Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: 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 46.7months (range, 12-124months). 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.
Abstract: BACKGROUND: Juvenile hyaline fibromatosis (JHF) is a rare autosomal recessive disease characterized histologically by deposition of hyaline material and clinically by multiple skin lesions. Clarification of the molecular and structural changes involved in JHF skin lesions may unravel targets for pharmacotherapy. OBJECTIVE: We sought to investigate the expression of glycosaminoglycans and their metabolizing enzymes in lesional as compared with lesion-free skin tissue specimens in JHF. METHODS: Glycosaminoglycans were isolated, purified, and fractionated by electrophoresis on cellulose acetate membranes and agarose gels. Hyaluronic acid (HA) was quantitated by enzyme-linked immunosorbent assay and the expression of HA metabolizing enzymes was investigated using reverse transcriptase-polypeptide chain reaction. RESULTS: JHF lesions exhibited significantly less HA and elevated amounts of dermatan sulfate and chondroitin sulfate, whereas gene expression of HA synthase-1 and HA synthase-3 was significantly down-regulated, as compared with lesion-free skin tissue specimens. LIMITATIONS: Because JHF is a rare disease, a limitation to our study was that we collected skin tissue specimens from only one patient. CONCLUSION: The significant alterations of HA homeostasis in JHF lesions provide further understanding of JHF pathogenesis and may offer a target for pharmacologic intervention to treat the skin lesions associated with JHF.
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.
Abstract: A 27-year-old male, who had developed diabetes mellitus type 1 (DMT1) since the age of eighteen and alopecia areata universalis nine months later, attended the outpatient clinics complaining of general fatigue and shortness of breath. A Schilling test was indicative of pernicious anemia. Antigastric parietal cell (AGPA) and anti-intrinsic factor antibodies were positive, confirming diagnosis of pernicious anemia. Thyroid and Addison's disease were excluded. Gastroscopy revealed atrophic gastritis without any evidence of carcinoid tumors. The aim of this case, which, to our knowledge, is the first one to describe a correlation between diabetes mellitus Type 1 (DMT1), pernicious anaemia, and alopecia areata universalis, is to remind the clinician of the increased risk of pernicious anaemia and gastric carcinoids in DMT1 patients. Screening for AGPA followed by serum gastrin and vitamin B(12) levels constitute the most evidence-based diagnostic approach.
Abstract: BACKGROUND: Various nonhormonal agents have been used for the treatment of hot flashes in women with natural or tamoxifen-induced menopause. Some studies have reported that gabapentin appears to be an effective and well-tolerated treatment modality. Objective: To investigate the efficacy and tolerability of gabapentin for the treatment of menopausal hot flashes, we performed a systematic review of all trials reporting on the efficacy and tolerability of gabapentin in women with hot flashes and a meta-analysis of the randomized controlled trials (RCTs) conducted in this patient population. METHODS: For the systematic review, a literature search was conducted through MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for articles published in English from inception of the databases through November 2008. The reference sections of retrieved articles were searched, and a manual search of key journals and abstracts from major meetings in clinical pharmacology was conducted. To be included in the meta-analysis, RCTs had to compare gabapentin with placebo in the treatment of hot flashes in women with natural or tamoxifen-induced menopause, regardless of the sample size, dosage used, duration of treatment, or frequency of the episodes. Uncontrolled and openlabel trials were reviewed but excluded from the meta-analysis. The percent reduction in hot flash frequency (relative to baseline) and the composite score (summation of the number of hot flashes in each severity category multiplied by the severity score) were used as primary outcome measures. Dropout rates and the incidences of frequently reported adverse events (eg, dizziness/unsteadiness, fatigue/somnolence) were also investigated. RESULTS: The systematic review included 7 trials conducted in 901 patients between 2002 and 2008. Study sizes ranged from 22 to 420 patients, total daily doses of gabapentin ranged from 900 to 2400 mg, and titration periods lasted 3 to 12 days. All of the trials were conducted in North America (6 in the United States and 1 in Canada); 4 of the trials enrolled subjects with a history of breast cancer, whereas the remaining 3 trials only enrolled postmenopausal women. Four RCTs were included in the meta-analysis. Data were expressed as weighted mean difference (WMD) or relative risk (RR), with the associated 95% CI. Women assigned to gabapentin reported a significantly greater percent reduction in both the frequency of hot flashes (WMD = 23.72 [95% CI, 16.46-30.97]; P < 0.001) and the composite score (WMD = 27.26 [95% CI, 21.24-33.29]; P < 0.001), with significant between-study heterogeneity (I(2) = 97.8% and 95.6%, respectively). Dropouts due to adverse events were more frequent in women randomized to gabapentin than in controls (RR = 2.09 [95% CI, 1.13-3.85]; P = 0.02; I(2) = 0%). The risk of symptom clustering also was significantly higher in the treatment group than in the controls (dizziness/unsteadiness: RR = 6.94 [95% CI, 3.19-15.13]; P < 0.001; I(2) = 63.1%; and fatigue/somnolence: RR = 4.78 [95% CI, 2.23-10.25]; P < 0.001; I(2) = 0%). CONCLUSIONS: Comparisons of gabapentin and placebo revealed reductions of 20% to 30% in the frequency and severity of hot flashes with gabapentin, although data across the studies were too heterogeneous to provide a reliable summary effect. Clusterings of dizziness/unsteadiness and fatigue/somnolence were the most frequently reported adverse events associated with gabapentin and resulted in a higher dropout rate due to adverse events in the gabapentin-treated patients than in the controls. More studies are needed to consolidate the outcomes and elucidate useful details regarding this treatment.
Abstract: BACKGROUND: Spinal-cord injury (SCI) is a leading cause of neuropathic pain (NP). Current pharmaceutical treatments for NP in SCI patients are not effective. Two promising options are gabapentin (GP) and pregabalin (PB). Their predominant mechanism of action is believed to be the inhibition of calcium currents, leading in turn to reduced neurotransmitter release and attenuation of postsynaptic excitability. This could explain much of their efficacy in the treatment of both seizure disorders and pain syndromes. However, evidence for their efficacy in attenuating NP of SCI is still controversial. OBJECTIVE: To efficiently integrate valid information and provide a basis for rational decision making, through determining PB and GP efficacy in treating NP in SCI. METHODS: Literature was systematically reviewed. Medline, Embase, CINAHL and Cochrane Database were searched using search terms 'gabapentin', 'pregabalin', 'neurontin', 'lyrica', 'neuropathic pain' and 'spinal-cord injury'. Studies were assessed independently by two authors. RESULTS: Five studies were eligible for inclusion. Two of them studied PB and three GP. Both GP and PB appear to be efficacious for NP in SCI. A clear comparison between the two drugs could not be performed. The literature data suggest that PB is more efficacious than GP in many important variables for NP in SCI, although PB use is followed by more side effects than GP. PB reduced Visual Analogue Score (VAS) in both studies (P < 0.001 and P = 0.016). On the other hand, for GP a maximum dosage of 3,600 mg/day reduced VAS score (P = 0.000), whereas a maximum dosage of 1,200 mg/day failed to do so. CONCLUSION: There is a lack of studies comparing GP and PB in treating NP in SCI. This systematic review indicates the possible efficacy of PB and GP in NP of SCI. Recommendations for future research to inform clinical practice should include cost-effectiveness studies and dose-response analysis in order to determine the schema employed and the duration of treatment.
Abstract: 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.
Abstract: 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.
Abstract: A case of a woman diagnosed to have rhabdomyolysis is presented. It was attributed to simvastatin she had been receiving for 1 year. Based on pathogenesis and medical examination, the diagnosis of statin-induced rhabdomyolysis was made. Simvastatin was discontinued with concomitant clinical improvement followed by serum creatine kinase decrease. Future course of therapy was decided after reviewing the literature using evidence-based medicine tools. The purpose of this case report is to share our experience so that physicians are reminded of the potential of rhabdomyolysis related to statin use and illustrate the value of evidence-based medicine in clinical practice.
