A Review Into the Effects of Pamidronic Acid and Zoledronic Acid on the Oral Mucosa in Medication-Related Osteonecrosis of the Jaw.

Medication-related osteonecrosis of the jaw (MRONJ) is a growing problem without an effective treatment, presenting as necrotic bone sections exposed via lesions in the overlying soft tissue. There is currently a lack of clarity on how the factors involved in MRONJ development and progression contribute to disease prognosis and outcomes. Bisphosphonates (BPs), the most common cause of MRONJ, affect bone remodeling, angiogenesis, infection, inflammation and soft tissue toxicity, all of which contribute to MRONJ development. This article reviews the cellular mechanisms through which BPs contribute to MRONJ pathology, with a focus on the effects on cells of the oral mucosa. BPs have been shown to reduce cell viability, reduce proliferation, and increase apoptosis in oral keratinocytes and fibroblasts. BPs have also been demonstrated to reduce epithelial thickness and prevent epithelial formation in three-dimensional tissue engineered models of the oral mucosa. This combination of factors demonstrates how BPs lead to the reduced wound healing seen in MRONJ and begins to uncover the mechanisms through which these effects occur. The evidence presented here supports identification of targets which can be used to develop novel treatment strategies to promote soft tissue wound healing and restore mucosal coverage of exposed bone in MRONJ.

Synthetic Hydroxyapatite Inhibits Bisphosphonate Toxicity to the Oral Mucosa In Vitro.

Medication-related osteonecrosis of the jaw (MRONJ) is a side effect of bisphosphonate therapy, characterised by exposed necrotic bone. The soft tissues of the oral mucosa no longer provide a protective barrier and MRONJ patients experience pain, infections and difficulties eating. We hypothesised that hydroxyapatite (Ca5(PO4)3(OH)) could reduce bisphosphonate concentrations and protect the oral mucosa by exploiting bisphosphonate's calcium binding affinity. The effect of zoledronic acid (ZA) and pamidronic acid (PA) on the metabolism of oral fibroblasts, oral keratinocytes and three-dimensional oral mucosa models was investigated and then repeated in the presence of hydroxyapatite granules. Without hydroxyapatite, ZA and PA significantly reduced the metabolic activity of oral cells in a dose-dependent manner. Both drugs reduced epithelial thickness and 30 µM ZA resulted in loss of the epithelium. Hydroxyapatite granules had a protective effect on oral cells, with metabolic activity retained. Oral mucosa models retained their multi-layered epithelium when treated with ZA in the presence of hydroxyapatite granules and metabolic activity was comparable to controls. These results demonstrate hydroxyapatite granules protected oral soft tissues from damage caused by bisphosphonate exposure. Porous hydroxyapatite granules are currently used for socket preservation and this data suggests their potential to prevent MRONJ in at-risk patients.

High-grade urothelial carcinoma with squamous differentiation metastasizing to the tongue.

Tumors metastasizing to the head and neck region are uncommon. Metastasis of urothelial carcinoma to the maxillofacial region is exceedingly rare and mostly involves the jaw. We present a case of urothelial carcinoma metastasizing to the tongue. Immunohistochemistry in conjunction with fluorescent in situ hybridization was used to confirm the relation between the primary and metastatic lesions, making it the first such reported case employing the UroVysion (Catalogue number 02 J27-025, Abbott Molecular Inc., Des Plaines, IL, USA) fluorescent in situ hybridization probe in a metastatic lesion in the head and neck region.

See-and-treat surgery for facial skin cancer.

See-and-treat surgery has been described as an efficient means of streamlining specialist diagnosis and treatment, and is commonly employed in gynaecology to reduce the delay between cytological screening and definitive treatment of cervical neoplasia. Relatively young patients with predominantly benign skin lesions have been treated in see-and-treat clinics but only in the context of referrals from primary care. The author describes the treatment of tertiary referrals for facial skin malignancies under local anaesthesia at these clinics, and analyses their acceptability to patients. A total of 100 consecutive patients were included. Data on age, coexisting conditions, diagnosis, site and size of lesion, operation, and outcomes including complications and completeness of excision, were collected. A questionnaire seeking patients' opinions was also used. Ninety patients were treated and 98 lesions were removed, 94% of which were malignant. The complete excision rate was 95%. There were no complications, and 98% of patients were satisfied with the service. See-and-treat surgery is an effective, safe, and acceptable means of providing surgical management of facial skin malignancies.

Access to dental services for head and neck cancer patients.

Dental assessment is important for patients with cancer of the head and neck who are to have radiotherapy, as many of these patients have poor dental health before they start treatment. This, compounded by the fact that radiotherapy to the head and neck has a detrimental effect on oral health, has led the National Institute for Clinical Excellence (NICE) to issue guidance that the dental health of these patients should be assessed before treatment. Unfortunately some multidisciplinary teams, such as the one at United Lincolnshire Hospitals, do not have access to a restorative dentist or a dental hygienist. In a retrospective survey we investigated access to general dental services by patients with head and neck cancer who were to have radiotherapy at our hospital and found that 37/71 (52%) had not been reviewed by a dentist within the past 12 months. A secondary national survey that investigated the availability of restorative dental and dental hygienic services showed that of the 56 multidisciplinary teams that deal with head and neck cancer in England, 19 (34%) do not have access to a restorative dentist and 23 (41%) do not have access to a dental hygienist, suggesting that this problem may be countrywide.

Ex vivo recovery and activation of dysfunctional, anergic, monocyte-derived dendritic cells from patients with operable breast cancer: critical role of IFN-alpha.

BACKGROUND: Dendritic cells (DCs) play a crucial role in initiating effective cell-mediated immune responses, but are dysfunctional and anergic in breast cancer. Reversal of this dysfunction and establishment of optimal DC function is a key prerequisite for the induction of effective anti-cancer immune responses. RESULTS: Peripheral blood DCs (PBDCs) and lymph node DCs (LNDCs) generated in vitro from adherent cultures of peripheral blood monocytes (PBMs) and lymph node monocytes (LNMs), respectively, using the 4 cytokine conditioned medium (CCM) (GM-CSF+IL-4+TNF-alpha+IFN-alpha) or 3 CCM (GM-CSF+IL-4+TNF-alpha) demonstrated a significantly higher degree of recovery and functional capacity in a mixed lymphocyte DC reaction (MLDCR, p < 0.001), expressed significantly higher levels of HLA-DR, CD86, compared with 2 CCM (GM-CSF+IL-4) or medium alone generated DCs from PBMs and LNMs (p < 0.001). The PBDCs generated with 3 CCM or 4 CCM showed a significantly (p < 0.001) enhanced macropinocytotic capability (dextran particles) and induced increased production and secretion of interleukin-12p40 (IL-12p40) in vitro (p < 0.001), compared with PBDCs generated from monocytes using 2 CCM or medium alone. Lipopolysaccharide (LPS) stimulation of PBDCs generated with 4 CCM demonstrated enhanced secretion of IL-6 but not IL-12p70, compared with control DCs unstimulated with LPS (p < 0.001). CONCLUSION: Dysfunctional and anergic PBDCs and LNDCs from patients with operable breast cancer can be optimally reversed by ex vivo culturing of precursor adherent monocytes using a 4 CCM containing IFN-alpha. Maximal immunophenotypic recovery and functional reactivation of DCs is seen in the presence of IFN-alpha. However, 4 CCM containing IFN-alpha generated-PBDCs, do not produce and secrete IL-12p70 in vitro.

Significant immunomodulatory effects of Pseudomonas aeruginosa quorum-sensing signal molecules: possible link in human sepsis.

Pathogenic bacteria use quorum-sensing signal molecules to co-ordinate the expression of virulence genes. Animal-based studies have demonstrated the immunomodulatory effects of quorum-sensing signal molecules. In the present study, we have examined the impact of these molecules on normal human immune function in vitro and compared this with immune changes in patients with sepsis where quorum-sensing signal molecules were detected in the sera of patients. Quorum-sensing signal molecules inhibited normal dendritic cell and T-cell activation and proliferation, and down-regulated the expression of co-stimulatory molecules on dendritic cells; in MLDCRs (mixed lymphocyte dendritic cell reactions), secretion of IL (interleukin)-4 and IL-10 was enhanced, but TNF-alpha (tumour necrosis factor-alpha), IFN-gamma (interferon-gamma) and IL-6 was reduced. Quorum-sensing signal molecules induced apoptosis in dendritic cells and CD4(+) cells, but not CD8(+) cells. Dendritic cells from patients with sepsis were depleted and ex vivo showed defective expression of co-stimulatory molecules and dysfunctional stimulation of allogeneic T-lymphocytes. Enhanced apoptosis of dendritic cells and differential CD4(+) Th1/Th2 (T-helper 1/2) cell apoptotic rate, and modified Th1/Th2 cell cytokine profiles in MLDCRs were also demonstrated in patients with sepsis. The pattern of immunological changes in patients with sepsis mirrors the effects of quorum-sensing signal molecules on responses of immune cells from normal individuals in vitro, suggesting that quorum-sensing signal molecules should be investigated further as a cause of immune dysfunction in sepsis.

Research training for oral and maxillofacial surgery.

The specialty of oral and maxillofacial surgery (OMFS) is unique among UK medical and dental specialties in having clinical and academic training pathways whose entry criteria, curricula and exit examinations are quite different. The Academic Advisory Committee for Oral and Maxillofacial Surgery (AACOMS) pathway offers a formal academic training but with a limited clinical curriculum, while training within the National Health Service (NHS) offers little or no access to research but a more comprehensive clinical curriculum. As a result, there are few doubly qualified consultants in senior university positions, and limited opportunities for dental and medical undergraduates to be exposed to the full scope of the specialty. A further consequence is that research in certain disciplines, such as head and neck oncology and facial trauma, is absent from the majority of universities. Until this situation is corrected, maxillofacial trainees who wish to undergo a comprehensive clinical and research training must find time and funding to support their research training outwith their clinical education. The purpose of this paper is to identify key steps in deciding when, where and how a maxillofacial trainee can gain accomplished research experience in the context of current UK maxillofacial training.