Ultrasmall MoS2 nanodots-wrapped perfluorohexane nanodroplets for dual-modal imaging and enhanced photothermal therapy.

Development of a multifunctional nanotherapeutic agent with high contrast-enhanced dual-modal imaging and photothermal therapy (PTT) efficacy is of great interest. Combination of ultrasound (US) and computed tomography (CT) imaging offers high spatial resolution images, showing great potential in medical imaging. Herein, the semiconducting perfluorohexane (PFH) nanodroplets, MoS2-PFH-PLLAs, are developed by stabilizing PFH droplets with the coating shell of poly (lactic-co-glycolic acid) (PLLA) and encapsulating the droplets with photoabsorbers of ultrasmall molybdenum disulfide (MoS2) nanodots. Upon near-infrared (NIR) irradiation, the MoS2-PFH-PLLAs can absorb the NIR light and convert it into heat, which not only promotes liquid-to-gas phase transition of PFH but also triggers photothermal heating, resulting in contrast-enhanced US/CT imaging and photothermal killing effect in vitro. Furthermore, the production of microbubbles can serve as the blasting agents to collaboratively enhance PTT efficacy after NIR irradiation. When intravenously injected into tumor-bearing mice, the MoS2-PFH-PLLAs exhibit a dual-modal US/CT imaging-guided synergistically therapeutic efficacy under NIR irradiation, resulting in tumor ablation. These nanotherapeutic agents demonstrate good biocompatibility, highly contrast-enhanced US/CT imaging, and combinational enhanced PTT efficacy.

Microarchitecture of medication-related osteonecrosis of the jaw (MRONJ); a retrospective micro-CT and morphometric analysis.

Medication-related osteonecrosis of the jaw (MRONJ) is a severe side effect of antiresorptive (AR) drugs such as bisphosphonates (BP) and denosumab (Dmab). Although several risk factors are described, the etiology of MRONJ is still not fully elucidated. Bone-strengthening is the primary aim of antiresorptive therapy; however, overly increased bone mass and microcrack accumulation are also discussed in MRONJ etiologies. The aim of this study is to evaluate the microarchitecture of jaw bones with micro-computed tomography (micro-CT) in AR-treated patients with or without MRONJ. Human jaw bone samples of AR-treated patients were separated into 11 groups by AR treatment bisphosphonate (BP), denosumab (Dmab), both (M) and control groups. Subgroups were divided according to the clinical localization as AR-exposed vital jaw bone (BPexp, Dmabexp, Mexp), osteonecrosis-margin of a sequestrum (BPOmar, DmabOmar, MOmar) and osteonecrosis-sequestrum (BPOseq, DmabOseq, MOseq). Healthy jaw bone (CHB) and osteoporotic jaw bone (COP) represent control groups. Samples underwent retrospective micro-CT and morphometric analysis in representative units by bone volume fraction (BV/TV), bone surface density (BS/BV), trabecular thickness (Tr.Th.), trabecular number (Tr.N.), trabecular space (Tr.Sp.), Euler characteristic for bone connectivity, bone mineral density (BMD) and tissue mineral density (TMD). A total of 141 samples from 78 patients were analyzed. BV/TV of Mexp group (mean: 0.46 ± 0.27) was significantly higher than in the COP group (mean: 0.14 ± 0.05; p = 0.0053). Tr.Th. differed significantly between the BPexp group (mean: 0.32 ± 0.15) and the Mexp group (mean: 0.57 ± 0.20; p = 0.0452) as well as between the BPOseq group (mean: 0.25 ± 0.10) and the MOseq group (mean: 0.39 ± 0.18; p = 0.0417). Signs of trabecular thickening and unorganized trabecular microarchitecture from AR-exposed- to sequestrum groups, were analyzed in 3D reconstructions. However, BS/BV, Tr.N., and Tr.Sp. showed no significant differences. Euler characteristic of the BPOseq group (median: 7.46) doubled compared to that of the BPexp group (median: 14.97; p = 0.0064). Mineralization parameters BMD and TMD were similar in all groups. Findings show evidence of enhanced bone mass and suspect microarchitecture in some AR-treated jaw bone compared to osteoporotic jaw bone. Despite increased bone mass, some MRONJ samples showed decreased trabecular connectivity by Euler characteristic compared to AR-treated jaw bone. These samples may indicate extensive ossification and ineffective bone mass with superficially higher bone mass without existing or even reduced mechanical stability, indicated by connectivity loss. This result might also suggest a high risk to microcrack accumulation. At some point, possibly some kind of over-ossification could lead to under-nourishment and microarchitectural weakness, creating instability, subsequently increasing vulnerability to MRONJ.

Adverse Drug Events in the Oral Cavity.

Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity. Targeted therapies and new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. This review describes the most common clinical presentations of oral mucosal reactions to medications, namely hyposalivation, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, reactive keratosis, dysesthesia, osteonecrosis, infection, angioedema, and malignancy.

Histologic analysis of medication-related osteonecrosis of the jaw compared with antiresorptive-exposed bone and other infectious, inflammatory, and necrotic jaw diseases.

OBJECTIVE: This study characterized histologic features of medication-related osteonecrosis of the jaw (MRONJ) through analysis of tissues from patients and healthy individuals. STUDY DESIGN: Bone biopsies were collected from various infectious, inflammatory, and necrotic jaw diseases. Samples were divided into bone exposed to bisphosphonates or denosumab, as well as bisphosphonate-related osteonecrosis of the jaw (BRONJ), denosumab-related osteonecrosis of the jaw (DRONJ), and mixed necrosis, enabling us to identify features of single agent necrosis without influence from previous therapies. Hematoxylin and eosin (H&E), receptor activator of nuclear factor κ-Β ligand (RANKL), tartrate-resistant acid phosphatase (TRAP), osteoprotegerin, toluidine blue, CD14, and CD68 staining and micro-computed tomography (micro-CT) analysis were performed. Groups were compared by using analysis of variance (ANOVA). RESULTS: In total, 156 bone samples were collected from 105 patients. MRONJ variants exhibited more infectious infiltration. Bisphosphonate (P < .001) and mixed necrosis (P = .002) demonstrated more RANKL- and TRAP-positive osteoclasts. Denosumab necrosis (P = .007), and bone exposed to bisphosphonates (P = .028) in combination with denosumab (P = .022) demonstrated significantly lower numbers of osteocytes per area. CD14 and CD68 positivity was increased for BRONJ (P = .008; P < .001, respectively). MRONJ variants exhibited the widest trabecular width and decreased medullary space to bone. No diminished vascular network in MRONJ samples was observed. CONCLUSIONS: Histologic features differ among MRONJ variants, with oversuppressed bone turnover, dysfunctional bone resorption, and a disturbed osteocyte network as potential mechanisms of pathogenesis.

Gingival fibroblasts and medication-related osteonecrosis of the jaw: Results by real-time and wound healing in vitro assays.

OBJECTIVE: This study investigated the effects of bisphosphonates and denosumab on human gingival fibroblasts (HGFs) that could influence inflammation, wound healing, and angiogenesis in medication-related osteonecrosis of the jaw (MRONJ). METHODS: A real-time in vitro assay was performed on HGFs with and without the addition of bacterial lipopolysaccharide and a mononuclear cell co-culture to observe the effects of zoledronate, ibandronate, alendronate, clodronate, denosumab, and combinations of zoledronate and denosumab at varied concentrations. A wound healing assay was performed, and gene and protein expression was analyzed for inflammatory, angiogenic, and osteoclastogenic cytokines and mediators including interleukin (IL)-1ß, IL-6, tumor necrosis factor alpha (TNFα), IL-8, vascular endothelial growth factor (VEGF), RANKL, and osteoprotegerin. RESULTS: Higher concentrations of antiresorptives resulted in impaired wound healing and HGF death, which also occurred without mechanical damage. These effects were increased with bacterial lipopolysaccharide and mononuclear cells. Increased levels of IL-1ß, TNFα, IL-8, VEGF, osteoprotegerin, and decreased levels of IL-6 were observed. CONCLUSIONS: Antiresorptive exposure was associated with HGF death and delayed wound healing, which could be attributed to an elevated inflammatory response and immune dysfunction contributing to MRONJ development. There was no evidence of anti-angiogenic effects. Our experiments present the first results of denosumab with HGFs.

Clinical course and therapeutic outcomes of operatively and non-operatively managed patients with denosumab-related osteonecrosis of the jaw (DRONJ).

PURPOSE: Details regarding risk factors, onset, and outcomes for denosumab-related osteonecrosis (DRONJ) are sparse. This study examines the clinical characteristics and operative and non-operative therapeutic outcomes in patients with DRONJ not previously exposed to other antiresorptives. METHODS: A retrospective medical record review was conducted, and data were collected, including clinical findings, management, healing outcomes, and radiologic, histologic, and micro-computed tomography (CT) analyses. RESULTS: Seventeen patients were treated with denosumab, with 14.1 ± 8.3 doses before DRONJ onset. The majority of lesions were observed at sites of dental prostheses (41%) and dental extractions (35%). Sixteen patients were managed non-operatively (10/16) or operatively (6/16) with either major (5/6) or minor surgery (1/6) and included in the follow-up analysis. Complete healing was significant in patients treated with major surgery (80%) compared to the non-operative group (20%; p < 0.035). Denosumab was discontinued in 60% of non-operative patients and major surgery patients with no effect on healing. Histologic findings of 4 patients analyzed exhibited a decreased number of osteocyte lacunae, and micro-CT of 3 patients scanned revealed trabecular thickening. CONCLUSION: DRONJ lesions occurred mostly at sites of prostheses sores after a mean of 14 doses of denosumab. Major surgery demonstrated more complete healing than non-operative management, and denosumab cessation did not improve healing outcomes.

Effect of bisphosphonates on macrophagic THP-1 cell survival in bisphosphonate-related osteonecrosis of the jaw (BRONJ).

OBJECTIVES: Immune deficiency and bacterial infection have been suggested to play a role in the pathophysiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). Zoledronate was previously found to promote THP-1 cell death. To examine this hypothesis with all commonly prescribed bisphosphonates, we tested the effect of (nitrogen-containing) ibandronate, risedronate, alendronate, pamidronate, and (non-nitrogen-containing) clodronate on macrophagic THP-1 cells. STUDY DESIGN: Activated THP-1 cells were exposed to .5 to 50 µM of nitrogen-containing bisphosphonates and .5 to 500 µM of clodronate. Cell adherence and survival were assessed in vitro using the xCELLigence real-time monitoring system. Results were confirmed histologically and verified with Live/Dead staining. RESULTS: All bisphosphonates inhibited THP-1 cell adherence and survival dose and time dependently, significant for zoledronate, alendronate, pamidronate, and clodronate in high concentrations (50 µM and 500 µM; P < .05). Low concentrations (0.5 µM) of risedronate, alendronate, and pamidronate prolonged the inflexion points of THP-1 cell survival compared with controls (P < .05). THP-1 cells exhibited no cytomorphologic changes at all concentrations. CONCLUSIONS: Commonly prescribed bisphosphonates inhibit the survival of macrophagic THP-1 cells dose-dependently without altering morphology. This may suggest a local immune dysfunction reflective of individual bisphosphonate potency leading to the pathogenesis of BRONJ.

Altered macrophagic THP-1 cell phagocytosis and migration in bisphosphonate-related osteonecrosis of the jaw (BRONJ).

OBJECTIVES: Local immune dysfunction via macrophages is a proposed aetiology of bisphosphonate-related osteonecrosis of the jaw (BRONJ). This study aimed to clarify the effects of various bisphosphonates on macrophage function using a THP-1 monocytic model to examine migration, phagocytosis, and fibrin structure. MATERIALS AND METHODS: THP-1 cell migration was measured in the presence and absence of zoledronate, ibandronate, risedronate, alendronate, pamidronate (0.5, 5 and 50 µM) and clodronate (125, 250 and 500 µM) using the real-time xCELLigence system. Phagocytosis and actin fibre assays were performed after 72 h with zoledronate, ibandronate, alendronate and clodronate. RESULTS: Time to maximum migration for THP-1 cells was significantly reduced (p < 0.05) for high dosages of zoledronate, ibandronate and alendronate compared to controls. All dosages of clodronate and a low dose of zoledronate exhibited prolonged migrations. Phagocytic capacity was significantly reduced in high dosages of all bisphosphonates and for 5 µM zoledronate and ibandronate (p < 0.05). Low bisphosphonate exposure was accompanied by overcharged phagosoms. Altered appearance in F-actin fibrin structure was observed in bisphosphonate-exposed cells. CONCLUSIONS: All bisphosphonates altered the migration of THP-1 cells dose-dependently. Low doses also prolonged migration and altered cell morphology. These findings support the idea of a disturbed local immune function of macrophages even in jaw bone exposed to low concentrations of bisphosphonate. CLINICAL RELEVANCE: These are the first real-time results for disrupted migration and function of macrophagic THP-1 cells in high doses. Low dosages also demonstrated altered macrophage phagocytosis and cell morphology, suggesting a disturbed local immune function in BRONJ pathogenesis.

Oral adverse events in cancer patients treated with VEGFR-directed multitargeted tyrosine kinase inhibitors.

OBJECTIVES: This study characterized the incidence and clinical features of oral adverse events among cancer patients who received VEGFR-directed multitargeted tyrosine kinase inhibitor (VR-TKI) therapies. METHODS: Electronic medical records of adult cancer patients treated with sunitinib, sorafenib, regorafenib, pazopanib, cabozantinib, imatinib, and bevacizumab therapy at Dana-Farber Cancer Institute from 2009 to 2012 were reviewed. Data collected included patient characteristics, oral and non-oral adverse events, and time to onset. Time oral adverse event-free was the primary outcome. RESULTS: A total of 747 patients with 806 individual courses of therapy were treated for a median of 3.9months with sunitinib (n=161), sorafenib (n=172), regorafenib (n=15), pazopanib (n=132), cabozantinib (n=23), imatinib (n=144), or bevacizumab (n=159) for lung cancer (21%), gastrointestinal stromal tumor (15%), and metastatic renal cell carcinoma (13%). An oral adverse event was reported in 23.7% of patients at a median of 1.9months after starting therapy. The most commonly reported oral adverse event was oral mucosal sensitivity (dysesthesia), occurring in 12% of patients, typically without clinical findings. Multivariate models showed patients who received VR-TKI therapy were at greater risk of any oral adverse event compared with patients treated with imatinib or bevacizumab. Patients receiving VR-TKI therapy who developed an oral adverse event were also at increased risk for hand-foot skin reaction (15.9%). CONCLUSIONS: VR-TKI associated oral adverse events are characterized primarily by dysesthesia with lack of clinical signs. Oral dysesthesia is more commonly associated with VR-TKIs than with bevacizumab or imatinib. Management is largely empirical and requires further investigation.

World Workshop on Oral Medicine VI: Patient-reported outcome measures and oral mucosal disease: current status and future direction.

OBJECTIVE: This systematic review aimed to (1) explore the patient-reported outcome measures (PROMs) currently used in the oral mucosal disease literature and report on the type and context of the use of these instruments and (2) provide a future direction for PROMs in Oral Medicine practice and research. STUDY DESIGN: A systematic review of published English-language articles relating to the use of PROMs in the oral mucosal diseases literature was performed in November 2013. RESULTS: In total, 131 articles met the inclusion criteria; these articles addressed the following oral mucosal conditions: lichen planus (75); recurrent aphthous stomatitis (30); mucous membrane pemphigoid/pemphigus vulgaris (14); orofacial granulomatosis (1); and multiple oral mucosal diseases (11). The most commonly used instruments were visual analog scales (VAS) and the oral health impact profile (OHIP). CONCLUSIONS: Limited progress has been achieved with use of PROMs in Oral Medicine in the last few decades in both clinical practice and a research setting. With the engagement of allied medical disciplines in PROM usage and the promotion of PROMs by national health care bodies globally, advancement of PROMs is imperative for Oral Medicine. Exposure through the World Workshop on Oral Medicine (WWOM), along with potential involvement in the Core Outcome Measures in Effectiveness Trials (COMET) or other such initiatives, will enable worldwide collaboration to promote the development and utilization of valid and reliable PROMs in oral medicine, and improve patient care.

Adverse drug events in the oral cavity.

Adverse reactions to medications are common and may have a variety of clinical presentations in the oral cavity. Targeted therapies and the new biologic agents have revolutionized the treatment of cancers, autoimmune diseases, and inflammatory and rheumatologic diseases but have also been associated with adverse events in the oral cavity. Some examples include osteonecrosis, seen with not only bisphosphonates but also antiangiogenic agents, and the distinctive ulcers caused by mammalian target of rapamycin inhibitors. As newer therapeutic agents are approved, it is likely that more adverse drug events will be encountered. This review describes the most common clinical presentations of oral mucosal reactions to medications, namely, xerostomia, lichenoid reactions, ulcers, bullous disorders, pigmentation, fibrovascular hyperplasia, white lesions, dysesthesia, osteonecrosis, infection, angioedema, and malignancy. Oral health care providers should be familiar with such events, as they will encounter them in their practice.

Emerging therapies for the prevention and treatment of oral mucositis.

INTRODUCTION: Oral mucositis remains a common, symptomatically devastating toxicity of common drug and radiation regimens used to treat cancer. The current limited treatment options are likely to be supplemented by an active pipeline in which innovative compounds are being developed which target the underlying biological pathways associated with the condition. AREAS COVERED: A systematic literature search to identify English-language articles published from January 1995 to December 2013 was performed using the PubMed/MEDLINE and Google databases. A supplemental search was conducted of the ClinTrials database. Searches were driven by the following keywords: oral mucositis, mucositis, stomatitis, radiation therapy toxicity, chemotherapy toxicity, and risk prediction. EXPERT OPINION: Discovery and implementation of effective interventions for oral mucositis have been difficult. To date, in the U.S. only palifermin (Kepivance) have been approved and its use is currently confined to patients undergoing stem cell transplant, a very small portion of individuals at risk for mucositis. Fortunately, with the identification of a number of mechanistic pathways which underlie the mucositis' pathogenesis, a rich and diverse pipeline of both topical and systemic compounds are in various stages of pre-clinical and clinical development.

Extensive dental caries in patients with oral chronic graft-versus-host disease.

The oral cavity is one of the sites most frequently affected by chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (alloHCT) and can be a significant source of patient morbidity due to both mucosal and salivary gland involvement. The development of dental decay is a potentially devastating oral complication that has only rarely been reported in the transplantation literature. The purpose of this study was to comprehensively characterize a cohort of patients with cGVHD who subsequently developed extensive dental caries. A retrospective case-record review was conducted for patients who had undergone alloHCT at Dana-Farber/Brigham and Women's Cancer Center between 1990 and 2010 and developed cGVHD-associated rampant dental decay. All patients underwent dental evaluation, involving soft and hard tissue examination and dental radiography, before and after alloHCT. Any dental caries diagnosed at the pre-alloHCT evaluation were treated definitively, such that all patients were considered free of caries at the time of admission for alloHCT. A total of 21 patients were identified, with a median time of cGVHD onset of 5.4 months (range, 2.2-18.5 months) after alloHCT. All patients were diagnosed with oral cGVHD, with 90% demonstrating mucosal involvement and 95% demonstrating salivary gland involvement. Post-alloHCT dental evaluation was performed at a median of 22 months (range, 4-81) after alloHCT, when 10 patients were diagnosed with gross caries and 8 patients had 4 or more affected teeth. Cervical and interproximal patterns of dental caries were frequently diagnosed. The proportions of patients with gross caries, one surface caries, and more than one surface caries (classified as 0, 1-3, and ≥4, respectively) were significantly higher after alloHCT than before alloHCT, with at least 50% of patients experiencing an increase. Patients with oral cGVHD who were free of caries at the time of transplantation developed extensive areas of cervical decay at a median of less than 2 years after alloHCT. This is the first comprehensive characterization of this severe late complication of alloHCT and oral cGVHD. Greater awareness by transplantation oncologists and dentists, as well as more aggressive preventive measures, are needed, as are further prospective studies to better elucidate the incidence of this complication, identify risk factors, and evaluate the effectiveness of preventive interventions.