Diagnosis and treatment of Merkel cell carcinoma: European consensus-based interdisciplinary guideline - Update 2022.

Merkel cell carcinoma (MCC) is a rare skin cancer, accounting for less than 1% of all cutaneous malignancies. It is found predominantly in white populations and risk factors include advanced age, ultraviolet exposure, male sex, immunosuppression, such as AIDS/HIV infection, haematological malignancies or solid organ transplantation, and Merkel cell polyomavirus infection. MCC is an aggressive tumour with 26% of cases presenting lymph node involvement at diagnosis and 8% with distant metastases. Five-year overall survival rates range between 48% and 63%. Two subsets of MCC have been characterised with distinct molecular pathogenetic pathways: ultraviolet-induced MCC versus virus-positive MCC, which carries a better prognosis. In both subtypes, there are alterations in the retinoblastoma protein and p53 gene structure and function. MCC typically manifests as a red nodule or plaque with fast growth, most commonly on sun exposed areas. Histopathology (small-cell neuroendocrine appearance) and immunohistochemistry (CK20 positivity and TTF-1 negativity) confirm the diagnosis. The current staging systems are the American Joint Committee on Cancer/Union for international Cancer control 8th edition. Baseline whole body imaging is encouraged to rule out regional and distant metastasis. For localised MCC, first-line treatment is surgical excision with postoperative margin assessment followed by adjuvant radiation therapy (RT). Sentinel lymph node biopsy is recommended in all patients with MCC without clinically detectable lymph nodes or distant metastasis. Adjuvant RT alone, eventually combined with complete lymph nodes dissection is proposed in case of micrometastatic nodal involvement. In case of macroscopic nodal involvement, the standard of care is complete lymph nodes dissection potentially followed by post-operative RT. Immunotherapy with anti-PD-(L)1 antibodies should be offered as first-line systemic treatment in advanced MCC. Chemotherapy can be used when patients fail to respond or are intolerant for anti-PD-(L)1 immunotherapy or clinical trials.

The soluble form of CD160 acts as a tumor mediator of immune escape in melanoma.

Melanoma is responsible for 90% of skin cancer-related deaths. Major therapeutic advances have led to a considerable improvement in the prognosis of patients, with the development of targeted therapies (BRAF or MEK inhibitors) and immunotherapy (anti-CTLA-4 or -PD-1 antibodies). However, the tumor constitutes an immunosuppressive microenvironment that prevents the therapeutic efficacy and/or promotes the development of secondary resistances. CD160 is an activating NK-cell receptor initially described as delineating the NK and CD8+ T-cell cytotoxic populations. Three forms of CD160 have been described: (1) the GPI isoform, constitutively expressed and involved in the initiation of NK-cells' cytotoxic activity, (2) the transmembrane isoform, neo-synthesized upon cell activation, allowing the amplification of NK cells' cytotoxic functions and (3) the soluble form, generated after cleavage of the GPI isoform, which presents an immuno-suppressive activity. By performing immunohistochemistry analyses, we observed a strong expression of CD160 at the primary cutaneous tumor site of melanoma patients. We further demonstrated that melanoma cells express CD160-GPI isoform and constitutively release the soluble form (sCD160) into the tumor environment. sCD160 was shown to inhibit the cytotoxic activity of NK-cells towards their target cells. In addition, it was found in the serum of melanoma patients and associated with increased tumor dissemination. Altogether these results support a role for sCD160 in the mechanisms leading to the inhibition of anti-tumor response and immune surveillance in melanoma.

When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report.

Immune-related hepatitis (IRH) is a frequent but poorly understood immune-related adverse event and its frequency increases since the use of combination therapy in several cancer types. Therefore, there is an urgent need to develop adapted guidelines to manage IRH.In the present letter, based on Ziogas et al report entitled 'When steroids are not enough in immune-related hepatitis: current clinical challenges discussed on the basis of a case report', several points are discussed: assessment of IRH severity and liver biopsy indication, immune-related cholangitis as a differential diagnosis for some IRH presentation, the need of steroids for IRH management or the indication for second line immunosuppressive treatment and finally, the possibility of immunotherapy resumption.

Severe immune-related hepatitis induced by immune checkpoint inhibitors: Clinical features and management proposal.

BACKGROUND: Immune-related hepatitis (IRH) occurs in 1 to 18% of immune checkpoint inhibitor (ICI)-treated patients. Steroids are usually recommended for grade≥3 IRH, but their impact on IRH resolution and patient survival remains unclear. METHODS: We retrospectively analyzed a prospective cohort of 339 patients treated at Saint-Louis Hospital (Paris, France) with ICIs for advanced melanoma. Cases of grade≥3 IRH were collected and analyzed. Two groups were compared for their biological features and time for IRH resolution and survival: patients who received steroids (steroids group: SG) and patients who did not (nonsteroids group: NSG). FINDINGS: Grade≥3 IRH was observed in 21 patients. Thirteen were treated with steroids (SG), and 8 were not (NSG). The median time for toxicity resolution was 49 days in SG and 24 days in NSG (P=0.62). All but one patient showed a favorable outcome. Two-year survival was 56% in SG and 54% in NSG (P=0.83). Higher transaminase (P=0.002) and bilirubin (P=0.008) and lower prothrombin (P=0.035) levels were observed in SG than in NSG. For 8 (4 SG/4 NSG) patients, ICI was resumed without any hepatitis relapse. INTERPRETATION: Favorable outcomes may be achieved spontaneously and with no steroids in patients with severe IRH. Steroid initiation should be discussed in cases of high bilirubin levels and decreased prothrombin levels. ICI could be resumed without hepatitis relapse. We propose a management algorithm for grade≥3 IRH that should be validated in larger and prospective cohorts.

Checkpoint inhibitor treatment induces an increase in HbA1c in nondiabetic patients.

Immunotherapy greatly improves clinical outcomes in treated patients with cancer. However, the long-lasting immune response and long duration of therapy could induce long-term adverse effects owing to the chronic inflammation induced. Type 2 diabetes is now recognized as an inflammatory disease. In addition, immunotherapy is concerned with increase in the production of tumor necrosis factor-α, interleukin-2, and interferon-γ, which are involved in the inflammatory process. Based on these observations, we hypothesized that anti-programmed cell death-1 (anti-PD-1) and/or anticytotoxic T-lymphocyte-associated protein-4 therapy could contribute to type 2 diabetes genesis in treated patients. Therefore, to evaluate this hypothesis, we studied HbA1c levels during follow-up in patients treated with anti-PD-1 and/or anticytotoxic T-lymphocyte-associated protein-4 therapy. A prospective and observational study was performed in an oncodermatology department (Saint-Louis Hospital, Paris, France) from March 2015 to February 2017. Sixty-two patients meeting the inclusion criteria were enrolled. Forty-three patients had paired HbA1c measurements during their follow-up period and were analyzed. The median follow-up was 3 months. We noted an increase in HbA1c levels from 5.3% [interquartile range (IQR): 5.1-5.5; range: 4.5-6.2) to 5.45% (IQR: 5.2-5.7; range: 4.7-6.2; P=0.037). This observation was confirmed in the subgroup of patients who did not receive concomitant glucocorticoids; their median HbA1c levels increased from 5.3% (IQR: 5.1-5.5; range: 4.7-6.2) to 5.5% (IQR: 5.2-5.7; range: 4.7-6.3; P=0.025). Variables such as age, BMI, and sex were not associated with the HbA1c level increase, but a tendency toward rising HbA1c levels was observed in treatments longer than 12 months. This study demonstrates that treatment with anti-PD-1 antibodies may impair glucose metabolism, as measured by increasing HbA1c levels.

Long-Term Survival in Patients Responding to Anti-PD-1/PD-L1 Therapy and Disease Outcome upon Treatment Discontinuation.

PURPOSE: Anti-PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types. However, the long-term outcome of cancer patients responding to these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti-PD-(L)1 monotherapy across multiple cancer types.Patients and Methods: Data from patients treated with an anti-PD-(L)1 monotherapy in a phase I trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (n = 19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied. RESULTS: Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RP) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively. No death occurred in the 21 complete responders (CR) during the overall follow-up. However, many partial responders (PR) showed subsequent tumor relapses to treatment. Long responders (response ≥2 years) represented 11.8% of the overall population. These findings should be validated in further prospective studies. CONCLUSIONS: There are currently no differences in therapeutic strategies between CRs and PRs to anti-PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratification strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.See related commentary by Cohen and Flaherty, p. 910.

Occurrence of type 1 and type 2 diabetes in patients treated with immunotherapy (anti-PD-1 and/or anti-CTLA-4) for metastatic melanoma: a retrospective study.

Anti-PD-1 and anti-CTLA-4 antibodies cause immune-related side effects such as autoimmune type 1 diabetes (T1D). It has also been suggested that by increasing TNF-α, IL-2 and IFN-γ production, anti-PD-1 and/or anti-CTLA-4 treatment could affect pancreatic beta cell function and insulin sensitivity. This study was based on a retrospective observational analysis from 2 July 2014 to 27 June 2016, which evaluated the occurrence of T1D and changes in glycemia and C-reactive protein (CRP) plasma concentrations in patients undergoing anti-PD-1 and/or anti-CTLA-4 treatment for melanoma at the Saint Louis Hospital. All cases of T1D that developed during immunotherapy registered in the French Pharmacovigilance Database (FPVD) were also considered. Among the 132 patients included, 3 cases of T1D occurred. For the remaining subjects, blood glucose was not significantly affected by anti-PD-1 treatment, but CRP levels (mg/l) significantly increased during anti-PD-1 treatment (p = 0.017). However, 1 case of type 2 diabetes (T2D) occurred (associated with a longer therapy duration). Moreover, glycemia of patients pretreated (n = 44) or concomitantly treated (n = 8) with anti-CTLA-4 tended to increase during anti-PD-1 therapy (p = 0.068). From the FPVD, we obtained 14 cases of T1D that occurred during immunotherapy and were primarily characterized by the rapidity and severity of onset. In conclusion, in addition to inducing this rare immune-related diabetes condition, anti-PD-1 treatment appears to increase CRP levels, a potential inflammatory trigger of insulin resistance, but without any short-term impact on blood glucose level.

Focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib in metastatic melanoma.

Therapeutic advances derived from targeted therapy and immune checkpoint inhibitors can improve melanoma prognosis. Since 2015, cobimetinib has been approved in combination with vemurafenib in the first-line treatment for BRAF-mutated melanoma. For NRAS-mutated melanomas, MEK inhibition seems to be a therapeutic target, and association with checkpoint inhibitor provides a further therapeutic perspective. Infraclinical creatine phosphokinase (CPK) elevation is an MEK inhibitor side effect. We describe a case of focal necrotizing myopathy with 'dropped-head syndrome' induced by cobimetinib, 1 month after its introduction. The clinical presentation comprised interscapular pain, axial fatigue with cervical hypotonia, CPK elevation, intense fluorine-18-fluorodeoxyglucose uptake in cervical muscles, and necrotizing myopathy was confirmed by muscle biopsy. Cobimetinib was temporarily discontinued, resulting in CPK normalization. Re-evaluation showed partial response, motivating continuation of combination therapy with a reduced dose of cobimetinib (40 mg/day). Because prescription of targeted therapies is likely to increase, this adverse event should be known.

Autoimmune diabetes induced by PD-1 inhibitor-retrospective analysis and pathogenesis: a case report and literature review.

Anti-PD-1 antibody treatment is approved in advanced melanoma and provides median overall survival over 24 months. The main treatment-related side effects are immune-related adverse events, which include rash, pruritus, vitiligo, thyroiditis, diarrhoea, hepatitis and pneumonitis. We report a case of autoimmune diabetes related to nivolumab treatment. A 73-year-old man was treated in second line with nivolumab at 3 mg/kg every two weeks for metastatic melanoma. At 6 weeks of treatment, he displayed diabetic ketoacidosis. Nivolumab was withheld 3.5 weeks and insulin therapy was initiated, enabling a normalization of glycaemia and the disappearance of symptoms. Laboratory investigations demonstrated the presence of islet cell autoantibodies, while C-peptide was undetectable. Retrospective explorations on serum banked at week 0 and 3 months before the start of nivolumab, already showed the presence of autoantibodies, but normal insulin, C-peptide secretion and glycaemia. Partial response was obtained at month 3, and nivolumab was then resumed at the same dose. The clinical context and biological investigations before, at and after nivolumab initiation suggest the autoimmune origin of this diabetes, most likely induced by anti-PD-1 antibody in a predisposed patient. The role of PD-1/PD-L1 binding is well known in the pathogenesis of type 1 diabetes. Therefore, this rare side effect can be expected in a context of anti-PD-1 treatment. Glycaemia should be monitored during PD-1/PD-L1 blockade. The presence of autoantibodies before treatment could identify individuals at risk of developing diabetes, but systematic titration may not be relevant considering the rarity of this side effect.

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome induced by nivolumab.

INTRODUCTION: A new articular syndrome described as immunrelated side effect of immunotherapy: PD-1 inhibitors have revolutionized the treatment of advanced melanoma but are responsible for immune-related toxicity. We report a case of remitting seronegative symetrical synovitis with pitting edema (RS3PE) syndrome induced by nivolumab. CASE REPORT: A 80 year-old man with stage IV BRAF-wild type and NRAS exon 2-mutated melanoma was treated first line by nivolumab 3mg/kg every 2 weeks. At week 4, before the 3rd infusion, he presented with inflammatory arthralgia, synovitis of proximal interphalangeal, wrist and ankle joints, and edema of both hands and forearms. Laboratory tests showed inflammatory syndrome (CRP = 8.4mg/dL), negative rheumatoid factor, and anti-CCP antibodies. Radiographs did not show any joint erosion but joint ultrasound displayed intra-articular effusion and tenosynovitis. PET/CT performed 6 and 3 months before treatment for melanoma work-up showed an isolated hypermetabolism of the shoulder girdle. The diagnosis of RS3PE was retained. A systemic corticosteroid treatment (0.5mg/kg/d) was initiated; nivolumab was hold during 4 weeks leading to remission of clinical symptoms within 10 days, CRP level normalization and without relapse when nivolumab was resumed. Corticosteroids were progressively tapered and stopped after 9 months. After 5 months, anti-PD1 was definitively stopped because of disease progression. CONCLUSION: With this atypical case, clinicians should remain alert on a whole range of autoimmune diseases susceptible to be induced.