Dermoscopic spectrum of mycosis fungoides: a retrospective observational study by the International Dermoscopy Society.

BACKGROUND: The dermoscopic features of classic patch stage mycosis fungoides (MF) have been described, but data on plaque and tumoral stage as well as rarer MF subtypes is limited. OBJECTIVE: To evaluate dermoscopic morphology and dermoscopic-pathological correlations of classic MF stages and investigate dermoscopic features of MF variants. METHODS: Patients with histopathologically confirmed lesions of classic MF (patch, plaque and tumoral stage) or folliculotropic, erythrodermic and poikilodermatous MF were included. Standardized evaluation of dermoscopic pictures of the included MF variants and comparative analysis and dermoscopic-pathological correlation assessment of different stages of classic MF were performed. RESULTS: A total of 118 instances were included (75 classic MF, 26 folliculotropic MF, 9 erythrodermic MF and 8 poikilodermatous MF). Linear/linear-curved vessels and white scales in the skin furrows were significantly associated with patch-stage MF, while clustered dotted vessels were related to plaque-stage MF and peripheral linear vessels with branches, ulceration and red globules separated by white lines to tumour-stage MF. Moreover, patchy white scales were significantly more common in patches and plaques compared to tumours, whereas focal bright white structureless areas were related to plaque and tumoral stage. Vessels histopathologically corresponded to dilated vascular structures in the dermis, orange structureless areas to either dermal hemosiderin (patch/plaque stage) or dense cellular infiltration (tumours), bright white lines/structureless areas to dermal fibrosis and ulceration to loss of epidermis. The main dermoscopic findings of folliculotropic MF were lack of hairs, dilated follicles and follicular plugs, while erythrodermic MF was mainly characterized by linear/dotted vessels, patchy white scales and focal orange structureless areas and poikilodermatous MF by focal white and brown structureless areas, white patchy scales and brown reticular lines. CONCLUSION: Dermoscopy may allow a more precise characterization of classic MF and reveal clues suggestive of the main MF variants.

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives.

Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients.

Antagonistic effects of chloroquine on autophagy occurrence potentiate the anticancer effects of everolimus on renal cancer cells.

Renal cell carcinoma is an aggressive disease often asymptomatic and weakly chemo-radiosensitive. Currently, new biologic drugs are used among which everolimus, an mTOR inhibitor, that has been approved for second-line therapy. Since mTOR is involved in the control of autophagy, its antitumor capacity is often limited. In this view, chloroquine, a 4-alkylamino substituted quinoline family member, is an autophagy inhibitor that blocks the fusion of autophagosomes and lysosomes. In the present study, we evaluated the effects of everolimus alone or in combination with chloroquine on renal cancer cell viability and verified possible synergism. Our results demonstrate that renal cancer cells are differently sensitive to everolimus and chloroquine and the pharmacological combination everolimus/chloroquine was strongly synergistic inducing cell viability inhibition. In details, the pharmacological synergism occurs when chloroquine is administered before everolimus. In addition, we found a flow autophagic block and shift of death mechanisms to apoptosis. This event was associated with decrease of Beclin-1/Bcl(-)2 complex and parallel reduction of anti-apoptotic protein Bcl(-)2 in combined treatment. At last, we found that the enhancement of apoptosis induced by drug combination occurs through the intrinsic mitochondrial apoptotic pathway activation, while the extrinsic pathway is involved only partly following its activation by chloroquine. These results provide the basis for new therapeutic strategies for the treatment of renal cell carcinoma after appropriate clinical trial.

Factors associated with virological success with raltegravir-containing regimens and prevalence of raltegravir-resistance-associated mutations at failure in the ARCA database.

Raltegravir (RAL) is the only licensed human immunodeficiency virus (HIV) integrase inhibitor. The factors associated with the virological response to RAL-containing regimens and the prevalence of integrase mutations associated with RAL failure deserve further investigation. From the Antiretroviral Resistance Cohort Analysis database, we selected triple-class-experienced subjects failing their current treatment with complete treatment history available. Selection criteria included HIV-RNA, CD4 count and HIV genotype within 3 months of RAL initiation. Factors associated with 24-week response were analysed; genotypic sensitivity scores (GSS) and weighted-GSS were evaluated. Virological response was achieved in 74.3% of 105 subjects. Mutations associated with RAL failure were detected in 12/24 subjects with an integrase genotype, with the prevalence of Q148H + G140S. Each extra unit of GSS (p 0.05, OR 2.62; 95% CI 1.00-6.87). was found to be a associated with response. Weighted-GSS had borderline statistical significance (p 0.063, OR 2.04; 95% CI 0.96-4.33) When stratifying for different cut-offs (<1 as reference, 1-1.49, ≥1.5), a borderline significant increase in the probability of response appeared for GSS ≥1.5 (p 0.053, OR 4.00; 95% CI 0.98-16.25). GSS ≥1 showed the highest sensitivity, 82.6%. Receiver operating characteristic curves depicted the widest area under the curve (0.663, p 0.054) of GSS ≥1. Unresponsiveness to RAL-containing regimens among triple-class-experienced subjects was low. The activity of the background regimen was strongly associated with response. Although few integrase genotypes were available at failure, half of these were without integrase resistance mutations. The substantial rate of RAL failure in the absence of known RAL-resistance mutations may be associated with adherence issues and this issue warrants further analysis in longer observations.

Relations between cardiovascular risk estimates and subclinical atherosclerosis in naive HIV patients: results from the HERMES study.

The aim of the study was to evaluate the cardiovascular risk factors associated with subclinical carotid atherosclerosis in antiretroviral therapy-naïve HIV-infected patients. The HERMES (HIV Exposure and Risk of Metabolic Syndrome) study enrolled therapy-naïve patients attending hospitals in the Italian coordination group for the study of allergies and HIV infection (CISAI [Coordinamento Italiano per lo Studio Allergia e Infezione da HIV]) in 2007. It was designed to identify metabolic syndrome (MS) and cardiovascular risk factors. The present analysis is a nested cross-sectional study with a subset of patients examined by carotid ultrasonography. Consecutive antiretroviral therapy-naïve HIV patients attending the facilities involved in the CISAI were included. Their 10-year probability of cardiovascular events was calculated using the Framingham Risk Score (FRS) and three other cardiovascular algorithms (the Global Framingham Risk Score - GFRS, 'Progetto Cuore' and 'SCORE'). Vascular age was estimated using a new model derived from GFRS and was compared with chronological age. The diagnosis of MS was based on the National Cholesterol Education Programme and International Diabetes Federation (IDF) definitions. Subclinical atherosclerosis was determined as ultrasound carotid intima-media thickness >0.9 mm. Out of 140 patients enrolled in the HERMES study by the four centres participating in the nested study, a total of 72 (51.4%) subjects, with no overt cardiovascular disease, were examined using carotid ultrasonography. The median age was 40 years, 79.2% men. The vascular age was 7.6 years higher than the chronological age. The factors associated with subclinical atherosclerosis were age (P < 0.0001), vascular age (P = 0.0002), body mass index (P = 0.003), waist circumference (P = 0.0002), MS (IDF definition, P = 0.004) and all the cardiovascular (CV) models (FRS, P = 0.01, GFRS, P = 0.002, Progetto Cuore, P = 0.018, SCORE, P = 0.03). Independent of other significant factors, waist circumference was significantly associated with pathological results (P = 0.007). The GFRS (area under the receiver-operating characteristic curves, 0.78; P < 0.001) had slightly better predictive accuracy than the other three CV models (FRS, areas under the curve [AUC] = 0.71, P = 0.003; Progetto Cuore, AUC = 0.74, P = 0.0005; SCORE, AUC = 0.77, P < 0.0001); 55% of patients at intermediate risk (6-20%) had subclinical carotid lesions. Subclinical carotid lesions had a highly significant direct association with all the CV risk predictors. The GFRS and vascular age were highly predictive. We recommend a carotid ultrasonographic examination at least among HIV patients with GFRS > or =6% or with an elevated waist circumference.

Prevalence of mutations and determinants of genotypic resistance to etravirine (TMC125) in a large Italian resistance database (ARCA).

OBJECTIVES: To evaluate whether etravirine (TMC125) might be effective in patients failing therapy with current nonnucleoside reverse transcriptase inhibitors (NNRTIs), we analysed the prevalence of TMC125 mutations and the possible determinants of genotypic resistance to this drug among sequences reported to a large database in Italy [Antiretroviral Resistance Cohort Analysis (ARCA)]. METHODS: We analysed the prevalence of TMC125 resistance-associated mutations (RAMs) and the TMC125 weighted genotypic score (WGS) together with the determinants of genotypic resistance. A total of 5011 sequences from 2955 patients failing NNRTI therapy were evaluated. RESULTS: Among the sequences in ARCA, 68% had at least one and 9.8% at least three TMC125 RAMs, whereas 31% had a WGS>2. Frequent RAMs were Y181C, G190A, K101E and A98G, whereas V179F, Y181V and G190S appeared in <5% of sequences. Multivariate analysis revealed a higher risk of developing at least three TMC125 RAMs associated with both nevirapine and efavirenz exposure, whereas CD4 counts > or = 200 cells/microL retained their protective effect. An increased risk of WGS>2 was linked to higher HIV RNA values (maximum risk at >5 log(10) copies/mL) and nevirapine exposure; CD4 counts > or = 200 cells/microL were protective. CONCLUSIONS: The prevalence of TMC125 resistance mutations in the ARCA cohort was 68%. The DUET studies showed that at least three TMC125-associated mutations were required to impair the efficacy of the drug and Y181C/V, V179F and G190S had the greatest effect on response. The prevalence of these mutations among the patients examined in our study was low. However, WGS>2 was found for one-third of our sequences. Previous nevirapine exposure was associated with an increased risk of having WGS>2 (adjusted odds ratio 1.76).

[The Dialysis Outcomes and Practice Patterns Study (DOPPS): results of the Italian cohort]. / Lo studio DOPPS (Dialysis Outcomes and Practice Patterns Study): risultati della coorte italiana.

BACKGROUND: The Dialysis Outcomes and Practice Patterns Study (DOPPS) is an international prospective, longitudinal, observational study examining the relationship between dialysis unit practices and outcomes for hemodialysis (HD) patients in seven developed countries France, Germany, Italy, Spain, United Kingdom, Japan and the United States. Results of the DOPPS in Italy are the subject of this report. METHODS: A national representative sample of 20 dialysis units (21 in Germany) was randomly selected in each of the European DOPPS countries (Euro-DOPPS). In these units, the HD in-center patients were included on a facility census, and their survival rates continuously monitored. A representative sample of incident (269 in Italy, 1553 in the Euro-DOPPS) and prevalent (600 in Italy, 3038 in the Euro-DOPPS) patients was randomly selected from the census for more detailed longitudinal investigation with regard to medical history, laboratory values and hospital admission. RESULTS: Comparing the Italian and Euro-DOPPS cohorts we found comparable mean age for prevalent patients (61.4 vs. 59.5 yrs), but incident patients were older in Italy. Italian prevalent patients had less cardiovascular disease, more satisfactory nutritional status and more frequent use of native vascular access. These data were associated with a comparable mortality (15.7 vs. 16.3 deaths/100 patient yrs), but morbidity was lower in Italy. Kt/V levels were comparable in the two cohorts (1.32 vs. 1.37), but 35% of Italian patients showed a Kt/V below the recommended target. Moreover, hemoglobin levels were below 11 g/dL in 60% of Italian patients. CONCLUSIONS: The DOPPS results bring to light several positive aspects and the opportunity for further possible improvements for Italian patients, but at the same time highlight some critical points that could represent a risk for dialysis quality.

Secondary lymphoid-tissue chemokine induced modulation of T cells.

In this study we were interested in investigating the extent to which stimulation through a chemokine receptor could modulate TCR function. We report that splenic T cells exposed to secondary lymphoid-tissue chemokine (SLC, CCL21) for 72, but not 2 or 24 hours, exhibited a decreased ability to produce IFN-gamma following CD3 crosslinking. Similar findings were observed with CCL2 and CCL5. The decrease in IFN-gamma production was not attributed to a decrease in T cell viability, was not accompanied with an increase in IL-4 production, and could be induced using a G protein coupled receptor agonist indicating involvement of chemokine receptors. One explanation for these findings was that following chemokine exposure the T cells were less efficient at TCR capping and exhibited a decrease in ZAP-70 protein expression. Consequently, these data indicate that CCL21 could modulate the function and expression of proteins necessary for T cell activation.

Adaptation of the "Conconi test" to children and adolescents.

A field test for the determination of anaerobic threshold (AT) based on the relationship between work intensity and heart rate was previously developed in adult runners (4) and then applied in various sports activities (3, 5, 9). In the current study the same relationship between running speed (S) and heart rate (HR) was determined in 274 healthy children and adolescents (169 males and 105 females). All tests were performed either outdoors on a 400-m track (n = 159, 110 males and 49 females) or indoors in a gymnasium (n = 115, 59 males and 56 females). The subjects increased their work intensity progressively from low to submaximal speeds. HR was determined by a heart rate monitor (Sport Tester TM PE 3000, Polar Electro, Kempele, Finland). In every subject examined, the linearity of the S-HR relationship was lost at a speed, called deflection speed (Sd), above which the increase in S exceeded the increase in HR. HR at Sd was defined as HRd. The respective test-retest correlation coefficients for Sd, HRd, and slope of the linear part of the graph were 0.990, 0.824, and 0.953 when determined outdoors and 0.996, 0.840, and 0.932 when determined indoors. The outdoor-indoor correlation coefficients were 0.934, 0.855, and 0.282, respectively, for Sd, HRd, and slope. The results suggest that application of this test to children and adolescents in running may prove useful in cross-sectional and longitudinal studies of the development of aerobic power during growth.

A field test for determining the speed obtained through anaerobic glycolysis in runners.

A field test for the evaluation of the speed generated by the anaerobic lactacid mechanism has been developed in runners. The test consists of 1200 m of continuous running: in the first 1000 m the speed corresponding to the anaerobic threshold is progressively reached; in the last 200 m an all-out sprint is performed. The speed at the anaerobic threshold is subtracted from the speed reached in the final 200-m all-out sprint. In 39 runners examined (marathon runners, n = 13; 5000-10000-m runners, n = 10; 400-800-m runners, n = 7; sprinters, n = 9), the additional speed generated above the anaerobic threshold was correlated with the venous blood lactate concentration reached 5 min after the all-out effort (r = 0.93). The anaerobic speeds measured by the test were in keeping with the characteristics of the runners under study, i.e., anaerobic speeds were highest for the sprinters, intermediate for the middle-distance runners, and lowest for the marathon runners. Since the speed generated above the anaerobic threshold by the aerobic fuel breakdown can be subtracted, the contribution of creatine phosphate is minimal, and the speed exceeding the anaerobic threshold is highly correlated with lactate accumulation, the present test should measure the speed generated by anaerobic glycolysis.

Noninvasive determination of the anaerobic threshold in swimming.

The relationship between swimming velocity (V) and heart rate (HR) was determined in 60 swimmers. The athletes were asked to increase their work intensity progressively, from low to submaximal velocities; HRs were determined by a telemetric cardiofrequency meter. In all the athletes examined and for each style employed, the linearity of the V3-HR relationship was maintained up to a submaximal velocity (deflection velocity, Vd), beyond which the increase in work intensity exceeded the increase in HR. The test-retest correlation for Vd determined in nine pent-athletes was 0.99. Vd and anaerobic threshold (AT), determined through lactate measurements, were correlated in six swimmers (r = 0.84). Vd and average swimming velocities in a modern pentathlon swimming race (300 m free-style) were also correlated (n = 9, r = 0.91), thus suggesting that AT is critical in determining the speed in middle-distance swimming events.

[Toxicity of several pesticides used in Tunisia, for Aphanius fasciatus Nardo, 1827 (Pisces, Cyprinodontidae.)]. / Toxicité de divers pesticides utilisés en Tunisie pour Aphanius fasciatus Nardo, 1827 (Pisces, Cyprinodontidae)

The acute toxicity of some pesticides used in Tunisia is determined for the species Aphanius fasciatus (Pisces - Cyprinodontidae). Bioassays conducted at temperature (19-20 degrees C) and salinity (37-38%) have allowed to calculate the CL50 48 h and 96 h. The classification of these pesticides, based on the CL50 96 h, and according to their toxicity for the test species, shows that the organic phosphorus (Murphotox, Bazudin, Dursban, Zithiol, Lebaycid, Imidan, Oleoparathion, Folimat; Nuvan, Actellic, Carbicron, Nexion, Dimecron, Roxion) have all the degrees of toxicity, but the majority are among the most toxic; the carbamates (Betanal, Dimetilan, Baygon), are generally less toxic than the organic phosphorus tested, except Nexion which is less toxic than the Betanal and Roxion less toxic than the three carbamates tested; the herbicides (2,4-D, Basagran, Printan) have a very low toxicity, and are less toxic than the insecticides tested, except Betanal and Suffix of which the toxicity is higher than some insecticides (Nexion, Dimecron, Baygon, Dimetilan, Roxion); Calixin (Fongicide) is more toxic than the herbicides tested but it is generally less toxic than the insecticides used. At higher temperature (28-29 degrees C) A. fasciatus is more sensible to organic phosphorus (Dursban, Folimat) than to carbamate (Betanal). The variation change of salinity (from 37 to 6.5 %) don't modify the sensibility of the test species face to face of three pesticides: Dursban, Folimat (organic phosphorus insecticide) and Betanal (carbamate herbicide). A. fasciatus is suitable for acute and chronic bioassays.

[Ecological data on the interstitial meiofauna of the lower part of the beaches of the gulf of Tunis]. / Données écologiques sur la méiofaune interstitielle du bas des plages du golfe de Tunis.

The density of the meiofauna in the mediolittoral zone can exceed 4.10(6) ind./m2; the Nematoda are the most important group but their percentage is lower as in constantly immersed biotops; the population has a great vertical extension. Near the mouth of Medjerda river, the low salinity brings about a strong impoverishment.