Aims To assess the proportion of patients with heart failure and reduced ejection fraction (HFrEF) who are eligible for sacubitril/valsartan (LCZ696) based on the European Medicines Agency/Food and Drug Administration (EMA/FDA) label, the PARADIGM‐HF trial and the 2016 ESC guidelines, and the association between eligibility and outcomes. Methods and results Outpatients with HFrEF in the ESC‐EORP‐HFA Long‐Term Heart Failure (HF‐LT) Registry between March 2011 and November 2013 were considered. Criteria for LCZ696 based on EMA/FDA label, PARADIGM‐HF and ESC guidelines were applied. Of 5443 patients, 2197 and 2373 had complete information for trial and guideline eligibility assessment, and 84%, 12% and 12% met EMA/FDA label, PARADIGM‐HF and guideline criteria, respectively. Absent PARADIGM‐HF criteria were low natriuretic peptides (21%), hyperkalemia (4%), hypotension (7%) and sub‐optimal pharmacotherapy (74%); absent Guidelines criteria were LVEF>35% (23%), insufficient NP levels (30%) and sub‐optimal pharmacotherapy (82%); absent label criteria were absence of symptoms (New York Heart Association class I). When a daily requirement of ACEi/ARB ≥ 10 mg enalapril (instead of ≥ 20 mg) was used, eligibility rose from 12% to 28% based on both PARADIGM‐HF and guidelines. One‐year heart failure hospitalization was higher (12% and 17% vs. 12%) and all‐cause mortality lower (5.3% and 6.5% vs. 7.7%) in registry eligible patients compared to the enalapril arm of PARADIGM‐HF. Conclusions Among outpatients with HFrEF in the ESC‐EORP‐HFA HF‐LT Registry, 84% met label criteria, while only 12% and 28% met PARADIGM‐HF and guideline criteria for LCZ696 if requiring ≥ 20 mg and ≥ 10 mg enalapril, respectively. Registry patients eligible for LCZ696 had greater heart failure hospitalization but lower mortality rates than the PARADIGM‐HF enalapril group.
Neopterin is a pyrazino-pyrimidine compound that belongs to the pteridine group. It is known to be a biochemical marker associated with cell-mediated immunity. It is produced by human monocytes/macrophages and dendritic cells from guanosine triphosphate (GTP) upon stimulation with interferon gamma (IFNγ), which is released by activated limphocytes Th. Neopterin is a very important clinic parameter, though the physiological role has not been exactly definited thus far. The level of neopterin reflects the stage of activation of the cellular immune system, which is important in the pathogenesis and progression of various diseases. Measuring its concentration in body fluids is used in many different areas of modern medicine, such as infectious disease, gastroenterology, transplantology and transfusiology, rheumatology or oncology. In neurological, cardio-vascular and autoimmune diseases, cell-mediated immunity is also activated, which is proved by the elevated level of this marker. Measurements of neopterin concentrations are also helpful in monitoring the therapy of patients infected with the HIV virus or treated by using immunomudulating therapy. As a result of measuring levels of neopterin in patients with neoplasms of digestive tract, increased concentration was proved, but it is not routinely used in everyday clinic practice.
Neutrophil gelatinase-associated lipocalin, known also as 24p3 lipocalin, lipocalin-2 or uterocalin (in mouse), is a small secretory protein binding small molecular weight ligands which takes part in numerous processes including apoptosis induction in leukocytes, iron transport, smell, and prostaglandins and retinol transport [19]. It was discovered in activated neutrophils as a covalent peptide associated with human gelatinase neutrophils [7]. Neutrophil lipocalin is secreted physiologically in the digestive system, respiratory tract, renal tubular cells, liver or immunity system. Systematic (circulated in plasma) neutrophil gelatinase come from multiple sources; it may be synthesized in the liver, secreted from activated neutrophils or macrophages, or derive from atherosclerosis or inflammatory endothelial cells [17]. NGAL is stored secondarily in granulates with lactoferrin, calprotectin or MAC-1, which take part in neutrophils' action and migration [13,19]. NGAL participates in acute and chronic inflammation (production of NGAL is indicated by factors conducive to cancer progression) [13,21]. NGAL levels increase in inflammatory or endothelial damage. NGAL level is measured in blood or urine. It is known as a kidney failure factor [7,20]. NGAL is therefore one of the most promising new generation biomarkers in clinical nephrology [6]. The role of NGAL in digestive system neoplasms has not been explored in detail. However, overexpression of this marker was proved in neoplasms such as esophageal carcinoma, stomach cancer, pancreatic cancer or colon cancer, which may indicate an association between concentration and neoplasm [3].
e16072 Background: RCC is resistant to most traditional DNA and DNA repair targeted chemotherapy; although modest response rates to nucleotide analog based therapy, including GC, have been reported. Bevacizumab has activity in RCC. We thus performed a single center phase II trial of GCB in pts with metastatic RCC. Methods: Eligibility included clear cell or unclassified histologies, performance status 0–1, measurable disease, normal organ function and no prior treatment with VEGF binding agents or pyramidine analogs. Following significant hematotoxicity in the first 7 of 8 pts, chemotherapy was modified to G 1,000 mg/m2 (days 1, 8), C 1,000 mg po bid (days 1–14) and B 15 mg/kg (day 1) on a 21 day cycle with disease re-evaluation every 3 cycles. Primary endpoint was objective response rate (ORR) using a Bayesian continuous reassessment method designed to detect an improvement in the ORR from a 15% historical rate to 27%. Maximum planned enrollment = 55. Results: 30 pts enrolled from March 2005-May 2008 of which 29 were evaluable: 1 never treated. Pt characteristics: male 83%, median age 58 (36–82), prior nephrectomy 83%, prior radiation 52%, prior cytokine therapy 28%, prior VEGFR tyrosine kinase inhibitor 69%. MSKCC prognostic group: good 24%, intermediate 66%, poor 10%. 7 pts had a partial response (24%). Median overall and progression free survival were 9.8 mo (95%CI: 6.2, 14.9) and 5.3 mo (95%CI: 3.9, 9.9). Grade 3 or 4 toxicities: leucopenia 17%, neutropenia 31%, thrombocytopenia 7%, anemia 14%, proteinuria 3%, rash/hand foot syndrome 7%, fatigue 21%. Average change in mean arterial pressure after 2 cycles: 5.6 (p = 0.040). Serious adverse events: bowel perforation resulting in death 1 pt (3%), sepsis 1 pt (3%), PE/DVT 3 pts (10%), seizure 1 pt (3%). Conclusions: The trial was terminated early despite not meeting protocol criteria for success or futility due to slow accrual and the fact that the historical response rate on which the trial was based became irrelevant with emerging data using sequential VEGF pathway directed therapies. Nevertheless, the observed progression free and overall survival compare favorably to other phase II trials in this population. [Table: see text]
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