Acral lentiginous melanoma treated with topical imiquimod cream: possible cooperation between drug and tumour cells.

An 85-year-old woman presented with a lesion on the sole of her right foot, which was histologically confirmed as acral lentiginous melanoma. Because of the large field involved and because the patient refused any invasive or painful treatment, topical treatment with imiquimod was commenced. At the 20-month follow-up, the patient was still continuing treatment with topical imiquimod, and no metastases to the lymph nodes or viscera were found, either clinically or in imaging studies. We believe that the success of the treatment cannot be explained only by the stimulation of the immune system induced by imiquimod. A possible explanation might be 'tumour dormancy', where a tumour grows very slowly because of a balance between the neoplasia and the immune (and nonimmune) mechanisms of tumour control. The use of imiquimod has so far allowed our patient to avoid surgery, and perturbation of the mechanisms of tumour regulation, such as local immunity and angiogenesis, has not taken place.

W+ W- production at hadron colliders in next to next to leading order QCD.

Charged gauge boson pair production at the Large Hadron Collider allows detailed probes of the fundamental structure of electroweak interactions. We present precise theoretical predictions for on-shell W+ W- production that include, for the first time, QCD effects up to next to next to leading order in perturbation theory. As compared to next to leading order, the inclusive W+ W- cross section is enhanced by 9% at 7 TeV and 12% at 14 TeV. The residual perturbative uncertainty is at the 3% level. The severe contamination of the W+ W- cross section due to top-quark resonances is discussed in detail. Comparing different definitions of top-free W+ W- production in the four and five flavor number schemes, we demonstrate that top-quark resonances can be separated from the inclusive W+ W- cross section without a significant loss of theoretical precision.

Immunotargeting and eradication of orthotopic melanoma using a chemokine-enhanced DNA vaccine.

DNA vaccines are attractive candidates for tumor immunotherapy. However, the potential of DNA vaccines in treating established malignant lesions has yet to be demonstrated. Here we demonstrate that transient alteration of either intratumoral or intradermal (ID) chemotactic gradients provide a favorable milieu for DNA vaccine-mediated activation of tumor-specific immune response in both prophylactic and therapeutic settings. Specifically, we show that priming of established B16 ID melanoma lesions via forced intratumoral expression of CCL21 boosted DNA vaccination-dependent systemic cytotoxic immune response leading to the regression of tumor nodules. In this setting, application of CCL20 was not effective likely due to the engagement of the regulatory T cells. However, priming of the skin at DNA vaccine administration sites outside the tumor bed with both CCL20 and CCL21 chemokines along with structural modifications of the DNA vaccine significantly improved vaccine efficacy. This optimized ID vaccination regimen led to the inhibition of distant established melanomas and prolonged tumor-free survival of mice observed in 60% of vaccinated animals with complete tumor remission in 30%. These effects were mediated by extranodal priming and activation of T cells at vaccine administration sites and progressive accumulation of systemic antigen-specific cytotoxic T cells (CTLs) on successive vaccinations. These results underscore the potential of chemokine-enhanced DNA vaccination to mount therapeutic immune response against established tumors.

Oestrogen receptor beta and melanoma: a comparative study.

BACKGROUND: Oncological research has focused on evaluating oestrogen receptors (ERs) in oestrogen-related tumours, and understanding the potential role of ERs in the pathophysiology of cancer. OBJECTIVES: To investigate the significance of oestrogen receptor beta (ERß) in melanoma. METHODS: We prospectively evaluated ERß expression in malignant melanoma (MM) tissue and adjacent healthy skin by quantitative immunohistochemistry at the Department of Dermatology of the University of Florence, from 1998 to 2010. RESULTS: ERß was detected with varying staining intensity in the 66 malignant melanocytic lesions. After adjusting for age and sex, we found that ERß expression was significantly lower in melanoma tissue compared with adjacent healthy skin (P < 0·0001). We also found significantly lower ERß levels in thick melanoma tissue compared with thin melanoma tissue. In addition, there was a positive association between Breslow thickness and the difference of ERß expression between healthy tissue and melanoma tissue (P = 0·0004). Consistent with sex differences in melanoma survival, men showed significantly lower levels of ERß than women in both melanoma (P = 0·05) and healthy tissues (P = 0·02). CONCLUSIONS: ERß expression is inversely associated with Breslow thickness and is significantly influenced by sex in MM.

Clinical and dermoscopic features of small Reed nevus (<6 mm).

BACKGROUND: The differential diagnosis between Reed nevi and melanoma becomes more difficult if the lesion to analyse presents a small size, with a diameter of 6 mm or smaller. Many studies have reported various dermoscopic features of Reed nevi during their growth phases. In early stages of evolution, the lesions generally show a characteristic globular appearance typically found in childhood, followed by the so-called starburst pattern. OBJECTIVE: The aim of the study was to identify the main dermoscopic features in small Reed nevi (<6 mm in size). METHODS: Using a computerized skin-imaging database for melanoma prevention surgery at the Department of Dermatology of the University of Florence, 15 Reed nevi were selected among 103 small (<6 mm) melanocytic lesions consecutively excised. Images of small Reed nevi, independently blinded to histopathological diagnosis, were administered to a dermatologist expert in dermoscopy, who separately examined the clinical and the dermatoscopic images of small Reed nevi and evaluated their clinical and dermoscopic parameters. RESULTS: Analysis of the main dermoscopic patterns showed that 40% had a reticular pattern, 20% had a starburst pattern, 6.5% had a globular pattern, 6.5% had a homogeneous pattern and 27% had an atypical pattern. CONCLUSION: We propose that small, early-stage Reed nevus are not characterized by an evolution of growth patterns to a phenotype typical of larger lesions. We assume that the patterns are distributed in a linear manner between age groups, may all be present at the outset and thus are independent from the various stages of nevus development.

Adding dermatoscopy to naked eye examination of equivocal melanocytic skin lesions: effect on intention to excise by general dermatologists.

BACKGROUND: According to the literature, dermatoscopy can improve diagnostic accuracy for melanoma. However, a weak point of the studies in the literature is that most were carried out in a 'privileged' setting of dermatologists who are expert in dermato-oncology, and who work in departments specializing in screening pigmented lesions. This study was set up to specifically evaluate whether the use of dermatoscopy by general dermatologists would also improve accuracy. AIM: To analyse the effect on intention to excise lesions (intervention yes/no) of adding either dermatoscopy (20 years after the advent of the method) or detailed lesion classification (melanoma yes/no) to clinical examination by the naked eye. More specifically, we evaluated whether the current practice of general dermatologists using dermatoscopy improves the sensitivity and specificity values, and thus the diagnostic accuracy. METHODS: Eight general dermatologists examined separately clinical images and combined (clinical and dermatoscopic) images of 200 melanocytic lesions that had been excised (64 melanomas and 136 melanocytic naevi). RESULTS: Focusing on intention to excise (intervention yes/no), addition of dermatoscopy to naked eye examination resulted in an increase in sensitivity for all observers (average gain +4.5%) but an overall nonsignificant reduction in specificity (-4.5%, P=0.10). Diagnostic accuracy, which increased when examination was focused on melanoma (yes/no) classification (+4.1%, P<0.05) remained unchanged (-1.62%; P=0.36). CONCLUSIONS: The effect of adding dermatoscopy to naked eye examination of melanocytic lesions on 'general dermatologists' changes according to the aim of the examination. Dealing with the intention to excise, the increase of sensitivity associated with dermatoscopy (lower risk of leaving a melanoma unexcised) is obtained at the expense of specificity (higher number of melanocytic naevi excised) without improving overall diagnostic accuracy.

Prevalence and distribution of melanocytic naevi on the scalp: a prospective study.

BACKGROUND: Few studies have examined the incidence and characteristics of naevi on the scalp. Most studies of scalp naevi have been performed in children, whose incidence of scalp naevi is relatively high, at about 0.5-11.7% of the total body count of common naevi. OBJECTIVES: To investigate the prevalence and distribution of scalp melanocytic naevi in patients of all ages. To our knowledge, ours is the first study to analyse in detail the relationships between melanocytic naevi on the scalp and total body naevi and total body atypical naevi. METHODS: We conducted a prospective study of patients visiting the dermatology outpatient clinic at the University of Florence, for examinations unrelated to the presence of naevi or melanoma. The study enrolled 795 subjects (417 females; 52.4%), with a median age of 35 years (range 4-80). RESULTS: The number of melanocytic naevi on the scalp increased significantly (r = 0.2057, P = 0.0008) as the number of total body melanocytic naevi increased and a correlation was found between the number of clinically atypical total body naevi and the number of scalp naevi. Relatively few naevi (15.5%) were located at the frontal region compared with other regions of the scalp, although the frontal region is more exposed to ultraviolet (UV) rays. Compared with subjects without alopecia, whose hair shields the scalp from UV rays, subjects with androgenetic alopecia showed no significant increase in number of scalp naevi. CONCLUSIONS: Despite practical difficulties, early diagnostic screening for melanoma or screening during follow-up examination for previous melanoma should involve examination of the entire skin surface, scalp included.

Multiple primary melanoma: the impact of atypical naevi and follow up.

BACKGROUND: Patients with melanoma are especially encouraged to have regular follow- up visits with their dermatologist and to perform total-body skin examination on a routine basis to identify new pigmented lesions or detect significant changes in existing naevi. OBJECTIVES: To identify main risk factors (sex, age, number of common and atypical naevi, family history, phototype) associated with multiple primary melanomas (MPM) and to investigate the association between regular follow up and tumour thickness of a second primary melanoma. METHODS: We performed a retrospective analysis of patients with MPM in order to evaluate risk factors for developing a second primary melanoma. Medical records of patients with melanoma who developed a second primary melanoma were selected from a database of all patients with histopathologically confirmed melanoma treated at the dermatology clinic of the University of Florence, Italy, from 2000 to 2004. Medical data culled from the patient records were as follows: medical history, number of typical naevi, presence of atypical naevi, Breslow thickness, Clark level and histotype of the melanomas, site of the melanomas and patient adherence to 6-month follow-up examinations. RESULTS: The presence of atypical naevi was associated with a higher risk of developing MPM (adjusted odds ratio 3·28, 95% confidence interval 1·35­7·44). Moreover, in the subjects who did not attend follow up, we noted that the thickness of the second melanoma was significantly higher, with a mean thickness of 1·22 mm, in comparison with patients with a careful adherence to follow up in whom the mean thickness was 0·36 mm (P = 0·0189). CONCLUSIONS: For the first time, the validity of this clinical approach has been supported by real comparison of thickness levels of second melanoma in patients with or without periodical follow up. Results obtained from this analysis show that follow up is an effective method for early detection of melanoma.

Prevalence and distribution of solitary oral pigmented lesions: a prospective study.

Solitary pigmented lesions are uncommon in the oral mucosa. A review of the literature reveals no information regarding the relative frequency of these lesions. The purpose of this study is to determine the relative prevalence of solitary oral pigmented lesions in a selected population of patients. This study includes 265 consecutive patients who accessed the dermatology out-patients' surgery of the Department of Dermatology, University of Florence between March 2006 and July 2007. The sample we studied presented 5.7% of oral pigmented lesions; the most frequent being vascular lesions. Despite the various methods used, the differential diagnosis for these particular lesions is not always easy. There is some difficulty in distinguishing between a benign pigmented lesion and a growing melanoma which, though rare (1% of all oral malignancies), is a serious and often fatal disease. Therefore, biopsy with histological exam represents the diagnostic gold standard.

Photodynamic treatment for viral infections of the skin.

Photodynamic therapy (ALA/MAL-PDT) is indicated for the treatment of actinic keratoses, for superficial, nodular basal cell carcinoma and for Bowen's disease; there is evidence that PDT can be active also against bacteria, viruses and fungi. The new indications for PDT include many types of viral skin infections human papilloma virus (HPV)-related as verrucae of feet and hands, Condylomata acuminata, periungueal warts, epidermodysplasia verruciformis, but also viral skin lesions non HPV related as molluscum contagiosum and herpes simplex can be successfully treated. The use of PDT in HPV infections is due to its anti-inflammatory and antiproliferative skills: in the lesions treated there is a release of cytotoxic radicals which damage keratinocytes infected by HPV, inducing their selective apoptosis and necrosis. The PDT application in this field of lesions is safe and successful; in comparison with the other techniques it has less side-effects and less recurrences, but the most important property is that it is not-invasive: it means a reduced risk of infections and excellent cosmetic results.

Trichilemmal cystis in metastatic melanoma: a case report.

The malignant melanoma is a neoplasm associated with a wide variety of cutaneous paraneoplastic syndromes, as dermatomyositis, systemic sclerosis, paraneoplastic pemphigus. We describe a case of four multiple trichilemmal cystis arising on frontal region in the same patient with brain metastasis and unknown primary melanoma and discuss their relationship.

Do inhaled corticosteroids affect perception of dyspnea during bronchoconstriction in asthma?

BACKGROUND: Some of the disagreements on the perception of dyspnea (PD) during bronchoconstriction in asthma patients could depend on the interrelationships among the following: (1) the influence of baseline airflow obstruction on the patient's ability to detect any further increase in airway resistance; (2) the effect of eosinophilic inflammation on the airway; (3) bronchial hyperresponsiveness (BHR); and (4) the effect of inhaled corticosteroids (ICSs). OBJECTIVE: We hypothesized that if the inflammation of the airway wall influences to some extent and in some way the PD in asthma patients, ICSs reverse the effect of airway inflammation on the PD. METHODS: We studied 100 asthma patients who were divided into the following four groups: patients with obstruction who were either ICS-naive (group I) or were treated with ICSs (group II); and nonobstructed patients who were either ICS-naive (group III) or were treated with ICSs (group IV). PD on the visual analog scale (VAS) was assessed during a methacholine-induced FEV(1) decrease and specifically was quantified as the VAS slope and score at an FEV(1) decrease of 5 to 20%. BHR was assessed in terms of the provocative concentration of methacholine causing a 20% fall in FEV(1) (PC(20)). Eosinophil counts in induced sputum samples also were performed. Regression analysis, univariate analysis of variance, and factor analysis were applied for statistical evaluation. RESULTS: For a 5 to 20% fall in FEV(1) from the lowest point after saline solution induction, VAS score was lowest in group II, slightly higher in group I, slightly higher still in group IV, and the highest in group III. In the patients as a whole, BHR related to PD, but age, clinical score, duration of the disease, and presence of baseline airway obstruction did not. In patients with obstruction who were treated with ICSs, eosinophil counts related to PD negatively. Factor analysis yielded the following four factors that accounted for 70% of the variance in the data: ICS; eosinophil counts; FEV(1); and PC(20) loaded on separated factors with PD loading on the same factors as PC(20). The post hoc analysis carried out dividing the patients into ICS-treated and ICS-naive, showed that in the former group eosinophil counts and BHR proved to be factors negatively associated with PD, while in the latter group eosinophil counts were positively associated with PD. CONCLUSIONS: We have shown that eosinophilic inflammation of the airway wall may increase PD and that the association of eosinophil counts with ICSs may result in lessening the PD.

Next-to-next-to-leading-order logarithmic corrections at small transverse momentum in hadronic collisions

We study the region of small transverse momenta in q&qmacr;- and gg-initiated processes with no colored particle detected in the final state. We present the universal expression of the O(alpha(2)(s)) logarithmically enhanced contributions up to next-to-next-to-leading-order logarithmic accuracy. From there we extract the coefficients that allow the resummation of the large logarithmic contributions. We find that the coefficient known in the literature as B((2)) is process dependent, since it receives a hard contamination from the one-loop correction to the leading-order subprocess. We present the general result of B((2)) for both quark and gluon channels.

Relevance of dyspnoea and respiratory function measurements in monitoring of asthma: a factor analysis.

Previous studies in patients with stable chronic obstructive pulmonary disease have demonstrated that objective measures (lung volumes and respiratory muscle force) and clinical or subjective measures (symptoms of breathlessness and exercise tolerance) are quantities that independently characterize the conditions of these patients. Such an evaluation has not been previously applied in patients with stable bronchial asthma. Sixty-nine patients with stable chronic asthma underwent evaluation of static (functional residual capacity, FRC) and dynamic [forced expiratory volume in 1 sec (FEV1) and forced vital capacity, FVC] lung volumes; respiratory muscle strength (RMS), by measuring maximal inspiratory and expiratory pressures, and exercise capacity by means of the 6-min walking distance (6MWD). Chronic exertional dyspnoea was assessed by the Baseline Dyspnoea Index (BDI) focal score and by the Medical Research Council (MRC) scale. Statistical evaluation was performed by applying factor analysis. Three factors accounted for 78% of the total variance in the data: FEV1, FVC loaded on a factor I; RMS, FRC and 6MWD loaded on a factor II; dyspnoea ratings loaded on a factor III. Post-hoc analysis by randomly dividing the patients into two subgroups gave the same results. In asthmatic patients, airway obstruction appeared as an independent dimension or factor. Dyspnoea independently characterized the condition of asthma. Submaximal exercise tolerance could not be associated with the symptom of breathlessness. Evidence of independent factors support the validity of routine, multi-factorial assessment and the primary goal of treatment to alleviate symptoms and improve functional capacity in stable asthmatics.

Efficacy of mexiletine in chronic ventricular arrhythmias: a multicentre double-blind medium-term trial.

In a multicentre double-blind, inpatient, placebo-controlled trial the effects on premature ventricular beats (PVBs) of mexiletine in a standard, submaximal dose were studied by Holter monitoring in 144 outpatients. After wash-out, mexiletine was administered for 14 days. The effects were re-tested, after one week of a placebo, in a second 14-day period of mexiletine administration. Of the patients 73% in the first period and 82.5% in the second period responded to mexiletine (a reduction of 75% or more of PVBs/24 h--p less than 0.001 compared with the placebo for both periods). Mexiletine also significantly reduced the Lown class of PVBs and the frequence of paired PBVs, ventricular tachycardia, multiform beats and R on T wave phenomenon. Mexiletine showed an equivalent effectiveness in the four main aetiological groups of arrhythmias. Fifty nine patients complained of adverse effects (gastrointestinal or neurological) the intensity of which led to the stopping of the treatment in 16 of them. These results show that mexiletine is highly effective, even in submaximal doses, in preventing ventricular arrhythmias of whatever origin.

Pharmacological treatment of exercise dyspnoea.

A better understanding of the mechanisms of dyspnoea improves the clinician's ability to treat patients with shortness of breath. Any intervention that: 1) reduces ventilatory demands; 2) reduces ventilatory impedance; or 3) improves inspiratory muscle function, may relieve dyspnoea. Reduced ventilatory demand may be obtained by reducing metabolic load. Supplemental oxygen during exercise reduces exertional breathlessness and improves exercise tolerance, the decrease in dyspnoea being proportional to decrease in minute ventilation. Reduced ventilatory demand may also be obtained by decreasing the central drive. Opiates have been shown to decrease minute ventilation at rest and during submaximal exercise. They can alter the central processing of neural signals within the central nervous system to reduce sensations associated with breathing. Contrastingly, no consistent improvement in dyspnoea (versus placebo) has been shown with anxolytics. Decreasing central drive may also be obtained by altering pulmonary afferent information. Interventions that alter transmittal of afferent information to the central controller, potentially reduce dyspnoea. Reduction of ventilatory impedance is obtained by administering B2, anticholinergics or theophylline. B2 and anticholinergics act by modulating the increase in operational lung volumes and the inspiratory muscle effort during exercise. The mechanism by which theophylline relieves dyspnoea is probably related to a mechanism other than its bronchodilation alone. Alterations in respiratory muscle function are currently being detected in patients with chronic obstructive pulmonary disease, due to alteration in respiratory muscle energy balance. Nutritional repletion may improve respiratory muscle function but uncertainty remains as to whether nutritional repletion may relieve dyspnoea. The cumulative benefit of interventions targeting the pathophysiologic mechanism of dyspnoea must be identified for optimum treatment of patients with shortness of breath.