Management of melanoma patients during COVID-19 pandemic in an Italian skin unit.

Due to the COVID-19 crisis, many scheduled medical and surgical activities have been suspended. This interruption to the healthcare system can negatively affect the diagnosis and management of melanoma. Neglecting melanoma throughout the outbreak may be associated with increased rates of mortality, morbidity, and healthcare expenses. We performed a retrospective review of all dermatological and surgical activity performed in our Melanoma Skin Unit between 23 February 2020 and 21 May 2020 and compared these data with those from the same period in 2019. During the lockdown period, we observed a decrease in dermatologic follow-up (DFU) (-30.2%) and in surgical follow-up (SFU) (-37%), and no modification of melanoma diagnosis (-3%). Finally, surgical excisions (SE) (+ 31.7%) increased, but sentinel lymph node biopsy (SLNB) (-29%) and lymph node dissections(LND) (-64%) decreased compared to the same period in 2019. Our experience supports the continuation of surgical and diagnostic procedures in patients with melanoma during the COVID-19 pandemic. Surgical and follow-up procedures for the diagnosis and treatment of melanoma should not be postponed considering that the pandemic is lasting for an extended period.

Electrochemotherapy Treatment in a Patient with an Extended Basal Cell Carcinoma of the Face: A Case Report.

BACKGROUND: Basal cell carcinomas (BCCs) are common human malignancies with a rising incidence in recent years. While BCCs have a low mortality rate, they are often associated with significant local skin damage characterized by erythema, skin ulceration, and persistent pigmentation. Surgery, radiotherapy, and systemic chemotherapy have traditionally been the principal treatments for these skin injuries. However, electrochemotherapy has recently been proposed as a novel local treatment with promising results for various skin cancers, including BCC, while avoiding the side effects of conventional therapies. ECT involves a local electrical stimulus that enhances cell membrane permeability, thereby enabling the targeted intracellular accumulation of the chemotherapeutic agent. CASE REPORT: We report a case of a 68-year-old man with an ulcerated BCC, following his progress up to 14 months post-ECT treatment, with positive outcomes. DISCUSSION AND CONCLUSIONS: We achieved a complete clinical response and noted an improvement in the patient's quality of life. This technique is fast, repeatable, requires minimal hospitalization, and reduces healthcare costs and adverse effects compared to major surgery. Therefore, it can be considered an alternative or complementary approach to traditional surgery for treating BCC of the head and neck.

Isolated Limb Perfusion and Immunotherapy in the Treatment of In-Transit Melanoma Metastases: Is It a Real Synergy?

BACKGROUND: Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT), such as immune checkpoint inhibitors, has changed the treatment landscape. METHODS: This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease-specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien-Dindo classification. Response to locoregional therapy was evaluated during follow-up according to the RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor). RESULTS: A total of 99 patients were treated with ILP and 88 with IT + ILP. The overall response rate was 67% in both groups. At 36 months, OS was 43% in the ILP group and 61% in the ILP + IT group (p = 0.02); DSS was 43% in the ILP group and 64% in the ILP + IT group (p = 0.02); local DFS was the 37% in ILP group and 53% in the ILP + IT group (p = 0.04); and distant DFS was 33% in the ILP group and 35% in the ILP + IT group (p = 0.40). Adjusting for age and lymph node involvement, receiving ILP + IT was associated with improved OS (p = 0.01) and DSS (p = 0.007) but not local DFS (p = 0.13) and distant DFS (p = 0.21). CONCLUSIONS: Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments and address the best timing of this combination to obtain the highest local response rate.

Therapeutic Treatment Options for In-Transit Metastases from Melanoma.

In-transit metastases (ITM) in melanoma present a significant therapeutic challenge due to their advanced stage and complex clinical nature. From traditional management with surgical resection, ITM treatment has evolved with the advent of systemic therapies such as immune checkpoint inhibitors and targeted therapies, which have markedly improved survival outcomes. This study aims to review and highlight the efficacy of both systemic and locoregional treatment approaches for ITM. Methods include a comprehensive review of clinical studies examining the impact of treatments like immune checkpoint inhibitors, targeted therapies, Isolated Limb Perfusion, and electrochemotherapy. The results indicate that combining systemic therapies with locoregional treatments enhances both local disease control and overall survival rates. The introduction of modern immunotherapies has not diminished the effectiveness of locoregional therapies but rather improved patient outcomes when used in conjunction. The conclusions emphasize that a multidisciplinary approach integrating systemic and locoregional therapies offers a promising strategy for optimizing the management of ITM in melanoma patients. This integrated treatment model not only improves survival rates but also enhances the quality of life for patients, suggesting a shift in standard care practices toward more comprehensive therapeutic regimens.

Kaposi's Sarcoma: Evaluation of Clinical Features, Treatment Outcomes, and Prognosis in a Single-Center Retrospective Case Series.

Kaposi's sarcoma (KS) is a rare angioproliferative tumor classified in four different clinical-epidemiological forms. The diagnosis is based on histopathological and immunohistochemical analyses. The treatment is heterogeneous and includes several local and systemic therapeutic strategies. Methods: This is a retrospective cohort study including 86 KS patients treated between 1993 and 2022 at the University Hospital of Padua (AOPD) and at the Veneto Institute of Oncology (IOV). The data were extracted from an electronic database. Survival curves were generated using the Kaplan-Meier method, and Cox regression models were employed to explore associations with overall and disease-free survival. The male sex (89.53%), classical variant (43.02%), and cutaneous involvement (77.9%) were predominant. More than 61.6% of patients received a single treatment. Surgery, antiretroviral therapy, and chemotherapy were the mostly adopted approaches. A persistent response was observed in approximately 65% of patients, with a 22% relapse rate (at least 2 years). The overall survival ranges from 90 to 70% at 2 to 10 years after the diagnosis. Iatrogenic KS demonstrated a higher mortality (52.9%). This study reflects our experience in the management of KS. Comorbidities are very frequent, and treatments are heterogeneous. A multidisciplinary approach involving multiple referral specialists is essential for the appropriate management of this disease during diagnosis, treatment, and follow-up.

Do Tumor SURVIVIN and MDM2 Expression Levels Correlate with Treatment Response and Clinical Outcome in Isolated Limb Perfusion for In-Transit Cutaneous Melanoma Metastases?

Isolated limb perfusion (ILP) involves the local administration of high doses of anticancer drugs into a limb affected by unresectable locally advanced tumors (with special regard to in-transit melanoma metastases), minimizing systemic side effects. Tumor response to anticancer drugs may depend on the expression of apoptosis-related genes, such as SURVIVIN and MDM2. This retrospective cohort study investigated the association between tumor SURVIVIN and MDM2 expression levels and treatment response or clinical outcomes in patients undergoing ILP for in-transit melanoma metastases. The study cohort consisted of 62 patients with in-transit metastases who underwent ILP with tumor necrosis factor (TNF) and melphalan. Tissue samples were taken from the in-transit metastases, and RNA was extracted for gene expression analysis. Patients' response to treatment was assessed using clinical and radiological criteria two months after ILP, and disease response was classified as complete, partial, or stable/progressive disease. Disease-free survival (DFS) and overall survival (OS) were also analyzed. Expression of SURVIVIN and/or MDM2 was observed in 48% of patients; in these cases, complete response to ILP occurred in 40% of cases, with the overall response rate (complete + partial) being 85%. Patients with expression of MDM2 alone had a lower complete response rate (28%), while patients with expression of SURVIVIN alone had a higher complete response rate (50%). The combined expression of MDM2 and SURVIVIN resulted in a complete response rate of 30%. Patients without expression (of SURVIVIN or MDM2) had the highest complete response rate (58%). Survival analysis showed that high MDM2 expression was independently associated with a lower probability of a complete response to ILP. In addition, patients with MDM2 expression were three times more likely to have an incomplete response to ILP. This study highlights the importance of considering SURVIVIN and MDM2 expression in patients undergoing ILP for in-transit cutaneous melanoma metastases. High MDM2 expression was found to be an independent factor associated with a reduced likelihood of achieving a complete response to ILP, suggesting potential mechanisms of chemoresistance. These data support further research to explore the role of already available targeted therapies (i.e., MDM2 inhibitors) in improving tumor response to ILP in patients with in-transit melanoma metastases.

Efficacy of Electrochemotherapy in Breast Cancer Patients of Different Receptor Status: The INSPECT Experience.

Electrochemotherapy has been proven to be an efficient treatment for cutaneous metastases of various cancers. Data on breast cancer (BC) patients with cutaneous metastases were retrieved from the INSPECT database. Patients were divided by their receptor status: HER2+, HR+ (ER/PgR+), and TN (triple negative). Groups were similar for histological subtype and location of the nodules. Most patients were previously treated with surgery/systemic therapy/radiotherapy. We found no differences in the three groups in terms of response ratio (OR per patient 86% HER2+, 80% HR+, 76% TN, p = 0.8664). The only factor positively affecting the complete response rate in all groups was small tumor size (<3 cm, p = 0.0105, p = 0.0001, p = 0.0266, respectively). Local progression-free survival was positively impacted by the achievement of complete response in HER2+ (p = 0.0297) and HR+ (p = 0.0094), while overall survival was affected by time to local progression in all groups (p = 0.0065 in HER2+, p < 0.0001 in HR+, p = 0.0363 in TN). ECT treatment is equally effective among groups, despite different receptor status. Response and local tumor control seem to be better in multiple small lesions than in big armor-like lesions, suggesting that treating smaller, even multiple, lesions at the time of occurrence is more effective than treating bigger long-lasting armor-like cutaneous lesions.

Bleomycin-based electrochemotherapy for the treatment of a Buschke-Löwenstein tumor (perianal giant condyloma) in an HIV-positive kidney transplant recipient: A case report.

The Buschke-Löwenstein tumor (BLT), also known as giant condyloma acuminatum, is a rare sexually transmitted disease often associated with human papillomavirus types 6 and 11. There are no specific guidelines for treating BLT. Surgery is the preferred treatment, although it can have profound consequences on a patient's quality of life. A 41-year old male, who was HIV-positive and a kidney transplant recipient treated with cyclosporine, was referred to the Veneto Institute of Oncology (Soft-Tissue, Peritoneum and Melanoma Surgical Oncology Unit) after a two-year history of perianal warts that always relapsed after surgical treatment. A multidisciplinary evaluation was conducted to assess an individually tailored treatment plan. Tailored bleomycin-based electrochemotherapy (ECT) was proposed in order to achieve local disease control and preserve kidney function. A total of three cycles of ECT with a 25%-reduced dose of intravenous bleomycin (11,250 IU/m2) were administered, and a complete response was achieved 20 months after the final ECT session.

Electrochemotherapy for the treatment of cutaneous squamous cell carcinoma: The INSPECT experience (2008-2020).

Introduction: Cutaneous squamous cell carcinoma (cSCC) is a frequent skin cancer with a high risk of recurrence characterized by tumor infiltration and, in advanced cases, a poor prognosis. ECT (electrochemotherapy) is an alternative treatment option for locally advanced or recurrent cSCC that is unsuitable for surgical resection. In this study, we aimed to evaluate the data in the InspECT (International Network for Sharing Practice on ECT) registry of the referral centers and to clarify the indications for the use of ECT as a treatment modality for cSCC. Materials and methods: Patients with primary, recurrent or locally advanced cSCC from 18 European centers were included. They underwent at least one ECT session with bleomycin between February 2008 and November 2020, which was performed following the European Standard Operating Procedures. Results: The analysis included 162 patients (mean age of 80 years; median, 1 lesion/patient). Side effects were mainly local and mild (hyperpigmentation, 11%; ulceration, 11%; suppuration, 4%). The response to treatment per patient was 62% complete and 21% partial. In the multivariate model, intravenous drug administration and small tumor size showed a significant association with a positive outcome (objective response). One-year local progression-free survival was significantly better (p<0.001) in patients with primary tumors (80% (95% C.I. 70%-90%) than in patients with locally advanced disease (49% (95% C.I. 30%-68%). Conclusion: In the present study, ECT showed antitumor activity and a favorable safety profile in patients with complex cSCC for whom there was no widely accepted standard of care. Better results were obtained in primary and small tumors (<3 cm) using intravenous bleomycin administration.

The Role of Electrochemotherapy in the Cutaneous and Subcutaneous Metastases From Breast Cancer: Analysis of Predictive Factors to Treatment From an Italian Cohort of Patients.

The treatment of cutaneous and subcutaneous localizations from breast cancer (BC) is still a therapeutic challenge. Electrochemotherapy (ECT) is one of the available options, and it is characterized by the association between the administration of a chemotherapic agent (Bleomycin) with the temporary raise of permeability of the cellular membrane induced by the local administration of electrical impulses (electroporation). ECT represents an effective therapy for loco-regional control of this disease. This study aimed to investigate the predictive factors of response in cutaneous and subcutaneous localizations from breast cancer treated with ECT. We decided to evaluate the response to this treatment in 55 patients who underwent ECT between January 2013 and March 2020 at our Institute. We performed a monocentric retrospective cohort study. ECT was administered following the ESOPE (European Standard Operative Procedure of Electrochemotherapy) guidelines, a set of criteria updated in 2018 by a panel of European experts on ECT who defined the indications for selecting the patients who can benefit from the ECT treatment and the ones for technically performing the procedure. The responses were evaluated with the RECIST criteria (Response Evaluation Criteria in Solid Tumor). We found after 12 weeks of treatment a complete response (CR) in 64% of our patients. From the analysis divided for subgroups of covariates is emerged that lower BMI, reduced body surface, and absence of previous radiation treatment could be predictive for a better complete response. This study suggests that the efficacy of the ECT treatment is related to the concurrent systemic therapies while administering ECT. The association between ECT and immunotherapy has offered better results than the association between ECT and chemotherapy (p-value = 0.0463). So, ECT is a valuable tool in the treatment of cutaneous and subcutaneous metastases from breast cancer and its efficacy in local control of these lesions improves when it is well planned in a therapeutic scenario.

Corrigendum: Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study.

[This corrects the article DOI: 10.3389/fonc.2021.627527.].

Melanoma of Unknown Primary: Evaluation of the Characteristics, Treatment Strategies, Prognostic Factors in a Monocentric Retrospective Study.

BACKGROUND: Melanoma of unknown primary (MUP), accounts for up to 3% of all melanomas and consists of a histologically confirmed melanoma metastasis to either lymph nodes, (sub)cutaneous tissue, or visceral sites without any evidence of a primary cutaneous, ocular, or mucosal melanoma. This study aimed to investigate the characteristics, treatment strategies, and prognostic factors of MUP patients, in order to shed some light on the clinical behavior of this malignancy. METHODS: All the consecutive patients with a diagnosis of MUP referring to our institutions between 1985 and 2018 were considered in this retrospective cohort study. The records of 173 patients with a suspected diagnosis of MUP were retrospectively evaluated for inclusion in the study. Patient selection was performed according to the Das Gupta criteria, and a total of 127 MUP patients were finally included in the study, representing 2.7% of the patients diagnosed with melanoma skin cancer at our institutions during the same study period. A second cohort of all consecutive 417 MKP patients with AJCC stages IIIB-IV, referring tions in the period considered (1985-2018), was included in the study to compare survival between MUP and MKP patients. All the diagnoses were based on histopathologic, cytologic and immunohistochemical examination of the metastases. All tumors were re-staged according to the 2018 American Joint Committee on Cancer (AJCC) 8th Edition. RESULTS: Median follow-up was 32 months (IQR: 15-84). 3-year progression-free survival (PFS) was 54%, while 3-year overall survival (OS) was 62%. Worse OS and PFS were associated with older age (P = 0.0001 for OS; P = 0.008 for PFS), stage IV (P < 0.0001 for OS; P = 0.0001 for PFS) and higher Charlson Comorbidity Index (P < 0.0001 for OS and P = 0.01 for PFS). Patients with lymph node disease showed longer PFS (P = 0.001) and OS (P = 0.0008) than those with (sub)cutis disease. Complete lymph node dissection (CLND) was the most common surgical treatment; a worse OS in these patients was associated with the number of positive lymph nodes (P = 0.01), without significant association with the number of retrieved lymph nodes (P = 0.79). Survival rates were lower in patients undergoing chemotherapy (CT) and target therapy (TT), and higher in those receiving immunotherapy (IT). 417 patients with AJCC stages IIIB-IV of Melanoma Known Primary (MKP) were included for the survival comparison with MUP. 3-year PFS rates were 54 and 58% in MUP and MKP, respectively (P = 0.30); 3-year OS rates were 62 and 70% in MUP and MKP, respectively (P = 0.40). CONCLUSIONS: The most common clinical scenario of our series was a male patient around 59 years with lymph node disease. We report that CLND associated with IT was the best treatment in terms of survival outcome. In the current era of IT and TT for melanoma, new studies have to clarify the impact of novel drugs on MUP.

Merkel Cell Carcinoma: Evaluation of the Clinico-Pathological Characteristics, Treatment Strategies and Prognostic Factors in a Monocentric Retrospective Series (n=143).

BACKGROUND: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC. METHODS: A retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens. RESULTS: 143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor. CONCLUSIONS: Autoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient.

Corrigendum: Melanoma in Adolescents and Young Adults (AYA): Evaluation of the Characteristics, Treatment Strategies, and Prognostic Factors in a Monocentric Retrospective Study.

[This corrects the article DOI: 10.3389/fonc.2021.725523.].

Melanoma in Adolescents and Young Adults: Evaluation of the Characteristics, Treatment Strategies, and Prognostic Factors in a Monocentric Retrospective Study.

The "Veneto Cancer Registry" records melanoma as the most common cancer diagnosed in males and the third common cancer in females under 50 years of age in the Veneto Region (Italy). While melanoma is rare in children, it has greater incidence in adolescents and young adults (AYA), but literature offers only few studies specifically focused on AYA melanoma. The aim of this study was to describe the characteristics, surgical treatment, and prognosis of a cohort of AYA melanoma in order to contribute to the investigation of this malignancy and provide better patient care. This retrospective cohort study included 2,752 Caucasian patients (702 AYA and 2,050 non-AYA patients) from the Veneto Region who were over 15 years of age at diagnosis, and who received diagnosis and/or treatment from our institutions between 1998 and 2014. Patients were divided in adolescents and youth (15-25 years), young adults (26-39 years) and adults (more than 39 years) for the analysis. We found statistically significant differences in gender, primary site, Breslow thickness, ulceration, pathologic TNM classification (pTNM) stage and tumor subtype among the age groups. Disease-specific survival and disease-free survival were also different among the age groups. Our findings suggest that the biological behavior of melanoma in young people is different to that in adults, but not such as to represent a distinct pathological entity. Additional and larger prospective studies should be performed to better evaluate potential biological and cancer-specific differences between AYAs and the adult melanoma population.

A Therapeutic and Diagnostic Multidisciplinary Pathway for Merkel Cell Carcinoma Patients.

Merkel Cell Carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin. Due to its rarity, the management of MCC is not standardized across centers. In this article, we present the experience of the Veneto region in the North-East of Italy, where a committee of skin cancer experts has proposed a clinical pathway for the diagnosis and treatment of MCC. Putting together the evidence available in the international literature, we outlined the best approach to the management of patients affected with this malignancy step- by- step for each possible clinical situation. Crucial in this pathway is the role of the multidisciplinary team to deal with the lack of robust information on each aspect of the management of this disease.

TNF-based isolated limb perfusion followed by consolidation biotherapy with systemic low-dose interferon alpha 2b in patients with in-transit melanoma metastases: a pilot trial.

BACKGROUND: Tumor necrosis factor (TNF)-based isolated limb perfusion (ILP) yields high tumor response rates in patients with in-transit melanoma metastases. However, most patients will ultimately experience disease recurrence. The aim of this pilot study was to test the hypothesis that systemic low-dose interferon alpha-2b (LDI) might consolidate the therapeutic effect of ILP. METHODS: A total of 12 patients with in-transit melanoma metastases not amenable to surgical excision were given LDI subcutaneously (3 million IU/day, 7 days/week for 12 months) after TNF-based ILP (TNF 1 mg + melphalan (L-PAM) 10 mg/L) (group A). The clinical outcome of these patients was historically compared with that of 19 patients with similar anthropometric and disease characteristics who underwent TNF-based ILP alone (group B). RESULTS: In group A, LDI was well tolerated, only grade 2 systemic toxicity being recorded in 50% of patients. The progression-free survival analysis showed a statistically significant advantage for group A patients as compared with group B (median time to progression: 26 and 17 months, respectively; log-rank test P-value: 0.037). This survival benefit was confirmed at multivariate analysis, where treatment was the only prognostic factor retained by the prediction model. The analysis of the risk of disease progression over time suggested that this survival benefit appears to vanish after LDI discontinuation, which further strengthens the hypothesis that LDI might consolidate the therapeutic effect of TNF-based ILP. CONCLUSIONS: These preliminary findings support the conduction of larger trials to formally assess the ability of LDI to improve the clinical outcome of melanoma patients with in-transit metastases undergoing TNF-based ILP.