Immunohistological evaluation of patients treated with intra-arterial chemoradiotherapy and surgery for oral cancer.

Preoperative intra-arterial chemoradiotherapy (IACRT) can improve the outcome and reduce the extent of surgery in patients with advanced oral cancer. However, the response to this regimen varies among patients, which may be related to the immune status of the tumor. We investigated the effects of proteins involved in tumor immunity on the outcomes of combined IACRT and surgery for oral cancer. We examined CD8 + and FoxP3 + tumor-infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) expression on immune cells and tumor cells in pretreatment biopsy samples from 69 patients diagnosed with oral cancer treated with IACRT at our institution during 2000-2020. Patients with abundant CD8 + TILs had significantly better 5-year disease-specific survival (DSS) compared to that of patients with less infiltration of these cells (P = 0.016). Patients with higher FoxP3 + T-cells invasion had significantly better DSS compared to that of less FoxP3 (P = 0.005). Patients with high PD-L1 expression in tumor cells and immune cells had significantly better DSS than that of patients with low PD-L1 expression in these cells (P = 0.009 and P = 0.025, respectively). Collectively, these results suggest that the tumor immune microenvironment could affect outcomes of IACRT treatment in oral cancer.

Injectate spread in ultrasound-guided inferior alveolar nerve block: a cadaveric study.

PURPOSE: Ultrasound-guided inferior alveolar nerve block (UGIANB) is a mandibular analgesic procedure in which local anesthetic is injected into the pterygomandibular space (PMS). Several studies have reported the clinical efficacy of UGIANB for mandibular surgeries; however, its effective range has never been investigated. We performed a cadaveric study to investigate the success rate of UGIANB injections and to determine whether injected dye could stain the mandibular nerve (MN) trunk and its branches. METHODS: We performed UGIANB on the bilateral faces of 4 Thiel-embalmed cadavers. A needle was advanced to the PMS under ultrasound guidance and 5 mL of dye was injected. The cadaver was dissected and inspected for the presence of dye in the PMS; the range of dye spread to any of the inferior alveolar nerve (IAN), lingual nerve (LN), buccal nerve (BN), mandibular nerve (MN), auriculotemporal nerve (ATN), or facial nerves; and for the presence of intravascular dye. RESULTS: We performed eight UGIANB procedures on four cadavers. Dye was observed in the PMS in 7/8 injections. Staining was observed in all IAN, LN, and BNs that could be identified at dissection. No MN or auriculotemporal nerves (ATNs) were stained in any injections. No intravascular dye was observed in any injections. CONCLUSIONS: UGIANB can administer anesthetic into the PMS with high accuracy. UGIANB injections reached the IAN, LN, and BNs, but did not reach the MN or ATNs located outside the PMS. The findings of this cadaveric study indicate that UGIANB can provide sufficient analgesia for mandibular surgeries.

Prognostic value of HLA class I expression in patients with oral squamous cell carcinoma.

Human leukocyte antigen (HLA) class Ⅰ molecules play a central role in anticancer immunity, but their prognostic value in oral squamous cell carcinoma (OSCC) remains unclear. We examined HLA class I expression in 2 distinct tumor compartments, namely, the tumor center and invasive front, and evaluated the association between its expression pattern and histopathological status in 137 cases with OSCC. Human leukocyte antigen class Ⅰ expression was graded semiquantitatively as high, low, and negative. At the invasive front of the tumor, HLA class I expression was high in 72 cases (52.6%), low in 44 cases (32.1%), and negative in 21 cases (15.3%). The HLA class I expression in the tumor center was high in 48 cases (35.0%), low in 58 cases (42.4%), and negative in 31 cases (22.6%). The 5-year overall survival and disease-specific survival rates were good in cases with high HLA class I expression at the invasive front; however, there was no significant difference in survival based on HLA class I expression in the tumor center. In addition, high HLA class I expression was correlated with high CD8+ T cell density, whereas negative HLA class I expression was correlated with low CD8+ T cell density at the invasive front. These results suggest that it is easier for CD8+ T cells to recognize presented peptides in the case of high HLA class Ⅰ expression at the tumor invasive front and could be a prognostic factor for OSCC.

Quantitative Evaluation of Cephalometric Radiographs of Patients With Hemifacial Microsomia.

OBJECTIVE: To clarify the morphological characteristics of hemifacial microsomia (HFM) by quantitative analysis of cephalometric radiographs. DESIGN: Retrospective study of imaging data. SETTING: Imaging data were obtained from the records of Sapporo Medical University Hospital. PATIENTS: A total of 183 patients with HFM. MAIN OUTCOME MEASURES: We used linear and angular measurements and analyzed the middle face and lower face. RESULTS: The ratios of the affected side to the unaffected (A/U) side of the lateral distance of the mandibular condyle, the mandibular ramus height, and the length of the body of the mandible in the HFM group were significantly lower than in the control group. The inclination of the body of the mandible was significantly larger in the side with HFM than in the unaffected side, and the extent of the mandibular ramus was significantly lower than in the unaffected side. The A/U ratios of the extent of the angle of the mandible and the inclination of the body of the mandible in the HFM group were larger than in the control group. Moreover, the length and the inclination of the body of the mandible had significant correlations with the distance of the shift of the menton. CONCLUSIONS: It is suggested that improving the hypoplasia of the length of the body of the mandible and the extent of the angle of the mandible on the affected side will lead to more effective treatment of jaw deformity in patients with HFM.

Diverticulum of the buccal mucosa: a rare case report and review of the literature.

BACKGROUND: Cases of diverticula of the buccal mucosa are extremely rare. Literature searches of databases such as PubMed/MEDLINE for this condition have revealed only 10 case reports. In this case report, we describe our experience in the management of this rare condition and review the previous 10 previously reported cases. CASE PRESENTATION: A 66-year-old man presented with a pouch containing inspissated food debris located posterior to the papilla of the parotid duct in his left buccal mucosa. The diagnosis of a diverticulum arising from the buccal mucosa was confirmed based on clinical and radiographic findings. Gross examination of the locally resected tissue specimen revealed a pouch measuring 14 mm in diameter and 8 mm in depth, that was whitish in color and had an elastic, soft, and smooth surface. Microscopic examination revealed a cyst-like lesion lined by stratified squamous epithelium and granulation tissue, with a chronic inflammatory infiltration in the peripheral stromal tissue of the epithelial layer. After surgical excision of the lesion, there was no recurrence during the follow-up period of 5 years and 10 months. CONCLUSIONS: We have presented a rare case of a diverticulum of the buccal mucosa. This is the first report of a case confirmed not only by the clinicopathological findings, but also by computed tomography and magnetic resonance imaging findings. From the magnetic resonance imaging and intraoperative findings, we inferred that the diverticulum was caused by an idiopathic developmental anomaly due to a partial defect of the buccinator muscle.

Relationship Between Mandibular Ramus Height and Masticatory Muscle Function in Patients With Unilateral Hemifacial Microsomia.

OBJECTIVE: To clarify the relationship between mandibular ramus height and function of masticatory muscles in patients with hemifacial microsomia. DESIGN: Retrospective study of imaging and physiological data. SETTING: Images and physiological data were obtained from the records of Sapporo Medical University Hospital. PATIENTS: A total of 29 patients with hemifacial microsomia who showed Pruzansky grades I, II deformity. MAIN OUTCOME MEASURES: Mandibular ramus height and masticatory muscle volume were evaluated with multi-detector row computed tomography. The electromyographic value was measured by the K7 Evaluation System. The hemifacial microsomia patients were classified into three groups based on the mandibular ramus height ratio of the affected and unaffected sides: group 0, >1.00; group 1, 1.00 to 0.85; group 2, <0.85. The Tukey-Kramer method and Games-Howell method were used to determine correlations between parameters. RESULTS: Decreased mandibular ramus height was significantly correlated with both reduced electromyographic values of the masseter muscle (P < .05) and the amount of mandibular lateral deviation at the time of maximum opening (P < .05) on the affected side. These differences were prominent in unilateral hemifacial microsomia patients classified as group 2. CONCLUSIONS: Decreased mandibular ramus height may cause dysfunction of the masseter muscles but not the temporal muscle on the affected side in patients with hemifacial microsomia.

Notch signaling genes and CD8+ T-cell dynamics: Their contribution to immune-checkpoint inhibitor therapy in oral squamous cell carcinoma: A retrospective study.

BACKGROUND: Aberrant Notch signaling pathway has been related with the tumorigenesis in head and neck region, involving oral cavity. Here, we report the correlation between mutations in the Notch signaling pathway and CD8+ T-cell infiltration via PD-L1, which lead to enhanced antitumor immunity and may target for immune-checkpoint inhibitors (ICIs) therapy. METHODS: This retrospective study analyzed the results of immunohistochemical staining for PD-L1 and CD8+ T-cell infiltration in 10 patients and whole-exome sequencing (WES) was conducted on five of these patients to identify frequently mutated genes. RESULTS: Four of 10 patients were positive for PD-L1 and CD8+ T. By analyzing WES in three of these four patients, we notably identified the mutations of NOTCH1, FBXW7, and noncoding RNA intronic mutation in NOTCH2NLR in two of these three patients. This study may enable better selection of ICI therapy with CD8+ T-cell infiltration via PD-L1 expression for oral squamous cell carcinoma patients with mutations in Notch signaling pathway.

Silencing of GLUT-1 inhibits sensitization of oral cancer cells to cisplatin during hypoxia.

BACKGROUND: During tumor development, cells are exposed to a hypoxic microenvironment. Tumor hypoxia also has a profound influence on the sensitivity of cancer chemotherapy. The objective of this study was to investigate the mechanism of cisplatin (CDDP) resistance of oral squamous cell carcinoma (OSCC) cells under hypoxia by analyzing gene expression profiles to identify key genes and factors involved. METHODS: Cell viability was measured following culture of the cells in the presence or absence of CDDP, under normoxic or hypoxic conditions, using a CCK-8 assay. Analysis of the expression of HIF target genes in hypoxia-treated cells was performed using an HIF-regulated cDNA plate array. Changes in the mRNA expression of selected HIF target genes were analyzed using RT-PCR, and changes in the protein levels of these genes were analyzed by Western blotting. Tumor cell apoptosis was assessed by flow cytometry. RESULTS: The OSCC cell lines responded differently to CDDP under normoxic and hypoxic conditions. The expression of glucose transporter protein-1 (GLUT-1) was up-regulated in human squamous cell carcinoma of mouth (HSC-2) cells under hypoxia. Furthermore, there was little correlation between the cisplatin sensitivity of human squamous cell carcinoma of tongue (SAS) in normoxia and hypoxia. After GLUT-1 knockdown, CDDP treatment resulted in increased rates of apoptosis under hypoxia as compared with normoxia in cell lines HSC-2, Ca9-22, and SAS (P = 0.025). CONCLUSION: The results of this study suggest that knockdown of GLUT-1 inhibits sensitization of oral squamous cells to CDDP during hypoxia in HSC-2, Ca9-22, and SAS cells.

Assessment of the shape of the inferior alveolar canal as a marker for increased risk of injury to the inferior alveolar nerve at third molar surgery: a prospective study.

PURPOSE: Morphologic evaluation of computed tomographic images is an important assessment tool before surgical removal of the lower third molar (LM3). The aim of this study was to ascertain whether the shape of the inferior alveolar canal (IAC) is a reliable predictor for inferior alveolar nerve (IAN) injury during M3 surgery. MATERIALS AND METHODS: This prospective study assessed samples with a high risk of IAN injury during M3 surgery based on orthopantomographic examination. The predictor variables were demographic factors (patient's age and gender), anatomic factors (angulation of the tooth), and radiographic factors (cortication status, buccolingual position, shape of the IAC, number of roots, and root shape). The outcome variable was IAN injury. The relation between predictor and outcome variables was analyzed using the Fisher exact test and a logistic regression model. RESULTS: One hundred sixty-nine LM3s (115 patients) were analyzed. IAN injury was observed in 12 of 115 patients and 13 of 169 LM3s (7.7%). All 13 cases with IAN injury exhibited absence of cortication. A dumb-bell-shaped IAC was considered a useful predictor for IAN injury (sensitivity, 69.2%; specificity, 84.6%). In cases with absence of cortication, logistic regression analysis indicated that a dumb-bell-shaped IAC was closely related to IAN injury (P = .005). CONCLUSION: The cortication status and shape of the IAC are reliable predictors for IAN injury at M3 surgery. Cases exhibiting absence of cortication and a dumb-bell-shaped IAC should be recognized as presenting a high risk of IAN injury at M3 surgery.

Accurate estimation of skeletal muscle mass by comparison of computed tomographic images of the third lumbar and third cervical vertebrae in Japanese patients with oral squamous cell carcinoma.

OBJECTIVES: We evaluated the accuracy of estimating the cross-sectional area (CSA) at the third lumbar vertebra (L3) based on the CSA at the third cervical vertebra (C3) using computed tomographic images, and we identified the sources of error and bias using the evaluation of absolute reliability in 89 Japanese patients with oral squamous cell carcinoma. METHODS: Skeletal muscle CSA was measured at the C3 and L3 on pretreatment computed tomographic images. We used the CSA at the C3 to estimate CSA at the L3 in an existing prediction formula. Correlation coefficients were used to evaluate the relative reliability of the estimate, and Bland-Altman analysis and minimum detectable change (MDC) were used to evaluate its absolute reliability. RESULTS: Estimated and actual CSAs at L3 were strongly correlated (r = 0.885, p < 0.001). The mean difference between the estimated and actual CSAs was - 1.0887 cm2, the 95% confidence interval was - 4.09 to 1.91 cm2 (p = 0.472), and the 95% limits of agreement were - 29.0 and 26.8 cm2. The MDC at the 95% level of confidence in estimated and actual CSAs was 27.9 cm2. CONCLUSIONS: The estimation of CSA at the L3 from the existing prediction formula with the CSA at the C3 had no systematic biases, but it did have random errors. Random errors resulted from measurement errors and biological variation. Usefulness of the existing formula is limited by physical differences in populations.

ACLP Activates Cancer-Associated Fibroblasts and Inhibits CD8+ T-Cell Infiltration in Oral Squamous Cell Carcinoma.

We previously showed that upregulation of adipocyte enhancer-binding protein 1 (AEBP1) in vascular endothelial cells promotes tumor angiogenesis. In the present study, we aimed to clarify the role of stromal AEBP1/ACLP expression in oral squamous cell carcinoma (OSCC). Immunohistochemical analysis showed that ACLP is abundantly expressed in cancer-associated fibroblasts (CAFs) in primary OSCC tissues and that upregulated expression of ACLP is associated with disease progression. Analysis using CAFs obtained from surgically resected OSCCs showed that the expression of AEBP1/ACLP in CAFs is upregulated by co-culture with OSCC cells or treatment with TGF-ß1, suggesting cancer-cell-derived TGF-ß1 induces AEBP1/ACLP in CAFs. Collagen gel contraction assays showed that ACLP contributes to the activation of CAFs. In addition, CAF-derived ACLP promotes migration, invasion, and in vivo tumor formation by OSCC cells. Notably, tumor stromal ACLP expression correlated positively with collagen expression and correlated inversely with CD8+ T cell infiltration into primary OSCC tumors. Boyden chamber assays suggested that ACLP in CAFs may attenuate CD8+ T cell migration. Our results suggest that stromal ACLP contributes to the development of OSCCs, and that ACLP is a potential therapeutic target.

CXCL12 is expressed by skeletal muscle cells in tongue oral squamous cell carcinoma.

BACKGROUND: The CXCL12/CXCR4 axis plays a pivotal role in the progression of various malignancies, including oral squamous cell carcinoma (OSCC). In this study, we aimed to clarify the biological and clinical significance of CXCL12 in the tumor microenvironment of OSCCs. METHODS: Publicly available single-cell RNA-sequencing (RNA-seq) datasets were used to analyze CXCL12 expression in head and neck squamous cell carcinomas (HNSCC). Immunohistochemical analysis of CXCL12, α-smooth muscle antigen (α-SMA), fibroblast activation protein (FAP) and CD8 was performed in a series of 47 surgically resected primary tongue OSCCs. Human skeletal muscle cells were co-cultured with or without OSCC cells, after which CXCL12 expression was analyzed using quantitative reverse-transcription PCR. RESULTS: Analysis of the RNA-seq data suggested CXCL12 is abundantly expressed in stromal cells within HNSCC tissue. Immunohistochemical analysis showed that in grade 1 primary OSCCs, CXCL12 is expressed in both tumor cells and muscle cells. By contrast, grade 3 tumors were characterized by disruption of muscle structure and reduced CXCL12 expression. Quantitative analysis of CXCL12-positive areas within tumors revealed that reduced CXCL12 expression correlated with poorer overall survival. Levels of CXCL12 expression tended to inversely correlate α-SMA expression and positively correlate with infiltration by CD8+ lymphocytes, though these relations did not reach statistical significance. CXCL12 was significantly upregulated in muscle cells co-cultured with OSCC cells. CONCLUSION: Our results suggest that tongue OSCC cells activate CXCL12 expression in muscle cells, which may contribute to tumor progression. However, CXCL12 is reduced in advanced OSCCs due to muscle tissue destruction.

Clinical significance of computed tomographic assessment and anatomic features of the inferior alveolar canal as risk factors for injury of the inferior alveolar nerve at third molar surgery.

PURPOSE: To assess the clinical features of the inferior alveolar canal (IAC) using computed tomography (CT) and to analyze the significance of CT examination at third molar surgery. MATERIALS AND METHODS: A retrospective cohort study was performed involving 99 patients (145 teeth). The relationship between cortication status, buccolingual position, and shape of the IAC on the CT image and inferior alveolar nerve (IAN) injury after third molar surgery were statistically analyzed. RESULTS: The shape of the IAC was categorized into 3 groups: round/oval, teardrop, and dumbbell. IAN injury was observed in 7 of 145 cases (4.8%). All 7 cases exhibited absence of cortication; 3 were dumbbell shape and 4 were round/oval. According to logistic regression analysis of cases with absence of cortication, IAC shape was closely related to IAN injury. CONCLUSIONS: These results suggest that assessment of the IAC shape and cortication status at third molar surgery may be clinically useful.

Clinical and histopathologic effects of neoadjuvant intra-arterial chemoradiotherapy with cisplatin in combination with oral S-1 on stage III and IV oral cancer.

OBJECTIVE: The aim of this study was to examine the clinical and histopathologic effects of neoadjuvant intra-arterial chemoradiotherapy (IACRT) using cisplatin in combination with oral S-1 (tegafur/gimeracil/oteracil potassium) on stage III and IV oral squamous cell carcinoma. STUDY DESIGN: Thirty patients received infusions of superselective intra-arterial cisplatin 60 mg/m2 by the Seldinger method and conventional external beam radiotherapy (total 40 Gy) combined with oral S-1 on the day of irradiation. Curative surgery and neck dissection were performed 4 to 6 weeks after IACRT. The clinical response of the primary lesion was evaluated approximately 4 weeks after IACRT. The surgically resected specimens were examined for histologic features according to the grading system for histologic evaluation and for residual tumor grade (RGrades). RESULTS: Histopathologic evaluation of the therapeutic effect was grade 2 in 10 patients and grade 3 in 16 patients. According to the distribution of RGrades, the remaining tumor cells were mostly in the central area of the primary lesion, as seen in 24 patients. CONCLUSIONS: These findings indicate that neoadjuvant IACRT with cisplatin and oral S-1 was an effective treatment, suggesting the possibility of reducing the extent of curative surgery based on RGrades.

Prognostic Value of CD45Ro+ T-Cell Expression in Patients With Oral Squamous Cell Carcinoma.

BACKGROUND/AIM: The role of tumour-infiltrating CD45Ro+ T-cells in oral squamous cell carcinoma (OSCC) is unclear. This study aimed to evaluate prognostic biomarkers for OSCC. PATIENTS AND METHODS: We determined the density of tumour-infiltrating CD45Ro+ T cells in the parenchyma and stroma at the tumour centre (TCe) and invasive front (IF) and examined the association between the density of these cells and histopathological status in 142 patients. RESULTS: Five-year overall survival (OS) and recurrence-free survival were favourable in patients with high CD45Ro+ T-cell density in the TCe stroma. OS was favourable in patients with high CD45Ro+ T-cell density in the IF stroma. Stepwise Cox regression model analysis indicated that CD45Ro+ T-cells in the stroma of the IF and TCe were an independent prognostic factor for OS. CONCLUSION: CD45Ro+ T-cells in the stroma of the IF and TCe play a role in cancer immune surveillance and may be a useful prognostic factor.

DLEU1 promotes oral squamous cell carcinoma progression by activating interferon-stimulated genes.

Long noncoding RNAs (lncRNAs) are deeply involved in cancer development. We previously reported that DLEU1 (deleted in lymphocytic leukemia 1) is one of the lncRNAs overexpressed in oral squamous cell carcinoma (OSCC) cells, where it exhibits oncogenic activity. In the present study, we further clarified the molecular function of DLEU1 in the pathogenesis of OSCC. Chromatin immunoprecipitation-sequencing (ChIP-seq) analysis revealed that DLEU1 knockdown induced significant changes in the levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3K27 acetylation (H3K27ac) in OSCC cells. Notably, DLEU1 knockdown suppressed levels of H3K4me3/ H3K27ac and expression of a number of interferon-stimulated genes (ISGs), including IFIT1, IFI6 and OAS1, while ectopic DLEU1 expression activated these genes. Western blot analysis and reporter assays suggested that DLEU1 upregulates ISGs through activation of JAK-STAT signaling in OSCC cells. Moreover, IFITM1, one of the ISGs induced by DLUE1, was frequently overexpressed in primary OSCC tumors, and its knockdown inhibited OSCC cell proliferation, migration and invasion. These findings suggest that DLEU1 exerts its oncogenic effects, at least in part, through activation of a series ISGs in OSCC cells.

Prognostic value of FoxP3 and CTLA-4 expression in patients with oral squamous cell carcinoma.

BACKGROUND: Tumor-infiltrating lymphocytes include tumor-reactive lymphocytes and regulatory T-cells. However, the prognostic value of tumor-infiltrating lymphocytes in oral squamous cell carcinoma (OSCC) remains unclear. METHODS: We used immunohistochemistry to evaluate the presence of tumor-infiltrating FoxP3⁺ T-cells and CTLA-4⁺ cells in four distinct histological compartments (tumor parenchyma and stroma at the tumor center, and parenchyma and stroma at the invasive front) and assessed the association between the prevalence of these cells and the histopathological status of 137 patients with OSCC. RESULTS: Five-year overall survival, disease-specific survival, and recurrence-free survival were favorable in patients with high numbers of FoxP3⁺ T-cells in the parenchyma of the invasive front. Recurrence-free survival and metastasis-free survival were decreased in patients with high numbers of CTLA-4⁺ cells in the parenchyma of the invasive front. CONCLUSIONS: The presence of FoxP3⁺ T-cells in the parenchyma of the invasive front may be a useful prognostic factor. Our results indicate that FoxP3⁺ T-cells may exert site-specific anti-tumor effects but may not play an immunosuppressive role in OSCC. In addition, our results suggest that CTLA-4+ cells suppress the function of FoxP3+ T-cells and promote anti-tumor immunity in OSCC.

The proximal promoter governs germ cell-specific expression of the mouse glutathione transferase mGstm5 gene.

To explain the tissue-selective expression patterns of a distinct subclass of glutathione S-transferase (GST), transgenic mice expressing EGFP under control of a 2 kb promoter sequence in the 5'-flanking region of the mGstm5 gene were produced. The intent of the study was to establish whether the promoter itself or whether posttranscriptional mechanisms, particularly at the levels of mRNA translation and stability or protein targeting, based on unique properties of mGSTM5, determine the restricted expression pattern. Indeed, the transgene expression was limited to testis as the reporter was not detected in somatic tissues such as brain, kidney or liver, indicating that the mGstm5 proximal promoter is sufficient to target testis-specific expression of the gene. EGFP expression was also more restricted vis-a-vis the natural mGstm5 gene and exclusively found in germ but not in somatic cells. Real-time quantitative PCR (qPCR) data were consistent with alternate transcription start sites in which the promoter region of the natural mGstm5 gene in somatic cells is part of exon 1 of the germ cell transcript. Thus, the primary transcription start site for mGstm5 is upstream of a TATA box in testis and downstream of this motif in somatic cells. The 5' flanking sequence of the mGstm5 gene imparts germ cell-specific transcription.

[Clinical investigation of bisphosphonate-related osteonecrosis of the jaws].

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.

A single-institute phase I/II trial combining nedaplatin dose escalation with a fixed dose of docetaxel for induction chemotherapy of oral squamous cell carcinoma.

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.