宮本 勲

Epstein-Barr virus陽性粘膜皮膚潰瘍(EBVMCU)は,口腔咽頭,皮膚,消化管に生じる成熟B細胞腫瘍である。2017年に造血器腫瘍のWHO分類においてEBVMCUの疾病概念が確立したが,口腔内に生じたEBVMCUの報告例は自験例を含め未だ稀である。今回,右側上顎歯肉部の有痛性腫瘤を1ヵ月前から認めた79歳女性の症例について報告する。患者は関節リウマチで11年間メトトレキサートを使用していた。生検標本の病理所見とPET-CTの画像所見よりEBVMCUの診断に至った。EBVMCUは化学療法を行わずとも寛解が期待できる疾患であり,今回,MTXを休薬することで自然寛解に至っており,その後18ヵ月間再発は認めていない。(著者抄録)

2010年1月～2020年12月に当院歯科・顎・口腔外科を受診した12歳以下の小児158名(男児97名、女児61名)を対象とする臨床的観察研究を行い、性別、年齢、受傷時刻、受傷原因、軟組織受傷、歯の外傷、顎顔面骨折の有無を調べた。年齢別にみると1歳と2歳児がそれぞれ20人と最も多く、低年齢児に多くみられ、0から5歳までが全体の60%を占めていた。受傷時刻は12時から18時の時間帯が73名(46.2%)と最も多く、受傷の原因は転倒が79名(50.0%)と大部分を占めていた。軟組織受傷は94名(59.5%)であり、受傷部位は口唇35名(37.3%)、歯肉24名(25.5%)、舌19名(20.2%)となっていた。歯の外傷は58名(36.7%)であり、3歳児に最も多くみられ(15.5%)、以下、4歳(13.8%)と5歳(13.8%)の順であった。顎顔面骨骨折は11名(7.0%)であり、下顎骨骨折が10名、上顎骨骨折が1名であった。

GTPases of immunity-associated protein 2 (GIMAP2) is a GTPase family member associated with T cell survival. However, its mechanisms of action in oral squamous cell carcinoma (OSCC) remain largely unknown. Therefore, the present study aimed to elucidate the possible role of GIMAP2 in OSCC development by investigating its expression levels and molecular mechanisms in OSCC. Reverse transcription quantitative PCR, immunoblotting and immunohistochemistry indicated that GIMAP2 expression was significantly upregulated (P<0.05) in OSCC-derived cell lines and primary OSCC specimens compared with that in their normal counterparts. GIMAP2-knockdown OSCC cells exhibited decreased cell growth, which was associated with cyclin-dependent kinase (CDK)4, CDK6 and phosphorylated Rb downregulation and p53 and p21 upregulation. In addition to cell cycle arrest, GIMAP2 affected anti-apoptotic functions in GIMAP2-knockdown cells by upregulating Bcl-2 and downregulating Bax and Bak. These findings indicated that GIMAP2 may significantly influence OSCC development and apoptosis inhibition and thus is a potential biomarker of OSCC.

Supernumerary teeth (ST) are common clinical dental anomalies characterized by the presence of excessive teeth. It can cause diverse complications in the developing jaw and dentition, which could prevent the acquisition of normal oral functions. The presence of multiple ST is rare and commonly associated with genetic syndromes or developmental anomalies. In such cases, the related clinical problems should be considered along with the treatment of multiple ST. Then, it is important to pay attention to the craniofacial, skeletal, and other physical findings. Herein, we report a rare case of eight ST in a patient without any associated syndromes. Early diagnosis and successive radiographic evaluations are critical for preventing the complications caused by ST.

Pneumatosis intestinalis (PI) is characterized by the presence of gas in the bowel wall and is associated with a wide range of clinical conditions, such as pulmonary, gastrointestinal, infectious, and autoimmune diseases, and an immunosuppressive state such as that resulting from cancer chemotherapy. It is not a distinct disease but rather a physical or radiographic finding and can be categorized into types: primary and secondary. Primary PI is idiopathic, while secondary PI occurs as a result of an underlying disease. Several theories were suggested for the etiology of this condition. Intestinal gas, mucosal integrity, intraluminal pressure, and bacterial flora play interactive roles in the development of PI yet, the mechanisms involved remain unclear. PI can be seen in benign or life-threatening situations. Choosing an appropriate treatment owing to the various interpretations of the clinical significance of PI is difficult. An urgent surgical procedure is necessary for patients with signs of bowel perforation, peritonitis, or necrotizing enterocolitis. Potentially, these life-threatening conditions should be ruled out, based on the physical and radiographic findings of the patient. Herein, we report a rare case of PI in a 72-year-old woman who was administrated cisplatin and radiation as adjuvant chemoradiotherapy for oral cancer. During the therapy, free air was detected via chest radiography. Based on the physical and computed tomographic findings, the development of free air was considered as a non-life-threatening PI phenomenon caused by the cancer chemotherapy.

Herein, we present a sporadic case of white sponge nevus (WSN) on the cheek mucosa in a 27-year-old Japanese man. A definite diagnosis of WSN was obtained using the typical clinical appearance and microscopic features of the lesions. Histopathological and cytological studies should be conducted to differentiate this condition from other oral premalignant white lesions. A molecular mutation analysis revealed a missense mutation in exon 1A of the keratin 4 gene, which is correlated with the development of WSN. Hence, genetic analysis must be performed to obtain an accurate diagnosis in sporadic cases. The temporary regression of the lesion after treatment with oral amoxicillin hydrate (AMPC) 750 mg/day indicates that antibiotics are effective in symptomatic cases.

頭頸部癌に対して分子標的薬であるセツキシマブ(Cmab)が2012年12月に適用承認がされた。今回,再発転移口扁平上皮癌に対して当科にてCmabとシスプラチン(CDDP)とフルオロウラシル(5-FU)の併用化学療法を施行した4症例を検討した。症例は36歳〜64歳,男性3例,女性1例であった。原発巣は舌3例,下顎歯肉1例であった。再発・転移部位は肺4例,頸部リンパ節3例,舌1例,胸椎1例,外腹膜壁1例,甲状腺1例であった(重複あり)。1例は経過中に心筋梗塞を発症し,Cmab併用化学療法を中止し,評価不能であった。2例においては転移腫瘍がやや縮小したが治療効果判定としてはstable disease(SD)であった。1例における治療効果判定はprogressive disease(PD)であった。副作用は皮膚毒性,口内炎,嘔気,心筋梗塞,肺塞栓症,infusion reaction(IR)などが出現した。心筋梗塞,肺塞栓症,IRなどは生命を危険にさらす重大な副作用であるので,Cmab併用化学療法には全身管理が非常に重要である。(著者抄録)

症例1は78歳女性で、近歯科医院にて右側上顎犬歯の歯肉息肉除去を行い、嚥下痛を訴えたため当科受診した。CO2レーザーによる右側頬部皮下気腫および縦隔気腫と診断し、感染予防のためCFPN-PIの投与を開始、気腫の消失を認めた。症例2は17歳男性で、外傷に伴う気管支断裂による縦隔気腫と診断し、ABPC/SBTの投与を開始、術後6日目のCT写真にて気腫の消失を認めた。症例3は54歳男性で、抜歯後に左側頬部の急激な腫脹を自覚し、左側頬部皮下気腫と診断した。感染予防のためCFPN-PIの投与を開始し、14日目のCTにて気腫の消失を認めた。症例4は73歳男性で、転落して右側頬部を打撲し右側頬部の急激な腫脹を認めたため当科受診した。右側頬部皮下気腫と診断し、感染予防のためにAMPCの投与を開始、28日目のCTで気腫の消失を認めた。

Dermoid cysts, which are lined by ectoderm elements, typically arise in skin, testicles, and ovaries. These cysts mostly occur during the second or third decade of life and rarely present in children. We describe a rare case of a dermoid cyst in a 6-year-old Japanese girl. Examination showed a smooth, well-defined cystic swelling approximately 30 × 20 mm2 in the midline of the oral floor. The cyst was excised via the intraoral approach under general anesthesia. The histopathologic diagnosis of a dermoid cyst was made. The clinical outcome was satisfactory without postoperative complications during the 26-month follow-up period.

Unc-93 homolog B1 (UNC93B1), a transmembrane protein, is correlated with immune diseases, such as influenza, herpes simplex encephalitis, and the pathogenesis of systemic lupus erythematosus; however, the role of UNC93B1 in cancers including human oral squamous cell carcinomas (OSCCs) remains unknown. In the current study, we investigated the UNC93B1expression level in OSCCs using quantitative reverse transcription-polymerase chain reaction, immunoblot analysis, and immunohistochemistry. Our data showed that UNC93B1 mRNA and protein expressions increased markedly (p < 0.05) in OSCCs compared with normal cells and tissues and that high expression of UNC93B1 in OSCCs was related closely to tumoral size. UNC93B1 knockdown (shUNC93B1) OSCC cells showed decreased cellular proliferation by cell-cycle arrest in the G1 phase with up-regulation of p21Cip1 and down-regulation of CDK4, CDK6, cyclin D1, and cyclin E. We also found that granulocyte macrophage colony-stimulating factor (GM-CSF) was down-regulated significantly (p < 0.05) in shUNC93B1 OSCC cells. Moreover, inactivation of GM-CSF using neutralization antibody led to cell-cycle arrest at the G1 phase similar to the phenotype of the shUNC93B1 cells. The current findings indicated that UNC93B1 might play a crucial role in OSCC by controlling the secretion level of GM-CSF involved in tumoral growth and could be a potential therapeutic target for OSCCs.

Lysyl hydroxylase 2 (LH2) is an endoplasmic reticulum (ER)-resident enzyme that catalyzes the hydroxylation of lysine residues in the telopeptides of fibrillar collagens. This is a critical modification to determine the fate of collagen cross-linking pathway that contributes to the stability of collagen fibrils. Studies have demonstrated that the aberrant LH2 function causes various diseases including osteogenesis imperfecta, fibrosis, and cancer metastasis. However, surprisingly, a LH2-deficient animal model has not been reported. In the current study, to better understand the function of LH2, we generated LH2 gene knockout mice by CRISPR/Cas9 technology. LH2 deficiency was confirmed by genotyping polymerase chain reaction (PCR), reverse transcriptase-PCR, and immunohistochemical analyses. Homozygous LH2 knockout (LH2-/-) embryos failed to develop normally and died at early embryonic stage E10.5 with abnormal common ventricle in a heart, i.e., an insufficient wall, a thin ventricular wall, and loosely packed cells. In the LH2-/- mice, the ER stress-responsive genes, ATF4 and CHOP were significantly up-regulated leading to increased levels of Bax and cleaved caspase-3. These data indicate that LH2 plays an essential role in cardiac development through an ER stress-mediated apoptosis pathway.

症例は68歳女性で、先天性第V因子欠乏症の既往歴があった。今回、左側舌縁部の潰瘍を指摘され、精査加療目的で当科紹介となった。造影CTで、左側舌縁部に28×23mm大の造影効果を示す境界不明瞭な腫瘤を認めた。また、左側レベルIIAに内部造影性不均一な12×12mm大の腫大したリンパ節を認めた。臨床診断は左側舌癌(T2N1MO、stage III)で、生検により扁平上皮癌の診断を得た。周術期の対応について当院血液内科に対診を行い、新鮮凍結血漿(FFP)の試験投与を施行した。FFP投与終了1時間後に、第V因子活性は12%から32%まで補正され、それに伴ってPTが13.8sec、APTT値が55.2secまで改善した。全身麻酔下に舌部分切除術、左側機能的頸部郭清術、気管切開術を施行した。手術は、術後出血を考慮し再建術は行わず、舌部分切除後は縫縮した。また、気管切開術は咽頭浮腫や後出血による気道閉塞を考慮し施行した。帰室後もFFPを6単位投与し、術後1日目から3日目までFFPを毎日6単位ずつ投与した。術後3日目に第V因子活性は75%まで上昇し、創部からの出血も認められなかったためFFPの投与を中止した。術後4日目には持続吸引ドレーン量が5mL以下となり、後出血なく経過したため、術後6日目に第V因子活性を確認してドレーンを抜去した。病理組織学的診断は、舌扁平上皮癌(pT4aN2bM0、stage IV A)であった。術後47日目より放射線治療を施行し、術後4年2ヵ月が経過した現在も再発所見はなく経過観察中である。

Centromere protein N (CENP-N), an important member of the centromere protein family, is essential for kinetochore assembly and chromosome segregation; however, the relevance of CENP-N in cancers remains unknown. The aim of this study was to investigate CENP-N expression and its functional mechanisms in oral squamous cell carcinoma (OSCC). CENP-N expression was up-regulated significantly in vitro and in vivo in OSCCs. Overexpressed CENP-N was closely (p < 0.05) correlated with tumor growth using quantitative reverse transcriptase-polymerase chain reaction, immunoblot analysis, and immunohistochemistry. CENP-N knockdown (shCENP-N) cells showed depressed cellular proliferation by cell-cycle arrest at the G1 phase with up-regulation of p21Cip1 and p27Kip1 and down-regulation of cyclin D1, CDK2, and CDK4. Interestingly, we newly discovered that calcitriol (1, 25-dihydroxyvitamin D3) controlled the CENP-N expression level, leading to inhibition of tumor growth similar to shCENP-N cells. These results suggested that CENP-N plays a critical role in determining proliferation of OSCCs and that calcitriol might be a novel therapeutic drug for OSCCs by regulating CENP-N.

症例は73歳女性で、左側上顎歯肉の違和感を主訴に受診した。パノラマX線写真で左上7番の根尖付近から上顎骨および上顎洞部にかけてのX線不透過像を指摘された。パノラマX線写真にて左上7番の根尖付近から上顎骨内に存在し、先端が上顎洞底線を越えて上顎洞内へ至るX線不透過像を認めた。デンタルX線写真では根分岐部から異物の断端にかけてX線透過像を認めた。CT写真では口蓋根根尖から上顎洞内にかけて約15mmの金属針様異物を認めた。左上7番は画像所見、臨床症状より保存不可能と判断し、局所麻酔下にて左上7番抜歯術および異物除去術を行った。抜歯したところ、根分岐部から口蓋根尖にかけて肉芽組織を認めた。抜歯窩の肉芽組織を掻爬し、抜歯窩骨面を精査すると、異物の断端を確認した。術後の抜歯窩の治癒経過は良好で、術前に訴えていた左側上顎歯肉の違和感は消失した。術後2ヵ月の診察時に口腔上顎洞瘻孔や副鼻腔炎症状を認めないことを確認し、経過観察を終了とした。

Angiopoietin-1 (Ang1) is a binding partner of endothelial cell-specific tyrosine-protein kinase receptor (Tie2), which serves important roles in vascular development and angiogenesis. Tie2 is closely associated with the metastasis of oral squamous cell carcinomas (OSCCs) however, little is known about the correlation between Tie2 and Ang1. In the present study, the functional mechanisms of the Tie2/Ang1 interaction were investigated using Tie2 overexpressed (oeTie2) OSCC cells and recombinant Ang1 protein. oeTie2 cells had increased cell-cell and cell-extracellular matrix adhesions compared with the control cells. Additionally, the adhesive activities increased following treatment with exogenous Ang1, indicating that Ang1 directly enhances Tie2 functions. In the clinical OSCC data from 10 cases positive for regional lymph node metastasis, all cases were negative for Tie2 expression and eight cases (80%) were negative for Ang1 expression. These results suggest that Tie2 and Ang1 serve important roles in cancer metastasis and may be potential biomarkers and therapeutic targets for OSCC metastasis.

Lymphocyte cytosolic protein 1 (LCP1), a member of actin-binding protein of the plastin family, has been identified in several malignant tumors of non-hematopoietic sites, such as the colon, prostate, and breast. However, little is known about the roles of LCP1 in oral squamous cell carcinomas (OSCCs). This present study sought to clarify the clinical relevance of LCP1 in OSCCs and investigate possible clinical applications for treating OSCCs by regulating LCP1 expression. We found up-regulation of LCP1in OSCCs compared with normal counterparts using real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunoblotting, and immunohistochemistry (P < 0.05). We used shRNA models for LCP1 (shLCP1) and enoxacin (ENX), a fluoroquinolone antibiotic drug, as a regulator of LCP1 expression. In addition to the LCP1 knockdown experiments in which shLCP1 cells showed several depressed functions, including cellular proliferation, invasiveness, and migratory activities, ENX-treated cells also had attenuated functions. Consistent with our hypothesis from our in vitro data, LCP1-positive OSCC samples were correlated closely with the primary tumoral size and regional lymph node metastasis. These results suggested that LCP1 is a useful biomarker for determining progression of OSCCs and that ENX might be a new therapeutic agent for treating OSCCs by controlling LCP1 expression.

Activin B, a homodimer of inhibin beta b (INHBB), is a multifunctional cytokine belonging to the transforming growth factor-β (TGF-β) family. However, the molecular functions and clinical relevance of activin B have not been determined in oral cancer. We investigated the critical roles of activin B in oral squamous cell carcinoma (OSCC). We performed quantitative reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemistry to study INHBB expression in OSCC-derived cell lines and OSCC clinical samples. The INHBB expression levels were significantly (P < 0.05) overexpressed in OSCCs compared to normal counterparts in vitro and in vivo. Activin B-positivity in OSCC cases was significantly (P < 0.05) correlated with regional lymph node metastasis. The INHBB knockdown (shINHBB) cells promoted cellular adhesion and suppression of cellular invasiveness and migration. After treatment of shINHBB cells with activin B, those activities were restored similar to the shMock cells. In the processes of invasiveness and metastasis, the cells cause epithelial-mesenchymal transition (EMT). TGF-β and its family members are promoters of the EMT process. To investigate whether activin B is related to EMT, we examined the expressions of EMT-related genes and found that INHBB was related closely to EMT. Our results suggested for the first time that activin B indicates tumoral metastasis in OSCCs and might be a useful biomarker for OSCC metastasis.

Tropomodulin1 (TMOD1), which regulates the length and depolymerization of actin filaments by binding to the pointed end of the actin filament, has been reported to be a powerful diagnostic marker for ALK-negative anaplastic large-cell lymphoma; however, little is known about the relevance of TMOD1 in the behavior of oral squamous cell carcinoma (OSCC). We evaluated TMOD1 expression in OSCC-derived cell lines and primary OSCC samples (n=200) using quantitative reverse transcriptase-polymerase chain reaction, immunoblotting and semi-quantitative immunohistochemistry. We also analyzed the clinical correlation between TMOD1 expression status and clinical parameters in patients with OSCC and performed a prospective study using 40 primary OSCC samples. TMOD1 expression was upregulated significantly (p<0.05) in OSCC in vitro and in vivo compared with normal counterparts. TMOD1 expression also was correlated significantly (p=0.0199 and p=0.0064, respectively) with regional lymph node metastasis (RLNM) and 5-year survival rates. This prospective study also showed that high TMOD1 expression was seen in 12 (75%) of 16 cases in RLNM-positive patients and 9 (37.5%) of 24 cases in RLNM-negative patients. The current data provide the first evidence that TMOD1 expression is a critical biomarker for RLNM and prognosis of patients with OSCC.

The endothelial-specific receptor, tyrosine kinase with immunoglobulin-like loops and epidermal growth factor homology domains-2 (Tie2) is a member of the tyrosine kinase family and is ubiquitous in normal tissues; however, little is known about the mechanisms and roles of Tie2 in oral squamous cell carcinomas (OSCCs). In the current study, we investigated the expression status of Tie2 in OSCCs by quantitative reverse transcriptase-polymerase chain reaction, immunoblotting, and immunohistochemistry and the functional mechanisms of Tie2 using its overexpressed OSCC (oeTie2) cells and Tie2 blocking by its antibody. We found that Tie2 expression was down-regulated significantly (p < 0.05) in OSCCs compared with normal counterparts in vitro and in vivo. Interestingly, oeTie2 cells showed higher cellular adhesion (p < 0.05) and lower cellular invasion (p < 0.05) compared with control cells; whereas there was similar cellular proliferation in both transfectants. Furthermore, cellular adhesion was inhibited and invasion was activated by Tie2 function-blocking antibody (p < 0.05), indicating that Tie2 directly regulates cellular adhesion and invasion. As expected, among the clinical variables analyzed, Tie2-positivity in patients with OSCC was correlated closely with negative lymph node metastasis. These results suggested for the first time that Tie2 plays an important role in tumor metastasis and may be a potential biomarker for OSCC metastasis.

63歳女性。近医の歯科にて左側頬粘膜部口内炎に対し歯科用炭酸ガスレーザーを照射後、左側頬部と顎下部に捻髪音を伴う腫脹が出現、腫脹は頸部まで拡大したため再度、近医の歯科を受診したが、皮下気腫を疑われ、著者らの施設へ紹介となった。受診時、口腔内所見では左側頬粘膜部にレーザー照射痕を認めたが、口腔清掃状態は良好でその他の異常は認められなかった。しかし、CT像では左側は上方が側頭隙、下方は鎖骨上、後方は後頭隙で、一方、右側は上方が乳様突起内側、下方は顎下部、後方は乳様突起まで及び、前方はオトガイ下隙にまで至る範囲で含気像と思われる所見が確認された。以後、感染予防および皮下気腫経過観察目的で入院となり、セフトリアキソンナトリウム(2g/日)の点滴投与を開始したところ、治療開始2日目から経時的に腫脹は軽減、治療開始14日目には消失した。更に治療開始21日目にはCT像にて皮下気腫の消失を確認し、その後は経過良好で終診とした。