Martina Sanlorenzo

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

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.

Association of Histologic Regression in Primary Melanoma With Sentinel Lymph Node Status: A Systematic Review and Meta-analysis

Importance The prognostic significance of regression in primary melanoma has been debated for many years. There is no consensus regarding the need for sentinel lymph node (SLN) biopsy when regression is present within the primary tumor. Objective To review the evidence that regression may affect SLN status. Data Sources A systematic review was performed by searching in MEDLINE, Scopus, and the Cochrane Library from January 1, 1990, through June 2014. Study Selection All studies that reported an odds ratio (OR) or data on expected and observed cases of SLN positivity and histologic regression were included. Data Extraction and Synthesis Primary random-effects meta-analyses were used to summarize ORs of SLN positivity and histologic regression. Heterogeneity was assessed using the χ2 test and I2 statistic. To assess the potential bias of small studies, we used funnel plots, the Begg rank correlation test, and the Egger weighted linear regression test. The methodologic quality of the studies was assessed according to the Strengthening of Reporting of Observational studies in Epidemiology (STROBE) checklist, and 2 different meta-analyses were performed based on those criteria. Main Outcomes and Measures Summary ORs of histologic regression of primary melanoma and SLN status. Results Of the 1509 citations found in the search, 94 articles were reviewed, and 14 studies comprising 10 098 patients were included in the analysis. In the combined 14 studies, patients with regression had a lower likelihood to have SLN positivity (OR, 0.56; 95% CI, 0.41-0.77) than patients without regression. On the basis of study quality, we found that patients with regression enrolled in high-quality studies had a lower likelihood to have SLN positivity (OR, 0.48; 95% CI, 0.32-0.72) compared with results of low-quality studies (OR, 0.73; 95% CI, 0.53-1.00). Examination of the funnel plot did not provide evidence of publication bias. Conclusions and Relevance The results of this analysis showed that the risk of SLN positivity was significantly lower in patients with histologic regression compared with those without. Regression may be used in these cases to make a selection of which patients should be the most appropriate for this procedure.

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.

Risk factors related to late metastases in 1,372 melanoma patients disease free more than 10 years

In many centers, Stage I–II melanoma patients are considered “cured” after 10 years of disease‐free survival and follow‐up visits are interrupted. However, melanoma may relapse also later. We retrospectively analyzed a cohort of 1,372 Stage I–II melanoma patients who were disease‐free 10 years after diagnosis. The aim of this study was to characterize patients who experienced a late recurrence and to compare them to those who remained disease‐free to identify possible predictive factors. Multivariate Cox proportional‐hazards regression analyses were carried out to evaluate the influence of different factors on the risk of recurrence. Seventy‐seven patients out of 1,372 (5.6%) relapsed, 52 in regional sites and 25 in distant ones. The majority of patients (31 out of 52) experienced late recurrence in regional lymph nodes. Brain and lung were the most common site of single distant recurrence (24% each). Patients with multiple distant metastases showed a brain and lung involvement in, respectively, 40 and 48% of cases. A Cox proportional‐hazards regression model analysis showed the independent role of age under 40 years, Breslow thickness >2 mm, and Clark Level IV/V in increasing the risk of Late Recurrence. These patients should be followed‐up for longer than 10 years. The pattern of recurrence suggests that melanoma cells can be dormant preferentially in lymph nodes, brain and lung. A particular attention should be reserved to these anatomic sites during the follow‐up after 10 years of disease‐free.

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

No data are available as to the phenotype of circulating lymphocyte subsets in pyoderma gangrenosum (PG).

Cytokine-Induced Killer Cells Kill Chemo-surviving Melanoma Cancer Stem Cells

Purpose: The MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSC) was explored, as CSCs are considered responsible for chemoresistance and relapses. Experimental Design: Putative mCSCs were visualized by engineering patient-derived melanoma cells (MC) with a lentiviral vector encoding eGFP under expression control by stemness gene promoter oct4. Their stemness potential was confirmed in vivo by limiting dilution assays. We explored the sensitivity of eGFP+ mCSCs to chemotherapy (CHT), BRAF inhibitor (BRAFi) or CIK cells, as single agents or in sequence, in vitro. First, we treated MCs in vitro with fotemustine or dabrafenib (BRAF-mutated cases); then, surviving MCs, enriched in mCSCs, were challenged with autologous CIK cells. CIK cell activity against chemoresistant mCSCs was confirmed in vivo in two distinct immunodeficient murine models. Results: We visualized eGFP+ mCSCs (14% ± 2.1%) in 11 MCs. The tumorigenic precursor rate in vivo was higher within eGFP+ MCs (1/42) compared with the eGFP− counterpart (1/4,870). In vitro mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells (n = 11, 8/11 autologous), with specific lysis ranging from 95% [effector:tumor ratio (E:T), 40:1] to 20% (E:T 1:3). In vivo infusion of autologous CIK cells into mice bearing xenografts from three distinct melanomas demonstrated significant tumor responses involving CHT-spared eGFP+ mCSCs (P = 0.001). Sequential CHT–immunotherapy treatment retained antitumor activity (n = 12, P = 0.001) reducing mCSC rates (P = 0.01). Conclusions: These findings are the first demonstration that immunotherapy with CIK cells is active against autologous mCSCs surviving CHT or BRAFi. An experimental platform for mCSC study and rationale for CIK cells in melanoma clinical study is provided. Clin Cancer Res; 23(9); 2277–88. ©2016 AACR.

Melanoma of the lower extremities: foot site is an independent risk factor for clinical outcome

Despite the better prognosis of melanomas localized on lower extremities, some studies have suggested that melanomas on the foot are related to a poorer survival and should be considered separately.

Efficacy of electrochemotherapy for eruptive legs keratoacanthomas.

Generalized eruptive keratoacanthoma, is considered a serious condition because the eruptions are diffuse, persistent, and recurrent. Constant pruritus, visceral neoplasms, and unsatisfactory response to treatment are ominous prognostic factors. Even if skin cancers are usually well controlled with surgical and/or radiotherapic approaches, there are some cases in which these two techniques are not effective. With respect to surgery, radiotherapy and other standard treatments, ECT acts rapidly on multiple lesions with limited side effects and no functional impairment; moreover, repeated sessions can be performed to achieve or maintain the clinical response. We report a case of generalized eruptive keratoacanthomas in which electrochemotherapy was effective in inducing local regression of skin lesions. A 72‐year‐old woman with eruptive and painful keratoacanthomas for 3 months on both the lower limbs in which the conventional treatments could not be cosmetically acceptable. One session of electrochemotherapy with bleomycin sulfate was then performed on all isolated skin lesions. The treatment was well tolerated and led to a rapid clinical regression of the treated lesions. Use of ECT should be considered as an excellent alternative to current therapies in treatment of painful eruptive keratoacanthomas with a significant improvement of quality of life.

BRAF and MEK inhibitors increase PD1-positive melanoma cells leading to a potential lymphocyte-independent synergism with anti-PD1 antibody

Purpose: BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti–PD-1 antibody. A portion of melanoma cells may express PD-1, and anti–PD-1 antibody could have a direct antitumor effect. Here, we explore whether BRAF/MEKi modulate rates of PD-1+ melanoma cells, supporting an additional—lymphocyte-independent—basis for their therapeutic combination with anti–PD-1 antibody. Experimental Design: With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, N = 61; validation cell lines, N = 7) and melanoma tumors (TCGA, N = 214). We explored in vitro how BRAF/MEKi affect rates of PD-1+, PD-L1/2+ melanoma cells, and characterized the proliferative and putative stemness features of PD-1+ melanoma cells. We tested the functional lymphocyte-independent effect of anti–PD-1 antibody alone and in combination with BRAF/MEKi in vitro and in an in vivo immunodeficient murine model. Results: PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1+ cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6–14.2) vs. 1.5% (0.7–3.2), P = 0.0156; N = 7], together with PD-L2+ melanoma cells [8.5% (0.0–63.0) vs. 1.5% (0.2–43.3), P = 0.0312; N = 7]. PD-1+ cells proliferate less than PD-1− cells (avg. 65% less; t = 7 days) and are preferentially endowed with stemness features. In vivo, the direct anti-melanoma activity of PD-1 blockage as monotherapy was negligible, but its association with BRAF/MEKi significantly delayed the development of drug resistance and tumor relapse. Conclusions: BRAF/MEKi increase the rates of PD-1+ melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti–PD-1 antibody. Clin Cancer Res; 24(14); 3377–85. ©2018 AACR.

Apremilast in psoriasis – a prospective real-world study

Apremilast is a novel oral phosphodiesterase‐4 inhibitor approved for psoriasis treatment. Randomized trials have documented its efficacy and safety, but data on real‐world patients are scarce.