Class of 2007 Abstract / Objectives: To evaluate the efficacy of carmustine wafers over placebo plus surgery in the treatment of primary glioblastoma multiforme. Methods: Searches of MEDLINE (1966-2007), ASH (American Society of Hematology) abstracts, and ASCO (American Society of Clinical Oncology) abstracts were conducted to obtain clinical outcomes data (meta- analysis, randomized controlled studies) for the carmustine wafers or for the traditional form of therapy, surgical resection of glioblastoma multiforme. Serious adverse events associated with the chemotherapeutic agent were identified and their respective rates of incidence calculated. Three prospective randomized controlled trials were used to provide point estimates and distributions for the Monte Carlo simulation. Parameters used to populate the Markov model were derived from the extant primary literature for patients undergoing surgical resection with either carmustine or placebo for glioblastoma multiforme. The base case was a 50 year old male with primary glioma. Results: Findings indicated that carmustine wafers increased survival over placebo from 54.05 months [95% confidence interval 46.25-61.07] to 69.87 months [95% confidence interval 67.02-71.94]. Serious side effects such as intracranial hemorrhage, seizures, and infections were also taken into account in the decision analytic model. Conclusions: Carmustine wafers significantly increase survival in patients undergoing surgical resection for glioblastoma multiforme. Therefore, carmustine wafers should be used as an adjunct to surgery in these patients.

A aterosclerose é uma doença inflamatória crônica e proliferativa que tem início quando fatores de risco alteram o endotélio vascular. As partículas da nanoemulsão lipídica LDE concentram-se em sítios inflamatórios e de intensa proliferação celular, como acontece nas lesões ateroscleróticas. A carmustina, um fármaco antiproliferativo usado na quimioterapia do câncer, não foi ainda explorada no tratamento da aterosclerose. Em trabalhos anteriores, mostrou-se que a associação com a LDE reduz drasticamente a toxicidade da carmustina, o que já foi demonstrado em pacientes com câncer avançado. O propósito do estudo é avaliar se a carmustina associada à LDE pode promover o efeito antiproliferativo nas lesões ateroscleróticas induzidas em coelhos. No presente trabalho, dezoito coelhos machos da raça New Zealand, receberam dieta rica em colesterol a 1% durante 8 semanas. Depois de 4 semanas foram divididos em dois grupos: grupo controle, que recebeu injeção endovenosa contendo apenas solução salina e grupo tratado, que recebeu LDE-carmustina na dose de 4mg/Kg semanalmente durante 4 semanas. Foram avaliados perfil hematológico, lipídico, bioquímico, ponderal e o consumo de ração. Após a eutanásia, foram medidas as lesões ateroscleróticas macroscópicas. Em seguida, o arco aórtico foi analisado por morfometria e por imunohistoquímica. Observou-se que não houve diferença no perfil ponderal e no consumo de ração entre os grupos de estudo. Não houve toxicidade hematológica, hepática e renal no grupo tratado. No perfil lipídico, ao final do estudo, as concentrações de colesterol total, não HDL-C e triglicerídeos aumentaram em todos os grupos. Portanto, o tratamento com LDE-carmustina inibiu as lesões ateroscleróticas em aproximadamente 90%, comparado ao grupo controle. LDE-carmustina também reduziu a presença de macrófagos, de células de músculo liso e das células reguladoras de linfócitos T na íntima arterial, bem como a expressão protéica de MMP9, das citocinas inflamatórias e dos receptores de lipoproteínas. O tratamento da aterosclerose induzida em coelho com LDE-carmustina resultou em marcante redução das lesões na aorta, da proliferação e invasão da íntima por macrófagos e células musculares lisas, características da doença, além dos fatores inflamatórios. Tendo em vista que, associada à LDE, a carmustina tem baixa toxicidade, a nova preparação LDE-carmustina tem grande potencial para a terapêutica das doenças cardiovasculares de natureza aterosclerótica / Atherosclerosis is a chronic inflammatory and proliferative disease that starts when risk factors alter vascular endothelium. The particles of the lipid nanoemulsion LDE concentrate on inflammatory sites and with intense cell proliferation, as occurs in atherosclerotic lesions. The carmustine, an antiproliferative drug used in cancer chemotherapy has not yet been explored for the treatment of atherosclerosis. In previous work, we showed that the association with LDE drastically reduces toxicity of carmustine, which has been demonstrated in patients with advanced cancer. The purpose of this study is to evaluate whether carmustine associated with LDE can promote antiproliferative effect on atherosclerotic lesions induced in rabbits. In this study, eighteen male New Zealand rabbits were given a diet rich in cholesterol 1% for 8 weeks. After 4 weeks they were divided into two groups: control group, which received an intravenous injection containing only saline and treated group receiving LDE-carmustine dose of 4 mg/kg weekly for 4 weeks. Hematology, lipid, biochemical, weight profile and feed intake were evaluated. After euthanasia, macroscopic atherosclerotic lesions were measured. Then, the aortic arch was analyzed by morphology and by immunohistochemistry. It was observed that there was no difference in weight and profile in feed intake between the study groups. There were not hematological, hepatic and renal toxicity in the treated group. Lipid profile at the end of the study, the concentrations of total cholesterol, non-HDL-C and triglycerides increased in all groups. Therefore, treatment with LDE-carmustine inhibit atherosclerotic lesions in approximately 90%, compared to the control group. LDE-carmustine also reduced the presence of macrophages, smooth muscle cells and regulatory T cells in the arterial intima as well as the protein expression of MMP9, inflammatory cytokines and lipoprotein receptors. Treatment of rabbits with induced atherosclerosis LDE-carmustine resulted in marked reduction of lesions in the aorta, proliferation and invasion by macrophages and intimal smooth muscle cells, disease characteristics, in addition to inflammatory factors. Given that, associated with LDE, carmustine has low toxicity, the new formulation LDE-carmustine has great potential for the therapy of atherosclerotic cardiovascular disease nature

A aterosclerose é uma doença inflamatória crônica e proliferativa que tem início quando fatores de risco alteram o endotélio vascular. As partículas da nanoemulsão lipídica LDE concentram-se em sítios inflamatórios e de intensa proliferação celular, como acontece nas lesões ateroscleróticas. A carmustina, um fármaco antiproliferativo usado na quimioterapia do câncer, não foi ainda explorada no tratamento da aterosclerose. Em trabalhos anteriores, mostrou-se que a associação com a LDE reduz drasticamente a toxicidade da carmustina, o que já foi demonstrado em pacientes com câncer avançado. O propósito do estudo é avaliar se a carmustina associada à LDE pode promover o efeito antiproliferativo nas lesões ateroscleróticas induzidas em coelhos. No presente trabalho, dezoito coelhos machos da raça New Zealand, receberam dieta rica em colesterol a 1% durante 8 semanas. Depois de 4 semanas foram divididos em dois grupos: grupo controle, que recebeu injeção endovenosa contendo apenas solução salina e grupo tratado, que recebeu LDE-carmustina na dose de 4mg/Kg semanalmente durante 4 semanas. Foram avaliados perfil hematológico, lipídico, bioquímico, ponderal e o consumo de ração. Após a eutanásia, foram medidas as lesões ateroscleróticas macroscópicas. Em seguida, o arco aórtico foi analisado por morfometria e por imunohistoquímica. Observou-se que não houve diferença no perfil ponderal e no consumo de ração entre os grupos de estudo. Não houve toxicidade hematológica, hepática e renal no grupo tratado. No perfil lipídico, ao final do estudo, as concentrações de colesterol total, não HDL-C e triglicerídeos aumentaram em todos os grupos. Portanto, o tratamento com LDE-carmustina inibiu as lesões ateroscleróticas em aproximadamente 90%, comparado ao grupo controle. LDE-carmustina também reduziu a presença de macrófagos, de células de músculo liso e das células reguladoras de linfócitos T na íntima arterial, bem como a expressão protéica de MMP9, das citocinas inflamatórias e dos receptores de lipoproteínas. O tratamento da aterosclerose induzida em coelho com LDE-carmustina resultou em marcante redução das lesões na aorta, da proliferação e invasão da íntima por macrófagos e células musculares lisas, características da doença, além dos fatores inflamatórios. Tendo em vista que, associada à LDE, a carmustina tem baixa toxicidade, a nova preparação LDE-carmustina tem grande potencial para a terapêutica das doenças cardiovasculares de natureza aterosclerótica / Atherosclerosis is a chronic inflammatory and proliferative disease that starts when risk factors alter vascular endothelium. The particles of the lipid nanoemulsion LDE concentrate on inflammatory sites and with intense cell proliferation, as occurs in atherosclerotic lesions. The carmustine, an antiproliferative drug used in cancer chemotherapy has not yet been explored for the treatment of atherosclerosis. In previous work, we showed that the association with LDE drastically reduces toxicity of carmustine, which has been demonstrated in patients with advanced cancer. The purpose of this study is to evaluate whether carmustine associated with LDE can promote antiproliferative effect on atherosclerotic lesions induced in rabbits. In this study, eighteen male New Zealand rabbits were given a diet rich in cholesterol 1% for 8 weeks. After 4 weeks they were divided into two groups: control group, which received an intravenous injection containing only saline and treated group receiving LDE-carmustine dose of 4 mg/kg weekly for 4 weeks. Hematology, lipid, biochemical, weight profile and feed intake were evaluated. After euthanasia, macroscopic atherosclerotic lesions were measured. Then, the aortic arch was analyzed by morphology and by immunohistochemistry. It was observed that there was no difference in weight and profile in feed intake between the study groups. There were not hematological, hepatic and renal toxicity in the treated group. Lipid profile at the end of the study, the concentrations of total cholesterol, non-HDL-C and triglycerides increased in all groups. Therefore, treatment with LDE-carmustine inhibit atherosclerotic lesions in approximately 90%, compared to the control group. LDE-carmustine also reduced the presence of macrophages, smooth muscle cells and regulatory T cells in the arterial intima as well as the protein expression of MMP9, inflammatory cytokines and lipoprotein receptors. Treatment of rabbits with induced atherosclerosis LDE-carmustine resulted in marked reduction of lesions in the aorta, proliferation and invasion by macrophages and intimal smooth muscle cells, disease characteristics, in addition to inflammatory factors. Given that, associated with LDE, carmustine has low toxicity, the new formulation LDE-carmustine has great potential for the therapy of atherosclerotic cardiovascular disease nature

Objective: To assess the safety and effectiveness of bis-chloroethylnitrosourea (BCNU) wafers in elderly patients with recurrent glioblastoma (GBM). Methods: Patients with recurrent GBM operated on between 2007 and 2014 were divided into 3 groups: >65 years with BCNU wafer implantation, >65 years without BCNU wafer implantation, and ≤ 65 years with BCNU wafer implantation. We compared survival and complications. Results: A total of 79 patients were identified: 24 in the older BCNU group (median age 68.2 years, 33.3% with a methylated MGMT promoter), 16 in the older non-BCNU group (median age 68.6 years, 31.3% with a methylated MGMT promoter), and 39 in the younger BCNU group (median age 56.8 years). Survival after progression was 9.2 months in the elderly BCNU group and 7.6 months in the elderly non-BCNU group ( p = 0.34); overall survival was 17.2 and 15.9 months, respectively ( p = 0.35). We found a tendency toward a higher rate of seizures and pneumonia in the older BCNU group. Conclusion: BCNU wafer implantation after resection of recurrent GBM is a reasonably safe treatment in patients aged >65 years. Seizures and systemic infections may occur more frequently, but the trade-off is still favorable as survival may be influenced positively. Higher age should not be regarded as a contraindication for BCNU wafers.

My thesis research began with a project in which we were trying to determine the function of embryonic stem cell (ESC)-specific miRNAs. Using luciferase constructs containing miRNA binding sites, luciferase expression was inhibited by endogenous miRNAs in ESCs, and by exogenous miRNAs in HeLa cells. Inhibition of luciferase expression by miRNAs was inhibited in HeLa cells using 2’O-methyl-oligonucleotides. In ESCs, 2’O-methyl-oligonucleotides were only effective in partially inhibiting miR290 function. Partial inhibition of miR290 did not result in any obvious phenotypic changes in mESCs. Later studies using 2’O-methyl-oligonucleotides in ESCs were also unsuccessful. The function of ESC-specific miRNAs has since been studied by re-introducing miRNAs into Dicer -/- cells which cannot make miRNAs. These studies have shown that ESC-specific miRNAs are involved in de novo DNA methylation, self-renewal, and cell-cycle regulation. Newly diagnosed glioblastoma (GBM) patients rarely survive more than two years even after surgery, radiotherapy, and chemotherapy using temozolomide (TMZ) or 1,3-bis(2-chloroethy)-1-nitrosourea (BCNU). Eventual regrowth of the tumor indicates that some tumor cells are resistant to therapy. GBM neurosphere-initiating cells (NICs) are thought to be similar to tumor-initiating cells in vivo, and will form invasive tumors in mice, making neurosphere cultures a good model system for studying GBMs. To test whether GBM NICs were resistant to chemotherapy, we used a neurosphere formation assay to measure the number of proliferating NICs in the presence of TMZ or BCNU. The concentrations of chemotherapy drugs required to inhibit neurosphere formation were much less than those required to inhibit bulk cell proliferation or to induce cell death in our neurosphere cultures. For some cultures, there was a robust recovery of neurosphere formation after chemotherapy treatment which appeared to be DNA damage independent. Some of the cultures that showed significant recovery of neurosphere formation underwent reversible cell cycle arrest, possibly reducing chemotoxicity in these cultures. Collectively, these results indicate that GBM neurosphere cultures can regrow after being treated with clinically relevant doses of chemotherapy drugs. Chemotherapy-treated neurosphere cultures remained viable, and formed tumors when injected into mice. Our experiments show that these in vitro assays may be useful in predicting in vivo responses to chemotherapeutic agents.