Guselkumab: a new etiological factor of Medication Related Osteonecrosis of the Jaw (MRONJ)? A case report.

Medication Related Osteonecrosis of the Jaw (MRONJ) has traditionally been mostly attributed to the exposure to antiresorptive agents such as bisphosphonates and denosumab. Nevertheless, following the development of new medications in oncology, the spectrum of drugs associated with MRONJ widened, with, for example, tyrosine kinase inhibitors, mTOR inhibitor, or monoclonal antibodies against VEGF. To date, MRONJ has not been assessed or reported in patients treated with guselkumab so far. Guselkumab is a fully human IgG1λ monoclonal antibody that selectively targets the p19 protein subunit of extracellular human IL-23 and inhibits its intracellular and downstream signalling. It consists of two identical light chains and two identical heavy chains. The four chains are linked together by covalent disulfide bonds and noncovalent protein-protein interactions. The aim of this article is to report a case of a patient with severe psoriasic arhtritis and plaque psoriasis who presented with a clinical condition that could resemble a MRONJ following guselkumab therapy and a dental root extraction.

The Oral Microbiome for Geographic Origin: An Italian Study.

The human oral microbiome has primarily been studied in clinical settings and for medical purposes. More recently, oral microbial research has been incorporated into other areas of study. In forensics, research has aimed to exploit the variation in composition of the oral microbiome to answer forensic relevant topics, such as human identification and geographical provenience. Several studies have focused on the use of microbiome for continental, national, or ethnic origin evaluations. However, it is not clear how the microbiome varies between similar ethnic populations across different regions in a country. We report here a comparison of the oral microbiomes of individuals living in two regions of Italy - Lombardy and Piedmont. Oral samples were obtained by swabbing the donors' oral mucosa, and the V4 region of the 16S rRNA gene was sequenced from the extracted microbial DNA. Additionally, we compared the oral and the skin microbiome from a subset of these individuals, to provide an understanding of which anatomical region may provide more robust results that can be useful for forensic human identification. Initial analysis of the oral microbiota revealed the presence of a core oral microbiome, consisting of nine taxa shared across all oral samples, as well as unique donor characterising taxa in 31 out of 50 samples. We also identified a trend between the abundance of Proteobacteria and Bacteroidota and the smoking habits, and of Spirochaetota and Synergistota and the age of the enrolled participants. Whilst no significant differences were observed in the oral microbial diversity of individuals from Lombardy or Piedmont, we identified two bacterial families - Corynebacteriaceae and Actinomycetaceae - that showed abundance trends between the two regions. Comparative analysis of the skin and oral microbiota showed significant differences in the alpha (p = 0.0011) and beta (Pr(>F)= 9.999e-05) diversities. Analysis of skin and oral samples from the same donor further revealed that the skin microbiome contained more unique donor characterising taxa than the oral one. Overall, this study demonstrates that whilst the oral microbiome of individuals from the same country and of similar ethnicity are largely similar, there may be donor characterising taxa that might be useful for identification purposes. Furthermore, the bacterial signatures associated with certain lifestyles could provide useful information for investigative purposes. Finally, additional studies are required, the skin microbiome may be a better discriminant for human identification than the oral one.

Oral Health in Breast Cancer Women with Vitamin D Deficiency: A Machine Learning Study.

Breast cancer (BC) survivors treated with aromatase inhibitors (AIs) commonly show several pathological issues, including poor oral health, bone health impairment, and vitamin D deficiency. However, to date, oral health issues in BC survivors treated with AIs have been poorly investigated and their relationship with vitamin D deficiency are far from being understood. This study aimed to evaluate the correlation between oral health and vitamin D status in BC survivors undergoing treatment with AIs through a machine learning approach. In this cross-sectional study, we included post-menopausal BC women with vitamin D deficiency undergoing AIs therapy. The outcome measures were the following: oral health indexes as the Decayed, Missing, and Filled Permanent Teeth Index (DMFT); serum levels of 25(OH)D3; Bone Mineral Density (BMD); and the diagnosis of osteoporosis. We included 41 post-menopausal BC women, mean aged 66.10 ± 8.47 years, with mean serum levels of vitamin D of 14.63 ± 6.62 ng/mL. Furthermore, 56.10% of patients had a diagnosis of osteoporosis and 36.59% were osteopenic. DMFT was significantly related to smoking (p-value = 0.005) and dental floss use (p-value = 0.001). There was a significant correlation between DMFT and vitamin D levels (Pearson's r: -0.73; p-value = 0.001). The regression machine learning model showed that vitamin D status and the use of dental floss were the most relevant variables in terms of correlation with DMFT. In conclusion, vitamin D deficiency, inadequate use of dental floss, and smoking had a negative impact on oral health in BC women. Thus, vitamin D deficiency screening and supplementation and a prompt oral rehabilitation plan should be suggested and implemented in the complex treatment framework of BC survivors undergoing treatment with AIs.

Implications on pathogenesis and risk of oral lichen planus neoplastic transformation: an ex-vivo retrospective immunohistochemical study.

AIMS: To evaluate OPN, MCM7, Ki-67, p53, Bcl-2 and 53BP1 presence, together with the abnormal adaptive CD4 and CD8 T-cell response markers expression in a series of oral lichen planus (OLP) affected patients and assess their combined contribution for a more objective disease classification. METHODS AND RESULTS: In this ex-vivo retrospective analysis, biopsy specimens from 28 adults with a clinical diagnosis of OLP at different progression degree (16 reticular, 2 plaque-like, 1 erosive and 9 mixed type) were collected. Sections were immunohistochemically investigated for the proinflammatory cytokine osteopontin (OPN), alpha-beta CD4 and CD8 positive T cells, DNA replication licensing factor (MCM7), proliferating cell marker (Ki-67), apoptotic and tumor antigen (p53), apoptosis modulator (Bcl-2) and cellular response regulator to double-strand breaks tumor suppressor p53-binding protein 1 expression. Statistical analysis revealed that 53BP1 is highly represented among the OLP study patients (p<0.05). Moreover, on the basis of the quantification results of the highly expressed parameters, two illness categories with different severity were evidenced. The classification hypothesis was confirmed by i) OLP lesion persistence, ii) the development of oral severe lesions in the patients belonging to high grade activity OLP group (HGA-OLPs) and iii) the ascertainment of the same evidence both in the oral squamous cell tumor controls (OSCC) and in HGA-OLP cases. CONCLUSION: This study completes the scenario with respect to early detection, thanks to a more precise histological analysis, for rationalizing the clinical and histological findings toward a sharable international disease scoring system.

Near infrared low-level laser therapy and cell proliferation: The emerging role of redox sensitive signal transduction pathways.

Lasers devices are widely used in various medical fields (eg, surgery, dermatology, dentistry, rehabilitative medicine, etc.) for different applications, ranging from surgical ablation of tissues to biostimulation and pain relief. Laser is an electromagnetic radiation, which effects on biological tissues strongly depends on a number of physical parameters. Laser wavelength, energy output, irradiation time and modality, temperature and tissue penetration properties have to be set up according to the clinical target tissue and the desired effect. A less than optimal operational settings, in fact, could result in a null or even lethal effect. According to the first law of photobiology, light absorption requires the presence of a specific photoacceptor that after excitation could induce the activation of downstream signaling pathways. Low-level lasers operating in the red/near infrared portion of the light spectra are generally used for biostimulation purposes, a particular therapeutic application based on the radiant energy ability to induce nonthermal responses in living cells. Biostimulation process generally promotes cell survival and proliferation. Emerging evidences support a low-level laser stimulation mediated increase in "good" reactive oxygen species, able to activate redox sensitive signal transduction pathways such as Nrf-2, NF-kB, ERK which act as key redox checkpoints.

Erbium Yttrium-Aluminum-Garnet Laser Versus Traditional Bur in the Extraction of Impacted Mandibular Third Molars: Analysis of Intra- and Postoperative Differences.

INTRODUCTION: Different osteotomy techniques have been proposed in order to improve postoperative course of impacted third molar extraction. The aim is to evaluate the possible advantages achieved with erbium yttrium-aluminum-garnet (Er:YAG) laser osteotomy compared with traditional burs. MATERIALS AND METHODS: Seventy-six extractions were randomly classified into 2 groups according to osteotomy instrument: group 1 (G1)-Er:YAG laser: 35 patients; group 2 (G2)-traditional bur: 41 patients. Intraoperative parameters: total time, stitches number, and patient compliance. Postoperative: pain, health-related quality of life (HR-QoL), need for analgesics, edema, trismus, intra- and extraoral hematoma, and postoperative complications. RESULTS: Mean time for G1 resulted 1069.4 seconds; for G2 1913.5 seconds (P < 0.0001). Mean number of stitches (P = 0.773) and patient compliance (P = 0.063) were not statistically different. Regarding pain, mean visual analog scale (VAS), and numeric rating scale (NRS) scores were lower in G1 than in G2. Statistically significant differences were highlighted at days 0, 1, and 3 with VAS scale and at days 0, 1, 3, and 7 with NRS scale. The HR-QoL scores resulted lower in G1 than in G2 (P < 0.0001). Mean facial swelling and trismus resulted statistically lower in G1 than in G2 at day 2 (P < 0.0001). Trismus resulted statistically lower in G1 than in G2 at days 2 (P < 0.0001) and 7 (P = 0.004). Two patients (5.71%) of subcutaneous emphysema was recorded in G1 and 2 patients (4.88%) of lip paresthesia in G2. CONCLUSION: Data confirm that the use of Er:YAG laser for osteotomy may achieve several advantages both technical and biological.

Combining Intraoral Scans, Cone Beam Computed Tomography and Face Scans: The Virtual Patient.

PURPOSE: The aim of this literature review was to provide an update on the current scientific knowledge in the field of 3D virtual patient science and to identify a possible easy, smart, and affordable method to combine different file formats obtained from different digital devices. METHODS: Electronic searches of the Medline database was performed, up to May 2017, for articles dealing with the construction of a 3D virtual patient; the matching of data acquired with different digital devices (cone beam computed tomography, CBCT; face scanner, FS; intraoral scanner, IOS; and desktop scanner, DS) was considered. The inclusion of studies was based on the superimposition of at least 2 different digital sources. RESULTS: Twenty-five studies were selected for subsequent examination. Only 3 studies analyzed the feasibility of superimposition of 3 different types of 3D data (CBCT + FS + IOS/DS). The most frequently used matching procedure was between CBCT and FS and CBCT and IOS/DS. CONCLUSION: The procedure of superimposition of data from CBCT, IOS, and FS is currently feasible and it is now possible to create a 3D "virtual patient" to better diagnose, plan the treatment, and communicate with patients.

Assessment of Atlanto-Axial and Mandibular Rotation by Cone Beam Computed Tomography.

The cranial portion of the vertebral segment together with the atlanto-occipital joint represents a very complex area. Since this system could be influenced by different atlas and mandibular position, the aim of this work was to assess atlanto-axial and mandibular rotation. Scanora 3-dimensional cone bean computed tomography images from 205 patients without signs or symptoms of temporomandibular disorder were evaluated. Using a digitalized images analyzer, the axial rotations of atlas and mandible rotation were calculated, measuring the angle with respect to the frontal plane. The same direction for the axial rotation of the mandible and for the atlanto-axial rotation (consistent group) was observed in 80.98% of the patients; opposite directions (inconsistent group) were observed in 19.02%. Among the consistent group, the left rotation was observed in 71.08% of the patients and the right rotation in 28.92%. Absolute values showed a more marked rotation for atlas than mandible and higher values for the left rotation were reported for both.Taking together these data represents important starting points for the knowledge of atlas and mandible relationship and its functional and clinical implication.

Prosthetic Complications Affecting Single-Tooth Morse-Taper Connection Implants.

PURPOSE: To evaluate the long-term cumulative implant survival rate (CISR%) and cumulative implant-crown success rate (CICSR%) of single-tooth Morse-taper connection implants, with particular attention to documenting the incidence of prosthetic complications. METHODS: The customized records of all patients who had been treated with single-tooth Morse-taper connection implants in 2 dental centers during the period between January 2002 and December 2012 were revisited. These records included patient-related (gender, age at surgery, smoking, bruxism), implant-related (date of insertion, site/location, and length/diameter of the implant, previous/concomitant bone regeneration), and restoration-related (date of delivery of the provisional and final crown) information. In addition, these records contained information about any implant failure and biologic and/or prosthetic complication that occurred during the follow-up period as well as the radiographic documentation. The follow-up period comprised between 5 and 15 years. The main outcomes were CISR% and CICSR%, with the latter being defined as the condition in which no complication had affected the surviving implant-supported crown during the entire follow-up. Life-table analysis was used for the analysis of CISR% and CICSR%. Peri-implant marginal bone resorption (PIMBR) at 5, 10, and 15 years was a secondary outcome of this study. RESULTS: In total, 578 patients who had received 612 implants were included in this study. The overall CISR% at 15 years was 94.8% (94.2% maxilla, 95.3% mandible). Among the surviving crowns, the overall CICSR% at 15 years was 94.5% (93.1% and 94.9% for anterior and posterior crowns, respectively), and the incidence of prosthetic complications was low (1.5%). The PIMBL amounted to 0.38 ±â€Š0.29 mm, 0.49 ±â€Š0.35 mm, and 0.94 ±â€Š0.58 mm at the 5-, 10-, and 15-year follow-ups, respectively. CONCLUSION: Morse-taper connection implants represent a reliable treatment procedure for the restoration of single-tooth gaps in the long term, with high CISR% (94.8%) at 15 years, a very low incidence of complications, and a high CICSR% (94.5%).

Charged polyhedral oligomeric silsesquioxanes trigger in vitro METosis via both oxidative stress and autophagy.

AIMS: Monocytes/macrophages are essential in innate immune response against pathogens also because their ability to release extracellular traps named METs (monocytes/macrophages extracellular traps). These structures are composed of DNA fibers decorated with nuclear and cytoplasmic proteins and their production process is called METosis. In this study attention has been focused on the ability of differently charged molecular systems (polyhedral oligomeric silsesquioxanes, POSS positively or negatively charged) to induce METosis. MAIN METHODS: METs formation was induced by lipopolysaccharide (250µg/ml, positive control) and POSS positive and negative (0.05-1mg/ml) treatment. METs were visualized and quantified by confocal microscopy using Sytox green staining. Oxidative stress, autophagy, as well as endocytosis involvement in the POSS induced METosis was evaluated. KEY FINDINGS: Results obtained indicate a POSS positive or negative dose dependent ability in inducing MET release independently to their charge and that this phenomenon is a consequence of POSS +/- internalization. Moreover, studies using many reactive oxidative species (ROS) blockers and autophagy inhibitor showed a strong reduction in POSS induced METosis indicating their involvement. SIGNIFICANCE: POSS +/- induce extracellular traps production in human monocytes/macrophages by oxidative and autophagic pathway.

Diode Laser Clinical Efficacy and Mini-Invasivity in Surgical Exposure of Impacted Teeth.

The gold standard to arrange impacted teeth in the dental arch is represented by a surgical approach followed by orthodontic traction force application. In the literature, many surgical approaches are proposed to reach such a scope. The aim of the present study is to demonstrate how laser technique could positively assist surgical approaches.Study population was composed by 16 patients undergoing orthodontic treatment of 20 impacted teeth. In 10 patients (population A) surgical exposure of the impacted teeth was performed using a 980 nm diode laser, while in the other 10 patients (population B), surgical incision was performed using a traditional lancet.Only 3 patients of the population A needed local anesthesia for surgical procedure while the remaining 7 patients reported only faint pain during surgery. Two patients referred postsurgical pain (numerical rating scale average value = 2) and needed to take analgesics. None of the patients showed other postsurgical side effects (bleeding, edema).All population B patients needed infiltrative anesthesia and referred postsurgical pain (numerical rating scale average value >4) treated with analgesics. Moreover, in such population, 4 patients referred lips edema while 4 showed bleeding and 6 needed surgical sutures of soft tissues.The lack of side effects of laser surgical approach to expose impacted teeth must persuade dental practitioners to choose such a clinical approach to closed surgical approach every time it is possible.

Laser-induced osteoblast proliferation is mediated by ROS production.

Low-level laser therapy (LLLT) is widely used in regenerative medicine and in dental therapy by virtue of its beneficial effects in a plethora of pathological conditions. In this study, the effect of a 980 nm diode laser on pre-osteoblasts proliferation has been evaluated, along with reactive oxygen species (ROS) production. We hypothesized that ROS were a key factor in LLLT-induced pre-osteoblasts proliferation, as it is known that ROS can induce the activation of many biological pathways, leading to cell proliferation, differentiation or apoptosis. Murine pre-osteoblasts MC3T3 cells were irradiated with different energy outputs (1-50 J) in the absence or presence of the antioxidant N-Acetyl-L-cysteine (NAC). Laser treatment, in the absence of NAC, was able to induce a fluence-dependent statistically significant increase in ROS generation, while the presence of NAC strongly inhibited it. Cell proliferation, measured after laser stimulation, was significantly increased both at low and higher energy, with a peak at 10 J in the absence of the antioxidant. On the contrary, in the presence of NAC, laser irradiation was not able to induce any cell proliferation, suggesting a crucial role of ROS in this laser-induced cell effect. These results suggest that LLLT may be a useful tool for bone regeneration therapy and an effective range of fluences to be used is indicated.

Decreasing frequency of osteonecrosis of the jaw in cancer and myeloma patients treated with bisphosphonates: the experience of the oncology network of piedmont and aosta valley (north-Western Italy).

Background. Data concerning frequency of Osteonecrosis of Jaws (ONJ) are mostly based on single center experiences. Patients and Methods. Since 2005 a multidisciplinary study group collected data of cases of ONJ in patients treated with Bisphosphonates (BP) and observed in oncology and hematology centers of a regional network. Results. By December 2008, 221 cases were registered. We report details of 200 cases, identified after cross-checking reports from centres of medical oncology, haematology, and oral care. Primary neoplasm was breast cancer (39%), myeloma (32%), prostate cancer (16%), and other types of cancer (8%). In about 50% of the cases a history of dental extraction was present. Zoledronic acid was administered (alone or with other BP) to 178 patients (89%). Median time from first infusion to ONJ diagnosis was 21.0 (zoledronic acid only) and 39.0 months (pamidronate only). The number of ONJ cases per year was 3 in 2003, 21 in 2004, 58 in 2005, 60 in 2006, 37 in 2007, and 21 in 2008. Conclusion. The number of new ONJ cases in cancer and myeloma patients increased until 2006 and then reduced. The possible reasons of this trend (introduction of zoledronic acid; increase of ONJ awareness; diffusion of preventive dental measures; late modifications of BP prescription) are herein discussed.

Low concentration amino-bisphosphonates stimulate human keratinocyte proliferation and in vitro wound healing.

Amino-bisphosphonates (N-BPs) are widely used to treat a great variety of clinical conditions involving altered calcium metabolism, as well as to prevent bone metastases. The use of N-BPs, however, display well-known side effects, including cellular toxicity, mainly at soft tissue and mucosal level, that arise from N-BPs ability to induce cell apoptosis when administered at clinically relevant concentrations. The aim of this study was to evaluate, in an in vitro wound healing model, the effect of N-BPs low concentration (10 nM-10 µM) stimulation on keratinocyte cellular behaviour. Human keratinocytes were treated with neridronate and zoledronate, two N-BPs with different chemical structure and clinical potency, but sharing a common pharmacological target: farnesyl pyrophosphate (FPP) synthase. Surprisingly, at the tested concentrations, both drugs stimulated keratinocytes proliferation, upregulating cytokeratin 5 while downregulating filaggrin expression, and wound healing ability, without any significant effect on matrix metalloproteinase (MMP)-9 activity. The lack of N-BPs effect on MMP-9 activity indicates that wound closure, in our experimental model, is mainly due to an increase in cell proliferation rather than to an increase in cell migration. Therefore, it can be hypothesised that the observed wound healing results could be ascribed to an N-BPs mediated reduction of FPP endogenous levels, thus suggesting new possible clinical applications for these compounds.

Chronic exposure to cigarette smoke increases matrix metalloproteinases and Filaggrin mRNA expression in oral keratinocytes: role of nicotine stimulation.

The vegetal alkaloid nicotine has been proved to modify the expression of many keratinocyte markers. In this study, the basal expression of MMP-2, MMP-9, MMP-28, and Filaggrin has been evaluated in oral keratinocytes, in order to collect information about the ability of cigarette smoke to modify the basal expression pattern of these key enzymes in the absence of evident clinical signs in the oral epithelium. MMP-2, MMP-9, MMP-28, and Filaggrin basal expression was investigated by RT-PCR in oral keratinocytes derived from smokers (n=11), non-smokers (n=11), and ex-smokers (n=6) healthy volunteers. Moreover keratinocytes from non-smokers volunteers were stimulated in vitro by a single dose administration of nicotine (10 µM) in order to estimate the effect of nicotinic receptors activation on the basal expression of the studied markers. RT-PCR analysis showed that all the markers studied were overexpressed in keratinocytes from smoker donors compared to control keratinocytes, while a single dose of nicotine was able to induce only Filaggrin expression in keratinocytes from non-smoking donors. Markers expression in ex-smoker donors was similar to that observed in normal non-smoker donors. These data indicate for the first time that cigarette smoking affects basal expression of some important markers in oral mucosa keratinocytes in vivo in the absence of clinical signs and that smoke quitting restores basal expression levels of these markers.

Nicotine modulates gelatinase B (MMP-9) and epilysin (MMP-28) expression in reconstituted human oral epithelium.

Oral epithelial keratinocytes express nicotinic cholinergic receptors which activation modulates keratinocytes differentiation and migration through different metabolic pathways. Matrix metalloproteinases (MMPs) are Zn-dependent enzyme involved in cell migration. Among them, gelatinase B (MMP-9) and epilysin (MMP-28) are two MMPs expressed by human keratinocytes during both wound healing and proliferation. Their expression has been investigated in a reconstituted human oral epithelium (HOE) exposed to nicotine (Nic, 1-50 µM) for 72 h both in the absence and presence of the nicotinic antagonist mecamylamine (Mec), H7, a PKC inhibitor and PD98059, a MAPK inhibitor (PD). At the end of treatment, MMP-28 expression has been analyzed in epithelium sections using an anti-MMP-28 antibody, whereas MMP-9 presence and activity has been measured in cell-conditioned medium analyzed by gelatine zymography. The expression of MMP-9 was reduced by Nic in a dose-dependent fashion and this effect was antagonized by Mec, H7 and PD. On the other hand, Nic increased the expression of MMP-28, and this effect was blocked both by H7 and PD, whereas Mec even enforced it. Nic effects on MMP-9 and MMP-28 expression by oral keratinocytes were not previously reported and these data suggest MMPs expression mediated by PKC and MAPK as a possible target for Nic toxicity in oral epithelium.

Benign fibrous histiocytoma of the lower lip.

Benign fibrous histiocytoma (BFH) is one of the most common tumors of the superficial and deep soft tissues; it is commonly localized on the skin of the extremities and presents as a slow growing solitary nodule, made up of a mixture of fibroblastic and histiocytic cells. To our knowledge, involvement of the soft tissue of the oral cavity is rare. We present a case of BFH of the lower lip in a 61-year-old white woman who presented with a painless, slow-growing lump inside the lower lip. The lesion was surgically removed. Histologically, it was characterized by uniform spindle-shaped cells arranged in a prominent whorled or storiform pattern. Scattered xanthomatous cells, multinucleated giants cells, lymphocytes, and deposits of hemosiderin were noted throughout the lesion. This rare tumor should be considered in the differential diagnosis of the oral soft-tissue neoplasms.

Saldino-Mainzer syndrome: nephronophthisis, retinitis pigmentosa, and cone-shaped epiphyses.

Saldino-Mainzer syndrome is part of a group disorders, the conorenal syndromes, that are characterized by cone-shaped epiphyses with chronic renal disease in childhood and are variously associated with retinitis pigmentosa, cerebral ataxia, and/or abnormalities of the proximal epiphyses and femur metaphyses. Saldino-Mainzer syndrome usually has sporadic presentation. The present report shows the unusual findings of a 23-year-old woman, affected by the Saldino-Mainzer syndrome and has undergone kidney transplantation, highlights the possible association with maxillofacial and cephalometric abnormalities.

Rapid expansion of the palate with a new surgical technique.

After briefly reviewing the literature concerning palatal expansion, a new technique combining surgical and medical orthodontic treatment is described. The technique, which entails detaching the nasal septum, is particularly appropriate in oral-breathing patients. Sixty-one patients (aged 10-32 years) were included in the study. The technique, which has low morbidity, gave good short- and long-term results.