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The exact impact of immune checkpoint inhibitors in the course and outcome of COVID-19 in cancer patients is currently unclear. Herein, we present the first description of an elderly melanoma patient who developed COVID-19 pneumonia while under treatment with nivolumab and bempegaldesleukin in combination with an investigational PEGylated interleukin (IL-2). We present the clinical characteristics and the laboratory and imaging findings of our patient during the course of COVID-19 pneumonia. Moreover, we discuss the currently available data regarding the mechanism of action of immune checkpoint inhibitors and IL-2 analogs in the treatment of COVID-19. The administration of these agents did not have a negative effect on the outcome of COVID-19 pneumonia in an elderly melanoma patient.Immune checkpoint inhibitors represent a major advance in the treatment of several solid malignancies, including melanoma. Bempegaldesleukin is an investigational PEGylated IL-2 that is being evaluated, in combination with nivolumab, in the management of a variety of cancers. The immunomodulation caused by these agents may also modify the immune response in COVID-19. Currently available data regarding the impact of immune checkpoint inhibitors in reducing the severity of COVID-19 in patients with cancer are mixed, whereas no clinical data are available for bempegaldesleukin. Herein, we report the case of an elderly female melanoma patient who developed COVID-19 pneumonia while under treatment with nivolumab and bempegaldesleukin. The administration of these agents did not have a negative effect on the outcome of COVID-19 pneumonia in our patient.

Introduction. The BNT162b2 vaccine against SARS-CoV-2 has a proven efficacy and a favorable safety profile. In cancer patients under immunotherapy in the form of immune checkpoint inhibitors (ICIs), the efficacy of the vaccine has not been thoroughly studied, while a theoretical concern about the triggering of immune related adverse events (irAEs) by the vaccine has also been raised. Patients and methods. We conducted a prospective, non-interventional study on the immunogenicity and safety of the BNT162b2 vaccine in patients with advanced or metastatic melanoma treated with ICIs. Blood samples were obtained 0-4 days before the first and 12-21 days after the second dose of the vaccine for the quantification of the SARS-CoV-2 anti-spike antibody with an ELISA and immunophenotyping of the T and myeloid cell subpopulations. Active recording of the AEs for a two-month period was conducted. Results. Forty patients were included in the study. All but one (97.3%) achieved seroconversion after two doses of the vaccine and no correlations of the antibody titers with any of the studied parameters (age, gender, stage and duration of the disease, type of ICI, previous treatment, etc.) were found. Moreover, no differences in the subpopulations of the T cells (including the T-regulatory cells) or the myeloid cells were found pre- and post-vaccination. All AEs were low-grade, while one case or arthritis exacerbation was noted.Discussion. The seroconversion rate in the studied population was high, comparable to that of healthy subjects, while no major safety issues were raised during the safety follow-up. Finally, no derangements in the subpopulations of T cells or myeloid cells were noted. This is the first study focusing on the immunogenicity, safety, and effect on the blood cell immunophenotype status of anti-SARS-Cov-2 vaccines in patients with melanoma treated with ICIs.

Background Immune‐checkpoint inhibitors have been shown to improve survival in melanoma patients, but can also trigger immune‐related endocrinopathies, especially hypophysitis and thyroid dysfunction. Methods To assess the incidence and the spectrum of endocrinopathies in melanoma patients treated with immunotherapy a prospective observational study was conducted. Forty out of 339 patients, treated with immune‐checkpoint inhibitors, developed endocrinopathies. All patients had hormonal functional tests at screening (before the initiation of immunotherapy) and during follow‐up. Results The total incidence of endocrinopathies was 11.8%, 13.4% due to anti‐PD1/PDL1, 5% due to anti‐CTLA4, and 18.5% due to sequential and/or combination treatment. Twenty‐one patients (6.2%) presented with isolated anterior hypophysitis, eleven (3.2%) with primary thyroid dysfunction and eight (2.4%) with both abnormalities. The most frequent anterior pituitary hormone deficiency was central adrenal insufficiency, followed by central hypothyroidism and hypogonadotrophic hypogonadism. None of the patients with corticotroph axis failure recovered during follow‐up. Endocrinopathies occurred after a median of 22 weeks (range: 4‐156) from treatment initiation. Of note, sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy. Only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism. Conclusions Our cohort demonstrated an increased incidence of hypophysitis with anti‐PD1/anti‐PDL1 in contrast to the rarity of primary thyroid dysfunction with anti‐CTLA4 treatment. These results could be attributed to genetic/ethnic differences. Sequential treatment is, for the first time to our knowledge, reported to increase the risk of developing hypophysitis to a level as high as that of combination therapy., A prospective observational study was conducted to assess the incidence and the spectrum of endocrinopathies in 339 melanoma patients treated with immune checkpoint inhibitors. Sequential and/or combination therapy with anti‐CTLA4 and anti‐PD1/anti‐PDL1 led to an almost threefold incidence of hypophysitis compared to either monotherapy, while only one of 120 patients receiving anti‐CTLA4 monotherapy developed primary hypothyroidism.

The epidemiologic correlation of melanoma and chronic lymphocytic leukemia (CLL) has been the subject of several population studies. In the present article, through the presentation of five illustrative cases of patients with melanoma and CLL, several aspects of this complex relationship are highlighted, with a focus on the increased incidence of melanoma in patients with CLL, its speculated etiology, and the impact of CLL stage and disease duration on the incidence and prognosis of melanoma. Furthermore, the rare entity of the synchronous diagnosis of melanoma and CLL in biopsied lymph nodes is discussed, along with its implications on the diagnostic and therapeutic procedures. In addition, the available data on the treatment choices in patients with melanoma and CLL are presented and the efficacy and safety of fludarabine, anti-CD20 monoclonal antibodies, new targeted therapies for CLL, and checkpoint inhibitors are further discussed. Finally, since no formal guidelines are available for the management of this group of patients, guidelines are proposed for skin-cancer screening in patients with CLL, for the correct interpretation of BRAF mutation analysis in lymph-node specimens with ‘collision of tumors,’ and for the optimal use of imaging studies in the diagnosis of metastatic disease in patients with CLL and melanoma, while a treatment approach for such patients is also suggested. The information and proposed guidelines provided in the present article comprise a useful guide for physicians managing such patients, focusing on diagnostic challenges and therapeutic dilemmas posed by the coexistence of the two disease entities.

Immune checkpoint inhibitors (ICI) have altered the prognosis of patients with melanoma over the past few years, with immune-related adverse effects (irAEs) being the only factor limiting their use. Neurologic and cardiac irAEs are rare, but usually severe. We reviewed the files of patients with melanoma treated with ICIs in one center to retrieve data from patients with neurologic irAEs. Patients with a combination of neurologic and cardiac manifestations were further analyzed. We also reviewed the literature for similar syndromes. Five out of 482 (1.01%) patients developed a neurologic syndrome and we present three patients with a constellation of neurologic and cardiac irAEs. A 66-year-old woman and a 68-year-old man presented with a constellation of findings after being treated with ipilimumab and nivolumab, respectively, for melanoma in the adjuvant setting and were eventually diagnosed with myasthenia gravis with cardiac involvement. An 80-year-old woman developed diffuse asymmetric muscle weakness, bilateral ptosis and asymptomatic high serum troponin levels after adjuvant treatment with nivolumab and ipilimumab for a stage IIIB melanoma. After excluding ischemic heart disease, she was diagnosed with axonal polyradiculoneuropathy and myocarditis. Neurologic or cardiac irAEs in patients treated with ICIs are uncommon (

The widespread use of immune checkpoint inhibitors has shed light to several unusual immune-related adverse effects of the drugs. Severe cutaneous adverse reactions are generally rare with anti-PD1 agents. We present in this paper the case of a 48-year-old patient with melanoma who developed bullous pemphigoid-like skin lesions along with fever, arthralgia and overt eosinophilia following adjuvant treatment with nivolumab. The condition was successfully treated with corticosteroids and a rechallenge with another anti-PD1 agent did not lead to recurrence of the skin lesions. We also reviewed the literature on the epidemiologic, clinical, and histopathologic characteristics of bullous pemphigoid as well as on the treatment and prognosis of this dermatologic condition in patients with melanoma or other malignancies under treatment with immune checkpoint inhibitors.

Immune-related adverse effects (AEs) of PD-1 inhibitors can affect almost every organ, but the skin, intestine, lung, eye, and liver are the most commonly affected organs. Here, we present the case of a 62-year-old female patient with stage IIIc melanoma treated with nivolumab in an adjuvant setting who sequentially developed hyperthyroidism, hypothyroidism, acute hepatitis, and pneumonitis. Six months before the emergence of pneumonitis, the patient had discontinued treatment with nivolumab because of acute hepatitis. Information on pneumonitis after nivolumab discontinuation in the literature is scarce, whereas most of the cases emerge during the first 2.5 months of treatment. Patients with multiple immune-related AEs comprise a group of special interest as the identification of factors affecting the susceptibility of patients to immune-related AEs of PD-1 inhibitors may lead to a more rational use of these drugs. Human leukocyte antigen haplotype and Fcγ receptor polymorphisms are possible targets of the relevant research.

Background Approximately one third of women who develop melanoma at childbearing age are diagnosed during gestation or the postpartum period, facing pregnancy-associated melanoma (PAM). However, only some retrospective studies with heterogeneous data have analyzed the impact of pregnancy on melanoma development, and no evidence exists about the behavior and the management of BRAF-mutated disease. Subjects, Materials, and Methods In order to better describe the evolution of BRAF V600E-mutated PAM, we present here all consecutive cases diagnosed in our site during the last 7 years, recording oncological, obstetrical, and perinatal parameters, as well as the therapeutic decisions for both melanoma and gestation. Based on our institutional experience, we weigh the current published evidence and discuss upcoming clinical considerations about the prognosis of PAM, the role of BRAF status, and the possible treatment options during pregnancy in localized or advanced/metastatic disease. Five women were diagnosed with newly metastatic or relapsed BRAF V600E-mutated PAM (four during gestation and one in the 1st year postpartum) between 2012 and 2019. All of them developed extensive metastatic disease with multiple organ involvement, and four developed brain metastases. All cases experienced melanoma progression in less than 6 months under targeted therapy and died soon independently of the followed sequence of treatments. All the neonates were delivered alive and healthy, but one developed melanoma earlier than the second year of life. Results Reviewing the literature to confirm our unfavorable outcomes, no specific data on BRAF-mutated PAM were retrieved and current evidence still supports that the prognosis of PAM should be guided by the established risk factors, whereas the management of advanced/metastatic PAM should be evaluated on a case-by-case basis. Conclusion More data are required to ascertain whether BRAF-mutated profile adversely affects PAM outcome, although the clinicians should be aware to detect any potential melanoma lesion during pregnancy as soon as possible, treating it locally, regardless of its BRAF status. Implications for Practice The prognosis and management of pregnancy-associated melanoma whether BRAF-mutated or wild type, is currently guided by the same parameters as in the nonpregnant condition. In this special nontrial subpopulation, BRAF-mutated status seems to have a detrimental effect on disease outcome, independently of the following treatments. In early stage melanoma, wide local excision with or without sentinel lymph node dissection may be curative at any trimester of gestation, while in advanced/metastatic setting, therapeutic strategy including immune-checkpoint or BRAF/MEK inhibitors, is more challenging, regardless of BRAF status, and should be based on an individualized decision in each case at a multidisciplinary level.

Immune checkpoint inhibitors (ICBs) have revolutionized cancer treatment producing remarkable and durable responses for a range of malignancies. However, the additional modulation of immune response by ICBs may rarely cause immune-related infectious complications, including re-activation of latent tuberculosis infection (LTBC) with detrimental effects on those patients’ outcome. Here, we present two “real-world” melanoma cases that were treated in our department with blockade of PD-1/PD-L1 and developed active Mycobacterium tuberculosis (MTB) during immunotherapy. In view of these cases, we review the literature for ICB-associated MTB reactivation and discuss our considerations about the possible interactions of immunotherapy and the underlying co-existent mycobacterial infection. Based on the current evidence from preclinical findings prior to this experience, we raise questions regarding cancer patients who are at higher risk for developing MTB infection, whether ICB-treated patients should be considered immunocompromised, and how they should be managed for latent and/or active tuberculosis. Aside from the well-established clinical benefit of immunotherapy, the blockade of PD-1/PD-L1 axis may concurrently disrupt the immune control of specific opportunistic infections such as tuberculosis that should be carefully and expectantly managed in order to avoid compromising the outcome of cancer treatment and the affected patient’s survival.

Survivin represents a key anti-apoptotic molecule that is highly expressed in the vast majority of tumors. The aim of the study was to examine the significance of survivin mRNA blood levels in melanoma patients.In this prospective translational research study, survivin mRNA blood levels were measured in melanoma patients treated with adjuvant interferon or systemic treatment for advanced disease.Sixty-four patients with melanoma and 40 healthy controls were included. The majority of them had tumor stages III and IV. The upper 95% confidence interval (95%CI) of survivin levels in controls was set as normal cut-off. Fifty-two (81.3%) patients had survivin levels above normal cut-off. Melanoma patients had higher survivin levels than controls (p0.0001). Survivin levels were non-significantly higher in stage III compared to stage IV patients. Patients with survivin levels above vs. below median had median progression-free survival (PFS) 19.5 months vs. 7.4 months (p=0.045), but median overall survival (OS) not reached vs. 18.4 months (p=0.091). Cox proportional hazard models showed that only tumor stage was associated with PFS and OS. There was no statistically significant change in survivin levels between baseline and during treatment (p=0.845) or during follow-up (p=0.101).Although melanoma patients had significantly higher survivin levels than controls, the study showed that survivin mRNA blood levels did not represent an independent prognostic factor for patients with melanoma. The role of circulating survivin should be further examined in larger studies.

This retrospective cohort study assessed the prognostic significance of distant metastasis-free interval (DMFI) in patients with relapsed BRAF-mutant melanoma treated with BRAF with or without MEK inhibitors (BRAFi ± MEKi). Patients with a DMFI of up to 24 months were compared with those with DMFI of more than 24 months, with regard to their postrelapse progression-free survival (PR-PFS) and overall survival (PR-OS). In total, 109 patients were included in the study. Median DMFI was 25.3 (range: 3.4-188.2) months. Median PR-PFS in patients with DMFI of more than 24 months was 7.9 months [95% confidence interval (CI): 6.2-9.7] compared with 5.4 (95% CI: 4.2-6.7) months of those with shorter DMFI (P = 0.016). Median PR-OS was 15.6 months (95% CI: 13.6-17.6) in patients with DMFI of more than 24 months and 12.0 months (95% CI: 9.0-15.0) with DMFI of up to 24 months (P = 0.289). Multivariate Cox regression analysis showed that DMFI was independently and strongly associated with improved PR-PFS (adjusted hazard ratio = 3.21, 95% CI: 1.78-5.77, ≤ 24 vs. > 24 months) and longer PR-OS (adjusted hazard ratio: 2.09, 95% CI: 1.15-3.80, ≤ 24 vs. > 24 months). The present cohort study is one of the first to confirm the association of DMFI of more than 24 months with an indolent disease course, as shown by longer PR-PFS and PR-OS, in patients with relapsed stage IV melanoma treated by BRAF inhibitor/MEK inhibitor.

Unleashing adaptive immunity via immune checkpoint inhibitors (ICPIs) in many cancer types led to durable antitumor responses and prolonged survivals and also added some new immune-related adverse events (irAEs) to the ‘old-fashioned’ safety profile of chemotherapy. Among bowel and endocrine irAEs, immune-mediated hepatotoxicity/hepatitis is a less common and far less well-studied toxicity, which, however, could develop into a serious complication, especially when it becomes persistent or refractory to steroids. Its incidence, onset and severity vary widely, depending on the type of underlying treated cancer, the class, the dosage and the duration of immunotherapy as well as the way of its administration (as a single agent or in combination with other ICPI or chemotherapy). In this study, we present a patient with metastatic melanoma who developed severe steroid-resistant ir-hepatitis after treatment with ipilimumab and required triple concurrent immunosuppression with prednisolone, mycofenolate mofetil and tacrolimus in order for his liver toxicity to be resolved. Intrigued by this case, we focused further on melanoma, as the disease-paradigm of immunotherapy in cancer, reviewed the reported incidence of hepatotoxicity among phase III ICPIs-containing trials on melanoma and discussed the main clinical considerations regarding the diagnosis and the management of persistent/steroid-refractory ir-hepatitis. As more clinical experience is gradually gained on this challenging topic, better answers are provided to questions about the appropriate diagnostic workup, the necessity of liver biopsy, the available immunosuppressive options beyond corticosteroids (their combinations and/or their sequence) as well as the correct decision on withdrawing or resuming immunotherapy. Nonetheless, a thorough multidisciplinary discussion is still required to individualize the overall approach in each case after failure of steroids.

Sarcoidosis and sarcoid-like reactions (SLR) have been repeatedly reported in patients with melanoma treated with BRAF and MEK inhibitors. In the current study we present three patients that developed SLR under treatment with BRAF and mitogen-activated protein kinase (MEK) inhibitors for melanoma. Two patients developed mediastinal lymphadenitis with histological features of an SLR while on targeted therapy in the adjuvant setting, whereas one patient with metastatic melanoma developed granulomatous nephritis while receiving combination treatment with BRAF/MEK inhibitors and atezolizumab. In addition, we review the published literature on the pathogenesis, clinical characteristics, histologic features, imaging findings, and other potential useful diagnostic tools. We also address the need for a common terminology for these cases and propose an algorithm for the accurate diagnosis of BRAF/MEK inhibitor-induced SLR. We also review the currently available data on the treatment of these patients and suggest a treatment approach for SLR in patients with melanoma, as well as for the management of melanoma when SLR emerges.

Introduction: Immune checkpoint inhibitors (ICIs) represent an important advance in the treatment of melanoma. ICIs may induce autoimmune phenomena caused by concurrent activation of the immune system against normal cells. During the last years, cases of musculoskeletal side effects, especially immune-mediated arthritis (IA), have been increasingly reported. Patient concerns: We present a 59-year-old woman, who was treated with pembrolizumab for a relapsed BRAF V600E mutated cutaneous malignant melanoma. The patient presented with right knee arthritis on week 30. Diagnosis: The erythrocyte sedimentation rate and serum C-reactive protein levels were elevated, while rheumatoid factor and anti-cyclic citrullinated peptide antibodies were negative. Imaging confirmed the presence of fluid mainly in the suprapatellar bursa. Synovial fluid analysis revealed an inflammatory effusion, while other etiologies of inflammatory arthritis were excluded. Interventions: Arthritis improved with an intra-articular injection of 8 mg dexamethasone. Twelve days later the arthritis relapsed in both knees, and although it was resistant to nonsteroidal anti-inflammatory treatment, it improved with systemic steroids. Tapering of methylprednisolone dose was feasible with the coadministration of leflunomide and subsequently hydroxychloroquine. Outcomes: Arthritis resolved and the patient is free of complications and disease activity 20 months after the initiation of the second line systemic treatment. Conclusions: We present an unusual case of IA associated with pembrolizumab treatment. The originality of the current report is based on the late occurrence, the monoarticular initial distribution, and uncommon location of IA at the knee.

Ophthalmological complications constitute a class effect of treatment with BRAF inhibitors. Encorafenib is a new BRAF inhibitor currently being tested in phase 3 clinical trials for advanced or metastatic melanoma as monotherapy or in combination with the MEK-inhibitor binimetinib. In this study, we present a case of severe bilateral panuveitis and neurosensory hearing loss in an elderly patient treated with encorafenib and binimetinib for metastatic BRAF-mutant melanoma. This constellation of findings is compatible with incomplete Vogt-Koyanagi-Harada (VKH) disease. VKH disease is a rare multisystem disease characterized by granulomatous panuveitis, serous retinal detachments, and neurologic and dermatologic manifestations. In patients with melanoma, its emergence has been correlated to a favorable prognosis of the underlying melanoma by several authors. The patient reported here had a severe panuveitis and bilateral retinal detachments causing permanent visual impairment. She was treated with a long course of systemic corticosteroids, but at the same time, she achieved complete remission of the melanoma lasting for 26 months after permanent encorafenib and binimetinib discontinuation, without further antineoplastic treatment. VKH disease is a rare entity and the need for interdisciplinary cooperation for its diagnosis in patients with melanoma and uveitis is emphasized.

Immune-mediated adverse effects of immune checkpoint inhibitors are rather common, but neuromyopathic immune-related adverse events are very rare. In this report, we present a unique case of a patient with a complex neuromyopathic syndrome with axonal neuropathy and inflammatory myopathy after a single dose of pembrolizumab. An 82-year-old patient with a previously untreated stage IIIc melanoma developed ptosis in the left eye, generalized weakness, and neck and shoulder pain 15 days after pembrolizumab administration. He had left-sided ptosis and miosis, with a normal pupillary light reflex, horizontal diplopia, and voice hoarseness, along with weakness of the neck muscles and a hypokinetic right vocal cord at laryngoscopy. The laboratory evaluation was remarkable for the marked increase in the serum lactate dehydrogenase and creatine phosphokinase levels. Further evaluation revealed findings compatible with axonal neuropathy and inflammatory myopathy. The patient was treated with corticosteroids, immunoglobulin, and plasmapheresis, with a minor response; the patient eventually died. This case represents a newly described syndrome probably associated with pembrolizumab administration.