Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Aging has been suggested to be associated with immune dysregulation. An understanding of alterations in the host immunity with advancing age is, therefore, important for designing immune therapy for elderly cancer patients. In this context, not much is known about age-associated alterations in the immune system in oral cancer. METHODS: To evaluate age-associated alterations in the immune system, which might affect anti-tumor immune responses in oral cancer, we performed a comparative analysis of the proportion of different immune cells, the proliferative capacity of T cell compartment, and the response against immune therapies targeting immune check point molecules between young and aged oral cancer-bearing mice. RESULTS: The proportion of immune regulatory cells, such as regulatory T cells and myeloid derived suppressor cells, was significantly increased in aged mice compared to that in young mice. Moreover, the expression of PD-1 and CTLA-4 on both CD4+ and CD8+ T cells was elevated in aged mice compared to that in young mice, and the proliferative abilities of CD4+ and CD8+ T cells derived from aged mice were significantly reduced following stimulation of T-cell receptors. Moreover, tumor growth was significantly enhanced in aged mice compared to that in young mice. However, immunotherapies targeting PD-1, CTLA-4, and PD-L1 resulted in faster tumor regression in aged mice than in young mice. CONCLUSIONS: Together, our results indicate that age-associated alterations in the immune system are directly associated with the impairment of anti-tumor immunity in aged mice bearing oral cancer, and might facilitate the progression of the tumor.

DOI： 10.1016/j.oraloncology.2019.104462

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The repurposing of existing FDA-approved non-cancer drugs is a potential source of new treatment options for cancer patients. An anti-inflammatory drug, 5-aminosalicylic acid (5-ASA), has been clinically used to treat inflammatory bowel disease. Hyperthermia (HT) is widely applicable addendum therapy with the existing cancer treatment modalities. Here, we addressed how 5-ASA combined with HT induces lethal effects in human oral squamous cell carcinoma (OSCC) HSC-3 cells. We found that 5-ASA/HT combination significantly inhibited the viability of HSC-3 cells, while cytotoxic effects in primary human dermal fibroblast cells were minor. Apoptotic endpoints were significantly increased by the 5-ASA/HT combined treatment, as evidenced by presence of Annexin V-FITC/PI positive cells, loss of MMP, Bcl-2/Bax ratio alteration, and increased Fas, cleaved Bid, and caspase expression. Interestingly, the enhancement of apoptosis was reversed in the presence of ON/ONOO- scavengers. These findings indicate that the combination treatment enhances apoptosis via ON/ONOO- mediated ER stress-Ca2+-mitochondria signaling and caspase-dependent apoptotic pathways. Our findings provide novel evidence that the combination of 5-ASA and HT is a promising approach for the enhancement of apoptosis; it may serve as an effective strategy for treating human OSCC.

DOI： 10.1016/j.canlet.2019.03.004

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OBJECTIVES: The immune status of the tumor microenvironment has a marked impact on clinical outcomes. Here we examined the immune environments of tumor-infiltrating leukocytes (TILes) in two murine models of squamous cell carcinoma and compared the effects of immunotherapeutic agents, including a TLR7 agonist and an immune checkpoint inhibitor, and a chemotherapeutic agent, gemcitabine, in these models. MATERIALS AND METHODS: TILes from NR-S1- and SCCVII-grafted mice were analyzed by flow cytometry. NR-S1-inoculated mice received resiquimod (a synthetic TLR7 agonist), an anti-PD-L1 antibody, or both, and tumor growth and TILs were examined. Gemcitabine was administered to deplete CD11b+ cells. RESULTS: More than 50% of TILes from NR-S1- and SCCVII-inoculated mice were CD11b+Gr-1+ cells. A major fraction of NR-S1 CD11b+ cells was Ly6GhighLy6Clow-negaF4/80- tumor-associated neutrophils (TANs) and the majority of SCCVII CD11b+ cells were Ly6GlowLy6C-F4/80+ tumor-associated macrophages. NR-S1 TANs did not express MHC class II and CD86, but did express reactive oxygen species and PD-L1. Resiquimod, alone and in combination with an anti-PD-L1 antibody, did not regress NR-S1 tumors, but the combination increased the CD8/regulatory T cell-ratio, and IFN-γ and PD-1 expression in CD8+ TILes. Pre-administration of low-dose gemcitabine prior to the combination treatment suppressed the progression of NR-S1 tumors. CONCLUSIONS: NR-S1 tumors with abundant recruitment of TANs were resistant to treatments with a TLR7 agonist, alone and in combination with PD-1 blockade, and required an additional gemcitabine treatment. The phenotype and status of tumor-infiltrating CD11b+ myeloid cells may influence the efficacy of immunotherapeutic agents.

DOI： 10.1016/j.oraloncology.2019.02.014

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Sulfasalazine (SSZ) is a well-known anti-inflammatory drug and also an inhibitor of the cystine-glutamate antiporter that is known to reduce intracellular glutathione (GSH) level and increase cellular oxidative stress, indicating its anti-tumor potential. However, the combination of SSZ with other physical modalities remains unexplored. Here, the effects of SSZ on cold atmospheric helium plasma (He-CAP), which produces approximately 24 x higher concentration of hydroxyl radicals (. OH) compared to X-irradiation (IR) in aqueous solution, and on IR-induced apoptosis in human leukemia Molt-4 cells were studied to elucidate the mechanism of apoptosis enhancement. Both the Annexin V-FITC/PI and DNA fragmentation assay revealed that pre-treatment of cells with SSZ significantly enhanced He-CAP and IR-induced apoptosis. Similar enhancement was observed during the loss of mitochondrial membrane potential, intracellular Ca2+ ions, and mitochondria- and endoplasmic reticulum-related proteins. The concentration of intracellular reactive oxygen species (ROS) was much higher in He-CAP treated cells than in X-irradiated cells. On the other hand, strong enhancement of Fas expression and caspase-8 and -3 activities were only observed in X-irradiated cells. It might be possible that the higher concentration of intracellular and extracellular ROS suppressed caspase activities and Fas expression in He-CAP-treated cells. Notably, pretreating the cells with an antioxidant N-acetyl-L-cysteine (NAC) dramatically decreased apoptosis in cells treated by He-CAP, but not by IR. These results suggest that IR-induced apoptosis is due to specific and effective ROS distribution since intracellular ROS formation is marginal and the high production of ROS inside and outside of cells plays unique roles in He-CAP induced apoptosis. We conclude that our data provides efficacy and mechanistic insights for SSZ, which might be helpful for establishing SSZ as a future sensitizer in He-CAP or IR therapy for cancer.

DOI： 10.1016/j.freeradbiomed.2018.10.434

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BACKGROUND/AIMS: The migration of mesenchymal cells is a fundamental cellular process that has been implicated in many pathophysiological conditions and is induced by chemoattractants such as platelet-derived growth factors (PDGFs). However, the regulatory mechanisms shaping this migration remain to be elucidated. METHODS: Here, we prepared mouse skin fibroblasts inactivated for different PDGF receptor genes and systematically measured their chemotactic responses within a gradient of different chemoattractants. RESULTS: We found that PDGFRαβ and PDGFRββ dimers were strong inducers of random and directionally-persistent migration, respectively, that was sustained for up to 24 h. MAPK and PI3K were necessary to mediate random and directional migration, respectively. Directional migration was accompanied by abundant ventral stress fiber formation and consistent cell shape with less frequent formation of branch-like processes. CONCLUSION: This is the first systematic study that characterized the chemotaxis mediated by three-different types of PDGFR dimers in mesenchymal cell migration. Our data demonstrate that PDGFR dimer formation is the critical step to determine the specific mode of fibroblast chemotaxis, while the accompanying cytoskeletal remodeling might contribute to migration persistence.

DOI： 10.1159/000495594

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Cold atmospheric plasmas (CAPs) have been proposed as a novel therapeutic method for its anti-cancer potential. However, its biological effects in combination with other physical modalities remain elusive. Therefore, this study examined the effects of cold atmospheric helium plasma (He-CAP) in combination with hyperthermia (HT) 42 °C or radiation 5 Gy. Synergistic enhancement in the cell death with HT and an additive enhancement with radiation were observed following He-CAP treatment. The synergistic effects were accompanied by increased intracellular reactive oxygen species (ROS) production. Hydrogen peroxide (H2O2) and superoxide (O2•-) generation was increased immediately after He-CAP treatment, but fails to initiate cell death process. Interestingly, at late hour's He-CAP-induced O2•- generation subsides, however the combined treatment showed sustained increased intracellular O2•- level, and enhanced cell death than either treatment alone. He-CAP caused marked induction of ROS in the aqueous medium, but He-CAP-induced ROS seems insufficient or not completely incorporated intra-cellularly to activate cell death machinery. The observed synergistic effects were due to the HT effects on membrane fluidity which facilitate the incorporation of He-CAP-induced ROS into the cells, thus results in the enhanced cancer cell death following combined treatment. These findings would be helpful when establishing a therapeutic strategy for CAP in combination with HT or radiation.

DOI： 10.1038/s41598-017-11877-8

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Cancer is often associated with dysregulation of both the humoral and cellular immune response, which in some instances is believed to result from changes in immune cell populations. For example, immunosuppressive CD11b(+)Gr-1(+) myeloid-derived suppressor cells have been shown to proliferate in the tumor microenvironment and surrounding tissues, highlighting the relationship between tumor growth and impairment of the immune response. However, the role of myeloid-derived suppressor cells in cancer progression has not been fully characterized because these cells are heterogeneous with properties influenced by the type and location of the tumor. Here, we show that CD11b(+)Gr-1(+) cells are elevated in the peripheral blood, spleen, and tumor of mice with oral squamous cell carcinoma. The phenotype and function of these cells varied depending on the tissue of origin. In particular, CD11b(+)Gr-1(+) cells in tumors expressed PD-L1 more abundantly than those in other tissues. Accordingly, CD11b(+)Gr-1(+) cells from tumors, but not from the spleen, suppressed T cell proliferation in vitro. The results suggest that tumor-derived or immune factors result in the accumulation of phenotypically and functionally diverse populations of CD11b(+)Gr-1(+) cells in mice with oral squamous cell carcinoma. The data also indicate that PD-L1 expression in CD11b(+)Gr-1(+) cells contributes to immune suppression, implying that targeting both myeloid-derived suppressor cells and PD-L1 would be an effective immunotherapeutic strategy against oral cancer.

DOI： 10.1016/j.oraloncology.2016.05.012

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：OMICS Publishing Group  

DOI： 10.4172/1948-5956.1000328

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVES: Gemcitabine (GEM) is a pyrimidine nucleoside analogue that is a new chemotherapeutic agent used for treating various cancers. Because accumulating evidence indicates that GEM may activate host immune responses, its potential as an immune modulator in cancer chemotherapy has generated considerable interest. MATERIALS AND METHODS: In the present study, we investigated the antitumor effects of GEM using a mouse oral cancer model using immunological analyses. We examined apoptotic cell death of tumor cells with GEM treatment both in vitro and in vivo. We also investigated whether in vivo administration of GEM affected the distributions of immune cells, tumor-cell surface expression levels of immune accessory molecules and T cell immune responses in tumor-bearing mice. RESULTS: GEM induced significant oral cancer-cell apoptosis in vitro, and in vivo GEM administration markedly attenuated established mouse tumor growth. In vivo GEM administration decreased the numbers of both myeloid-derived suppressor cells (MDSCs) and B cells in tumor-bearing mice and enhanced dendritic cell maturation. Moreover, GEM treatment upregulated tumor-cell surface expressions of several immune accessory molecules and adhesion molecules, including CD80, CD86, CD40, ICAM-1, VCAM-1, and P-selectin. Remarkably, these tumor cells augmented tumor specific T-cell responses. CONCLUSION: These results suggest that GEM can induce host antitumor immune responses, which would facilitate antitumor effects in the treatment of oral cancer.

DOI： 10.1016/j.oraloncology.2014.01.013

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BACKGROUND: Cancer may be derived from cancer stem-like cells (CSCs), which are tumor-initiating cells that have properties similar to those of stem cells. Identification and isolation of CSCs needs to be improved further. MATERIALS AND METHODS: CSCs markers were examined in human oral cancer cell lines by flow cytometry. The stem cell properties of subpopulations expressing different markers were assessed further by in vitro sphere formation assays, expression of stemness genes, drug resistance assays, and the ability to form tumors in nude mice. RESULTS: We demonstrated that CSCs could be isolated by the cell surface markers CD44 and stage-specific embryonic antigen-4 (SSEA-4). CD44+SSEA-4+ cells exhibited cancer stem-like properties, including extensive self-renewal into the bulk of cancer cells. In vivo xenograft experiments indicated that CD44+SSEA-4+ cells exhibit the highest tumorigenic capacity compared with the remaining subpopulations and parental cells. Double-positive cells for CD44 and SSEA-4 exhibited preferential expression of some stemness genes and were more resistant to the anticancer drugs, cisplatin and 5-fluorouracil (5-FU). In addition, cells expressing CD44 and SSEA-4 were detected in all tumor specimens analyzed, while coexpression of CD44 and SSEA-4 was not detectable in normal oral mucosa. CONCLUSION: Our findings suggest that CD44+SSEA-4+ cells exhibit the characteristics of CSCs in oral squamous cell carcinoma and provide a target for the development of more effective therapies.

DOI： 10.1016/j.oraloncology.2013.04.012

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Increasing evidence has revealed the incidence of cancer augments with aging, which could be attributed to a multitude of age-associated changes including the dysregulation of the immune system. Although many reports demonstrate the efficacy of cancer immunotherapies in numerous preclinical studies, most experiments have been performed in young animals. Studies from our group and others show that cancer immunotherapy could be ineffective in old mice, even though the same therapeutic treatment works efficiently in young mice. Given that cancer occurs mostly in the elderly, we should take age-associated immune dysregulation into consideration to achieve the effectiveness of immunotherapeutic interventions in the old. Understanding both age-related and tumor-related immune alterations might be equally important in improving the effectiveness of immunotherapy. This article reviews a number of age-associated immune alterations with specific attention given to the impact on antitumor responses, and also discusses possible strategies for optimization of immunotherapeutic interventions in the elderly.

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Because most patients with cancer are aged and because immunological functions are altered during aging, it is important to account for aging-associated immunological alterations in the design of new cancer immunotherapies. We thus compared immune populations in young and aged mice and found that B7-DC(+) (PD-L2/CD273) B cells, a minor population in young mice, were significantly increased in aged mice. Induction of both Th1 and Th17 cells was significantly augmented by B7-DC(+) B cells from aged mice, and this effect was blocked with anti-B7-DC antibodies in vitro and in vivo. Moreover, retardation of tumor growth in aged mice was largely B7-DC dependent. Tumor growth in young mice was significantly inhibited by immunization with B7-DC(+) B cells from aged mice owing to increased induction of tumor antigen-specific cytotoxic T lymphocytes. These data indicate that B7-DC(+) B cells could play an important role in aging-associated cancer immunopathology as well as in other aging-associated diseases and further suggest that B7-DC(+) B cells have potential for future cancer immunotherapy.

DOI： 10.1111/j.1474-9726.2011.00764.x

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Both innate and adaptive immune systems are considered important for cancer prevention, immunosurveillance, and control of cancer progression. It is known that, although both systems initially eliminate emerging tumor cells efficiently, tumors eventually escape immune attack by a variety of mechanisms, including differentiation and recruitment of immunosuppressive CD11b(+)Gr-1(+) myeloid suppressor cells into the tumor microenvironment. However, we show that CD11b(+)Gr-1(+) cells found in ascites of epithelial ovarian cancer-bearing mice at advanced stages of disease are immunostimulatory rather than being immunosuppressive. These cells consist of a homogenous population of cells that morphologically resemble neutrophils. Moreover, like dendritic cells, immunostimulatory CD11b(+)Gr-1(+) cells can strongly cross-prime, augmenting the proliferation of functional CTLs via signaling through the expression of costimulatory molecule CD80. Adoptive transfer of these immunostimulatory CD11b(+)Gr-1(+) cells from ascites of ovarian cancer-bearing mice results in the significant regression of s.c. tumors even without being pulsed with exogenous tumor Ag prior to adoptive transfer. We now show for the first time that adaptive immune responses against cancer can be augmented by these cancer-induced granulocyte-like immunostimulatory myeloid (CD11b(+)Gr-1(+)) cells, thereby mediating highly effective antitumor immunity in an adoptive transfer model of immunity.

DOI： 10.4049/jimmunol.0903519

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The caliber and magnitude of T cell responses are regulated by costimulatory molecules following the engagement of TCRs and MHC molecules. B7-DC has the highest homology with B7-H1 in the B7 family, and both of them bind an immunoregulatory molecule, programmed death 1. Previous studies have demonstrated that B7-DC stimulates T cell proliferation and CTL generation, which sharply contrasts the inhibitory role of B7-H1. Th2 cytokines prompt B7-DC expression, which in turn enhances Th1 responses. In this study, we used an intestinal nematode, Nippostrongylus brasiliensis, to induce strong Th2 responses and to evaluate B7-DC function under Th2-polarizing conditions in vivo. By either blocking B7-DC expression during N. brasiliensis infection or by examining N. brasiliensis-infected B7-DC knockout mice, we observed enhanced eosinophilia, the overproduction of serum IgE, and increased Th2 cytokine production along with decreased Th1 cytokine production (particularly IFN-gamma production), indicating that B7-DC inhibits Th2 responses. Our results further demonstrate that the inhibition of Th2 responses by B7-DC occurs independently of programmed death 1 but conceivably acts through an as yet unknown alternative receptor that enhances Th1 responses. Although the deficiency of B7-DC expression that enhanced the production of IL-13 paradoxically resulted in better protection against N. brasiliensis infection, our results show that B7-DC plays an important role in bolstering a robust Th1 response that is required for effective antiviral and anticancer immunity, even under a strong Th2-polarizing environment induced by N. brasiliensis infection.

DOI： 10.4049/jimmunol.0804051

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Sendai virus vector is emerging as a promising vector for gene therapy, and angiopoietin-1 (Ang-1) has been reported to improve the blood flow recovery in the ischemic limb or heart. In this study, we constructed a human Ang-1-expressing Sendai viral vector (SeVhAng-1) and injected it into the ischemic limb of rats. We found that SeVhAng-1 improved the blood flow recovery and increased the capillary density of the ischemic limb, compared with the controls. We also found that SeVhAng-1 increased p-Akt during the early period of limb ischemia, and decreased apoptosis in ischemic limb. It suggests that SeVhAng-1 may serve as a potential therapeutic tool in ischemic limb disease.

DOI： 10.1007/s10456-009-9144-6

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The purpose of this clinical trial was to assess the toxicity and efficacy of docetaxel plus nedaplatin induction chemotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). Twenty-one patients were enrolled in this phase I/II clinical study. The toxicities, response rates, and the maximum tolerated dose of nedaplatin that could be safely given preoperatively were assessed. Patients received escalating doses of nedaplatin (60, 70, 80, 90 mg/m2) combined with a fixed dose of docetaxel (60 mg/m2) on day one. Dose-limiting toxicity (DLT), grade 4 leukopenia lasting for two days or more, was seen in one patient at dose level 3; no other DLT was observed at any dose level. The overall response rate was 66.7%. The response rate was 100% at nedaplatin dose level 4, while that at dose level 1 was low (33.3%). Given these results, the recommended dose of nedaplatin in this regimen combined with fixed dose docetaxel (60 mg/m2) was determined to be 90 mg/m2. Docetaxel 60 mg/m2 plus nedaplatin 90 mg/m2 induction chemotherapy can be recommended for patients with locally advanced oral squamous cell carcinoma. Based on these results, an early phase II clinical study using this dose level was conducted; docetaxel plus nedaplatin induction chemotherapy appears to be a useful regimen for the treatment of OSCC. A late phase II clinical study is warranted.

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Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.1038/sj.gt.3303056

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Other Link： http://www.nature.com/articles/3303056

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CD154 (CD40-ligand) is a critical transmembrane molecule with potent immune-stimulatory properties that is used in clinical applications of gene therapy for leukemia and lymphoma. However, CD154 is cleaved into a soluble form, and high levels of sCD154 contribute to systemic inflammatory and cardiovascular diseases, suggesting a deleterious side effect of CD154 gene therapy. In this study, we engineered noncleavable mutants of human CD154 with point mutations to develop a potentially less toxic molecule in vivo. In contrast to wild-type CD154 (CD154-WT) subsequently released as sCD154, both mutants CD154-M3 and CD154-M4 were resistant to cleavage in tumor cells. Also, CD40-expressing leukemia B cells transfected with CD154-M3 mutant were highly effective stimulators in a mixed lymphocyte-leukemia reaction, indicating that CD154-M3 mutant did not lose biologic activity. In mice transplanted with tumors expressing CD154-WT, we found increased plasma levels of human sCD154 followed by various systemic inflammatory reactions such as glomerulonephritis and an increased number of infiltrating mononuclear cells in the liver. However, CD154-M3 mutant did not induce any systemic inflammatory effects in vivo. As such, the noncleavable mutant of CD154 is fully capable of inducing the immune response with less toxic properties and is a useful tool for CD154 immune gene therapy.

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The CD40-ligand (CD40L) is a key molecule for the activation of dendritic cells (DCs), followed by the induction of DC maturation and cytokine production. Here we found that DC infected with adenovirus vector encoding human CD40L (CD40L-DC) displayed significantly higher levels of immune accessory molecules and IL-12 production than did uninfected cells, and that CD40L-DC produced much higher levels of IFN-gamma. To investigate whether CD40L-DC-derived these soluble factors could stimulate NK cells without physical cell-to-cell contact, we cocultured NK cells with CD40L-DC in transwell culture plates. NK cells showed up-regulated cytotoxic activity toward various squamous oral cell carcinoma (OSC-70, HSC-2, HSC-3), and we determined that both IL-12 and IFN-gamma contributed to the CD40L-DC-mediated NK cell activation. NK cells stimulated with CD40L-DC resulted in the induction of the cell surface expression of TRAIL, the production of IFN-gamma and intracellular accumulation of granzyme B. The cytotoxic activity of NK cells stimulated with CD40L-DC could be mostly inhibited by neutralizing antibody for TRAIL and completely abrogated by the combination of antibody and exocytosis inhibitor, indicating that this was mainly mediated by a TRAIL-TRAIL-receptor interaction and granule exocytosis. Moreover, CD40L-DC-activated NK cells could induce up-regulation of a death-receptor TRAIL-R2 (DR5) and down-regulation of a decoy receptor TRAIL-R3 (DcR1) on carcinoma cells. Overall, these results have revealed that CD40L-DC could activate an innate immune reaction by stimulating NK cells followed by carcinoma cells, supporting that administration of CD40L-DC may have potential as an anticancer therapy.

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PURPOSE: A major problem when using the adenoviral vectors for gene therapy applications is thought to be related to low transduction efficiency in cancer cells or to side effects in normal cells. There is an urgent requirement to improve the specificity of gene delivery in the context of cancer gene therapy. EXPERIMENTAL DESIGN: We constructed a genetically modified adenovirus incorporating an IgG Fc-binding motif from the Staphylococcus protein A, Z33, within the HI loop (Adv-FZ33). A remarkable degree of targeted gene delivery to gastric cancer cells was obtained with Adv-FZ33 with the fully human anti-carcinoembryonic antigen (CEA) monoclonal antibody, C2-45. RESULTS: In vitro LacZ or EGFP gene expression after Adv-FZ33 infection via C2-45 was 20 times higher than control monoclonal antibody in MKN-45 at 1,000 viral particles/cell. We generated Ax3CAUP-FZ33 (UP-FZ33), which is an Adv-FZ33 derivative vector expressing a therapeutic gene (i.e., Escherichia coli uracil phosphoribosyltransferase), which converts 5-fluorouracil (5-FU) directly to 5-fluoro-UMP. UP-FZ33 with C2-45 enhanced the cytotoxicity of 5-FU by 10.5-fold in terms of IC(50) against MKN-45 compared with control IgG4. In a nude mouse peritoneal dissemination model, tumor growth in mice treated with UP-FZ33/C2-45/5-FU was significantly suppressed, and tumor volumes were less than one-fourth of those of the control IgG4 group (P < 0.05). The median survival time of the UP-FZ33/C2-45/5-FU group was significantly longer than those treated with PBS or 5-FU only (P < 0.01). CONCLUSIONS: These data suggest that CEA-targeted FZ33 mutant adenovirus-mediated gene delivery offers a strong and selective therapeutic modality against CEA-producing cancers.

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BACKGROUND: Apoptosis is an important cause of early graft loss after heart transplantation. Bcl-xL was reported to protect the heart against normothermic ischemia and reperfusion injury. In this study, we determined whether overexpression of Bcl-xL could inhibit tissue injury resulting from prolonged cold preservation followed by warm reperfusion of heart transplants. METHODS AND RESULTS: Lewis rat hearts were transduced with an adenovirus vector harboring Bcl-xL cDNA (AxCAhBclxL) 4 days before collection of tissue. After preservation in University of Wisconsin solution at 4 degrees C for 24 hours, the heart was either perfused with a Langendorff device ex vivo or used for heterotopic heart transplantation in vivo. Bcl-xL gene transfer significantly reduced the infarct size (23.0+/-2.6% versus 47.7+/-7.0% in saline control and 48.6+/-6.1% in vector control, P<0.01) after 2-hour reperfusion at 37 degrees C with the Langendorff device and significantly decreased creatine kinase release (0.82+/-0.27 IU, versus 1.57+/-0.33 and 1.50+/-0.37 IU in saline and vector controls, respectively; P<0.05). In heart transplantation, overexpression of Bcl-xL inhibited Bax translocation from the cytosol to the mitochondria, resulting in decreased cytochrome c release from the mitochondria; it also significantly decreased cardiac cell apoptosis and improved graft survival rate after long cold preservation, followed by warm reperfusion. CONCLUSIONS: Bcl-xL gene transfer inhibited the translocation of Bax and prolonged the cold preservation time of cardiac transplants. This may be a potential therapeutic method in clinical practice.

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Background/Objectives: Cancer organoids have emerged as a valuable tool of three-dimensional (3D) cell cultures to investigate tumor heterogeneity and predict tumor behavior and treatment response. We developed a 3D organotypic culture model of oral squamous cell carcinoma (OSCC) to recapitulate the tumor–stromal interface by co-culturing four cell types, including patient-derived cancer-associated fibroblasts (PD-CAFs). Methods: A stainless-steel ring was used twice to create the horizontal positioning of the cancer stroma (adjoining normal oral mucosa connective tissue) and the OSCC layer (surrounding normal oral mucosa epithelial layer). Combined with a structured bi-layered model of the epithelial component and the underlying stroma, this protocol enabled us to construct four distinct portions mimicking the oral cancer tissue arising in the oral mucosa. Results: In this model, α-smooth muscle actin-positive PD-CAFs were localized in close proximity to the OSCC layer, suggesting a crosstalk between them. Furthermore, a linear laminin-γ2 expression was lacking at the interface between the OSCC layer and the underlying stromal layer, indicating the loss of the basement membrane-like structure. Conclusions: Since the specific 3D architecture and polarity mimicking oral cancer in vivo provides a more accurate milieu of the tumor microenvironment (TME), it could be crucial in elucidating oral cancer TME.

DOI： 10.3390/biomedicines12102373

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OBJECTIVE: To analyze the clinical characteristics of patients with oral squamous cell carcinoma aged ≥80 years, focusing on surgical treatments. STUDY DESIGN: We reviewed patients with oral squamous cell carcinoma aged ≥80 years who underwent surgery between 2005 and 2018. Basic information, comorbidities, multiple primary cancers, initial treatment, complications, and outcomes were evaluated. RESULTS: Of 197 patients aged ≥80 years, 119 patients underwent surgery (50 males, 69 females; mean age: 83.5 years). The gingiva was the most common primary tumor site (63 patients, 52.9 %). The stage classification was stage I in 35 patients (29.4 %), stage II in 44 (37 %), stage III in 16 (13.4 %), stage IVA in 22 (18.5 %), and stage IVB in 2 (1.7 %). Comorbidities were identified in 112 patients (94.1 %). Surgery was the initial treatment in 111 patients (93.3 %). Eight (6.7 %) patients received postoperative adjuvant chemotherapy/radiotherapy; 20 patients (16.8 %) underwent free tissue transplantation. Perioperative complications were observed in 36 patients (30.3 %). The cumulative 5-year and 10-year overall survival rates were 82 % and 68.3 %, respectively; the disease-specific survival rates were 90 %. CONCLUSION: Good treatment outcomes were obtained with radical surgery. Surgery should be the first choice if quality of life is assured and there are no issues with surgical tolerance, regardless of age.

DOI： 10.1016/j.suronc.2024.102146

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PURPOSE: Oral mucositis is a severe adverse event in patients undergoing chemotherapy and radiotherapy that may lead to the termination of cancer treatment. This study aimed to elucidate the relationship between salivary inflammatory mediators and oral mucositis in patients undergoing chemotherapy. METHODS: This prospective cohort study included 167 patients who underwent chemotherapy at our institution between June 2020 and November 2023. We evaluated the association between chemotherapy-induced oral mucositis and salivary inflammatory mediators using multiple comparison tests and logistic regression analyses. RESULTS: Of the 167 patients, 67 (40.1%) had oral mucositis. Dunn's multiple comparison test revealed that interleukin-6 was significantly higher in oral mucositis of grades 2 and ≥ 3 (P < 0.01) and tumor necrosis factor (TNF)-α was significantly higher in oral mucositis of grades 3-4 (P < 0.01). Logistic regression analysis showed that the risk of oral mucositis was significantly higher for tumor necrosis factor (TNF)-α > 4.4 pg/mL than for TNF-α ≤ 4.4 pg/mL (adjusted odds ratio, 2.4; 95% confidence interval, 1.1-5.3; P = 0.03). CONCLUSION: Saliva is useful in evaluating inflammation in patients with chemotherapy-induced oral mucositis. Furthermore, TNF-α may be a predictive marker for the severity of oral mucositis in patients undergoing chemotherapy.

DOI： 10.1007/s00520-024-08836-1

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Authorship：Last author,　Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

The fatty acid receptor CD36 is expressed on various malignant cells and is suggested to contribute to tumor progression. CD36 is also expressed by several immune cells and involved in immune responses and may be a potential target in cancer immunotherapy. In this study, we investigated whether the selective inhibition of CD36 can inhibit tumor progression and facilitate an antitumor immune response in oral squamous carcinoma cells (OSCCs). We assessed the effects of sulfosuccinimidyl oleate sodium (SSO), a CD36 inhibitor, on the proliferation apoptosis and alteration in tumor cell surface expression levels of immune accessory molecules in vitro. We also assessed whether SSO-treated OSCCs could promote a T cell response via a Mixed Lymphocyte Reaction (MLR) assay. We also investigated the direct antitumor effects and immunomodulatory effects of SSO using a mouse oral cancer OSCC model. SSO treatment significantly inhibited OSCC proliferation, increased apoptotic cell death, and upregulated the cell surface expression of several immune accessory molecules, including CD83, MHC-Class II, and PD-L1. SSO-treated OSCCs augmented T cell proliferation following MLR. In vivo SSO administration significantly attenuated mouse tumor growth with an increased proportion of immune cells, including CD4+ T, CD8+ T, and dendritic cells; it also decreased the proportion of immune suppressive cells, such as myeloid-derived suppressor and regulatory T cells. These results suggest that the selective inhibition of CD36 can induce direct and indirect antitumor effects by facilitating host antitumor immune responses in OSCCs.

DOI： 10.3390/ijms25179438

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

DOI： 10.7759/cureus.67882

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Language：English  

DOI： 10.1007/s11626-024-00968-2

PubMed

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

Given that the original tumor microenvironment of oral cancer cannot be reproduced, predicting the therapeutic effects of irradiation using monolayer cultures and animal models of ectopic tumors is challenging. Unique properties of carbon-ion irradiation (CIR) characterized by the Bragg peak exert therapeutic effects on tumors and prevent adverse events in surrounding normal tissues. However, the underlying mechanism remains unclear. The biological effects of CIR were evaluated on three-dimensional (3D) in vitro models of normal oral mucosa (NOMM) and oral cancer (OCM3 and OCM4) consisting of HSC-3 and HSC-4 cells. A single 10- or 20-Gy dose of CIR was delivered to NOMM, OCM3, and OCM4 models. Histopathological and histomorphometric analyses and labeling indices for Ki-67, γH2AX, and TUNEL were examined after CIR. The concentrations of high mobility group box 1 (HMGB1) were measured. NOMM exhibited epithelial thinning after CIR, which could be caused by the decreased presence of Ki-67-labeled basal cells. The relative proportion of the thickness of cancer cells to the underlying stroma in cancer models decreased after CIR. This finding appeared to be supported by changes in the three labeling indices, indicating CIR-induced cancer cell death, mostly via apoptosis. Furthermore, the three indices and the HMGB1 release levels significantly differed among the OCM4 that received different doses and with different incubation times after CIR while those of the OCM3 models did not, suggesting more radiosensitivity in the OCM4. The three 3D in vitro models can be a feasible and novel tool to elucidate radiation biology.

DOI： 10.1007/s11626-024-00958-4

PubMed

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Authorship：Last author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Verruca vulgaris (VV), widely known as warts, is a common benign skin lesion, which is caused by human papilloma virus. In some cases, VV can be developed within the oral cavity. Surgical excision is considered as the most preferred treatment modality for both cutaneous and oral VV which could be challenge to deal with. CASE REPORT: Herein, a short-term case of a 64-year-old male patient with a large oral VV, involving the lower and upper lips, and commissure was reported. The patient underwent a wide surgical excision, resulting in a significant lip defect. The modified Estlander flap technique was applied to treat the defect and restore lip function. At one year post operation, no signs of recurrence were recorded, and the Estlander flap technique displayed satisfactory outcomes. CONCLUSIONS: Surgical management of oral VV involving lips may leaves large defect, which requires consideration in defect reconstruction. This case report shows that reconstruction of the defect with a modified estlander flap resulted in a good outcome, with satisfactory functionality for the patient. Key words:Estlander flap, verruca vulgaris, surgical excision.

DOI： 10.4317/jced.61814

PubMed

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

Aim

To prevent oral mucositis, it is important to understand its associated risk factors, such as highly cytotoxic chemotherapeutic agents, sex, and low body weight. However, to the best of our knowledge, no study has investigated the association between chemotherapy‐induced myelosuppression and oral mucositis in Japan. In this study, we examined the relationship between chemotherapy‐induced leukopenia and the severity of oral mucositis.

Methods

We conducted a retrospective cohort study of patients who received oral care interventions during cancer chemotherapy. Hematological values were obtained at the initiation of chemotherapy and on the proximal day of changes in the grade (Gr) of oral mucositis. The Gr of oral mucositis was assessed by dentists and dental hygienists using the Common Terminology Criteria for Adverse Events (version 5.0).

Results

The data of 79 patients were analyzed during the study period. The incidence of oral mucositis was 7/79 (8.9%). The incidences of grades 1–4 were 4/79 (5.1%), 2/79 (2.5%), 0/79 (0%), and 1/79 (1.3%), respectively. Notably, the incidence of oral mucositis was significantly higher in patients with lower white blood cell and neutrophil counts (p &lt; 0.01). Logistic regression analysis further revealed that patients with Gr 2 or higher leukopenia had a significantly higher risk of developing Grade 2 or higher oral mucositis (adjusted odds ratio: 5.2; 95% confidence interval: 1.60–17.0; p = 0.0062).

Conclusion

Cancer chemotherapy induced‐oral mucositis may be at great risk in patients with Gr 2 or higher leukopenia.

DOI： 10.1002/osi2.1263

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Authorship：Last author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumours, warranting novel treatments. Here, we examined the therapeutic efficacy of inhibiting p21 activated kinase 4 (PAK4) in OSCC and determined its immunomodulatory effect by focusing on the enhancement of anti-tumour effects. We examined PAK4 expression in OSCC cells and human clinical samples and analysed the proliferation and apoptosis of OSCC cells following PAK4 inhibition in vitro. We also investigated the effects of in vivo administration of a PAK4 inhibitor on immune cell distribution and T-cell immune responses in OSCC tumour-bearing mice. PAK4 was detected in all OSCC cells and OSCC tissue samples. PAK4 inhibitor reduced the proliferation of OSCC cells and induced apoptosis. PAK4 inhibitor significantly attenuated tumour growth in mouse and was associated with increased proportions of IFN-γ-producing CD8+ T-cells. Furthermore, PAK4 inhibitor increased the number of dendritic cells (DCs) and up-regulated the surface expression of various lymphocyte co-stimulatory molecules, including MHC-class I molecules, CD80, CD83, CD86, and CD40. These DCs augmented CD8+ T-cell activation upon co-culture. Our results suggest that PAK4 inhibition in OSCC can have direct anti-tumour and immunomodulatory effects, which might benefit the treatment of this malignancy.

DOI： 10.1038/s41598-024-64126-0

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)  

Objectives: In this study, we investigated the antitumor immunomodulatory effects of rapamycin in oral cancer. Study Design: We examined the proliferation, apoptosis, and migration of cancer cells and investigated the cell surface expression levels of immune accessory molecules and T cell immune responses in vitro. We investigated the effect of in vivo administration of rapamycin on immune cell distribution and T cell immune responses in oral tumor-bearing mice. Results: Rapamycin treatment significantly inhibited OSCC cell proliferation and migration, increased apoptotic cell death, and upregulated cell surface expression of several immune accessory and adhesion molecules, including CD40, CD83, PD-L1, PD-L2, MHC class I, P-selectin, and VCAM-1. These cancer cells augmented T cell proliferation. In vivo rapamycin administration significantly attenuated mouse tumor growth with an increased proportion of immune cells, including CD4+ T cells, CD8+ T cells, and dendritic cells (DCs); decreased the proportion of immune suppressive cells, such as myeloid-derived suppressor cells and regulatory T cells; enhanced DC maturation and upregulated the surface expression of CD40, CD86, and ICAM-1. Conclusions: Our results suggest that the therapeutic effect of mTOR inhibition in oral cancer can cause direct antitumor and immunomodulatory effects.

DOI： 10.3390/biomedicines12051078

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：John Wiley & Sons Australia, Ltd  

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Language：English  

KEY CLINICAL MESSAGE: Nivolumab has been clinically successful in prolonging the overall survival of patients with recurrent and metastatic head and neck cancer, complete remission is rare. Synergistic combinations of immunotherapy and conventional cancer treatments, such as radiotherapy or chemotherapy, are likely to be the most viable strategies for improving patient responses. ABSTRACT: Immune checkpoint inhibitors have revolutionized recurrent, metastatic oral cancer treatment; however complete remission in advanced stages is unusual. We present a case of complete remission of advanced oral squamous cell carcinoma for >4 years in a 64-year-old Japanese woman, that responded poorly to chemoradiotherapy but well to subsequent nivolumab treatment.

DOI： 10.1002/ccr3.8219

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

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

DOI： 10.1016/j.ajoms.2023.11.007

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Language：English  

Herein, we report two cases of patients diagnosed with nivolumab-refractory distant metastatic squamous cell carcinoma of the tongue who were successfully treated with a combination of paclitaxel and cetuximab. Case 1 had controllable local recurrence and distant metastasis. Case 2 had controllable distant metastatic disease. Thus, demonstrating that some nivolumab-refractory patients with recurrent or distant metastatic oral squamous cell carcinoma may benefit from subsequent salvage chemotherapy.

DOI： 10.7759/cureus.49198

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Language：Japanese   Publisher：(公社)日本顎顔面インプラント学会  

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Language：Japanese   Publisher：(公社)日本顎顔面インプラント学会  

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

We previously reported that the cell and colony motion of oral keratinocytes are correlated with proliferative capacity, and speculated that this may be a specific index for monitoring cell quality. However, how cell motility and proliferation are regulated by signaling pathways remains unelucidated. Here, we found that the regulation of cell motility and proliferative capacity of oral keratinocytes can be attributed to the epidermal growth factor/epidermal growth factor receptor (EGF/EGFR) axis. The EGFR downstream cascade involving the Src/PI3K/Akt/mTOR signaling pathway showed a major effect on cell motility and proliferative capacity in oral keratinocytes. Furthermore, both EGFR and Src attenuated E-cadherin expression. Taken together, these findings provide a potential basis for future quality control of cells for therapeutic use.

DOI： 10.1002/2211-5463.13653

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Publishing type：Research paper (scientific journal)   Publisher：Wiley  

Abstract

In cancer treatment, perioperative oral functional management is used as a part of supportive care. Its main objectives are as follows: (1) preventing and reducing adverse events, (2) maintaining or improving nutritional status, (3) improving cancer treatment outcomes, (4) maintaining or improving quality of life, (5) providing high quality medical care through comprehensive oral care, (6) controlling odontogenic foci of infection, and (7) maintaining or improving oral function. A literature search was conducted using the electronic databases of Medical Journal and PubMed. Electronic database searches were performed using various combinations of the following key words: cancer, surgery, treatment, chemotherapy, radiotherapy and dental disease, oral care, oral management, dental intervention, oral health, dental care, and dental management. The selection of literature for inclusion in the review was restricted to dental management of patients receiving cancer treatment. In the course of the literature review, hand searches were also added as needed. The guideline was developed by summarizing the results of the review. Based on a review of the literature on the management of dental foci of infection in the oral functional management of patients undergoing cancer treatment, a guideline was developed by summarizing the results of the review. This report is a secondary publication of our previous review report “J. Stomatol. Soc. 70(4): 279–289. Dec 2021.”

DOI： 10.1002/osi2.1209

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

ObjectivesManaging perioperative anxiety improves postoperative recovery significantly by reducing postoperative pain. However, little is known about association between preoperative anxiety and postoperative pain in oral surgical procedures. In the present study, we examined the effect between preoperative anxiety and postoperative pain in mandibular third molar extraction and the anxiolytic effect of Yokukansan (YKS) during the perioperative period. Materials and methodsWe conducted a prospective cohort study from September 2021 to May 2022. For patients with a complaint of insomnia on the day before surgery, 2.5 g per package of YKS was administered before sleep on the day before surgery. Twelve patients were administered YKS, and 23 patients were not (non-YKS). ResultsPerioperative anxiety was assessed by the Hospital Anxiety and Depression Scale (HADS) and amylase in saliva, and perioperative pain was assessed by the Numerical Rating Scale (NRS) and the total number of times pain medication. There were no significant differences in HADS and amylase in saliva between the YKS and non-YKS. The median postoperative NRS was 5 for YKS and 7 for non-YKS. The maximum use of pain medication was 16 in YKS and 24 in non-YKS. Although no significant difference was observed in the anxiolytic effects and the improvement of postoperative pain during the perioperative period of mandibular third molar extraction between patients who took YKS and those who did not, NRS and the maximum use of pain medication were less in the YKS patients. ConclusionsTherefore, YKS may be useful for managing postoperative pain through the preoperative anxiolytic effect in oral surgical procedures.

DOI： 10.1002/osi2.1202

Web of Science

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

A subscapular system free-flap is extremely useful for maxillofacial reconstruction since it facilitates the simultaneous harvesting of multiple flaps using one subscapular artery (SSA) alone. However, cases of aberrations in the SSAs have been reported. Therefore, the morphology of SSA needs to be confirmed preoperatively before harvesting the flaps. Recent developments in imaging, such as three-dimensional (3D) computed tomography angiography (3D CTA), facilitate obtain high-quality images of blood vessel images. Therefore, we examined the utility of 3D CTA in navigating the course of the SSA before harvesting subscapular system free-flaps. We examined the morphology and aberrations of the SSA using 39 sides of the 3D CTA data and 22 sides of Japanese cadavers. SSAs can be classified into types S, I, P, and A. Type S SSAs are significantly long (mean length = 44.8 mm). Types I and P SSAs have short mean lengths, measuring ≤2 cm in approximately 50% of cases. In type A, the SSA is absent. The frequency of types S, I, P, and A SSAs were 28.2%, 7.7%, 51.3%, and 12.8%, respectively. Type S can be advantageous for harvesting the SSA in subscapular system free-flaps, because it is significantly longer. In contrast, types I and P might be dangerous because their mean lengths are shorter. In type A, caution is needed not to injure the axillary artery because the SSA is absent. When surgeons need to harvest the SSA, presurgical 3D CTA is recommended.

DOI： 10.1002/ca.24053

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

PURPOSE: Oral mucositis is a severe adverse event in patients with head and neck cancer (HNC) receiving chemotherapy and radiotherapy that may cause the termination of cancer treatment. In this study, we aimed to reveal the benefits of pharmacist interventions in oral health care for patients with HNC receiving concurrent chemoradiotherapy (CCRT). METHODS: We conducted a multicenter, prospective cohort study on 173 patients from September 2019 to August 2022. We evaluated the association between the occurrence of oral mucositis during CCRT and various factors in the absence or presence of direct medication instructions from hospital pharmacists. RESULTS: Sixty-eight patients received medication instructions from pharmacists (the pharmacist intervention group), whereas 105 patients did not receive instructions (the control group). Logistic regression analysis showed that grade 2 (Gr 2) oral mucositis was significantly lower in patients receiving pharmacist interventions than in patients in the control group (adjusted odds ratio [aOR], 0.42; 95% confidence interval [CI], 0.18-0.96; P = 0.04). The time to onset of Gr 2 oral mucositis was significantly longer in the pharmacist intervention group than in the control group (hazard ratio, 0.53; 95% CI, 0.29-0.97; P = 0.04). CONCLUSION: Direct intervention, especially when provided by hospital pharmacists, can have a real effect in supporting patients with HNC experiencing severe side effects of treatments. Moreover, the integration of pharmacists into the oral healthcare team is becoming even more essential to reduce the severity of side effects.

DOI： 10.1007/s00520-023-07784-6

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

Pemphigus vulgaris (PV) is a rare autoimmune disease characterized by blisters on the skin and mucous membrane. Since it often appears in the oral mucosa first, it may be diagnosed by oral mucosal cytology. Although the cytologic finding is characterized by acantholytic cells, that is, Tzanck cells, it is important to distinguish PV from neoplastic lesions of the oral mucosal epithelium, including differentiation from atypical parabasal/basal cells, which appear in squamous cell carcinoma (SCC). In this study, we examined the cellular findings in two cases of PV and a case of well-differentiated SCC with loss of epithelial cell cohesion. The samples were prepared using liquid-based cytology, which showed small round-shaped and deeply stained atypical, orangeophilic keratinocytes not only in SCC but also in PV, which made differentiation between the two difficult. However, Tzanck cells found in PV differ from the deep atypical parabasal/basal cells of SCC, suggesting that the cell outline is indistinct and small protrusions and brush-like structures are observed. This feature of Tzanck cells may be useful in cytological judgment.

DOI： 10.1002/dc.25117

PubMed

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Authorship：Last author  

J-GLOBAL

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Publishing type：Research paper (scientific journal)  

DOI： 10.1007/s12663-023-01955-y

Scopus

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Authorship：Last author  

J-GLOBAL

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J-GLOBAL

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

OBJECTIVES: Immunotherapy with nivolumab for patients with recurrent/metastatic oral squamous cell carcinoma has not been evaluated. Here, we aimed to examine the efficacy, safety, and prognostic factors of nivolumab in these patients. MATERIALS AND METHODS: This multicenter retrospective observational study involved patients who received nivolumab between April 2017 and June 2019. The patient characteristics were evaluated for association with progression-free and overall survival. Progression-free and overall survival rates were calculated; parameters that were significant in the univariate analysis were used as explanatory variables. Independent factors for progression-free and overall survival were identified using multivariate analysis. RESULTS: Totally, 143 patients were included. The overall response and disease control rates were 27.3% and 46.2%, respectively. The median, 1- and 2-year progression-free survival rates were 2.7 months, 25.4%, and 19.2%, respectively; those for overall survival were 11.2 months, 47.3%, and 33.6%, respectively. The independent factors affecting progression-free survival were performance status and immune-related adverse event occurrence, whereas those affecting overall survival were performance status, target disease, and number of previous lines of systemic cancer therapy. Eight patients reported grade ≥3 immune-related adverse events. CONCLUSION: Nivolumab was effective for recurrent/metastatic oral squamous cell carcinoma treatment and was well tolerated by patients.

DOI： 10.1111/odi.14471

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Publishing type：Research paper (scientific journal)  

The number of patients administered oral antithrombotic drugs who require elective surgery has increased. Perioperative heparin bridging needs to be considered for patients at a high risk of thromboembolism. The present study investigated the effects of perioperative heparin bridging therapy on perioperative complications (postoperative bleeding and thrombotic events) in oral cancer surgery. The medical records of 98 patients who underwent oral cancer surgery with perioperative bridging therapy were retrospectively analyzed. Postoperative hemorrhage occurred in 16 patients (16.3%) and thrombotic events (deep venous thrombosis) in 5 (5.1%), which were higher than in other surgeries. A multivariate analysis identified the administration of prostaglandins as the only significant independent risk factor for postoperative hemorrhage, and a longer duration of postoperative heparin bridging therapy was associated with the incidence of deep venous thrombosis. The present results suggest a higher incidence of thrombotic and bleeding events in patients who underwent oral cancer surgery with heparin bridging, and the nature of surgery (such as revascularization and prolonged bed rest) may be a contributing factor. Future studies are needed to establish whether heparin bridging is effective in oral cancer surgery.

DOI： 10.1016/j.ajoms.2022.06.008

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Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Adenosquamous carcinoma (ASC) is an aggressive subtype of squamous cell carcinoma (SCC). Due to its poor prognosis, a precise pathological diagnosis of ASC is essential but challenging because its pathological criteria are still unclear. Here, we present a rare case of oral ASC accompanied by acantholytic features. The tumor was raised in the mandibular gingiva and recurred locally approximately 13 months after the initial surgery with cervical lymph node metastasis. Pathological specimens of the primary lesion showed acantholysis in a large area of the SCC. Mucous cells, the characteristic finding indicating glandular differentiation, were imperceptible in the initial surgical specimen but increased in the locally recurrent and metastatic lymph node specimens. In a comprehensive literature review of oral ASC cases, the present case was the only case of ASC with acantholytic features. We reconfirmed that ASC has poor prognoses, such as low 5-year overall survival and disease-free survival, high locoregional recurrence, and high distant metastasis rates. A precise diagnosis of ASC is required for estimating prognosis and undergoing close follow-up, even if the adenocarcinomatous component is limited to a small area in the lesion.

DOI： 10.3390/diagnostics12102398

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

Cytology is a simple and non-invasive screening method for oral cancer. However, this method is not yet routinely used by clinicians because of its high false negative rate (FNR) and due to lack of sufficient studies examining the factors for high FNRs. The present retrospective study aimed to compare the screening performance of conventional cytology (CC) and liquid-based cytology (LBC) through histological validation, and to elucidate factors inducing false negative screening in oral cytology. Cytological specimens with histological examination and intraoral digital images of the lesion were retrospectively collected between January 2017 and December 2018 for CC and between October 2019 and September 2021 for LBC. Oral cytological screening was conducted based on the oral Bethesda system for oral cytology. Clinical subtypes were re-evaluated using intraoral digital images. The screening accuracy of oral cytology was calculated considering the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for detecting the malignant transformation of oral lesions. No statistically significant difference was noted in the inadequate rate between CC and LBC groups. For CC and LBC, the sensitivities were 60.9 and 59.2%, the specificities were 87.3 and 79.1%, the PPVs were 85.8 and 76.2%, and the NPVs were 63.9 and 63.2%, respectively. Thus, the screening accuracy was similar between methodologies. Among the clinicopathological factors investigated, histological diagnosis and cellularity contributed to false negative results. Homogeneous findings of oral epithelial dysplasia and the superficial growth of carcinoma in situ/squamous cell carcinoma resulted in false negative findings for CC and LBC. Furthermore, LBC samples with a lower cell number (<2,000 squamous cells) exhibited statistically significantly increased FNRs. The present study found that the cytological methods did not affect the inadequate rate and screening accuracy, whereas clinical subtype and cellularity decreased screening accuracy. Therefore, cytological screening and subsequent follow-up should be performed while considering clinical findings and the cellularity of cytology smears.

DOI： 10.3892/ol.2022.13505

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Tetanus is an acute and vaccine-preventable disease caused by anaerobic bacteria, Clostridium tetani. This bacterium can enter the human body via a deep wound, burn injury or medical procedure; however, certain cases also originate from odontogenic infection. In the present study, a tetanus infection associated with dental origin in a 44-year-old man is reported. The case was complicated by lockjaw and difficulty swallowing that worsened over a few days, followed by a generalized spasm. Furthermore, a literature review was performed, in which six reported cases of tetanus, presumed to be of dental or oral origin, were identified between 2011and 2021. General practitioners, especially dentists, should be aware of tetanus associated with odontogenic origin even without a history of an external penetrating wound or other medical procedures:.

DOI： 10.1016/j.heliyon.2022.e10810

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Authorship：Last author   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

DOI： 10.1016/j.ajoms.2022.02.007

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Publisher：Authorea, Inc.  

<p id="p1">Herein, we report two cases of patients diagnosed withnivolumab-refractory distant metastatic squamous cell carcinoma of thetongue who were successfully treated with a combination of paclitaxeland cetuximab, thus demonstrating that some nivolumab-refractorypatients with recurrent or distant metastatic oral squamous cellcarcinoma may benefit from subsequent salvage chemotherapy.</p>

DOI： 10.22541/au.165881754.43971495/v1

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

Preoperative assessment is essential to prevent inferior alveolar nerve (IAN) injury during surgical extraction of the lower third molar (LM3). Here, we aimed to establish an assessment system to predict IAN injury during surgical extraction of the LM3. We conducted a retrospective cohort study on 115 patients diagnosed as 'high-risk' based on our previous risk assessment method involving three anatomical features of the inferior alveolar canal using computed tomographic (CT) images. We evaluated the occurrence of neurosensory impairment in these high-risk patients, and its association with novel anatomic features based on CT images. Neurosensory impairments were observed in 19 patients (16.5%). The inferior alveolar canal major diameter (p < 0.0001) and lingual bone thickness (p = 0.0039) were significantly associated with the occurrence of neurosensory impairment during LM3 extraction. Receiver operating characteristic curves were used to determine cut-off values of these quantitative factors to specifically predict IAN injury. Preoperative risk assessment with quantitative factors based on anatomical features observed on CT images may facilitate more appropriate surgical planning for patients at a high risk of IAN injury.

DOI： 10.1016/j.bjoms.2021.09.014

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Language：Japanese   Publisher：(一社)日本口腔ケア学会  

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OBJECTIVE: To examine the safety and efficacy of hyperdry amniotic membrane (HDAM) for wound closure after palatoplasty in cleft palate patients. METHODS: HDAMs were prepared by washing and drying under infrared rays and microwaves at temperatures less than 60°C using a hyperdrying device. A total of 16 cleft palate patients (8 males, 8 females), aged 1 to 3 years (mean age 1 year 9 months), received one-stage pushback palatoplasty. The remaining raw wound after surgery was covered by an HDAM and a plastic cover plate. The cover plate was removed 1 week after surgery and parameters including temperature, feeding, allergic reactions, postoperative bleeding, re-epithelialization, wound dehiscence, and infection were monitored during the follow-up period of 31.2 months. RESULTS: All patients could adequately ingest at 5 days postoperation and after removal of the cover plate. None of the patients had a persistent fever or allergic reactions. Ingestion was feasible immediately in all patients, and no postoperative bleeding was observed during ingestion. No secondary hemorrhages were observed during follow-up. No postoperative wound dehiscence on the midline of the palate was observed. No infections were observed after the removal of the cover plate. No patients suffered from severe scar formation or contracture of the wound in the follow-up period. Hemorrhage, undue epithelialization, and scar contracture did not occur in any patient. The mean evaluation score was 7.75 points. CONCLUSION: HDAM can be used safely and effectively for wound closure following palatoplasty in cleft palate infants. Future studies testing the safety of patient's own amnion for palatoplasty, are required.

DOI： 10.1177/10556656221075937

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

The long-term administration of tamoxifen to estrogen receptor α (ERα)-positive breast cancer patients is an established treatment that reduces mortality and recurrence. However, resistance to tamoxifen and an increased risk of endometrial cancer may occur; therefore, the mechanisms by which tamoxifen causes these adverse effects warrant further study. Tamoxifen has been shown to activate mitogen-activated protein kinase (MAPK) in an ERα-independent manner; therefore, we investigated its effects on the MAPK-mediated non-canonical activation of EphA2, a critical event regulating cell migration. Tamoxifen at slightly higher concentrations induced the rapid phosphorylation of EphA2 at Ser-897 via the MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK-ribosomal S6 kinases (RSK) pathway in HeLa cells. In addition, tamoxifen significantly enhanced the migration ability of ERα-negative MDA-MB-231 breast cancer cells in RSK- and EphA2-dependent manners. Phosphorylated EphA2 was internalized and re-localized to the plasma membrane, including lamellipodia, in an RSK-dependent manner. Collectively, the present results provide novel insights into the tumor-promoting activity of tamoxifen.

DOI： 10.1248/bpb.b21-00567

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

Although the dosage of oral antibiotics (OA) for the mandibular third molar extraction (MTME) varies among the administration periods according to the current guideline, our previous reports suggested that it might be possible to further shorten the administration period without increasing the incidence of surgical site infection (SSI). In the present study, we retrospectively evaluated the relationship between the incidence of SSI and the administration period of OA in patients who underwent the MTME in our hospital. This retrospective cohort study included 348 patients who underwent the MTME in our dental outpatient clinic from June 2020 to March 2022. The administrated antibiotic was amoxicillin (AMPC) in all patients. Patients were divided into two groups based on the administration period of AMPC single and three times before the surgery. The following information was collected: (1) patient factors (age, gender, body mass index, diagnosis, mandibular third molar status); (2) surgical factors (operation time, presence/absence of wound closure, presence/absence of hemostat, experience of surgeons); (3) relationship between administration period of OA and SSI occurrence; and (4) details of SSI. There were 217 cases in the single group and 131 cases in the three times group. The incidence of SSI was 1.1% (4/348), with 1.4% (3/217) in the single group and 0.8% (1/131) in the three times group; there was no significant difference between the two groups. Our result suggests that single administration of AMPC before the MTME would be sufficient for the prevention of SSI in Japanese patients without risk factors.

DOI： 10.1248/yakushi.22-00163

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J-GLOBAL

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J-GLOBAL

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Authorship：Lead author,　Corresponding author  

J-GLOBAL

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Sepsis is a systemic reaction to an infection and resulting in excessive production of inflammatory cytokines and chemokines. It sometimes results in septic shock. The present study aimed to identify quinolone antibiotics that can reduce tumor necrosis factor alpha (TNFα) production and to elucidate mechanisms underlying inhibition of TNFα production. We identified quinolone antibiotics reduced TNFα production in lipopolysaccharide (LPS)-stimulated THP-1 cells. Sitafloxacin (STFX) is a broad-spectrum antibiotic of the quinolone class. STFX effectively suppressed TNFα production in LPS-stimulated THP-1 cells in a dose-dependent manner and increased extracellular signal-regulated kinase (ERK) phosphorylation. The percentage of intracellular TNFα increased in LPS-stimulated cells with STFX compared with that in LPS-stimulated cells. TNFα converting enzyme (TACE) released TNFα from the cells, and STFX suppressed TACE phosphorylation and activity. To conclude, one of the mechanisms underlying inhibition of TNFα production in LPS-stimulated THP-1 cells treated with STFX is the inhibition of TNFα release from cells via the suppression of TACE phosphorylation and activity. STFX may kill bacteria and suppress inflammation. Therefore, it can be effective for sepsis treatment.

DOI： 10.1038/s41598-021-03511-5

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

BACKGROUND: The immune checkpoint inhibitor (ICI) nivolumab has revolutionized the treatment for recurrent or metastatic advanced oral cancer. Because the response rate remains low, the identification of predictive indicators of the response to nivolumab is among the most critical issues. The neutrophil-to-lymphocyte ratio(NLR)is a potential predictive marker of the response to nivolumab in patients with various cancer types. However, the utility of the NLR as a biomarker for predicting the response of oral cancer patients to ICIs is poorly understood. PATIENTS AND METHODS: In this retrospective cohort study, we evaluated the association between NLR and nivolumab treatment outcome in 13 patients diagnosed with recurrent or metastatic oral squamous cell carcinoma(OSCC)treated with nivolumab at the Toyama University Hospital between December 2017 and December 2019. RESULTS: Complete response(CR)and partial response(PR)rates of 38.5%(5/13)and 0% (0/13), respectively, were observed in responders; stable disease(SD)and progressive disease(PD)rates of 7.7%(1/13) and 53.8%(7/13), respectively, were observed in non-responders. After nivolumab treatment, the median NLR among responders decreased to 3.3(3.0-3.9)from 4.1(3.7-4.3)during pre-treatment assessment and increased from 5.6(3.2- 9.2)at pre-treatment to 9.4(5.3-17.9)among non-responders. Moreover, patients with higher NLRs(≥5)in the post- treatment group had a significantly worse overall survival than those with lower NLRs(<5). Specifically, patients with a higher post-treatment NLR(≥10)had significantly worse outcomes for post-nivolumab salvage chemotherapy. CONCLUSION: The NLR could be a useful marker for predicting the treatment response to nivolumab or post-nivolumab salvage chemotherapy in OSCC patients.

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Authorship：Corresponding author   Language：English  

Intraosseous mucoepidermoid carcinoma of the jaw is a rare lesion that has been suggested to originate from the odontogenic epithelium. We report an unusual case of central mucoepidermoid carcinoma in an 18-year-old Japanese man with an odontogenic cyst.

DOI： 10.1002/ccr3.4928

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/osi2.1095

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

Cleft lip and cleft alveolus are caused by incomplete fusion of the frontonasal and maxillary prominences. However, milder forms of cleft lip are rarely accompanied by cleft alveolus. Here, we report a rare case of mini-microform cleft lip with complete cleft alveolus and cleft palate. No findings suggestive of cleft lip were evident on initial examination. However, three-dimensional facial measurements confirmed the presence of cleft lip despite no evidence of orbicularis oris muscle (OOM) rupture on ultrasonography. Collapsed nostril, as observed in this case, is usually associated with OOM rupture. However, it can also be caused by skeletal abnormalities, such as cleft alveolus. Three-dimensional facial measurements and ultrasonography can assist in accurate diagnosis when visual examination is ambiguous.

DOI： 10.1111/cga.12415

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Paranasal sinus aplasia is a rare condition. Here, we report an extremely rare case of total paranasal sinus aplasia accompanied by 18 impacted teeth. A 77-year old man presented with a complaint of diffuse swelling in the anterior maxilla. Radiographs revealed well-demarcated radiolucent cystic lesions in the swollen maxilla. However, 14 teeth were impacted in the maxilla, and 4 were impacted in the mandible. Furthermore, paranasal sinuses were completely obliterated. The patient then underwent cystectomy and five impacted anterior maxillary teeth were extracted under general anesthesia. Furthermore, no systemic diseases, including metabolic and endocrine abnormalities, and bone diseases including osteogenesis imperfecta, which may have resulted in total paranasal sinus aplasia, were identified. The patient is healthy with no maxillary osteitis 1 year after cystectomy. To our knowledge, three cases of total paranasal sinus aplasia have been reported thus far (in English); however, no studies have reported cases of total paranasal aplasia with multiple impacted teeth. Therefore, while computed tomography is required to detect total paranasal sinus aplasia, maxillary sinus aplasia can be detected through panoramic radiography in general dental practice; hence, dental practitioners should consider the possibility, since paranasal sinus aplasia may result from severe systemic diseases or syndromes. (C) 2020 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.ajoms.2020.09.012

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

Anti-laminin 332 mucous membrane pemphigoid (MMP) is characterized by circulating anti-laminin 332 autoantibodies, with a high risk of concurrent malignant neoplasms. We report a case of anti-laminin 332 MMP manifesting as a desquamative gingivitis. A 45-year-old woman experienced painful erythema and occasional bullous lesions on the gingiva despite good oral hygiene and plaque control. Intraoral examination revealed gingival inflammation with desquamation. Biopsy showed subepithelial cleft formation suggesting a subepidermal blister. Direct immunofluorescence revealed the deposition of IgG and IgA in the epithelium. Accordingly, we diagnosed anti-laminin 332 MMP and treated with systemic corticosteroids. The oral lesion resolved after 3 months.

DOI： 10.1002/osi2.1073

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Authorship：Corresponding author  

J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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J-GLOBAL

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Authorship：Corresponding author   Language：Japanese   Publisher：(一社)日本小児口腔外科学会  

1歳8ヵ月男児。3ヵ月前に転倒により両側上顎乳中切歯を受傷し、前医で外傷性歯冠破折と診断された。破折歯の処置は行われず、抗菌薬と鎮静剤の内服で経過観察となった。3ヵ月後、発熱と頭痛が出現し、当科紹介受診となった。両側上顎乳中切歯が水平方向に歯冠破折し、破折部から歯髄息肉を認め、両側上顎乳中切歯の歯冠破折による慢性増殖歯髄炎と診断した。MRIで左前頭葉に脳の正中偏位を伴う膿瘍を認め、救命目的に脳膿瘍に対し穿頭ドレナージ手術を施行した。術直後に膿瘍腔は縮小し、脳の正中偏位が改善した。術後の心エコーで2～3mmの卵円孔開存を認めたが、心機能は正常であった。穿頭ドレナージの膿液からStreptococcus intermedius、Parvimonas micraが検出され、歯科疾患が原因と判断した。両側上顎乳中切歯を抜歯したところ、発熱や頭痛、左前頭葉の膿瘍が完全消失し、抜歯後30日に退院となった。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2020&ichushi_jid=J02675&link_issn=&doc_id=20201124430005&doc_link_id=%2Fcb2syone%2F2020%2F003001%2F005%2F0032-0036%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcb2syone%2F2020%2F003001%2F005%2F0032-0036%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1002/osi2.1031

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

The amniotic membrane is highly biocompatible, possesses anti-inflammatory properties, and has been used for reconstructive surgeries in various areas. However, there have been persistent problems related to its preparation, storage, and sterilization. Hyperdried human amniotic membrane (HD-AM) was developed at the Toyama University to resolve these problems of fresh amnion. The aim of this study was to evaluate the clinical effects of the surgical repair of oral mucosal defects by using HD-AM. In total, 29 patients with oral precancerous lesions or early-stage cancer were included. After resection of the oral lesions, surgical defects of the oral mucosa were covered with HD-AM in 15 patients (HD-AM group) and with commercial collagen graft material in 14 patients (CGM group). Postoperative pain, feeding state, epithelialization, the scarring of the wound, and oral function were evaluated. The postoperative medication period of nonsteroidal anti-inflammatory drug use was significantly shorter (P = 0.0457) and the recovery period for resumption of oral feeding was also significantly earlier (P = 0.0414) in the HD-AM group than in the CGM group, without specific complications. HD-AM reduced the postoperative inflammation; it can be used as a novel dressing material for the surgical repair of oral mucosal defects.

DOI： 10.1002/osi2.1003

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE INC  

Methotrexate (MTX) is an antifolate that has been used as a chemotherapeutic agent for the treatment of neoplasm, such as leukemia and osteosarcoma. Moreover, MTX is also commonly used for treatment of chronic rheumatoid arthritis (RA). Here, we report a case of severe stomatitis in a patient with RA, which was caused by misuse of MTX. An 83-year-old female patient visited our department with the chief complaint of oral mucosal pain, accompanied by extreme fatigue. Severe stomatitis lesions were observed throughout her oral mucosa. Moreover, blood examination revealed pancytopenia. The patient reported a history of RA, and had been prescribed MTX since 2004. Although 6 mg MTX should be used twice per week, the patient mistakenly used MTX every day following her last consultation, for a period of 1 month. These findings led to a diagnosis of severe stomatitis, pancytopenia, and sepsis, all induced by misuse of MTX. Ultimately, she was treated with blood transfusion, antibiotics, and intravenous hyper alimentation, as well as administration of granulocyte colony-stimulating factor.MTX for the treatment of RA should be carefully managed to limit the risk of its misuse, especially in elderly patients, because of the severity and potential lethality of symptoms.

DOI： 10.1016/j.ajoms.2018.06.009

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Malignant peripheral nerve sheath tumors (MPNSTs) are sarcomas that originate in peripheral nerves or neurilemma cells. Here, we report an extremely rare case of an intraosseous MPNST in the mandible of a patient with neurofibromatosis type 1 (NF1). A 57-year-old woman with a history of NF1 was referred to our hospital because she had abnormal sensations at her left mandible. She was diagnosed with MPNST and underwent radical resection, although local recurrence and multiple metastases were detected during follow-up. Despite receiving palliative radiotherapy, the patient died at 13 months after the initial diagnosis. (C) 2018 Japanese Stomatological Society. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/S1348-8643(18)30007-7

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Authorship：Corresponding author   Publishing type：Research paper (scientific journal)   Publisher：Wiley  

DOI： 10.1016/s1348-8643(18)30004-1

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCI LTD  

Scimitar syndrome is a rare congenital cardiac condition with a poor prognosis. It is frequently accompanied by concordant pulmonary hypoplasia and aortopulmonary collateral arteries connected to the hypoplastic lung. Here we report a case involving a 58-year-old woman with scimitar syndrome who developed stage II oral cancer. Surgical treatment was deemed high risk because of difficulty in respiratory management through mechanical ventilation during general anesthesia, and hence, she was treated with chemoradiotherapy, which was successfully completed. The findings from this case suggest that chemoradiotherapy is a useful strategy that can contribute to improved clinical outcomes for oral cancer in patients with scimitar syndrome. (C) 2017 Published by Elsevier Ltd on behalf of Japanese Stomatological Society.

DOI： 10.1016/S1348-8643(17)30043-5

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BACKGROUND: Major risk factors for oral squamous cell carcinoma (SCC) are tobacco smoking, a betel quid chewing habit, and heavy alcohol consumption. However, around 15% of oral SCCs cannot be explained by these risk factors. Although oral SCC associated with dental implants is quite rare, there has been a recent gradual accumulation of reports about it. Here, we report a case of primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ (OIN/CIS) in a woman without the major risk factors for oral SCC. CASE PRESENTATION: A 65-year-old woman was referred to our clinic with a tumor in the right lower gingiva. She had no history of tobacco smoking and only drank socially. Ten years previously, mandibular right posterior teeth had been replaced with an implant-supported porcelain-fused-to-metal restoration in a dental clinic. About 7 years later, she noticed swelling on the lingual side of the gingiva around the implant-supported restoration, and was eventually referred to our clinic with the suspicion of a neoplasia around the dental implant. The upper part of the implant body was exposed on the implant corresponding to the first molar of the right side of the mandible; this was associated with painless, elastic soft, and relatively well circumscribed gingival swelling on the lingual site. A panoramic radiograph showed slight vertical bone resorption around the implants. An incisional biopsy was conducted under the suspicion of neoplasia. Pathological microscopic examination of the biopsy specimen revealed thickened squamous epithelia with slight nuclear atypism and disorders of the epithelial rete pegs. Immunohistochemical findings showed positive staining for keratin 17 and a negative staining mosaic pattern for keratin 13. High p53, p63, and Ki-67 reactivity was also observed. From these findings, OIN/CIS of the gingiva was pathologically diagnosed, and a wide local excision with rim resection of the mandible, including the implants, was performed. The pathological findings for the resected specimen were same as those for the biopsy specimen. After 1 year of follow-up, there was no evidence of recurrence. CONCLUSION: In this case, prolonged peri-implant mucositis or peri-implantitis may have been a plausible risk factor for carcinogenesis.

DOI： 10.1186/s40729-017-0109-z

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

症例は61歳男性で、直径約90cmのパラグライダーのプロペラを研磨していた際に、プロペラが弾かれて顔面を直撃した。顔面の裂創を認めたため救急要請した。左鼻根部から頬部と、右頬部からオトガイ部の2ヶ所に裂傷を認め、一部は上顎洞前壁と右下顎前歯部の歯槽骨に達していた。下顎前歯部では歯槽骨の骨折と歯根破折を認め、さらに歯冠の破折により残根状態となっていた。左頬部の裂傷は耳下腺の導管に達し、導管の断裂を認めた。顔面裂傷、左耳下腺管断裂、右下2、3、4、5部歯槽骨骨折・歯根破折と診断した。全身麻酔下に創縫合術、右下2、3、4、5抜歯術、耳下腺導管再建術を施行した。術後10日目に退院し、外来にて経過観察を行っていた。左頬部の瘢痕拘縮が著明となったため、術後4ヵ月に全身麻酔下に瘢痕修正術を施行した。創部は瘢痕の形成も少なく良好に治癒した。審美性の改善が得られ、耳下腺乳頭からの唾液の流出も良好に認めた。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2017&ichushi_jid=J05290&link_issn=&doc_id=20171030220004&doc_link_id=10.24787%2Fjsomft.16.2_67&url=https%3A%2F%2Fdoi.org%2F10.24787%2Fjsomft.16.2_67&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Osteosarcoma, the most common primary bone malignancy, has an extremely poor prognosis and a high rate of local recurrence and distal metastases. Because osteosarcomas of the head and neck region are rare, accounting for less than 10% of all osteosarcoma cases, limited information is available about their treatment and prognosis. Because of the high rate of distal metastases associated with extragnathic osteosarcoma, surgery combined with chemotherapy is currently considered essential in its treatment. However, the role of chemotherapy has not been well elucidated in the treatment of head and neck osteosarcoma because of the rarity of this condition. CASE PRESENTATION: In this report, we present the case of a 58-year-old Japanese woman with osteosarcoma of the mandible that was treated with radical surgery combined with neoadjuvant and adjuvant chemotherapy. Because the tumor showed rapid growth during neoadjuvant chemotherapy, neoadjuvant chemotherapy was suspended and surgical resection was performed, followed by adjuvant chemotherapy. No evidence of local recurrence and distal metastasis was found 14 months after initial treatment. Local control is considered a principal prognostic factor for head and neck osteosarcoma. CONCLUSIONS: Wide surgical excision should be considered a primary goal even during neoadjuvant chemotherapy, especially in cases that respond poorly to neoadjuvant chemotherapy.

DOI： 10.1186/s13256-017-1386-0

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The effect of resveratrol on various human cancer cells was investigated with special focus on apoptotic cell death, in an attempt to further characterize its mechanism of action. There were great differences in the anti-viability effect of resveratrol between different types of human cancer cells. While the inhibition of cell viability by resveratrol was marked in U937 and MOLT-4 leukemia cells, resveratrol moderately inhibited cell viability in MCF-7 breast, HepG2 liver, and A549 lung cancer cells, and the effect was slight on cell viability in Caco-2, HCT116, and SW480 colon cancer cells. Following resveratrol treatment, U937 and MOLT-4 markedly increased the population of late apoptotic cells but MCF-7 and HepG2 underwent apoptosis with an increased population of early apoptosis, and resveratrol-induced DNA fragmentation was observed only in leukemic cells. Activation of sirtuin 1 and adenosine-monophosphate-activated protein kinase was not responsible for resveratrol-induced cancer cell death. Instead, resveratrol significantly reduced Akt activation with the downregulation of H-Ras, resulting in facilitation of Bax translocation to mitochondria in leukemic cells. This study suggests that resveratrol can induce apoptotic cell death in human leukemic cells to a greater extent than in human solid tumor cells via reducing Akt activation due to Ras downregulation.

DOI： 10.3892/ijo.2017.3859

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Salivary duct carcinoma (SDC) is a high-grade salivary gland malignancy that is associated with an aggressive clinical behavior and poor prognosis. Herein, we report on a long surviving case of SDC of the minor salivary gland with multiple lymph node metastases (LNMs). CASE PRESENTATION: An 83-year-old woman presented with a history of lymphadenopathy in the right side of the neck and recent onset and rapid growth of a mass in the right buccal region. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional LNMs. The patient was treated with neoadjuvant chemotherapy. Tumor excision and ipsilateral radical neck dissection were performed, followed by adjuvant chemoradiotherapy. Postoperative histological examination revealed a tumor with irregular nests of atypical ductal epithelial cells, a cribriform growth pattern, and comedo-like central necrosis that lead to a final diagnosis of SDC. LNMs were observed in six lymph nodes of the right side of the neck. The patient underwent postoperative chemotherapy using single-agent cisplatin that was administered concurrently with radiotherapy (total, 65 Gy). There was no evidence of local recurrence or distant metastasis for >6 years. CONCLUSIONS: Although available data on treatment modalities for SDC remain limited, multimodal therapy may contribute to improved clinical outcomes in patients with advanced intraoral SDC.

DOI： 10.1186/s12957-016-1090-3

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Invasive micropapillary salivary duct carcinoma (SDC) is a rare variant of SDC. Although several cases involving major salivary glands have been reported, no cases arising de novo in minor salivary glands have been reported to date. Here we report the first case of invasive micropapillary SDC that arose in a minor salivary gland of the parapharyngeal space. METHODS: A 72-year-old male patient presented with an enlarging mass in the left parapharyngeal region along with trismus and swollen lymph nodes. Clinical examinations and biopsy findings were suggestive of a salivary gland malignant tumor with regional lymph node metastases. The tumor, therefore, was excised with partial mandibulectomy with unilateral radical neck dissection. RESULTS: Histologically, the tumor consisted of an invasive micropapillary growth pattern of SDC and mixed with mucinous component of SDC. Local recurrence and lung metastasis developed, and the patient died of disease 13 months after the initial treatment. CONCLUSIONS: We describe the clinical and histologic features of this extremely rare case of minor salivary gland SDC that was histologically characterized by the presence of both invasive micropapillary growth pattern and mucinous component.

DOI： 10.1016/j.oooo.2015.10.012

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Direct antitumor effects of bisphosphonates (BPs) have been demonstrated in various cancer cells in vitro. However, the effective concentrations of BPs are typically much higher than their clinically relevant concentrations. Oral cancers frequently invade jawbone and may lead to the release of Ca(2+) in primary lesions. We investigated the effects of the combined application of zoledronic acid (ZA) and Ca(2+) on proliferation and apoptosis of oral cancer cells. Human oral cancer cells, breast cancer cells, and colon cancer cells were treated with ZA at a wide range of concentrations in different Ca(2+) concentration environments. Under a standard Ca(2+) concentration (0.6mM), micromolar concentrations of ZA were required to inhibit oral cancer cell proliferation. Increasing extracellular Ca(2+) concentrations greatly enhanced the potency of the ZA cytocidal effect. The ability of Ca(2+) to enhance the cytocidal effects of ZA was negated by the Ca(2+)-selective chelator EGTA. In contrast, the cytocidal effect of ZA was less pronounced in breast and colon cancer cells regardless of whether extracellular Ca(2+) was elevated. In oral cancer cells incubated with 1.6mM Ca(2+), ZA up-regulated mitochondrial Bax expression and increased mitochondrial Ca(2+) uptake. This was associated with decreased mitochondrial membrane potential and increased release of cytochrome c. We suggest that ZA can specifically produce potent cytocidal activity in oral cancer cells in an extracellular Ca(2+)-dependent manner, implying that BPs may be useful for treatment of oral squamous cell carcinoma with jawbone invasion leading to the hypercalcemic state.

DOI： 10.1016/j.ejphar.2015.04.032

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Language：Japanese   Publisher：(公社)日本口腔外科学会  

61歳男。10年前より右下唇の腫瘤を自覚するも放置し、最近になり増大傾向を認めた。初診時、右下唇に小指頭大の腫脹を認め、内部に長径15mmの類円形、弾性硬で可動性のある腫瘤を触知した。生検の結果、脂腺癌と診断され、全身麻酔下に腫瘍切除術を施行した。病理診断も脂腺癌であった。術後2年の現在、再発や転移はなく経過良好である。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2015&ichushi_jid=J01073&link_issn=&doc_id=20150507250003&doc_link_id=10.5794%2Fjjoms.61.217&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.61.217&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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

The growth of maxillary bone and the development of dentition are often impaired in patients who have had pushback operations for repair of a cleft palate. There has been considerable discussion about the most suitable technique or material used in such repairs to resolve the problem. Hyperdry amniotic membrane, a new preservable material derived from human amnion, has recently been introduced in several procedures. We have evaluated its use during pushback surgery in animal studies to try to correct the inhibition of growth and development of the maxilla. Mucosal defects were created in 3-week-old rats, and then covered with hyperdry amniotic membrane or not. Healing was assessed by histological and morphological examination at 1 week and 7 weeks postoperatively. In the group treated with hyperdry amniotic membrane, submucosal tissue was reconstructed successfully during the early postoperative period. Lateral palatal growth was not inhibited as much, and medial inclination of the teeth was less, after a period of growth using this material. The results suggest that hyperdry amniotic membrane is a suitable new dressing material for use in the treatment of cleft palate.

DOI： 10.1016/j.bjoms.2015.01.018

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier Ltd  

This study aimed to assess the effects of induction chemotherapy (ICT) using intra-arterial high-dose cisplatin (CDDP) infusion and concurrent peroral tegafur (TS-1) for the management of locally advanced oral cancer. We analyzed 30 patients diagnosed with locally advanced oral squamous cell carcinoma who were treated at our university hospital from April 2007 to March 2011. Eleven patients were diagnosed with stage II tumors, 10 with stage III, and 9 with stage IVA. Six patients demonstrated complete response to ICT, and the overall response rate, including the partial response rate, was 77%. Definitive therapies comprised "wait and see" for 3 patients, chemoradiotherapy for 3, brachytherapy for 1, and ablation surgery for 23 (limited, standard, and extended surgeries in 9, 13, and 1 patients, respectively). Locoregional recurrence was observed in 7 patients, 4 of whom died. ICT can potentially predict good outcome in the management of locally advanced oral cancer. Definitive therapy should be determined on the basis of patients' response to ICT. Further investigations to determine the criteria indicating the appropriate therapy to be employed after ICT are required.

DOI： 10.1016/j.ajoms.2013.06.003

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Salivary duct carcinoma (SDC) is an uncommon neoplasm that most commonly occurs in major salivary glands, mainly the parotid gland. SDC is rarely found in the minor salivary glands of the oral cavity. This report presents an extremely rare case of sarcomatoid SDC originating in a minor salivary gland of the palate. The tumor was histologically characterized by the presence of both carcinomatous and sarcomatoid components. The patient presented with a painless mass in the right palate, which slowly increased in size over 20 years. The clinical course of the present case suggests that the tumor most probably developed as a result of malignant transformation of a preexisting benign tumor of the palatal salivary gland. This report describes the clinical and histologic features of this extremely rare case of sarcomatoid SDC with reference to the relevant literature.

DOI： 10.1016/j.oooo.2014.08.007

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Surgical extraction of the third molar is the most commonly performed surgical procedure in the clinical practice of oral surgery. Third molar surgery is warranted when there is inadequate space for eruption, malpositioning, or risk for cyst or odontogenic tumor formation. Preoperative assessment should include a detailed morphologic analysis of the third molar and its relationship to adjacent structures and surrounding tissues. Due to developments in medical engineering technology, computed tomography (CT) now plays a critical role in providing the clear images required for adequate assessment prior to third molar surgery. Removal of the maxillary third molar is associated with a risk for maxillary sinus perforation, whereas removal of the mandibular third molar can put patients at risk for a neurosensory deficit from damage to the lingual nerve or inferior alveolar nerve. Multiple factors, including demographic, anatomic, and treatment-related factors, influence the incidence of nerve injury during or following removal of the third molar. CT assessment of the third molar prior to surgery can identify some of these risk factors, such as the absence of cortication between the mandibular third molar and the inferior alveolar canal, prior to surgery to reduce the risk for nerve damage. This topic highlight presents an overview of the clinical significance of CT assessment in third molar surgery.

DOI： 10.4329/wjr.v6.i7.417

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Verrucous carcinoma (VC) is a distinct form of oral carcinoma, which occurs mainly as an exophytic growth on the buccal mucosa and gingiva. VC that occurs as an intraosseous lesion of the jaws is extremely rare and very few cases about it have been reported until date. We present a rare case of VC of the maxilla, where the patient's chief complaint was a painless exophytic lesion in the upper left quadrant of the jaw over one year. On examination, it was observed that the lesion involved the underlying bone with expansion into the maxillary sinus. It was resected by partial maxillectomy. Histopathological examination of the excised specimen revealed a verrucous surface with parakeratinized clefts, bulbous rete ridges, and a pushing border with no invasion, which was consistent with the diagnosis of VC. Moreover, the patient had a history of an odontogenic cyst in the left maxillary region
therefore, we presumed that the present lesion probably originated from the previous cystic lesion. © 2012 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI.

DOI： 10.1016/j.ajoms.2012.04.001

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Language：Japanese   Publisher：(株)癌と化学療法社  

目的:近年、悪性腫瘍の骨転移や多発性骨髄腫の治療に用いられるビスフォスフォネート(以下BP)注射剤の重篤な有害事象として、顎骨壊死(bisphosphonate related osteonecrosis of the jaw:BRONJ)が注目されている。本研究ではBRONJの現状を把握する目的で臨床的検討を行った。対象:2006年7月～2008年10月までの2年3ヵ月間にBP注射剤投与に関連して当科を受診した36例を対象とした。結果:BP剤投与前顎骨精査依頼は12例で、BP剤投与患者24例であった。BP投与患者7例にBRONJが認められ、17例は発症しなかった。7例はBP剤投与中に抜歯や急性歯性感染症を契機にBRONJを発症していた。BP投与前およびBRONJを発症していない患者に対する歯性感染症の原因除去治療は新たなBRONJの発生を予防した。結論:BRONJは通常の骨髄炎の治療に反応せず、極めて難治性であることが最大の問題点である。したがって、現状ではBRONJ発症予防に重点を置いた対応が最も効果的であり、医科と歯科の良好な連携が必要であると考えられた。また、BRONJの治療は抗生剤を主とした保存的アプローチが患者のQOLの維持や向上につながると考えられた。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2009&ichushi_jid=J00296&link_issn=&doc_id=20091221480018&doc_link_id=%2Fab8gtkrc%2F2009%2F003613%2F019%2F2587-2592%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2009%2F003613%2F019%2F2587-2592%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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

We examined the clinical features of bisphosphonate(BP)-related osteonecrosis of the jaws(BRONJ), a serious complication resulting from intravenous BP treatment for multiple myeloma and malignant tumors with bone metastasis. We retrospectively reviewed the medical records of 36 patients who received intravenous BP therapy for the above-mentioned conditions, at Sapporo Medical University Hospital between July 2006 and October 2008. BP therapy caused BRONJ in 7 of 24 patients, but did not affect the bones of the other 17 patients. The other 12 of the 36 patients involved in the study were prescribed BP only after they had undergone an oral examination and treatment for dental inflammation. Of these patients, 7 developed BRONJ with BP treatment, after tooth extraction or acute dental inflammation. Treating dental inflammation before prescribing BP prevented the development of BRONJ. BRONJ is highly intractable and does not resolve with the standard treatment for osteomyelitis. Therefore, preventive therapy, which can be achieved by cooperation between medical doctors and dentists, is currently the most effective strategy for BRONJ. Conservative treatment with antibiotics may also be useful for maintaining or improving the quality of life of BRONJ patients.

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Secondary cancers are severe complications in patients who have had allogeneic bone marrow transplantation for childhood leukemia. We describe here a case of squamous cell carcinoma (SCC) of the buccal mucosa in a young adult patient who had had allogeneic bone marrow transplantation for childhood acute leukemia. METHODS AND RESULTS: The primary tumor was treated with interstitial brachytherapy, and lymph node metastasis was treated by supraomohyoid neck dissection. The patient had a history of acute lymphoblastic leukemia (ALL) at 11 years of age and had received an allogeneic bone marrow transplant from a female donor. Further investigation of the tissue specimens by fluorescent in situ hybridization (FISH) revealed that an XX chromosome pattern was dominant in the tumor region, and this suggested that donor-derived cells might affect carcinogenesis in the recipient. CONCLUSIONS: This case presents an incidence of secondary oral cancer associated with allogeneic bone marrow transplantation.

DOI： 10.1002/hed.20931

PubMed

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Publishing type：Research paper (scientific journal)  

Background: Although tumour depth appears to be a powerful predictor of regional lymph node metastasis in squamous cell carcinoma of the oral tongue, measurement is usually based on histological findings following surgical resection. The predictive value of clinical findings on lymph node metastasis in the absence of surgical intervention is unclear. Methods: We retrospectively evaluated 90 previously untreated cases of stage I/II squamous cell carcinoma of the oral tongue to analyse the relationship between greatest dimension, growth pattern, depth of tumour and regional lymph node metastasis. Results: Lymph node metastasis was recognised in 15 of 90 cases. A positive correlation between greatest dimension and tumour depth was seen for endophytic-type tumours only. Logistic regression analysis revealed that growth pattern was an independent predictor of lymph node metastasis (P = 0.0014). Conclusion: Combination analysis of tumour growth pattern and greatest dimension may predict lymph node metastasis of squamous cell carcinoma of the oral tongue. © 2008 John Wiley & Sons A/S.

DOI： 10.1111/j.1752-248X.2008.00042.x

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

PURPOSE: To predict the relationship between lower third molars and the inferior alveolar canal (IAC) from panoramic radiographs, and to establish criteria for using computed tomography (CT). MATERIALS AND METHODS: A retrospective cohort study was performed involving 443 patients (695 teeth). Predictor variables were the distance between the third molar and the IAC, and findings according to the Rood's criteria. Outcome variables were the absence of cortication between the third molar and the IAC on the CT image, and injury of the inferior alveolar nerve (IAN). Statistical analysis was performed to assess the relationship between predictor and outcome variables. RESULTS: All patients had preoperative panoramic radiographs, and 71 patients (119 teeth) also had CT images. On CT examination, 48 teeth (40.3%) showed absence of cortication. Injury of the IAN was reported in 7 cases (1.0%), 5 of which exhibited absence of cortication; the remaining 2 did not have CT scans. Five of the 48 cases showing absence of cortication exhibited IAN injury, and none of the cases with cortication exhibited IAN injury. On the panoramic images, the following signs were strongly correlated with absence of cortication: a superimposed relationship between the third molar and the IAC; darkness of the root; and diversion and narrowing of the IAC. CONCLUSION: Presence of Rood's criteria was a predictor for a contact relationship between the third molar and the IAC, and an indication for CT examination. However, a superimposed relationship and the absence of Rood's criteria did not necessarily signify a separate relationship between third molar and the IAC.

DOI： 10.1016/j.joms.2008.06.042

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Authorship：Lead author   Language：Japanese   Publisher：(公社)日本口腔外科学会  

52歳女。8ヵ月前頃より左頬部の無痛性腫瘤を自覚し、縮小傾向がないため歯科口腔外科を受診したが、生検で確定診断は得られず、精査目的で当科紹介された。左頬粘膜部、耳下腺乳頭下部に25mm大の境界明瞭、可動性で弾性硬の腫瘤を触知した。CTでは左咀嚼筋隙に、下顎枝前縁から咬筋の内側、内側翼突筋の外側に接する境界明瞭で均一な造影性を示す腫瘤を認め、MRIのT1強調像で低信号、T2強調像では高信号を呈した。前医での病理所見は異型性に乏しい紡錘形細胞が主体であったことより、生検瘢痕組織を含め腫瘍摘出術を施行した。術後1年6ヵ月で再発・転移の徴候はない。病理組織学的所見で、病変は線維性被膜内に限局していた。腫瘍細胞は短紡錘形細胞が不規則かつびまん性に増殖し、細胞異型は乏しく、ごく少数の核分裂像を認めた。腫瘍間質はstaghorn vesselsや扁平な内皮細胞と壁の薄い血管周囲に膠原線維の形成を伴っていた。免疫染色ではCD34およびvimentinが陽性、Ki-67陽性細胞数は少なく標識率2.1%で、孤在性線維性腫瘍と病理診断した。

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2008&ichushi_jid=J01073&link_issn=&doc_id=20080229420003&doc_link_id=10.5794%2Fjjoms.54.54&url=https%3A%2F%2Fdoi.org%2F10.5794%2Fjjoms.54.54&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Osteonecrosis of the jaw is a severe new complication in cancer patients with bone metastases receiving bisphosphonate. Currently, there is no effective treatment for bisphosphonate-related osteonecrosis of the jaw, and the pathogenesis of this complication has not been completely elucidated. It has been shown that a potential risk factor for the complication is dentoalveolar trauma including extraction of teeth during bisphosphonate therapy. Attention should be paid to dental care in patients prior to the initiation of bisphosphonate therapy, and extraction of teeth during bisphosphonate therapy should be avoided to prevent this complication. Therefore, the communication between general physicians prescribing bisphosphonate and dentists is important.

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Language：Japanese   Publisher：(株)篠原出版新社  

広範囲切除・再建術を伴う進行口腔癌の治療では長期の経腸栄養が必要であり、消化管合併症の対策が重要である。糖尿病を有する舌再建後の患者に粘度可変型流動食を使用し、術後の回復に有効であった症例を報告する。患者は67歳の男性で、合併症に糖尿病を認めた。右側舌癌T4aN0M0の診断の下、可動部舌亜全摘、頸部郭清術、広背筋皮弁再建術、胃瘻造設術を施行した。術後から糖尿病用濃厚流動食を開始したが、術後1ヵ月から難治性の下痢が出現した。粘度可変型流動食への変更を行ったところ、投与後から下痢症状の改善を認め、術後4ヵ月で退院となった。粘度可変型流動食は糖尿病を有する口腔癌患者の術後回復期に有効であると考えられた。(著者抄録)

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JOHN WILEY & SONS LTD  

Web of Science

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Language：English   Publisher：日本がん免疫学会  

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Language：Japanese   Publisher：日本がん免疫学会  

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