In resting cells, the NFAT1 transcription factor is kept inactive in the cytoplasm by phosphorylation on multiple serine residues. These phosphorylated residues are primarily contained within two types of serine-rich motifs, the SRR-1 and SP motifs, which are conserved within the NFAT family. Several different kinases have been proposed to regulate NFAT, but no single candidate displays the specificity required to fully phosphorylate both types of motifs; thus, the identity of the kinase that regulates NFAT activity remains unclear. Here we show that the NFAT1 serine motifs are regulated by distinct kinases that must coordinate to control NFAT1 activation. CK1 phosphorylates only the SRR-1 motif, the primary region required for NFAT1 nuclear import. CK1 exists with NFAT1 in a high-molecular-weight complex in resting T cells but dissociates upon activation. GSK3 does not phosphorylate the SRR-1 region but can target the NFAT1 SP-2 motif, and it synergizes with CK1 to regulate NFAT1 nuclear export. We identify a conserved docking site for CK1 in NFAT proteins and show that mutation of this site disrupts NFAT1-CK1 interaction and causes constitutive nuclear localization of NFAT1. The CK1 docking motif is present in proteins of the Wnt, Hedgehog, and circadian-rhythm pathways, which also integrate the activities of CK1 and GSK3.

Purpose Patients with advanced cancer experience potentially burdensome transitions of care after hospitalizations. We examined predictors of discharge location and assessed the relationship between discharge location and survival in this population. Methods We conducted a prospective study of 932 patients with advanced cancer who experienced an unplanned hospitalization between September 2014 and March 2016. Upon admission, we assessed patients' physical symptoms (Edmonton Symptom Assessment System) and psychological distress (Patient Health Questionnaire-4). The primary outcome was discharge location (home without hospice, postacute care [PAC], or hospice [any setting]). The secondary outcome was survival. Results Of 932 patients, 726 (77.9%) were discharged home without hospice, 118 (12.7%) were discharged to PAC, and 88 (9.4%) to hospice. Those discharged to PAC and hospice reported high rates of severe symptoms, including dyspnea, constipation, low appetite, fatigue, depression, and anxiety. Using logistic regression, patients discharged to PAC or hospice versus home without hospice were more likely to be older (odds ratio [OR], 1.03; 95% CI, 1.02 to 1.05; P < .001), live alone (OR, 1.95; 95% CI, 1.25 to 3.02; P < .003), have impaired mobility (OR, 5.08; 95% CI, 3.46 to 7.45; P < .001), longer hospital stays (OR, 1.15; 95% CI, 1.11 to 1.20; P < .001), higher Edmonton Symptom Assessment System physical symptoms (OR, 1.02; 95% CI, 1.003 to 1.032; P < .017), and higher Patient Health Questionnaire-4 depression symptoms (OR, 1.13; 95% CI, 1.01 to 1.25; P < .027). Patients discharged to hospice rather than PAC were more likely to receive palliative care consultation (OR, 4.44; 95% CI, 2.12 to 9.29; P < .001) and have shorter hospital stays (OR, 0.84; 95% CI, 0.77 to 0.91; P < .001). Patients discharged to PAC versus home had lower survival (hazard ratio, 1.53; 95% CI, 1.22 to 1.93; P < .001). Conclusion Patients with advanced cancer who were discharged to PAC facilities and hospice had substantial physical and psychological symptom burden, impaired physical function, and inferior survival compared with those discharged to home. These patients may benefit from interventions to enhance their quality of life and care.

Background Although hospitalized patients with advanced cancer have low chance of surviving cardiopulmonary resuscitation (CPR), the processes by which they change their code status from full code to Do-Not-Resuscitate (DNR) are unknown. Methods We conducted a mixed-methods study on a prospective cohort of hospitalized patients with advanced cancer. Two physicians used a consensus-driven medical record review to characterize processes leading to code status order transitions from full code to DNR. Results We reviewed 1047 hospitalizations among 728 patients. Admitting clinicians did not address code status in 53.0% of hospitalizations resulting in code status orders of ‘presumed full’. 275 patients (26.3%) transitioned from full code to DNR and 48.7% (134/275) of those had an order of ‘presumed full’ upon admission but upon further clarification, the patients expressed that they had wished to be DNR prior to the hospitalization. We identified three additional processes leading to order transition from full code to DNR: acute clinical deterioration (15.3%), discontinuation of cancer-directed therapy (17.1%), and education about the potential harms/futility of CPR (15.3%). Compared to discontinuing therapy and education, transitions due to acute clinical deterioration were associated with less patient involvement (P=0.002), shorter time to death (P<0.001), and higher likelihood of inpatient death (P=0.005). Conclusions Half of code status order changes among hospitalized patients with advanced cancer were due to full code orders in patients who had a preference for DNR prior to hospitalization. Transitions due to acute clinical deterioration were associated with less patient engagement and higher likelihood of inpatient death.

127 Background: Disruption of the immune system with immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude of irAE’s in the real-world, particularly inpatient is unclear. Methods: Data was collected on patients with advanced malignancy who experienced a suspected irAE needing admission to an academic hospital (Feb 2011 to June 2017). Each case was reviewed comprehensively by minimum of two reviewers, including one sub-specialist. In addition, oncologists at our institution were surveyed regarding their confidence about managing patients with irAEs. Results: Over a span of 6 years, there were 343 hospitalizations for suspected irAEs and the majority (65%; N = 223) were confirmed irAEs that required treatment with immunosuppression or therapy stopped as result. The mean length of stay was 6.3 days (range 1 to 31 days), readmission rate for another irAE event 25%, total readmission rate 61.7%, and inpatient mortality 8%. The most common irAEs were enterocolitis (43.9%), pulmonary (16%), hepatic (15%), neurological (8.9%), endocrinopathies (7.1%), rheumatological (4%), dermatological (3%), cardiovascular (3%), renal (1.8%), and allergy (1.3%). Over the past 5 years, there was a significant increase in admissions due to irAEs (admissions in 2016 vs 2011, odds ratio = 3.07; p < 0.01). The Cancer Center survey (N = 26) revealed majority of oncologists do not feel very comfortable managing irAEs, and 48% felt that irAE complications should be managed on a different service. Conclusions: irAEs from immune checkpoint inhibitors can result in prolonged hospitalizations, high rate of readmissions, and mortality. The number of patients admitted due to irAEs has significantly increased by more than three-fold in the recent years, but majority of oncologists do not feel very comfortable managing irAEs. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research program for early detection and intervention.