Purpose Retrospective analysis of irAEs in melanoma patients treated with nivolumab. Experimental Design Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of irAEs were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in OS in the presence or absence of irAEs. Results IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had Grade III rash, 2 (1.35%) had asymptomatic Grade III elevation in amylase/lipase, and 2 (1.35%) had Grade III colitis. A statistically significant OS difference was noted amongst patients with any grade of irAE versus those without (p=<0.001), and OS benefit was noted in patients who reported 3 or more irAE events (p=<0.001). Subset analyses showed statistically significant OS differences with rash (p=0.001 [HR 0.423, 95% CI 0.243 to 0.735]) and vitiligo (p=0.012 [HR 0.184, 95% CI 0.036 to 0.94]). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (p=0.004 and p=0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis). Conclusions Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses.
The checkpoint inhibitor nivolumab is active in metastatic melanoma patients who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3-4 drug related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. Response rate for ipilimumab-refractory patients was 30% (95%CI: 21% - 41%). Median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when followed up a median of 16 months. One and two year survivals were 68.4% and 31.2%, respectively. Ipilimumab-naïve and -refractory patients showed no significant difference in survival. The 21 patients with prior grade 3–4 toxicity to ipilimumab that was managed with steroids, tolerated nivolumab well, with 62% (95%CI: 38% - 82%) having complete or partial remissions or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSCs) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3-4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab.
Highlights Implementation process of Electronic Health Records (EHRs) is critical for success. Vast literature available on EHR implementations in different settings and contexts. Organizational, Human and Technological factors influence success across settings. Dynamic interaction of the identified factors trigger success. Consideration of the specific healthcare context and end-users is important.
The light regime is an ecologically important factor in pelagic habitats, influencing a range of biological processes. However, the availability and importance of light to these processes in high Arctic zooplankton communities during periods of 'complete' darkness (polar night) are poorly studied. Here we characterized the ambient light regime throughout the diel cycle during the high Arctic polar night, and ask whether visual systems of Arctic zooplankton can detect the low levels of irradiance available at this time. To this end, light measurements with a purpose-built irradiance sensor and coupled all-sky digital photographs were used to characterize diel skylight irradiance patterns over 24 hours at 79°N in January 2014 and 2015. Subsequent skylight spectral irradiance and in-water optical property measurements were used to model the underwater light field as a function of depth, which was then weighted by the electrophysiologically determined visual spectral sensitivity of a dominant high Arctic zooplankter, Thysanoessa inermis. Irradiance in air ranged between 1–1.5 x 10-5 μmol photons m-2 s-1 (400–700 nm) in clear weather conditions at noon and with the moon below the horizon, hence values reflect only solar illumination. Radiative transfer modelling generated underwater light fields with peak transmission at blue-green wavelengths, with a 465 nm transmission maximum in shallow water shifting to 485 nm with depth. To the eye of a zooplankter, light from the surface to 75 m exhibits a maximum at 485 nm, with longer wavelengths (>600 nm) being of little visual significance. Our data are the first quantitative characterisation, including absolute intensities, spectral composition and photoperiod of biologically relevant solar ambient light in the high Arctic during the polar night, and indicate that some species of Arctic zooplankton are able to detect and utilize ambient light down to 20–30m depth during the Arctic polar night.
Bioluminescence commonly influences pelagic trophic interactions at mesopelagic depths. Here we characterize a vertical gradient in structure of a generally low species diversity bioluminescent community at shallower epipelagic depths during the polar night period in a high Arctic fjord with in situ bathyphotometric sampling. Bioluminescence potential of the community increased with depth to a peak at 80 m. Community composition changed over this range, with an ecotone at 20–40 m where a dinoflagellate-dominated community transitioned to dominance by the copepod Metridia longa. Coincident at this depth was bioluminescence exceeding atmospheric light in the ambient pelagic photon budget, which we term the bioluminescence compensation depth. Collectively, we show a winter bioluminescent community in the high Arctic with vertical structure linked to attenuation of atmospheric light, which has the potential to influence pelagic ecology during the light-limited polar night.
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