Cytotoxic cutaneous adverse drug reactions during anti-PD-1 therapy

PURPOSE: Immunotherapy experienced impressive progresses in cancer treatment. Antibodies against PD-1 improved survival in different types of cancer including melanoma. They are generally well tolerated. However, skin toxicities including pruritus, rashes and vitiligo are reported. Although frequent, they are have not been further characterized yet. In this analysis we aimed to systematically assess and characterize the adverse cutaneous reactions observed in melanoma patients treated with anti-PD-1 antibodies. EXPERIMENTAL DESIGN: Melanoma patients were treated with anti-PD-1 antibodies within clinical trials and early access program. Adverse cutaneous eruptions emerged in our melanoma patient cohort were systematically investigated and classified using histology and gene expression profiling in comparison to maculopapular drug rash, cutaneous graft versus host disease and the severe drug eruption toxic epidermal necrolysis. RESULTS: Between Feb 2013 and Sept 2015, 68 stage IV melanoma patients were treated at the University Hospital Zurich; 15 patients (22%) developed cutaneous reactions and 10 (15%) vitiligo. The cutaneous reactions ranged from small erythematous papules with mild pruritus to disseminated erythematous maculopapular rashes without signs of epidermal involvement to severe maculopapular rashes including epidermal detachment and mucosal involvement. Although skin involvement varied from mild rash to bullous drug eruptions, gene expression profiling pathogenically classified all investigated cases as toxic epidermal necrolysis-like reactions. CONCLUSIONS: As predicted by the PD-1 knock out mouse, anti-PD-1 antibodies frequently cause adverse cutaneous reactions. Gene expression profiling reminds in all cases to a toxic epidermal necrolysis-like pattern suggesting that PD-1/PD-L1 interaction is required to preserve epidermal integrity during inflammatory skin reactions

SARS-CoV-2 variant B.1.1.7 susceptibility and infectiousness of children and adults deduced from investigations of childcare centre outbreaks, Germany, 2021

We investigated three SARS-CoV-2 variant B.1.1.7 childcare centre and related household outbreaks. Despite group cohorting, cases occurred in almost all groups, i.e. also among persons without close contact. Children’s secondary attack rates (SAR) were similar to adults (childcare centres: 23% vs 30%; p = 0.15; house-holds: 32% vs 39%; p = 0.27); child- and adult-induced household outbreaks also led to similar SAR. With the advent of B.1.1.7, susceptibility and infectiousness of children and adults seem to converge. Public health measures should be revisited accordingly.Peer Reviewe

Positivenanteile, RNA-Kopien und Anzüchtbarkeit von Proben zum Isolationsende von SARS-CoV-2 VOC B.1.1.7 („Alpha“) positiven Fallpersonen; LK Bergstraße; März 2021

Die Virusvariante B.1.1.7 („Alpha“), die seit Dezember 2020 in Deutschland zirkuliert und seit etwa Ende Februar 2021 das In¬fektionsgeschehen dominiert, gilt als transmissibler als die bis dato zirkulierenden Va¬rianten. Unklar ist, ob sie sich auch deshalb in der Population durchsetzt, weil infizierte Personen län¬ger vermehrungsfähige Viren ausscheiden, d. h. länger ansteckend sind. Für die im Epidemiologischen Bulletin 25/2021 veröffentlichte Studie wurden im Rahmen eines Amtshilfeersuchens des Landkreises Bergstraße Proben von 53 B.1.1.7-infizierten Fallpersonen zum Ende ihrer Isolations¬zeit abgenommen und am RKI untersucht. Mehr als 80 % der Proben waren bis ein¬schließlich Tag 14 noch PCR-positiv, jedoch ließ sich aus keiner dieser Proben Virus anzüchten. Somit er¬scheint eine Isolationsdauer von 14 Tagen mit einem abschließenden negativen Antigentest bei Fallperso¬nen mit einem Verdacht oder einem Nachweis von B.1.1.7 als ausreichend sicher.Peer Reviewe

Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy

BackgroundAnti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to anti- PD-1 monotherapy.MethodsA total of 315 patients with advanced melanoma treated with pembrolizumab (2 or 10 mg kg-1 Q2W or Q3W) or nivolumab (3 mg kg-1 Q2W) at four cancer centres between 2011 to 2013 served as the setting for the present cohort study. Variables with significant association to response on a univariate analysis were entered into a forward stepwise logistic regression model and were given a score based on ORs to calculate a clinical prediction scale.ResultsThe developed clinical prediction scale included elevated LDH (1 point), age <65 years (1 point), female sex (1 point), history of ipilimumab treatment (2 points) and the presence of liver metastasis (2 points). The scale had an area under the receiver-operating curve (AUC) of 0.73 (95% CI 0.67, 0.80) in predicting response to therapy. The predictive performance of the score was maintained in the validation cohort (AUC 0.70 (95% CI 0.58, 0.81)) and the goodness-to-fit model demonstrated good calibration.ConclusionsBased on a large cohort of patients, we developed and validated a simple five-factor prediction scale for the clinical activity of PD-1 antibodies in advanced melanoma patients. This scale can be used to stratify patients participating in clinical trials