IMPORTANCE: Management of checkpoint inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti-tumor... Show moreIMPORTANCE: Management of checkpoint inhibitor-induced immune-related adverse events (irAEs) is primarily based on expert opinion. Recent studies have suggested detrimental effects of anti-tumor necrosis factor on checkpoint-inhibitor efficacy. OBJECTIVE: To determine the association of toxic effect management with progression-free survival (PFS), overall survival (OS), and melanoma-specific survival (MSS) in patients with advanced melanoma treated with first-line ipilimumab-nivolumab combination therapy. DESIGN, SETTING, AND PARTICIPANTS: This population-based, multicenter cohort study included patients with advanced melanoma experiencing grade 3 and higher irAEs after treatment with first-line ipilimumab and nivolumab between 2015 and 2021. Data were collected from the Dutch Melanoma Treatment Registry. Median follow-up was 23.6 months. MAIN OUTCOMES AND MEASURES: The PFS, OS, and MSS were analyzed according to toxic effect management regimen. Cox proportional hazard regression was used to assess factors associated with PFS and OS. RESULTS: Of 771 patients treated with ipilimumab and nivolumab, 350 patients (median [IQR] age, 60.0 [51.0-68.0] years; 206 [58.9%] male) were treated with immunosuppression for severe irAEs. Of these patients, 235 received steroids alone, and 115 received steroids with second-line immunosuppressants. Colitis and hepatitis were the most frequently reported types of toxic effects. Except for type of toxic effect, no statistically significant differences existed at baseline. Median PFS was statistically significantly longer for patients treated with steroids alone compared with patients treated with steroids plus second-line immunosuppressants (11.3 [95% CI, 9.6-19.6] months vs 5.4 [95% CI, 4.5-12.4] months; P=.01). Median OS was also statistically significantly longer for the group receiving steroids alone compared with those receiving steroids plus second-line immunosuppressants (46.1 months [95% CI, 39.0 months-not reached (NR)] vs 22.5 months [95% CI, 36.5 months-NR]; P=.04). Median MSS was also better in the group receiving steroids alone compared with the group receiving steroids plus second-line immunosuppressants (NR [95% CI, 46.1 months-NR] vs 28.8 months [95% CI, 20.5 months-NR]; P=.006). After adjustment for potential confounders, patients treated with steroids plus second-line immunosuppressants showed a trend toward a higher risk of progression (adjusted hazard ratio, 1.40 [95% CI, 1.00-1.97]; P=.05) and had a higher risk of death (adjusted hazard ratio, 1.54 [95% CI, 1.03-2.30]; P=.04) compared with those receiving steroids alone. CONCLUSIONS AND RELEVANCE: In this cohort study, second-line immunosuppression for irAEs was associated with impaired PFS, OS, and MSS in patients with advanced melanoma treated with first-line ipilimumab and nivolumab. These findings stress the importance of assessing the effects of differential irAE management strategies, not only in patients with melanoma but also tumor types. Show less
Rijn, R. van; Schurink, I.J.; Vries, Y. de; Berg, A.P. van den; Cerisuelo, M.C.; Murad, S.D.; ... ; DHOPE DCD Trial Investigators 2021
BACKGROUNDTransplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion... Show moreBACKGROUNDTransplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited.METHODSIn this multicenter, controlled trial, we randomly assigned patients who were undergoing transplantation of a liver obtained from a donor after circulatory death to receive that liver either after hypothermic oxygenated machine perfusion (machine-perfusion group) or after conventional static cold storage alone (control group). The primary end point was the incidence of nonanastomotic biliary strictures within 6 months after transplantation. Secondary end points included other graft-related and general complications.RESULTSA total of 160 patients were enrolled, of whom 78 received a machine-perfused liver and 78 received a liver after static cold storage only (4 patients did not receive a liver in this trial). Nonanastomotic biliary strictures occurred in 6% of the patients in the machine-perfusion group and in 18% of those in the control group (risk ratio, 0.36; 95% confidence interval [CI], 0.14 to 0.94; P=0.03). Postreperfusion syndrome occurred in 12% of the recipients of a machine-perfused liver and in 27% of those in the control group (risk ratio, 0.43; 95% CI, 0.20 to 0.91). Early allograft dysfunction occurred in 26% of the machine-perfused livers, as compared with 40% of control livers (risk ratio, 0.61; 95% CI, 0.39 to 0.96). The cumulative number of treatments for nonanastomotic biliary strictures was lower by a factor of almost 4 after machine perfusion, as compared with control. The incidence of adverse events was similar in the two groups.CONCLUSIONSHypothermic oxygenated machine perfusion led to a lower risk of nonanastomotic biliary strictures following the transplantation of livers obtained from donors after circulatory death than conventional static cold storage. Show less
Rijn, R. van; Berg, A.P. van den; Erdmann, J.I.; Heaton, N.; Hoek, B. van; Jonge, J. de; ... ; Porte, R.J. 2019
This study combines historical data and the principles of bone functional adaptation to examine variation in terrestrial mobility in men and women from pre-industrial urban (Alkmaar 7M, 9F) and... Show moreThis study combines historical data and the principles of bone functional adaptation to examine variation in terrestrial mobility in men and women from pre-industrial urban (Alkmaar 7M, 9F) and rural (Klaaskinderkerke 12M, 8F; Middenbeemster 21M, 22F) Dutch populations. Cross-sectional properties of the femoral and tibial midshaft are determined to investigate variation in lower limb mechanical loading. All populations had comparable age ranges. Rural Middenbeemster males had significantly more elliptically shaped tibiae compared to the other populations. Rural males from Klaaskinderkerke had significantly greater femoral cross-sectional area and torsional rigidity compared to females. In the tibia, the males from both rural populations had greater torsional rigidity and cross-sectional area compared to females. In the rural Middenbeemster population the males also had significantly more elliptically shaped tibiae compared to females. While no sexual dimorphism was found in the urban Alkmaar, significantly greater variation in lower limb cross-sectional properties was found for both males and females relative to the rural populations. These results conform to predictions based on the historical literature of greater lower limb loading in rural males compared to females as well as a greater variety of tasks performed in urban environments. The lack of significant differences in lower limb torsional rigidity or shape between populations in either sex suggests that rural life was not necessarily more physically strenuous than urban life in pre-industrial Dutch populations. However, variation in sexual dimorphism suggests that labor between males and females was differently organized in the rural and urban samples. Show less
Heinen, C.; Losekoot, M.; Sun, Y.; Watson, P.; Fairall, L.; Joustra, S.; ... ; Trotsenburg, P. van 2016
This thesis describes the development of a combined high-pressure/ultrahigh-vacuum flow reactor for the study of model catalysts by means of surface x-ray diffraction and grazing incidence small... Show moreThis thesis describes the development of a combined high-pressure/ultrahigh-vacuum flow reactor for the study of model catalysts by means of surface x-ray diffraction and grazing incidence small angle scattering. The system was used to measure a stability diagram for the different oxide phases (surface oxide, bulk-like oxides) that exist on Pd(100) during catalytic CO oxidation at near ambient pressures. As soon as an oxide was present the reactivity of the surface was found to be mass transfer limited by the flux of CO molecules reaching the surface. Experiments on spontaneous reaction oscillations of the CO oxidation rate on Pd(100) reveal that a high density of steps strongly alters the stability of the thin, catalytically active palladium oxide film. It is shown that stabilization of the metal, caused by the steps and consequent destabilization of the oxide, is at the heart of the well-known reaction rate oscillations exhibited during CO oxidation at atmospheric pressure. Lastly reaction oscillations on supported Pd nanoparticles are shown to be accompanied by shape changes of the particles consistent with the formation and removal of a thin palladium oxide film on the particles. Show less
