Efficacy of superficial and deep regional hyperthermia combined with systemic chemotherapy and radiotherapy in metastatic melanoma

Background and Objective: Response rates of cutaneous‐subcutaneous or lymph node metastases of melanoma to systemic chemotherapy are rather low. We report our clinical experience with superficial and deep regional hyperthermia in combination with radiotherapy and/or chemotherapy with carboplatin. Patients/Methods: We treated 15 patients with metastatic melanoma (6 men, 9 women; age 39 – 84 years, mean age 60 years) by using superficial or deep regional hyperthermia produced by electromagnetic energy. Superficial hyperthermia was delivered to skin or lymph node metastases in combination with radiochemotherapy in 12 patients, while deep regional hyperthermia was administered with an annular array applicator to lymph node metastases either in combination with radiochemotherapy (1 patient) or with carboplatin alone (2 patients). The clinical response was assessed by clinical evaluation and/or computer tomography and/or ultrasonography at monthly intervals. Results. Both superficial and deep regional hyperthermia was well tolerated. We observed 5 complete local remissions (34 %), 6 partial local remissions (40 %) and 2 patients with stable disease (13 %). The best results were obtained in cutaneous or retroperitoneal metastases. Conclusions. Local response can be achieved in inoperable metastatic melanoma using superficial or deep regional hyperthermia in combination with radiochemotherapy or chemotherapy.     

Vemurafenib and cobimetinib‐induced toxic epidermal necrolysis in a patient with metastatic melanoma

Combination therapy in the treatment of metastatic melanoma has been associated with more durable response rate compared to monotherapy. However, previous studies have shown that combined target therapy commonly causes a wide spectrum of adverse events. These adverse reactions are usually manageable, however, it is always necessary to compare drug efficacy with its potential adverse effects. Toxic epidermal necrolysis represents severe mucocutaneous reaction, usually triggered by medications and characterized by extensive necrosis and detachment of the epidermis. Here we present a first case of toxic epidermal necrolysis induced by combined target therapy (vemurafenib plus cobimetinib). The case was observed in a young patient with BRAF mutant melanoma who was started on first‐line metastatic immunotherapy with pembrolisumab.     

Intralesional granulocyte-monocyte colony-stimulating factor followed by subcutaneous interleukin-2 in metastatic melanoma: a pilot study in elderly patients.

AIM AND BACKGROUND: Recent data in the literature indicate that antigen-presenting cells (APC) are inactive in tumour tissue because of local immunosuppression. Tumour-infiltrating lymphocyte (TIL) signal activation transducing mechanisms are also seriously impaired. Administration of granulocyte macrophage-colony stimulating factor (GM-CSF) may lead to APC recovery and interleukin (IL)-2 may restore local TIL activation. Moreover, IL-2 increases the systemic lymphocyte population, an event that seems to correlate with a better prognosis. STUDY DESIGN: The present phase I-II study was carried out to examine whether intralesional injection of GM-CSF followed by subcutaneous IL-2 would induce a clinical response in advanced, pretreated elderly melanoma patients. METHODS: Sixteen patients over 60 years of age received intralesional GM-CSF (150 ng per lesion on day 1), generally divided between the two largest cutaneous lesions, followed by perilesional subcutaneous IL-2 (3,000,000 IU) for 5 days (days 3-7 inclusive) every 3 weeks. RESULTS: Four clinical responses [two partial (PR) and two minimal (MR)] (25%), which also involved lesions that had not been directly treated, and nine cases of stable disease were observed. The response duration for PR and MR was 9, 4, 4 and 2.5 + months, respectively. Stable disease (56%) recorded in the nine patients was short-term (3-6 months). Three patients rapidly progressed after two, two and one therapy cycles, respectively. The patient who reached the best PR had a fairly high absolute lymphocyte count (1600-2400/mm3). The second one, who reached complete remission after subsequent locoregional chemotherapy and hyperthermia, however, had a low absolute lymphocyte count that had doubled by the end of treatment. Blood lymphocyte values in the other patients were too varied to allow any correlation with clinical response. Therapy was well tolerated and only mild fever was observed, with the exception of one patient who had grade 3 fever, with muscle pain and arthralgia. CONCLUSIONS: Considering the very low toxicity observed, this treatment might be indicated in elderly patients for whom systemic therapy is no longer a viable option. Improved scheduling and timing could result from further studies.     

Intralesional interleukin‐2: A novel option to maximize response to systemic immune checkpoint therapy in loco‐regional metastatic melanoma

The management of metastatic melanoma has been transformed by the development of immune checkpoint inhibitors. However, disease control in patients with extensive locoregional metastases remains a significant challenge. In this context, intralesional interleukin 2 (IL‐2) presents a useful therapeutic option to maximize intratumoural drug concentration and minimize systemic toxicity. The utility of combined intralesional IL‐2 and systemic immune checkpoint therapy, particularly in loco‐regional disease, is unknown. We report the clinical and cellular effects of combined anti‐programmed death‐1 blockade and intralesional IL‐2 therapy in two patients with loco‐regional metastatic melanoma. Combined intralesional and systemic therapy induced a lasting resolution of the injected skin tumors; maintained for up to 2 years. This impressive response was associated with increased PD‐L1 expression and CD8 T cell infiltration. To our knowledge, this is the first report that raises the possibility of a synergistic effect between intralesional IL‐2 and systemic checkpoint inhibition. The lasting remission of injected metastases may be in part due to an altered tumor microenvironment; characterized by increased PD‐L1 expression and increased CD8 T cell infiltration. If this interesting and novel preliminary observation is confirmed in larger studies, combined local and systemic immunotherapy could highlight a novel treatment strategy for extensive loco‐regional disease.     

Diagnostic and therapeutic procedures for management of melanoma during pregnancy: risks for the fetus?

In the treatment of malignant melanoma, various stage‐dependent diagnostic and therapeutic procedures are widely accepted.The situation becomes more complicated in pregnant women due to potential hazardous side effects to the fetus. We report on a 36‐year‐old woman, who was admitted with a high‐risk malignant melanoma on the right cheek. Prior to surgery we performed computed tomography (CT)‐scans that were unremarkable with the exception of “two small cysts of the uterus” The primary melanoma was excised and a sentinel node biopsy was performed under general anesthesia using radioactive tracers. Afterwards, adjuvant therapy with interferon alpha 2b was initiated. Five weeks later our patient reported that she was pregnant with twins in their eleventh week of gestation, although she previously denied several questions regarding a potential pregnancy. She declined the offer of an abortion and elected to continue with the interferon treatment against our medical advice. In the 36^th week of gestation, she developed regional lymph node metastases. Consequently, labor was induced, resulting in the delivery of healthy twins. Six months later our patient developed lung metastases. Despite several chemotherapy regimens, she died one year later. An interdisciplinary approach to obtaining informed consent and managing female high risk melanoma patients with potential or present pregnancy is presented.     

Treatment and side effect management of CTLA‐4 antibody therapy in metastatic melanoma

Immune‐modifying monoclonal antibodies may induce or enhance the natural immune response against tumor cells. The complex interaction between antigen‐presenting cells and T lymphocytes as an immune response is strongly affected by anti‐CD152 (CTLA‐4)‐antibodies. The cytotoxic T‐lymphocyte (CTLA‐4) receptor binds molecules of the B7‐family which leads to a suppression of T cells. Specific CTLA‐4 antibodies induce an unrestrained T‐cell activation. Treatment with the CTLA‐4 antibodies ipilimumab and tremelimumab has been investigated in metastatic melanoma only within clinical trials. Currently, the critical phase III trial on ipilimumab is in the final analysis process and expected to lead to approval. CTLA‐4 antibodies belong to the most promising new molecules for the treatment of advanced melanoma. During treatment with CTLA‐4 antibodies, distinct adverse events may occur. Treating physicians must be familiar with their appropriate treatment and prophylaxis. The most frequently observed side effects are diseases such as an autoimmune colitis which is typically characterized by a mild to moderate, but occasionally also severe and persistent diarrhea. Other autoimmune‐mediated side effects like hypophysitis, hepatitis, iridocyclitis or an exacerbation of lupus nephritis have been reported in the literature. Their early recognition and treatment are mandatory to reduce the risk of sequelae for CTLA‐4‐antibod‐treated patients. Autoimmune‐mediated side effects are reported to correlate positively with treatment response. We review the mechanisms of action, provide an update on clinical trials with the two CTLA‐4‐antibodies for metastatic melanoma, and present detailed recommendations for managing the side effects of these new agents.     

Intralesional therapy for the treatment of keratoacanthoma

Keratoacanthoma (KA) is a common epidermal tumor that originates from the hair follicle of the skin. It is generally considered as a benign neoplasm, but in rare cases, it can also transform into squamous cell carcinoma. Although surgical excision with a safety margin is considered to be the gold standard treatment for most subtypes of KA, several other treatment options are also available. Intralesional therapy is one of these options, which could be cosmetically and functionally a better alternative to surgical removal, while it provides similar outcomes. It is more effective than topical treatments, yet fewer side effects may be seen than in systemic treatments. Based on the literature, the most commonly used intralesional agent is methotrexate, followed by 5‐fluorouracil and interferon alpha. Regardless of the advantages, which make intralesional therapy a desirable treatment alternative, guidelines for the intralesional treatment of KA are not yet established. A histopathological confirmation before the start of treatment is still recommended to prevent any possible misdiagnosis of KA for SCC. In our present study, we set out to review the current state of the art of the intralesional treatment of KA.     

Klinische Wertigkeit einer dermatoskopischen Klassifikation von Clark‐Nävi

Background and objectives: The aim of this study was to evaluate the practical value of the dermatoscopic classification of Clark nevi Patients and methods: Dermatoscopic images of 268 lesions clinically and dermatoscopically diagnosed as Clark nevi were presented to 2 dermatologists without knowledge of the histological diagnosis. The dermatologists evaluated the lesions according to a simplified version of the classification scheme for Clark nevi proposed by Hofmann‐Wellenhof and differentiated between 12 different types of Clark nevi. Results: The most common type of Clark nevus was the reticular‐homogenous type (n = 64, 23,9 %), followed by the globular‐homogeneous type (n = 32, 12 %) and by the homogenous type (n = 30, 11,2 %). The overall inter‐rater agreement between the examiners was moderate to good (kappa = 0,58). The highest level of agreement was found for the peripheral hyperpigmented type (kappa = 0,83). Histologically, 17 lesions (6,3 %) were diagnosed as melanomas. The frequency of melanoma was highest among the peripheral‐hyperpigmented type for one observer and among the homogenous type for the other observer. No melanoma was found among the globular, reticular‐globular, and the central‐hyperpigmented types. Conclusions: A dermatoscopic classification of Clark nevi is practically feasible and allows – to some extent – a risk stratification of Clark nevi, which could be useful for clinical management.     

A case of epidermotropic metastatic malignant melanoma with multiple nodular lesions of the scalp

Epidermotropic metastatic malignant melanoma (EMMM) is a form of metastatic malignant melanoma that has dermal cell nests with epidermotropism and specific histopathological features. We report a patient with eight nodular lesions of the scalp with histopathological findings compatible with EMMM. The tumors developed one year before consultation and increased in size simultaneously. The histopathological findings of all eight tumors were very similar. The tumor cells were located mainly in the dermis and partly in the basal layer of the epidermis. They contained melanin pigments and were positive for anti-HMB45 antibody. The tumors did not respond to combination chemotherapy with dacarbazine, nimustine, vincristine, and interferon-beta. Therefore, all the tumors were surgically removed. No local relapse, distant metastasis or re-elevation of plasma 5-S-cysteinyldopa was identified during nine months of follow-up. Histopathologically, all eight tumors lacked apparent vascular invasion, which may be related to a slow clinical course of the present case.     

Severe de‐novo palmoplantar and nail psoriasis complicating Nivolumab treatment for metastatic melanoma

Nivolumab, a fully human IgG4 immune checkpoint modulator, binds to the programmed cell death 1 (PD‐1) receptor on T cells and blocks their inhibition. Thus, it increases the anticancer host immune response by allowing T cells to attack tumor cells. Although anti‐PD‐1 immunotherapy is typically well accepted, deregulation of immune tolerance caused by nivolumab may determine immune‐related adverse events, among which skin toxicities represent the most common. We report a case of severe new‐onset palmoplantar and nail psoriasis after receiving nivolumab treatment for metastatic melanoma.     

Intralesional vincristine as first‐line therapy for nodular lesions in classic Kaposi sarcoma: a prospective study in 151 patients

Background Classic Kaposi sarcoma is a rare angioproliferative neoplasm with varying biological behaviour. Depending on the clinical stage, local or systemic therapy can be used. Vincristine has proven to be effective as systemic chemotherapy and in very few reports as intralesional treatment. Objectives Our aim was to determine the efficacy and safety of intralesional vincristine in the treatment of classic Kaposi sarcoma nodular lesions. Methods We conducted a prospective, open‐label, single‐centre clinical trial in 151 patients with stage IB classic Kaposi sarcoma. Vincristine was injected in a single nodule (0·3–0·8 mm) on the lower limb. Another similar lesion on the same limb, at a distance of ≥ 10 cm, or on the contralateral limb, was kept under clinical observation as control. Adverse effects were evaluated after 1 week, and efficacy after 4 and 12 weeks. Results One hundred and fifty‐one patients were enrolled. At final evaluation, 115 patients presented complete response (76·1%), 28 had partial response (18·5%), six had improvement (4%), one had stable disease (0·7%) and only one patient had tumour progression (0·7%). Therefore the total response rate was 98·7% (149 patients). Therapy was generally well tolerated. The most frequently registered adverse events, observed in 21 patients (13·9%), were erythema and itching. Conclusions Intralesional vincristine is an effective and safe treatment for nodular lesions in classic Kaposi sarcoma and can be recommended as first‐line therapy in initial stages and as support therapy in advanced stages.     

Efficacy of combined radiotherapy and anti‐programmed death 1 therapy in acral and mucosal melanoma

Some studies showed that clinical response to immune check point inhibitors is lower in acral and mucosal melanoma than in cutaneous melanoma. Although the synergistic effect of radiotherapy (RT) and ipilimumab has been reported in patients with brain metastasis, the efficacy of combined RT and anti‐programmed death 1 (PD‐1) therapy for acral and mucosal melanoma is unclear. The present study aimed to evaluate the efficacy of combined RT and anti‐PD‐1 therapy for acral and mucosal melanoma. We retrospectively analyzed patients with acral or mucosal melanoma who were treated with anti‐PD‐1 and RT at Sapporo Medical University Hospital. In 10 patients (acral, 3; mucosal, 7), the response rate (RR) and the disease control rate (DCR) were 40% and 60%, respectively. As regards mucosal melanoma, four of the seven patients had achieved complete response + partial response, and three had progressive disease (RR = 57.1%). Meanwhile, two of the three patients with acral melanoma had stable disease and one had progressive disease (RR and DCR were 0% and 66.6%, respectively). Except for the patients treated with palliative RT for bone metastasis in the present study, the RR was 50% (4/8 patients), and the DCR was 75% (6/8 patients). Vitiligo developed after RT in five (50%) patients at a median duration of 2 months after RT. The clinical response and the high occurrence of vitiligo suggest that the combination of RT and anti‐PD‐1 therapy could be effective in some patients with mucosal melanoma.     

Comparative analysis of BRAF,NRAS and c‐KIT mutation status between tumor tissues and autologous tumor cell‐lines of stage III/IV melanoma

In the last decade, advances in molecular biology have provided evidence of the genotypic heterogeneity of melanoma. We analysed BRAF, NRAS and c‐KIT alterations in tissue samples from 63 stage III/IV melanoma patients and autologous cell‐lines, using either allele‐specific or quantitative PCR. The expression of BRAF V600E protein was also investigated using an anti‐BRAF antibody in the same tissue samples. 81% of FFPE samples and tumor cell‐lines harboured a genetic alteration in either BRAF (54%) or NRAS (27%) oncogenes. There was a strong concordance (100%) between tissue samples and tumor cell‐lines. The BRAF V600E mutant‐specific antibody showed high sensitivity (96%) and specificity (100%) for detecting the presence of a BRAF V600E mutation. The correlation was of 98% between PCR and immunohistochemistry results for BRAF mutation. These results suggest that BRAF and NRAS mutation status of tumor cells is not affected by culture conditions.     

Management of side effects of immune checkpoint blockade by anti‐CTLA‐4 and anti‐PD‐1 antibodies in metastatic melanoma

CTLA‐4 and PD‐1 are potential targets for tumor‐induced downregulation of lymphocytic immune responses. Immune checkpoint‐modifying monoclonal antibodies oppose these effects, inducing T cell‐mediated immune responses to various tumors including melanoma. Both anti‐CTLA‐4 and anti‐PD‐1 antibodies modify the interaction between tumor, antigen‐presenting cells, and T lymphocytes. With respect to overall survival, clinical studies have shown a major benefit for the anti‐CTLA‐4 antibody ipilimumab as well as the two anti‐PD‐1 antibodies nivolumab and pembrolizumab. Following approval of ipilimumab in 2011, the latter two achieved market authorization in the summer of 2015. Immune responses thus induced and enhanced inevitably entail autoimmune phenomena, affecting various organs to varying degrees. Knowledge of these side effects is crucial with regard to prevention and management by treating physicians. Typically occurring early on and presenting with pronounced and persistent diarrhea, colitis represents a major and severe side effect. Other immune‐mediated disorders include dermatitis, hypophysitis, thyroiditis, hepatitis, iridocyclitis as well as other less common autoimmune phenomena. Early recognition and initiation of treatment can reduce risks and sequelae for patients. This review describes the mechanisms of action of immune checkpoint blockade as well as its clinical effects in metastatic melanoma, with a detailed focus on the spectrum of adverse events and their therapeutic management.     

Increased levels of circulating platelet‐derived microparticles are associated with metastatic cutaneous melanoma

We investigated the plasma levels of PMPs in patients with 45 stage III and 45 stage IV melanoma. PMPs were characterised by flow cytometry and their thrombogenic activity. We also investigated the link between PMPs circulating levels and tumor burden. The circulating levels of PMPs were significantly higher in stage IV (8500 μL^?1) than in patients with stage III (2041 μL^?1) melanoma (P=.0001). We calculated a highly specific (93.3%) and predictive (91.7%) cut‐off value (5311 μL^?1) allowing the distinction between high‐risk stage III and metastatic stage IV melanoma. The thrombogenic activity of PMPs was significantly higher in patients with stage IV melanoma (clotting time: 40.7 second vs 65 second, P=.0001). There was no significant association between the radiological tumoral syndrome and the plasma level of PMPs. Our data suggest the role of PMPs in metastatic progression of melanoma.     

Phase I study of pegylated interferon‐alpha‐2b as an adjuvant therapy in Japanese patients with malignant melanoma

In the adjuvant setting for malignant melanoma, interferon (IFN)‐α‐2b and pegylated (PEG) IFN‐α‐2b were approved in several countries including the USA before these were approved in Japan. To resolve the “drug‐lag” issue, this phase I study was designed to evaluate the safety and tolerability in Japanese patients with stage II or III malignant melanoma who had undergone surgery, by treating with PEG IFN‐α‐2b. As with a previously reported phase III study, patients were to receive PEG IFN‐α‐2b 6 μg/kg per week s.c. during an 8‐week induction phase, followed by a maintenance phase at a dose of 3 μg/kg per week up to 5 years. Dose‐limiting toxicity and pharmacokinetics were assessed during the initial 8 weeks. Of the nine patients enrolled, two patients had dose‐limiting toxicities that resolved after discontinuation of treatment. The most frequently reported drug‐related adverse events (DRAE) included pyrexia, decreased neutrophil and white blood cell counts, and arthralgia. Grade 3 DRAE included decreased neutrophil count. No deaths, serious adverse events and grade 4 adverse events were reported. Distant metastasis occurred in one patient. No apparent differences in area under the concentration–time curve and maximum observed serum concentration were observed between Japanese and historical non‐Japanese pharmacokinetic data, suggesting no marked racial differences. No neutralizing antibody was detected in these patient samples. PEG IFN‐α‐2b was tolerated in Japanese patients, and eventually approved in Japan in May 2015 for adjuvant therapy in patients with stage III malignant melanoma. Because the number of patients was limited, further investigation would be crucial.     

The ultrastructure of dysplastic naevi: comparison with superficial spreading melanoma and common naevocellular naevi

Summary Eleven dysplastic melanocytic naevi with various degrees of dysplasia, as judged by light microscopy, were studied by transmission electron microscopy, and their intra-epidermal melanocytes compared with those of five superficial spreading melanomas and seven common benign naevocellular naevi. Intra-epidermal melanocytes in dysplastic naevi exhibited signs of cellular atypia, which were most pronounced in the dysplastic naevi with histological high-grade dysplasia. A correlation between the degree of dysplasia at the light microscopic level and the degree of cytological atypia at the ultrastructural level was noted, and melanocytes in dysplastic naevi with a high degree of dysplasia had ultrastructural features similar to the melanocytes in superficial spreading melanomas. Our observations support the concept that dysplastic naevi fill the biological gap between benign naevocellular naevi and malignant melanomas and suggest that at least some of the dysplastic naevi must be regarded as potential precursor lesions of malignant melanoma, particularly those exhibiting a high degree of histological dysplasia.Presented at the 16th Annual Meeting of the Society for Cutaneous Ultrastructure Research, June 9 and 10 1989, Cologne, FRG     

Oncogenic BRAF signalling increases Mcl‐1 expression in cutaneous metastatic melanoma

The Bcl‐2 family member Mcl‐1 is essential for melanoma survival; however, the influence of oncogenic BRAF signalling remains elusive. In this study, Mcl‐1 splice variant expression was determined in a panel of melanoma cell lines in relation to BRAF mutational status. Mcl‐1L mRNA expression was increased in melanoma cells compared with primary melanocytes with significantly increased mRNA and protein expression observed in BRAF^V600E mutant melanoma cells. Although no change in Mcl‐1S mRNA was observed, Mcl‐1S protein expression also increased in BRAF mutant melanoma cells. Additionally, while over‐expression of mutant BRAF^V600E increased both Mcl‐1L and Mcl‐1S expression, inhibition of hyperactive BRAF signalling resulted in decreased Mcl‐1L expression. These studies suggest that the regulation of Mcl‐1 expression by BRAF signalling is increased by oncogenic activation of BRAF, revealing a mechanism of apoptotic resistance which may be overcome by the use of more specifically targeted Mcl‐1 inhibitors.