ABSTRACT
BACKGROUND: The initial systolic blood pressure (SBP) in patients presenting to the hospital with acute heart failure (AHF) informs prognosis, diagnosis, and guides initial treatment. However, over time AHF presentations with elevated SBP appear to have declined. The present study examined whether the frequency of AHF presentations with systolic hypertension (SBP >160 mmHg) declined over a nearly two-decade time interval. METHODS: This study compares four historical, cross-sectional cohorts with AHF who were admitted to tertiary care medical centres in the North-eastern USA in 1995, 2000, 2006, and 2011-13. The main outcome was the proportion of AHF patients presenting with an initial SBP >160 mmHg. RESULTS: 2,366 patients comprised the study sample. The average age was 77 years, 55% were female, 94% white, and 75% had prior heart failure. In 1995, 34% of AHF patients presented with an initial SBP >160 mmHg compared to 20% in 2011-2013 (p<0.01). Multivariate logistic regression demonstrated reduced odds of presenting with a SBP >160 mmHg in 2006 (0.64, 95% CI 0.42-0.96) and 2011-13 (0.46, 95% CI 0.28-0.74) compared with patients in 1995. CONCLUSION: The proportion of patients with AHF and initial SBP >160 mmHg significantly declined over the study time period. There are several potential reasons for this observation and these findings highlight the need for ongoing surveillance of patients with AHF as changing clinical characteristics can impact early treatment decisions.
ABSTRACT
Genetic alterations in the fibroblast growth factor receptor (FGFR) pathway are promising therapeutic targets in many cancers, including intrahepatic cholangiocarcinoma (ICC). The FGFR inhibitor BGJ398 displayed encouraging efficacy in patients with FGFR2 fusion-positive ICC in a phase II trial, but the durability of response was limited in some patients. Here, we report the molecular basis for acquired resistance to BGJ398 in three patients via integrative genomic characterization of cell-free circulating tumor DNA (cfDNA), primary tumors, and metastases. Serial analysis of cfDNA demonstrated multiple recurrent point mutations in the FGFR2 kinase domain at progression. Accordingly, biopsy of post-progression lesions and rapid autopsy revealed marked inter- and intralesional heterogeneity, with different FGFR2 mutations in individual resistant clones. Molecular modeling and in vitro studies indicated that each mutation led to BGJ398 resistance and was surmountable by structurally distinct FGFR inhibitors. Thus, polyclonal secondary FGFR2 mutations represent an important clinical resistance mechanism that may guide the development of future therapeutic strategies.Significance: We report the first genetic mechanisms of clinical acquired resistance to FGFR inhibition in patients with FGFR2 fusion-positive ICC. Our findings can inform future strategies for detecting resistance mechanisms and inducing more durable remissions in ICC and in the wide variety of cancers where the FGFR pathway is being explored as a therapeutic target. Cancer Discov; 7(3); 252-63. ©2016 AACR.See related commentary by Smyth et al., p. 248This article is highlighted in the In This Issue feature, p. 235.
