Response durability after cessation of immune checkpoint inhibitors in patients with metastatic Merkel cell carcinoma: a retrospective multicenter DeCOG study.

BACKGROUND: Immune checkpoint inhibitors (ICI) have led to a prolongation of progression-free and overall survival in patients with metastatic Merkel cell carcinoma (MCC). However, immune-mediated adverse events due to ICI therapy are common and often lead to treatment discontinuation. The response duration after cessation of ICI treatment is unknown. Hence, this study aimed to investigate the time to relapse after discontinuation of ICI in MCC patients. METHODS: We analyzed 20 patients with metastatic MCC who have been retrospectively enrolled at eleven skin cancer centers in Germany. These patients have received ICI therapy and showed as best overall response (BOR) at least a stable disease (SD) upon ICI therapy. All patients have discontinued ICI therapy for other reasons than disease progression. Data on treatment duration, tumor response, treatment cessation, response durability, and tumor relapse were recorded. RESULTS: Overall, 12 of 20 patients (60%) with MCC relapsed after discontinuation of ICI. The median response durability was 10.0 months. Complete response (CR) as BOR to ICI-treatment was observed in six patients, partial response (PR) in eleven, and SD in three patients. Disease progression was less frequent in patients with CR (2/6 patients relapsed) as compared to patients with PR (7/11) and SD (3/3), albeit the effect of initial BOR on the response durability was below statistical significance. The median duration of ICI therapy was 10.0 months. Our results did not show a correlation between treatment duration and the risk of relapse after treatment withdrawal. Major reasons for discontinuation of ICI therapy were CR (20%), adverse events (35%), fatigue (20%), or patient decision (25%). Discontinuation of ICI due to adverse events resulted in progressive disease (PD) in 71% of patients regardless of the initial response. A re-induction of ICI was initiated in 8 patients upon tumor progression. We observed a renewed tumor response in 4 of these 8 patients. Notably, all 4 patients showed an initial BOR of at least PR. CONCLUSION: Our results from this contemporary cohort of patients with metastatic MCC indicate that MCC patients are at higher risk of relapse after discontinuation of ICI as compared to melanoma patients. Notably, the risk of disease progression after discontinuation of ICI treatment is lower in patients with initial CR (33%) as compared to patients with initial PR (66%) or SD (100%). Upon tumor progression, re-induction of ICI is a feasible option. Our data suggest that the BOR to initial ICI therapy might be a potential predictive clinical marker for a successful re-induction.

Clinical evaluation of Toxi.Prep: a semiautomated solid-phase extraction system for screening of drugs in urine.

A prototype Toxi.Prep (TP) system that utilizes solid-phase extraction (SPE) has been developed as a method for broad-spectrum drug screening and identification of tetrahydrocannabinol (THC) metabolites in urine. TP can simultaneously extract up to seven specimens while automating the process of sample extraction, washing, and elution onto a chromatogram. TP was compared with the Toxi. Lab A (TL-A) system for extraction of basic drugs only. In a blind study, 33 distinct drugs and metabolites were detected in 55 urines over 13 runs. Of the drug occurrences, 68.8% (141 of 205) were detected on both TP and TL-A. Of the 13 runs, quinidine and quinine, nortriptyline metabolites, and diphenhydramine were noted more frequently on TP than TL-A, whereas nicotine and metabolites, morphine, and methadone metabolites were more frequently noted on TL-A. Twenty specimens were analyzed for THC metabolites. Of the cases positive for THC metabolites, 100% (16 of 16) were positive by both methods. Time and motion studies for all runs proved an overall labor reduction for extraction and spotting by approximately 40%.

[Tissue lipid peroxidation in nutritional encephalomalacia of broiler chickens]. / Zur Erfassung der Gewebs-Lipidperoxidation bei der Nutritiven Enzephalomalazie des Broilers.

The consequences of different dietary fats in combination with two vitamin E levels on peroxidative tissue damage of chicken brain and liver and its meaning for development of nutritional encephalomalacia (NE) were investigated. A feeding experiment was performed with 1-day-old chickens from hens on a vitamin-E-poor diet. The animals received a vitamin-E-deficient basic diet containing 10% fat, rich in either C18:3n3-, C18:2n6- or C18:1n9-fatty acids. The fat was given either fresh or oxidized (peroxidation number: 250) and 0 or 50 ppm alpha-tocopherylacetate was added. Typical symptoms of NE occurred mainly in those groups fed with n6-fatty acids beginning on day 7. In order to evaluate oxidative tissue damage, conjugated dienes, fluorescent pigments and TBA-reactive substances were determined in liver, cerebrum and cerebellum. Brain was examined histologically. In liver and cerebrum, the feeding of oxidized fats led to a 20% increase in conjugated dienes. Fluorescent pigments could be determined only in the brain tissues. However, feeding conditions had no effect, although autofluorescence was observed histologically in the affected animals. TBA-reactive substances were heightened in cerebrum (30%) and liver (130%) as a result of feeding linolenic acid. Vitamin E deficiency doubled TBA-reactive substances only in the liver. The parameters measured did not show intensified lipid peroxidation in the cerebellum of the animals fed the NE producing diet. Rather, the liver seems to be affected by the oxidative stress.