Predictors of persistence of post-chemotherapy symptoms among survivors of solid tumor cancers.

CONTEXT: Late or residual symptoms diminish quality of life for many cancer survivors after completion of treatment. OBJECTIVES: Examine risk factors associated with persisting symptom burden after chemotherapy and the lack of symptom improvement over time. METHODS: Survivors who completed curative-intent chemotherapy within two years for solid tumors were enrolled into a symptom management trial. There were 375 survivors with two or more comorbid conditions or one comorbid condition and elevated depressive symptoms (pre-defined risk factors in the trial design) who received interventions and 71 survivors without these risk factors who did not receive interventions. For all survivors, symptoms were assessed at intake, 4, and 13 weeks and categorized as mild, moderate, or severe based on the interference with daily life. The probabilities of moderate or severe symptoms and symptom improvement were analyzed using generalized mixed-effects models in relation to comorbidity, depressive symptoms, age, sex, race/ethnicity, employment, time since chemotherapy completion, and physical function. Multiple symptoms were treated as nested within the survivor. RESULTS: Moderate or severe symptoms at baseline and the lack of improvement over time were associated with younger age and lower physical function over and above a greater number of comorbidities and elevated severity of depressive symptoms. CONCLUSION: Risk factors identified in this research (younger age, lower physical function, greater comorbidity, and higher depressive symptoms) can be used to allocate resources for post-treatment symptom management for cancer survivors in order to relieve symptoms that do not necessarily resolve with time.

Lack of CFTR alters the ferret pancreatic ductal epithelial secretome and cellular proteome: Implications for exocrine/endocrine signaling.

BACKGROUND: Cystic fibrosis (CF) related diabetes is the most common comorbidity for CF patients and associated with islet dysfunction. Exocrine pancreas remodeling in CF alters the microenvironment in which islets reside. Since CFTR is mainly expressed in pancreatic ductal epithelium, we hypothesized altered CF ductal secretions could impact islet function through paracrine signals. METHOD: We evaluated the secretome and cellular proteome of polarized WT and CF ferret ductal epithelia using quantitative ratiometric mass spectrometry. Differentially secreted proteins (DSPs) or expressed cellular proteins were used to mine pathways, upstream regulators and the CFTR interactome to map candidate CF-associated alterations in ductal signaling and phenotype. Candidate DSPs were evaluated for their in vivo pancreatic expression patterns and their functional impact on islet hormone secretion. RESULTS: The secretome and cellular proteome of CF ductal epithelia was significantly altered relative to WT and implicated dysregulated TGFß, WNT, and BMP signaling pathways. Cognate receptors of DSPs from CF epithelia were equally distributed among endocrine, exocrine, and stromal pancreatic cell types. IGFBP7 was a downregulated DSP in CF ductal epithelia in vitro and exhibited reduced CF ductal expression in vivo. IGFBP7 also altered WT islet insulin secretion in response to glucose. Many CFTR-associated proteins, including SLC9A3R1, were differentially expressed in the CF cellular proteome. Upstream regulators of the differential CF ductal proteome included TGFß, PDX1, AKT/PTEN, and INSR signaling. Data is available via ProteomeXchange with identifier PXD025126. CONCLUSION: These findings provide a proteomic roadmap for elucidating disturbances in autocrine and paracrine signals from CF pancreatic ducts and how they may alter islet function and maintenance.