Predictors of radiation necrosis in long-term survivors after Gamma Knife stereotactic radiosurgery for brain metastases.

BACKGROUND: The long-term risk of necrosis after radiosurgery for brain metastases is uncertain. We aimed to investigate incidence and predictors of radiation necrosis for individuals with more than 1 year of survival after radiosurgery for brain metastases. METHODS: Patients who had a diagnosis of brain metastases treated between December 2006 and December 2014, who had at least 1 year of survival after first radiosurgery were retrospectively reviewed. Survival was analyzed using the Kaplan-Meier estimator, and the incidence of radiation necrosis was estimated with death or surgical resection as competing risks. Patient and treatment factors associated with radiation necrosis were also analyzed. RESULTS: A total of 198 patients with 732 lesions were analyzed. Thirty-four lesions required salvage radiosurgery and 10 required salvage surgical resection. Median follow-up was 24 months. The estimated median survival for this population was 25.4 months. The estimated per-lesion incidence of radiation necrosis at 4 years was 6.8%. Medical or surgical therapy was required for 60% of necrosis events. Tumor volume and male sex were significant factors associated with radiation necrosis. The per-lesions incidence of necrosis for patients undergoing repeat radiosurgery was 33.3% at 4 years. CONCLUSIONS: In this large series of patients undergoing radiosurgery for brain metastases, patients continued to be at risk for radiation necrosis throughout their first 4 years of survival. Repeat radiosurgery of recurrent lesions greatly exacerbates the risk of radiation necrosis, whereas treatment of larger target volumes increases the risk modestly.

Tumor volume as a predictor of survival and local control in patients with brain metastases treated with Gamma Knife surgery.

OBJECT: The aim of this study was to examine tumor volume as a prognostic factor for patients with brain metastases treated with Gamma Knife surgery (GKS). METHODS: Two hundred fifty patients with 1-14 brain metastases who had initially undergone GKS alone at a single institution were retrospectively reviewed. Patients who received upfront whole brain radiation therapy were excluded. Survival times were estimated using the Kaplan-Meier method. Univariate and multivariate analyses using Cox proportional hazard regression models were used to determine if various prognostic factors could predict overall survival, distant brain failure, and local control. RESULTS: Median overall survival was 7.1 months and the 1-year local control rate was 91.5%. Median time to distant brain failure was 8.0 months. On univariate analysis an increasing total tumor volume was significantly associated with worse survival (p = 0.031) whereas the number of brain metastases, analyzed as a continuous variable, was not (p = 0.082). After adjusting for age, Karnofsky Performance Scale score, and extracranial disease on multivariate analysis, total tumor volume was found to be a better predictor of overall survival (p = 0.046) than number of brain metastases analyzed as a continuous variable (p = 0.098). A total tumor volume cutoff value of ≥ 2 cm(3) (p = 0.008) was a stronger predictor of overall survival than the number of brain metastases (p = 0.098). Larger tumor volume and extracranial disease, but not the number of brain metastases, were predictive of distant brain failure on multivariate analysis. Local tumor control at 1 year was 97% for lesions < 2 cm(3) compared with 75% for lesions ≥ 2 cm(3) (p < 0.001). CONCLUSIONS: After adjusting for other factors, a total brain metastasis volume was a strong and independent predictor for overall survival, distant brain failure, and local control, even when considering the number of metastases.

Short- and long-term adverse effects of cocaine abuse during pregnancy on the heart development.

The effect of cocaine on the developing fetus is a topic of considerable interest and debate. One of the potential effects of fetal cocaine exposure is damage to the developing heart. This review provides an overview of the current understanding of the short- and long-term effects of fetal cocaine exposure on the heart in both humans and animal models. Human studies are still preliminary but have suggested that fetal cocaine exposure impacts on the developing heart. Studies in animal models provide strong evidence for a programming effect resulting in detrimental long-term changes to the heart induced by fetal cocaine exposure. In the rat model, fetal cocaine results in apoptosis in the term heart, left ventricular remodeling and myocyte hypertrophy, as well as increased sensitivity to ischemia/reperfusion injury in the adult male offspring. The rat model has also shown evidence of epigenetic modifications in response to intrauterine cocaine. Increased DNA methylation of promoter regions leads to a long-term decrease in the expression of the cardioprotective gene, PKCepsilon. The current data shows fetal cocaine exposure has significant immediate and long-term cardiac consequences in animal models and while human studies are still incomplete they suggest this phenomenon may also be significant in humans exposed to cocaine during development.

Fetal exposure to cocaine causes programming of Prkce gene repression in the left ventricle of adult rat offspring.

Previous studies demonstrated that maternal cocaine administration caused a significant decrease in protein kinase C epsilon (PRKCE) abundance in the left ventricle and an increase in susceptibility of the heart to ischemic injury in adult male offspring. The present study tested the hypothesis that epigenetic modification has a key role in cocaine-mediated programming of cardiac Prkce gene repression. Pregnant Sprague-Dawley rats were administered saline or cocaine (30 mg/kg/day i.p.) from Days 15 to 21 of gestational age, and hearts of 3-mo-old adult offspring were studied. Cocaine exposure significantly decreased Prkce mRNA levels in the left ventricle of male but not female offspring. CpG dinucleotides identified in Bhlhb2, Pparg, E2f, and Egr1 binding sites at the Prkce gene promoter were densely methylated in males and females and were unaffected by cocaine exposure. In contrast, methylation of CpGs in the two Sp1 binding sites (-346 and -268) was low and was significantly increased by cocaine exposure in male offspring. In females, methylation of the Sp1 binding site at -268 but not -346 was increased. Reporter gene assays showed that both Sp1 binding sites had a strong stimulatory role in Prkce gene activity. Methylation of the Sp1 binding sites significantly decreased SP1 binding to the Prkce promoter. Cocaine exposure did not affect nuclear SP1 protein levels but decreased the SP1 binding affinity to its binding site at -268. The results demonstrate an epigenetic mechanism of DNA methylation in programming of cardiac Prkce gene repression, linking fetal cocaine exposure and pathophysiological consequences in the heart of adult male offspring in a gender-dependent manner.

Prenatal cocaine exposure abolished ischemic preconditioning-induced protection in adult male rat hearts: role of PKCepsilon.

Prenatal cocaine exposure in rats resulted in decreased PKCepsilon protein expression in the heart of adult male but not female offspring. The present study determined its functional consequence of inhibiting cardioprotection mediated by ischemic preconditioning. Pregnant Sprague-Dawley rats were administered intraperitoneally saline or cocaine (30 mg.kg(-1).day(-1)) from day 15 to day 21 of gestational age. Hearts were isolated from 3-mo-old offspring and were subjected to ischemia and reperfusion injury in a Langendorff preparation, with or without prior ischemic preconditioning. Preischemic values of left ventricular function were the same between the saline control and cocaine-treated animals. Ischemic preconditioning of two episodes of 5-min ischemia significantly decreased infarct size and enhanced postischemic functional recovery of the left ventricle in the saline control animals. This ischemic preconditioning was associated with increased phospho-PKCepsilon, but not phospho-PKCdelta, levels and was blocked by a PKCepsilon translocation inhibitor peptide. Prenatal cocaine treatment abolished the ischemic preconditioning-mediated increase in phospho-PKCepsilon and cardioprotection in the heart of male offspring. In contrast, the cardioprotective effect was fully maintained in female offspring that were exposed to cocaine before birth. The results suggest that prenatal cocaine exposure causes a sex-specific loss of cardioprotection by ischemic preconditioning in adult offspring, which is most likely due to fetal programming of PKCepsilon gene repression, resulting in a downregulation of PKCepsilon function in the heart of adult male offspring.