The effect of zoledronic acid and denosumab on the mandible and other bones: a 18F-NaF-PET study.

OBJECTIVES: The primary purpose of this study was to determine whether both zoledronic acid (ZA) and denosumab (Dmab) equally suppress bone remodeling of the normal mandible, and the secondary purpose was to determine the influence of ZA and Dmab on other normal bones. METHODS: 18F-sodium fluoride-positron-emission-tomography (18F-NaF-PET) was used to perform quantitative analysis of the bone metabolism in various parts. The end points of the study were the mean standardized uptake value (SUV) of each member of the ZA group (n = 9), the Dmab group (n = 16), and the Control group (n = 23). RESULTS: The SUV at the thoracic vertebrae in the ZA group were significantly lower than those of the Dmab and Control group (p < 0.05) In addition, the mean SUVs of the cervical vertebrae in the ZA group were significantly lower than those in the Control group (p < 0.05). There was no significant difference among ZA, Dmab and Control group in the other sites. There was no significant difference between the Dmab and Control groups at all sites. CONCLUSIONS: The remodeling of mandible was not suppressed due to the treatment with anti-resorptive agents. Differences in the mechanisms of action between the BP and Dmab caused the specificity of the effect on the metabolism of normal bone.

Oral microorganisms and bloodstream infection in allogeneic hematopoietic stem cell transplantation.

OBJECTIVES: We aimed to compare oral and pathogenic microorganisms in bloodstream infections (BSIs) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). We also investigated the relationship between BSIs and oral mucositis to identify the ratio of BSIs caused by oral microorganisms and the pathogenic microorganisms involved. MATERIALS AND METHODS: We collected data on BSIs in 96 patients who underwent allo-HSCT in our institute between April 2009 and December 2019, including BSI pathogens isolated from blood cultures (BBSIs) and microorganisms isolated from washing the oral cavity with sterile distilled water. Oral microorganisms obtained at the onset of BSI (OBSIs) and during allo-HSCT (OSCTs) were defined as isolates collected during the week of blood culturing. Study entry was limited to samples collected up to 1 month after allo-HSCT without BSI. When the BBSI and OBSI were the same, we considered the oral microorganism to have caused the BSI. RESULTS: The incidence rate of BSIs was 27%, and the predominant microorganism was coagulase-negative Staphylococci. Normal bacterial flora were decreased to 15.8% in OBSIs and 25.5% in OSCTs. The distribution of microorganisms without normal bacterial flora showed significant difference between BBSIs and OSCTs (p < 0.05). Oral mucositis was found in 72.9%, and BSI caused by oral microorganisms occurred in 46.2% of BSIs in allo-HSCT patients. CONCLUSION: The distribution of microorganisms obtained from blood in patients with BSI during allo-HSCT was found to be similar to that of microorganisms from oral cultures. CLINICAL RELEVANCE: Oral microorganism monitoring may be able to predict BSI during allo-HSCT.

Bone metabolism of the jaw in response to bisphosphonate: a quantitative analysis of bone scintigraphy images.

We examined the changes in the bone metabolism of the jaw in response to BP treatment, and we used bone SPECT-CT to analyze the site-specific bone metabolism between the jaw and other sites of bone. We compared the changes in the bone metabolism of each part of bone in response to BP treatment by performing a quantitative analysis of bone scintigraphy images between patients treated with low-dose BP for osteoporosis (LBP group; n = 17), those treated with high-dose BP for metastatic bone tumor (HBP group; n = 11), and patients with other oral disease who required bone scintigraphy, with no history of BP treatment (control group; n = 40). The study endpoint was the mean standardized uptake value (SUV) of the uptake of Tc-99 m methylene diphosphonate (MDP) in each group. The mean SUVs of the HBP group were significantly lower at the axial bone of the cervical vertebra, thoracic vertebra, sternum, and rib compared to those of the LBP and control groups. The LBP group's mean SUV was significantly higher at the temporal bone, the anodontia part of the alveolar bone in maxilla, the vital teeth part of alveolar bone in the mandible, and the temporomandibular joint. There was no significant difference among the three groups at the mandibular angle and mandibular ramus. Our analyses revealed that the bone metabolism of the jaw and temporal bone in the BP-treated patients was enhanced, and no suppression of bone remodeling in the jaw by BP was observed.

Treatment outcomes of adjunctive teriparatide therapy for medication-related osteonecrosis of the jaw (MRONJ): A multicenter retrospective analysis in Japan.

BACKGROUND: Therapeutic strategies for patients with medication-related osteonecrosis of the jaw (MRONJ) remain controversial. The aim of the present study was to clarify the effectiveness and safety of teriparatide therapy in Japanese MRONJ patients based on a large number of case series with a multicenter retrospective analysis. PATIENTS AND METHODS: Between January 2012 and December 2016, 29 patients who were diagnosed with MRONJ at 10 hospitals were treated with teriparatide. The medical records of these patients were retrospectively reviewed to assess the efficacy and safety of teriparatide therapy for MRONJ patients. RESULTS: Adverse events occurred in 17.2% of patients (5/29). One patient developed severe arthralgia and discontinued teriparatide therapy after 12 days, while others continued the treatment. Among 29 patients, the median period of administration of teriparatide was 14.0 months (range, 0.3-26 months), and treatment outcomes were evaluated as effective in 75.9% of patients with complete resolution in 65.5%. Among patients treated with oral bisphosphonates (BPs), 83.3% were effectively treated with teriparatide and 40% with intravenous BPs. The oral administration of BPs was associated with successful treatment outcomes with teriparatide (p = 0.062). CONCLUSIONS: Teriparatide therapy has potential as an effective treatment option for MRONJ.

Quasi-Randomized Trial of Effects of Perioperative Oral Hygiene Instruction on Inpatients with Heart Diseases Using a Behavioral Six-Step Method.

The assessor-blinded, parallel-design, quasi-randomized study (alternating allocation) aimed to determine the effects of the six-step method on postoperative numbers of oral bacteria, periodontal status, and atrial fibrillation (AF) among inpatients with heart diseases and periodontitis. Seventy inpatients who received preoperative periodontal treatment were quasi-randomly assigned to intervention and control groups at University Hospital. The intervention group received intensive oral hygiene instruction using a six-step method for 15 minutes per week and the control group received routine oral hygiene instruction. Significantly fewer oral bacteria were identified on the tongue at discharge compared with baseline in the intervention than the control group (ANCOVA) (large effect size, p = 0.02). Changes in scores for self-efficacy, plaque scores, probed pocket depth, and bleeding on probing between baseline and discharge were significantly greater in the intervention, than in the control group (p < 0.05). The period of postoperative AF (days) was significantly shorter in the intervention, than in the control group (p = 0.019). In conclusion, oral hygiene instruction using the six-step method decreased the numbers of oral bacteria on the tongue and improved self-efficacy, oral health behaviors, oral hygiene status, periodontal status, and period of postoperative AF among inpatients with periodontitis and heart diseases.

Symposium: Imaging modalities for drug-related osteonecrosis of the jaw (6), assessment of mandibular metabolism due to long-term administration of an anti-resorptive agent by bone scintigraphy (secondary publication).

It is not yet known why anti-resorptive agent-related osteonecrosis specifically affects the jaw. Here we assessed changes in the bone metabolism of the mandible in response to long-term bisphosphonate (BP) therapy, and we compared the bone metabolism changes of the mandible with those of other bone sites using a quantitative analysis by bone scintigraphy. The region of interest was selected by identifying without an abnormal accumulation of the mandible, humerus, second and fourth lumbar vertebrae, iliac crest, intertrochanteric femur and diaphysis. Bone scintigraphy images were quantified using a value we termed the 'bone uptake value (BUV)'. In the low-dose bisphosphonate (LBP) group (n = 21), the patients were undergoing osteoporosis treatment with low-dose BP. The high-dose BP (HBP) group consisted of 12 bone metastasis patients undergoing high-dose BP treatment. The Control group was 47 subjects with oral disease who had never been treated with an anti-resorptive agent. Our analyses demonstrated that with long-term BP administration, the bone metabolism of the iliac crest and intertrochanteric femur was suppressed but that of the mandible was enhanced. There was no significant difference in bone metabolism with either the low-dose BP or high-dose BP treatment. The effects of the long-term administration of BP were site-specific.

Clinical impact of sarcopenia and relevance of nutritional intake in patients before and after allogeneic hematopoietic stem cell transplantation.

PURPOSE: We conducted a retrospective study to evaluate the effect of rehabilitation on minimizing sarcopenia during hematopoietic stem cell transplantation (HSCT) therapy. METHODS: We developed a protocol to test for retention of physical function during HSCT. Muscle strength, muscle circumference, and muscle function before and after HSCT were measured. Consecutive patients with hematological malignancies who underwent HSCT treatment were recruited in this research. RESULTS: We included 34 patients (16 females, 18 males; median age, 51.5 years). Bodyweight significantly decreased after HSCT (p < 0.001). Nine females and three males had sarcopenia prior to allogeneic HSCT. After HSCT, bilateral hand grip strength and bilateral knee extensor strength decreased significantly. The total caloric intakes for pre-conditioning, during preparation regimen, and after transplant were 1709, 1024, and 1445 kcal, respectively, and were significantly attenuated in the post-transplant period. Serum albumin was significantly decreased in the final period. Conversely, C-reactive protein was slightly but significantly increased across the transplantation process. Multivariate regression analysis revealed that oral caloric intake after the transplantation period and sex were significantly related to muscle weakness (p = 0.033 and 0.036, respectively). CONCLUSIONS: Sarcopenia during HSCT was affected by oral caloric intake during the preparation regimen and after transplantation. Physical therapy in conjunction with nutritional therapy may help prevent weakness in HSCT recipients.

The utility of bone scintigraphy in the assessment of mandibular metabolism during long-term bisphosphonate administration.

The duration of antiresorptive therapy is an important risk factor for medication-related osteonecrosis of the jaw. We performed a pilot study using quantitative analysis by bone scintigraphy to test the hypothesis that mandibular metabolism is affected by long-term bisphosphonate (BP) therapy. Our primary objectives were to assess changes in bone metabolism of the mandible in response to long-term BP therapy and compare the bone metabolism changes of the mandible with other bone sites. We compared the metabolic difference at the site in the mandible unaffected by disease, the humerus and the femur between 14 osteoporosis patients who were being treated with BP (BP group) and 14 patients who were not being treated with BP (control group) using a quantitative analysis and bone scintigraphy. Study endpoints were the mean and maximum bone uptake values (BUVs) quantified using bone scintigraphy images of the mandible, humerus and femur. Quantified images of the site in the mandible unaffected by disease had significantly higher mean and maximum BUVs compared to the controls (mean, 0.74 vs. 0.49, p = 0.019; max., 1.29 vs. 0.85, p = 0.009, respectively). The mean and maximum BUV of femur ROIs in the BP group were significantly lower than those in control patients (mean BUV, 0.23 vs. 0.30, p = 0.039; max. BUV, 0.43 vs. 0.53, p = 0.024, respectively). This is the first report of mandible changes in response to long-term BP treatment, using bone scintigraphy. The results using bone scintigraphy demonstrated that the bone metabolism of the intact mandible is affected by a long-term administration of BP.

Superselective Intra-arterial Infusion Chemotherapy with Nedaplatin for Oral Cancer: A Pharmacological Study of the Dose Clearance.

INTRODUCTION: Nedaplatin (cis-diammine-glycolate platinum) is a new anticancer agent developed in Japan. It is especially designed to reduce adverse side effects of CDDP such as renal toxicity and neurotoxicity. AIM: We used nedaplatin as a superselective intra-arterial infusion chemotherapy for oral cancers and carried out a pharmacological study of the dose clearance of nedaplatin based on renal function as well as evaluating its efficacy, including hematological side effects. PATIENTS AND METHODS: Typical regimens of this chemotherapy consisted of 5-days straight of 24-h continuous intravenous infusion of 5-Fu with a single shot of nedaplatin via transfemoral artery on day 4. The dose of nedaplatin was calculated based on the 24-h creatine clearance. A total of 37 patients who had oral cancer and had received 68 courses (total) of chemotherapy were found to be eligible for this study. RESULTS: Total and free platinum concentrations in the plasma were measured at each of the time points, and the area under the curve (AUC, measured in units of µg h/ml) was calculated based on the platinum concentration with the following formula: CL (clearance of free platinum: l/h) = 0.042 × CCr (ml/min) + 5.84. The response rate was 70.1 % (in CR 51 %, in PR 19 %). Histological CR was seen in 28.6 % of surgical specimens. Moderate hematological side effects were seen. However, severe adverse events were not observed, including those associated with cannulation of the femoral artery. CONCLUSION: The dose-clearance formula that was established by our study can most likely be utilized to accurately predict the optimal administered dose of nedaplatin for arterial infusion chemotherapy.

Metastasis in the gingiva from colon adenocarcinoma.

A case of gingival metastatic tumor from a colon adenocarcinoma is reported. The patient had been diagnosed with colon carcinoma and underwent a colectomy with D2 dissection, followed by chemotherapy. Nine months after the initial treatment, she noticed a periodontal gingival swelling at the site of her right lower second premolar and was referred to our clinic. The clinical diagnosis was an epulis granulomatosa or pyogenic granuloma. A metastatic adenocarcinoma in the gingiva from colon carcinoma was identified after the histopathological examination. Although rare, oral metastatic tumors should be included in the differential diagnosis, particularly if the patient has a prior history of malignancies.

Adjunct teriparatide therapy with monitoring of bone turnover markers and bone scintigraphy for bisphosphonate-related osteonecrosis of the jaw.

The management of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is still difficult in many cases that do not respond to conservative treatments. We report a case of BRONJ treated by adjunctive teriparatide therapy for 6 months with monitoring of bone turnover markers (at baseline, at 1, 3, and 6 months of treatment, and after 9 months off therapy) and bone scintigraphy (at baseline, 3 and 6 months, and after 9 months off therapy). The patient was a 78-year-old woman with osteoporosis and BRONJ. She had not responded to previous conventional treatment. Teriparatide was added for resolution of BRONJ. The pain disappeared after 1 month, and remarkable bone regeneration was obtained after 6 months, with significantly increasing bone formation and resorption markers. Bone scintigraphy showed regression of the uptake area. This case suggests the usefulness of monitoring bone turnover markers and using bone scintigraphy to increase the effectiveness of teriparatide therapy.

Fludarabine and melphalan conditioning with tacrolimus as GVHD prophylaxis for allogeneic stem cell transplant recipients is an effective reduced-intensity combination regimen compared to the conventional regimen.

BACKGROUND: As a reduced-intensity stem-cell transplantation (RIST) regimen, the combination of fludarabine and melphalan (FM) with an appropriate immunosuppressant reduces nonrelapse mortality (NRM). METHODS: We retrospectively compared the efficacy of a RIST regimen with FM with that of a conventional stem cell transplantation (CST) regimen. Eighty-two consecutive hematological patients who underwent allogeneic stem-cell transplantation (SCT) at our hospital were enrolled. Preparation for RIST consisted of 25 mg/m(2) fludarabine and melphalan 70 mg/m(2). The conventional regimen employed high-dose cyclophosphamide and total-body irradiation (12 Gy) or busulfan and high-dose cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis for RIST consisted of tacrolimus alone or in conjunction with short-term methotrexate for unrelated donors. RESULTS: Of the 82 patients, 42 received the conventional CST regimen (median age, 35 years) and 40 received the RIST regimen (median age, 51 years). The probability of NRM was 17% (7/42) in the CST group and 8% (3/40) in the RIST group. Grade II to IV GVHD occurred in significantly more CST patients (38%) than RIST patients (28%). However, the overall survival was the same in the two groups (43%). CONCLUSION: The RIST regimen with FM incorporating tacrolimus and methotrexate demonstrated low TRM incidence and moderate control of GVHD and had efficacy comparable to that of the CST regimen, despite the advanced age of the RIST patient group.

Multivariate analysis of factors influencing oral mucositis in allogeneic hematopoietic stem cell transplantation.

Little information is available regarding the effect of oral intervention on the outcome of hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the incidence of oral mucositis after allogeneic HSCT with or without oral intervention among 96 consecutive patients in our hospital between January 1988 and March 2006. We combined two oral intervention strategies: cryotherapy and oral health care. The former was applied beginning in 2003 for patients being treated with melphalan, and the latter, which was the study's main strategy, was applied to all HSCT recipients beginning in 2004. Oral mucositis was evaluated according to NCI CTCAE v3.0. The incidence of oral mucositis was 30.9% (17/55) in reduced-intensity stem cell transplantation (RIST), which was significantly lower than the 90.2% (37/41) in conventional stem cell transplantation (CST; P < 0.001). Among these 96 patients, severe oral mucositis was observed in 19 (46.3%) CST cases and in 6 (10.9%) RIST cases (P < 0.001). The occurrence of oral mucositis apparently decreased after oral health care instructions were given. Multiple logistic analysis revealed that the conditioning regimen and oral health care were independent risk factors for the incidence of oral mucositis. The cryotherapy did not exert enough potency to prevent oral mucositis in patients who had undergone CST or RIST. We concluded that oral health care improved tissue damage due to an overall upgrade in oral hygiene during chemotherapy.

[Topical steroid injection for refractory oral chronic graft-versus-host disease].

The standard treatment for refractory oral chronic graft versus host disease (GVHD) has not been established. We present a case of AML accompanied by oral chronic GVHD in a 55-year-old man after allogeneic stem cell transplantation. The stomatitis of the patient was prolonged for a year and resistant to standard immunosuppressant therapy, including systemic administration of prednisolone and tacrolimus; however, local injection of 0.2% dexamethasone (0.5 mg per cm2) into the ulcerative area was drastically effective in improving refractory mucositis and mitigated a vicious cycle of mucosal damage and poor oral hygiene.

Risk Factors for Methicillin-Resistant Staphylococcus aureus (MRSA) and Use of a Nasal Mupirocin Ointment in Oral Cancer Inpatients.

PURPOSE: Elimination of methicillin-resistant Staphylococcus aureus (MRSA) is of critical importance in oral and maxillofacial surgery because control is very difficult once infection of an oral tumor or oral wound with MRSA is established. PATIENTS AND METHODS: We retrospectively investigated the risk factors for acquiring MRSA in 518 patients with oral cancer among 1,877 inpatients in our department between 1984 and 2005. RESULTS: The patients with oral cancer demonstrated a high rate of MRSA colonization and infection (77.8%) relative to the population as a whole with MRSA isolated percentage in our department after 1991. The risk factors for MRSA in oral cancer patients are also related to systemic diseases and physiological and iatrogenic conditions, including cerebrovascular diseases (77.8%), peripheral arterial catheterization (69.2%), diabetes (50.0%), tracheotomy (50.0%), renal failure (50.0%), long-term broad-spectrum antibiotic use (45.7%), and malnutrition (43.3%). However, the highest risk of MRSA seems to be related to poor hygienic care. CONCLUSIONS: Beginning in 1999, we implemented a strategy for reducing infection by MRSA that included nasal mupirocin ointment for patients at high risk of MRSA; since then, the detection rate has decreased. We suggest that the administration of nasal mupirocin ointment and provision of scrupulous hygienic care for high-risk patients are useful and effective measures for decreasing the incidence of MRSA infection.

[Clinical study for determination of the dosage formula for intra-arterial infusion chemotherapy with nedaplatin].

Area under the curve (AUC) is a very important parameter for determination of optimal dosage of antineoplastic agents in order to avoid side effects and achieve high effectiveness. Also, even if a certain dosage is administered, measured AUC is different in each individual. Therefore, it is important to determine the formula of the dosage of antineoplastic agents. We treated oral cancer using an intra-arterial infusion chemotherapy with nedaplatin (CDGP). Eighteen patients were treated with CDGP at the Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Kagawa Medical University, from October 1998 to June 2002. The correlation among expected AUC, dosage, CDGP clearance and 24 hr creatinine clearance in all chemotherapy was monitored and examined. The obtained formula in the dosage of intra-arterial infusion chemotherapy with Nedaplatin was as follows. dosage = AUC x (0.027 x CCr + 7.17).

[Clinical study of the area under the blood concentration-time curve of targeting intra-arterial infusion chemotherapy with nedaplatin for primary oral cancer].

We treated oral cancer using a targeting intra-arterial infusion chemotherapy with CDGP (nedaplatin); dosages were determined by the original formula. We compared the expected AUC (area under the curve) with the actual AUC in primary oral cancer cases to assess the optimal dosage of CDGP for intra-arterial chemotherapy and to study relevance of AUC, effectiveness of independent chemotherapy and side effects. Eleven cases were treated at the Department of Oral and Maxillofacial Surgery, Faculty of Medicine, Kagawa Medical University, from October 1998 to June 2002. The results are as follows. 1) A correlation was seen between the AUC and degree of thrombocytopenia. 2) AUC may reveal renal function, especially for GFR. 3) The response rate of the targeted intra-arterial infusion chemotherapy with CDGP was remarkably high and serious side effects were not observed. It appears that the set-up of the optimum dose should be decided based on the actual AUC. 4) There was about a 4/3 difference between the value of the expected AUC and the actual AUC. The equation for dosages based on the actual AUC needs to be studied further.

Dual-isotope SPECT using (99m)Tc-hydroxymethylene diphosphonate and (201)Tl-chloride to assess mandibular invasion by intraoral squamous cell carcinoma.

UNLABELLED: We examined mandibular invasion of intraoral squamous cell carcinoma by simultaneous bone and tumor dual-isotope SPECT using (99m)Tc-hydroxymethylene diphosphonate ((99m)Tc-HMDP) and (201)Tl-chloride ((201)Tl) and by CT. METHODS: Early and delayed simultaneous bone and tumor dual-isotope SPECT and CT were performed on 39 patients suspected of having tumor invasion of the mandible by intraoral squamous cell carcinoma. SPECT images were superimposed to project tumor location from tumor SPECT onto the osseous structures shown by bone SPECT. The CT imaging protocol consisted of 5-mm contiguous axial images. RESULTS: Histopathologic examination revealed invasion of the mandible in 13 patients and no tumor invasion in 26 patients. The results of delayed dual-isotope SPECT were exactly the same as those of early dual-isotope SPECT. On early and delayed dual-isotope SPECT, the sensitivity, specificity, and accuracy in detecting mandibular invasion by intraoral squamous cell carcinoma were 100% (13/13), 88.5% (23/26), and 92.3% (36/39), respectively. The corresponding values using CT were 45.5% (5/11), 94.7% (18/19), and 76.7% (23/30), respectively, when 9 patients were excluded because of dental artifacts. CONCLUSION: Our results suggest that superimposed early bone and tumor dual-isotope SPECT images alone may be sufficient in the diagnostic evaluation of mandibular invasion by intraoral squamous cell carcinoma.