Paraskevi Savvari

Hypomethylation of retrotransposable elements correlates with genomic instability in non-small cell lung cancer

LINE‐1 and Alu elements are non‐LTR retrotransposons, constituting together over 30% of the human genome and they are frequently hypomethylated in human tumors. A relationship between global hypomethylation and genomic instability has been shown, however, there is little evidence to suggest active role for hypomethylation‐mediated reactivation of retroelements in human cancer. In our study, we examined by Pyrosequencing the methylation levels of LINE‐1 and Alu sequences in 48 primary nonsmall cell carcinomas and their paired adjacent tissues. We demonstrate a significant reduction of the methylation levels of both elements (p = 7.7 × 10−14 and 9.6 × 10−7, respectively). The methylation indices of the 2 elements correlated (p = 0.006), suggesting a possible common mechanism for their methylation maintenance. Genomic instability was measured utilizing 11 fluorescent microsatellite markers located on lung cancer hot‐spot regions such as 3p, 5q 9p, 13q and 17p. Hypomethylation of both transposable elements was associated with increased genomic instability (LINE, p = 7.1 × 10−5; Alu, p = 0.008). The reduction of the methylation index of LINE‐1 and Alu following treatment of 3 lung cell lines with 5‐aza‐2′‐deoxycitidine, consistently resulted in increased expression of both elements. Our study demonstrates the strong link between hypomethylation of transposable elements with genomic instability in non‐small cell lung cancer and provides early evidence for a potential active role of these elements in lung neoplasia. As demethylating agents are now entering lung cancer trials, it is imperative to gain a greater insight into the potential reactivation of silent retrotransposons in order to advance for the clinical utilization of epigenetics in cancer therapy.

Association Between Obesity and Mortality After Acute First-Ever Stroke: The Obesity–Stroke Paradox

Background and Purpose— Limited data exist concerning obesity and survival in patients after acute stroke. The objective of this study was to investigate the association between obesity and survival in patients with acute first-ever stroke. Methods— Patients were prospectively investigated based on a standard diagnostic protocol over a period of 16 years. Evaluation was performed on admission, at 7 days, at 1, 3, and 6 months after discharge, and yearly thereafter for up to 10 years after stroke. The study patients were divided into 3 groups according to body mass index (BMI): normal weight (<25 kg/m2), overweight (25–29.9 kg/m2), and obese (≥30 kg/m2). Overall survival during follow-up was the primary end point. The secondary end point was the overall composite cardiovascular events over the study period. Results— Based on our inclusion criteria, 2785 patients were recruited. According to BMI, 1138 (40.9%) patients were of normal weight, 1113 (41.0%) were overweight, and 504 (18.1%) were obese. NIHSS score on admission (mean, 11.28±8.65) was not different among the study groups. Early (first week) survival in obese (96.4%; 95% CI, 94.8%–97.9%) and overweight patients (92.8%; 95% CI, 91.2%–94.4%) was significantly higher compared to that of normal-weight patients (90.2%; 95% CI, 88.4%–92.0%). Similarly, 10-year survival was 52.5% (95% CI, 46.4%–58.6%) in obese, 47.4% (95% CI, 43.5%–51.3%) in overweight, and 41.5% (95% CI, 39.7%–45.0%) in normal-weight patients (log-rank test=17.7; P<0.0001). Overweight (HR, 0.82; 95% CI, 0.71–0.94) and obese patients (HR, 0.71; 95% CI, 0.59–0.86) had a significantly lower risk of 10-year mortality compared to normal-weight patients after adjusting for all confounding variables. Conclusions— Based on BMI estimation, obese and overweight stroke patients have significantly better early and long-term survival rates compared to those with normal BMI.

CHADS2, CHA2DS2-VASc, and long-term stroke outcome in patients without atrial fibrillation

Objective: CHADS2 and CHA2DS2-VASc scores are used to assess stroke risk in patients with atrial fibrillation (AF). We investigated whether these scores are associated with stroke outcome in non-AF stroke patients. Methods: Consecutive patients with acute first-ever ischemic stroke but without AF were classified into subgroups according to prestroke CHADS2 and CHA2DS2-VASc scores and followed up for 5 years. The end points were death, stroke recurrence, and a composite of major cardiovascular events. Results: Among 1,756 patients (aged 67.2 ± 12.3 years, 68.2% males), there were 258 (14.7%), 617 (35.3%), and 878 (50.0%) patients with low, intermediate, and high CHADS2 score, respectively. The corresponding figures for CHA2DS2-VASc subgroups were 110 (6.3%), 255 (14.5%), and 1,391 (79.2%). There were significant differences between CHADS2 subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 12.3, p = 0.002), and cardiovascular events (log-rank test = 19.4, p < 0.001). Similarly, there were significant differences between CHA2DS2-VASc subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 10.6, p = 0.005), and cardiovascular events (log-rank test = 16.4, p < 0.001). Compared with the low-risk group, patients in intermediate- and high-risk CHADS2 subgroups had higher 5-year mortality (hazard ratio [HR]: 2.22 [95% confidence interval {CI}: 1.78–2.77] and 3.66 [95% CI: 2.38–5.62], respectively), stroke recurrence (HR: 1.74 [95% CI: 1.09–2.79] and 1.71 [95% CI: 1.08–2.71], respectively), and cardiovascular events (HR: 1.78 [95% CI: 1.23–2.57] and 1.86 [95% CI: 1.30–2.67], respectively). Compared with the low-risk group, patients in the high-risk CHA2DS2-VASc subgroup also had higher 5-year mortality (HR: 3.56, 95% CI: 1.89–6.70), stroke recurrence (HR: 2.93, 95% CI: 1.30–6.61), and cardiovascular events (HR: 2.71, 95% CI: 1.49–4.95). Conclusions: Prestroke CHADS2 and CHA2DS2-VASc scores predict long-term stroke outcomes in non-AF patients with acute ischemic stroke. These scores may provide a simple way of stroke prognostic risk stratification among non-AF stroke patients.

Paraneoplastic Humorally Mediated Hypercalcemia Induced by Parathyroid Hormone-Related Protein in Gynecologic Malignancies: A Systematic Review

Humoral hypercalcemia of malignancy (HHM) is a metabolic phenomenon that is mediated by the paraneoplastic secretion of parathyroid hormone-related peptide (PTHrP). Gynecologic malignant neoplasms complicated by HHM have been reported for organs such as the uterus, cervix, ovary, vulva and the vagina. The purpose of our study was to perform a review of the published cases in the literature and, further, to identify parameters with effect on outcome. Among 34 women with gynecologic neoplasms, 22 suffered from ovarian and 6 from uterine malignancies, while 3 had vulvar and another 3 cervical cancer. Furthermore, clear cell carcinoma was the predominant histology associated with PTH-rP expression. A significant correlation was found between serum calcium and PTH-rP levels. Treatment of hypercalcemia was successful in all cases; pamidronate was utilized in 8 patients. Ovarian cancer patients with severe hypercalcemia and high PTH-rP serum levels had shorter survival compared to their counterparts with mild hypercalcemia or moderately elevated PTH-rP serum levels, but the differences were not statistically significant.

Increased expression of bFGF is associated with carotid atherosclerotic plaques instability engaging the NF-κB pathway

Unstable atherosclerotic plaques of the carotid arteries are at great risk for the development of ischemic cerebrovascular events. The degradation of the extracellular matrix by matrix metalloproteinases (MMPs) and nitric oxide induced apoptosis of vascular smooth muscle cells (VSMCs) contribute to the vulnerability of the atherosclerotic plaques. Basic fibroblast growth factor (bFGF) through its mitogenic and angiogenic properties has already been implicated in the pathogenesis of atherosclerosis. However, its role in plaque stability remains elusive. To address this issue, a panel of human carotid atherosclerotic plaques was analysed for bFGF, FGF‐receptors‐1 and ‐2 (FGFR‐1/‐2), inducible nitric oxide synthase (iNOS) and MMP‐9 expression. Our data revealed increased expression of bFGF and FGFR‐1 in VSMCs of unstable plaques, implying the existence of an autocrine loop, which significantly correlated with high iNOS and MMP‐9 levels. These results were recapitulated in vitro by treatment of VSMCs with bFGF. bFGF administration led to up‐regulation of both iNOS and MMP‐9 that was specifically mediated by nuclear factor‐κB (NF‐κB) activation. Collectively, our data demonstrate a novel NF‐κB‐mediated pathway linking bFGF with iNOS and MMP‐9 expression that is associated with carotid plaque vulnerability.

Long-term outcome in posterior cerebral artery stroke

Introduction:  Previous studies on posterior cerebral artery (PCA) strokes focused mainly on topography and underlying pathophysiology. However, there are no data on long‐term prognosis and its association with the localization of the infarct.

Burkitt's lymphoma in pregnancy with bilateral breast involvement: case report with review of the literature.

Background: Burkitt‘s lymphoma (BL) in pregnancy presenting with breast involvement is a rare clinical entity, and only 13 cases have been reported so far. Case Report: We describe the case of a 28-year-old postpartum woman who presented with markedly enlarged breasts caused by BL. She was treated with 8 cycles of the CALGB 10002 regimen, as well as with irradiation to both breasts. After achieving a complete objective response, the patient received consolidation with high dose BEAM followed by autologous stem cell transplantation. 20 months after the initial diagnosis, our patient remains alive and relapse-free. Data extracted from the published case reports include information regarding demographic details, type of treatment, sites of disease, and survival. The clinical outcome of the reviewed cases was very unfavorable. Conclusions: BL affecting breasts during pregnancy or lactation is a rare entity that requires a prompt diagnosis and an aggressive therapeutic approach.