Athanassios Kyrgidis

The International Criteria for Behcet's Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria

Behçets disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment.

Longitudinal Cohort Study of Risk Factors in Cancer Patients of Bisphosphonate-Related Osteonecrosis of the Jaw

PURPOSE The reported incidence of osteonecrosis of the jaw (ONJ) ranges from 0.94% to 18.6%. This cohort study aimed to calculate the incidence of and identify the risk factors for ONJ in patients with cancer treated with intravenous zoledronate, ibandronate, and pamidronate. PATIENTS AND METHODS Data analyzed included age, sex, smoking status, underlying disease, medical and dental history, bisphosphonates (BP) type, and doses administered. Relative risks, crude and adjusted odds ratios (aORs), and cumulative hazard ratios for ONJ development were calculated. RESULTS We included 1,621 patients who received 29,006 intravenous doses of BP, given monthly. Crude ONJ incidence was 8.5%, 3.1%, and 4.9% in patients with multiple myeloma, breast cancer, and prostate cancer, respectively. Patients with breast cancer demonstrated a reduced risk for ONJ development, which turned out to be nonsignificant after adjustment for other variables. Multivariate analysis demonstrated that use of dentures (aOR = 2.02; 95% CI, 1.03 to 3.96), history of dental extraction (aOR = 32.97; 95% CI, 18.02 to 60.31), having ever received zoledronate (aOR = 28.09; 95% CI, 5.74 to 137.43), and each zoledronate dose (aOR = 2.02; 95% CI, 1.15 to 3.56) were associated with increased risk for ONJ development. Smoking, periodontitis, and root canal treatment did not increase risk for ONJ in patients receiving BP. CONCLUSION The conclusions of this study validated dental extractions and use of dentures as risk factors for ONJ development. Ibandronate and pamidronate at the dosages and frequency used in this study seem to exhibit a safer drug profile concerning ONJ complication; however, randomized controlled trials are needed to validate these results. Before initiation of a bisphosphonate, patients should have a comprehensive dental examination. Patients with a challenging dental situation should have dental care attended to before initiation of these drugs.

Bisphosphonate-Related Osteonecrosis of the Jaws: A Case-Control Study of Risk Factors in Breast Cancer Patients

PURPOSE Osteonecrosis of the jaws (ONJ) was initially described in 2001 in patients receiving intravenous bisphosphonate (BP) treatment. The objective of the present study was to determine whether routine dental procedures can be considered as possible risk factors for the development of ONJ in breast cancer patients receiving BP. PATIENTS AND METHODS Twenty breast cancer patients who developed ONJ receiving BP treatment were included in group A, whereas group B consisted of 40 matched controls (breast cancer patients who did not progress to ONJ receiving BP treatment). Routine dental care, smoking habits, history of tooth extraction, use of dentures, and root canal therapy were recorded. RESULTS Our results indicate that history of tooth extraction during zoledronic acid treatment (adjusted odds ratio [OR] = 16.4; 95% CI, 3.4 to 79.6) and the use of dentures (adjusted OR = 4.9; 95% CI, 1.2 to 20.1) increase the risk of developing ONJ. CONCLUSION The outcome of the present study suggests early referral by oncologists for dental evaluation for every patient to be treated with BP. These results raise the current American Society of Clinical Oncology Level of Evidence linking certain dental procedures with ONJ from V to III. Further studies are needed to assess other possible risk factors and also to highlight the etiopathogenesis mechanism of ONJ.

Re‐evaluation of the risk for major adverse cardiovascular events in patients treated with anti‐IL‐12/23 biological agents for chronic plaque psoriasis: a meta‐analysis of randomized controlled trials

Objective  To detect a detrimental or beneficial effect of anti‐IL‐12/23 biological agents (ustekinumab and briakinumab) for the treatment of chronic plaque psoriasis on major adverse cardiovascular events (MACEs).

Denosumab-related osteonecrosis of the jaws

Dear Editors, Denosumab is a human monoclonal IgG2 antibody that binds selectively and with high affinity to the receptor activator of nuclear factor-κB ligand(RANK-L) and pharmacologically mimics the effect of osteoprotegerin on RANK-L [1, 2] thereby blocking the binding of RANK-L to the receptor activator of nuclear factor-κB(RANK) [1]. Denosumab rapidly decreases bone turnover markers resulting in a significant increase in bone mineral density and reduction in fracture risk [3]. Osteonecrosis of the jaws (ONJ) was initially erroneously ascribed to being a later chemotherapy effect [2, 4]. ONJ became one of the most discussed adverse events in advanced malignancy [5]. Importantly, ONJ has never been reported to be associated with other pharmaceutical agents, except bisphosphonates [2, 4]. The case of a cancer patient who developed ONJ without previous history of irradiation or bisphosphonate administration has been published [6]. In this patient, ONJ was reported to have healed completely following sequestration, 15 months after drug discontinuation [6]. Despite the fact that this is the only case published to date, additional evidence published in scientific meeting proceedings suggest that the condition of ONJ may not be solely associated to bisphosphonates [7, 8]. Results from two randomized clinical trials (RCTs; NCT00321464 [8], NCT00330759 [7]) of denosumab in cancer patients with bone metastases report that ONJ occurred infrequently [7, 8] (Table 1). Both studies have current or prior intravenous or oral bisphosphonate administration in their exclusion criteria [7, 8], thus bisphosphonates as an etiopathological factor for ONJ in those participants who received denosumab can be ruled out. Since ONJ has not been previously described to be associated with other drugs agents administered to cancer patients [2], it can be suggested that these cases of ONJ are related to denosumab administration. The role of dosing interval and cumulative dose appears to be important regarding development of denosumabrelated ONJ. All denosumab RCTs published to date include a dosing interval longer than 3 months and a cumulative dose of not more than 210 mg per 6 months [3]. None of these studies does report any cases of ONJ. On the contrary, preliminary results of both RCTs studying denosumab for the treatment of bone metastases in cancer patients include a monthly dosing interval and a dose of 120 mg per month [7, 8]. It is evident that denosumabrelated ONJ could be a dose-related adverse effect. This latter argument has also been reported to apply to bisphosphonate administration [4, 9]. ONJ has been reported to be a much more common event in those patients receiving bisphosphonates for the treatment and prevention of cancer-related skeletal events (mainly intravenously), rather than in those patients receiving bisphosphonates (mainly orally) for non-malignancy indications [10, 11]. Similar to bisphosphonate-related ONJ pharmacosurveillance and reporting history [4], one could anticipate that broad introduction of denosumab into clinical practice, would allow for the recognition of the denosumab-related ONJ adverse effect in a much wider spectrum of prescription indications, including those for non-malignancy [10]. A. Kyrgidis (*) Department of Oral and Maxillofacial Surgery, School of Dentistry, Aristotle University of Thessaloniki, 3 Papazoli St, Thessaloniki 546 30, Greece e-mail: akyrgidi@gmail.com

Cutaneous squamous cell carcinoma (SCC) of the head and neck: risk factors of overall and recurrence-free survival.

BACKGROUND Head and neck cutaneous squamous cell carcinoma (HNCSCC) although rarely fatal has significant adverse public health effects due to high medical costs, compromised quality of life, functional impairment and other serious consequences. The present longitudinal cohort study of HNCSCC was designed to determine whether certain clinical-pathologic features of HNCSCC are associated with reduced overall and recurrence-free survival, as suggested by previous data. PATIENTS The cohort sample consisted of 315 consecutive patients presenting with primary HNCSCC of the head and neck. Life-table analysis and Kaplan-Meier survival analysis were performed. Multivariate Coxs proportional hazards regression models were used to assess the effects of covariates on the length of the interval. RESULTS There were 145 male and 170 female Caucasian patients. At the time of analysis, 222 patients were alive. The mean follow-up time of a patient after enrolment has been 46.7 months (range, 12-124 months). Broders differentiation grade, perineural involvement, the presence of inflammation and T-stage were independent adjusted predictors for overall survival. pT and N-stage, inflammation and perineural involvement were significant predictors for recurrence-free survival while adjuvant irradiation was associated with a 92% reduced risk for recurrence. Life-table analysis showed that 87% and 69% study patients were free from recurrence at years 3 and 5, respectively. CONCLUSIONS Certain clinico-pathological predictors can be used to discriminate subsets of high-risk patients that could benefit from long-term follow-up. After excision in negative margins, patients with HNCSCC should be referred to specialised multidisciplinary oncology clinics for counselling on adjuvant radiotherapy and follow-up.

Classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy

BACKGROUND The current guidelines for the management of basal cell carcinoma (BCC) suggest a different therapeutic approach according to histopathologic subtype. Although dermatoscopic and confocal criteria of BCC have been investigated, no specific studies were performed to evaluate the distinct reflectance confocal microscopy (RCM) aspects of BCC subtypes. OBJECTIVES To define the specific dermatoscopic and confocal criteria for delineating different BCC subtypes. METHODS Dermatoscopic and confocal images of histopathologically confirmed BCCs were retrospectively evaluated for the presence of predefined criteria. Frequencies of dermatoscopic and confocal parameters are provided. Univariate and adjusted odds ratios were calculated. Discriminant analyses were performed to define the independent confocal criteria for distinct BCC subtypes. RESULTS Eighty-eight BCCs were included. Dermatoscopically, superficial BCCs (n=44) were primarily typified by the presence of fine telangiectasia, multiple erosions, leaf-like structures, and revealed cords connected to the epidermis and epidermal streaming upon RCM. Nodular BCCs (n=22) featured the classic dermatoscopic features and well outlined large basaloid islands upon RCM. Infiltrative BCCs (n=22) featured structureless, shiny red areas, fine telangiectasia, and arborizing vessels on dermatoscopy and dark silhouettes upon RCM. LIMITATIONS The retrospective design. CONCLUSION Dermatoscopy and confocal microscopy can reliably classify different BCC subtypes.

Extrinsic ageing in the human skin is associated with alterations in the expression of hyaluronic acid and its metabolizing enzymes

Abstract:  Extrinsic skin ageing or ‘photoageing’, as opposed to intrinsic skin ageing, is the result of exposure to external factors, mainly ultraviolet irradiation. Glycosaminoglycans (GAG) and particularly hyaluronic acid (HA) are major components of the cutaneous extracellular matrix involved in tissue repair. However, their involvement in extrinsic skin ageing remains elusive. In this study, we investigated the expression of HA and its metabolizing enzymes in photoexposed and photoprotected human skin tissue specimens, obtained from the same patient. Total GAG were isolated, characterized using specific GAG‐degrading enzymes and separated by electrophoresis on cellulose acetate membranes and polyacrylamide gels. Quantitation of HA in total GAG was performed using ELISA. Gene expression of hyaluronan synthases (HAS), hyaluronidases (HYAL) and HA receptors CD44 and receptor for HA‐mediated motility (RHAMM) was assessed by RT‐PCR. We detected a significant increase in the expression of HA, of lower molecular mass, in photoexposed skin as compared with photoprotected skin. This increase was associated with a significant decrease in the expression of HAS1 and an increase in the expression of HYAL1‐3. Furthermore, the expression of HA receptors CD44 and RHAMM was significantly downregulated in photoexposed as compared with photoprotected skin. These findings indicate that extrinsic skin ageing is characterized by distinct homoeostasis of HA. The elucidation of the role of HA homoeostasis in extrinsic skin ageing may offer an additional approach in handling cutaneous ageing.

Association of ustekinumab and briakinumab with major adverse cardiovascular events An appraisal of meta-analyses and industry sponsored pooled analyses to date

Safety concerns have been raised regarding possible association of major adverse cardiovascular events (MACEs) with use of anti-IL-12/23 biologic agents for the treatment of chronic plaque psoriasis (CPP). Ten MACEs have been recorded in actively-treated patients during the placebo-controlled phase of phase II and III studies compared with zero events in placebo-treated patients, along with a total of 53 MACEs (26 ustekinumab, 27 briakinumab) and five cardiovascular deaths (1 ustekinumab, 4 briakinumab) across all phases of these studies. Two industry-independent meta-analyses of randomized, double-blind, placebo-controlled, monotherapy trials calculated risk for MACEs. One detected statistically significant increase in cardiovascular risk using Peto method (p = 0.04), while the other utilized Mantel-Haenszel fixed-effects model with absolute risk differences as effect measure, but did not achieve significance (p = 0.11). Statistical theory reports that Peto method is more suitable for meta-analyses of studies with baseline event rates of 1% or less and randomization ratios ranging from 1:5 to 1:1 as is the case in these meta-analyses. Potential of anti-IL-12/23 biologic agents to further increase cardiovascular morbidity cannot be excluded and a class effect cannot be denied. Clinicians should screen CPP patients for manageable cardiovascular risk factors before initiating anti-IL-12/23 agents along with intensive monitoring of these patients.

Osteonecrosis of the jaw and bisphosphonate use in breast cancer patients.

It is renowned that breast cancer patients suffer from a number of cancer-related skeletal events, while drugs recently added to the practitioners’ quiver, such as aromatase inhibitors, intensify the need to preserve bone mass in this group of patients. Bisphosphonates are potent inhibitors of both normal and pathologic bone resorption. Besides their apoptotic and antiproliferative activity on osteoclasts, bisphosphonates can also exert various effects on macrophages, keratinocytes and fibroblasts. Bisphosphonate-related osteonecrosis of the jaw is a complication that emerged after broad clinical use of bisphosphonates, and which has not yet been adequately described in a clinical trial setting. The purpose of this review is to critically reflect the incidence, etiopathogenesis, prevention and treatment of osteonecrosis of the jaw. Succinct suggestions are provided to ensure clinicians prevent and detect the complications early.