Favourable prognostic role of histological regression in stage III positive sentinel lymph node melanoma patients.

BACKGROUND: Sentinel lymph node (SLN)-positive melanoma patients are a heterogeneous group of patients with survival rates ranging from ∼20 to over 80%. No data are reported concerning the role of histological regression on survival in stage III melanoma. METHODS: The study included 365 patients with positive SLN from two distinct hospitals. The model was developed on patients from 'AOU Città della Salute e della Scienza di Torino', and externally validated on patients from IRCCS of Candiolo. Survival analyses were carried out according to the presence of regression and adjusted for all other prognostic factors. RESULTS: Among patients followed at 'AOU Città della Salute e della Scienza di Torino' (n=264), the median follow-up time to death or censoring (whatever two events occurred earlier) was 2.7 years since diagnosis (interquartile range: 1.3-5.8). In all, 79 patients died from melanoma and 11 from other causes. Histological regression (n=43) was associated with a better prognosis (sub-HR=0.34, CI 0.12-0.92), whereas the other factors above showed an inverse association. In the external validation, the concordance index was 0.97 at 1 year and decreased to 0.66 at 3 years and to 0.59 at 5 years. Adding histological regression in the prognostic model increased the discriminative ability to 0.75 at 3 years and to 0.62 at 5 years. Finally, using a cutoff of 20% for the risk of death led to a net re-classification improvement of 15 and 11% at 3 and 5 years after diagnosis, respectively. CONCLUSIONS: Histological regression could lead to an improvement in prognostic prediction in patients with stage III-positive SLN melanoma.

Prognostic role of histological regression in primary cutaneous melanoma: a systematic review and meta-analysis.

The prognostic significance of histological regression in primary melanoma has been debated for many years. We aim to review the evidence to see how histological regression may affect prognosis. A systematic review was performed by searching in MEDLINE, Scopus and the Cochrane Library from 1 January 1966 to 1 August 2015. All studies reporting hazard ratios or data on survival and histological regression were included. Primary random-effects meta-analyses were used to summarize outcome measures. Heterogeneity was assessed using the χ2 -test and I2 -statistic. To assess the potential bias of small studies we used funnel plots and the Begg and Mazumdar adjusted rank correlation method. Summaries of survival outcomes were measured as hazard ratios or relative risk of death at 5 years according to the presence of histological regression of primary melanoma. In total, 183 articles were reviewed out of 1876 retrieved. Ten studies comprising 8557 patients were included. Patients with histological regression had a lower relative risk of death (0·77, 95% confidence interval 0·61-0·97) than those without. Examination of the funnel plot did not provide evidence of publication bias. The results showed that histological regression is a protective factor for survival.

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.

BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.

Prediction of high naevus count in a healthy U.K. population to estimate melanoma risk.

BACKGROUND: Despite recent discoveries of germline and somatic mutations in melanoma, naevus count remains the most important risk factor for melanoma. Counting naevi on the whole body is time consuming. In order to identify patients at risk for melanoma, many studies have used naevus count on selected body sites as a proxy for total body naevus count (TBNC). OBJECTIVES: The main aim of this study was to assess the predictive value of naevus count on 17 different body sites in estimating TBNC in a large cohort of healthy U.K. Caucasian female subjects. Once the site with the best predictive value for TBNC was determined, a second aim was to estimate the cut-off values of naevus counts at this anatomical site that best predict the presence of 50 or 100 naevi, respectively. METHODS: The most predictive body site for TBNC was assessed in a cohort of healthy female twins. This finding was replicated on a control group from a U.K. case-control study and a prediction model was performed afterwards. The area under the receiver operating characteristics curve was used to evaluate the best cut-off for the prediction of having a TBNC of more than 50 or 100. RESULTS: There were 3694 female twins included. The TBNC showed a steady decline after the age of 30 years (P < 0·001). The most predictive sites for TBNC were the arms and legs: the adjusted correlation coefficients were 0·50 and 0·51 (P < 0·001) for the right and left arm, respectively, and 0·49 and 0·48 for the right and left legs, respectively (P < 0·001). The arm remained the most predictive site for TBNC when replicated in a control population including both sexes. In the twin study, women with more than 11 naevi on the right arm were approximately nine times more likely to have more than 100 naevi (odds ratio = 9·38, 95% confidence interval 6·71-13·11). CONCLUSIONS: The ability to estimate TBNC quickly by counting naevi on one arm could be a very useful tool in assessing melanoma risk in primary care.

Phenotypical characterization of circulating cell subsets in pyoderma gangrenosum patients: the experience of the Italian immuno-pathology group.

BACKGROUND: No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG). AIM: To analyse the expression of different chemokine receptors associated to T-helper (Th)1 (CCR5), Th2 (CCR4) and Th17 (CCR6), as well as the regulatory T-cell subset (Treg) and dendritic cell polarization in the blood of newly diagnosed untreated PG patients. MATERIALS AND METHODS: Multi-parameter flow cytometry was performed on blood samples from 10 PG patients collected at first diagnosis among centres belonging to the Italian Immuno-pathology Group. Blood samples from 10 age- and sex-matched healthy controls (HC) were used as controls. RESULTS: PG patients are characterized by an over-expression in the blood of the CD4+CCR5+ and CD4+CCR6+ and a down-regulation of CD4+CCR4+ counts with respect to healthy subjects. Moreover, they show increased levels of myeloid derived dendritic cells type1 and reduced levels of the Treg CD4+CD25highFOXP3+ subset. CONCLUSIONS: The pattern of chemokine expression argues in favour of a Th1 (CCR5+) and Th17 (CCR6+) polarization with a down-regulation of Th2 (CCR4+).

Sentinel Lymph Node Biopsy in Thick-Melanoma Patients (N=350): What is Its Prognostic Role?

BACKGROUND: Sentinel lymph node biopsy (SLNB) is currently recommended for patients with intermediate-thickness melanomas (T2-T3). Historically, T4 melanoma patients have not been considered good candidates for SLNB because of the high risk of distant progression. However, some authors suggest that T4 melanoma patients could be considered as a heterogeneous group that could benefit from SLNB. METHODS: We retrospectively analyzed 350 patients with thick (>4 mm) melanomas between 1999 and 2011. Patients were stratified into three groups depending on the results of SLNB: (1) 94 SLNB-negative; (2) 84 SLNB-positive; and (3) 172 SLNB not performed (observation group). The associations of clinical-pathologic features with the result of SLNB, disease-free interval (DFI), and disease-specific survival (DSS) were analyzed. RESULTS: Multivariate analyses confirmed a better prognosis for SLN-negative patients compared with patients in the observation group (DSS hazard ratio [HR] 0.62, p = 0.03; DFI HR 0.47, p < 0.001). The observation group was shown to have the same prognosis as the positive-sentinel lymph node group, when adjusted for principal confounders in the model. CONCLUSIONS: We confirmed that thick-melanoma patients are a heterogeneous group with different prognosis. In our experience, SLNB allowed for an appropriate stratification of patients in different survival groups. On the basis of our results, we strongly recommend the routine execution of SLNB in cases of primary melanoma thicker than 4 mm.

Favourable prognostic role of regression of primary melanoma in AJCC stage I-II patients.

BACKGROUND: The prognostic significance of regression in primary melanoma has been debated over the past few years. Once it was considered to be a negative prognostic factor, as it may have prevented proper melanoma thickness measurement, therefore affecting the staging of the tumours. For this reason, it was considered to be an indication for sentinel lymph node biopsy (SLNB) in melanoma < 1 mm. OBJECTIVES: To ascertain the utility of SLNB in thin melanoma and to clarify the role of regression in disease-free survival (DFS) and overall survival (OS) in our series. METHODS: We analysed data collected from 1693 consecutive patients with AJCC (American Joint Committee on Cancer) stage I-II melanoma. RESULTS: Globally, SLNB was performed in 656 out of 1693 patients. Regression was present in 349 patients and 223 of them were characterized by thin lesions. SLNB was performed in 104 cases of thin melanoma with regression. The majority of regional lymph node metastases were observed in patients who did not undergo SLNB (89 out of 132). Among the remaining 43 'false negative' patients only three showed regression in the primary. Using the Cox multivariate model, histological regression maintained a significant protective role [hazard ratio (HR) 0·62, P = 0·012 for DFS; HR 0·43, P = 0·008 for OS] when corrected for the principal histopathological and clinical features, despite SLNB. CONCLUSIONS: We confirmed that regression alone should not be a reason to perform SLNB in thin melanoma and, on the contrary, it can be considered a favourable prognostic factor in patients with AJCC stage I-II melanoma.

Relevance of multiple basin drainage and primary histologic regression in prognosis of trunk melanoma patients with negative sentinel lymph nodes.

BACKGROUND: Lymphatic drainage to multiple basins (MLBD) is frequently observed in patients with primary melanoma located in the trunk. Conflicting data regarding the prognostic impact of MLBD are reported. OBJECTIVE AND METHODS: We reviewed our case series of 352 patients with trunk melanoma to evaluate the pattern of basin drainage and to analyse whether different basin drainages may have different significance in negative sentinel lymph node (SLN) patients. The presence of single/multiple basin drainage, the status of SLN, the presence of melanoma regression, Breslow thickness, ulceration and type of melanoma were recorded for each patients and correlated to Disease Free Survival (DFS) and Overall Survival (OS). RESULTS: MLBD occurred in 77 patients (21.9%) and single basin lymphatic drainage (SLBD) occurred in 275 patients (79.1%). The presence of metastases in SLN was not significantly different in patients with MLBD compared to those with SLBD (26% vs. 19.6%). No differences in OS and DFS were found in SLBD/MLBD independently from SLN status. However DFS was higher in patients with MLBD and negative SLN (P = 0.0001), in addition, in patients with negative SLN and SLBD disease recurrence was 19% while was only 7% in patients with negative SLN obtained from MLBD (P = 0.03). Multivariate analysis showed that Breslow thickness <2 mm, MLBD pattern and regression of melanoma were favourable variables for DFS of patients with negative SLN. CONCLUSIONS: An accurate study of the drainage basin and of all the SLNs obtained from MLBD is recommended because of the impact in prognosis of melanoma of the trunk.

Melanoma in patients younger than 20 years.

AIM: Melanoma is rare in children and uncommon in adolescents. Clinical and prognostic factors can differ from adult population. There is often a delay in diagnosis and the therapeutic management is not unequivocally established. The aim of this study was to review our monocentric case series to establish the characteristics of the population and the possible different behaviour of the malignancy compared to adults. METHODS: From 1975 to 2011 we selected 36 out of 43 patients with a diagnosis of melanoma before the age of 20. We reported a female predominance, the most common site of primary lesions for both sexes were the lower extremities and according to adulthood population the most common histotype was Superficial Spreading Melanoma. RESULTS: None of our patients presented distant metastasis at diagnosis, but 29.4% showed a progression, and the 17.6% died during the follow-up. A significant difference based on gender was found at the multivariate analysis on Disease free survival as well as Breslow thickness, but only Breslow thickness was the only parameter that maintained a role on survival at multivariate analysis when corrected for gender and age. We performed the sentinel lymph node biopsy in 3 patients and they all resulted negative. CONCLUSION: Despite our small case series we observed some important differences of melanoma in children compared to adults. It remains difficult to establish the prognostic factors in younger melanoma patients. Similar to adults, the detection of melanoma in an early phase of development, with a low Breslow thickness, is the most important prognostic factor.

Investigation of liver-targeted peripheral focused ultrasound stimulation (pFUS) and its effect on glucose homeostasis and insulin resistance in type 2 diabetes mellitus: a proof of concept, phase 1 trial.

BACKGROUND: Mechanical waves produced by ultrasound pulses have been shown to activate mechanosensitive ion channels and modulate peripheral nerves. However, while peripheral ultrasound neuromodulation has been demonstrated in vitro and in pre-clinical models, there have been few reports of clinical tests. AIM: We modified a diagnostic imaging system for ultrasound neuromodulation in human subjects. We report the first safety and feasibility outcomes in subjects with type 2 diabetes (T2D) mellitus and discuss these outcomes in relation to previous pre-clinical results. DESIGN: The study was performed as an open label feasibility study to assess the effects of hepatic ultrasound (targeted to the porta hepatis) on glucometabolic parameters in subjects with T2D. Stimulation (peripheral focused ultrasound stimulation treatment) was performed for 3 days (i.e. 15 min per day), preceded by a baseline examination and followed by a 2-week observation period. METHODS: Multiple metabolic assays were employed including measures of fasting glucose and insulin, insulin resistance and glucose metabolism. The safety and tolerability were also assessed by monitoring adverse events, changes in vital signs, electrocardiogram parameters and clinical laboratory measures. RESULTS AND CONCLUSION: We report post-pFUS trends in several outcomes that were consistent with previous pre-clinical findings. Fasting insulin was lowered, resulting in a reduction of HOMA-IR scores (P-value 0.01; corrected Wilcoxon signed-rank test). Additional safety and exploratory markers demonstrated no device-related adverse impact of pFUS. Our findings demonstrate that pFUS represents a promising new treatment modality that could be used as a non-pharmaceutical adjunct or even alternative to current drug treatments in diabetes.

Disease progression in melanoma patients with negative sentinel lymph node: does false-negative specimens entirely account for this phenomenon?

BACKGROUND: Sentinel lymph node (SLN) status is the most important prognostic factor for subjects with primary melanoma thicker than 1 mm. OBJECTIVE: We focused our study on patients with disease progression after negative SLN biopsy (SLNB), with the aim of elucidating their clinical and histopathological characteristics, outcome and real incidence of false negative. METHODS: A total of 688 melanoma patients who underwent SLNB (1 May 1998-31 December 2008) were analysed; all patients had Breslow >1 mm or Breslow <1 mm and at least one of the following features: regression, ulceration and/or Clark level IV-V. RESULTS: Progression developed in 114 of 503 negative SLN patients (22.7%); the first metastatic site was regional in 64% and distant in 36% of these cases. Thirty-nine patients had nodal metastases in the SLN basin as first site of progression. High-risk melanomas (P = 0.001) and elderly patients (P = 0.0005) had an increased probability of progression. Women with a higher median age and lower limbs primary melanoma developed mainly regional skin metastases, while an increased probability of distant metastases was demonstrated in patients with primary on the trunk and axillary SLN (P = 0.003, P = 0.001 respectively). Age at diagnosis, Breslow thickness and regression showed a prognostic relevance in univariate and multivariate analyses on disease-free survival and overall survival. CONCLUSIONS: Even if SLN status remains the most important prognostic factor for melanoma patients, progressive disease after a negative SLNB is a relatively frequent event. However, in our opinion, only a part of negative SLNB patients with metastatic spreading should be considered as false negative (7.75%).

Clinical and prognostic reports from 270 patients with multiple primary melanomas: a 34-year single-institution study.

BACKGROUND: Development of more than one primary melanoma in a sole patient is frequent, accounting for 1.2-8.2% of melanoma patients in most recent series. OBJECTIVE AND METHODS: Clinical, histological and epidemiological characteristics of 270 multiple primary melanomas patients were reviewed. RESULTS: Two-hundred and seven patients (76.7%) had two melanomas, whereas in the remaining 63 the number of primary ranged from three to eight; on the whole, 639 multiple primary melanomas were identified. Synchronous melanomas developed more frequently in patients with three or more lesions; median age was significantly lower in the group of patients with more than three melanomas than in the others. Mean Breslow's thickness significantly decreases (P<0.001) from the first (1.77±1.76 mm) to subsequent primaries (0.85±1.25 mm for the second and 0.66±0.48 mm for the third melanoma). Percentage of 'in situ' melanomas was 5.6% as first diagnosis, but increased to 24.8% for the second melanoma; number of nodular melanomas was significantly lower for succeeding diagnosis. AJCC stage at diagnosis showed a statistical prognostic significance, whereas outcome and survival did not depend on the number of primary lesions. Multivariate analysis confirmed the prognostic role of Breslow's thickness, ulceration, gender and patient age, and the better prognosis of patients with multiple melanomas, respect to those with single primary melanoma. CONCLUSIONS: Skin examination and long-term follow-up are mandatory for patients affected by melanoma, with the intent to promptly diagnose not only a disease progression but also possible new primary melanomas.

Vitiligo is an independent favourable prognostic factor in stage III and IV metastatic melanoma patients: results from a single-institution hospital-based observational cohort study.

BACKGROUND: The clinical features and the prognostic relevance of vitiligo lesions in melanoma patients are still controversial. This prospective observational study was designed to characterise the clinical features of melanoma-associated vitiligo, to analyse the association with other autoimmune manifestations and to ascertain whether the development of vitiligo lesions carries a prognostic relevance on the clinical course of melanoma. MATERIALS AND METHODS: A total of 2954 consecutive patients have been included; multivariate analyses of distant metastasis-free survival (DMFS) and overall survival (OS) were carried out to ascertain the independent prognostic role of vitiligo as a time-dependent covariate. RESULTS: Vitiligo was demonstrated in 83 of 2954 melanoma patients (2.8%). A significantly higher percentage of autoimmune diseases was demonstrated in vitiligo patients (7 of 83) with respect to patients without vitiligo (80 of 2871) (P = 0.004). Multivariate analyses selected the time-dependent covariate vitiligo as the favourable independent prognostic variable associated to a longer DMFS in stage III and a higher OS in both stage III and stage IV. CONCLUSION: Melanoma-associated vitiligo should be considered as a distinct clinical entity, separate from vitiligo vulgaris, and identifies a subgroup of patients characterised by a high prevalence of immune-mediated diseases and by a favourable prognosis.

Regulatory T cells in the skin lesions and blood of patients with systemic sclerosis and morphoea.

BACKGROUND: Systemic sclerosis (SSc) and morphoea are connective tissue diseases characterized by fibrosis of the skin. Although to date their pathogenesis has not been clearly defined, it is thought that autoimmunity may play a role in the development of the skin lesions observed in both these diseases. As regulatory T cells (Tregs) play a key role in the modulation of immune responses, it has recently been suggested that Treg impairment may lead to the development of autoimmune diseases. OBJECTIVES: To investigate the presence of Tregs and their immunomodulatory cytokines, transforming growth factor (TGF)-beta and interleukin (IL)-10, in patients with SSc and morphoea. PATIENTS/METHODS: Fifteen patients with SSc and 15 with morphoea were enrolled. Immunohistochemistry was applied to identify FoxP3+ (forkhead/winged helix transcription factor) Tregs, TGF-beta+ cells and IL-10+ cells in the skin, cytofluorometry to detect CD4+CD25+FoxP3+ Tregs in the blood, and enzyme-linked immunosorbent assays to analyse TGF-beta and IL-10 serum levels. RESULTS: Fewer FoxP3+ Tregs and TGF-beta+ and IL-10+ cells were found in the skin of patients with scleroderma than in controls. Similarly, there were reduced TGF-beta and IL-10 serum levels and fewer circulating CD4+CD25brightFoxP3+ cells in patients with SSc or morphoea, than in controls. CONCLUSIONS: The quantitative reduction of Tregs, together with that of TGF-beta and IL-10 serum levels, may be responsible for the loss of tolerance observed in both SSc and morphoea.

Electrochemotherapy with intravenous bleomycin in the local treatment of skin melanoma metastases.

BACKGROUND: Electrochemotherapy (ECT) combines chemotherapy and electroporation to increase drug uptake. Its role in cutaneous melanoma metastasis treatment is not well defined; indeed, few studies have been reported, without complete follow-up data. AIM: To prospectively evaluate clinical activity and tolerability of ECT with i.v. bleomycin, and to analyze the response increase associated to repeated sessions, in the largest series of cutaneous melanoma metastases reported to date (n = 233). PATIENTS AND METHODS: 14 stage III relapsed/refractory patients were enrolled according to European Standard Operating Procedures of Electrochemotherapy (ESOPE) guidelines and treated under general sedation using the Cliniporator(TM) pulse generator. RESULTS: A response was obtained in 13/14 patients (93%) after the first ECT, with a complete regression (CR) in 7 (50%). Seven patients underwent a second and three a third ECT on newly appearing and residual lesions, all achieving a response. Overall, a response was obtained in 93% metastases, with lower response rates in >1 cm(2) lesions. The CR rate was 58%; none of the CR nodules relapsed. The repeated ECT sessions gave rise to a new response in 21/29 (72%) re-treated lesions. The local tumor control rate was 74.5% at 2 years. CONCLUSION: ECT is a safe procedure, easily performed in terms of toxicities and cost-effectiveness ratios, and constitutes a therapeutic tool for relapsed/refractory cutaneous melanoma patients. The repeated ECT sessions are associated with a response increase in re-treated lesions which could allow to overcome the reduced activity in >1 cm(2) sized metastases.