SNP of Aromatase Predict Long-term Survival and Aromatase Inhibitor Toxicity in Patients with Early Breast Cancer: A Biomarker Analysis of the GIM4 and GIM5 Trials

Purpose: In estrogen receptor–positive (ERþ) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole. Experimental Design: We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method. Results: No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04–2.94)], rs749292 [sHR 2.11, (1.12–3.94)], and rs727479 [sHR 2.62, (1.17–5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P 1⁄4 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P 1⁄4 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P 1⁄4 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P 1⁄4 0.026). Conclusions: SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ERþ early breast cancer, opening an opportunity for better treatment individualization

Eculizumab treatment: stochastic occurrence of C3 binding to individual PNH erythrocytes

C5 blockade by eculizumab prevents complement-mediated intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH). However, C3-bound PNH red blood cells (RBCs), arising in almost all treated patients, may undergo extravascular hemolysis reducing clinical benefits. Despite the uniform deficiency of CD55 and of CD59, there are always two distinct populations of PNH RBCs, with (C3+) and without (C3-) C3 binding

Identification and molecular characterization of a novel 55 kb deletion recurrent in Southern Italy: the Italian (G) γ((A) γδβ)°-thalassemia

OBJECTIVES: To characterize the molecular basis of a β-thalassemia defect in subjects with mild microcytosis associated with normal Hb A2 and increased levels of Hb F. METHODS: Six subjects from 3 apparently unrelated families from Campania (Southern Italy) have been investigated by using DNA restriction analysis, Inverse PCR, cloning, sequencing, Multiplex ligation-dependent probe amplification (MLPA), quantitative Real Time PCR, gap-PCR. RESULTS: We have identified a novel 55 kb β-globin gene cluster deletion in three unrelated families: the Italian (G) γ((A) γδβ)°-thalassemia. This deletion removes most of β-globin cluster. The 5' breakpoint was within the (A) γ-globin exon 2 and the 3' breakpoint was within a 160 bp palindrome: the breakpoint-flanking regions present a micro-homology (5'-TGGG-3') that, together with the palindromic structure, may have contributed to the recombination. CONCLUSIONS: Large deletions of β-globin gene cluster are usually found in single families. Here we report about the novel Italian (G) γ((A) γδβ)°-thalassemia we have found in three families. Twenty years ago the characterization of the first family was challenging, whereas that of the other families has taken advantage of nowadays techniques. The relatively high frequency of this novel deletion in Southern Italy suggests that it should be tested, together with the Sicilian (δβ)°-thalassemia, in Italian and Mediterranean families with microcytosis, normal Hb A2 and increased Hb F levels

Ischemic stroke. Clinical pathway impact

Purpose: A clinical pathway for patients with acute ischemic stroke was implemented in 2014 by one Italian teaching hospital multidisciplinary team. The purpose of this paper is to determine whether this clinical pathway had a positive effect on patient management by comparing performance data. Design/methodology/approach: Volume, process and outcome indicators were analyzed in a pre-post retrospective observational study. Patients’ (admitted in 2013 and 2015) medical records with International Classification of Diseases, ICD-9 code 433.x (precerebral artery occlusion and stenosis), 434.x (cerebral artery occlusion) and 435.x (transient cerebral ischemia) and registered correctly according to hospital guidelines were included. Findings: An increase context-sensitive in-patient numbers with more severe cerebrovascular events and an increase in patient transfers from the Stroke to Neurology Unit within three days (70 percent, p=0.25) were noted. Clinical pathway implementation led to an increase in patient flow from the Emergency Department to dedicated specialized wards such as the Stroke and Neurology Unit (23.7 percent, p<0.001). Results revealed no statistically significant decrease in readmission rates within 30 days (5.7 percent, p=0.85) and no statistically significant differences in 30-day mortality. Research limitations/implications: The pre-post retrospective observational study design was considered suitable to evaluate likely changes in patient flow after clinical pathway implementation, even though this design comes with limitations, describing only associations between exposure and outcome. Originality/value: Clinical pathway implementation showed an overall positive effect on patient management and service efficiency owing to the standardized application in time-dependent protocols and multidisciplinary/integrated care implementation, which improved all phases in acute ischemic stroke care