To our knowledge, we report the first case of sarcoid-like granulomatous reaction induced by nivolumab, a fully human IgG4 anti-programmed death 1 (PD-1) immune checkpoint inhibitor antibody. A ...57-year-old man was treated with nivolumab 3 mg/kg for 2 weeks for a desmoplastic melanoma stage III American Joint Commission on Cancer, with no BRAF , NRAS , and cKit mutations. At 10 months, although melanoma complete response was achieved, he developed sarcoid-like granulomatous reaction in the mediastinal lymph node and skin, which resumed after nivolumab arrest. Melanoma did not relapse after 12 months of follow-up. Considering the recently demonstrated role of activated PD-1/PDL-1 axis in sarcoidosis, granulomatous reaction in the patient seems to be a paradoxical reaction, but similar observations have been reported with ipilimumab, another immune checkpoint inhibitor. Sarcoid-like granulomatous reaction during immunotherapy treatment could be a manifestation of cell-mediated immunity induced by these drugs. Impact of granulomatous reaction induced by immune checkpoint inhibitor on melanoma progression is not known and requires further study. Melanoma patients treated by immunotherapy (anti-cytotoxic T-lymphocyte-associated protein-4/anti-PD-1) should be considered for developing sarcoid-like granulomatous reaction that must not be confused with tumor progression.
Background A rare variant of mycosis fungoides (MF), syringotropic MF (STMF) is characterized by a particular tropism of the lymphocytic infiltrate for the eccrine structures, and included in the ...follicular subtype of MF in the World Health Organization–European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas. Objective We sought to determine the clinicopathologic features and disease course of patients with STMF. Methods A retrospective study was conducted to identify patients with STMF from 1998 to 2013. Results Nineteen patients were included: 15 men and 4 women, mean age 55 years (range, 24-86). Most had multiple lesions (n = 16, 84%) with associated alopecia (n = 12, 63%) and/or punctuated aspect (n = 12, 63%). Palms or soles were involved in 10 cases (53%). Folliculotropism was found in 13 cases (68%). After a median follow-up of 70 months (range, 2-140), 3 patients died, 1 from disease-related death. The 5-year overall and disease-specific survival were 100%. The disease-specific survival was significantly higher than in 54 patients with folliculotropic MF without syringotropism (5-year disease-specific survival, 74%; 95% confidence interval, 58%-94%, P = .02). Limitations Retrospective setting is a limitation. Conclusions In the spectrum of adnexotropic MF, STMF appears as a distinct entity from follicular MF, with peculiar clinical characteristics and natural history.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Abstract 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. A 80 year-old man with stage IV BRAF wild type, NRAS exon 2 mutated melanoma was treated first line by Nivolumab 3 mg/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 8.4 mg/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 three 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 (0.5 mg/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. With this atypical case, clinicians should remain alert on a whole range of autoimmune diseases susceptible to be induced.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK, ZRSKP
Background Hidradenitis suppurativa (HS) is a chronic and debilitating disorder. Despite its significant prevalence, few reports of therapeutic studies are available. Recent case studies have ...reported the efficacy of antitumor necrosis factor monoclonal antibodies in treating the condition. In the study presented here, we assessed the safety and efficacy of infliximab in a series of patients with severe HS. Methods We reviewed all consecutive patients with severe HS and treated with infliximab between October 2004 and December 2005. They were evaluated using the Sartorius severity score, a physician and patient overall assessment, and the Skindex-29 quality-of-life index. A substantive response was defined as marked or moderate overall improvement assessed by both physician and patient. Results Seven patients were reviewed. All received at least 3 infusions of infliximab (5 mg/kg) in weeks 0, 2, and 6, and 5 patients received a fourth infusion at week 10. At week 6, a substantive improvement was seen in 5 patients. With the other 2 patients, any improvement was minimal or nonexistent. At week 10, there was a substantive response in 2 of the 5 patients. Adverse events occurred in 3 patients: abdominal pain caused by colon cancer, a multifocal motor neuropathy with conduction block, and a severe allergic reaction. Limitations We have reported on only 7 patients. All had severe and chronic disease. Conclusion The efficacy of infliximab in patients with severe HS seems transient and is associated with significant toxicity. Prospective randomized studies are required to better assess the benefit-risk ratio of antitumor necrosis factor agents for this indication.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Background Kaposi's sarcoma (KS), a virus-associated neoplasm, can be treated locally or systemically with interferon alfa. Therefore, imiquimod, an immune response modifier able to induce ...interferon-α secretion in situ, could prove a good local treatment for KS skin lesions. Objective We sought to determine the efficacy and safety of imiquimod 5% cream for the topical treatment of classic or endemic KS skin lesions in patients who are HIV negative. Methods We conducted a prospective, open-label, single center, phase II clinical trial. Imiquimod cream was applied under occlusion 3 times a week for 24 weeks. The main efficacy end points were the safety of topical imiquimod and the overall clinical response in patients evaluated on the basis of modified AIDS Clinical Trials Group criteria at 36 weeks. The statistical analysis was based on the intent-to-treat data set. Results Seventeen patients were enrolled. Eight (47%) presented objective overall clinical response (2 complete and 6 partial responses). Tumor progression was noted in 6 patients. The most frequent side effects were local itching and erythema, seen in 9 patients (53%). Limitations This was not a randomized placebo-controlled study and was restricted to a small number of patients. Conclusion Topical imiquimod 5% cream had antitumor activity in about half the patients with classic and endemic KS and was generally well tolerated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Background Very few studies have focused on fat redistribution induced by corticosteroids. Objective To establish the incidence and risk factors of facial (“moon face”) and cervical (“buffalo hump”) ...lipodystrophy due to long-term (≥3 months), high dosage (≥20 mg/d) systemic corticosteroid therapy. Methods Between June 2003 and May 2005 we conducted a prospective study in two French tertiary centers. All consecutive patients starting long-term systemic corticosteroid therapy at an initial daily dosage of 20 mg or more were enrolled in this study. Three investigators assessed the development of facial and cervical corticosteroid-induced lipodystrophy (CIL) from standardized photographs. Demographic, clinical, and nutritional data were examined to assess risk factors of CIL. Results Eighty-eight patients were enrolled (women: 75%, mean age: 57.4 ± 17.9 years, mean baseline dosage of prednisone: 56 ± 15 mg/d). The cumulative incidence rate of CIL at months 3 and 12 was 61% ± 8% and 69% ± 9%, respectively. In multivariate analyses the risk of CIL at the third month was higher in women (odds ratio OR: 10.87 2.43-58.82), in subjects younger than 50 years of age (OR: 11.11 2.19-37.89), in subjects with a high initial body mass index (OR: 1.56 1.21-2.03 per increment of 1 kg/m2 ) and in subjects with high energy intake (OR: 6.11 1.35-27.75 when higher than 30 kcal/d/kg). Limitations Photographic analysis is not a conventional method for the diagnosis of CIL. Conclusion CIL frequently occurs, especially in overweight subjects and in women, who are also at higher risk to develop other forms of lipodystrophies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK
Summary Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, ...but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% 95·9% CI 21·9–43·1) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Interpretation Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Funding Merck KGaA, Darmstadt, Germany.
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Summary Background Ipilimumab is an approved treatment for patients with advanced melanoma. We aimed to assess ipilimumab as adjuvant therapy for patients with completely resected stage III melanoma ...at high risk of recurrence. Methods We did a double-blind, phase 3 trial in patients with stage III cutaneous melanoma (excluding lymph node metastasis ≤1 mm or in-transit metastasis) with adequate resection of lymph nodes (ie, the primary cutaneous melanoma must have been completely excised with adequate surgical margins) who had not received previous systemic therapy for melanoma from 91 hospitals located in 19 countries. Patients were randomly assigned (1:1), centrally by an interactive voice response system, to receive intravenous infusions of 10 mg/kg ipilimumab or placebo every 3 weeks for four doses, then every 3 months for up to 3 years. Using a minimisation technique, randomisation was stratified by disease stage and geographical region. The primary endpoint was recurrence-free survival, assessed by an independent review committee, and analysed by intention to treat. Enrollment is complete but the study is ongoing for follow-up for analysis of secondary endpoints. This trial is registered with EudraCT, number 2007-001974-10, and ClinicalTrials.gov , number NCT00636168. Findings Between July 10, 2008, and Aug 1, 2011, 951 patients were randomly assigned to ipilimumab (n=475) or placebo (n=476), all of whom were included in the intention-to-treat analyses. At a median follow-up of 2·74 years (IQR 2·28–3·22), there were 528 recurrence-free survival events (234 in the ipilimumab group vs 294 in the placebo group). Median recurrence-free survival was 26·1 months (95% CI 19·3–39·3) in the ipilimumab group versus 17·1 months (95% CI 13·4–21·6) in the placebo group (hazard ratio 0·75; 95% CI 0·64–0·90; p=0·0013); 3-year recurrence-free survival was 46·5% (95% CI 41·5–51·3) in the ipilimumab group versus 34·8% (30·1–39·5) in the placebo group. The most common grade 3–4 immune-related adverse events in the ipilimumab group were gastrointestinal (75 16% vs four <1% in the placebo group), hepatic (50 11% vs one <1%), and endocrine (40 8% vs none). Adverse events led to discontinuation of treatment in 245 (52%) of 471 patients who started ipilimumab (182 39% during the initial treatment period of four doses). Five patients (1%) died due to drug-related adverse events. Five (1%) participants died because of drug-related adverse events in the ipilimumab group; three patients died because of colitis (two with gastrointestinal perforation), one patient because of myocarditis, and one patient because of multiorgan failure with Guillain-Barré syndrome. Interpretation Adjuvant ipilimumab significantly improved recurrence-free survival for patients with completely resected high-risk stage III melanoma. The adverse event profile was consistent with that observed in advanced melanoma, but at higher incidences in particular for endocrinopathies. The risk–benefit ratio of adjuvant ipilimumab at this dose and schedule requires additional assessment based on distant metastasis-free survival and overall survival endpoints to define its definitive value. Funding Bristol-Myers Squibb.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPUK