Immune-checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4 (CTL A-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death 1 ligand 1 (PD-L1) antibodies, are arguably the most important development in cancer therapy over the past decade. The indications for these agents continue to expand across malignancies and disease settings, thus reshaping many of the previous standard-of-care approaches and bringing new hope to patients. One of the costs of these advances is the emergence of a new spectrum of immune-related adverse events (irAEs), which are often distinctly different from the classical chemotherapy-related toxicities. Owing to the growing use of ICIs in oncology, clinicians will increasingly be confronted with common but also rare irAEs; hence, awareness needs to be raised regarding the clinical presentation, diagnosis and management of these toxicities. In this Review, we provide an overview of the various types of irAEs that have emerged to date. We discuss the epidemiology of these events and their kinetics, risk factors, subtypes and pathophysiology, as well as new insights regarding screening and surveillance strategies. We also highlight the most important aspects of the management of irAEs.

IMPORTANCEThere are limited comparative data on the durability of neutralizing antibody (nAb) responses elicited by messenger RNA (mRNA) vaccines against the SARS-CoV-2 variants of concern (VOCs) in immunocompromised patients and healthy controls.OBJECTIVE To assess the humoral responses after vaccination with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccines. DESIGN, SETTING, AND PARTICIPANTSIn this prospective, longitudinal monocentric comparative effectiveness study conducted at the Lausanne University Hospital, binding IgG anti-spike antibody and nAb levels were measured at 1 week, 1 month, 3 months, and 6 months after vaccination with mRNA-1273 (24.6% of participants) or BNT162b2 (75.3% of participants).INTERVENTIONS All participants received 2 doses of either mRNA-1273 or BNT162b2 vaccines 4 to 6 weeks apart. MAIN OUTCOMES AND MEASURESThe primary outcome of the study was the persistence of nAb responses against the original, nonvariant SARS-CoV-2 (2019-nCoV) and different VOCs at 6 months after vaccination. Key secondary outcomes were associations of the type of mRNA vaccine, the underlying disease, and the treatment with the response to vaccination. RESULTS Among the 841 participants enrolled between January 14 and August 8, 2021, the patient population comprised 637 participants (mean [SD] age, 61.8 [13.7] years; 386 [60.6%] female), and the healthy control population comprised 204 participants (mean [SD] age, 45.9 [12.0] years; 144 [70.6%] female). There were 399 patients with solid cancers, 101 with hematologic cancers, 38 with solid organ transplants, 99 with autoimmune diseases, and 204 healthy controls. More than 15 000 nAb determinations were performed against the original, nonvariant 2019-nCoV and the Alpha, Beta, Gamma, and Delta variants. The proportions of nAbs and their titers decreased in all study groups at 6 months after vaccination, with the greatest decreases for the Beta and Delta variants. For Beta, the proportion decreased to a median (SE) of 39.2% (5.5%) in those with hematologic cancers, 44.8% (2.7%) in those with solid cancers, 23.1% (8.3%) in those with solid organ transplants, and 22.7% (4.8%) in those with autoimmune diseases compared with 52.1% (4.2%) in healthy controls. For Delta, the proportions decreased to 41.8% (5.6%) in participants with hematologic cancer, 51.9% (2.7%) in those with solid cancers, 26.9% (8.7%) in those with solid organ transplants, and 30.7% (5.3%) in those with autoimmune diseases compared with 56.9% (4.1%) healthy controls. Neutralizing antibody titers decreased 3.5-to 5-fold between month 1 and month 6, and the estimated duration of response was greater and more durable among those participants vaccinated with mRNA-1273. In participants with solid cancers, the estimated duration of nAbs against the Beta variant was 221 days with mRNA-1273 and 146 days with BNT162b2, and against the Delta variant, it was 226 days with mRNA-1273 and 161 with BNT162b2. The estimated duration of nAbs in participants with hematologic cancers was 113 and 127 days ag...

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Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males; 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e. nonmonomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ (98%) CD4- (94%) CD5- (97%) CD7+ (97%) CD8+ (90%) CD56+ (86%) CD103+ (80%) cytotoxic marker+ (98%)) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with nonmonomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%) JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signalling and encompasses genetic and morphologic variants associated with very high clinical risk.

Patients with haemophilia appear to have a reduced incidence of coronary artery disease and of its related mortality [1], principally because they are less prone to develop acute occluding thrombi. However, they might not be protected from atherosclerosis as revealed by clinical studies [2] and autopsy of haemophiliacs with fatal myocardial infarction showing extensive atherosclerotic lesions but only rare fresh thrombi [3].In recent decades major advances have been made in the management of haemophilia resulting in an increase in life expectancy which is now estimated to range between 60 and 70 years. The prevalence of cardiac disease in the haemophiliac population is, therefore, likely to increase, which will, in turn, require greater need for cardiac investigation and treatment.At present, 36 cases of myocardial infarction in patients diagnosed with haemophilia A have been reported in the literature [3]. In 25 of these cases the infarction occurred during or after the infusion of one or more of the following products: factor VIII (FVIII) concentrates, activated and non-activated prothrombin complex concentrates, recombinant factor VIIa (rfVIIa), desmopressin and antifibrinolytic drugs.We report here the case of a 57-year-old male patient with a history of severe haemophilia A (W255R mutation of the exon 7) who was referred to our hospital because of an acute coronary syndrome.The day of the hospitalization he had two episodes of severe chest pain radiating to his neck and left arm. The pain occurred after a physical effort and was relieved by sublingual nitroglycerine. He did not receive infusion of recombinant factor VIII (rfVIII), prothrombin complex concentrates or rfVIIa preparations in the previous 2 weeks.The patient was diabetic, obese (body mass index = 31 kg m )2 ) and was treated for hypertension and mild hypercholesterolemia. A recent liver biopsy demonstrated a non-alcoholic steato-hepatitis. When the patient arrived to the emergency room, he was hypertensive (160/100 mmHg) but free of chest pain. The rest of the examination was unremarkable. Initial laboratory analysis showed blood count, creatinin, creatin phosphokinase and troponin I within the normal range. Prothrombin time was normal whereas activated partial thromboplastin time (APTT) was 72 s and FVIII level <1%, consistent with the diagnosis of severe haemophilia A. An electrocardiogram (ECG) revealed an acute ischemia in the inferior territory.During his stay in the emergency room, the patient had a third episode of chest pain. He was therefore transferred to the intensive care unit and treated with aspirin 100 mg day )1 , clopidogrel 300 mg loading dose followed by 75 mg day )1 and continuous intravenous perfusion of heparin. Thirty minutes before the initiation of intravenous heparin, he received a bolus injection of 50 IU kg )1 of rfVIII, 25 IU kg )1 4 h later, and then a continuous intravenous infusion was started with an initial rate of 3 IU kg )1 h )1 , to achieve a FVIII level of 80%. Factor VIII plasma level was measured daily in a...