Real-Life Outcomes of Adjuvant Targeted Therapy and Anti-PD1 Agents in Stage III/IV Resected Melanoma.

This study was carried out at the Dermatologic Clinic of the University of Turin, Italy, to assess the effectiveness and safety of adjuvant therapy in patients who received either targeted therapy (TT: dabrafenib + trametinib) or immunotherapy (IT: nivolumab or pembrolizumab) for up to 12 months. A total of 163 patients participated, including 147 with stage III and 19 with stage IV with no evidence of disease. The primary outcomes were relapse-free survival (RFS), distant metastasis-free survival (DMFS), and overall survival (OS). At 48 months, both TT and IT approaches yielded comparable outcomes in terms of RFS (55.6-55.4%, p = 0.532), DMFS (58.2-59.8%, p = 0.761), and OS (62.4-69.5%, p = 0.889). Whilst temporary therapy suspension was more common among TT-treated patients compared to IT-treated individuals, therapy discontinuation due to adverse events occurred at comparable rates in both groups. Predictors of relapse included mitoses, lymphovascular invasion, ulceration, and positive sentinel lymph nodes. Overall, the proportion of BRAF-mutated patients receiving IT stood at 7.4%, lower than what was observed in clinical trials.

Treatment Patterns and Outcomes of Stage III Melanoma Patients with Positive Sentinel Lymph Node Biopsy: A Real-Life Experience.

Background: Advancements in managing stage III melanoma have involved the implementation of adjuvant therapies alongside a simultaneous decrease in the utilization of completion lymph node dissection (CLND) following positive sentinel node biopsy (SLNB). Methods: This retrospective study from the University of Turin's Dermatology Clinic analyzed relapse-free survival (RFS) and overall survival (OS) among stage III melanoma patients (n = 157) who underwent CLND after positive SLNB versus those who did not receive such procedure. Results: Patients without CLND had a median RFS of 49 months (95% CI 42-NA), while CLND recipients showed 51 months (95% CI 31-NA) (p = 0.139). The 48-month OS for non-CLND patients was 79.8% (95% CI 58.2-91.0) versus 79.2% (95% CI 67.5-87.0) for CLND recipients (p = 0.463). Adjusted Hazard Ratios through inverse probability treatment weighting revealed the impact of CLND to be insignificant on RFS (aHR 0.90, 95% CI 0.37-2.22) and marginal on OS (aHR 0.41, 95% CI 0.13-1.21). Conversely, adjuvant therapy significantly reduced the risk of relapse (aHR 0.46, 95% CI 0.25-0.84), irrespective of CLND. Conclusions: This study corroborates the growing evidence that CLND after positive SLNB does not enhance RFS or OS, while emphasizing the crucial role of adjuvant therapy, be it immunotherapy or targeted therapy, in reducing the risk of relapse in melanoma patients with positive SLNB.

Cutaneous T-cell Lymphoma Diagnostic and Therapeutic Trends amidst the COVID-19 Pandemic.

is missing (Short communication).

Advances in the pharmacological management of cutaneous T-cell lymphoma.

INTRODUCTION: Current treatment guidelines for cutaneous T cell lymphoma (CTCL) advocate a stage-driven approach, considering clinical presentation, symptom burden, and patient comorbidities. Therapy selection hinges on factors like disease subtype, severity, and treatment availability. The primary goal is to enhance the quality of life by mitigating symptoms, as achieving lasting complete remission is infrequent. AREAS COVERED: Over the past decade (2013-2023), the therapeutic landscape of CTCL has experienced substantial transformation with the introduction of innovative therapies. This review explores the main pivotal developments in traditional treatment schedules and recently introduced drugs, aiming to offer clinicians and researchers a thorough perspective on the decade's progress in the field. EXPERT OPINION: Despite the progress made in CTCL therapeutics, ranging from topical chemotherapeutics to immunomodulatory agents, several unmet needs persist. Firstly, there is a pressing need for the incorporation of readily available predictors for treatment response, encompassing clinical, pathological, and molecular features. Secondly, a more profound comprehension of the tumor microenvironment is imperative to optimize the landscape of targetable molecules. Lastly, the undertaking of studies on combination regimens should be encouraged as it enhances therapy efficacies by synergistically combining agents with diverse modes of action.

Eosinophilic Dermatosis of Hematologic Malignancy: Emerging Evidence for the Role of Insect Bites-A Retrospective Clinico-Pathological Study of 35 Cases.

Background/Objectives: Eosinophilic dermatosis of hematologic malignancy (EDHM) is a rare cutaneous disorder associated with various hematologic malignancies, most commonly chronic lymphocytic leukemia. Detailed clinicopathologic studies of EDHM are lacking and the pathogenesis remains enigmatic. Initially thought to be a hypersensitivity reaction to insect stings, subsequent reports have challenged this understanding. The prognostic implications of EDHM remain unclear. Methods: A retrospective clinicopathologic study was performed on patients diagnosed with EDHM. Hematologic and dermatologic data were reviewed. Histologic specimens were re-evaluated and lesions were classified into acute/subacute, fully developed, and chronic/regressing. Results: The study included 35 patients. In 80% of these patients, EDHM was diagnosed after the hematologic disorder. Approximately 45% of the cohort experienced hematologic disease progression or relapse, while 65% required therapeutic intervention during the course of their hematologic disease. In total, 15/19 CLL patients had non-mutated IgHV, a marker of a more aggressive hematologic disease course. Dermatologic lesion morphology was heterogeneous, with most lesions occurring on exposed areas, and a significant 94% of patients demonstrated lesion seasonality. Histopathologic findings were consistent with features typically associated with insect bites. In addition, examination of lesions at different chronological stages revealed substantial similarities with Wells syndrome. Conclusions: Our findings support the potential role of insect bites in triggering EDHM in the context of adaptive immune dysfunction. EDHM may be associated with a more aggressive disease course or may be a marker of disease progression. The observed co-occurrence of features typical of Wells syndrome in EDHM patients suggests that these conditions are part of a spectrum of disorders that vary in clinical expression.

Prognostic biomarkers in melanoma: a 2023 update from clinical trials in different therapeutic scenarios.

INTRODUCTION: Over the past decade, significant advancements in the field of melanoma have included the introduction of a new staging system and the development of immunotherapy and targeted therapies, leading to changes in substage classification and impacting patient prognosis. Despite these strides, early detection remains paramount. The quest for dependable prognostic biomarkers is ongoing, given melanoma's unpredictable nature, especially in identifying patients at risk of relapse. Reliable biomarkers are critical for informed treatment decisions. AREAS COVERED: This review offers a comprehensive review of prognostic biomarkers in the context of clinical trials for immunotherapy and targeted therapy. It explores different clinical scenarios, including adjuvant, metastatic, and neo-adjuvant settings. Key findings suggest that tumor mutational burden, PD-L1 expression, IFN-γ signature, and immune-related factors are promising biomarkers associated with improved treatment responses. EXPERT OPINION: Identifying practical prognostic factors for melanoma therapy is challenging due to the tumor's heterogeneity. Promising biomarkers include tumor mutational burden (TMB), circulating tumor DNA, and those characterizing the tumor microenvironment, especially the immune component. Future research should prioritize large-scale, prospective studies to validate and standardize these biomarkers, emphasizing clinical relevance and real-world applicability. Easily accessible biomarkers have the potential to enhance the precision and effectiveness of melanoma management.

Immunotherapy in cutaneous melanoma and biologics in psoriatic disease: similarities and differences from a clinical multidisciplinary perspective.

INTRODUCTION: Immunomodulating therapies harness the power of the immune system to combat disease. In advanced melanoma, immune checkpoint inhibitors have significantly improved survival outcomes by activating the immune system to recognize and eliminate cancer cells. In psoriasis, interleukin inhibitors effectively suppress inflammation and improve disease symptoms. AREAS COVERED: We provide a meta-opinion-based consensus paper on the analogies and differences in treatment mechanisms, duration, frequency between immunotherapy for advanced melanoma and biologics for psoriasis. Combining the current scientific evidence with expert insights, we provide valuable guidance for future research and decision-making processes. EXPERT OPINION: The development of immunological treatments in melanoma and psoriasis has revolutionized dermatology, but the quest for tailored therapies that maximize efficacy continues. Managing cutaneous exacerbations during melanoma immunotherapy in psoriatic patients remains challenging. Similarly, treating oncologic psoriasis patients resistant to traditional therapies requires individualized approaches. Research is needed to identify response predictors in both conditions and address the sustainability of healthcare systems due to the high cost of biologics. Drug delay studies for psoriasis and longer follow-up evaluations after immunotherapy discontinuation in melanoma are essential for optimizing treatment outcomes and resource allocation.

Emerging prognostic biomarkers in advanced cutaneous melanoma: a literature update.

INTRODUCTION: Over the past two years, the scientific community has witnessed an exponential growth in research focused on identifying prognostic biomarkers for melanoma, both in pre-clinical and clinical settings. This surge in studies reflects the need of developing effective prognostic indicators in the field of melanoma. AREAS COVERED: The aim of this work is to review the scientific literature on the most recent findings on the development or validation of prognostic biomarkers in melanoma, in the attempt of providing both clinicians and researchers with an updated broad synopsis of prognostic biomarkers in cutaneous melanoma. EXPERT OPINION: While the field of prognostic biomarkers in melanoma appears promising, there are several complexities and limitations to address. The interdependence of clinical, histological, and molecular features requires accurate classification of different biomarker families. Correlation does not imply causation, and adjustments for confounding factors are often overlooked. In this scenario, large-scale studies based on high-quality clinical trial data can provide more reliable evidence. It is essential to avoid oversimplification by focusing on a single biomarker, as the interactions among multiple factors contribute to define the disease course and patient's outcome. Furthermore, implementing well-supported evidence in real-life settings can help advance prognostic biomarker research in melanoma.

Predictors of Recurrence and Progression in Poorly Differentiated Cutaneous Squamous Cell Carcinomas: Insights from a Real-Life Experience.

INTRODUCTION: Surgery represents the primary treatment option for cutaneous squamous cell carcinoma (cSCC) aiming for complete tumor resection (R0). Recurrence and metastasis significantly affect survival and outcomes, and poorly differentiated (G3) cSCC is associated with a higher risk of recurrence. However, the specific clinical and histopathological features that predict recurrence and progression in G3-cSCC remain unclear. METHODS: A retrospective analysis was conducted on a series of patients with primary G3-cSCC diagnosed at the Turin University Hospital between January 2016 and January 2021. After independent histological revision, logistic regression models were used to identify clinico-pathological predictors of cutaneous recurrence, lymphnode/metastatic progression, and both types of progression. RESULTS: Among the 161 G3-cSCC patients, 80.1% (129/161) showed no signs of local recurrence or metastatic progression, while 19.9% (32 patients) had progressed. In the univariate logistic regression, tumor clinical diameter, depth of infiltration (DOI), and lymphovascular invasion (LVI) were identified as significant predictors across the various types of progression (p < 0.05). In the context of multivariate logistic regression, distinct models proved to be significant. For skin recurrence, a 3-variable model incorporating DOI (OR 1.16, 95% CI, 1.01-1.35, p = 0.050), LVI (OR 3.61, 95% CI, 1.11-11.8, p = 0.034), and desmoplasia (OR 3.45, 95% CI, 1.25-9.5, p = 0.017) was selected. Regarding lymphnode/metastatic progression, a 3-variable model combining pT2 (OR 6.10, 95% CI, 1.15-32.35, p = 0.034), pT3 (OR 14.33, 95% CI, 2.79-73.63, p = 0.001), and LVI (OR 3.86, 95% CI, 1.10-13.62, p = 0.036) was identified. Lastly, a 2-variable model for both types of progression consisted of vertical tumor thickness (OR 5.45, 95% CI, 1.11-27.32, p = 0.039) and LVI (OR 1.15, 95% CI, 1.04-1.26, p = 0.006). CONCLUSION: Tumor size, DOI, and LVI were significant predictors of recurrence and metastatic progression. Notably, the size of histologically defined tumor-free margins did not affect the risk of recurrence, whilst LVI emerged as a key predictor of all forms of progression. These findings provide insights into risk stratification and suggest that close monitoring and potential adjuvant therapies, such as radiation therapy, may be necessary especially for patients with lymphovascular involvement.

Synchronous occurrence of primary cutaneous B-cell lymphoma and cutaneous Rosai-Dorfman disease in distinct lesions: A unique association.

Rosai-Dorfman disease, also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a rare subtype of reactive histiocytosis which is seldom associated with Hodgkin's and non-Hodgkin's lymphomas. To date, the coexistence in the same patient of extra nodal SHML and primary cutaneous B-cell lymphoma (PCBCL) has been reported in the literature, as metachronous diagnosis in the anatomical area of the original PCBCL or synchronous occurrence in the same lesions. However, no data have been published as for synchronous occurrence of the two pathological entities in distinct anatomical sites. Herein, we report the first ever described synchronous occurrence of PCBCL and SHML, detected in distinct lesions, affecting the same patient. The complete resolution of the patient's PCBCL after rituximab treatment and the concomitant regression of SHML suggest that this clinically benign reactive histiocytic proliferation, potentially triggered by the lymphoma microenvironment itself, may take place not only in the site of the PCBCL lesion, but also in other distant areas not directly affected by the primary cutaneous lymphoma.

Exploring Psoriasis Inflammatory Microenvironment by NanoString Technologies.

Psoriasis is a chronic inflammatory skin disease whose molecular mechanisms and microenvironment are poorly understood. We performed gene expression analysis through the nCounter® PanCancer Immune Profiling Panel (NanoString Technologies, Seattle, WA, USA) on 22 FFPE punch biopsies from 19 psoriasis-affected patients. A subset of five cases was analyzed before (T0) and after 6 months (T6) of treatment with dimethyl fumarate (DMF) to address immune microenvironment changes. Molecular comparisons according to biopsy site and age of onset showed a different distribution of innate immune cells (mast cells, macrophages, NK cells, and DC cells) and pathways (complement regulation and transporter functions). The analysis according to PASI (Psoriasis Area and Severity Index) led to non-significant results, suggesting no link between molecular expression profile and clinical amount of skin disease. In DMF-treated patients, we observed a strong immunomodulatory effect after treatment: A subversion of exhausted CD8 T cells, NK CD56dim cells, Tregs, neutrophils, CD45+ cells, T cells, B cells, and macrophages was reported between the two analyzed time-points, as well as the reduction in pro-inflammatory pathways and molecules, including cytotoxicity, pathogen defense, antigen processing, adhesion, cell cycle, chemokines, cytokines, and interleukins. The inflammatory psoriatic microenvironment can be modulated using DMF with encouraging results, achieving an immune-tolerant and non-inflammatory condition through the regulation of both innate and adaptive immunity.

Phenotypic and Dermoscopic Patterns of Familial Melanocytic Lesions: A Pilot Study in a Third-Level Center.

Cutaneous melanoma is a highly aggressive skin cancer. It is estimated that 5% to 10% of the underlying mutations are hereditary and responsible for familial (or hereditary) melanoma. These patients are prone to the early development and higher risk of multiple melanomas. In recent years, an increasing number of genes have been identified thanks to genetic testing, allowing the subsequent surveillance of individuals at risk, yet it is still difficult to predict the presence of these mutations on a clinical basis. In this scenario, specific phenotypic and dermoscopic features could help clinicians in their identification. The aim of this work has been to correlate mutations to prevalent dermoscopic patterns, paving the way for reference models useful in clinical practice. In our cohort, out of 115 patients referred to genetic counseling for melanoma, 25 tested positive (21.7%) for critical mutations: CDKN2A (n = 12), MITF (n = 3), BAP1 (n = 1), MC1R (n = 3), PTEN (n = 1), TYR (n = 2), OCA2 (n = 1), and SLC45A2 (n = 2). The phenotype profiles obtained through the digital acquisition, analysis, and description of both benign and malignant pigmented lesions showed a predominance of the type II skin phenotype, with an elevated mean total nevus number (182 moles, range 75-390). As for dermoscopic features, specific mutation-related patterns were described in terms of pigmentation, areas of regression, and vascular structures. Although further studies with larger cohorts are needed, our work represents the beginning of a new approach to the study and diagnosis of familial melanoma, underlining the importance of clinical and dermoscopic patterns, which may constitute a reference model for each gene, enabling comparison.

Dermoscopic predictors of melanoma in small diameter melanocytic lesions (mini-melanoma): a retrospective multicentric study of 269 cases.

BACKGROUND: Incidence of cutaneous melanoma is steadily growing, and its early recognition is of paramount importance. Small, pigmented lesions often represent a challenge for the clinician, as predictors of melanoma have not yet been uniquely identified in this setting. OBJECTIVES: To identify dermoscopic features that aid in distinguishing small diameter melanomas (≤5 mm) from equivocal melanocytic nevi measuring ≤5 mm. METHODS: A retrospective multicenter study was conducted to collect demographics, clinical and dermoscopic pictures of (i) histology-proven flat melanomas, measuring ≤5 mm, (ii) histology-proven but clinically/dermoscopically equivocal melanocytic nevi measuring ≤5 mm, and (iii) histology-proven flat melanomas, measuring >5 mm. An independent dermoscopic evaluation was performed. Differences in predefined dermoscopic features were assessed across the three groups. RESULTS: A total of 103 melanomas measuring ≤5 mm were collected; 166 control lesions, comprising 85 large (>5 mm) melanomas and 81 dubious, clinically equivocal melanocytic nevi measuring ≤5 mm were included. Of the 103 mini-melanomas, only 44 were melanoma in situ. Five dermoscopic predictors of melanoma were identified for the assessment of flat, non-facial melanocytic lesions measuring ≤5 mm, namely: atypical pigment network, blue-white veil, pseudopods, peripheral radial streaks, and presence of more than one color. The latter were combined into a predictive model capable of identifying melanoma with 65% sensitivity and 86.4% specificity, at a cut-off score of 3. Among melanomas measuring ≤5 mm, presence of a blue-white veil (P = 0.0027) or negative pigment network (P = 0.0063) was associated with invasiveness. CONCLUSION: A set of five dermoscopic predictors of melanoma, atypical pigment network, blue-white veil, pseudopods, peripheral radial streaks, and presence of more than one color is proposed for the assessment of flat, non-facial melanocytic lesions measuring ≤5 mm.

Obesity and immune-checkpoint inhibitors in advanced melanoma: A meta-analysis of survival outcomes from clinical studies.

Obesity is a chronic inflammatory condition that has been associated with different types of cancer. However, its role in melanoma incidence, progression, and response to immune-checkpoint-inhibitors (ICI) is still controversial. On the one hand, increased levels of lipids and adipokines can promote tumor proliferation and several genes associated with fatty acid metabolism have been found to be upregulated in melanomas. On the other hand, immunotherapy seems to be more effective in obese animal models, presumably due to an increase in CD8 + and subsequent decrease in PD-1 + T-cells in the tumor microenvironment. In humans, several studies have investigated the role of BMI (body mass index) and other adiposity-related parameters as potential prognostic markers of survival in advanced melanoma patients treated with ICI. The aim of this research has been to systematically review the scientific literature on studies evaluating the relationship between overweight/obesity and survival outcomes in patients with advanced melanoma treated with ICI and to perform a meta-analysis on those sharing common characteristics. After screening 1070 records identified through a literature search, 18 articles assessing the role of BMI-related exposure in relation to survival outcomes in ICI-treated patients with advanced melanoma were included in our review. In the meta-analysis of the association between overweight (defined as BMI>25 or BMI 25-30), overall survival (OS), and progression free survival (PFS), 7 studies were included, yielding a summary HR of 0.87 (95% CI: 0.74-1.03) and 0.96 (95% CI: 0.86-1.08), respectively. Our results show that, despite few suggestive findings, the use of BMI as a valuable predictor of melanoma patients' survival in terms of PFS and OS should not be currently recommended, due to the limited evidence available.