell carcinoma (SCC). To investigate the role of bax gene expression in modulating cisplatin (CDDP)-induced apoptosis in vitro, an established CDDP-resistant human head and neck SCC (IMC-3 cell line) was transfected with bax gene-bearing mammalian expression vector. Overexpression of the bax gene in CDDP-resistant IMC-3 cells elevated the CDDP susceptibility of tumor cells to a level similar to that of the parental IMC-3 cells. In an in vivo study, percutaneous transfer of apoptosis-promoting bax gene by particle-mediated (gene gun) delivery caused overexpression of Bax in SCC, which was confirmed by immunohistochemical staining, and inhibited the growth of mouse CDDP-resistant SCC. Furthermore, combination therapy with bax gene transfer and subcutaneous administration of CDDP at 3-day intervals markedly inhibited the growth of mouse SCC. Thus, overexpression of bax in SCC by a gene gun system appears to be a rational approach to improving the efficacy of chemotherapy and treatment outcome. We suggest that exogenous bax expression may have therapeutic applications for enhancing chemotherapy in SCC.

Although patient death due to nasopharyngeal carcinoma (NPC) is increasing, few epidemiological analyses of NPC in Japan have been conducted since Sawaki's report in 1979. To determine the current incidence of NPC in Japan we examined NPC case in the Chubu area from 1986 to 1995. The leaders and reporting representatives of all otorhinolaryngological groups in the area were asked for their support of this epidemiological research. A total of 607 cases (445 male and 162 female NPC patients) were analyzed epidemiologically, histologically, serologically and clinically in this study. The incidence of NPC gradually increased with age. The mean age of the patients was 54.1 years. The age-standardized annual incidence in the Chubu region was 0.28 per 10(5) persons per year. The incidence in prefectures bordering Japan Sea (0.36) was significantly higher than that of prefectures facing the Pacific Ocean (0.21, P

p27Kip1, a cyclin-dependent kinase inhibitor, is a negative regulator of the cell cycle, and apoptosis is a genetically encoded program of cell death. To clarify the relationship between the cell cycle and apoptosis, we investigated expression of p27, cyclin D1 and apoptosis-related proteins (p53, Bax, Bcl-2 and c-Myc) in 60 cases of oral and oropharyngeal squamous-cell carcinoma (SCC) using an immuno-histochemical approach, and evaluated spontaneous apoptosis in vivo. Our most notable finding was that spontaneous apoptosis in the p27-positive group was significantly higher than that in the p27-negative group (p = 0.028). In addition, the percentage of p27-positive cells was clearly correlated with that of Bax-positive cells (gamma = 0.288, p = 0.028) and with that of cyclin D1-positive cells (gamma = 0.416, p = 0.002). Expression of p27 was inversely associated with the clinical stage of total tumor progression (p = 0.027). However, no correlation was found between p27 expression and the following parameters: gender, tumor size, lymph node metastasis, overall survival and disease-free survival. Our results give evidence that the action of the cell-cycle regulator p27 is closely linked with apoptosis in clinical samples from patients and indicate that over-expression of p27 might induce apoptosis in cancer cells through elevation of Bax expression, thereby acting on tumor progression.

We investigated the expression of apoptosis-related factors, p53, Bax, Bcl-2, and spontaneous apoptosis in 57 cases of oral and oropharyngeal squamous cell carcinoma (SCC) by immunochemical staining and ApopTag kit. Positive expression of Bax was inversely associated with advanced tumor stage (P = 0.0225), lymph node metastasis (P = 0.0225), clinical stage (P = 0.0083) and poor prognosis (P = 0.0478). Positive expression of p53 was related to poor prognosis (P = 0.0445) and was associated with negative expression of Bax (P = 0.0439). The apoptosis index did not correlate with clinical outcome. These results suggest that abnormality of Bax expression plays an important role in tumor progression in oral and oropharyngeal SCC.

Objective: A cyclin-dependent kinase inhibitor, p27 kip1 , is recognized as a negative regulator of the cell cycle. To clarify whether immunohistochemical detection of p27 might provide prognostic information, we investigated the expression of p27 in laryngeal squamous cell carcinoma (SCC). Study Design: A retrospective study of patients was performed in 109 cases of laryngeal SCC. In addition, we investigated the expression of p53 and granulocyte colony-stimulating factor receptor (GCSF-R) to examine the prognostic significance of them in the same samples. Methods: Immunohistochemical staining by specific monoclonal antibodies was performed using the avidin-biotin-peroxidase complex technique. Results: Advanced tumor size and clinical stage and the occurrence of lymph node metastasis were associated with the absence ofp27 expression, but not correlated with p53 expression and GCSF-R expression. The overall 5-year survival rate in the p27-positive group was significantly higher than that in the p27-negative group. In the Cox proportional hazard model, p27 was demonstrated to be the most powerful prognostic factor among gender, tumor size, lymph node metastasis, stage of disease, and p53 and GCSF-R expression. Conclusions: We concluded that assessment of p27 expression is useful as a prognostic factor for laryngeal SCC and of value in selecting patients with laryngeal SCC for aggressive therapy.

BACKGROUND Interleukin-10 (IL-10) has been implicated as an important modulator of lymphoid cells, and its sequence is homologous to an open reading frame in the Epstein–Barr virus (EBV) genome. Nasopharyngeal carcinoma (NPC) is a representative tumor related to EBV infection. METHODS The authors investigated the expression of IL-10 in 21 primary NPCs by using an immunohistochemical approach to examine its prognostic significance. RESULTS IL-10 staining was positive in 12 of 21 primary NPCs (57%). There was no association between IL-10 expression and gender, tumor size, the occurrence of lymph node metastases, clinical stage, or recurrence. However, there was a significant difference in overall survival between the negative expression and positive expression of IL-10 (P = 0.0348). Although 87.5% of the IL-10 negative group survived for 5 years, only 15.6% of IL-10 positive patients survived for that length of time by the Kaplan–Meier method. IL-10 expression was significant as an independent prognostic indicator of overall survival by multivariate analysis using the Cox proportional hazards model (odds ratio, 26.64; P = 0.0019). CONCLUSIONS The results imply that expression of IL-10 is a prognostic factor in patients with NPC and may prove valuable in selecting patients with NPC who are candidates for aggressive therapy. Cancer 1999;85:1439–45. © 1999 American Cancer Society.

We investigated the expression of IL-10 in oral and oropharyngeal squamous cell carcinoma (SCC) specimens by an immunohistochemical technique. Of 58 SCC, 13 (22%) and 35 (60%) cases showed intense and moderate positive staining of IL-10, respectively. There was no association between the staining of IL-10 and clinicopathological features. However, the patients with intense staining of IL-10 had a significantly lower overall survival rate than those with moderate or negative staining of IL-10 (P = 0.019). In addition, the patients with intense staining of IL-10 had the highest score of platelet-derived endothelial cell growth factor (PD-ECGF), which is established as a poor prognostic indicator (P = 0.0105). These results suggested that IL-10 contributes to the clinical outcome of oral and oropharyngeal SCC.

Tunicamycin (TM), a naturally occurring antibiotic, blocks the first step in the biosynthesis of N-linked oligosaccharides in cells. In this study, we investigated whether changes in N-linked glycosylation affect the sensitivity of head-and-neck carcinoma cell lines to cis-diaminedichloroplatinum(II) (cisplatin) in vitro and in vivo. In vitro treatment of the IMC-3 and KB cell lines with TM significantly decreased the 50% inhibitory concentration (IC50) of cisplatin, as determined by the MTT assay (24.15 to 10.97 microg/ml, p 100 to 14.4 microg/ml, p < 0.05) to levels similar to those against parental IMC-3 cells. TM treatment decreased the number of Con A- and L-PHA-binding sites on the surface of tumor cells but had no effect on the intracellular platinum concentration. Induction of apoptosis in vitro by TM plus cisplatin in combination was increased compared with that by cisplatin alone. Furthermore, in vivo administration of TM plus cisplatin in combination significantly inhibited local tumor growth in the cisplatin-resistant in vivo C3H/He mouse model as compared with the control group (p < 0.05) and increased in vivo apoptosis of tumor cells. Our results suggest that the manipulation of glycosylation by TM in tumor cells might be a useful therapeutic strategy for successful chemotherapy using cisplatin against head-and-neck cancer.

抗癌剤耐性は, 現在の癌化学療法を施行するうえで最も深刻な問題の一つである。CDDPは頭頸部癌において現在その中心的な役割を担っているが, 癌細胞がCDDP耐性を獲得することは, 癌化学療法の範囲をせばめるだけでなく患者の予後に重大な影響を与えることが予想される。今回, CDDP耐性頭頸部癌細胞株を樹立し, その耐性機序と耐性克服の可能性を検討した。CDDP耐性株では, 細胞内薬剤蓄積量の低下がみられ, これは, グルタチオンとMRPの協調したGS-Xポンプの高発現による機能亢進によるものと, DNA修復能の亢進によるものであった。これら二つの機序が, CDDP耐性の重要な因子になっていると考えられた。さらに, イソチオシアネート誘導体 (hITC) の併用により, 耐性克服の可能性が示唆された。

A very rare case of numerous transorbital wooden foreign bodies penetrating into the sphenoid sinus in a 47-year-old male is reported. His right eye was nonreactive to light, and the oculomotor, trochlear and abducens nerves were completely disturbed. Although a minor injury was observed on the inner side of the right eyebrow, the wound was not serious or infectious. Computed tomographic scanning of the orbit and parasinus revealed an isodense linear shadow to muscle and an irregular shadow of the lamina papyracea. However, the findings were difficult to discriminate from an optic canal fracture preoperatively. We detected foreign bodies penetrating the optic nerve rise, which were successfully removed in combination with an endoscopic transethmoidal and transorbital approach. Various and careful imaging examinations are recommended to diagnose and manage paraorbital trauma, when a penetrating wound of the face is observed.

The thicknesses of three dermal flaps, platysma, forearm, and fibula, which are often used for oropharyngeal reconstruction, were measured in 21 subjects using 15 MHz Doppler ultrasonography. The mean (SD) thicknesses were 2.2 (0.3), 3.1 (0.5), and 3.8 (0.6) mm, respectively. The free peroneal skin flap from the leg was used in 14 patients with head and neck cancer. These flaps were successfully transplanted in 13 of 14 patients (93%) with no problems at the donor site. This flap offers many advantages, including its distance from the head and neck, its cosmetic superiority to a forearm flap, it allows two flaps with two cutaneous branches, it is possible to close the donor site primarily without a skin graft, and it has thin subcutaneous tissue. We found that the free peroneal skin flap is particularly useful for oropharyngeal reconstruction.

Sodium periodate (IO 4 ) exerts a number of biological effects including the enhancement of lymphocyte activation. In this study, we investigated its effects on cytotoxicity of human peripheral blood lymphocytes (PBL) and explored the mechanism whereby it exerted these effects. In vitro treatment of human PBL with IO 4 augmented their cytotoxicity against K562 myelogenous leukemia cells. IO 4 oxidative treatment increased the frequency of effector-to-target cell binding. It also increased cellular ATP levels in effector cells, suggesting that the post-binding cytolytic functions of these cells were also enhanced after treatment with IO 4 . Moreover, IO 4 treatment significantly increased the protein kinase C (PKC) activity of effector cells and induced the translocation of activity in the membrane fraction from the cytosol. H-7, a potent PKC inhibitor, significantly reduced this enhancement of membrane-associated PKC activity at 10 μ M and significantly reduced the enhanced cytotoxicity of PBL at the same concentration. These results indicated that IO 4 enhanced the binding capacity and post-binding cytolytic functions of PBL and that PKC activation was one mechanism to explain the IO 4 -induced cellular activation.

Background: Human CD1 has recently emerged as a third family of antigen-presenting molecules that is distinct from either major histocompatibility complex class I or class II. Objective: We investigated whether the CD1b-restricted T-cell interaction with antigen alters human IgG subclass and IgE isotype production. Methods: CD1b-restricted antigen-specific T cells derived from the skin lesion of a patient with leprosy were stimulated with their cognate antigen, lipoarabinomman (LAM) of Mycobacterium leprae , in the presence of CD1 antigen-presenting cells and tested for their ability to alter IgG subclass and IgE production from IgD B cells. Results: CD1-restricted T cells cultured with CD1 antigen-presenting cells in the absence of LAM induced IgG1, IgG3, IgG4, and IgE, whereas CD1b-restricted T cells cultured in the presence of LAM induced IgG1 and IgG3 and inhibited production of IgG4 and IgE. Production of IgG4 and IgE was rescued in the CD1-restricted system by the addition of anti-interferon-γ. IgG2 production was not induced under any circumstances. Conclusion: In this study we demonstrated that a specific CD1b-restricted T-cell line can behave similarly to classically-restricted T h1 -type T cells. CD1b-restricted T-cells of this type may regulate immune responses to microbial pathogens by simultaneously enhancing cell-mediated immunity and downregulating IgG4 and IgE responses.

CD40はB細胞上に存在し, T細胞上などのCD40-ligand (CD40L) と結合し, B細胞の増殖, クラススイッチを含む分化, 生存に関するシグナルが伝達される。さらにこのシグナルはアポトーシスに関連があるシグナルとされてきた。そこで今回B細胞以外にも頭頸部癌細胞株でCD40が存在しないかどうか, フローサイトメトリーを用いて検討してみた。IMC-2, IMC-3, KB, HTC/C3, CA-19.9の5つの細胞株の中で甲状腺癌由来のHTC/C3だけがCD40陽性であった。そこで抗CD40抗体を培養系に添加してCD40を刺激してみると, HTC/C3のコロニー形成が, 抗CD40抗体濃度依存性に抑制した。一方CD40陰性であった他の細胞株に抗CD40抗体を添加しても全く影響を及ぼさなかった。抗CD40抗体はHTC/C3に対する殺細胞効果はなかったが, Bcl-2を誘導するとともに, 抗Fas抗体によるアポトーシスを抑制した。さらにBcl-2のアンチセンスオリゴを導入すると, 抗CD40抗体の作用は解除された。つまり抗CD40抗体によるHTC/C3細胞増殖抑制は, Bcl-2のG1 arrest によるものであることが判明した。臨床的に成長がゆっくりな甲状腺癌由来の細胞にのみCD40が陽性であったことは, 非常に興味深いと思われた。

Although platysma myocutaneous flap (PTMCF) is suitable for a small intraoral defect, combination with neck dissection (ND) decreases the viability. Therefore, a version of PTMCF was devised to increase the viability. This version consists of three points: preservation of the external jugular vein (EJV), preservation of the facial artery after skeletonization from the submandibular gland, and a new incision around the flap. This procedure was applied to 21 patients with intraoral cancer. All 21 patients underwent some kind of ND. The average viable area of transferred skin was 80%. This rate was significantly better than that for 46 previous cases using Farr’s modification with ND, in which the facial artery was divided. Viability of the flaps was analyzed by the vessels preserved, especially by EJV. ND is not a contraindication with this version.

頭頸部悪性腫瘍の治療では, その機能と形態の保存上, CDDPを中心とした化学療法に対する期待が大きいが, 初回治療後に出現するCDDP耐性が, 化学療法の障害となっている。我々はヒト上顎癌由来細胞 (IMC-3) とそのCDDP耐性細胞 (IMC-3-DDP) を用いて40℃加温との同時併用効果を検討した。両細胞の40℃感受性は同等であった。40℃加温によって, IMC-3, IMC-3-DDP細胞のCDDP感受性は37℃に比べて, それぞれ1.48, 1.94倍に増強された。また細胞内Pt量は, 耐性細胞において親株の約6割に減少していたが, 40℃加温時のPt量は37℃に比べて, IMC-3で1.4倍, 一方IMC-3-DDP細胞では1.8倍と増加していた。CDDP感受性の40℃加温による増感効果は正感受性細胞より耐性細胞において大きく, またその程度は, 細胞内Pt量の変化を良好に反映していた。

Most of the previously reported loci for total immunoglobulin E (IgE) levels are related to Th2 cell-dependent pathways. We undertook a genome-wide association study (GWAS) to identify genetic loci responsible for IgE regulation. A total of 479,940 single nucleotide polymorphisms (SNPs) were tested for association with total serum IgE levels in 1180 Japanese adults. Fine-mapping with SNP imputation demonstrated 6 candidate regions: the PYHIN1/IFI16, MHC classes I and II, LEMD2, GRAMD1B, and chr13∶60576338 regions. Replication of these candidate loci in each region was assessed in 2 independent Japanese cohorts (n = 1110 and 1364, respectively). SNP rs3130941 in the HLA-C region was consistently associated with total IgE levels in 3 independent populations, and the meta-analysis yielded genome-wide significance (P = 1.07×10(-10)). Using our GWAS results, we also assessed the reproducibility of previously reported gene associations with total IgE levels. Nine of 32 candidate genes identified by a literature search were associated with total IgE levels after correction for multiple testing. Our findings demonstrate that SNPs in the HLA-C region are strongly associated with total serum IgE levels in the Japanese population and that some of the previously reported genetic associations are replicated across ethnic groups.

Background:: Chronic rhinosinusitis (CRS), which is clinically classified into CRS without nasal polyps (CRSsNP) and CRS with nasal polyps (CRSwNP), shows considerable geographic differences and heterogeneity. Eosinophilic (E) CRS with nasal polyps (ECRSwNP) has a higher degree of disease severity and higher frequency of comorbid asthma. Epidemiologic studies in different ethnic populations have improved understanding of the pathophysiology of the disease. Here we report the clinical characteristics of Japanese patients with medically refractory CRS undergoing endoscopic sinus surgery (ESS). Methods:: We recruited a total of 210 CRS patients and assessed them by nasal endoscopy, the Lund-Mackay score using computed tomography (CT), peripheral eosinophilia and smoking status. We also examined the comorbidity of asthma, effects of age and lung functions in the patients. Results:: In this study, 13% of CRSwNP patients and 20% of CRSwNP patients with peripheral blood eosinophilia exhibited obstructive lung dysfunction (FEV1/FVC

Objective In anticipation of the development of guidelines for antigen-specific subcutaneous immunotherapy (SCIT), we present recommendations that can serve as guiding principles based on a review of the scientific literature. Methods Clinical questions (CQs) concerning SCIT were prepared. Literature searches for publications between January 1990 and February 2011 were performed in PubMed, the Cochrane Library, and Japana Centra Revuo Medicina Web version 4. Qualified studies were analyzed and the results were evaluated, consolidated, and codified. Results We present answers for 13 CQs on the indications, methods, effectiveness and mechanisms of SCIT, with evidence-based recommendations. Conclusion The guiding principles are intended to be applied to children (≤15 years old) and adults (≥16 years old) with allergic rhinitis (AR). These principles can be used by otorhinolaryngologists for diagnosis of AR, evaluation of severity and rhinoscopic findings, performance of antigen challenge tests, and management of systemic anaphylactic reactions associated with SCIT.

Objective Predicting whether dysphagia will resolve is very difficult, but is obviously important for patients and their families as well as for physicians. This study retrospectively evaluated potential prognostic indicators for dysphagia in order to examine the feasibility of predicting the outcome. Methods Data on 123 patients who received initial treatment for dysphagia between April 2008 and March 2010 were reviewed. The patient population included 63 men and 60 women, with a mean age of 81.4 years. All the patients underwent physical examination and video-endoscopy (VE) at the initial assessment, and video-fluorography (VF) was also done if necessary. We used the “Food Intake Level Scale” (FILS) to classify the severity of dysphagia as follows: “no oral intake” (FILS score: 1–3), “oral intake and alternative nutrition” (FILS score: 4–6), and “oral intake alone” (FILS score: 7–10). The patient's age, primary disease, cognitive ability, and general condition were evaluated as potential factors associated with the severity of dysphagia. Each patient underwent assessment at every 2 weeks to evaluate the progress of their dysphagia. Results Forty-six patients were classified as “no oral intake” (FILS score: 1–3) at the initial examination and subsequently showed improvement to “oral intake and alternative nutrition” (FILS score: 4–6) or “oral intake alone” (FILS score: 7–10). They were compared with 43 patients who were also “no oral intake” at the second examination after training in swallowing. The combination of stroke and cognitive dysfunction showed a sensitivity of 75.9% (22/29) and specificity of 78.3% (18/23) for predicting no improvement of dysphagia, and was a statistically significant parameter. The presence of disuse syndrome showed a sensitivity of 66.0% (31/47) and specificity of 71.4% (30/42) for predicting no improvement of dysphagia, and this was also a significant parameter. Conclusion The results of this study suggest that a combination of factors other than stroke, including cognitive dysfunction and a decrease in activity of daily living (ADL) influence the outcome of dysphagia. It is not rare for patients who resume oral intake to be readmitted within a year for symptoms such as fever. Therefore, effective rehabilitation programs should be developed for the impairments of elderly patients and common disabilities such as dysphagia.

Profound edema or formation of a pseudocyst containing plasma proteins is a prominent characteristic of nasal polyps (NP). However, the mechanisms underlying NP retention of plasma proteins in the submucosa remain unclear. Recently, we reported that impairment of fibrinolysis causes excessive fibrin deposition in NP and this might be involved in the retention of plasma proteins. Although the coagulation cascade plays a critical role in fibrin clot formation at extravascular sites, the expression and role of coagulation factors in NP remain unclear.The objective of this study was to investigate the expression of coagulation factors in patients with chronic rhinosinusitis (CRS).Sinonasal tissues were collected from patients with CRS and control subjects. We assayed mRNA for factor XIII-A (FXIII-A) by using real-time PCR and measured FXIII-A protein by means of ELISA, immunohistochemistry, and immunofluorescence.FXIII-A mRNA levels were significantly increased in NP tissue from patients with CRS with NP (P.001) compared with uncinate tissue from patients with CRS or control subjects. Similarly, FXIII-A protein levels were increased in NP. Immunofluorescence analysis revealed that FXIII-A expression in inflammatory cells and FXIII-A(+) cell numbers were significantly increased in NP. Most FXIII-A staining was observed within CD68(+)/CD163(+) M2 macrophages in NP. Levels of FXIII-A correlated with markers of M2 macrophages, suggesting that M2 macrophages are major FXIIIA-producing cells in NP.Overproduction of FXIII-A by M2 macrophages might contribute to the excessive fibrin deposition in the submucosa of NP, which might contribute to the tissue remodeling and pathogenesis of CRS with NP.

Seasonal allergic rhinitis (SAR) to the Japanese cedar, Cryptomeria japonica (JC) pollen is an IgE-mediated type I allergy affecting nasal mucosa. However, the molecular events underlying its development remain unclear. We sought to identify SAR-associated altered gene expression in nasal epithelial cells during natural exposure to JC pollen. We recruited study participants in 2009 and 2010 and collected nasal epithelial cells between February and April, which is the period of natural pollen dispersion. Fifteen patients with SAR-JC and 13 control subjects were enrolled in 2009, and 17 SAR-JC patients, 13 sensitized asymptomatic subjects (Sensitized), and 15 control subjects were enrolled in 2010. Total RNA was extracted from nasal epithelial cells and 8 SAR-JC patients and 6 control subjects in 2009 were subjected to microarray analysis with the Illumina HumanRef-8 Expression BeadChip platform. Allergen-stimulated histamine release was examined in the peripheral blood basophils isolated from patients with SAR. We identified 32 genes with significantly altered expression during allergen exposure. One of these, CST1 encodes the cysteine protease inhibitor, cystatin SN. CST1 expression in nasal epithelial cells was significantly upregulated in both the 2009 and 2010 SAR-JC groups compared with the control groups. Immunohistochemical staining confirmed the increased expression of CST1 in the nasal epithelial cells of SAR patients. Addition of exogenous CST1 to basophils inhibited JC allergen-stimulated histamine release in vitro. We propose that CST1 may contribute to inactivation of protease allergens and help re-establish homeostasis of the nasal membranes.

癌の悪性化は抗癌剤耐性, 転移能, 増殖能の獲得などが代表的であるが, 癌細胞がアポトーシスのメカニズムに異常をきたし, アポトーシスを回避することにより悪性の性質を獲得するという従来とは異なる別の機構も考えられている。そこで, アポトーシスを誘導することによって抗癌剤感受性を高めることを目的として, アポトーシスを誘起する Fas 抗原および抑制するBcl-2に着目した。まず, 頭頸部癌細胞株における Fas およびBcl-2蛋白の発現を調べ, CDDP感受性との関連について検討し, bcl-2のアンチセンスオリゴヌクレオチドを用いてその発現を抑制することによるCDDP感受性の変化を検討した。さらに, 頭頚部癌摘出標本を用いて免疫組織化学的に Fas およびBcl-2の発現を検討し, 抗癌剤感受性との関連について検討した。その結果, これらの発現をコントロールすることにより, より効果的な化学療法を行いうる可能性が示唆された。

Objective: To determine whether heat-treated thyroid cancer cells augment the susceptibility of target cells to lysis by autologous lymphokine-activated killer cells. Design: Peripheral blood lymphocytes from patients with thyroid cancer were incubated with recombinant interleukin 2 (100 U/mL) for 7 days, and thyroid cancer cells obtained from surgical specimens were heated at 44°C for 20 minutes and incubated at 37°C for 18 hours before performing the radioactive chromium Cr 51 release assay. Results: The susceptibility of heat-treated thyroid cancer cells to lysis by autologous and allogeneic lymphokine-activated killer cells was significantly greater than that of untreated tumor cells. The mechanism of enhanced susceptibility was unclear. However, the effect depended on de novo protein synthesis, because inhibition of RNA synthesis by dactinomycin completely abolished the heat-enhanced susceptibility of tumor cells. Conclusion: Immunotherapy combined with hyperthermia may be useful in management of thyroid cancer. (Arch Otolaryngol Head Neck Surg. 1995;121:1009-1014)

Atopic dermatitis is a common inflammatory skin disease caused by interaction of genetic and environmental factors. On the basis of data from a genome-wide association study (GWAS) and a validation study comprising a total of 3,328 subjects with atopic dermatitis and 14,992 controls in the Japanese population, we report here 8 new susceptibility loci: IL1RL1-IL18R1-IL18RAP (P(combined) = 8.36 × 10(-18)), the major histocompatibility complex (MHC) region (P = 8.38 × 10(-20)), OR10A3-NLRP10 (P = 1.54 × 10(-22)), GLB1 (P = 2.77 × 10(-16)), CCDC80 (P = 1.56 × 10(-19)), CARD11 (P = 7.83 × 10(-9)), ZNF365 (P = 5.85 × 10(-20)) and CYP24A1-PFDN4 (P = 1.65 × 10(-8)). We also replicated the associations of the FLG, C11orf30, TMEM232-SLC25A46, TNFRSF6B-ZGPAT, OVOL1, ACTL9 and KIF3A-IL13 loci that were previously reported in GWAS of European and Chinese individuals and a meta-analysis of GWAS for atopic dermatitis. These findings advance the understanding of the genetic basis of atopic dermatitis.

Cysteinyl leukotriene and leukotriene receptor occupancy have been linked to several processes in seasonal allergic rhinitis (SAR), including nasal congestion, rhinorrhea, and recruitment of inflammatory cells. We investigated whether add-on loratadine, an antihistamine, might be effective for SAR patients showing unsatisfactory control of symptoms with the leukotriene receptor antagonist (LTRA) montelukast alone. Patients with SAR caused by Japanese cedar pollen (SAR-JCP; mean age, 29.4 years) were given prophylactic montelukast for 1 month before peak JCP dispersal. Patients recorded the severity of the symptoms (sneezing, rhinorrhea, nasal congestion, and ocular symptoms) daily on visual analog scale (VAS). We selected patients with VAS scores of >50 for any of the symptoms just before the peak pollen season (March 2 to March 8) and designated them as "poorly controlled" patients. Then, in the peak JCP season (from March 9), we conducted a randomized, double-blind, placebo-controlled study to determine whether add-on loratadine might be effective for these "poorly controlled" patients. Montelukast alone was effective, as evaluated by improvement of the VAS scores, in 95 of the 137 patients (69.3%). Add-on loratadine significantly decreased the total scores for nasal symptoms (p < 0.05), sneezing (p < 0.05), and rhinorrhea (p < 0.05) when compared with placebo. The symptoms of SAR in two of three SAR-JP patients could be controlled (VAS score[s] under 50) by prophylactic treatment with montelukast alone under the condition of mild JCP dispersal. Furthermore, the effect of add-on antihistamine on sneezing and rhinorrhea was found in selected SAR-JCP patients.

Objective: Swainsonine (SW), an inhibitor of mammalian Golgi α-mannosidase II, blocks the processing of high mannose to complex type oligosaccharides. In this study, the effect of SW on the cytotoxicity of lymphokine-activated killer (LAK) cells against autologous thyroid cancer was investigated. Design: Peripheral blood lymphocytes from patients with thyroid cancer were incubated with recombinant interleukin 2 (100 U/mL) and 0.5 mg/L of SW for 7 days, and thyroid cancer cells obtained from surgical specimens were pretreated with SW (0.5 mg/L) for 18 hours. The cytotoxicity of SW-treated LAK cells against tumor cells tested in a standard 4-hour radioactive chromium Cr 51 release assay. Results: The cytotoxicity of SW-treated LAK cells against autologous thyroid cancer cells was found to be significantly greater than that of standard LAK cells incubated with interleukin 2 alone. The N-α-benzyloxycarbonyl–L-lysine thiobenzyl ester esterase activity of LAK cells, this activity being a cytotoxic factor that is necessary for the lethal hit stage, was also increased by SW treatment. Further, thyroid cancer cells incubated with SW, as compared with nontreated tumor cells, showed much higher susceptibility to LAK killing. Conclusions: Our results suggest that SW might have potential immunomodulatory properties in the treatment of thyroid cancer. (Arch Otolaryngol Head Neck Surg. 1994;120:389-394)