Differences Between Medication-Related Osteonecrosis of the Jaw Caused by Bisphosphonates and Denosumab: Histological, Molecular Biological, and Clinical Studies.

Purpose Medication-related osteonecrosis of the jaw (MRONJ) is a serious side effect of antiresorptive agents such as bisphosphonates (BPs) and denosumab (DMB). We investigated whether a difference exists between BP- and DMB-related osteonecrosis of the jaw (ONJ). Patients and methods Histological images of 30 patients with BP-related ONJ and 13 patients with DMB-related ONJ were observed using hematoxylin-eosin and cathepsin K staining. Moreover, bone metabolism markers in the blood and bone mineral density were measured in 18 patients with BP-related ONJ and five patients with DMB-related ONJ. Furthermore, we conducted a quantitative analysis of local bone metabolism-related genes using surgical specimens through real-time reverse transcription polymerase chain reaction. Additionally, a retrospective study of 298 patients with MRONJ examined the differences in the characteristics of BP- and DMB-related ONJ and the factors associated with treatment outcomes. Results Histological examination revealed that patients treated with DMB had more severe osteoclast suppression than those treated with BP. No significant difference was observed in blood-bone metabolism markers between the two drugs; however, the suppression of local bone metabolism-related genes was stronger in patients treated with DMB. Clinical studies indicate that DMB-related ONJ is more frequently observed without osteolysis. Conclusion BP-associated ONJ and DMB-associated ONJ were shown to differ slightly. Clinical studies indicate that osteolysis is often unclear in DMB-related ONJ, and methods of bone resection during surgery need to be established.

Risk factors for the development of medication-related osteonecrosis of the jaw and effects of tooth extraction with local infection.

Background/purpose: Tooth extraction has been avoided in patients receiving antiresorptive agent (ARA) therapy. This study aimed to investigate dental findings associated with medication-related osteonecrosis of the jaw (MRONJ) development in patients. Materials and methods: First, in patients treated with high-dose ARAs, the relationship between dental findings and MRONJ development was examined. Next, in patients with MRONJ undergoing surgery, the relationship between dental findings and MRONJ occurring at a site distant from the initial site was examined. Results: MRONJ occurred in 13 of 172 patients (80 of 3725 teeth) during observation. Multiple tooth loss, periodontal ligament space enlargement, alveolar bone loss, periapical osteosclerosis, and local infection symptoms were associated with MRONJ development. Tooth extraction significantly reduced MRONJ development. Regarding other-site recurrence, new MRONJ developed at other sites in 54 of 357 patients with MRONJ (171 of 5038 teeth). Multiple tooth loss, apical lesions, periodontal ligament space enlargement, and periapical osteosclerosis were significantly associated with MRONJ development. In patients with malignant tumors, tooth extraction significantly reduced the subsequent incidence of MRONJ, while in patients with osteoporosis, there was no difference in the incidence of MRONJ between patients with and without tooth extraction. Conclusion: MRONJ was more likely to develop from teeth with local infections. Extraction of teeth with local infection in patients with malignancy may be more effective than tooth preservation in preventing MRONJ.

Bone resection methods in medication-related osteonecrosis of the jaw in the mandible: An investigation of 206 patients undergoing surgical treatment.

Background /purpose: The standard treatment for medication-related osteonecrosis of the jaw (MRONJ) is surgery. However, reports on the appropriate extent of bone resection are few. We aimed to examine the relationship between the extent of bone resection and postoperative outcomes in patients with mandibular MRONJ. Materials and methods: The clinical and imaging findings and treatment outcomes of 206 patients (258 surgeries) with mandibular MRONJ undergoing surgery were reviewed. Imaging findings were evaluated using computed tomography (CT) to sequestrum, osteolysis, periosteal reaction, and mixed-type osteosclerosis, and determine the extent of resection. In some cases, samples were taken from within the bone, and real-time polymerase chain reaction was used to confirm the presence of bacteria and fungi. Results: The three-year cumulative cure rate was 81.7%. Patients with malignant tumors showing no osteolysis and undergoing sequestrum removal or marginal mandibulectomy had significantly worse prognosis than those with osteoporosis showing osteolysis and undergoing segmental mandibulectomy. Furthermore, patients with residual osteolysis, periosteal reactions, and mixed-type osteosclerosis on CT were more likely to develop recurrence. Eleven patients showed no osteolysis on CT images. Patients with cancer administered with high-dose denosumab had significantly poorer prognosis. Bacteria and fungi were also detected in samples obtained from gap-type periosteal reaction and mixed-type osteosclerosis. Conclusion: Surgery for MRONJ requires resection of the infected bone. Aside from the osteolysis area, the gap-/irregular-type periosteal reaction and mixed-type osteosclerosis must also be included in the resection area. Methods for determining the extent of bone resection in MRONJ without osteolysis are a future challenge.

Medication-related osteonecrosis of the upper jaw involving the zygomatic bone: A case report.

INTRODUCTION AND IMPORTANCE: Osteonecrosis of the jaw resulting from treatment with antiresorptive agents, such as bisphosphonates and denosumab, is widely recognized as medication-related osteonecrosis of the jaw (MRONJ). However, to the best of our knowledge, there are no reports of medication-related osteonecrosis of the upper jaw extending to the zygomatic bone. CASE PRESENTATION: An 81-year-old woman treated with denosumab for multiple lung cancer bone metastases presented to the authors' hospital with a swelling in the upper jaw. Computed tomography showed osteolysis, periosteal reaction of the maxillary bone, maxillary sinusitis, and osteosclerosis of the zygomatic bone. The patient underwent conservative treatment; however, osteosclerosis of the zygomatic bone progressed to osteolysis. CLINICAL DISCUSSION: If the maxillary MRONJ extends to the surrounding bony structures, such as the orbit and skull base, serious complications may occur. CONCLUSION: It is important to detect early signs of maxillary MRONJ, before it involves the surrounding bones.

Surgical treatment and prognosis of posteriorly invading oral cancer: Potential clinical significance of pterygomandibular raphe.

Background/purpose: The prognosis of oral squamous cell carcinoma (OSCC) with posterior invasion is poor. We examined whether the pterygomandibular raphe (PMR) is useful for the diagnosis of invasion and determination of surgical methods. Materials and methods: Of 390 patients with OSCC treated surgically at our hospital between June 2009 and June 2020, 80 patients with posterior invasion were included in the study. Preoperative magnetic resonance imaging was used to classify the lesions into three types: non-contact with PMR (non-contact type), contact with PMR (contact type), and invasion beyond PMR (invasion type). We compared the local control, recurrence, and survival rates of each of the three types. Results: The invasion type showed a significantly higher recurrence rate than the non-contact type (P < 0.001) and contact type (P = 0.018). Overall survival rate comparisons showed that the invasion type had significantly worse prognosis than the non-contact (P = 0.004) and contact types (P = 0.041). Conclusion: OSCCs with posterior invasion beyond the PMR showed a poor treatment outcome and, therefore, should be treated with caution. The initial surgery is especially important and must ensure local control. This study indicates that the PMR is an important criterion for surgical method determination and that invasion beyond the PMR is a predictor of local recurrence and poor prognosis.

Complete response of recurrent oral squamous cell carcinoma treated with cetuximab in combination with radiotherapy: A case series.

Salvage surgery for recurrent oral squamous cell carcinoma (OSCC) often leads to a poor quality of life (QOL). The present study described three cases that resulted in favorable locoregional control with cetuximab in combination with radiotherapy (Cmab + RT). Case 1 had regional recurrence of OSCC at the lower right mastoid area 4 months after primary surgery. Case 2 had regional recurrence of OSCC at the parotid area 7 months after primary surgery. Case 3 had local recurrence of OSCC at the masticatory muscle and Rouviere's lymph nodes 1 year and 3 months after primary surgery. In all cases, Cmab + RT was performed, and disease-free survival was confirmed 4 months, 2 years and 6 months, and 10 months after Cmab + RT, respectively. Immunohistochemically, all resected tumors had no expression of 110-kDa catalytic subunit of class IA phosphatidylinositol 3-kinase (PI3Kp110α). In conclusion, if salvage surgery for recurrent OSCC results in a significantly low QOL, then shifting to chemoradiotherapy may be appropriate as a treatment strategy. In addition, strong evidence indicated that PI3Kp110α expression is associated with Cmab therapy efficacy.

Ineffectiveness of Antiresorptive Agent Drug Holidays in Osteoporosis Patients for Treatment of Medication-Related Osteonecrosis of the Jaw: Consideration from Immunohistological Observation of Osteoclast Suppression and Treatment Outcomes.

In patients with osteoporosis receiving antiresorptive agents (ARs), it has been widely practiced to withdraw ARs for several months before tooth extraction and during treatment if medication-related osteonecrosis of the jaw (MRONJ) develops. This study examined the effects of drug holidays on recovery from osteoclast suppression and the treatment outcomes. The relationship between the period of the drug holidays and treatment outcomes was examined retrospectively in 166 osteoporosis patients with MRONJ who received ARs. Histological examinations using hematoxylin and eosin staining and cathepsin K stains were performed to observe the recovery from osteoclast suppression in 43 patients in whom living bone was observed in the resection margins of the surgical specimens. Three-month AR drug holidays were not significantly correlated with the treatment outcomes of the 139 patients who underwent surgical treatment and the 27 who underwent conservative treatment. Of the 43 patients who underwent histological investigations, 16 had drug holidays from 7 to 678 days. Osteoclast suppression was observed in almost all patients, except in one without a drug holiday and one with a 261-day drug holiday. These findings suggest that AR drug holidays for approximately 3 months neither recover osteoclast suppression nor affect treatment outcomes.

Efficacy of 3% hydrogen peroxide solution in cleaning tongue coating before and after surgery: a randomized phase II study.

BACKGROUND: Increased bacterial presence in the tongue coating and thereby, the saliva, may be a risk factor for postoperative complications such as surgical site infection or postoperative pneumonia after cancer surgery. However, no method for cleaning tongue coating has been established experimentally. The purpose of this study was to verify the effect of brushing with 3% hydrogen peroxide on suppression of the number of bacteria in tongue coating. METHODS: Sixteen patients with gastric cancer or colorectal cancer undergoing surgery were randomly allocated to control and intervention groups. In the control group, the tongue was brushed for 30 s with a water-moistened toothbrush, while in the intervention group, the tongue was brushed for 30 s with a toothbrush moistened with 3% hydrogen peroxide. Bacterial counts on tongue coating were measured before and 30 s after cleaning the tongue coating using the Rapid Oral Bacteria Quantification System. RESULTS: In the control group, the number of bacteria on the tongue did not decrease significantly after tongue cleaning on the day before surgery, but did on the day after surgery. In contrast, in the intervention group, the number of bacteria on the tongue decreased significantly after tongue cleaning both on the day before and the day after surgery. Furthermore, when comparing the control and intervention groups, the intervention group had a greater reduction effect. CONCLUSIONS: Tongue brushing with 3% hydrogen peroxide is a useful method to reduce the number of bacteria on the tongue in patients with gastrointestinal cancer undergoing surgery. Trial registration jRCTs071200020 (July 3, 2020).

Relationship between drug holiday of the antiresorptive agents and surgical outcome of medication-related osteonecrosis of the jaw in osteoporosis patients.

A drug holiday of 3 months does not promote separation of sequestra and is not correlated with treatment outcomes after surgical therapy in osteoporosis patients who receive antiresorptive agents and who have medication-related osteonecrosis of the jaw. Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse effect of antiresorptive agents alone or in combination with immune modulators or antiangiogenic medications, in the absence of radiation exposure to the head and neck region. The effectiveness of surgical treatment for MRONJ has been reported, but the timing of the operation remains controversial. The purpose of this study was to clarify whether preoperative drug holidays of antiresorptive agents promote sequestrum separation and improve treatment outcomes in patients who receive low doses of antiresorptive agents. This retrospective study included 173 patients who received low-dose antiresorptive agents and underwent surgical therapy. The effects of a drug holiday on the separation of sequestra and treatment outcomes were analyzed using logistic and Cox regression analyses. Multivariate analysis revealed that administration of an antiresorptive agent for more than 4 years, a high number of lymphocytes, and an extensive osteolytic area were significantly correlated with separation of sequestra, but drug holiday did not promote sequestrum separation. Furthermore, a drug holiday of 90, 120 or 180 days did not show any improvement in treatment outcomes. The drug holiday of the antiresorptive agents for the treatment of MRONJ is unnecessary, and surgical therapy should be performed early.

Retrospective Analysis of Treatment Outcomes of Maxillary Sinusitis Associated with Medication-Related Osteonecrosis of the Jaw.

Although maxillary sinusitis often occurs in patients with medication-related osteonecrosis of the jaw (MRONJ) of the upper jaw, there have been few reports on the treatment and outcomes for maxillary sinusitis associated with maxillary MRONJ. This study aimed to retrospectively investigate the treatment outcomes of maxillary sinusitis in patients with MRONJ of the upper jaw. There were 34 patients diagnosed with maxillary MRONJ and sinusitis by preoperative computed tomography who underwent surgery in our institution between January 2011 and December 2019. Age, sex, primary disease, stage of MRONJ, class and administration period of an antiresorptive agent, corticosteroid administration, preoperative leukocyte count and serum albumin level, periosteal reaction, sinusitis grade, maxillary sinus surgical procedure, and treatment outcomes of MRONJ and sinusitis were examined. There were 7 male and 27 female patients (average age, 74.7 years). Complete healing of MRONJ was obtained in 29 of 34 patients (85.3%). Maxillary sinusitis resolved or improved in 21 patients (61.8%) but did not change or worsen in 13 patients (38.2%). We found that complete resection of necrotic bone with intraoperative irrigation of the maxillary sinus may provide good treatment outcomes for maxillary sinusitis associated with MRONJ, although our findings were not statistically significant owing to the small number of patients.

Risk factors for developing medication-related osteonecrosis of the jaw when preserving the tooth that can be a source of infection in cancer patients receiving high-dose antiresorptive agents: a retrospective study.

PURPOSE: To retrospectively investigate whether apical lesion, alveolar bone loss, probing pocket depth, or local infectious symptoms were associated with the onset of medication-related osteonecrosis of the jaw (MRONJ) in patients treated with high-dose antiresorptive agents who did not undergo tooth extraction. METHODS: The study included 92 patients receiving high-dose antiresorptive agent therapy who had teeth with apical lesion ≧ 3 mm, alveolar bone loss ≧ 1/2, probing pocket depth ≧ 4 mm, or local infection symptoms such as swelling, pain, and pus discharge, but did not undergo tooth extraction. Univariate and multivariate Cox regression analyses were performed to determine the relationship between each variable and MRONJ onset. RESULTS: MRONJ developed in 15 of 92 patients (35 of 404 teeth) from 74 to 1883 days (median, 383 days) after the first visit. Multiple Cox regression analysis revealed that a lower number of teeth, diabetes, increased leukocyte count, administration of antiresorptive agents for 180 days or more, local infection symptoms, apical lesion ≧ 3 mm, and probing pocket depth ≧ 4 mm were significantly correlated with the development of MRONJ. CONCLUSION: It is recommended that teeth with apical lesion ≧ 3 mm, probing pocket depth ≧ 4 mm, or local infection symptoms are extracted before or as early as possible after beginning of medication in cancer patients receiving high-dose antiresorptive agent therapy to prevent the development of MRONJ.

Relationship between Drug Holidays of Antiresorptive Agents and Surgical Outcomes in Cancer Patients with Medication-Related Osteonecrosis of the Jaw.

It is controversial as to whether the withdrawal of antiresorptive (AR) agents is necessary while treating medication-related osteonecrosis of the jaw (MRONJ). In this study, we investigated whether a drug holiday promoted sequestrum separation and improved the surgical outcomes of MRONJ patients with malignant tumors, who were undergoing high-dose AR therapy. In total, we included 103 MRONJ patients with malignant tumors as their primary disease who underwent surgery at Nagasaki University Hospital or Kansai Medical University Hospital from January 2009 to December 2020. We recorded the patients' age, sex, primary disease, MRONJ stage, type and administration period of the AR agent, presence of diabetes, corticosteroid use, drug holiday period, white blood cell count, serum albumin, serum creatinine, outcomes, and computed tomography findings. The relationships between a drug holiday and sequestrum separation, and between a drug holiday and outcome, were analyzed. Drug holidays of 60, 90, and 120 days were not significant factors of sequestrum separation and did not influence patients' surgical outcomes as per the univariate and multivariate analyses. MRONJ patients with cancer as their primary disease should be operated upon immediately and without drug holidays if their general condition permits surgery.

Inhibitory effect of topical antibiotics/antiseptics administration on bacterial growth in the open wound of the jawbone surgery: Randomized controlled, preliminary study.

BACKGROUND/PURPOSE: TThe bone cavities after extirpation of cysts or tumor of the jawbone requires the insertion of gauze containing various antibiotics/antiseptics to minimize the risk of pain, bleeding, and surgical site infection (SSI). However, there have been few reports on the efficacy of topical administration of antibiotics/antiseptics to an open wound of the jawbone. To compare the inhibitory effects of topical povidone-iodine gel and tetracycline ointment on the jawbone wound bacterial growth after extirpation of cyst or tumor. MATERIALS AND METHODS: This is a preliminary, randomized controlled, open-labeled trial. Eighteen patients were randomly assigned into two groups. In povidone-iodine (PI) group, gauze mixed with povidone-iodine gel was inserted into the bone cavity wound, and in tetracycline (TC) group gauze mixed with tetracycline ointment was inserted after extirpation of cyst or tumor of the jaw bone. In both groups, gauze was removed 48 h after surgery, and examined by bacterial culture and real-time polymerase chain reaction (PCR) using primers detecting total bacteria and MRSA. RESULTS: The topical application of tetracycline ointment was superior to that of povidone-iodine gel concerning inhibitory effects of total bacteria and methicillin-resistant Staphylococcus aureus (MRSA). CONCLUSION: This preliminary study suggests that the insertion of gauze mixed with tetracycline ointment is recommended for bone wounds after extirpation of cyst or tumor of the oral cavity.

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.

Treatment strategies for and outcomes of older patients with oral squamous cell carcinoma.

OBJECTIVE: The purpose of this study was to investigate factors that have a significant impact on decision making regarding treatment strategies and on the resultant outcomes in older patients with oral squamous cell carcinoma (OSCC). STUDY DESIGN: To define fit, vulnerable, and frail patients, as well as treatment strategies/outcomes, in patients 75 years of age and older with primary OSCC were retrospectively reviewed from the medical records. RESULTS: Among patients with stage I and II tumors, those with a Geriatric 8 (G8) score of 11.5 or greater had favorable outcomes and those with a score less than 11.5 had acceptable outcomes (5-year self-reliance [SR] rates: 80.8 and 53.5%, respectively). Among patients with stage III and IV tumors, those with the Eastern Cooperative Oncology Group-Performance status (ECOG-PS) score less than 2 and/or a G8 score 11.5 or greater mainly received standard therapy, had favorable outcomes (5-year SR rate: 66.7%). The 5-year SR rates of stage IV patients with an ECOG-PS score 2 or greater and those with a G8 score less than 11.5 were poor regardless of any treatment strategy. Although the 5-year SR rate of patients with standard therapy was 73.4%, that of patients receiving other curative therapies was 0%. CONCLUSIONS: In patients with stage III/IV, ECOG-PS 2 or greater, and/or G8 score less than 11.5, treatment was difficult, and the prognosis was poor.

Clinical Roles of Interleukin-6 and STAT3 in Oral Squamous Cell Carcinoma.

The effect inflammation has on cancer prognosis is marked by the presence of cytokines and chemokines. Interleukin-6 (IL-6) is one a multifunctional cytokine that regulates inflammatory responses. We investigated the roles of IL-6 and STAT3 and examined the relationship between IL-6 signaling and clinicopathological factors in patients with oral squamous cell carcinoma (OSCC). We retrospectively examined 116 patients who underwent radical surgery for OSCC. IL-6 and STAT3 expression were detected by immunohistochemistry. IL-6 and STAT3 positivity were detected by IHC, at 78.4 and 80.2 %, respectively. IL-6 expression was significantly associated with pattern of invasion (P = 0.004), vascular invasion (P = 0.003), and pathological nodal status (P = 0.019). Multivariate logistic regression analysis revealed that IL-6 expression was significantly associated with vascular invasion (P = 0.044). Meanwhile, there was no significant association between STAT3 expression and clinicopathological factors and no significant relationship between IL-6 and STAT3 expression. IL-6 expression was significantly associated with 5-year disease-free survival. These results suggest that IL-6 is involved in lymphangiogenesis and recurrence in OSCC.

Regulation and Biological Significance of Formation of Osteoclasts and Foreign Body Giant Cells in an Extraskeletal Implantation Model.

The implantation of biomaterials induces a granulomatous reaction accompanied by foreign body giant cells (FBGCs). The characterization of multinucleated giant cells (MNGCs) around bone substitutes implanted in bone defects is more complicated because of healing with bone admixed with residual bone substitutes and their hybrid, and the appearance of two kinds of MNGCs, osteoclasts and FBGCs. Furthermore, the clinical significance of osteoclasts and FBGCs in the healing of implanted regions remains unclear. The aim of the present study was to characterize MNGCs around bone substitutes using an extraskeletal implantation model and evaluate the clinical significance of osteoclasts and FBGCs. Beta-tricalcium phosphate (ß-TCP) granules were implanted into rat subcutaneous tissue with or without bone marrow mesenchymal cells (BMMCs), which include osteogenic progenitor cells. We also compared the biological significance of plasma and purified fibrin, which were used as binders for implants. Twelve weeks after implantation, osteogenesis was only detected in specimens implanted with BMMCs. The expression of two typical osteoclast markers, tartrate-resistant acid phosphatase (TRAP) and cathepsin-K (CTSK), was analyzed, and TRAP-positive and CTSK-positive osteoclasts were only detected beside bone. In contrast, most of the MNGCs in specimens without the implantation of BMMCs were FBGCs that were negative for TRAP, whereas the degradation of ß-TCP was detected. In the region implanted with ß-TCP granules with plasma, FBGCs tested positive for CTSK, and when ß-TCP granules were implanted with purified fibrin, FBGCs tested negative for CTSK. These results showed that osteogenesis was essential to osteoclastogenesis, two kinds of FBGCs, CTSK-positive and CTSK-negative, were induced, and the expression of CTSK was plasma-dependent. In addition, the implantation of BMMCs was suggested to contribute to osteogenesis and the replacement of implanted ß-TCP granules to bone.

Cetuximab for the treatment of locally advanced and recurrent/metastatic oral cancer: An investigation of distant metastasis.

The aim of this retrospective study was to assess the efficacy and safety of cetuximab therapy for patients with locally advanced (LA) and recurrent/metastatic (R/M) oral squamous cell carcinoma (OSCC), with a specific focus on distant metastases (DMs). Data from 21 patients with unresectable LA and R/M OSCC treated with cetuximab therapy in our department between December, 2012 and July, 2015 were reviewed. The endpoint was the time-to-progression and the assessments made were tumor response rate, progression-free survival (PFS), overall survival (OS) and safety. The overall response rate was 57.1%, with a complete response (CR) rate of 33.3%. The overall median PFS and OS were 5.5 and 8.0 months, respectively. For patients with DMs, the overall response rate was 60.0%, with a CR rate of 40.0%. The median PFS and OS were 3.8 and 5.8 months, respectively. In addition, improved 1-year OS was observed following approval of cetuximab, although the differences between the group of patients treated after that time and historical controls were not statistically significantly (P=0.246). Grade 3-4 adverse events included infusion reaction (4 cases), neutropenia, hypophosphatemia, upper gastrointestinal hemorrhage, liver toxicity and mucositis (1 case each). There was one cetuximab-related death due to interstitial pneumonia. An acne-like rash was observed in all cases, but no grade 3 or 4 rash was reported. Hypomagnesemia was observed in 10 cases. Our results suggest that cetuximab may display significant therapeutic efficacy in patients with unresectable LA and R/M OSCC, including those with DMs.

Diversity of multinucleated giant cells by microstructures of hydroxyapatite and plasma components in extraskeletal implantation model.

UNLABELLED: Foreign body giant cells (FBGCs) and osteoclasts are multinucleated giant cells (MNGCs), both of which are formed by the fusion of macrophage-derived mononuclear cells. Osteoclasts are distinct from FBGCs due to their bone resorption ability; however, not only morphological, but also functional similarities may exist between these cells. The characterization and diversity of FBGCs that appear in an in vivo foreign body reaction currently remain incomplete. In the present study, we investigated an in vivo foreign body reaction using an extraskeletal implantation model of hydroxyapatite (HA) with different microstructures. The implantation of HA granules in rat subcutaneous tissue induced a foreign body reaction that was accompanied by various MNGCs. HA granules composed of rod-shaped particles predominantly induced cathepsin K (CTSK)-positive FBGCs, whereas HA granules composed of globular-shaped particles predominantly induced CTSK-negative FBGCs. Plasma, which was used as the binder of ceramic granules, stimulated the induction of CTSK-positive FBGCs more strongly than purified fibrin. Furthermore, the implantation of HA composed of rod-shaped particles with plasma induced tartrate-resistant acid phosphatase (TRAP)-positive MNGCs in contrast to HA composed of globular-shaped particles with purified fibrin, which predominantly induced CTSK-negative and TRAP-negative typical FBGCs. These results suggest that CTSK-positive, TRAP-positive, and CTSK- and TRAP-negative MNGCs are induced in this subcutaneous implantation model in a manner that is dependent on the microstructure of HA and presence or absence of plasma. STATEMENT OF SIGNIFICANCE: We attempted to elucidate the mechanisms responsible for the foreign body reaction induced by the implantation of hydroxyapatite granules with different microstructures in rat subcutaneous tissue with or without plasma components as the binder of ceramic granules. By analyzing the expression of two reliable osteoclast markers, we detected tartrate-resistant acid phosphatase-positive multinucleated giant cells, cathepsin K-positive multinucleated giant cells, and tartrate-resistant acid phosphatase- and cathepsin K-negative multinucleated giant cells. The induction of tartrate-resistant acid phosphatase-positive multinucleated giant cells was plasma component-dependent while the induction of cathepsin K-positive multinucleated giant cells was influenced by the microstructure of hydroxyapatite. This is the first study to show the conditions dividing the three kinds of multinucleated giant cells in the foreign body reaction.

Denosumab-associated osteonecrosis of the jaw affects osteoclast formation and differentiation: Pathological features of two cases.

Medication-related osteonecrosis of the jaw (ONJ) is caused by antiresorptive (bisphosphonates and denosumab) and antiangiogenic agents, with the first report of denosumab-related ONJ emerging in 2010. To date, although certain case reports on denosumab-related ONJ have been published, those of ONJ caused by a single application of the drug are scarce. In addition, only one report described the histopathological features of this condition, although not completely; only the sequestrum resected by conservative surgery was evaluated. Although conservative treatment is recommended, the effectiveness of extensive surgery in the early stages of bisphosphonate-related ONJ has been described in recent years. Here we report the clinical and histopathological features of denosumab-related ONJ caused by single application of the drug, which was treated by extensive surgery in two patients. Histopathological analysis revealed a decreased number of osteoclasts in viable bone around the sequestrum, and these appeared morphologically immature, as indicated by the presence of very few nuclei. These findings are different from those for bisphosphonate-related ONJ and may assist in elucidating the mechanism underlying denosumab-related ONJ. Furthermore, extensive surgery may be effective for the management of this condition.