Melanoma in children and adolescents: analysis of susceptibility genes in 123 Italian patients.

BACKGROUND: A polygenic inheritance involving high, medium and low penetrance genes has been suggested for melanoma susceptibility in adults, but genetic information is scarce for paediatric patients. OBJECTIVE: We aim to analyse the major high and intermediate melanoma risk genes, CDKN2A, CDK4, POT1, MITF and MC1R, in a large multicentre cohort of Italian children and adolescents in order to explore the genetic context of paediatric melanoma and to reveal potential differences in heritability between children and adolescents. METHODS: One-hundred-twenty-three patients (<21 years) from nine Italian centres were analysed for the CDKN2A, CDK4, POT1, MITF, and MC1R melanoma predisposing genes. The rate of gene variants was compared between sporadic, familial and multiple melanoma patients and between children and adolescents, and their association with clinico-pathological characteristics was evaluated. RESULTS: Most patients carried MC1R variants (67%), while CDKN2A pathogenic variants were found in 9% of the cases, the MITF E318K in 2% of patients and none carried CDK4 or the POT1 S270N pathogenic variant. Sporadic melanoma patients significantly differed from familial and multiple cases for the young age at diagnosis, infrequent red hair colour, low number of nevi, low frequency of CDKN2A pathogenic variants and of the MC1R R160W variant. Melanoma in children (≤12 years) had more frequently spitzoid histotype, were located on the head/neck and upper limbs and had higher Breslow thickness. The MC1R V92M variant was more common in children than in adolescents. CDKN2A common polymorphisms and MC1R variants were associated with a high number of nevi. CONCLUSION: Our results confirm the scarce involvement of the major high-risk susceptibility genes in paediatric melanoma and suggest the implication of MC1R gene variants especially in the children population.

Vulval hidradenoma papilliferum: a clinical and dermoscopic study.

Hidradenoma papilliferum (HP) is a rare, slow-growing, benign adnexal tumour with apocrine differentiation. It usually affects the anogenital region in adult women and is clinically polymorphous, mimicking other benign or malignant neoformations. The dermoscopic features of vulval HP have not been reported yet. We report the clinical and dermoscopic features in a case series of histopathologically proven vulval HPs. Dermoscopy may be a useful tool for the diagnosis of vulval HP. To our knowledge, our paper represents the first report of dermoscopic findings in a series of vulval HPs in a multiracial population.

Thin vulvar melanoma: a challenging diagnosis. Dermoscopic features of a case series.

BACKGROUND: Vulvar melanoma (VM) is rare and is often diagnosed late. Dermoscopy may aid in its recognition, differentiating VM from other more common vulvar lesions, such as melanosis and naevi. However, little is known about the dermoscopic features of thin VM. AIM: To retrospectively analyse a series of histopathologically diagnosed thin VMs and to highlight their most suggestive dermoscopic features. METHODS: A multicentre, retrospective study was conducted, including histopathologically proven thin VMs, either intraepidermal or with Breslow thickness ≤ 0.5 mm, diagnosed during the period 2016-2018. We particularly focused on their dermoscopic characteristics to highlight the most suggestive dermoscopic diagnostic clues. RESULTS: In total, 14 cases of early-stage VM were included, in women with a mean age at diagnosis of 64.86 years. The most frequently affected sites were the labia minora. Of these, 11 cases were unifocal. Dermoscopy most often revealed structureless areas, grey globules and areas, irregular black-brown dots, blue and white structures, and red areas. CONCLUSIONS: In our experience, early-stage VM often exhibits dermoscopic features that are more typical of thicker cutaneous melanomas. Dermoscopy may provide useful clues for the prompt diagnosis of thin VM.

Risk of second primary malignancies among 1537 melanoma patients and risk of second primary melanoma among 52 354 cancer patients in Northern Italy.

BACKGROUND: The number of melanoma survivors has been increasing for decades due to early diagnosis and improved survival. These patients have an increased risk of developing a second primary cancer (SPC); also, melanoma is frequently diagnosed among patients firstly diagnosed with an extracutaneous malignancy. OBJECTIVE: We evaluated the risk of developing a SPC among 1537 melanoma patients, and the risk of second primary melanoma (SPM) in 52 354 extracutaneous cancer patients, who were treated at the European Institute of Oncology in Milan, Italy, during 2000-2010. MATERIAL AND METHODS: We calculated standardized incidence ratios (SIR) by applying gender-, age-, year- and region-specific reference rates to the follow-up time accrued between the diagnosis of the first and the second primary malignancies. RESULTS: Seventy-six SPC were diagnosed during a median follow-up of 4 years, of which 49 (64%) during the first 2 years upon melanoma diagnosis. The SIR was increased for cancer of breast (4.10, 95% CI 2.79-6.03), thyroid (4.67, 95% CI 1.94-11.22), brain (6.13, 95% CI 2.30-16.33) and for non-Hodgkin lymphoma (3.12, 95% CI 1.30-7.50). During a median follow-up of 4 years, 127 SPM were diagnosed: thick lesions were less frequent than for melanoma diagnosed as first cancer. The SIR was increased for cancer of breast (5.13, 95%CI 3.91-6.73), thyroid (16.2, 95%CI: 5.22-50.2), head and neck (5.62, 95%CI 1.41-22.50), soft tissue (8.68, 95%CI 2.17-34.70), cervix (12.5, 95% CI 3.14-50.20), kidney (3.19, 95%CI 1.52-6.68), prostate (4.36, 95%CI 2.63-7.24) and acute myeloid leukaemia (6.44, 95%CI 2.42-17.20). CONCLUSIONS: The most likely causes of these associations are the clustering of lifestyle risk factors in the same subgroups of population, mainly on a sociocultural basis and surveillance bias. This raises important questions about how to best follow cancer survivors by avoiding an inefficient use of resources and an excessive medicalization of these patients' lives.

A phase I-II study of the histone deacetylase inhibitor valproic acid plus chemoimmunotherapy in patients with advanced melanoma.

We explored in a phase I/II clinical trial the combination of valproic acid (VPA), a clinically available histone deacetylase inhibitor, with standard chemoimmunotherapy in patients with advanced melanoma, to evaluate its clinical activity, to correlate the clinical response with the biological activity of VPA and to assess toxicity. Patients were treated initially with VPA alone for 6 weeks. The inhibition of the target in non-tumour peripheral blood cells (taken as a potential surrogate marker) was measured periodically, and valproate dosing adjusted with the attempt to reach a measurable inhibition. After the treatment with valproate alone, dacarbazine plus interferon-alpha was started in combination with valproate. Twenty-nine eligible patients started taking valproate and 18 received chemoimmunotherapy and are assessable for response. We observed one complete response, two partial remissions and three disease stabilisations lasting longer than 24 weeks. With the higher valproate dosages needed to reach a measurable inhibition of the target, we observed an increase of side effects in those patients who received chemoimmunotherapy. The combination of VPA and chemoimmunotherapy did not produce results overtly superior to standard therapy in patients with advanced melanoma and toxicity was not negligible, casting some doubts on the clinical use of VPA in this setting (at least in the administration schedule adopted).

The impact of rotary blood pump in conjunction with mechanical ventilation on ventricular energetic parameters - numerical simulation.

OBJECTIVES: Aim of this work is to study the impact of left ventricular rotary blood pump assistance, on energetic variables, when mechanical ventilation (MV) of the lungs is applied. METHODS: Computer simulation was used to perform this study. Lumped parameter models reproduce the circulatory system. Variable elastance models reproduce the Starling's law of the heart for each ventricle. After the reproduction of ischemic heart disease left ventricular assistance was applied using a model of rotary blood pump. The pump speed was changed in steps and was assumed to be constant during each step. The influence of mechanical ventilation was introduced by different values of positive mean thoracic pressure. RESULTS: The increase of the rotational speed has a significant influence on some ventricular energetic variables. In fact it decreased left ventricular external work, left and right ventricular pressure-volume area and the left ventricular efficiency. Finally, it increased the right ventricular efficiency but had no influence on the right ventricular external work. The increase of thoracic pressure from -2 to +5 mmHg caused a significant decrease of external work, pressure-volume area (right ventricular pressure-volume area dropped up to 50%) and an increase of right ventricular efficiency (by 40%) while left ventricular efficiency remained almost stable. CONCLUSIONS: Numerical simulation is a very suitable tool to predict changes of not easily measurable parameters such as energetic ventricular variables when mechanical assistance of heart and/or lungs is applied independently or simultaneously.

Modelling in the study of interaction of Hemopump device and artificial ventilation.

The aim of this work is to evaluate in different ventricular conditions the influence of joint mechanical ventilation (MV) and Hemopump assistance. To perform this study, we used a computer simulator of human cardiovascular system where the influence of MV was introduced changing thoracic pressure to positive values. The simulation confirmed that haemodynamic variables are highly sensitive to thoracic pressure changes. On the other hand, Hemopump assistance raises, among the others, mean aortic pressure, total cardiac output (left ventricular output flow plus Hemopump flow) and coronary flow. The simulation showed that the joint action of Hemopump and positive thoracic pressure diminishes these effects.

Dabrafenib in metastatic melanoma: a monocentric 'real life' experience.

Dabrafenib is a potent BRAF-kinase inhibitor. Its activity was evaluated on 40 consecutive metastatic melanoma patients (pts) harboring the V600BRAF mutations. Dabrafenib was administered orally at the dosage of 150 mg b.i.d. daily. ORR was 82%, with 7% CR, 62% PR, 13% SD and 18% PD. The median PFS and OS were seven and 17 months, respectively (median follow-up: 8.5 months). Increased risk of progression was found in pts with elevated LDH, ECOG PS >1 and more than two metastatic sites. Grade 3-4 adverse events were recorded in 4 pts. In this retrospective analysis, Dabrafenib confirmed its role as the standard clinical option in metastatic melanoma pts.

In vivo and simulation study of artificial ventilation effects on energetic variables in cardiosurgical patients.

OBJECTIVES: The analysis of energetic ventricular variable changes during artificial ventilation, obtained by numerical simulation was done. Twenty-one sets of hemodynamic parameters for eight cardiosurgical patients were used to estimate left and right stroke work. The data were collected for three methods of ventilation: conventional, lung-protective (with minute ventilation diminished by half) and high frequency ventilation (with frequency 5, 10, or 15 Hz). METHODS: The computer simulator (CARDIOSIM) of the cardiovascular system, was used as a tool to calculate values of energetic ventricular variables for conditions that corresponded to these during in vivo measurements. Different methods of ventilation caused differences of intrathoracic pressure, haemodynamic and finally energetic ventricular variables. The trends of these variable changes were the same in in vivo and simulation studies, in the whole range of intrathoracic pressure changes (Pt = 1.5-3.5 mmHg). RESULTS: As values of main hemodynamic variables like cardiac output or arterial, systemic and pulmonary pressures were very close in both studies. Cardiac index and left ventricular stroke work also differed less than 10% for all examined patients and computer simulation. In a case of right ventricular stroke work the difference between in vivo data and simulation was a bit greater than 10% for two of eight patients under study. CONCLUSIONS: Our comparative analysis proved that numerical simulation is a very useful tool to predict changes of main hemodynamic and energy-related ventricular variables caused by different levels of positive Pt. It means that it can help an anesthesiologist to choose an appropriate method of artificial ventilation for cardiosurgical patients.

Development of a hybrid (numerical-hydraulic) circulatory model: prototype testing and its response to IABP assistance.

Merging numerical and physical models of the circulation makes it possible to develop a new class of circulatory models defined as hybrid. This solution reduces the costs, enhances the flexibility and opens the way to many applications ranging from research to education and heart assist devices testing. In the prototype described in this paper, a hydraulic model of systemic arterial tree is connected to a lumped parameters numerical model including pulmonary circulation and the remaining parts of systemic circulation. The hydraulic model consists of a characteristic resistance, of a silicon rubber tube to allow the insertion of an Intra-Aortic Balloon Pump (IABP) and of a lumped parameters compliance. Two electro-hydraulic interfaces, realized by means of gear pumps driven by DC motors, connect the numerical section with both terminals of the hydraulic section. The lumped parameters numerical model and the control system (including analog to digital and digital to analog converters)are developed in LabVIEW environment. The behavior of the model is analyzed by means of the ventricular pressure-volume loops and the time courses of arterial and ventricular pressures and flows in different circulatory conditions. A simulated pathological condition was set to test the IABP and verify the response of the system to this type of mechanical circulatory assistance. The results show that the model can represent hemodynamic relationships in different ventricular and circulatory conditions and is able to react to the IABP assistance.

Retinal pigment epithelium function in alopecia areata.

Electroretinography (ERG) and electro-oculography (EOG) were performed in 98 patients affected by alopecia areata (AA) free from ophthalmologic disorders, and in 40 healthy subjects, in order to evaluate whether or not the retinal pigment epithelium of AA patients shows bioelectrical changes. ERG was normal. EOG, on the contrary, showed a significantly depressed mean value in the AA patient group. Furthermore, depressed EOG occurred more frequently in patients affected by alopecia totalis or universalis as compared with multiple patchy alopecia. These findings prompt the authors to believe that the melanocytes may play a prominent part in the pathogenesis of AA.

Metal ion removal from water by sorption on paper mill sludge.

Chromatographic columns packed with paper mill sludge are employed for metal ion recovery from water. The breakthrough curves show that cadmium, copper, lead and silver are removed from acid solutions (pH 2, 4); the affinity series is Pb(II)>Cu(II)>Ag(I)>Cd(II). Both the amount of metal retained and the metal-matrix interaction are pH dependent; the sorptive capacity increases with increasing pH. When the metals are present together at the same initial concentrations a competition among the different ions occurs although the affinity order remains unchanged. In metal recovery from the paper mill sludge column, the total amount of the cadmium and copper is displaced by HCl 1.0 M, 65% of the lead by HCl 0.1 M and 75% of the silver by HNO(3) 0.1 M. More than 95% of copper and lead and less than 20% of cadmium were recovered with HCl 0.1 M when the metals were present at the same time.

A desk-top computer model of the circulatory system for heart assistance simulation: effect of an LVAD on energetic relationships inside the left ventricle.

The study of the interaction between a pneumatic left ventricle assist device (LVAD), driven with different control strategies, and the cardiovascular system is the subject of this paper. It is performed by a modular numerical model of the cardiovascular system connected to a numerical model of the LVAD. The circulatory system is simulated by a lumped parameter numerical model. The ventricle is represented by a time-varying elastance model to reproduce the Starling law of the heart. The effect of the LVAD on the cardiovascular system is evaluated, on the left ventricle alone, by an open-loop circuit consisting of the models of the ventricle, the LVAD and the arterial tree. The analysis is performed in terms of energy variables (such as external work and oxygen consumption and cardiac mechanical efficiency versus control strategy. The LVAD is driven by different control strategies: a fixed heart rate (with different delays from the onset of the natural ventricle contraction) and a variable heart rate.

Effect of magnetic fluids on the efficiency of an electromagnetic actuator prototype.

An electromagnetic actuator to substitute ventricular function presents some advantages compared with different energy converters. The drastic reduction of the moving parts leads to greater reliability and an accurate control system can be set up. Its major limitations concern weight, heat dissipation and, finally, the overall pump efficiency which is usually rather low. We investigated the possibility of using magnetic fluids in an electromagnetic actuator. Limitations intrinsic to the magnetic fluids prevent their being used as pumping elements but they can be useful to increase the pump efficiency by reducing losses in the magnetic circuit. A remarkable increase in pump efficiency was attained. It is necessary to point out that in designing the electromagnetic actuator the focus was on the pump efficiency with and without the magnetic fluids more than on its performance.

A simple method for E(max) evaluation: in vitro results.

E(max) is an important parameter to evaluate the state of the heart and of its contractile capability. Its determination is not easy and rather inaccurate: However, it can be clinically relevant during mechanical and/or pharmacological heart assistance as it can suggest how to modify pharmacological therapy or the control strategy of the device. Aim of this study is to develop a method based on ventricular energetics to evaluate E(max). If arterial elastance line slope is modified, for example by a slight peripheral resistance increase, E(max) (assuming that it is constant) can be evaluated computing the energy transferred to the arterial elastance before and after the change. The corresponding equation contains known or easily computable variables and the difference delta between end diastolic volume and ventricular rest volume. If the ratio of deltas before and after the disturbance is near to 1, the equation returns a fair estimation of E(max). The method was tested in vitro, in different circulatory conditions, using an open loop numerical model of the circulation built out of a variable elastance model of the ventricle connected to a modified windkessel representing the systemic arterial tree. The results obtained in in vitro experiments suggest clinically testing this method.