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

BACKGROUND: 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. METHODS: 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. RESULTS: 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 antigrowth 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. CONCLUSIONS: 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' 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.

New concepts for basal cell carcinoma. Demographic, clinical, histological risk factors, and biomarkers. A systematic review of evidence regarding risk for tumor development, susceptibility for second primary and recurrence.

Basal cell carcinoma (BCC) is the commonest cancer in Caucasians and its incidence is increasing. Whilst ultraviolet radiation (UVR) is recognized as the main etiological factor, the relationship between exposure and host phenotype is still unclear. We systematically searched Medline, Embase, and the Cochrane databases for studies assessing the genetic basis of host response to UVR DNA damage, the effect of UVR on generation of reactive oxygen species (ROS), and their detoxification, UVR induced skin immunity modifications, and the role of genomic instability with a focus on the potential use of these biomarkers to the surgical treatment planning and prognosis of BCC patients. Data suggest that risk for BCC development is likely to result from the combined effect of many genes, each with a relatively weak individual contribution. Certain genomic alterations have been associated with increased or reduced risk for BCC development, with a second primary BCC or with recurrence of BCC. However, use of these biomarkers in everyday practice should be supported by further studies, mainly for its cost-effectiveness. In addition, not enough information exists on the prognostic value of existing demographic and clinical risk predictors for BCC regarding development of second primary or recurrent tumors. Information reviewed suggests that these predictors are of higher predictive value compared with biomarkers whilst they are indisputably cheaper and easier to monitor even in developing countries. Conclusively, we suggest that further studies aimed in investigating second primary or recurrent BCC are needed to provide better information on the predictive value of certain demographic, clinical and histological factors.

Clinical, histological and demographic predictors for recurrence and second primary tumours of head and neck basal cell carcinoma. A 1062 patient-cohort study from a tertiary cancer referral hospital.

Basal cell carcinoma (BCC) accounts for nearly 25% of all cancers in the human body and for almost 75% of skin malignancies; approximately 85% of basal cell carcinomas develop in the head and neck region. Limited demographic, clinical and histological predictors for second primary and/or recurrent BCC have been identified to date. Our objective was to identify predictors of recurrence and second primary tumour development of BCC in the head and neck region. We included 1062 patients with a histologically confirmed diagnosis of BCC. Multivariate and Cox regression analysis were used to access demographic, clinical and histological predictors. Study follow up included 4,302 patient-years, each patient was followed-up for an average 4.0 +/- 1.8 years (range 1-12). Overall recurrence rate was 4%. High-risk histology type was associated with an increased risk for recurrence (odds ratio (OR) = 3.47, 95%CI: 1.07-11.25). We calculated a 4-fold increased risk for recurrence with positive excision margins (OR = 4.31, 95%CI: 1.82-10.22), a 21% increased risk for recurrence (OR = 1.21, 95%CI: 1.06-1.37) and a 25% increased risk for second primary BCC development (OR = 1.25, 95%CI: 1.17-1.34) per year of follow-up. The median time free of second primary tumour was 7 years, while the median time free of recurrence was 12 years. The strongest predictors for recurrence are positive excision margins and high-risk histology type, indicating the need for additional patient care in such cases.

Erythema elevatum diutinum with rare distribution as a first clinical sign of non-Hodgkin's lymphoma: a novel association?

We present a case of a 78-year-old man with erythema elevatum diutinum as a first clinical sign of non-Hodgkin's lymphoma. The patient developed erythema elevatum diutinum with an unusual distribution involving the trunk. Erythema elevatum diutinum is a rare dermatosis that is considered to be a localized, low-grade form of leukocytoclastic vasculitis associated with neoplastic, autoimmune and infectious processes. It is probably mediated by immune complexes. Recent studies report hematological disease as the most common factor associated with erythema elevatum diutinum. Many hematological diseases, such as myeloma, myelodysplastic syndrome and immunoglobulin (Ig)A monoclonal gammopathy, have been reported in association with erythema elevatum diutinum, but none with IgM monoclonal gammopathy and only one with malignant lymphoma. We would like to add IgM monoclonal gammopathy and non-Hodgkin's lymphoma as one of the diseases associated with erythema elevatum diutinum considering that the activity of erythema elevatum diutinum and non-Hodgkin's lymphoma fluctuated in parallel in the present case.

An evidence-based review of risk-reductive strategies for osteonecrosis of the jaws among cancer patients.

PURPOSE: Bone antiresorptive treatment is associated with osteonecrosis of the jaws. Interventions used to treat this complication are diverse, controversial, and largely empirical but certain risk factors could help in its avoidance. The aim of this evidence-based review is to elucidate any interventions that are effective in reducing the risk for development of ONJ in cancer patients receiving bone antiresorptive therapy and to quantify the effectiveness of such interventions. MATERIALS & METHODS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), and other trial registries through January 2012. We selected randomized controlled trials (RCTs). Cohort studies were included only as long as there are no RCTs on the same modality. RESULTS: Twelve studies were included in the systematic review while nine studies contributed to the various comparisons. Prescribing denosumab (DSB) instead of zoledronic acid (ZA) may not be expected to reduce risk ONJ (RR:0.71 [99% CI: 0.41-1.24], I2=0%). Prescribing clodronate (RR:10.15 [99% CI: 2.43-42.35], I2=0%) or pamidronate (RR:4.41 [99% CI: 1.90-10.24], I2=16%) instead of ZA may reduce risk for ONJ. Dental extractions remain the most potent risk factor for ONJ (RR:14.04, [99% CI: 10.36-19.03], I2=0%) and their avoidance can be considered an effective risk-reductive intervention. ONJ risk can be reduced by dental prophylactic measures (RR:0.45, [99% CI: 0.23-0.85], I2=7%). CONCLUSIONS: DSB and ZA might cause ONJ more frequently compared with chlodornate or pamidronate. Prescription pamidronate and clodronate helps avoid the complication. Reducing the administered dose for denosumab and zoledronic acid might reduce risk for ONJ as well. More randomized clinical trials comparing reduced doses of these regimens against those currently approved are needed.

Effect of non-steroidal anti-inflammatory drugs on bone turnover: an evidence-based review.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for acute and chronic pain control and treatment of inflammation, osteoarthritis and rheumatoid arthritis. NSAIDs have been shown to inhibit bone healing in animal studies due to the inhibition of prostaglandin synthesis. However, little evidence exists regarding the effect of NSAID exposure on human bone metabolism. This systematic review summarizes the current literature of randomized controlled trials (RCTs) investigating NSAIDs with bone remodeling-related outcomes in humans. After performing computerized searches in the most widely indexed databases, study selection, data abstraction and risk of bias assessment were conducted in duplicate. The results were controversial regarding the association of NSAID with bone formation or resorption. Increased bone mineral density following NSAID exposure was reported by some studies. Based on the levels of biochemical markers, no effect was seen on bone formation, while some evidence was found for a decreased rate of bone resorption in NSAID patients. Trials investigating the effects of NSAID treatment on bone metabolism outcomes of human patients are limited. Further research is required to confirm or refute the findings of this systematic review.

Novel antimicrobial agents for the management of maxillofacial and neck infections.

BACKGROUND: Maxillofacial and head & neck infections often jeopardize patients' lives. Regional intracranial spread to the cavernous sinus, but also to the mediastinum is common for those left untreated. The divergence of the upper peptic and respiratory tracts from the pharynx, the presence of the brain vasculature, the fine sensory instruments for vision, hearing and taste-smell, and the unique feature of mucosa directly attached to facial bones in the paranasal sinuses, oral cavity and external auditory meatus make this region the most exposed to infections in the human body. Special immune mechanisms have evolved in this area, however infections are still very common. METHODS & RESULTS: We review the unique pathophysiological features of maxillofacial and head & neck infections. We describe novel investigational anti-infective agents, and analyze their potential clinical utility with regard to mechanisms of action and site preference. DISCUSSION: We emphasize on the need for more antimicrobial drug research and discuss on the current skews in pharmaceutical research and manufacturing practices that make new categories of antimicrobial drugs an exceptional entity. Drug patents may need to be expanded both longitudinally in terms of time period but also squarely, potentially including the drug class in the patent rather than the drug itself. Clinicians need to be aware of these limitations and prescribe antibiotics to their patients with parsimony.

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.

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 Cox's 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). Broder's 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.

Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation.

BACKGROUND: Lesions of cutaneous lupus erythematosus (CLE) are refractory to a wide range of topical or systemic therapies. The pathogenesis of CLE is multifactorial and polygenic, and many of its details remain unclear. However, immunologic evidence suggests the possible therapeutic use of tacrolimus and pimecrolimus. CLE is one of the most common dermatological autoimmune disorders worldwide, which includes systemic lupus erythematosus (SLE) with malar rash, subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE). OBJECTIVE: Our aim was to determine the efficacy of topical pimecrolimus and tacrolimus in the treatment of cutaneous lupus erythematosus. METHODS: The literature was systematically reviewed. Medline, Embase, and the Cochrane Database were searched for systemic reviews, randomised controlled trials and nonrandomised clinical trials using the search terms "pimecrolimus", "Elidel", "SDZ ASM 981", "tacrolimus", "Protopic", "FK506" and "cutaneous lupus erythematosus". Studies were assessed independently by two authors. RESULTS: Five studies were eligible for inclusion in this review. Only one of them was a randomised controlled trial (RCT). There was no significant difference between tacrolimus and clobetasol; however, evidence indicates the highest tolerability of tacrolimus compared with corticosteroids. This review indicates the efficacy of tacrolimus and pimecrolimus in, at least initial, cutaneous lesions of SLE. However, in SCLE and DLE lesions, the efficacy appears to be lower, perhaps due to the chronicity of those lesions. CONCLUSION: The lack of RCTs is characteristic. Future studies should focus on efficacy, short- and long-term effects and cost-effectiveness. However, tacrolimus and pimecrolimus show efficacy, and such effort is worthwhile.