Publisher：Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology  

Objectives: To investigate the use of an oral moisture meter to aid in the diagnosis of Sjögren's syndrome (SS) by measuring the moisture values and salivary flow rate (SFR) simultaneously. Methods: The SFR and moisture values of the dorsum of the tongue and buccal mucosa were measured in 40 patients with SS and 29 healthy controls using an oral moisture meter. In addition, a visual analogue scale (VAS) was used to determine the degree of subjective oral symptoms (xerostomia, decreased saliva production, drinking during eating, oral pain, dysphagia, and dysgeusia). Results: The moisture values of the dorsum of the tongue and buccal mucosa were significantly lower in SS patients than in healthy subjects (both p < 0.01). SFR, especially when measured by the spitting test, correlated positively with the moisture values of the dorsum of the tongue (p < 0.0001) and buccal mucosa (p < 0.0003). Furthermore, the sensitivity, specificity, and accuracy of the oral moisture meter measurements of the dorsum of the tongue and buccal mucosa were 92.5%, 68.9%, and 82.6%, and 70.0%, 82.8%, and 73.9%, respectively. The moisture values of the dorsum of the tongue had a moderate negative correlation with the VAS scores of secondary subjective oral symptoms of xerostomia (oral pain, dysphagia, and dysgeusia), whereas a weak negative correlation was observed for subjective oral symptoms directly related to xerostomia (xerostomia and decreased saliva production). Conclusions: The oral moisture meter accurately reflected the results of the SFR tests and chronic subjective oral symptoms, and therefore might be a diagnostic criterion for SS.

DOI： 10.1016/j.ajoms.2024.02.007

Web of Science

Scopus

Language：English   Publisher：エルゼビア・ジャパン(株)  

Language：English   Publisher：エルゼビア・ジャパン(株)  

Language：Japanese   Publisher：日本口腔顎顔面外傷学会  

下顎骨関節突起骨折(MCF)におけるRisdon approach(RA)とhigh perimandibular approach(HPA)の手術時間や術後合併症の発症率の差異について検討した。2013年3月～2022年3月の10年間に当科を受診したMCF 90例105側のうち、観血的整復固定術を施行した22例22側を対象とした。患者を、RA施行群11例(男性8例、女性3例、中央値33歳)11側とHPA施行群11例(男性8例、女性3例、中央値49歳)11側に分類した。手術時間中央値はRA群が89分、HPA群が55分であり、HPA群の方が有意に短かった。顔面神経下顎縁枝麻痺の発症はRA群が8例(72.7%)、HPA群が0例であり、HPA群の方が有意に少なかった。RAおよびHPAの両群において術後の整復固定状況は良好で、開口障害の残存は認められなかった。MCFに対して、HPAはRAより術後の顔面神経下顎縁枝麻痺のリスクが低く、手術時間を短縮できる有用な手法であることが示唆された。

Language：Japanese   Publisher：(NPO)日本顎変形症学会  

researchmap

Language：Japanese   Publisher：日本口腔顎顔面外傷学会  

researchmap

Language：English   Publisher：Elsevier  

Background/purpose / Radiolucent lesions of the mandible, including ameloblastoma, odontogenic keratocyst (OKC), dentigerous cyst (DC) and simple bone cyst (SBC), are frequently encountered in clinical practice. However, they vary in type and occasionally in appearance. Each lesion needs a different treatment and approach; therefore, accurate diagnosis is crucial before treatment. However, the radiographic findings, including computed tomography (CT), are often similar. This study aimed to compare the CT findings of 41 ameloblastomas, 74 OKCs, 87 DCs, and 13 SBCs in the mandible. / / Materials and methods / Patients were evaluated on initial CT images focusing on features such as long/short diameters, relationship with adjacent teeth, cortex appearance, locularity, scalloped margins, and sclerotic rims. Multivariate logistic regression analysis was performed to determine the most useful features for differential diagnosis. Criteria for differential diagnosis were finally established for three lesions, excluding SBC, which had a relatively small number of cases. / / Results / The relationship with the affected tooth, short diameters, sclerotic rims, and locularity were found to be significant features in the differential diagnosis. Ameloblastomas were characterized by relatively larger short diameters, frequently accompanied by root resorption and adjacent tooth displacement, while SBCs lacked these features. Sclerotic rims were commonly observed in OKCs and DCs, and most DCs were unilocular, containing a crown within the lesion. Based on these results, criteria were established for differential diagnosis with a diagnostic accuracy of 84.2%. / / Conclusion / This is the first study to attempt to characterize each lesion's radiological features, and these criteria are likely to assist in clinical diagnosis.

CiNii Research

Language：Japanese   Publisher：日本メディカルイラストレーション学会  

researchmap

Language：Others   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

Unilateral scissor bite is one of the rare forms of malocclusion that is accompanied by deep bite and collapsed arch. This report describes the treatment of unilateral scissors bite improved by maxillary and mandibular posterior segmental osteotomy with orthodontic treatment. The patient was a 16-year-old woman with unilateral collapsed maxillary and mandibular arch and a scissor bite of the right buccal segment, and without facial asymmetry. At first, intrusion of right maxillary molars with implant miniscrew was planned, but failure to move. To improve, posterior segmental subapical maxillary osteotomy and mandibular corticotomy were applied without changing facial appearance. Following the surgery, the expansion of the collapsed right mandibular segment bucally using an appliance during comprehensive orthodontic treatment was planned. There was no sensory or motor paralysis. After post-surgical orthodontic treatment, her occlusion improved without alteration of facial appearance and disorder of her speech. Transverse widths at the maxillary premolars and first molars were nearly stable over the 4 years postoperative interval in our patient, and her overall long-term stability showed excellent results. To our knowledge, this case was the first case to combinate two segmental subapical osteotomies without Le Fort I and sagittal split ramous osteotomy. The results indicate that this technique is useful for unilateral expansion of distorted mandibular alveolar process and maxillary and mandibular subapical osteotomy with subsequent orthodontic treatment can be used to successfully treat unilateral scissor bite.

DOI： 10.1016/j.ajoms.2024.01.006

Web of Science

Scopus

researchmap

Publisher：Journal of Dental Sciences  

Background/purpose: Radiolucent lesions of the mandible, including ameloblastoma, odontogenic keratocyst (OKC), dentigerous cyst (DC) and simple bone cyst (SBC), are frequently encountered in clinical practice. However, they vary in type and occasionally in appearance. Each lesion needs a different treatment and approach; therefore, accurate diagnosis is crucial before treatment. However, the radiographic findings, including computed tomography (CT), are often similar. This study aimed to compare the CT findings of 41 ameloblastomas, 74 OKCs, 87 DCs, and 13 SBCs in the mandible. Materials and methods: Patients were evaluated on initial CT images focusing on features such as long/short diameters, relationship with adjacent teeth, cortex appearance, locularity, scalloped margins, and sclerotic rims. Multivariate logistic regression analysis was performed to determine the most useful features for differential diagnosis. Criteria for differential diagnosis were finally established for three lesions, excluding SBC, which had a relatively small number of cases. Results: The relationship with the affected tooth, short diameters, sclerotic rims, and locularity were found to be significant features in the differential diagnosis. Ameloblastomas were characterized by relatively larger short diameters, frequently accompanied by root resorption and adjacent tooth displacement, while SBCs lacked these features. Sclerotic rims were commonly observed in OKCs and DCs, and most DCs were unilocular, containing a crown within the lesion. Based on these results, criteria were established for differential diagnosis with a diagnostic accuracy of 84.2%. Conclusion: This is the first study to attempt to characterize each lesion's radiological features, and these criteria are likely to assist in clinical diagnosis.

DOI： 10.1016/j.jds.2024.04.013

Scopus

Language：Japanese   Publisher：Japanese Society of Oral and Maxillofacial Traumatology  

In recent years, various surgical procedures have been reported for the open reduction and internal fixation （ORIF） of mandibular condyle fracture. In our department, the Risdon approach （RA） had been used for the ORIF of mandibular condyle fracture in the past, but since 2019, the high perimandibular approach （HPA） has been adopted. In this study, to clarify the differences between RA and HPA in mandibular condyle fracture, we compared the fracture site, operative time, postoperative facial nerve palsy, postoperative fixation, and amount of opening at discharge and at the end of opening training of these two techniques. Ninety cases and 105 sides with mandibular condyle fracture were diagnosed at our department during the ten years from 2013 to 2022. Twenty-two cases and 22 sides with ORIF were divided into the following two groups: RA group （11 cases and 11 sides） and HPA group （11 cases and 11 sides）, and then examined retrospectively. The operating time of the HA group （median time: 55 min） was significantly shorter than that of the RA group （median time: 89 min） （P＜0.01）. Postoperative facial paralysis was observed in 8 of 11 patients （72.7％） in the RA group only. No postoperative occlusal dysfunction or oral opening disorder was observed in either group. The results suggest that HPA is a useful technique that causes less postoperative paralysis in the mandibular marginal branch of the facial nerve and shorter operative time than RA.

DOI： 10.24787/jsomft.23.1_15

CiNii Research

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Immunology  

BACKGROUND: Cancer immunotherapy targeting CD8+ T cells has made remarkable progress, even for oral squamous cell carcinoma (OSCC), a heterogeneous epithelial tumor without a substantial increase in the overall survival rate over the past decade. However, the therapeutic effects remain limited due to therapy resistance. Thus, a more comprehensive understanding of the roles of CD4+ T cells and B cells is crucial for more robust development of cancer immunotherapy. METHODS: In this study, we examined immune responses and effector functions of CD4+ T cells, CD8+ T cells and B cells infiltrating in OSCC lesions using single-cell RNA sequencing analysis, T cell receptor (TCR) and B cell receptor (BCR) repertoire sequencing analysis, and multi-color immunofluorescence staining. Finally, two Kaplan-Meier curves and several Cox proportional hazards models were constructed for the survival analysis. RESULTS: We observed expansion of CD4+ cytotoxic T lymphocytes (CTLs) expressing granzymes, which are reported to induce cell apoptosis, with a unique gene expression patterns. CD4+ CTLs also expressed CXCL13, which is a B cell chemoattractant. Cell-cell communication analysis and multi-color immunofluorescence staining demonstrated potential interactions between CD4+ CTLs and B cells, particularly IgD- CD27- double negative (DN) B cells. Expansion of CD4+ CTLs, DN B cells, and their contacts has been reported in T and B cell-activated diseases, including IgG4-related disease and COVID-19. Notably, we observed upregulation of several inhibitory receptor genes including CTLA-4 in CD4+ CTLs, which possibly dampened T and B cell activity. We next demonstrated comprehensive delineation of the potential for CD8+ T cell differentiation towards dysfunctional states. Furthermore, prognostic analysis revealed unfavorable outcomes of patients with a high proportion of CD4+ CTLs in OSCC lesions. CONCLUSION: Our study provides a dynamic landscape of lymphocytes and demonstrates a systemic investigation of CD4+ CTL effects infiltrating into OSCC lesions, which may share some pathogenesis reported in severe T and B cell-activated diseases such as autoimmune and infectious diseases.

DOI： 10.3389/fimmu.2023.1305783

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Oral lichen planus (OLP) is a chronic inflammatory disease associated with T cell infiltration. The crosstalk between oral epithelium and mucosal T cells was considered to be crucial in the pathogenesis of OLP. Here, we selectively extracted the normal epithelium (NE) and lesional epithelium (LE) of buccal mucosa specimens from three patients with OLP by laser capture microdissection due to identify the pathogenic factors. Cathepsin K (CTSK) was identified as one of common upregulated genes in the LE by DNA microarray. Immunohistochemically, CTSK was distinctly detected in and around the LE, while it was rarely seen in the NE. Recent studies showed that CTSK enhanced Toll-like receptor 9 (TLR9) signaling in antigen-presenting cells, leading to Th17 cell differentiation. TLR9 expression mainly co-localized with CD123+ plasmacytoid dendritic cells (pDCs). The number of RORγt-positive cells correlated with that of CTSK-positive cells in OLP tissues. CD123+ pDCs induced the production of Th17-related cytokines (IL-6, IL-23, and TGF-β) upon stimulation with TLR9 agonist CpG DNA. Moreover, single cell RNA-sequencing analysis revealed that TLR9-positive pDCs enhanced in genes associated with Th17 cell differentiation in comparison with TLR9-negative pDCs. CTSK could induce Th17-related production of CD123+ pDCs via TLR9 signaling to promote the pathogenesis of OLP.

DOI： 10.1038/s41598-023-46090-3

Web of Science

Scopus

PubMed

researchmap

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.celrep.2023.112630

Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.celrep.2023.112630

Publisher：Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology  

Objectives: Appropriate differential diagnosis between odontogenic keratocysts (OKCs) and ameloblastomas before treatment is crucial, but the radiographic findings, including computed tomography (CT), are often similar. This study, therefore, aimed to compare the CT findings of OKCs and ameloblastomas in the mandible. Methods: Forty-one OKC and 28 ameloblastoma patients were radiologically evaluated by using initial CT images focusing on features such as long/short diameters, CT values, the appearance of the cortex, locularity, scalloped margins, sclerotic rims, and high-density structures. Subtypes of ameloblastoma were also considered. Statistical analyses, including multivariate logistic regression analysis, were performed to determine the features that were helpful for differential diagnosis. Results: Short diameters and locularity were found to be significant features in the differential diagnosis. Between unicystic and conventional ameloblastomas, the frequency of sclerotic rims and buccal disappearance was significantly different. Based on these results, criteria were established for differential diagnosis between OKCs and ameloblastomas, and the diagnostic accuracy was 92.8 %. Conclusion: This finding indicates that several CT findings are strikingly different between OKCs and ameloblastomas, and that these criteria for differential diagnosis are clinically useful.

DOI： 10.1016/j.ajoms.2022.07.016

Web of Science

Scopus

Language：English   Publisher：エルゼビア・ジャパン(株)  

下顎骨の歯原性角化嚢胞(OKC)およびエナメル上皮腫のCT所見を比較した。2007～2021年に当院を受診したOKC患者41名とエナメル上皮腫患者28名を組み入れた。初診時のCT画像を評価した結果、両病理を鑑別診断する有意な特徴として、病巣の短径と単房性/多房性の違いが同定された。単嚢胞型エナメル上皮腫と通常型エナメル上皮腫の間では、硬化縁および頬側皮質骨消失の所見頻度に有意差が認められた。得られた所見に基づき、OKCとエナメル上皮腫を鑑別診断するための基準を作成したところ、その診断精度は92.8%となった。以上から、いくつかのCT所見はOKCとエナメル上皮腫の間ではっきり異なることが示された。

Language：English   Publishing type：Research paper (scientific journal)  

Sjögren's syndrome is a chronic autoimmune disorder whose pathogenesis is poorly understood and that lacks effective therapies. Detailed quantitative and spatial analyses of tissues affected by Sjögren's syndrome were undertaken, including the quantitation of the frequency of selected cell-cell interactions in the disease milieu. Quantitative analyses of CD4+ T cell subsets and of CD8+ T cells in the labial salivary glands from untreated patients with primary Sjögren's syndrome revealed that activated CD8+ cytotoxic T cells (CD8+CTLs) were the most prominent T cells in these infiltrates. An accumulation of apoptotic glandular epithelial cells, mainly ductal and acinar cells, was observed, consistent with the impaired salivary secretion often observed in patients with this disease. FasL expressing activated CD8+ T cells were seen to accumulate around Fas expressing apoptotic epithelial cells. Quantitative analyses of apoptotic cell types and of conjugates between cytotoxic T cells and epithelial cells undergoing apoptosis suggest that Sjögren's syndrome is primarily driven by CD8+CTL mediated execution of epithelial cells mainly represented by ductal and acinar cells.

DOI： 10.1038/s41598-022-19397-w

Language：English   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publisher：(NPO)日本口腔科学会  

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Allergy and Clinical Immunology  

BACKGROUND: How T follicular (Tfh) cells contribute to many different B-cell class-switching events during T cell-dependent immune responses has been unclear. Diseases with polarized isotype switching offer a unique opportunity for the exploration of Tfh subsets. Secondary and tertiary lymphoid organs (SLOs and TLOs) in patients with elevated tissue expression levels of IgE (Kimura's disease, KD) and those of IgG4 (IgG4-related disease, IgG4-RD) can provide important insights regarding cytokine expression by Tfh cells. OBJECTIVE: To identify disease-specific Tfh cell subsets in SLOs and TLOs expressing IL-10 or IL-13 and thus identify different cellular drivers of class switching in two distinct types of fibrotic disorders: allergic fibrosis (driven by type 2 immune cells) and inflammatory fibrosis (driven by cytotoxic T lymphocytes). METHODS: Single-cell RNA-sequencing, in situ sequencing, and multi-color immunofluorescence analysis was used to investigate B cells, Tfh cells and infiltrating type 2 cells in lesion tissues from patients with KD or IgG4-RD. RESULTS: Infiltrating Tfh cells in TLOs from IgG4-RD were divided into six main clusters. We encountered abundant infiltrating IL-10-expressing LAG3+ Tfh cells in patients with IgG4-RD. Furthermore, we found that infiltrating AID+CD19+B cells expressing IL-4, IL-10, and IL-21 receptors correlated with IgG4 expression. In contrast, we found that infiltrating IL-13-expressing Tfh cells were abundant in affected tissues from patients with KD. Moreover, we observed few infiltrating IL-13-expressing Tfh cells in tissues from patients with IgG4-RD, despite high serum levels of IgE (but low IgE in the disease lesions). Cytotoxic T cells were abundant in IgG4-RD, and in contrast Type 2 immune cells were abundant in KD. CONCLUSIONS: This single-cell dataset revealed a novel subset of IL10+LAG3+Tfh cells infiltrating the affected organs of IgG4-RD patients. In contrast, IL13+Tfh cells and type 2 immune cells infiltrated those of KD patients.

DOI： 10.1016/j.jaci.2022.03.034

Web of Science

Scopus

PubMed

researchmap

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Immunology  

Many studies have been performed in severe COVID-19 on immune cells in the circulation and on cells obtained by bronchoalveolar lavage. Most studies have tended to provide relative information rather than a quantitative view, and it is a combination of approaches by various groups that is helping the field build a picture of the mechanisms that drive severe lung disease. Approaches employed to date have not revealed information on lung parenchymal T cell subsets in severe COVID-19. Therefore, we sought to examine early and late T cell subset alterations in the lungs and draining lymph nodes in severe COVID-19 using a rapid autopsy protocol and quantitative imaging approaches. Here, we have established that cytotoxic CD4+ T cells (CD4 + CTLs) increase in the lungs, draining lymph nodes and blood as COVID-19 progresses. CD4 + CTLs are prominently expanded in the lung parenchyma in severe COVID-19. In contrast CD8+ T cells are not prominent, exhibit increased PD-1 expression, and no obvious increase is seen in the number of Granzyme B+ CD8+ T cells in the lung parenchyma in severe COVID-19. Based on quantitative evidence for re-activation in the lung milieu, CD4 + CTLs may be as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

DOI： 10.1016/j.clim.2022.108991

Web of Science

Scopus

PubMed

researchmap

Language：Others   Publisher：MDPI AG  

<jats:p>This review summarizes recent progress in understanding the pathogenesis of IgG4-related disease (IgG4-RD), with a focus on fibrosis. Several studies reported that CD4+ T cells with cytotoxic activity promoted by the secretion of granzyme and perforin, cytotoxic CD4+ T cells (CD4+CTLs), and disease-specific activated B cells, infiltrated inflamed tissues and cooperated to induce tissue fibrosis in autoimmune fibrotic diseases such as IgG4-RD, systemic sclerosis, and fibrosing mediastinitis. An accumulation of cells undergoing apoptotic cell death induced by CD4+CTLs and CD8+CTLs followed by macrophage-mediated clearing and finally tissue remodeling driven by cytokines released by CD4+CTLs, activated B cells, and M2 macrophages may contribute to the activation of fibroblasts and collagen production. In IgG4-RD, this process likely involves the apoptosis of non-immune, non-endothelial cells of mesenchymal origin and subsequent tissue remodeling. In summary, CD4+CTLs infiltrate affected tissues where they may cooperate with activated B cells, CD8+CTLs, and M2 macrophages, to induce apoptosis by secreting cytotoxic cytokines. These immune cells also drive fibrosis by secreting pro-fibrotic molecules in IgG4-RD.</jats:p>

DOI： 10.3390/immuno2010013

Web of Science

Scopus

CiNii Research

researchmap

Other Link： https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18H03003/

Language：Japanese  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English  

The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19. In Brief: In severe COVID-19 cytotoxic CD4+ T cells accumulate in draining lymph nodes and in the lungs during the resolving phase of the disease. Re-activated cytotoxic CD4+ T cells and cytotoxic CD8+ T cells are present in roughly equivalent numbers in the lungs at this stage and these cells likely collaborate to eliminate virally infected cells and potentially induce fibrosis. A large fraction of epithelial and endothelial cells in the lung express HLA class II in COVID-19 and there is temporal convergence between CD4+CTL accumulation and apoptosis in the lung. Highlights: In severe COVID-19, activated CD4+ CTLs accumulate in the lungs late in diseaseThese cells likely participate in SARS-CoV-2 clearance, collaborating with CD8+ T cells many of which exhibit an exhausted phenotypeT cells likely contribute to the late exacerbation of inflammationCD4+CTLs have been linked to fibrosis in many disorders and could also be responsible for the eventual induction of fibrosis in a subset of COVID-19 patients. Summary: The contributions of T cells infiltrating the lungs to SARS-CoV-2 clearance and disease progression are poorly understood. Although studies of CD8+ T cells in bronchoalveolar lavage and blood have suggested that these cells are exhausted in severe COVID-19, CD4+ T cells have not been systematically interrogated within the lung parenchyma. We establish here that cytotoxic CD4+ T cells (CD4+CTLs) are prominently expanded in the COVID-19 lung infiltrate. CD4+CTL numbers in the lung increase with disease severity and progression is accompanied by widespread HLA-DR expression on lung epithelial and endothelial cells, increased apoptosis of epithelial cells and tissue remodeling. Based on quantitative evidence for re-activation in the lung milieu, CD4+ CTLs are as likely to drive viral clearance as CD8+ T cells and may also be contributors to lung inflammation and eventually to fibrosis in severe COVID-19.

DOI： 10.1101/2021.03.23.21253885

Language：English  

DOI： 10.1016/j.ejim.2021.02.006

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Although fibrotic disorders are frequently assumed to be linked to TH2 cells, quantitative tissue interrogation studies have rarely been performed to establish this link and certainly many fibrotic diseases do not fall within the type 2/allergic disease spectrum. We have previously linked two human autoimmune fibrotic diseases, IgG4-related disease and systemic sclerosis, to the clonal expansion and lesional accumulation of CD4+CTLs. In both these diseases TH2 cell accumulation was found to be sparse. Fibrosing mediastinitis linked to Histoplasma capsulatum infection histologically resembles IgG4-related disease in terms of the inflammatory infiltrate and fibrosis, and it provides an example of a fibrotic disease of infectious origin in which the potentially profibrotic T cells may be induced and reactivated by fungal Ags. We show in this study that, in this human disease, CD4+CTLs accumulate in the blood, are clonally expanded, infiltrate into disease lesions, and can be reactivated in vitro by H. capsulatum Ags. TH2 cells are relatively sparse at lesional sites. These studies support a general role for CD4+CTLs in inflammatory fibrosis and suggest that fibrosing mediastinitis is an Ag-driven disease that may provide important mechanistic insights into the pathogenesis of idiopathic fibrotic diseases.

DOI： 10.4049/jimmunol.2000433

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand Protein S (ProS1) have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis. METHODS: MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively. RESULTS: MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren syndrome and interacted with apoptotic cells and ProS1 expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-β and their numbers declined following rituximab induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD. CONCLUSIONS: The MerTK-ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.

DOI： 10.1093/rheumatology/keab096

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: IgG4-related disease (IgG4-RD) is an immune-mediated fibrotic disorder that has been linked to CD4+ cytotoxic T lymphocytes (CD4+CTLs). The effector phenotype of CD4+CTLs and the relevance of both CD8+ cytotoxic T lymphocytes (CD8+CTLs) and apoptotic cell death remain undefined in IgG4-RD. OBJECTIVE: We sought to define CD4+CTL heterogeneity, characterize the CD8+CTL response in the blood and in lesions, and determine whether enhanced apoptosis may contribute to the pathogenesis of IgG4-RD. METHODS: Blood analyses were undertaken using flow cytometry, cell sorting, transcriptomic analyses at the population and single-cell levels, and next-generation sequencing for the TCR repertoire. Tissues were interrogated using multicolor immunofluorescence. Results were correlated with clinical data. RESULTS: We establish that among circulating CD4+CTLs in IgG4-RD, CD27loCD28loCD57hi cells are the dominant effector subset, exhibit marked clonal expansion, and differentially express genes relevant to cytotoxicity, activation, and enhanced metabolism. We also observed prominent infiltration of granzyme A-expressing CD8+CTLs in disease tissues and clonal expansion in the blood of effector/memory CD8+ T cells with an activated and cytotoxic phenotype. Tissue studies revealed an abundance of cells undergoing apoptotic cell death disproportionately involving nonimmune, nonendothelial cells of mesenchymal origin. Apoptotic cells showed significant upregulation of HLA-DR. CONCLUSIONS: CD4+CTLs and CD8+CTLs may induce apoptotic cell death in tissues of patients with IgG4-RD with preferential targeting of nonendothelial, nonimmune cells of mesenchymal origin.

DOI： 10.1016/j.jaci.2020.05.022

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Humoral responses in coronavirus disease 2019 (COVID-19) are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined post mortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers and a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+ TFH cell differentiation together with an increase in T-bet+ TH1 cells and aberrant extra-follicular TNF-α accumulation. Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+ TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections, and suggest that achieving herd immunity through natural infection may be difficult.

DOI： 10.1016/j.cell.2020.08.025

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English  

Humoral responses in COVID-19 disease are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined postmortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers, a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+TFH&nbsp;cell differentiation together with an increase in T-bet+TH1 cells and aberrant extra-follicular TNF-a accumulation.&nbsp; Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific "disease-related" B cell populations. These data identify defective Bcl-6+TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections and suggest that achieving herd immunity through natural infection may be difficult. Funding: This work was supported by NIH U19 AI110495 to SP, NIH R01 AI146779 to AGS, NIH R01AI137057 and DP2DA042422 to DL, BMH was supported by NIGMS T32 GM007753, TMC was supported by T32 AI007245. Funding for these studies from the Massachusetts Consortium of Pathogen Readiness, the Mark and Lisa Schwartz Foundation and Enid Schwartz is also acknowledged. Conflict of Interest: None. Ethical Approval: This study was performed with the approval of the Institutional Review Boards at the Massachusetts General Hospital and the Brigham and Women's Hospital.

DOI： 10.2139/ssrn.3652322

Language：English   Publishing type：Research paper (scientific journal)  

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal reaction that has been variably implicated in both tumor growth and tumor suppression. B-lymphocytes have been recently implicated in PDAC progression but their contribution to the characteristic stromal desmoplasia has never been assessed before. In the present work, we aimed to verify whether B-lymphocytes contribute to stromal cell activation in PDAC. CD19+ B-lymphocytes purified from peripheral blood of patients with PDAC were cultivated in the presence of human pancreatic fibroblasts and cancer-associated fibroblasts. Released pro-fibrotic soluble factors and collagen production were assessed by ELISA and Luminex assays. Quantitative RT-PCR was used to assess fibroblast activation in the presence of B cells. The expression of selected pro-fibrotic and inflammatory molecules was confirmed on PDAC tissue sections by multi-color immunofluorescence studies. We herein demonstrate that B-cells from PDAC patients (i) produce the pro-fibrotic molecule PDGF-B and stimulate collagen production by fibroblasts; (ii) express enzymes implicated in extracellular matrix remodeling including LOXL2; and (iii) produce the chemotactic factors CCL-4, CCL-5, and CCL-11. In addition we demonstrate that circulating plasmablasts are expanded in the peripheral blood of patients with PDAC, stimulate collagen production by fibroblasts, and infiltrate pancreatic lesions. Our results indicate that PDAC is characterized by perturbations of the B-cell compartment with expansion of B-lymphocyte subsets that directly contribute to the stromal reaction observed at disease site. These findings provide an additional rationale for modulating B-cell activity in patients with pancreatic cancer.

DOI： 10.1080/2162402X.2020.1794359

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Systemic sclerosis (SSc) is an autoimmune fibrotic disease whose pathogenesis is poorly understood and lacks effective therapies. We undertook quantitative analyses of T cell infiltrates in the skin of 35 untreated patients with early diffuse SSc and here show that CD4+ cytotoxic T cells and CD8+ T cells contribute prominently to these infiltrates. We also observed an accumulation of apoptotic cells in SSc tissues, suggesting that recurring cell death may contribute to tissue damage and remodeling in this fibrotic disease. HLA-DR-expressing endothelial cells were frequent targets of apoptosis in SSc, consistent with the prominent vasculopathy seen in patients with this disease. A circulating effector population of cytotoxic CD4+ T cells, which exhibited signatures of enhanced metabolic activity, was clonally expanded in patients with systemic sclerosis. These data suggest that cytotoxic T cells may induce the apoptotic death of endothelial and other cells in systemic sclerosis. Cell loss driven by immune cells may be followed by overly exuberant tissue repair processes that lead to fibrosis and tissue dysfunction.

DOI： 10.1172/JCI131700

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE OF REVIEW: To summarize recent advances in the understanding of the pathogenesis of IgG4-related disease. RECENT FINDINGS: Limited data exist to explain genetic susceptibility to IgG4-related disease and the underlying triggers for this disease have not yet been identified. Cytotoxic CD4 T cells and activated B cells infiltrate affected organs and express proinflammatory and profibrotic molecules. Antigen presented by activated B cells likely reactivates cytotoxic CD4 T cells in disease tissues and these T cells in turn induce the targeted apoptotic death of host cells in certain organs - which presumably present the same antigenic peptide on human leukocyte antigen class II molecules of relevance that was also presented on B cells during reactivation. A subsequent exaggerated tissue remodeling process is orchestrated by cytokines, chemokines, and enzymes secreted by both activated B cells and CD4CTLs. These molecules induce an overexuberant repair process resulting in fibrosis and loss of target organ function. SUMMARY: In IgG4-related disease, presumably self-reactive cytotoxic CD4 T cells infiltrate tissues, are reactivated by T cells and induce apoptotic death. Molecules secreted by activated B cells and by CD4CTLs drive an exaggerated wound healing response resulting in fibrosis and compromised tissue function.

DOI： 10.1097/BOR.0000000000000686

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing. OBJECTIVE: In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG4-RD. METHODS: Total circulating CD19+ B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG4-RD were cultivated with human fibroblasts. Profibrotic soluble factors and collagen production in cocultures were assessed by using ELISAs and Luminex assays. RNA sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as induction of profibrotic pathways in B-cell subsets. Relevant profibrotic and inflammatory molecules were confirmed in vitro by using functional experiments and on IgG4-RD tissue sections by using multicolor immunofluorescence studies. RESULTS: B cells from patients with IgG4-RD (1) produced the profibrotic molecule platelet-derived growth factor B and stimulated collagen production by fibroblasts; (2) expressed enzymes implicated in extracellular matrix remodeling, such as lysyl oxidase homolog 2; (3) produced the chemotactic factors CCL4, CCL5, and CCL11; and (4) induced production of these same chemokines by activated fibroblasts. Plasmablasts expressed sets of genes implicated in fibroblast activation and proliferation and therefore represent cells with intrinsic profibrotic properties. CONCLUSION: We have demonstrated that B cells contribute directly to tissue fibrosis in patients with IgG4-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for wound-healing processes in physiologic conditions.

DOI： 10.1016/j.jaci.2019.07.004

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

Language：Others   Publishing type：Research paper (scientific journal)  

© 2019 Asian AOMS(+) ASOMP(+) JSOP(+) JSOMS(+) JSOM(+) and JAMI Objective: Cytokeratin (CK) 19 is a member of the acidic type I CK family. Recently, CK19 expression has been found in various tumor tissues; however, the significance of this remains unknown. The purpose of this study is to clarify the roles of CK19 in the progression of oral squamous cell carcinoma (OSCC). Methods: A total of 100 patients who had been diagnosed with OSCC at our department between January 2011 and December 2016 was included. The patients were divided into three groups based on an optimal cut-off points (5&#37; and 77&#37;) of the labeling index (LI) as follows: group A; LI < 5&#37;, group B; 5&#37;≤ LI < 77&#37;, group C; LI ≥ 77&#37;. Then, clinicopathological features and survival rates were compared among the groups. Results: Histologically high-grade tumors were significantly more common in group C than in groups A and B. Furthermore, the incidence of nodal metastasis was significantly higher in group C than in other groups. Intense CK19 immunoreactivity was detected in metastatic lymph nodes of groups B and C, but not from group A. Moreover, patients with advanced pN stage and extranodal extension were more common in groups B and C than group A. Disease-specific survival curves revealed poorer prognoses in group C. Conclusions: These results suggest that CK19 is involved in OSCC invasion and metastasis and could be a novel biomarker of highly invasive OSCC with metastatic potential.

DOI： 10.1016/j.ajoms.2019.10.007

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

RATIONALE: Kimura disease (KD) is a rare, chronic inflammatory disorder characterized by subcutaneous granuloma in the head and neck region, as well as increased eosinophil counts and high serum immunoglobulin E (IgE) levels. Kimura disease is suspected to be an IgE-mediated disease, associated with an allergic response, in which antigen-specific B cells are stimulated to undergo specific IgE class switching with disease-specific CD4+ T (Th) cells help. Thus, exploration of the Th cells in affected tissues with KD is a highly promising field of the investigation. However, there have been no reports with direct evidence to implicate Th cells in affected lesions with KD. Here we quantitatively demonstrate that CD4+ GATA3+ T cells and interleukin (IL)-4+ IgE+ c-kit+ mast cells prominently infiltrate in affected lesion with KD. PATIENT CONCERNS: A 56-year-old Japanese man who exhibited painless swelling in the left parotid region. DIAGNOSES: Diagnosis of KD was made based on characteristic histopathologic findings, in conjunction with peripheral eosinophilia and elevated serum IgE levels. INTERVENTIONS: The patient underwent corticosteroid therapy and had been followed for 2 years. OUTCOMES: We report a rare case of KD of the parotid region in a 56-year-old man, followed by corticosteroid therapy for 2 years. The mass decreased in size and skin itchiness decreased after therapy. He was discharged without any complications. Furthermore, we quantitatively demonstrate the dominance of CD4+ GATA3+ T cells in affected tissues of KD and detect IL-4+ IgE+ c-kit+ mast cells in lesions by multicolor staining approaches. LESSONS: The findings from this case suggest that peripheral blood eosinophilia might serve as a marker of recurrent disease, long-term follow-up is necessary due to the possibility of recurrent. Interactions among expanded IgE+ B cells, CD4+ GATA3+ T cells, eosinophils, and activated mast cells might play a critical role in the pathogenesis of KD.

DOI： 10.1097/MD.0000000000018300

Language：Japanese  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

Tumor-associated macrophages (TAMs) promote tumor progression and inhibit anti-tumor immune response by producing various mediators and preferentially express CD163, CD204, and CD206. However, the role of these TAM subsets in oral squamous cell carcinoma (OSCC) remains unclear. Here we investigated the expression and function of TAM subsets in OSCC, especially in cancer cell proliferation. Biopsy sample from 44 patients with OSCC were examined for the expression of TAM markers and EGF by immunohistochemistry. EGF production of TAM subsets isolated from OSCC patients was assessed by flow cytometry. We also examined the effect of conditioned medium from TAM subsets on the proliferation of OSCC cells. CD163+ cells were detected diffusely all over the tumor and connective tissue area, while CD204+ and CD206+ cells were mainly detected in/around the tumors. Flow cytometric analysis found that CD206+ TAMs strongly produced EGF compared with CD163+ and CD204+ TAMs. Cell proliferation and invasion of OSCC cells cultured with conditioned medium of CD206+ TAMs were strongly enhanced and inhibited by anti-EGFR. The number of CD206+ TAMs positively correlated with worse clinical prognosis. Our results revealed differences in localization and EGF production among these TAM subsets. CD206+ TAMs might play a critical role in the proliferation of OSCC via EGF production.

DOI： 10.1038/s41598-019-51149-1

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

We previously revealed that epithelial-to-mesenchymal transition (EMT) was mediated by ΔNp63β, a splicing variant of ΔNp63, in oral squamous cell carcinoma (OSCC). Recent studies have highlighted the involvement of microRNA (miRNA) in EMT of cancer cells, though the mechanism remains unclear. To identify miRNAs responsible for ΔNp63β-mediated EMT, miRNA microarray analyses were performed by ΔNp63β-overexpression in OSCC cells; SQUU-B, which lacks ΔNp63 expression and displays EMT phenotypes. miRNAs microarray analyses revealed miR-205 was the most up-regulated following ΔNp63β-overexpression. In OSCC cells, miR-205 expression was positively associated with ΔNp63 and negatively with zinc-finger E-box binding homeobox (ZEB) 1 and ZEB2, potential targets of miR-205. miR-205 overexpression by miR-205 mimic transfection into SQUU-B cells led to decreasing ZEB1, ZEB2, and mesenchymal markers, increasing epithelial markers, and reducing cell motilities, suggesting inhibition of EMT phenotype. Interestingly, the results opposite to this phenomenon were obtained by transfection of miR-205 inhibitor into OSCC cells, which express ΔNp63 and miR-205. Furthermore, target protector analyses revealed direct regulation by miR-205 of ZEB1 and ZEB2 expression. These results showed tumor-suppressive roles of ΔNp63β and miR-205 by inhibiting EMT thorough modulating ZEB1 and ZEB2 expression in OSCC.

DOI： 10.1002/jcp.26267

Language：Japanese  

Language：English  

Language：English   Publishing type：Research paper (scientific journal)  

Programmed cell death ligand 1 (PD-L1) and its receptor PD-1 are immune checkpoint molecules that attenuate the immune response. Blockade of PD-L1 enhances the immune response in a variety of tumours and thus serves as an effective anti-cancer treatment. However, the biological and prognostic roles of PD-L1/PD-1 signalling in oral squamous cell carcinoma (OSCC) remain to be elucidated. The purpose of this study was to examine the correlation of PD-L1/PD-1 signalling with the prognosis of OSCC patients to assess its potential therapeutic relevance. The expression of PD-L1 and of PD-1 was determined immunohistochemically in 97 patients with OSCC and the association of this expression with clinicopathological characteristics was examined. Increased expression of PD-L1 was found in 64.9&#37; of OSCC cases and increased expression of PD-1 was found in 61.9&#37;. Univariate and multivariate analysis revealed that increased expression of PD-L1 and PD-1 positively correlated with cervical lymph node metastasis. The expression of CD25, an activated T-cell marker, was negatively correlated with the labelling index of PD-L1 and PD-1. Moreover, the patient group with PD-L1-positive and PD-1-positive expression showed a more unfavourable prognosis than the group with PD-L1-negative and PD-1-negative expression. These data suggest that increased PD-L1 and PD-1 expression is predictive of nodal metastasis and a poor prognosis and is possibly involved in cancer progression via attenuating the immune response.

DOI： 10.1016/j.ijom.2018.01.004

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：English   Publishing type：Research paper (scientific journal)  

We previously reported that epithelial-to-mesenchymal transition (EMT) was mediated by ΔNp63β in oral squamous cell carcinoma (OSCC). In this study, DNA microarray analyses were performed using ΔNp63β-overexpressing OSCC cells to identify genes associated with ΔNp63β-mediated EMT. Thereby, we focused on kallikrein-related peptidase (KLK) 6, most up-regulated following ΔNp63β-overexpression, that activates protease-activated receptors (PARs). In RT-PCR analyses, ΔNp63 was positively associated with KLK6 and PAR2 and negatively with PAR1 in OSCC cells. By ΔNp63 knockdown, KLK6 and PAR2 expression was decreased and PAR1 was increased. Furthermore, KLK6 knockdown led to enhancing migration and invasion, and inhibiting proliferation, suggesting EMT-phenotypes. Although, in the KLK6 or PAR2 knockdown cells, phosphorylation of ERK was reduced, it was restored in the KLK6 knockdown OSCC cells treated with recombinant KLK6 proteins. Immunohistochemistry showed ΔNp63, KLK6, and PAR2 were more strongly expressed in the epithelial dysplasia and central region of OSCC than normal oral epithelium, whereas PAR1 expression was undetectable. Interestingly, at the invasive front of OSCC, ΔNp63, KLK6, and PAR2 were reduced, but PAR1 was elevated. In addition, the OSCC patients with decreasing KLK6 expression at the invasive front had more unfavourable prognosis. These results suggested differential roles of KLK6 in malignant transformation and EMT; high ΔNp63β expression up-regulates KLK6-PAR2 and down-regulates PAR1, inducing malignant transformation in oral epithelium with stimulating proliferation through ERK signal activation. Moreover, KLK6-PAR2 expression is down-regulated and PAR1 is up-regulated when ΔNp63β expression is decreased, leading to EMT with enhancing migration and invasion through ERK signal reduction at the invasive front.

DOI： 10.1016/j.oraloncology.2017.11.004

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: We previously showed that ΔNp63β, a splicing variant of ΔNp63, mediated EMT and affected cell motility. DNA microarray was thus performed to elucidate the mechanism that ΔNp63β affects cell motility. As the results, Wnt5a was significantly down-regulated by ΔNp63β overexpression in tongue SCC cell line (SQUU-B) with EMT phenotype. MATERIALS AND METHODS: Seven OSCC cell lines were used. Expression of ΔNp63, Wnt5a, its receptor Ror2, and matrix metalloproteinases (MMPs) were analyzed by RT-PCR, real-time PCR, and western blotting, and gelatin zymography. Furthermore, we examined the effects of siRNA for Wnt5a or Ror2 and recombinant human Wnt5a (rhWnt5a) on motility of tongue SCC cells. Biopsy specimens from tongue SCC patients were used for immunohistochemical staining of Wnt5a and Ror2. RESULTS: Wnt5a and Ror2 were expressed only in SQUU-B cells without ΔNp63 expression, and negatively associated with ΔNp63 expression in other cells. ΔNp63β overexpression in SQUU-B cells decreased Wnt5a and Ror2 expression. By Wnt5a or Ror2 knockdown, cell motility was remarkably inhibited, but EMT markers expression was unaffected. MMP-2 expression and the activities inversely correlated with ΔNp63 expression, and were inhibited by Wnt5a or Ror2 knockdown. Cell motility and MMP-2 activities were recovered by adding rhWnt5a in the cells with Wnt5a knockdown, but not in those with Ror2 knockdown. Moreover, immunohistochemical analyses in tongue SCC specimens found that high expression of Wnt5a or Ror2 was associated with poorer prognosis. CONCLUSION: Wnt5a-Ror2 signaling enhanced tongue SCC cell aggressiveness and promoted production of MMP-2 following ΔNp63β-mediated EMT.

DOI： 10.1016/j.oraloncology.2017.03.019

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

多形腺腫は最も高頻度の唾液腺腫瘍であるが、舌下腺に生じるのはまれである。また舌下腺腫瘍の多くは悪性であるため、診断に苦慮することも多い。われわれは舌下腺多形腺腫の1例を経験したので、文献的考察を加え報告する。症例は60歳代男性で、左側口底部の腫瘤を主訴に来院、外科的切除を行い、多形腺腫の診断を得た。術後1年6ヵ月経過した現在、再発は認めていない。舌下腺腫瘍を疑う際は、悪性に準じた対応が重要である。(著者抄録)

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

今回われわれは、頸部郭清術後にリンパ漏を認め、陰圧閉鎖療法(NPWT)を行って治癒し得た2症例を経験したので報告する。【症例1】71歳、男性。左側頬粘膜扁平上皮癌(T2N2bM0)に対し、術前放射線化学療法後、根治的頸部郭清術(RND)、上顎部分切除術、頬粘膜部分切除術、下顎区域切除術、前外側大腿皮弁とチタンプレートによる再建術を施行。術後より、鎖骨上窩にリンパ液貯留を認めていた。術後12日目、左側頸部の出血を認めたため、止血処置およびリンパ漏出部位の結紮を行った。しかし、術後もリンパ液貯留が継続したため、再手術から3日後にNPWTを開始した。開始1週間でリンパ漏は消退した。【症例2】64歳、男性。左側舌扁平上皮癌術後に頸部リンパ節後発転移を認め、RNDを施行。術後15日目に鎖骨上窩にリンパ液貯留を認め、症例1と同様にNPWTを開始した。徐々にリンパ漏は消失し、NPWTは26日間で終了した。NPWTは頸部郭清術後リンパ漏に対し、有用な治療法の1つになり得ると考えられた。(著者抄録)

Language：Japanese  

Language：English  

Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Paraneoplastic syndrome generally results from tumor-derived hormones or peptides that cause metabolic derangements. Common metabolic conditions include hyponatremia, hypercalcemia, hypoglycemia, and Cushing's syndrome. Herein, we report a very rare case of tongue carcinoma presenting with leukocytosis and hypercalcemia. CASE PRESENTATION: A 57-year-old man was admitted to our hospital with tongue squamous cell carcinoma (cT4aN0M0, stage IV). He underwent radical resection following preoperative chemoradiotherapy, but locoregional recurrence was detected 2 months after surgery. He presented with marked leukocytosis and hypercalcemia with elevated serum levels of granulocyte colony-stimulating factor (G-CSF) and parathyroid hormone-related protein (PTHrP). He was therefore managed with intravenous fluids, furosemide, prednisolone, elcatonin, and pamidronate. However, the patient died 1 month later of carcinomatous pleuritis following distant metastasis to the lung. Immunohistochemical analyses of the resected specimens revealed positive staining for PTHrP and G-CSF in the cancer cells. CONCLUSIONS: In this case, it was considered that tumor-derived G-CSF and PTHrP caused leukocytosis and hypercalcemia.

DOI： 10.1186/s12957-016-0918-1

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

今回、舌粘膜疹を主訴に来院した第2期梅毒の1例を経験した。症例は20歳代の女性で、舌尖および舌縁部の白色病変と両手掌の丘疹性紅斑を認めた。梅毒血清検査にて陽性であったため第2期梅毒と診断し、抗菌薬内服を開始した。その後、口腔粘膜疹および皮疹は消退し、梅毒血清検査は陰性化した。近年、本症例のように口腔粘膜疹が梅毒の初発症状となる症例が増えており、今後注意を要すると考えられた。(著者抄録)

Language：English  

Language：Japanese  

Language：English   Publishing type：Research paper (scientific journal)  

Recent studies have revealed that cancer cells are exacerbated by chronic inflammation. The present study examined the immunohistochemical expression for interleukin-6 (IL-6), a pleiotropic inflammatory cytokine, in oral squamous cell carcinoma (OSCC) to elucidate the association of IL-6 expression with tumor progression, chemoresistance and prognosis. Seventy-eight patients with primary OSCC were analyzed by immunohistochemical staining for IL-6. These labeling indexes (LIs) were calculated and evaluated in association with the clinicopathologic characteristics and prognosis in the OSCC patients. The patients were divided into three groups as follows: negative group = LI <5&#37;; low IL-6 group = 5&#37; ≤ LI <30&#37;; high IL-6 group = LI ≥30&#37;. The patient numbers of the negative, low and high expression groups were 24, 22 and 32, respectively. In the high IL-6 expression group, IL-6 receptor (IL-6R), phosphor-signal tranducer and activator of transcription 3 (p-STAT3) were also detected in almost all the cancer cells. The prevalence of the cervical lymph node or the distant metastasis in the high expression group was significantly higher than those in the negative and low expression groups. Furthermore, the high expression group had a significantly poorer tumor response to the preoperative chemoradiotherapy and a more unfavourable prognosis than the negative and the low expression groups. Interestingly, IL-6, IL-6R and p-STAT3 were expressed in the residual cancer cells of all the patients in the high expression group with poor response to chemoradiotherapy. These results suggested that IL-6 signaling possibly is involved in the progression and treatment-resistance of OSCC and IL-6 expression in cancer cells could be a useful predictive factor of poor response to chemoradiotherapy and unfavorable prognosis.

DOI： 10.3892/or.2015.3838

Language：Japanese  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese   Publishing type：Research paper (scientific journal)  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese  

Language：Japanese