Superior early diagnostic performance of a sensitive cardiac troponin assay as compared to a standard troponin test in the diagnosis of acute myocardial infarction

Background: New generation cardiac troponin assays have sufficient precision to detect and quantify plasma troponin concentrations below the lower threshold of detection of the currently employed troponin tests. However, diagnostic performance of the newer generation assays in daily clinical practice is not well established. Aim: To evaluate the diagnostic performance of a sensitive assay as compared to a standard assay in a single reading at admission in the diagnosis of acute myocardial infarction (AMI) in patients presenting to the Emergency Department with chest pain. Methods: The study comprised 187 consecutive patients admitted to the Institute of Cardiology in Warsaw in June and July 2010 with chest pain in whom the attending physician ordered troponin assay to rule AMI in or out. In all of these patients, in addition to the standard Dimension Flex Troponin I (Siemens Healthcare Diagnostics, Inc.) the sensitive Architect Stat Troponin I (Abbott Diagnostics) test was assayed. The triage of patients as well as all diagnostic and treatment decisions were left to the discretion of the attending physician who was blinded to the sensitive troponin test readings. The final diagnosis was adjudicated by a team of two cardiologists on the basis of all the available medical records except for sensitive troponin test results. Results: Mean age of the study cohort (n = 187) was 64.3 ± 13.9 years and 119 (63.6%) were males. The final diagnosis of AMI was adjudicated in 84 (44.9%) patients (mean age 67.5 ± 12.9 years; 119 [63.6%] males). Receiver operating characteristic (ROC) analysis showed greater area under the curve (AUC) for the sensitive cardiac troponin assay compared to the standard assay (AUC = 0.916, 95% CI = 0.866–0.951 vs AUC = 0.863, 95% CI = 0.806–0.909, respectively; p = 0.02) in a single reading at admission. Sensitive assay was characterised by higher sensitivity (87%), specificity (88%), positive (86%) and negative (89%) predictive values in the detection of AMI compared to the standard troponin test (82%, 81%, 78%, and 85% respectively). Conclusions: The newer generation sensitive cardiac troponin assay presented superior diagnostic accuracy in the diagnosis of AMI compared to the standard troponin test in a single reading at admission with improved sensitivity and specificity. The sensitive troponin assay has the potential to improve early detection and/or exclusion of AMI.Background: New generation cardiac troponin assays have sufficient precision to detect and quantify plasma troponin concentrations below the lower threshold of detection of the currently employed troponin tests. However, diagnostic performance of the newer generation assays in daily clinical practice is not well established. Aim: To evaluate the diagnostic performance of a sensitive assay as compared to a standard assay in a single reading at admission in the diagnosis of acute myocardial infarction (AMI) in patients presenting to the Emergency Department with chest pain. Methods: The study comprised 187 consecutive patients admitted to the Institute of Cardiology in Warsaw in June and July 2010 with chest pain in whom the attending physician ordered troponin assay to rule AMI in or out. In all of these patients, in addition to the standard Dimension Flex Troponin I (Siemens Healthcare Diagnostics, Inc.) the sensitive Architect Stat Troponin I (Abbott Diagnostics) test was assayed. The triage of patients as well as all diagnostic and treatment decisions were left to the discretion of the attending physician who was blinded to the sensitive troponin test readings. The final diagnosis was adjudicated by a team of two cardiologists on the basis of all the available medical records except for sensitive troponin test results. Results: Mean age of the study cohort (n = 187) was 64.3 +- 13.9 years and 119 (63.6%) were males. The final diagnosis of AMI was adjudicated in 84 (44.9%) patients (mean age 67.5 +- 12.9 years; 119 [63.6%] males). Receiver operating characteristic (ROC) analysis showed greater area under the curve (AUC) for the sensitive cardiac troponin assay compared to the standard assay (AUC = 0.916, 95% CI = 0.866–0.951 vs AUC = 0.863, 95% CI = 0.806–0.909, respectively; p = 0.02) in a single reading at admission. Sensitive assay was characterised by higher sensitivity (87%), specificity (88%), positive (86%) and negative (89%) predictive values in the detection of AMI compared to the standard troponin test (82%, 81%, 78%, and 85% respectively). Conclusions: The newer generation sensitive cardiac troponin assay presented superior diagnostic accuracy in the diagnosis of AMI compared to the standard troponin test in a single reading at admission with improved sensitivity and specificity. The sensitive troponin assay has the potential to improve early detection and/or exclusion of AMI

Evaluation of the role of downregulation of SNF5/INI1 core subunit of SWI/SNF complex in clear cell renal cell carcinoma development

Clear cell renal cell carcinoma (ccRCC) is characterized by stabilization of hypoxia-inducible factor (HIF1), and mutations in von Hippel-Lindau (VHL) gene. Additionally, in about 40% of ccRCC cases the mutation in PBRM1 (POLYBROMO1) gene coding for a non-core subunit of SWI/SNF chromatin remodeling complex was found suggesting potential impairment of this complex function in ccRCC. In this study we assessed the extent to which the core SWI/SNF complex subunit - INI1 (hSNF5/SMARCB1) is affected in ccRCC and whether it has any consequences on the development of this type of cancer. The evaluation of INI1 protein level in samples from 50 patients with diagnosed ccRCC, including three displaying rhabdoid features, showed the INI1 positive staining in rhabdoid cells while the conventional ccRCC cells exhibited reduced INI1 level. This indicated the rhabdoid component of ccRCC as distinct from other known rhabdoid tumors. The reduced INI1 protein level observed in all conventional ccRCC cases used in this study correlated with decreased SMARCB1 gene expression at the transcript level. Consistently, the overexpression of INI1 protein in A498 ccRCC cell line resulted in the elevation of endogenous SMARCB1 transcript level indicating that the INI1-dependent regulatory feedback loop controlling expression of this gene is affected in ccRCC Moreover, the set of INI1 target genes including i.e. CXCL12/CXCR7/CXCR4 chemokine axis was identified to be affected in ccRCC. In summary, we demonstrated that the inactivation of INI1 may be of high importance for ccRCC development and aggressiveness

Sorafenib dose escalation in treatment-naïve patients with metastatic renal cell carcinoma: a non-randomised, open-label, Phase 2b study.

Objective To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC).Patients and methods Intra-patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non-randomised, open-label, Phase 2b study, treatment-naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent-to-treat (mITT) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression-free survival (PFS) and safety.Results In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5-69.2] and 17.9% (n = 12/67; 95% CI 9.6-29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0-11.7) months (ITT). The most common AEs of any grade were hand-foot skin reaction (66.3%) and diarrhoea (63.9%).Conclusion Sorafenib demonstrated clinical benefit in treatment-naïve patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment-naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored

Succinate Dehydrogenase-Deficient Renal Cancer Featuring Fructose-1,6-Biphosphatase Loss, Pyruvate Kinase M2 Overexpression, and SWI/SNF Chromatin Remodeling Complex Aberrations: A Rare Case Report

Succinate dehydrogenase (SDH)-deficient renal cancer is a rare renal cancer subtype recently accepted by the World Health Organization as a unique subtype of renal cell carcinoma (RCC). Here we report a case of 17-year old man. The detailed evaluation indicated occurrence of the SDHB-deficient RCC. The genetic testing revealed no germline mutation in SDH genes. Immunohistochemistry showed SDHB deficiency, overexpression of pyruvate kinase M2 and dramatic downregulation of fructose-1,6-bisphosphatase metabolic enzymes, and unaltered levels of phosphorylated AMP-activated protein kinase and mammalian target of rapamycin. Strong upregulation of INI1 and BRG1 and overexpression of BAF180, subunits of SWI/SNF ATP-dependent chromatin remodeling complex, were also found. The identified tumor pathologically did not resemble clear cell renal cell carcinoma (ccRCC), but some metabolic alterations are common for both cancer types. Thus, we postulate that the phenotypical differences between ccRCC and SDHB-deficient RCC may be related to distinct molecular and metabolic alterations