Published papers

Carcinoma ex pleomorphic adenoma （Ca-ex-PA） mainly arises from the major salivary glands （i.e., parotid gland）, and adenocarcinoma not otherwise specified and salivary duct carcinoma are common histological types. Here, we report a case of a patient with Ca-ex-PA, with myoepithelial cancer derived from the minor salivary glands of the cheek. A 74-year-old woman was admitted to our hospital with swelling of her left cheek. MRI revealed a lobular mass lesion that surrounded the anterior margin of the left masseter muscle. A biopsy revealed the coexistence of malignant components with pleomorphic adenoma, which led to the diagnosis of Ca-ex-PA. Tumor resection and supraomohyoid neck dissection were performed, followed by anterolateral thigh flap transplantation. The patient had a good postoperative course, but about five months after the operation, died from another illness. As Ca-ex-PA is a rare disease in the minor salivary gland, it is desirable to establish preoperative diagnostic methods and treatment strategies by accumulating cases from multiple institutions.

オスラー病は皮膚や粘膜,全身臓器の血管異常をきたす常染色体優性遺伝疾患である.その診断にはCuracao criteriaと呼ばれる臨床診断が広く用いられている.今回われわれは,オスラー病を有する患者の上顎正中埋伏過剰歯の抜歯の1例を経験したためその概要を報告する.患者は8歳の男児,上顎正中埋伏過剰歯の精査・加療目的に当科を受診した.既往歴,家族歴から7歳時にオスラー病と診断されていた.上顎正中埋伏過剰歯は鼻腔底粘膜に接しており,反復性鼻出血の既往があることから入院・全身麻酔下に抜歯術を実施,術中・術後の異常出血は認められず経過は良好であった.本症例では術前からオスラー病と診断されていたが,既往歴や臨床所見,治療を契機として発見される可能性もあり,本疾患への理解を深める必要があると思われる.(著者抄録)

Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.

The number of osteoarthritis patients is increasing with the rise in the number of elderly people in developed countries. Osteoarthritis, which causes joint pain and deformity leading to loss of activities of daily living, is often treated surgically. Here we show that mechanical stress promotes accumulation of reactive oxygen species (ROS) in chondrocytes in vivo, resulting in chondrocyte apoptosis and leading to osteoarthritis development in a rat model. We demonstrate that mechanical stress induces ROS accumulation and inflammatory cytokine expression in cultured chondrocytes in vitro and that both are inhibited by treatment with the anti-oxidant N-acetyl cysteine (NAC). In vivo, osteoarthritis development in a rat osteoarthritis model was also significantly inhibited by oral administration of NAC. MMP13 expression and down-regulation of type II collagen in chondrocytes, both of which indicate osteoarthritis, as well as chondrocyte apoptosis in osteoarthritis rats were inhibited by NAC. Interestingly, osteoarthritis development in sham-operated control sides, likely due to disruption of normal weight-bearing activity on the control side, was also significantly inhibited by NAC. We conclude that osteoarthritis development in rats is significantly antagonized by oral NAC administration. Currently, no oral medication is available to prevent osteoarthritis development. Our work suggests that NAC may represent such a reagent and serve as osteoarthritis treatment.

This study investigated a case of spindle cell carcinoma (SpCC) in tongue pathological lesions. The patient experienced a local recurrence and distant metastasis after surgical intervention. Although standard chemotherapy was administered, a granulomatous mass continued to develop. This aggressive growth led to survival of the tumor. Secondary debulking surgery was performed to improve the patient’s quality of life at the request of the patient. Using a tissue sample derived from the secondary debulking surgery, we performed an analysis of the tumor’s cell surface antigens, differentiation potential, metastatic ability, and inhibition potential by anticancer reagents. In vitro analysis revealed that the cell population grown under adherent culture conditions expressed the mesenchymal stem cell (MSC) markers CD73, CD90, and CD105. The cell line established from this SpCC contained colony-forming unit fibroblasts (CFU-Fs) and exhibited multipotent differentiation into several mesenchymal lineages, including bone, cartilage, and fat. The SpCC cells also displayed vigorous mobilization. These characteristics suggested that they had the differentiation potential of mesenchymal cells, especially MSCs, rather than that of epithelial cells. The surgical specimen analyzed in this study resisted the molecular target reagent cetuximab, which is an epidermal growth factor receptor inhibitor. This clinical insight revealed that chemotherapy-resistant SpCC cells have different characteristics compared to most other cancer cells, which are sensitive to cetuximab. Our cell death assay revealed that SpCC cell death was induced by the anticancer drug imatinib, which is known to inhibit protein tyrosine kinase activity of ABL, platelet-derived growth factor receptor α (PDGFRα), and KIT. Here, we report recurrent SpCC with characteristics of MSCs and potential for treatment with imatinib.

INTRODUCTION: Osteonecrosis of the jaw (ONJ) occurring after invasive dental treatment often adversely affects patients' activities of daily living. Long-term administration of strong anti-bone resorptive agents such as bisphosphonates prior to invasive dental treatment is considered an ONJ risk factor; however, pathological mechanisms underlying ONJ development remain unclear. MATERIALS AND METHODS: We developed an ONJ mouse model in which a tooth is extracted during treatment with the bisphosphonate zoledronate. RESULTS: We observed induction of apoptosis in osteocytes, resulting in formation of empty lacunae in jaw bones at sites of tooth extraction but not in other bones of the same mice. We also observed elevated levels of inflammatory cytokines such as TNFα, IL-6 and IL-1 in jaw bone at the extraction site relative to other sites in zoledronate-treated mice. We also report that treatment in vitro with either zoledronate or an extract from Porphyromonas gingivalis, an oral bacteria, promotes expression of inflammatory cytokines in osteoclast progenitor cells. We demonstrate that gene-targeting of either TNFα, IL-6 or IL-1 or treatment with etanercept, a TNFα inhibitor, or a neutralizing antibody against IL-6 can antagonize ONJ development caused by combined tooth extraction and zoledronate treatment. CONCLUSIONS: Taken together, the cytokine storm induced by invasive dental treatment under bisphosphonate treatment promotes ONJ development due to elevated levels of inflammatory cytokine-producing cells. Our work identifies novel targets potentially useful to prevent ONJ.

Estrogen deficiency can be caused by ovarian dysfunction in females. Mechanisms underlying osteoporosis in this condition have been characterized in animal models, such as ovariectomized mice and rats, although it remains unclear how hypothalamic dysfunction promotes osteoporosis. Here, we show that administration of a gonadotropin-releasing hormone antagonist (GnRHa) significantly decreases uterine weight, a manifestation of hypothalamic dysfunction, and promotes both cortical and trabecular bone loss in female mice in vivo. We also report that osteoclast number significantly increased in mice administered GnRHa, and that the transcription factor hypoxia inducible factor 1 alpha (HIF1α) accumulated in those osteoclasts. We previously reported that treatment of mice with the active vitamin D analogue ED71, also known as eldecalcitol, inhibited HIF1α accumulation in osteoclasts. We show here that in mice, co-administration of ED71 with GnRHa significantly rescued the reduced cortical and trabecular bone mass promoted by GnRHa administration alone. GnRHa-dependent HIF1α accumulation in osteoclasts was also blocked by co-administration of ED71. We conclude that hypothalamic dysfunction promotes HIF1α accumulation in osteoclasts and likely results in reduced bone mass. We conclude that treatment with ED71 could serve as a therapeutic option to counter osteoporotic conditions in humans.

Vitamin D deficiency is a recognized risk factor for sarcopenia development, but mechanisms underlying this outcome are unclear. Here, we show that low vitamin D status worsens immobilization-induced muscle atrophy in mice. Mice globally lacking vitamin D receptor (VDR) exhibited more severe muscle atrophy following limb immobilization than controls. Moreover, immobilization-induced muscle atrophy was worse in neural crest-specific than in skeletal muscle-specific VDR-deficient mice. Tnfα expression was significantly higher in immobilized muscle of VDR-deficient relative to control mice, and was significantly elevated in neural crest-specific but not muscle-specific VDR-deficient mice. Furthermore, muscle atrophy induced by limb immobilization in low vitamin D mice was significantly inhibited in Tnfα-deficient mice. We conclude that vitamin D antagonizes immobilization-induced muscle atrophy via VDR expressed in neural crest-derived cells.

Auto-inflammatory syndromes are rare diseases characterized by arthritis and joint destruction, symptoms similar to but distinct from rheumatoid arthritis (RA). Therapeutic targets have not been well characterized for auto-inflammatory syndromes, although the E3 ligase Synoviolin was previously shown to be a novel therapeutic target for RA. Here, we show that Synoviolin loss has little impact on a model of auto-inflammatory diseases. We previously established such a model, the hIL-1 cTg mouse, in which IL-1 signaling was constitutively activated, and animals exhibit symptoms recapitulating auto-inflammatory syndromes such as major joint dominant arthritis. Here, we crossed hIL-1 cTg with Synoviolin flox'd mice to yield hIL-1 cTg/Synoviolin cKO mice. Synoviolin gene expression was ablated in adult hIL-1 cTg/Synoviolin cKO mice by injection of pIpC to activate Mx1 promoter-driven Cre recombinase. However, symptoms seen in hIL-1 cTg mice such as arthritis and joint destruction were not alleviated by targeting Synoviolin, ruling out Synoviolin as a therapeutic target for auto-inflammatory disease. Our results indicate that although similar, RA and auto-inflammatory diseases are different diseases, and treatment strategies should differ accordingly.

Changes in bone metabolism occur in mothers during pregnancy or lactation that may decrease bone mass and result in fragility fractures after partum. However, use of drugs during pregnancy or lactation to counteract these effects is often prohibited or strongly discouraged. Therefore, approaches to protect mothers from fragility fractures have not been established. Here we show that bone mineral density was significantly lower in female mice after partum than in age-matched female mice without partum. We also show that temporary administration of the bisphosphonate alendronate, either just before or just after pregnancy, to female mice was protective against bone loss due to pregnancy or lactation and had no adverse effects on offspring, such as growth retardation. Furthermore, we show that alendronate administration to female mice during lactation was effective in increasing bone mass in mothers without promoting bone abnormalities or growth retardation in offspring. Calcium levels in milk from female mice administered alendronate during lactation were equivalent to those in milk from mothers not treated with alendronate. Overall, we propose that alendronate administration to mothers could prevent bone loss and fragility fractures during pregnancy and lactation.

We herein report a rare case of undifferentiated carcinoma that originated in the mandible with the same pathological findings as seen in the liver. A 64-year-old man underwent surgery for a hepatic tumor in October 2006, and the pathological diagnosis was undifferentiated carcinoma. The patient was referred to our department in January 2007, when whole-body positron emission tomography/computed tomography showed the uptake of fluorodeoxyglucose in the right mandibular ramus. The patient underwent right hemimandibulectomy in April 2007. The resected tumor was also undifferentiated carcinoma. In May 2014, seven years after the lower mandibular operation, the tumor recurred at the site corresponding to the right mandibular ramus after resection, and tumor resection and right neck dissection were performed. As a result of the histopathological examination, the undifferentiated carcinoma findings were the same as before. There have been no signs of local recurrence or metastases for over six years since the second mandibular surgery.

AbstractInvasive dental treatment such as tooth extraction following treatment with strong anti-bone resorptive agents, including bisphosphonates and denosumab, reportedly promotes osteonecrosis of the jaw (ONJ) at the extraction site, but strategies to prevent ONJ remain unclear. Here we show that in mice, administration of either active vitamin D analogues, antibiotics or anti-inflammatory agents can prevent ONJ development induced by tooth extraction during treatment with the bisphosphonate zoledronate. Specifically, tooth extraction during treatment with zoledronate induced osteonecrosis in mice, but administration of either 1,25(OH)2D3 or ED71, both active vitamin D analogues, significantly antagonized osteonecrosis development, even under continuous zoledronate treatment. 1,25(OH)2D3 or ED71 administration also significantly inhibited osteocyte apoptosis induced by tooth extraction and bisphosphonate treatment. Administration of either active vitamin D analogue significantly inhibited elevation of serum inflammatory cytokine levels in mice in response to injection of lipopolysaccharide, an infection mimetic. Furthermore, administration of either anti-inflammatory or antibiotic reagents significantly blocked ONJ development following tooth extraction and zoledronate treatment. These findings suggest that administration of active vitamin D, anti-inflammatory agents or antibiotics could prevent ONJ development induced by tooth extraction in patients treated with zoledronate.

Diffuse sclerosing osteomyelitis of the mandible (DSOM) is a nonsuppurative osteomyelitis mainly characterized by recurrent local mandibular swelling and pain. Because of the unknown pathophysiological mechanism underlying DSOM, treatment can be challenging. Reported treatment options include long-term analgesic medication, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, corticosteroids, hyperbaric oxygen, and surgical treatment. However, these treatments cannot reliably lead to a long-lasting reduction of complaints. Recently, bisphosphonates has been reported effective in managing DSOM. We herein report a case of DSOM with a favorable response to a single infusion of zoledronate without prior treatment of other bisphosphonates. The patient was a 19-year-old woman who visited our hospital complaining of swelling and remarkable spontaneous pain in the right mandibular angle region. Under the diagnosis of osteomyelitis of the mandible, the clinical symptoms were improved by administering an antimicrobial agent and anti-inflammatory analgesic, but computed tomography (CT) showed exacerbation of bone resorption. A biopsy showed fibrosis between the bone tissue and trabeculae, a finding consistent with post-inflammatory changes. 99mTc scintigraphy showed an abnormal accumulation in the right mandibular ramus. Based on these results, she was diagnosed with DSOM. As a result of discussing with the physician in charge of internal medicine, it became the policy of the bisphosphonates and the intravenous administration of zoledronate 4 mg was enforced. Her bone sclerosis and bone resorption showed an improving trend on CT three months after the zoledronate administration, and there have been no symptoms or exacerbation of findings in three years since the administration.

Abstract In women, the female athlete triad, marked by low energy availability, functional hypothalamic amenorrhea and osteoporosis, is a recognized risk for stress fractures. Stress injuries also occur in men, but by contrast risks and mechanisms underlying them are less characterized. Here we propose that low energy availability puts men at risk for stress injuries as well. Male low energy availability model mice, established by limiting food intake, exhibited significantly reduced testicle weight, serum testosterone levels and bone mass. Such losses in bone mass were enhanced by exercise in food-restricted (FR) male mice. Histological analysis revealed that both bone-resorbing and -forming activities were significantly reduced in FR or FR plus exercise (FR+ex) mice, mimicking a state of low bone turnover. Significantly reduced bone mass in FR or FR+ex male mice was significantly rescued by treatment with 1,25(OH)2D3 (1.25) or ED71 (ED), both active vitamin D analogues, with significant restoration of osteoblastic activities. Serum levels of insulin-like growth factor I (IGF-I), which activates osteoblastic activities and is critical for bone remodeling, were significantly lower in FR versus control male mice, but restored by administration of either of vitamin D analogue. However, administration of recombinant IGF-I did not rescue reduced bone mass in FR male mice, and administration of either active vitamin D analogue could increase bone mass even in IGF-I conditional knockout FR male mice. Taken together, conditions comparable to the female athlete triad are also a risk for male stress injuries, and low energy availability is upstream of gonadal dysfunction and osteoporosis in males. Active vitamin D analogues could serve as therapeutic or preventive options for stress injuries in men.

Objective: We report a case where oral symptoms, initially suspected as adverse effects of chemoradiotherapy, evolved into systemic mucositis and dermatitis, leading to a toxic epidermal necrolysis (TEN) diagnosis. Case Report: An 80-year-old man presented for conservative treatment of tongue cancer. Based on his preference, superselective intra-arterial chemoradiotherapy was chosen instead of surgery. Thirty-six days after treatment began, the patient developed a fever of 38.4°C and worsening oral mucositis (grade 3 CTCAE Ver. 4.0). Subsequently, facial dermatitis appeared and was initially diagnosed as radiation dermatitis, leading to topical steroid therapy. However, skin symptoms with blisters and erosions spread across the body. Stevens-Johnson syndrome (SJS) and TEN were strongly suspected, and systemic corticosteroid therapy was initiated. A biopsy and clinical symptoms confirmed TEN. Corticosteroids were tapered and discontinued by day 62. The patient’s symptoms improved. Seventeen months later, multiple lung metastases were observed, and the patient died of primary disease. Results: Severe drug eruptions during chemoradiotherapy are difficult to diagnose because they must be differentiated from adverse events caused by the therapy itself. Conclusion: We should consider a possibility of SJS/TEN during chemoradio-therapy for head and neck cancer.

It is well known that the World Health Organization （WHO） Classification of Head and Neck Tumours is an essential tool and glossary for standardizing diagnostic practices worldwide. This report provides an overview of the revisions to the WHO Classification of Head and Neck Tumours （5th edition） regarding oral potentially malignant disorders and oral epithelial dysplasia related to superficial lesions among epithelial tumors in the oral cavity. In 2017, the fourth edition of the WHO Classification of Head and Neck Tumours described oral potentially malignant disorders for the first time. A major topic at that time was the integration of the concepts of previous precancerous conditions and precancerous lesions. In this revision, three disorders were deleted, one was incorporated into a familial cancer syndrome, and three new disorders were added: proliferative verrucous leukoplakia, oral lichenoid lesions, and oral graft-versus-host disease. Oral epithelial dysplasia is defined as a lesion with oral potentially malignant disorders and carries a risk of malignant transformation to squamous cell carcinoma. The grading of oral epithelial dysplasia has become a histopathological evaluation tool for potentially malignant disorders of the oral cavity. On the other hand, the revisions to oral epithelial dysplasia may be interpreted as contradictory. We outline the issues and the Oral Superficial Cancer Working Group’s thinking on oral epithelial dysplasia.

Objective: Post-extraction bleeding, which is difficult to stop, is rare. However, arterial hemorrhage may lead to a state in which hemostasis is difficult to obtain. We herein report a case in which arterial embolization effectively stopped hemorrhagic bleeding due to mandibular third molar extraction. Case Report: The patient was a 24-year-old man who suffered from abnormal bleeding during tooth no. 48 extraction. As hemostasis via compression with gauze would be difficult, the patient was referred to our department for emergency treatment to stop the bleeding. There was nothing special to note in terms of his vital signs at the time of his initial visit, with pulsatile bleeding from the extraction socket of the left mandible. A panoramic radiograph showed the root of tooth no. 48 was suitably separated. On the day of his visit, hemostasis was performed via compression using tie-over gauze. No significant bleeding was observed after the removal. However, the patient visited the emergency department with a complaint of re-bleeding, and arterial bleeding from the extraction socket was observed upon the release of compression with gauze. A traumatic pseudoaneurysm consistent with the site of tooth extraction was observed by a selective angiographic examination during hospitalization. Hemostatic treatment with transcatheter arterial embolization (TAE) was performed at the Department of Diagnostic Radiology. Results: Post-extraction bleeding is a recognized and frequently encountered complication in oral and maxillofacial surgery. Conclusion: The course was favorable following treatment on the seventh day after extraction, and the patient was discharged from the hospital in remission.

BACKGROUND: Desmoid-type fibromatosis is defined as an intermediate tumor that rarely occurs in the head and neck of children. There is no doubt as to the value of complete surgical excision for desmoid-type fibromatosis. However, in pediatric patients, surgeons may often be concerned about making a wide excision because of the potential for functional morbidity. Some studies have reported a lack of correlation between margin status and recurrence. Therefore, we discussed our findings with a focus on the state of surgical margins. CASE PRESENTATION: We report an unusual case of a 9-month-old Japanese girl who prior to presenting at our hospital underwent debulking surgery twice with chemotherapy for desmoid-type fibromatosis of the tongue at another hospital. We performed a partial glossectomy and simultaneous reconstruction with local flap and achieved microscopic complete resection. We also reviewed available literature of pediatric desmoid-type fibromatosis in the head and neck. CONCLUSIONS: We described successful treatment for the refractory case of pediatric desmoid-type fibromatosis. The review results showed that some microscopic incomplete resections of tumors in pediatric patients with desmoid-type fibromatosis tended to be acceptable with surgical treatment.

The objective of this study was to determine the appropriate timing of aprepitant administration in patients with oral cancer by comparing the antiemetic effect of aprepitant administered on the first day (first-day group) and third day (third-day group) of combination chemotherapy with docetaxel, nedaplatin (divided doses for 5 days), and 5-fluorouracil. 1. In both groups, very few cases of vomiting were observed. Therefore, we could not compare the incidence of vomiting. 2. The mean highest grade of nausea in the third-day group was significantly higher than that in the first-day group (2.33±0.71 vs 0.78±0.22, p=0.002; U-test). 3. In addition, the mean area under the curve of the chronological changes in the grade of nausea in the third-day group was significantly higher than that in the first-day group (13.44±9.58 vs 3.11±3.59, p=0.019; U-test). 4. The incidence of nausea of grade 2 or higher in the first-day group was significantly lower than that in the third-day group (11.1% [1/9] vs 88.9% [8/9], p<0.001; c 2 test). These results indicate that initiation of aprepitant administration on the first day of combination chemotherapy with docetaxel, nedaplatin, and 5-fluorouracil successfully prevented the development of nausea in patients with oral cancer.