The Facial Skeleton in Patients with Osteoporosis: A Field for Disease Signs and Treatment Complications

Osteoporosis affects all bones, including those of the facial skeleton. To date the facial bones have not drawn much attention due to the minimal probability of morbid fractures. Hearing and dentition loss due to osteoporosis has been reported. New research findings suggest that radiologic examination of the facial skeleton can be a cost-effective adjunct to complement the early diagnosis and the follow up of osteoporosis patients. Bone-mass preservation treatments have been associated with osteomyelitis of the jawbones, a condition commonly described as osteonecrosis of the jaws (ONJ). The facial skeleton, where alimentary tract mucosa attaches directly to periosteum and teeth which lie in their sockets of alveolar bone, is an area unique for the early detection of osteoporosis but also for the prevention of treatment-associated complications. We review facial bone involvement in patients with osteoporosis and we present data that make the multidisciplinary approach of these patients more appealing for both practitioners and dentists. With regard to ONJ, a tabular summary with currently available evidence is provided to facilitate multidisciplinary practice coordination for the treatment of patients receiving bisphosphonates

Evidence-based approach to the treatment of hidradenitis suppurativa/acne inversa, based on the European guidelines for hidradenitis suppurativa

Hidradenitis suppurativa/acne inversa (HS) is a chronic inflammatory skin disease characterized by painful, recurrent nodules and abscesses that rupture and lead to sinus tracts and scarring. To date, an evidence-based therapeutic approach has not been the standard of care and this is likely due to the lack of evidence based treatment guidelines. The purpose of this study was to promote a holistic evidence-based approach which implemented Level of Evidence and Strength of Recommendation for the treatment of HS. Based upon the European Dermatology Forumguidelines for the management of HS, evidence-based approach was explored for the treatment of HS. The diagnosis of HS should be made by a dermatologist or other healthcare professional with expert knowledge in HS. All patients should be offered adjuvant therapy as needed (pain management, weight loss, tobacco cessation, treatment of super infections, and application of appropriate dressings). The treating physician should be familiar with disease severity scores, especially Hurley staging, physician global assessment and others. The routine use of patient’reported outcomesincluding DLQI, itch and pain assessment (Visual Analogue Scale) is strongly recommended. The need for surgical intervention should be assessed in all patients depending upon type and extent of scarring, and an evidence-based surgical approach should be implemented. Evidence-based medical treatment of mild disease consists of topical Clindamycin 1 % solution/gel b.i.d. for 12 weeks or Tetracycline 500 p.o. b.i.d. for 4 months (LOE IIb, SOR B), for more widespread disease. If patient fails to exhibit response to treatment or for a PGA of moderate-to-severe disease, Clindamycin 300 p.o. b.i.d. with Rifampicin 600 p.o. o.d. for 10 weeks (LOE III, SOR C) should be considered. If patient is not improved, then Adalimumab 160 mg at week 0, 80 mg at week 2; then 40 mg subcutaneously weekly should be administered (LOE Ib, SOR A). If improvement occurs then therapy should be maintained as long as HS lesions are present. If the patient fails to exhibit response, then consideration of second or third line therapy is required. A growing body of evidence is being published to guide the treatment of HS. HS therapy should be based upon the evaluation of the inflammatory components as well as the scarring and should be directed by evidence-based guidelines. Treatment should include surgery as well as medical treatment. Future studies should include benefit risk ratio analysis and long term assessment of efficacy and safety, in order to facilitate long term evidence based treatment and rational pharmacotherapy

Hidradenitis suppurativa/acne inversa: a practical framework for treatment optimization – systematic review and recommendations from the HS ALLIANCE working group

Hidradenitis suppurativa (HS)/acne inversa is a debilitating chronic disease that remains poorly understood and difficult to manage. Clinical practice is variable, and there is a need for international, evidence-based and easily applicable consensus on HS management. We report here the findings of a systematic literature review, which were subsequently used as a basis for the development of international consensus recommendations for the management of patients with HS. A systematic literature review was performed for each of nine clinical questions in HS (defined by an expert steering committee), covering comorbidity assessment, therapy (medical, surgical and combinations) and response to treatment. Included articles underwent data extraction and were graded according to the Oxford Centre for Evidence-based Medicine criteria. Evidence-based recommendations were then drafted, refined and voted upon, using a modified Delphi process. Overall, 5310 articles were screened, 171 articles were analysed, and 65 were used to derive recommendations. These articles included six randomized controlled trials plus cohort studies and case series. The highest level of evidence concerned dosing recommendations for topical clindamycin in mild disease (with systemic tetracyclines for more frequent/widespread lesions) and biologic therapy (especially adalimumab) as second-line agents (following conventional therapy failure). Good-quality evidence was available for the hidradenitis suppurativa clinical response (HiSCR) as a dichotomous outcome measure in inflammatory areas under treatment. Lower-level evidence supported recommendations for topical triclosan and oral zinc in mild-to-moderate HS, systemic clindamycin and rifampicin in moderate HS and intravenous ertapenem in selected patients with more severe disease. Intralesional or systemic steroids may also be considered. Local surgical excision is suggested for mild-to-moderate HS, with wide excision for more extensive disease. Despite a paucity of good-quality data on management decisions in HS, this systematic review has enabled the development of robust and easily applicable clinical recommendations for international physicians based on graded evidence

Extracellular matrix molecules in intrinsic and extrinsic skin ageing

Human ageing is a complex and multifactorial process, affected by hereditary and various environmental factors. Nowadays, ageing is a social, demographic and financial problem, with deep and profound effects. Skin ageing is also a multifactorial process, with two independent, clinical and biological, phenomena. The first is intrinsic or innate skin ageing, the so called “biological clock” which affects skin in the same manner that affects all internal organs. The second is extrinsic skin ageing or photo-ageing, which is the result of exposure to environmental factors, mainly UV (Ultraviolet) irradiation. Skin is the main human organ, in which age-related changes are most obvious. Extracellular matrix molecules are highly implicated in skin pathophysiology and diseases, however their expression and role in skin ageing are under-examined. The aim of this study was to examine the expression of extracellular matrix molecules in intrinsic and extrinsic skin ageing. To achieve this we collected human photo-protected samples from juvenile and adult (mean value of 5 and 70 years old) age groups and photo-exposed and photo-protected skin samples from the same patients from an adult age group. Furthermore, we developed primary skin fibroblasts cultures derived from photo-protected skin from female healthy donors of various age groups. Lastly, a model to study the paracrine effect of 17-b-estradiol in the metabolism of hyaluronan was developed. Our results indicate that extrinsic skin ageing is characterized by an increase of fragmented hyaluronan, reduced expression of hyaluronan synthases and hyaluronan receptors and increased expression of hyaluronidases. Proteoglycans expression was in agreement with other characteristic changes of photo-aged skin in collagen, elastin and epidermis. Gelatinolytic activity of matric metalloproteinases 2 and 9 was found to be upregulated. On the other hand, intrinsic skin ageing was characterized by a dramatic decrease in hyaluronan metabolic rate and reduced expression of all proteoglycans, except of aggrecan. These data are in good agreement with the well known decrease of fibroblasts biosynthetic activity, which characterizes the intrinsic ageing of all human organs. Lastly, 17-b-estradiol was found to positively affect hyaluronan homeostasis via its paracrine action to fibroblasts. Overall, our results indicate the distinct profiles of extrinsic and intrinsic skin ageing. Regarding extrinsic skin ageing, our results regarding hyaluronan homeostasis, proteoglycans and matrix metalloproteinases expression fully correlate with the already known characteristic changes of skin and can be considered responsible for the chronic inflammatory procedures. The molecular profile of extracellular matrix molecules in intrinsic skin ageing, on the other hand, proves the dramatic age-related decrease of biosynthetic activity and can be considered a strong indication that intrinsic skin ageing is a mirror for the ageing of the whole human organism. All the above mentioned results, along with the positive effect of 17-b-estradiol in hyaluronan homeostasis, can lead to new novel pharmacological targets to confront with skin ageing.Η γήρανση στον άνθρωπο είναι μια πολύπλοκη και πολυπαραγοντική διαδικασία, με τη συμμετοχή τόσο κληρονομικών όσο και ποικίλων περιβαλλοντικών παραγόντων. Σήμερα η γήρανση αποτελεί ένα κοινωνικό, οικονομικό, δημογραφικό και επιδημιολογικό φαινόμενο, με οικονομικές επιπτώσεις και βαθύ και πολυεπίπεδο αντίκτυπο. Η δερματική γήρανση είναι και αυτή μια πολυπαραγοντική διαδικασία, η οποία μπορεί να διακριθεί σε δύο ανεξάρτητα, κλινικά και βιολογικά, φαινόμενα που επηρεάζουν το δέρμα ταυτόχρονα. Το πρώτο είναι η φυσιολογική ή ενδογενής γήρανση του δέρματος, το λεγόμενο «βιολογικό ρολόι», το οποίο επηρεάζει το δέρμα με τον ίδιο τρόπο που επηρεάζει και όλα τα εσωτερικά όργανα, δηλαδή με μη αναστρέψιμη εκφύλιση του ιστού, κυρίως του συνδετικού. Η δεύτερη αποτελεί την εξωγενή δερματική γήρανση, τη λεγόμενη φωτογήρανση, η οποία είναι αποτέλεσμα της έκθεσης σε εξωγενείς παράγοντες, με κυριότερο την UV (Ultraviolet - υπεριώδη) ακτινοβολία. Το δέρμα άλλωστε αποτελεί το κύριο όργανο στο οποίο είναι ιδιαίτερα εμφανείς οι αλλαγές της γήρανσης. Τα μόρια του εξωκυτταρίου στρώματος, αν και ασκούν κρίσιμο και σημαντικό ρόλο στο χόριο του δέρματος, δεν έχουν πλήρως διευκρινισθεί στη δερματική γήρανση. Σκοπός της παρούσης διατριβής ήταν η μελέτη της έκφρασης των μορίων του εξωκυτταρίου στρώματος στην εξωγενή και ενδογενή δερματική γήρανση. Για το σκοπό αυτό ελήφθησαν φωτο-προστατευμένα δείγματα από νεανική και ενήλικη (5 και 70 έτη μέσος όρος) ηλικιακή ομάδα και φωτο-εκτεθειμένα και φωτο-προστατευμένα δείγματα από τον ίδιο ασθενή από ενήλικη ηλικιακή ομάδα. Επιπλέον, αναπτύχθηκαν πρωτογενείς καλλιέργειες δερματικών ινοβλαστών προερχόμενων από φωτο-προστατευμένο δέρμα υγειών γυναικών διαφόρων ηλικιακών ομάδων. Τέλος, αναπτύχθηκε ένα μοντέλο για τη μελέτη της παρακρινούς δράσης της 17-β-οιστραδιόλης στο μεταβολισμό του υαλουρονικού οξέος. Τα αποτελέσματά καταδεικνύουν ότι η εξωγενής γήρανση χαρακτηρίζεται από παθολογικής αύξηση του υαλουρονικού οξέος, το οποίο όμως είναι καταβολισμένο, πτώση των συνθετασών και των λειτουργικών του υποδοχέων καθώς και αύξηση των υαλουρονιδασών. Η έκφραση των πρωτεογλυκανών βρέθηκε να συνάδει με τις χαρακτηριστικές αλλαγές του κολλαγόνου, της ελαστίνης και της επιδερμίδας στην εξωγενή γήρανση, ενώ η ζελατινολυτική δραστηριότητα των μεταλλοπρωτεϊνασών 2 και 9 βρέθηκε αυξημένη. Από την άλλη πλευρά, η ενδογενής δερματική γήρανση χαρακτηρίστηκε από δραματική πτώση του μεταβολικού ρυθμού του υαλουρονικού και πτώση της γονιδιακής έκφρασης όλων των πρωτεογλυκανών, πλην της αγγκρεκάνης, δεδομένα που συνάδουν απόλυτα με την πτώση της βιοσυνθετικής λειτουργίας των ινοβλαστών, που χαρακτηρίζει την ενδογενή γήρανση όλων των οργάνων του ανθρωπίνου σώματος. Τέλος, η 17-β-οιστραδιόλη βρέθηκε να ασκεί ευεργετική επίδραση στο μεταβολισμό του υαλουρονικού με την παρακρινή της δράση στους ινοβλάστες. Τα αποτελέσματα αυτά αποδεικνύουν το διακριτό χαρακτήρα της εξωγενούς και ενδογενούς γήρανσης. Η ομοιοστασία του υαλουρονικού στην εξωγενή γήρανση καθώς και το προφίλ των πρωτεογλυκανών και μεταλλοπρωτεϊνασών συνάδει απόλυτα με τις χαρακτηριστικές αλλαγές του συνδετικού ιστού στη φωτογήρανση και μπορεί να θεωρηθεί υπεύθυνο για τις χρόνιες φλεγμονώδεις διεργασίες της. Το προφίλ των μορίων του εξωκυτταρίου στρώματος στην ενδογενή γήρανση, από την άλλη, αποδεικνύει την πτώση της βιοσυνθετικής δραστηριότητας με την ηλικία και επιβεβαιώνει σε ικανό βαθμό ότι η ενδογενής δερματική γήρανση αντανακλά τη γήρανση όλου του ανθρώπινου οργανισμού. Όλα τα παραπάνω δεδομένα καθώς και η ευεργετική επίδραση της 17-β-οιστραδιόλης στο μεταβολισμό του υαλουρονικού οξέος και η αποσαφήνιση του μοριακού αυτού δρόμου μπορεί να οδηγήσει σε νέους φαρμακολογικούς στόχους για την εκλογικευμένη θεραπεία της δερματικής γήρανσης

Melanoma: Stem cells, sun exposure and hallmarks for carcinogenesis, molecular concepts and future clinical implications

<b>Background</b> :The classification and prognostic assessment of melanoma is currently based on morphologic and histopathologic biomarkers. Availability of an increasing number of molecular biomarkers provides the potential for redefining diagnostic and prognostic categories and utilizing pharmacogenomics for the treatment of patients. The aim of the present review is to provide a basis that will allow the construction-or reconstruction-of future melanoma research. <b> Methods:</b> We critically review the common medical databases (PubMed, EMBASE, Scopus and Cochrane CENTRAL) for studies reporting on molecular biomarkers for melanoma. Results are discussed along the hallmarks proposed for malignant transformation by Hanahan and Weinberg. We further discuss the genetic basis of melanoma with regard to the possible stem cell origin of melanoma cells and the role of sunlight in melanoma carcinogenesis.<b> Results: </b> Melanocyte precursors undergo several genome changes -UV-induced or not- which could be either mutations or epigenetic. These changes provide stem cells with abilities to self-invoke growth signals, to suppress anti-growth signals, to avoid apoptosis, to replicate without limit, to invade, proliferate and sustain angiogenesis. Melanocyte stem cells are able to progressively collect these changes in their genome. These new potential functions, drive melanocyte precursors to the epidermis were they proliferate and might cause benign nevi. In the epidermis, they are still capable of acquiring new traits via changes to their genome. With time, such changes could add up to transform a melanocyte precursor to a malignant melanoma stem cell. <b>Conclusions</b> : Melanoma cannot be considered a "black box" for researchers anymore. Current trends in the diagnosis and prognosis of melanoma are to individualize treatment based on molecular biomarkers. Pharmacogenomics constitute a promising field with regard to melanoma patients&#x2032; treatment. Finally, development of novel monoclonal antibodies is expected to complement melanoma patient care while a number of investigational vaccines could find their way into everyday oncology practice

Randomized Controlled Trials for the Treatment of Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is a chronic, inflammatory, recurrent, debilitating skin disease. Several treatment modalities are available, but most of them lack high-quality evidence. A systematic search was performed to identify all randomized controlled trials for the treatment of HS in order to review and evaluate the evidence. Recommendations for future randomized controlled trials include using validated scores, inclusion of patient rated outcomes, and thorough report of side effects. Evidence for long-term treatment and benefit/risk ratio of available treatment modalities is needed in order to enhance evidence-based treatment in daily clinical practice. Combining surgery with antiinflammatory treatment warrants further investigatio

Interventions for melanoma in situ, including lentigo maligna

BACKGROUND: Malignant melanoma is a form of skin cancer associated with significant mortality once it has spread beyond the skin. Melanoma in situ (MIS) is the earliest histologically recognisable stage of malignant melanoma and represents a precursor of invasive melanoma. Lentigo maligna (LM) represents a subtype of pre-invasive intraepidermal melanoma associated specifically with chronic exposure to ultraviolet (UV) radiation. Over the past two decades, the incidence of MIS has increased significantly, even more than the invasive counterpart. There are several treatment options for MIS, but no consensus exists on the best therapeutic management of this condition. OBJECTIVES: To assess the effects of all available interventions, surgical and non-surgical, for the treatment of melanoma in situ, including LM. SEARCH METHODS: We searched the following databases up to November 2014: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2014, Issue 10), MEDLINE (from 1946), Embase (from 1974), LILACS (from 1982), African Index Medicus (from inception), IndeMED of India (from inception), and Index Medicus for the South-East Asia Region (IMSEAR) (from inception). We scanned the references of included and excluded studies for further references to relevant trials and searched five trials registries. We checked the abstracts of major dermatology and oncology conference proceedings, and we shared our lists of included and excluded studies with industry contacts and other experts in the field of melanoma to try to identify further relevant trials. SELECTION CRITERIA: We included randomised controlled trials (RCT) on the management of MIS, including LM, that compared any intervention to placebo or active treatment. We included individuals, irrespective of age and sex, diagnosed with MIS, including LM, based on histological examination. DATA COLLECTION AND ANALYSIS: Two authors independently evaluated possible studies for inclusion; extracted data from the included study using a standard data extraction form modified for our review; assessed risk of bias; and analysed data on efficacy, safety, and tolerability. They resolved any disagreements by discussion with a third author. We collected adverse effects information from included studies. MAIN RESULTS: Our search identified only 1 study eligible for inclusion (and 1 ongoing study in active recruitment stage), which was a single centre, open label, parallel group, 2-arm RCT with 90 participants, who had 91 histologically proven LM lesions.Forty-four participants, with 44 LM lesions, were treated with imiquimod 5% cream 5 days per week plus tazarotene 0.1% gel 2 days/week for 3 months, and 46 participants, with 47 LM lesions, were treated with imiquimod 5% cream 5 days per week for 3 months. Two months after cessation of topical treatment, the initial tumour footprint was excised using 2 mm margins via a staged excision. This study was open label, and analysis was not intention-to-treat, leading to a high risk of incomplete outcome data.Our primary outcome 'Histological or clinical complete response' was measured at 5 months in 29/44 participants (66%) treated with imiquimod plus tazarotene (combination therapy) and 27/46 participants (59%) treated with imiquimod (monotherapy). The difference was not statistically significant (risk ratio (RR) 1.12, 95% confidence interval (CI) 0.81 to 1.55, P value = 0.48).With regard to our secondary outcomes on recurrence and inflammation, after a mean follow up of 42 months, no local recurrences were observed among complete responders. Difference in overall inflammation score between the 2 groups was significant (mean difference (MD) 0.6, 95% CI 0.2 to 1, P value = 0.004), with the mean overall inflammation score being significantly higher in the combination group.The study authors did not clearly report on side-effects. Because of adverse effects, there was a dropout rate of 6/44 participants (13.7%) in the combination group compared with 1/46 (2.2%) in the imiquimod monotherapy group (due to excessive inflammation) before the cessation of topical treatment (first 3 months), but this was not statistically significant (RR 6.27, 95% CI 0.79 to 50.02, P value = 0.08). AUTHORS' CONCLUSIONS: There is a lack of high-quality evidence for the treatment of MIS and LM.For the treatment of MIS, we found no RCTs of surgical interventions aiming to optimise margin control (square method, perimeter technique, 'slow Mohs', staged radial sections, staged "mapped" excisions, or Mohs micrographic surgery), which are the most widely used interventions recommended as first-line therapy. The use of non-surgical interventions in selected cases (patients with contraindications to surgical interventions) may be effective and may be considered preferable for experienced providers and under close and adequate follow up.For the treatment of LM, we found no RCTs of surgical interventions, which remain the most widely used and recommended available treatment. The use of non-surgical interventions, such as imiquimod, as monotherapy may be effective and may be considered in selected cases where surgical procedures are contraindicated and used preferentially by experienced providers under close and adequate follow up. The use of topical therapies, such as 5-fluorouracil and imiquimod, as neoadjuvant therapies warrants further investigation. There is insufficient evidence to support or refute the addition of tazarotene to imiquimod as adjuvant therapy; the current evidence suggests that it can increase topical inflammatory response and withdrawal of participants because of treatment-related side-effects