Insight into the pathogenesis of sporadic basal cell carcinoma

Sporadic basal cell carcinoma (BCC) is the commonest human cancer. Although its aggressiveness is low and metastatic potential negligible, the increasing incidence of the tumor in the Western world drives attention to its pathogenesis. In 1996, germ-line mutations in the patched receptor of the Sonic hedgehog (Shh) signaling pathway were described in the Gorlin-Goltz syndrome in association with multiple nevoid BCCs. Later, the aberrant activation of the Shh was identified in sporadic BCCs as well. Recently, the role of other tumor suppressors and DNA repair gene mutations and their relationship with UV radiation-induced DNA damage have been elucidated.     

Neurotoxic esterase in rooster testis

Neurotoxic esterase (NTE) is the putative target protein in the nervous system for the initiation of organophosphorus-induced delayed neuropathy. Here it is reported that NTE activity is present in rooster testis. Complete titration of rooster testis phenyl valerate esterases with paraoxon shows that about 15% of the enzymic activity is resistant to paraoxon. NTE activity after complete mipafox titration accounts for 30% of paraoxon-resistant phenyl valerate esterases and corresponds to 7.93 +/- 0.39 nmol/min/mg of protein (mean +/- SD, n = 7). Testis NTE is inhibited in vitro similarly to brain NTE by several organophosphorus compounds. Subcellular fractionation studies of the testis indicate that most NTE activity is particle bound. Testis NTE is also inhibited in vivo by several organophosphorus esters but to a lesser extent than brain NTE. Birds doses with organophosphorus compounds, causing delayed neuropathy, became grossly ataxic, but no testicular pathology was noted by light microscopy in roosters killed 15 days after administration. Serum testosterone levels also measured 15 days after dosing were not different from those of a control group. Recovery of NTE activity was faster in testis than in brain (4 days vs 6 days to recover to 50% of initial activity) in animals that received a high dose of an organophosphorus ester which cause delayed neuropathy.     

Targeted and combination treatments for vitiligo. Comparative evaluation of different current modalities in 458 subjects

The current treatment of vitiligo is not satisfactory according to the opinions of both the patient population and the dermatologists. Recently, combination therapies have been introduced, which are both systemic and targeted (microphototherapy). To evaluate the effects of topical treatments given alone or in combination with 311-nm narrow-band microphototherapy. We evaluated the efficacy and safety of: (1) 311-nm narrow-band microphototherapy;(2) tacrolimus 0.1% ointment twice a day; (3) pimecrolimus 1% cream twice a day; (4) betamethasone dipropionate 0.05% cream twice a day; (5) calcipotriol ointment 50 microg/g twice a day; and (6) 10%l-phenylalanine cream twice a day, for the treatment of exclusively vitiligo patches. A 311-nm narrow-band microphototherapy (Bioskin) was given alone or in combination with the above-mentioned popular local treatments. Four hundred and seventy patients suffering from vitiligo that affected less than 10% of the skin surface were evaluated. The patients were divided into 11 groups according to the selected treatment modalities. Four hundred and fifty-eight patients completed the study period of 6 months. Excellent repigmentation (> 75%) was achieved by 72% of the patients in group 1, 76.5% in group 2, 76.1% in group 3, 90.2% in group 4, 75.6% in group 5, 74.8% in group 6, 61% in group 7, 54.6% in group 8, 71.2% in group 9, 59.1% in group 10, and 29.3% in group 11. Marked repigmentation (50-75%) was evident in 19.8% of the patients in group 1, 18.2% in group 2, 20.1% in group 3, 6.7% in group 4, 14.1% in group 5, 11.3% in group 6, 16.1% in group 7, 18.4% in group 8, 25% in group 9, 10.6% in group 10, and 8.1% in group 11. Moderate results (25-50% repigmentation) were seen in 4.6% of the patients in group 1, 3.3% in group 2, 2.7% in group 3, 2.2% in group 4, 7.4% in group 5, 10.1% in group 6, 18.4% in group 7, 21.7% in group 8, 2.1% in group 9, 27.1% in group 10, and 55% in group 11. Finally, minimal (< 25%) or no response was achieved in 3.6% of the patients in group 1, 2% in group 2, 1.1% in group 3, 0.9% in group 4, 2.9% in group 5, 3.8% in group 6, 4.5% in group 7, 5.3% in group 8, 1.75% in group 9, 3.2% in group 10, and 7.6% in group 11. Side effects were skin atrophy (76% in group 4 and 81% in group 9), stinging and burning (groups 2, 3, 7, and 8). Targeted combination therapies in vitiligo are remarkably more effective than single treatments. When single treatments are considered alone, 311-nm narrow-band UVB microfocused phototherapy and 0.05% betamethasone dipropionate cream are the most effective treatments in our study. When combined therapies are chosen, 0.05% betamethasone dipropionate cream plus 311-nm narrow-band UVB microfocused phototherapy apparently give the highest repigmentation rate. In the short term, the only side-effects registered have been cutaneous atrophy with corticosteroid cream, and stinging and burning with 0.1% tacrolimus ointment and, less frequently, with 1% pimecrolimus cream.     

The concept of psoriatic disease: Can cutaneous psoriasis any longer be separated by the systemic comorbidities?

Psoriasis is a general inflammatory status in which the skin is usually visibly involved. Recent papers show that several comorbidities, including psoriatic arthritis, metabolic syndrome, cancer, osteoporosis, cardiovascular disease, chronic inflammatory bowel disease etc., are significantly associated with psoriasis. Detecting association between psoriasis and comorbidities, properly evaluate confounders and make a correct distinction among absolute risk, relative risk and clinical relevance is mandatory, before embracing the fact the psoriasis is, in fact, a complex and common international disease.     

Vitiligo as a systemic disease

Vitiligo is an acquired depigmentary skin disorder of unknown etiology. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located on various parts of the body. The involvement of skin melanocytes is the most visible one, but a systemic involvement of melanocytes can be observed. Some types of vitiligo (nonsegmental vitiligo) may also be associated with various diseases, mainly with autoimmune pathogenesis. Vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses, causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement.     

Tumour necrosis factor-α antagonists in patients with concurrent psoriasis and hepatitis B or hepatitis C: a retrospective analysis of 17 patients

Introduction Tumour necrosis factor (TNF)‐α antagonists are effective for the treatment of plaque‐type psoriasis and psoriatic arthritis, but concerns remain about the safety of these agents in the presence of chronic infections, including past hepatitis B (HBV) and chronic hepatitis C virus (HCV) infections. Objective To assess the safety of TNF‐α therapy in patients with plaque‐type psoriasis and concurrent past HBV or chronic HCV. Methods Data were collected retrospectively from patients in the PsoCare Centre, Division of Dermatology II, Florence University. Patients with plaque‐type psoriasis who were receiving anti‐TNF‐α therapy were retrospectively reviewed for the presence of HBV or HCV by a serological evaluation. Results Seventeen patients (13 men and four women, age 36–74 years) with plaque‐type psoriasis associated with hepatitis infections (11 with past HBV infection, five with chronic HCV infection and one affected by both HBV and HCV) were identified. Fourteen patients had received etanercept, two adalimumab and one adalimumab as a second biologic treatment after an unsuccessful trial of etanercept. In none of the cases were changes in serum aminotransferases or viral load reported. Conclusions In our analysis, the use of anti‐TNF‐α therapy appears to be safe as it did not affect serum aminotransferases or viral load. However, repeated monitoring is necessary throughout the treatment period. Systematic, large‐scale studies are also needed to assess the risks and benefits of TNF‐α antagonists in these patients.     

Celecoxib upregulates multidrug resistance proteins in colon cancer: lack of synergy with standard chemotherapy

Recent phase II randomised trials in colorectal cancer failed to demonstrate any advantage of celecoxib combined with standard chemotherapy; some authors even reported that the addition of celecoxib to irinotecan and oxaliplatin in colon cancer results in an inferior response rate. This observation leads to the hypothesis that there are pharmacokinetic interactions between celecoxib and chemotherapeutic drugs. The aim of the study was to investigate the induction by celecoxib of some multidrug resistance proteins, MRP1, MRP2, MRP4 and MRP5, involved in the transport of irinotecan and 5-FU. WiDr and COLO-205 cells were treated with celecoxib at a clinically relevant concentration. A viability assay was performed by treating cells with chemotherapy alone and chemotherapy plus celecoxib. The expression of MRP1, MRP2, MRP4 and MRP5 was analysed by RT-PCR and Western blot analysis. The sub cellular localization of MRP4 and MRP5 was investigated by cryoimmunoelectron microscopy. In both cell lines celecoxib induced MRP4 and MRP5 over-expression at RNA and protein levels. No induction of MRP1 and MRP2 was observed in treated cells compared to controls. Cryoimmunoelectron microscopy showed increased MRP4 and MRP5 immunolabeling in celecoxib treated cells both at cytoplasmic level and along the plasma membrane. Our findings suggest that the low response rate observed in clinical trials using celecoxib added to 5-fluorouracil and irinotecan may reflect celecoxib-mediated extrusion of chemotherapeutic drugs from cancer cells through the up regulation of ATP-binding cassette proteins. Our findings, together with the results of clinical trials, may suggest that the combined use of celecoxib and drugs that are substrate for MRP4/MRP5 should be avoided.