Toshiyuki Koizumi

Direct action of nitric oxide on osteoblastic differentiation

The effect of nitric oxide (NO) on osteoblastic differentiation was examined in cultured mouse osteoblasts. Interleukin‐1β and tumor necrosis factor‐α expressed inducible NO synthase gene with little effect on constitutive NO synthase gene. These cytokines increased NO production, which was inhibited by l‐NMMA pretreatment, and decreased alkaline phosphatase (AIPase) activity, which was not restored by l‐NMMA. Furthermore, NO donors, sodium nitroprusside and NONOate dose‐dependently elevated AIPase activity and expression of osteocalcin gene. These results suggest that NO directly facilitates osteoblastic differentiation and the cytokine‐induced inhibition of AIPase activity is mediated via mechanism other than NO.

Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for stage III and IV oral cancer: Analysis of therapeutic results in 112 cases

PURPOSEnTo evaluate the therapeutic results and rate of organ preservation in patients with stage III or IV oral cancer treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy.nnnMATERIALS AND METHODSnOne hundred and twelve patients with stage III and IV oral squamous cell carcinoma underwent intra-arterial chemoradiotherapy. Catheterization from the superficial temporal and occipital arteries was performed. Treatment consisted of superselective intra-arterial chemotherapy (docetaxel, total 60mg/m(2), cisplatin, total 150mg/m(2)) and daily concurrent radiotherapy (total of 60Gy) for 6 weeks.nnnRESULTSnThe median follow-up for all patients was 46.2 months (range, 10-76 months). After intra-arterial chemoradiotherapy, primary site complete response was achieved in 98 (87.5%) of 112 cases. Five-year survival and local control rates were 71.3% and 79.3%, respectively. Grade 3 or 4 toxicities included mucositis in 92.0%, neutropenia in 30.4%, dermatitis in 28.6%, anemia in 26.8%, and thrombocytopenia in 7.1% of patients. Grade 3 toxicities included dysphagia in 72.3%, nausea/vomiting in 21.4%, fever in 8.0%, and renal failure in 0.9% of patients.nnnCONCLUSIONnRetrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for stage III and IV oral cancer provided good overall survival and local control.

Strain- and age-dependent loss of sarcoglycan complex in cardiomyopathic hamster hearts and its re-expression by δ-sarcoglycan gene transfer in vivo

The δ‐sarcoglycan (SG) gene is deleted in hamsters with hereditary cardiomyopathies. Immunological analyses of heart before, but not after, the progression of cardiomyopathy (CM) revealed that the BIO 14.6 strain, a model of hypertrophic CM, heterogeneously preserved α‐ and γ‐SG with loss of β‐ and δ‐SG. In contrast, the TO‐2 strain, a model of dilated CM, did not show either SG. Furthermore, in vivo transfer of the full length δ‐SG gene to TO‐2 hearts expressed all four SGs. Thus, this age‐ and strain‐dependent features suggest a more feasible setting for TO‐2 than BIO 14.6 to verify both CM progression and the efficacy of gene therapy.

Thermochemoradiation Therapy Using Superselective Intra-arterial Infusion via Superficial Temporal and Occipital Arteries for Oral Cancer With N3 Cervical Lymph Node Metastases

PURPOSEnTo evaluate the therapeutic results and histopathological effects of treatment with thermochemoradiation therapy using superselective intra-arterial infusion via the superficial temporal and occipital arteries for N3 cervical lymph node metastases of advanced oral cancer.nnnMETHODS AND MATERIALSnBetween April 2005 and September 2010, 9 patients with N3 cervical lymph node metastases of oral squamous cell carcinoma underwent thermochemoradiation therapy using superselective intra-arterial infusion with docetaxel (DOC) and cisplatin (CDDP). Treatment consisted of hyperthermia (2-8 sessions), superselective intra-arterial infusions (DOC, total 40-60 mg/m(2); CDDP, total 100-150 mg/m(2)) and daily concurrent radiation therapy (total, 40-60 Gy) for 4-6 weeks.nnnRESULTSnSix of 9 patients underwent neck dissection 5-8 weeks after treatment. In four of these 6 patients, all metastatic lymph nodes, including those at N3, were grade 3 (non-viable tumor cells present) or grade 4 (no tumor cells present) tumors, as classified by the system by Shimosato et al (Shimosato et al Jpn J Clin Oncol 1971;1:19-35). In 2 of these 6 patients, the metastatic lymph nodes were grade 2b (destruction of tumor structures with a small amount of residual viable tumor cells). The other 3 patients did not undergo neck dissection due to distant metastasis after completion of thermochemoradiation therapy (n=2) and refusal (n=1). The patient who refused neck dissection underwent biopsy of the N3 lymph node and primary sites and showed grade 3 cancer. During follow-up, 5 patients were alive without disease, and 4 patients died due to pulmonary metastasis (n=3) and noncancer-related causes (n=1). Five-year survival and locoregional control rates were 51% and 88%, respectively.nnnCONCLUSIONSnThermochemoradiation therapy using intra-arterial infusion provided good histopathologic effects and locoregional control rates in patients with N3 metastatic lymph nodes. However, patients with N3 metastatic lymph nodes experienced a high rate of distant metastases.

Radiation therapy with concurrent retrograde superselective intra-arterial chemotherapy for gingival carcinoma.

PurposeThe aim of this study was to review the efficacy and toxicity of radiation therapy with concurrent retrograde superselective intra-arterial chemotherapy in the treatment of gingival carcinoma.Methods and materialsIn all, 34xa0patients (21xa0men and 13xa0women) with squamous cell carcinoma of the gingiva underwent radiation therapy with concurrent retrograde superselective intra-arterial chemotherapy. Treatment consisted of daily external irradiation and concurrent retrograde superselective intra-arterial infusion with cisplatin and docetaxel. A median total dose of 60xa0Gy in 30xa0fractions was delivered to tumors.ResultsOf the 34xa0patients, 29 (85u2009%) achieved a complete response (CR) and 5xa0had residual tumors. Of the 29xa0patients with a CR, 2 had local recurrences and 1 had distant metastasis 1–15xa0months after treatment. Twenty-six of the 36xa0patients had survived at a median follow-up time of 36xa0months (range 12–79xa0months); 4 died of cancer and 4 died of non-cancer-related causes. At both 3 and 5xa0years after treatment, the overall survival rates were 79u2009% and the cause-specific survival rates were 85u2009%. Osteoradionecrosis of the mandibular bone only developed in 1xa0patient after treatment.ConclusionRadiation therapy with concurrent retrograde superselective intra-arterial chemotherapy was effective and safe in the treatment of gingival carcinoma. This treatment may be a promising curative and organ-preserving treatment option for gingival carcinoma.ZusammenfassungHintergrund und ZielDas Ziel dieser Studie war die Überprüfung der Effizienz und Toxizität einer Strahlenbehandlung des Gingivakarzinoms mit gleichzeitiger retrograder, superselektiver intraarterieller Chemotherapie.Patienten und MethodenInsgesamt 34xa0Patienten (21xa0Männer und 13xa0Frauen) mit Zahnfleischplattenzellkarzinom erhielten eine Strahlenbehandlung mit gleichzeitiger retrograder, superselektiver intraarterieller Chemotherapie. Die Behandlung umfasste eine tägliche externe Bestrahlung mit gleichzeitiger retrograder, superselektiver intraarterieller Infusion von Cisplatin und Docetaxel. Die Tumore wurden mit einer durchschnittlichen Gesamtdosis von 60xa0Gy in 30xa0Fraktionen bestrahlt.ErgebnisseEine komplette Remission (CR) wurde bei 29 der 34xa0Patienten (85u2009%) erzielt; 5xa0Patienten hatten Resttumore. Von den 29xa0Patienten mit einer CR wiesen 2 Patienten lokale Rezidive und 1xa0Patient 1–15xa0Monate nach der Behandlung Fernmetastasen auf. Nach einer durchschnittlichen Beobachtungszeit von 36xa0Monaten (12–79xa0Monate) hatten 26 der 36xa0Patienten überlebt; 4xa0Patienten verstarben an Krebs und 4 verstarben an anderen, nicht krebsbezogenen Ursachen. Sowohl 3 und 5xa0Jahre nach der Behandlung betrug die Gesamtüberlebensrate 79u2009% und die ursachenspezifische Überlebensrate 85u2009%. Eine Osteoradionekrose des Unterkiefers trat nach der Behandlung bei 1xa0Patienten auf.SchlussfolgerungDie Strahlenbehandlung mit gleichzeitiger retrograder, superselektiver intraarterieller Chemotherapie war effektiv und sicher bei der Behandlung des Gingivakarzinoms. Diese Therapie kann eine vielversprechende, heilende und organsparende Behandlungsmöglichkeit für Gingivakarzinome darstellen.

Clinical outcomes of retrograde intra-arterial chemotherapy concurrent with radiotherapy for elderly oral squamous cell carcinoma patients aged over 80 years old

BackgroundThe aim of this retrospective observational study was to evaluate toxicities, overall survival, and locoregional control in elderly oral squamous cell carcinoma patients who had undergone retrograde intra-arterial chemotherapy combined with radiotherapy.MethodsThirty-one elderly patients over 80xa0years old with oral squamous cell carcinoma were enrolled in present study. The treatment schedule consisted of intra- arterial chemotherapy (docetaxel, total 60xa0mg/m2; cisplatin, total 150xa0mg/m2) and daily concurrent radiotherapy (total, 60xa0Gy) for 6xa0weeks.ResultsThe median patient age was 82.5xa0years old (range, 80–88xa0years). Of the 31 patients, six (19%) had stage II, 6 (19%) had stage III, 17 (55%) had stage IVA, and 2 (6%) had stage IVB. The median follow-up period for all patients was 37xa0months (range, 7–86xa0months). The 3-year overall survival and locoregional control rates were 78% and 81%, respectively. The major acute grade 3 adverse events were oral mucositis in 22 (71%) patients, neutropenia in 16 (52%), and dermatitis in 11 (35%). With respect to late toxicities, 1 patient (3%) developed grade 3 osteoradionecrosis of the jaw. No grade 4 or higher toxicities were observed during the treatment and follow-up periods.ConclusionsRetrograde intra-arterial chemotherapy combined with radiotherapy was effective in improving overall survival and locoregional control even for elderly patients.

Retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy for T2-4N0 tongue cancer: Control of occult neck metastasis

OBJECTIVEnTo evaluate the therapeutic results and control of occult neck metastasis in patients with T2-4N0 oral tongue squamous cell carcinoma treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy.nnnSTUDY DESIGNnForty-two patients with T2-4N0 tongue cancer (17 with late T2; 13 with T3; and 12 with T4a disease, M0) were treated with intra-arterial chemoradiotherapy. Treatment consisted of retrograde superselective intra-arterial chemotherapy (docetaxel 50-70xa0mg/m2, cisplatin 125-175xa0mg/m2) and daily concurrent radiotherapy (50-70xa0Gy) for 5-7xa0weeks.nnnRESULTSnThe median follow-up for all patients was 46.5xa0months (range, 8-105xa0months). Primary-site complete response was achieved in 42 of 42 cases (100%). Three-year overall survival, progression-free survival, and local control rates were 85.0%, 77.8%, and 91.7%, respectively. Delayed neck metastasis was detected in 5 of 42 cases (11.9%). Grade 3 or 4 toxic changes included oral mucositis in 92.9%, neutropenia in 21.4%, and thrombocytopenia in 4.8%. Grade 3 toxicities included anemia in 16.7%, radiation dermatitis in 9.5%, nausea in 4.8%, and fever in 2.4%.nnnCONCLUSIONSnRetrograde superselective intra-arterial chemotherapy for T2-4N0 tongue cancer provided good overall survival and local control rates and was effective for occult neck metastasis.

Intravenous Dexamethasone Administration Before Orthognathic Surgery Reduces the Postoperative Edema of the Masseter Muscle: A Randomized Controlled Trial

PURPOSEnDexamethasone seems to suppress postoperative swelling. However, the standard administration dose of dexamethasone for bilateral sagittal split osteotomy (BSSO) has not been reported. This study focused on clarifying the most effective dose of dexamethasone for BSSO.nnnMATERIALS AND METHODSnThis research was planned as a prospective, randomized controlled, double-blind study. Patients undergoing BSSO were randomly assigned to receive intravenous preoperative dexamethasone under 3 different dose conditions: 16xa0mg, 8xa0mg, and 0xa0mg (control). The endpoints of this study were 1) postoperative changes in masseter muscle thickness and buccal soft tissue thickness; 2) postoperative changes in maximum incisal opening; 3) postoperative changes in sensation of the chin and lower lip region; 4) postoperative changes in blood examination findings (white blood cell count, neutrophil count, C-reactive protein level, and lymphocyte count); and 5) types of complications. Data were recorded at 2 to 4 time intervals: before surgery, postoperative day 1, postoperative day 2, and postoperative day 3. Average age, gender, average body mass index, average surgery time, and average blood loss also were examined. Data were analyzed by 1-way analysis of variance (Bonferroni multiple-comparisons test) after the Bartlett test.nnnRESULTSnWe enrolled 24 patients, including 5 men and 19 women, in this study. The rate of increase in the thickness of the masseter muscle 24xa0hours after BSSO was 38.4% in the 16-mg group (nxa0= 8), 57.7% in the 8-mg group (nxa0= 8), and 56.1% in the 0-mg group (nxa0= 8). The rate of increase in masseter muscle thickness in the 16-mg group was significantly lower than that in the 0-mg group (P < .05). Regarding the number of lymphocytes after surgery, the 16-mg and 8-mg groups maintained preoperative levels whereas there was a reduced number of lymphocytes in the control group. No statistically significant results were obtained for the following study endpoints: postoperative changes in maximum incisal opening and postoperative changes in sensation of the chin and lower lip region.nnnCONCLUSIONSnThis investigation showed that the most effective dose of dexamethasone for BSSO is 16xa0mg.

Prognostic value of 2-[18 F]fluoro-2-deoxy-D-glucose positron emission tomography for patients with oral squamous cell carcinoma treated with retrograde superselective intra-arterial chemotherapy and daily concurrent radiotherapy

OBJECTIVEnTo investigate whether 2-[(18) F]fluoro-2-deoxy-D-glucose (FDG) uptake of primary tumor in oral squamous cell carcinoma (OSCC) could predict prognosis.nnnSTUDY DESIGNnSixty-nine patients with OSCC who underwent retrograde superselective intra-arterial chemoradiotherapy were recruited and underwent dual-time-point FDG positron emission tomography twice, before treatment and 4 weeks after treatment. FDG uptake was defined as the standardized uptake value (SUVmax). The retention index (RI) and the percent change in SUV (% change SUV), derived from the dual-time-point scan, were calculated.nnnRESULTSnOn univariate analysis, patients with high pre-SUV, RI, and percent change SUV values had significantly worse overall survival and disease-free survival compared with patients with low values. On multivariate analysis, high pre-RI (≥20.6%) and high percent change SUV (≥60.0%) (delayed-image) were associated with significantly worse overall survival. High pre-SUV (≥9.6) (delayed-image) and high pre-RI (≥20.6%) were associated with significantly shorter disease-free survival.nnnCONCLUSIONSnDual-time-point FDG positron emission tomography in OSCC provided prognostic information and predicted patient outcome.

Chemoradiotherapy using retrograde superselective intra-arterial infusion for tongue cancer: Analysis of therapeutic results in 118 cases

OBJECTIVESnTo evaluate the therapeutic results and rate of organ preservation in patients with squamous cell carcinoma of the tongue treated with retrograde superselective intra-arterial chemoradiotherapy.nnnMATERIALS AND METHODSnBetween June 2006 and June 2015, 118 patients with tongue cancer were treated with intra-arterial chemoradiotherapy. Treatment consisted of radiotherapy (total 50-70u202fGy) and daily concurrent intra-arterial chemotherapy (docetaxel, total 50-70u202fmg/m2; cisplatin, total 125-175u202fmg/m2) for 5-7u202fweeks. Locoregional control and overall survival rates were calculated by the Kaplan-Meier method. Coxs proportional hazards model was used for both univariate and multivariate analyses.nnnRESULTSnThe median follow-up for all patients was 38.5u202fmonths (range, 3-129u202fmonths). After intra-arterial chemoradiotherapy, primary site complete response was achieved in 113 (95.8%) of 118 cases. Three-year locoregional control and overall survival rates were 80.3% and 81.5%, respectively. Grade 3 or 4 toxicities included neutropenia in 16.1% and mucositis in 87.3%. Grade 3 toxicities included anemia in 12.7%, thrombocytopenia in 3.4%, nausea/vomiting in 3.4%, dermatitis in 45.7%, dysphagia in 74.6%, and fever in 2.5% of patients. Late toxicity consisting of grade 3 osteoradionecrosis of the jaw occurred in 4.2% of patients. On univariate analysis, T stage and overall stage were significantly associated with locoregional control, and N stage and overall stage were significantly associated with overall survival. On multivariate analysis, the only significant predictor of overall survival was overall stage classification.nnnCONCLUSIONnRetrograde superselective intra-arterial chemoradiotherapy for tongue cancer provided good overall survival and locoregional control.