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Author Sloan, A.E.; Fung, H.; Reese, J.; Rogers, L.R.; Murphay, C.; Lazrus, H.; Dropulic, B.; Gerson, S.L.
Title (up) 141 Phase I Trial of Genetically Modified Hematopoietic Progenitor Cells Facilitate Bone Marrow Chemoprotection and Enabling TMZ/O6BG Dose Escalation Resulting in Improved Survival Type Journal Article
Year 2016 Publication Neurosurgery Abbreviated Journal Neurosurgery
Volume 63 Suppl 1 Issue Pages 157
Keywords
Abstract INTRODUCTION: Glioblastoma (GBM) is the most common malignant brain tumor with a median survival of 15 months despite surgery and aggressive radiochemotherapy. The most important mechanism of temozolomide (TMZ) resistance is the O-methylguanine-DNA methyltransferase (MGMT) gene that repairs temozolomide-induced DNA methylation. The MGMT inhibitor O-benzylguanine (BG) has demonstrated efficacy in depleting MGMT and maximizing tumor response in early-phase clinical trials. However, because MGMT expression is also low in hematopoietic cells, this has resulted in unacceptable bone marrow toxicity, and this approach has been abandoned. We hypothesized that chemoprotection of hematopoietic progenitor cells (HPC) with an MGMT mutant (MGMT-P140K) characterized by normal methyltransferase activity coupled with low affinity for BG, would maximize antitumor response while enabling patients to tolerate TMZ and BG dose escalation with minimal toxicity. We thus performed a phase I trial to test this hypothesis. METHODS: We treated 10 consecutive newly diagnosed GBM patients with standard surgery and radiation, followed by transplantation with autologous CD34 hematopoietic progenitor cells engineered to express MGMT-P140K using a lentiviral vector using 3 different arms. To assess chemoprotection, patients' blood counts and transgene marking were monitored during the treatment as was tumor growth and survival. RESULTS: The viral transduction rates were 2.5% to 75% and were clearly improved in the third arm with intrapatient dose escalation. P140K-MGMT gene markings in peripheral blood and bone marrow cells increased 3- to 26-fold with only mild (Grade 2-3) myelosuppression consistent with chemoselection and chemoprotection as hypothesized. Survival ranged from 20 to 36 months, which exceeded their recursive partitioning analysis-predicted survival by 1.9- to 3.2-fold suggesting clinical benefit (mean 2.0). Viral insertion site analysis failed to demonstrate clonal dominance. CONCLUSION: These preliminary results demonstrate that this chemoprotection strategy is tolerable, safe, and facilitates TMZ and BG dose escalation resulting in increased survival. A phase II study is ongoing.
Address
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0148-396X ISBN Medium
Area Expedition Conference
Notes PMID:27399420 Approved no
Call Number ref @ user @ Serial 96646
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Author Furtado, F.M. de S.F.; Santos, J.A.G.; Loredanna, S.; Araujo, E.; Saldanha, A.A.W.; Silva, J. da
Title (up) 30 years later: Social Representations about AIDS and sexual practices of rural towns residents Type Journal Article
Year 2016 Publication Revista da Escola de Enfermagem da U S P Abbreviated Journal Rev Esc Enferm USP
Volume 50 Spec Issue Pages 74-80
Keywords
Abstract In the 30 years of the AIDS pandemic in Brazil, it is recognized the HIV virus internalization of the phenomenon as a challenge to care and current health policies. In this sense, it aimed to verify sex practices and social representations that rural towns residents have about the disease. Attended by 789 people, men and women, between 18 and 90 years old, residents in 41 towns with fewer than 11,000 inhabitants in the state of Paraiba / Brazil. Data were collected by a questionnaire and the free association of words test. The results showed low concern about disease, perception of invulnerability to HIV infection and not using condoms during sexual intercourse, and confidence in the major reason related partner. Also showed endure derogatory and stereotypical representations, revealing that still persist in rural areas, beliefs and representations concerning the beginning of the epidemic. From these findings, it is possible to point out deficiencies in the care provided by the health services in these localities, which may result in increased vulnerability of this population to diseases, so there is the need to intensify information campaigns and intervention. The results reveal the existence of three different types of modes of learning health literacy skills in informal context: : i) learning that takes place in action, in achieving daily tasks; ii) learning processes that result from problem solving; iii) learning that occurs in an unplanned manner, resulting from accidental circumstances and, in some cases, devoid of intentionality. Nos 30 anos da pandemia da Aids no Brasil, reconhece-se o fenomeno da interiorizacao do virus HIV como um desafio ao cuidado e as politicas de saude atuais. Neste sentido, objetivou-se conhecer praticas sexuais e as representacoes sociais que residentes de cidades rurais tem acerca da doenca. Participaram 789 pessoas, homens e mulheres, entre 18 e 90 anos de idade, residentes em 41 cidades com menos de 11.000 habitantes no estado da Paraiba/Brasil. Os dados foram coletados por um meio de um questionario e o teste de associacao livre de palavras. Os resultados mostraram baixa preocupacao com doenca, percepcao de invulnerabilidade a contaminacao pelo HIV e o nao uso do preservativo nas relacoes sexuais, sendo a confianca no parceiro o principal motivo relacionado. Tambem mostraram perdurar representacoes de natureza pejorativa e estereotipada, revelando que ainda perduram, no meio rural, crencas e representacoes referentes ao inicio da epidemia. A partir de tais achados, e possivel apontar deficiencias em termos de cuidados oferecidos pelos servicos de saude nestas localidades, o que pode resultar em maiores vulnerabilidades dessa populacao ao adoecimento, havendo assim a necessidade da intensificacao de campanhas de informacao e intervencao.
Address Universidade Federal da Paraiba-UFPB, Joao Pessoa, Paraiba, Brazil
Corporate Author Thesis
Publisher Place of Publication Editor
Language Portuguese Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 0080-6234 ISBN Medium
Area Expedition Conference
Notes PMID:27384279 Approved no
Call Number ref @ user @ Serial 97672
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Author Garrity-Park, M.M.; Loftus, E.V.J.; Bryant, S.C.; Smyrk, T.C.
Title (up) A Biomarker Panel to Detect Synchronous Neoplasm in Non-neoplastic Surveillance Biopsies from Patients with Ulcerative Colitis Type Journal Article
Year 2016 Publication Inflammatory Bowel Diseases Abbreviated Journal Inflamm Bowel Dis
Volume 22 Issue 7 Pages 1568-1574
Keywords
Abstract BACKGROUND: Patients with ulcerative colitis (UC) are at risk for colorectal neoplasia. Challenges associated with surveillance colonoscopy with random biopsies for detection of dysplasia/cancer are well-documented. This study extended our findings in UC-associated colorectal cancer to include low-grade dysplasia (LGD) patients, testing whether our biomarker panel detects any UC-associated neoplasm. METHODS: DNA from the LGD area and the corresponding nonadjacent, non-dysplastic section from 171 UC-LGD patients was extracted. TaqMan SNP Genotyping Assays for TNF-alpha, IL-1beta, and IL23R were used to evaluate polymorphisms for each gene. Bisulfite-treated DNA was used for methylation testing of RUNX3, COX2, and MINT1. LGD data were combined with UC-cancer patient data for statistical testing. Logistic regression analyses determined associations between genetic/epigenetic/clinical variables and UC-associated neoplasia. Receiver operating characteristic analyses were performed to determine the final synchronous neoplasm detection panel. RESULTS: Comparison of nonadjacent, non-dysplastic DNA from UC-neoplasm patients versus UC-controls indicated that TNF-alpha, IL-1beta, and methylation of RUNX3, MINT1, and COX2 were significantly different (P < 0.0001). In multivariable analysis, all remained significant with an area under the curve of 0.85, exceeding the clinical variable panel area under the curve. Combining clinical and experimental variables yielded a neoplasm biomarker panel with an area under the curve of 0.95 (sensitivity and specificity of 82% and 91%, respectively). Analysis of DNA from LGD with known progression compared with LGD without progression indicated a significant difference in RUNX3 methylation. CONCLUSIONS: A combined clinical, genetic, and epigenetic model for detecting synchronous neoplasm by testing of non-neoplastic colonic tissue had favorable operating characteristics and could complement current patient care.
Address Divisions of *Experimental Pathology and Medicine, daggerGastroenterology and Hepatology, double daggerBiostatistics, and section signAnatomic Pathology, Mayo Clinic, Rochester, Minnesota
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1078-0998 ISBN Medium
Area Expedition Conference
Notes PMID:27135485 Approved no
Call Number ref @ user @ Serial 96380
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Author Lambert, C.S.; Alexander, B.H.; Ramachandran, G.; MacLehose, R.F.; Nelson, H.H.; Ryan, A.D.; Mandel, J.H.
Title (up) A case-control study of mesothelioma in Minnesota iron ore (taconite) miners Type Journal Article
Year 2016 Publication Occupational and Environmental Medicine Abbreviated Journal Occup Environ Med
Volume 73 Issue 2 Pages 103-109
Keywords
Abstract OBJECTIVES: An excess of mesothelioma has been observed in iron ore miners in Northeastern Minnesota. Mining and processing of taconite iron ore generate exposures that include elongate mineral particles (EMPs) of amphibole and non-amphibole origin. We conducted a nested case-control study of mesothelioma in a cohort of 68 737 iron ore miners (haematite and taconite ore miners) to evaluate the association between mesothelioma, employment and EMP exposures from taconite mining. METHODS: Mesothelioma cases (N=80) were identified through the Minnesota Cancer Surveillance System (MCSS) and death certificates. Four controls of similar age were selected for each case with 315 controls ultimately eligible for inclusion. Mesothelioma risk was evaluated by estimating rate ratios and 95% CIs with conditional logistic regression in relation to duration of taconite industry employment and cumulative EMP exposure [(EMP/cc)xyears], defined by the National Institute for Occupational Safety and Health (NIOSH) 7400 method. Models were adjusted for employment in haematite mining and potential exposure to commercial asbestos products used in the industry. RESULTS: All mesothelioma cases were male and 57 of the cases had work experience in the taconite industry. Mesothelioma was associated with the number of years employed in the taconite industry (RR=1.03, 95% CI 1.00 to 1.06) and cumulative EMP exposure (RR=1.10, 95% CI 0.97 to -1.24). No association was observed with employment in haematite mining. CONCLUSIONS: These results support an association between mesothelioma and employment duration and possibly EMP exposure in taconite mining and processing. The type of EMP was not determined. The potential role of commercial asbestos cannot be entirely ruled out.
Address Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota, USA
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 1351-0711 ISBN Medium
Area Expedition Conference
Notes PMID:26655961 Approved no
Call Number ref @ user @ Serial 90808
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Author Arita, H.; Yamasaki, K.; Matsushita, Y.; Nakamura, T.; Shimokawa, A.; Takami, H.; Tanaka, S.; Mukasa, A.; Shirahata, M.; Shimizu, S.; Suzuki, K.; Saito, K.; Kobayashi, K.; Higuchi, F.; Uzuka, T.; Otani, R.; Tamura, K.; Sumita, K.; Ohno, M.; Miyakita, Y.; Kagawa, N.; Hashimoto, N.; Hatae, R.; Yoshimoto, K.; Shinojima, N.; Nakamura, H.; Kanemura, Y.; Okita, Y.; Kinoshita, M.; Ishibashi, K.; Shofuda, T.; Kodama, Y.; Mori, K.; Tomogane, Y.; Fukai, J.; Fujita, K.; Terakawa, Y.; Tsuyuguchi, N.; Moriuchi, S.; Nonaka, M.; Suzuki, H.; Shibuya, M.; Maehara, T.; Saito, N.; Nagane, M.; Kawahara, N.; Ueki, K.; Yoshimine, T.; Miyaoka, E.; Nishikawa, R.; Komori, T.; Narita, Y.; Ichimura, K.
Title (up) A combination of TERT promoter mutation and MGMT methylation status predicts clinically relevant subgroups of newly diagnosed glioblastomas Type Journal Article
Year 2016 Publication Acta Neuropathologica Communications Abbreviated Journal Acta Neuropathol Commun
Volume 4 Issue 1 Pages 79
Keywords 1p19q; Glioblastoma; Glioma; Idh1/2; Molecular classification; Prognostic factor; Tert; Temozolomide
Abstract The prognostic impact of TERT mutations has been controversial in IDH-wild tumors, particularly in glioblastomas (GBM). The controversy may be attributable to presence of potential confounding factors such as MGMT methylation status or patients' treatment. This study aimed to evaluate the impact of TERT status on patient outcome in association with various factors in a large series of adult diffuse gliomas. We analyzed a total of 951 adult diffuse gliomas from two cohorts (Cohort 1, n = 758; Cohort 2, n = 193) for IDH1/2, 1p/19q, and TERT promoter status. The combined IDH/TERT classification divided Cohort 1 into four molecular groups with distinct outcomes. The overall survival (OS) was the shortest in IDH wild-type/TERT mutated groups, which mostly consisted of GBMs (P < 0.0001). To investigate the association between TERT mutations and MGMT methylation on survival of patients with GBM, samples from a combined cohort of 453 IDH-wild-type GBM cases treated with radiation and temozolomide were analyzed. A multivariate Cox regression model revealed that the interaction between TERT and MGMT was significant for OS (P = 0.0064). Compared with TERT mutant-MGMT unmethylated GBMs, the hazard ratio (HR) for OS incorporating the interaction was the lowest in the TERT mutant-MGMT methylated GBM (HR, 0.266), followed by the TERT wild-type-MGMT methylated (HR, 0.317) and the TERT wild-type-MGMT unmethylated GBMs (HR, 0.542). Thus, patients with TERT mutant-MGMT unmethylated GBM have the poorest prognosis. Our findings suggest that a combination of IDH, TERT, and MGMT refines the classification of grade II-IV diffuse gliomas.
Address Division of Brain Tumor Translational Research, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. kichimur@ncc.go.jp
Corporate Author Thesis
Publisher Place of Publication Editor
Language English Summary Language Original Title
Series Editor Series Title Abbreviated Series Title
Series Volume Series Issue Edition
ISSN 2051-5960 ISBN Medium
Area Expedition Conference
Notes PMID:27503138 Approved no
Call Number ref @ user @ Serial 96639
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