Showing papers by "Atlantic Health System published in 2012"

A clinical trial of bevacizumab, temozolomide, and radiation for newly diagnosed glioblastoma.

Abstract: Object The presence of angiogenesis is a hallmark of glioblastoma (GBM). Vascular endothelial growth factor (VEGF), which drives angiogenesis, provides an additional target for conventional therapy. The authors conducted a prospective clinical trial to test the effectiveness of bevacizumab, an inhibitor of VEGF, in newly diagnosed GBM. Methods From 2006 through 2010, 51 eligible patients with newly diagnosed GBM were treated with involved-field radiation therapy and concomitant temozolomide (75 mg/m2 daily for 42 days) along with bevacizumab (10 mg/kg every 2 weeks), starting 29 days after surgery. This was followed by 6 cycles of adjuvant temozolomide therapy (150 mg/m2 on Days 1–7 of a 28-day cycle) with bevacizumab administered at 10 mg/kg on Days 8 and 22 of each 28-day cycle. Results The 6- and 12-month progression-free survival (PFS) rates were 85.1% and 51%, respectively. The 12- and 24-month overall survival (OS) rates were 85.1% and 42.5%, respectively. Grade III/IV toxicities were noted in 10 pa...

Change in Pattern of Relapse After Antiangiogenic Therapy in High-Grade Glioma

Abstract: Purpose Local recurrence is the dominant pattern of relapse in high-grade glioma (HGG) after conventional therapy The recent use of antiangiogenic therapy has shown impressive radiologic and clinical responses in adult HGG The preclinical data suggesting increased invasiveness after angiogenic blockade have necessitated a detailed analysis of the pattern of recurrence after therapy Methods and Materials A total of 162 consecutive patients with HGG, either newly diagnosed ( n = 58) or with recurrent disease ( n = 104) underwent therapy with bevacizumab at 10 mg/kg every 2 weeks and conventional chemotherapy with or without involved field radiotherapy until disease progression The pattern of recurrence and interval to progression were the primary aims of the present study Diffuse invasive recurrence (DIR) was defined as the involvement of multiple lobes with or without crossing the midline Results At a median follow-up of 7 months (range, 1–37), 105 patients had recurrence, and 79 patients ultimately developed DIR The interval to progression was similar in the DIR and local recurrence groups (65 and 63 months, p = 296) The hazard risk of DIR increased exponentially with time and was similar in those with newly diagnosed and recurrent HGG (R 2 = 0957) The duration of bevacizumab therapy increased the interval to recurrence ( p p p = 253) Conclusion Along with an increase in median progression-free survival, bevacizumab therapy increased the risk of DIR in HGG patients The risk of increased invasion with prolonged angiogenic blockade should be addressed in future clinical trials

FLT3 mutation status is a predictor of early death in pediatric acute promyelocytic leukemia: a report from the Children's Oncology Group.

Abstract: Background FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL). Procedure Diagnostic specimens from 104 pediatric APL patients were screened for FLT3/Mut (FLT3/ITD or FLT3/ALM). FLT3/Mut status was correlated with disease characteristics and clinical outcome for patients treated on CALGB C9710 (n = 50). Results Forty-two of the 104 patients (40%) had either FLT3/ITD (n = 28, 27%) or FLT3/ALM (n = 15, 14%). Median diagnostic WBC count was 23,400 cells/µl vs. 3,600 cells/µl for those with and without FLT3/Mut (P 10,000 (P = 0.004), microgranular variant histology (P = 0.035), and a lower remission rate (P = 0.009). In patients who received ATRA (C9710 or CCG-2911, n = 58), those with FLT3/Mut had an induction death rate of 30% (7/23) compared to 3% (1/35) in FLT3/WT patients (P = 0.005). In patients with high WBC counts (>10,000), those with FLT3/Mut had a significantly higher risk of induction death versus FLT3/WT patients (47% vs. 0%, P = 0.05). FLT3/Mut was not associated with adverse outcome in those who survived induction therapy. Conclusions FLT3/Mut are prevalent in pediatric APL and are associated with high WBC count and increased induction death. This study provides further evidence for testing APL patients for FLT3/Mut and the potential role for FLT3 inhibitors in this disease. Pediatr Blood Cancer 2012;59:662–667. © 2012 Wiley Periodicals, Inc.

Endothelin-Converting Enzymes and Related Metalloproteases in Alzheimer's Disease

Abstract: The efficient clearance of amyloid-β (Aβ) is essential to modulate levels of the peptide in the brain and to prevent it from accumulating in senile plaques, a hallmark of Alzheimer's disease (AD) pathology.We and others have shown that failure in Aβ catabolism can produce elevations in Aβ concentration similar to those observed in familial forms of AD. Based on the available evidence, it remains plausible that in late-onset AD, disturbances in the activity of Aβ degrading enzymes could induce Aβ accumulation, and that this increase could result in AD pathology. The following review presents a historical perspective of the parallel discovery of three vasopeptidases (neprilysin and endothelin-converting enzymes-1 and -2) as important Aβ degrading enzymes. The recognition of the role of these vasopeptidases in Aβ degradation, beyond bringing to light a possible explanation of how cardiovascular risk factors may influence AD risk, highlights a possible risk of the use of inhibitors of these enzymes for other clinical indications such as hypertension. We will discuss in detail the experiments conducted to assess the impact of vasopeptidase deficiency (through pharmacological inhibition or genetic mutation) on Aβ accumulation, as well as the cooperative effect of multiple Aβ degrading enzymes to regulate the concentration of the peptide at multiple sites, both intracellular and extracellular, throughout the brain.

Antenatal calcium channel blocker exposure and subsequent patent ductus arteriosus in extremely low-birth-weight infants.

Abstract: This study aimed to assess whether tocolytic fetal exposure to antenatal calcium channel blockers (aCCB) increases the risk for hemodynamically significant patent ductus arterioses (hsPDA) in extremely low-birth-weight (ELBW) infants. This case-control study investigated ELBW infants (<1,000 g) without cardiac defects in a level 3 neonatal intensive care unit who had survived at least 7 days. Nifedipine was the only aCCB used for this study population. The measurements included the history of aCCB exposure, selected maternal data, hsPDA diagnosis, gestational age at birth, birth weight, mode of delivery, sex, maternal race, location of birth, Apgar scores, and selected neonatal morbidities. The end point of the study was hsPDA, defined as an echocardiographically confirmed PDA with clinical symptoms. A total of 180 infants met the study criteria. The diagnosis was hsPDA for 56% of these patients, 20% of whom had aCCB exposure. Of the infants without hsPDA, 11% had aCCB exposure (p = 0.09). No statistically significant associations were found between aCCB exposure and hsPDA after adjustment for gestational age (odds ratio [OR], 1.5; 95% confidence interval [CI], 0.6–3.7) or for gestational age and cumulative aCCB exposure of 100 mg or more (OR, 2.0; 95% CI, 0.6–6.5). A history of aCCB exposure does not appear to increase hsPDA risk in ELBW infants. Studies using neonatal serum nifedipine concentrations after antenatal exposure should be performed to confirm this conclusion.