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1
Palle, Josefine. „Optimizing Chemotherapy in Childhood Acute Myeloid Leukemia“. Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9189.
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Despite major advances in our understanding of the biology of childhood acute myeloid leukemia (AML) and the development of new cytotoxic drugs, the prognosis of long-term survival is still only 60-65 %.
In the present research, we studied the pharmacokinetics of drugs used in the induction therapy of childhood AML and performed in vitro drug sensitivity testing of leukemic cells from children with AML.
The aims of the studies were to correlate the results of the analysis to biological and clinical parameters and to identify subgroups of AML with specific drug sensitivity profiles in order to better understand why treatment fails in some patients and how therapy may be improved.
Blood samples were analysed to study the pharmacokinetics of doxorubicin (n=41), etoposide (n=45) and 6-thioguanine (n=50). Doxorubicin plasma concentration and total body clearance were correlated to the effect of induction therapy, and doxorubicin plasma concentration was an independent factor for complete remission, both in univariate and multivariate analysis including sex, age, and white blood cell count at diagnosis. For etoposide and 6-thioguanine no correlation was found between pharmacokinetics and clinical effect. Children with Down syndrome (DS) tended to reach higher blood concentrations of etoposide and thioguanine nucleotides, indicating that dose reduction may be reasonable to reach the same drug exposure as in children without DS.
Leukemic cells from 201 children with newly diagnosed AML, 15 of whom had DS, were successfully analysed for in vitro drug sensitivity by the fluorometric microculture cytotoxicity assay (FMCA). We found that samples from children with DS were highly sensitive to most drugs used in AML treatment. In non-DS children, the t(9;11) samples were significantly more sensitive to cytarabine (p=0.03) and doxorubicin (p=0.035) than other samples. The findings might explain the very favorable outcome reported in children with DS and t(9;11)-positive AML. A specific drug resistance profile was found for several other genetic subgroups as well. A detailed study of MLL-rearranged leukemia showed that cellular drug sensitivity is correlated both to partner genes and cell lineage, findings that support the strategy of contemporary protocols to include high-dose cytarabine in the treatment of patients with MLL-rearrangement, both in AML and acute lymphoblastic leukemia (ALL).
Our results indicate that drug resistance and pharmacokinetic studies may yield important information regarding drug response in different sub-groups of childhood AML, helping us to optimize future chemotherapy in childhood AML.
2
Masquelier, Michèle. „Leukemia chemotherapy : experimental studies on pharmacological optimisation /“. Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-046-X/.
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3
Kwok, Suet-kei Gladys. „The effectiveness of a chemotherapy educational programme (CEP) for Leukaemia and Lymphoma patients“. Click to view the E-thesis via HKUTO, 2004. http://sunzi.lib.hku.hk/hkuto/record/B31972937.
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4
O'Connor, Brian 1961. „Studies towards the synthesis of the novel antileukemic agent CI-920 and the addition of cuprates to vinyltriphenylphosphonium bromide : a synthesis of 1,5-disubstituted 1Z,4Z-pentadienes“. Thesis, McGill University, 1987. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=75443.
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A new method for the preparation of 1,5-disubstituted-1Z,4Z-pentadienes by the addition of alkenyl cuprates to vinyltriphenylphosphonium bromide followed by an aldehyde is described. This method is used for the syntheses of 6Z,9Z-heneicosadiene and 15,15-(diethyldithio)-13S-t-butyldiphenylsilyloxy-6Z,9Z,11E-pentadecatriene. Syntheses of $(-)$-(5R)-argentilactone and (+)-(5R)-goniothalamin are described. Model studies towards the synthesis of the novel antileukemic agent CI-920 were carried out.
5
李富榮 und Foo-wing Lee. „Pharmacokinetics of homoharringtonine in Chinese leukemia patients“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1990. http://hub.hku.hk/bib/B31209233.
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6
Fuentes, Gari Maria. „A mathematical model of cell cycle heterogeneity for personalizing leukemia chemotherapy“. Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/26301.
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Acute myeloid leukemia is a type of blood cancer characterized by an excessive build-up of immature blood cells in the bone marrow and blood streams. As a result, healthy stem cells become space- and resource-limited, and do not produce enough functional cells for the body to operate normally. Treatment is required immediately, consisting of intensive chemotherapy. Chemotherapy dosage and schedule are derived from established protocols which do not account for patient-specific and disease-specific heterogeneity. Over- or under- dosage are thus common; a more rational and personalized approach to chemotherapy treatments is required. Specifically, incorporating the effect of chemotherapy in a cell cycle phase-specific manner would be highly beneficial. In this work, we developed a population balance model (PBM) of the cell cycle based on the underlying biology that captures the progress of cells within and between phases. It was validated with three leukemia cell lines separately for the duration of one cell cycle, and in variable mixtures where forward and backward kinetics as well as clonal identification were successfully performed. The model was compared against two other cell cycle models: an existing ODE model and a newly developed DDE model featuring phase durations as delays. The PBM outperformed the other two in recapitulating biological features, and displayed a higher sensitivity to treatment when coupled to an existing pharmacokinetic/pharmacodynamic model of chemotherapy treatment. The PBM was further used in the prediction of clonal evolution during chemotherapy, highlighting the important heterogeneity in treatment response between clones but also the competitive features among them that could be critical in the success of the treatment. Finally, the first steps towards implementing this technology at clinical level were taken by defining converted, measurable data sets. A prototype application, "ChemoApp", was developed at the user interface level for the introduction of this research into clinical practice.
7
Kam, Kevin, und 甘季燐. „Therapeutic potential of demethylation agents and histone deaceytlase inhibitors in NK-cell lymphoma and leukemia“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011564.
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8
Gregory, Bradley Barnes Battaglini Claudio L. „In-hospital individualized prescriptive exercise intervention for acute leukemia patients undergoing chemotherapy“. Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2006. http://dc.lib.unc.edu/u?/etd,678.
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Thesis (M.A.)--University of North Carolina at Chapel Hill, 2006.Title from electronic title page (viewed Oct. 10, 2007). "... in partial fulfillment for the degree of Master of Arts in the Department of Exercise and Sport Science (Exercise Physiology)." Discipline: Exercise and Sports Science; Department/School: Exercise and Sport Science.
9
Frost, Britt-Marie. „Chemotherapy in Childhood Acute Lymphoblastic Leukemia : In vitro cellular drug resistance and pharmacokinetics“. Doctoral thesis, Uppsala University, Department of Women's and Children's Health, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2664.
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The aims of the studies described in this thesis were to investigate the pharmacokinetics of and cellular resistance to chemotherapy as causes of treatment failure in childhood acute lymphoblastic leukemia (ALL).
Leukemic cells from 370 children with newly diagnosed ALL were tested by the Fluorometric Microculture Cytotoxicity Assay to measure their resistance to each of ten standard cytotoxic drugs. In the high-risk group, increased in vitro resistance to each of the drugs dexamethasone, etoposide and doxorubicin was associated with a worse clinical outcome. Combining the results for these drugs yielded a drug resistance score, showing a relative risk of relapse in the most resistant group that was 9.8 times higher than in the most sensitive group. In the standard-risk and intermediate-risk groups, final evaluation must await longer follow-up.
The new cytotoxic agent CHS 828 was equally active in vitro in samples from children with acute myeloblastic leukemia (AML) and ALL, with 50% cell kill at concentrations achievable in vivo. In AML samples CHS 828 also displayed high frequencies of synergistic interactions with four standard drugs. The well-known differences in clinical outcome between Down´s syndrome (DS) and non-DS children with acute leukemia may partly be explained by our finding of differences in drug resistance at the cellular level.
Pharmacokinetic studies were performed at the start of induction treatment of ALL. Doxorubicin was assayed by reversed-phase liquid chromatography with fluorometric detection, and vincristine by high performance liquid chromatography with electrochemical detection. Plasma doxorubicin concentrations were measured in 107 children after 23 h of a 24-h infusion. The median steady-state concentration in children 4-6 years old, a group known to have a favorable outcome of treatment, was about 50% higher than in those 1-2 and >6 years old Vincristine pharmacokinetics was evaluated in 98 children. There was no correlation between age and total body clearance or any other pharmacokinetic parameters.
In vitro testing of cellular drug resistance might be useful in predicting the outcome in high-risk ALL. The further exploration of CHS 828 in childhood leukemia seems warranted. There is no pharmacokinetic rationale for the common practice of administering relatively lower doses of vincristine to adolescents than to younger children.
10
Landier, Wendy. „Predictors of Non-Adherence to Oral Chemotherapy in Children with Acute Lymphoblastic Leukemia“. Diss., University of Hawaii at Manoa, 2010. http://hdl.handle.net/10125/22058.
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Overall survival for pediatric patients with acute lymphoblastic leukemia (A.L.L.) treated with contemporary therapy now exceeds 85%; however, approximately 20% will experience relapse. Since A.L.L. is the most common malignancy in children, relapsed
patients comprise a large proportion of the total number of children with cancer. The prognosis for long-term survival following relapse is generally poor; thus, relapsed A.L.L. is a significant contributor to cancer-related mortality in children.
Poor adherence to oral medication is a substantial problem in contemporary health care and may contribute to unexplained relapses in children with A.L.L. Therapy for pediatric A.L.L. includes a prolonged “maintenance” phase that requires daily 6- mercaptopurine (6MP), a self- or parent/caregiver-administered oral chemotherapy agent given for approximately two years. 6MP has been shown to be a critical component of the curative regimen for A.L.L.; thus, children with A.L.L. who fail to adhere to oral 6MP chemotherapy as prescribed may be at increased risk of leukemia relapse.
This study used extant questionnaire data from a cohort of children with A.L.L enrolled on a Children’s Oncology Group study (AALL03N1) to determine the prevalence of self/parent-reported non-adherence to oral 6MP during the maintenance phase of A.L.L. therapy, and to identify sociodemographic and behavioral predictors of non-adherence to oral 6MP.
Twenty-two percent of children in the cohort were non-adherent to oral chemotherapy, defined as missing more than one dose of 6MP for non-medical reasons over the 112-day observation period. The risk of non-adherence was significantly increased for those who failed to perceive the severity of the child’s illness (Odds ratio [OR] 1.89, 95% Confidence Interval [CI] 1.00-3.55, P=0.049) or the benefits of treatment with oral 6MP (OR 1.78, 95%CI 1.07-2.94, P=0.025). Vulnerable subgroups included Hispanic ethnicity (OR 2.25, 95%CI 1.30-3.90, P=0.004) and older age (OR 1.07 per year, 95%CI 1.02-1.12, P=0.005).
Study findings suggest that even occasional reports of missed 6MP doses may herald a significant adherence problem; that patients and their parents may need ongoing reminders regarding the subclinical and asymptomatic nature of leukemia in remission;
and that frequent review with families regarding the purpose, function, and proper administration of oral 6MP is imperative.
11
Kwok, Suet-kei Gladys, und 郭雪琪. „The effectiveness of a chemotherapy educational programme (CEP) for Leukaemia and Lymphoma patients“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B31972937.
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12
Hui, Pui-yan, und 許珮茵. „The combined effect of Chinese medicinal extract polysaccharide peptide (PSP) and the chemotherapeutic agents-cytarabine, doxorubicinand etoposide in human leukemic cells and normal human T-lymphocytes“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2003. http://hub.hku.hk/bib/B27776311.
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13
Larery, Angela R. D. „Hierarchical neuropsychological functioning in pediatric survivors of acute lymphoblastic leukemia“. Thesis, University of North Texas, 2007. https://digital.library.unt.edu/ark:/67531/metadc3949/.
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Acute lymphocytic leukemia (ALL) is one of the most common types of pediatric cancers. Improvements in treatment within the last 20 years have resulted in reduced mortality and a greater focus upon quality of life. Several researchers have documented neuropsychological impairments in children following treatment for ALL; however, there have not been any comparative studies documenting differences in neuropsychological functioning based upon treatment modality despite the documented effects of radiation therapy and combined radiation/chemotherapy upon the developing brain. In addition, past studies have focused on unitary measures, ignoring the hierarchical relationship between basic cognitive functions and more abstract skills. This study examined the neuropsychological functioning of 81 children who were treated for ALL at a metropolitan children's hospital. All children were tested a minimum of two years after the final treatment session and were administered the NEPSY. Results do not support any interactions or main effects with the exception of the age of the child at diagnosis. Children diagnosed prior to the age of 5 showed greater impairments on tasks measuring attention, memory, and visuospatial reasoning in comparison to peers diagnosed after age 6.
14
Tada, Kohei. „Abacavir, an anti-HIV-1 drug, targets TDP1-deficient adult T cell leukemia“. Kyoto University, 2015. http://hdl.handle.net/2433/202797.
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15
Moleski, Maria. „Intellectual and mathematical functioning as impacted by central nervous system prophylactic chemotherapy for acute lymphoblastic leukemia“. Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/284158.
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Acute lymphoblastic leukemia (ALL), the most common childhood cancer, is currently survivable in approximately 70 percent of cases. Better therapeutic regimes are responsible for improved survival rates, and therapy has been refined throughout the past 30 years to reflect the balance struck between effective treatment and possible adverse side effects. Current treatment protocols for standard-risk patents usually consist of either intrathecal (IT) or intravenous (IV) chemotherapy, or both. Chemotherapy without cranial radiation therapy (CRT) is a relatively new form of treatment, and no consensus has been reached about its possible adverse effects on IQ or academic achievement. When deficits in academic achievement are found, they tend to differentially manifest in the area of mathematics rather than language skills. However, none of the studies examining mathematics achievement in ALL survivors have used a comprehensive test to evaluate mathematics functioning. Thus, fifteen children (x = 11.86 years) who are long-term ALL survivors, and 15 comparison group children (x = 11.75 years) were tested on a measures of general intellectual functioning, mathematics achievement, spelling, word usage and single word reading. Survivors of ALL consistently demonstrated significantly lower scores on measures of IQ and mathematics achievement. No significant differences between groups on measures of spelling, word usage, and word reading were found. Further studies that address neuropsychological functioning in ALL survivors could help to illuminate the specific abilities responsible for these decrements.
16
Tsutsumi, Ikuyo. „Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study“. Kyoto University, 2020. http://hdl.handle.net/2433/245837.
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17
Finn, Nnenna Adimora. „Role of redox systems in doxorubicin metabolism and doxorubicin-mediated cell signaling: a computational analysis“. Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/41149.
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Insensitivity to chemotherapy is an ongoing issue in cancer treatment, one that appears to be highly dependent on patient-specific variations. It has been shown clinically that while a subset of patients will successfully respond to a particular chemotherapeutic regimen, there exists another subset of patients who when exposed to the same course of therapy will remain resistant to treatment or exhibit signs of relapse after treatment has been administered. This discrepancy raises interesting questions regarding the role that patient-specific variations play in controlling the efficacy of chemotherapy treatment regimens. Doxorubicin (Dox) is a common chemotherapeutic agent used in the treatment of a variety of solid tumors and leukemias and resistance to Dox treatment is a major issue in cancer chemotherapy, oftentimes leading to patient relapse. To gain a deeper understanding of the processes that influence Dox resistance, we must first understand the mechanisms that underlie and contribute to Dox's toxicity. To this end, the metabolic reactions that activate Dox have been implicated as major determinants of Dox cytoxicity and as possible factors that control Dox resistance in cancer cells.
There are several lines of evidence that redox-dependent metabolism plays a large role in Dox toxicity. The Dox bioactivation network is comprised of a system of reduction/oxidation (redox) reactions that lead to the formation of toxic Dox metabolites and reactive oxygen species (ROS). Moreover, multi-drug resistant acute lymphoblastic leukemia cells derived from relapsed patients have elevated levels of the antioxidant glutathione and show insensitivity to Dox treatment. The redox dependence of Dox bioactivation, the understanding that Dox treatment generates ROS, and the evidence that Dox resistant cells exhibit increased antioxidant capacity, suggest the possibility that redox pathways modulate the efficacy of Dox treatment in cancer cells. The overall objectives of the proposed dissertation, therefore, were to investigate how the redox properties of the Dox bioactivation network influence Dox toxicity in acute lymphoblastic leukemia cells, and to provide evidence that cell-specific variations in the intracellular levels of these redox components influences the degree to which Dox treatment will induce cancer cell death.
The significant findings of this study are that the redox reactions involved in Dox metabolism are dual-natured, containing a toxicity-generating module characterized by nicotinamide adenine dinucleotide phosphate (NADPH)-dependent Dox reductive conversion, as well as an ROS signal-generating module characterized by NADPH- and oxygen-dependent Dox redox cycling. The balance between the coupled redox reactions that comprise the toxicity- and ROS signal-generating modules of Dox bioactivation determines the sensitivity-phenotype of leukemia cells and phenotypic changes in the Dox-sensitivity of leukemia cells can be induced by the successful modulation of the Dox bioactivation network through the pharmacological inhibition of NADPH in a concentration- and cell type-dependent manner.
This study highlights the importance of the intracellular redox network in controlling chemotherapy-induced ROS. The unequal distribution in antioxidant burden across the various intracellular antioxidant enzymes suggests a significant role for NADPH supply, as controlled by the enzyme glucose-6-phosphate dehydrogenase (G6PD), to the intracellular ROS buffering capacity of cells during instances of oxidative stress. Changes in G6PD activity were shown to promote protein-S-glutathionylation during oxidative stress conditions, thereby implicating G6PD in the modulation of redox-sensitive signal transduction pathways. The intracellular glutathione redox balance, a measure of the intracellular redox environment, can effectively regulate Dox-induced NF-κB signal transduction in leukemia cells. The systematic modulation of intracellular glutathione redox balance in leukemia cells by N-acetylcysteine (NAC) revealed an important role for protein S-glutathionylation mechanisms in the control of NF-κB signal transduction induced by Dox treatment. These findings identify the glutathione redox network as a potential therapeutic target for the systematic modulation of Dox sensitivity in cancer cells and elucidate the complex role that antioxidants such as NAC can play in modulating the effectiveness of Dox chemotherapy treatment regimens.
Lastly, this study highlights the need for and the capacity of computational models to accurately describe the complex redox-reactions that contribute to Dox metabolism in leukemia cells. This study is groundbreaking in its use of computational modeling to analyze reversible electron transfer events between proteins using mass-action kinetics. The models developed in this study can accurately explain cytosolic doxorubicin bioactivation, intracellular hydrogen peroxide clearance, and kinase-specific S-glutathionylation, thereby showing that the use of comprehensive and/or relatively simple computational models can provide semi-quantitative predictions about the behavior of redox systems in mammalian cells as they relate to Dox-induced toxicity and Dox-induced cell signaling.
18
Haylock, David Norman. „Ex vivo expansion of human haemopoietic progenitor cells“. Title page, abstract and contents only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phh4181.pdf.
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"December 2001." Includes bibliographical references (leaves 178-225) Focuses on the ex vivo growth of human haemopoietic progenitor cells with the objective of defining culture conditions for generating myeloid post-progenitor cells for therapy
19
Tinsley, Sara Marie. „A Comparison of Quality of Life between Intense and Non-Intense Treatment for Patients with Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome“. Scholar Commons, 2015. http://scholarcommons.usf.edu/etd/5786.
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Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS) are hematologic malignancies that occur most frequently in the sixth and seventh decades of life. Both disorders are associated with a poor prognosis, with median survival of one year or less. An overall five-year survival rate for both disorders, regardless of treatment, is less than 10%. A primary goal of treatment is to improve quality of life (QOL) because cure is improbable. The purpose of this longitudinal cohort study was to compare QOL between groups, intensive, non-intensive therapy, and supportive care. The sample consisted of 85 patients with high risk MDS and AML recruited from Moffitt Cancer Center. Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) was used to measure QOL. The aims for the study were to: 1) To compare the difference in QOL scores measured by the Functional Assessment of Cancer Therapy –Leukemia version for intensive chemotherapy, non-intensive therapy and supportive care within 7 days of new treatment and one month after initiation of treatment; 2) To determine QOL predictors of AML and high risk MDS from age, comorbidity, fatigue, and diagnosis; 3) To test the moderating effect of treatment with age, comorbidity, and fatigue on QOL.
The first aim was analyzed with repeated measures analysis of variance (ANOVA). The supportive care group was not included in the analysis because of low accrual. Results indicated that there was a significant group by time interaction (with p=.040). Follow up tests revealed that the intensive treatment group had a significant improvement in their QOL scores at 1 month post treatment (p=.020). The second aim was conducted using Pearson’s correlations with age, comorbidity, fatigue, and diagnosis with significant correlations found between fatigue and QOL (r=-.693, p< .001). These findings identify an important relationship between fatigue and QOL. This was a negative correlation, showing that as fatigue increases QOL decreases. The third aim was explored using regression with Hayes (2013) application for moderation analysis. Scores for QOL for age, comorbidity, and fatigue were not moderated by treatment.
These findings suggest that the most intensive treatment approach improves QOL. In addition, fatigue is a significant predictor of QOL. As fatigue increases, QOL scores decrease. Additional studies with a larger, more diverse sample is needed to explore the relationship between treatment approaches and QOL. In addition, intervention studies can be developed in AML and high risk MDS focused on fatigue management. It is anticipated that the results of this study will be used to inform patients and health care providers when making decisions concerning treatment based on QOL outcomes.
20
Ristic, Marko. „ROS/SUMO relationship in the chemotherapeutic treatment of Acute Myeloid Leukemia“. Thesis, Montpellier, 2015. http://www.theses.fr/2015MONTT047.
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Les leucémies aiguë myéloïde (LAM) sont un groupe d’hémopathies malignes, dont le traitement est généralement composé de deux génotoxiques : la cytarabine (Ara-C) et la daunorubicine (DNR). Nous avons montré que l’Ara-C et la DNR induisent la déconjugaison rapide de SUMO (Small Ubiquitin-related Modifier) de ses protéines cibles. Cette deSUMOylation est dûe à l'inactivation des enzymes E1 et E2 de SUMOylation par les espèces réactives de l'oxygène (ROS) produites par l’Ara-C et la DNR et est impliquée dans l'activation de l'apoptose. En outre, cet axe ROS/SUMO est anergisé dans les LAM chimiorésistantes. Cependant, il peut être réactivé par des pro-oxydants ou par inhibition de la voie SUMO par l'acide anacardique. Pour identifier les protéines contrôlées par l’axe ROS/SUMO nous avons effectué une approche de spectrométrie de masse quantitative (SILAC). Parmi les 1000 protéines SUMOylées identifiées, la plupart des 114 protéines qui perdent leur SUMOylation lors du traitement sont impliquées dans la régulation de l'expression des gènes. De plus, un ChIP-Seq avec des anticorps anti SUMO-2 a permis de montrer que les génotoxiques, en particulier la DNR, induisent une diminution massive de la présence de protéines SUMOylées sur la chromatine. La recherche de motifs au sein des séquences fixant SUMO a permis d’identifier le motif de liaison de CTCF à l’ADN. De plus, CTCF a été trouvé dans la SILAC comme l’une des protéines déSUMOylées par les traitements. En utilisant des données publiques de Chip-Seq pour CTCF, nous avons identifié 55 gènes qui fixent à la fois CTCF et SUMO et dont l’expression est régulée par les traitements. Dans la dernière partie de ce travail, nous avons étudié le groupe de 19 protéines dont la SUMOylation augmente suite aux traitements génotoxiques. Parmi ces protéines, nous avons trouvé diverses protéines centromériques, y compris CENP-B et CENP-C. En utilisant le PLA (Proximity Ligation Assay) nous avons pu montrer que CENP-B et CENP-C colocalisent avec SUMO et yH2AX après traitement. Cela suggère que la SUMOylation des protéines centromériques se produit sur les sites de cassure et pourrait jouer un rôle dans la réparation des dommages de l'ADNAcute Myeloid Leukemias (AML) are a group a severe hematological malignancies, which treatment is generally composed of two genotoxics: Cytarabine (Ara-C) and Daunorubicin (DNR). We have shown that these drugs induce the rapid deconjugation of the Small Ubiquitin-related Modifier (SUMO) from its target protein. This is due to the inactivation of SUMO E1 and E2 enzymes by Reactive oxygen species (ROS). This deSUMOylation participated in the activation of specific genes and is involved the induction of apoptosis. In addition, this ROS/SUMO axis is anergized in chemoresistant AMLs. However, it can be reactivated by pro-oxidants or inhibition of the SUMO pathway with anacardic acid, an inhibitor of the SUMO E1. To identify which proteins are regulated by this ROS/SUMO axis, we performed a quantitative mass spectrometry approach. Among the 1000 identified SUMO targets, most of the 114 proteins, which SUMOylation decrease upon treatment, are involved in the regulation of gene expression. In addition, we showed by ChIP-Seq with SUMO-2 antibodies that genotoxics, in particular DNR, induce a massive decrease of the presence of SUMOylated proteins on the chromatin. Motif search analysis of the SUMO binding sequences in these genes identified CTCF binding motif. Interestingly, CTCF was found in the SILAC as deSUMOylated by the drugs. Using publicly available ChIP-Seq data for CTCF, we found 55 genes which are occupied by both SUMO-2 and CTCF and which expression is regulated by the drugs. In the last part of this work, we got interested in the 19 proteins that get up-SUMOylated upon treatment. Among them, we found centromeric proteins, including CENP-B and CENP-C. Using Proximity Ligation Assay, we could show that CENP-B and CENP-C colocalize with both SUMO and yH2AX upon DNR treatment. Altogether, this suggests that centromeric protein up-SUMOylation occurs at sites of DNA damage and might play a role in DNA damage repair
21
Kuss, Bryone Jean. „Molecular and gene expression studies of the genes involved in the breakpoints of the inv(16) leukaemias“. Title page, abstract and contents only, 1996. http://web4.library.adelaide.edu.au/theses/09PH/09phk972.pdf.
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22
Larery, Angela R. D. McGill Jerry C. „Hierarchical neuropsychological functioning among pediatric survivors of acute lymphoblastic leukemia“. [Denton, Tex.] : University of North Texas, 2007. http://digital.library.unt.edu/permalink/meta-dc-3949.
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23
Russell, Kathy, Marion Slack, Janet Cooley und Kelly Mathews. „Impact of a Specialty Pharmacy-Based Oral Chemotherapy Adherence Program on Patient Adherence“. The University of Arizona, 2016. http://hdl.handle.net/10150/614015.
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Class of 2016 AbstractObjectives: Patient medication adherence is a basic requirement for treating chronic myelogenous leukemia (CML) with oral tyrosine kinase inhibitors (TKIs). When imatinib adherence rates are less than 80 or 90 percent, major and complete molecular responses, respectively, do not happen. The purpose of this study was to determine the effect of a real-time medication monitoring (RTMM) reminder system adherence program on the medication possession ratio (MPR). Methods: This analytic study was a retrospective cohort study and used data extracted from chart reviews for patients who received services from 2011 to 2015. It was approved by the Institutional Review Board. The study consisted of an intervention group and a control group (50 patients each). MPRs, demographic, descriptive, and categorical variables were summarized using means, standard deviations (SD), and frequencies/percentages. Results: The study population consisted of adult patients (mean age=62.2, SD=2.7, 50% male) treated by Avella Specialty Pharmacy who received imatinib or nilotinib as treatment for CML, gastrointestinal stromal tumors (GIST), or a similar positive Philadelphia chromosome cancer. Only 4% of patients in the intervention group had an < 85% MPR, compared to 46% in the control group (p < 0.001). Conclusions: In those patients who had an MPR of ≥ 85%, the difference between the groups was statistically significant. As past studies have shown, adherence rates greater than 90% have a higher likelihood of a major or complete molecular response and a greatly reduced risk of disease progression.
24
Frank, Morgan Caroline, und Morgan Caroline Frank. „Prevention and Improvement of Cognitive Deficits in Childhood Acute Lymphoblastic Leukemia (All) Survivors Treated With Chemotherapy: Evidence-Based Information For Parents“. Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/621919.
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This thesis summarizes what is known about the cognitive changes in childhood acute
lymphoblastic leukemia (ALL) survivors treated with chemotherapy, as well as associated risk
factors and intervention strategies. An educational pamphlet was developed compiling this
information to serve as anticipatory guidance for parents of children diagnosed with ALL.
ALL is a cancer of the blood and bone marrow and is the most common pediatric
malignancy, accounting for 25% of cancers in children under 15 years of age. Treatments are
extremely successful, with survival rates of 90% for children younger than 15 years.
Unfortunately, treatment side effects increase with the increase of survival rates. Ureatmentrelated cognitive deficits occur in up to 40% of childhood ALL survivors, and is becoming increasingly common. Results from the literature review indicate that children with ALL treated with chemotherapy have cognitive impairment in the areas of total intelligence quotient (IQ), working memory, attention, information processing speed, fine motor speed, visual IQ, verbal IQ, performance IQ, problem solving, and sequential reasoning. These cognitive problems can have a significant impact on the child’s quality of life and transition back to school after treatment. Interventions that are effective in improving cognitive outcomes include cognitive and/or problem-solving interventions.
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Koishi, Seiji. „Biomarkers in long survivors of Pediatric acute lymphoblastic leukemia Patients : late effects of cancer chemotherapyに関する研究“. Kyoto University, 2000. http://hdl.handle.net/2433/151425.
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Fung, Kwong-lam, und 馮廣林. „The effect of microtubule targeting chemotherapeutic agents on bone marrow derived mesenchymal stromal cells and its interaction withacute lymphoblastic leukemia blasts“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085660.
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Kozlowski, Piotr. „Prognostic factors, treatment and outcome in adult acute lymphoblastic leukemia : Population-based studies in Sweden“. Doctoral thesis, Örebro universitet, Institutionen för hälsovetenskaper, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-47424.
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Acute lymphoblastic leukemia (ALL) has poor prognosis in older/elderly adults and in high-risk/relapsed disease. Recommended treatment of ALL was evaluated (study I-IV). Data was obtained from the Swedish Acute Leukemia registries and from patient records. I. We assessed ALL relapse treatment and outcome in 76 patients aged 15-65 years (y). Complete remission (CR) was achieved in 50/71 patients (70%). Of them, 29 underwent allogeneic hematopoietic stem cell transplantation (hSCT). Five year overall survival (OS) was 15%, but close to 50% in 19 patients <35y after hSCT. II. We studied outcome of treatment with the Hyper-CVAD protocol in 19 of 24 patients with T-ALL aged 18-72y. CR was reached in 89%, but 5y leukemia-free survival was only 29%, and 20% in 15 patients not transplanted in CR1. Six patients received hSCT in CR2. Finally, 5y OS in all 19 patients was 47%. The only negative prognostic factor found was age ≥35y. III. We evaluated minimal residual disease (MRD) monitoring in 35 patients with Philadelphia (Ph) negative B-ALL aged 46-79y and treated with the ABCDV protocol. The CR rate was 91%. MRD was measured by flow cytometry in 73% in CR1 (MRD1) and omitted in those >70y or with high-risk ALL. Five patients received hSCT (only one due to MRD). Five year OS in the whole cohort was 47%. Continuous CR but not OS was improved in patients with MRD1 <0.1 %. IV. We studied 155 patients with ALL (Ph+ in 35%) aged 55-85y and treated with remission induction/palliation (124/31). Both, intensive, and palliative treatment resulted in the CR rates of 70/83/16% and 3y OS of 26/32/3%. OS was negatively influenced by age and platelet count ≤35×109/L (but not Ph+). OS was not enhanced by introduction of an age-adapted protocol. We concluded that intensive treatment with subsequent allogeneic hSCT is the most reasonable option in younger patients with ALL recurrence (I). Hyper-CVAD has low relapse-preventing efficacy (II). MRD guided intensification is probably feasible in only a minority of older patients (III). Prognosis in elderly ALL is poor, but no longer impaired by Ph+ (IV).
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Figliolia, Suzana Luzia Coelho. „Fatores de risco para mucosite bucal em pacientes com leucemia linfóide aguda submetidos a diferentes protocolos de tratamento“. Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/25/25136/tde-22062007-141538/.
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A mucosite bucal está entre as principais complicações decorrentes do tratamento antineoplásico em pacientes com leucemia linfóide aguda (LLA). Entre os fatores de risco para sua ocorrência destacam-se a idade, o gênero e a leucometria inicial, além das drogas quimioterápicas com comprovada ação estomatotóxicas. O objetivo deste estudo foi investigar a prevalência e os fatores de risco para a mucosite bucal em pacientes com LLA submetidos a diferentes protocolos de tratamento quimioterápicos. Um total de 169 prontuários clínicos de pacientes oncológicos pediátricos submetidos a diferentes protocolos de tratamento para LLA no Setor de Oncologia Pediátrica do Hospital Infantil Darcy Vargas, na cidade de São Paulo, no período compreendido entre 1994 a 2005 foram, retrospectivamente, avaliados. Os dados demográficos (idade e gênero) e clínicos (leucometria inicial, protocolo de tratamento a que foi submetido, evolução, ocorrência de mucosite e outras lesões bucais) foram registrados. A associação da mucosite bucal com as variáveis clínicas e demográficas foi obtida pelos testes do qui-quadrado e análise de regressão logística multivariada. Os resultados demonstraram uma freqüência de mucosite bucal em 46% dos pacientes oncológicos pediátricos com LLA sem correlação estatisticamente significativa entre sua ocorrência e o gênero (p=0,08), a idade (p=0,33) e a leucometria inicial (p=0,34). Na análise multivariada o protocolo de tratamento do grupo Berlim- Frankfurt-Munique de 1995 (ALL-BFM 95), de acordo com as variáveis avaliadas neste estudo, mostrou ser o fator mais significativo (p=0,009) para a ocorrência da mucosite bucal. Esses resultados fortemente sugerem uma maior estomatotoxicidade do protocolo ALL-BFM 95 comprovadas pela maior freqüência de mucosite bucal nos pacientes ontológicos pediátricos com LLA. Portanto, concluímos que a mucosite bucal deveria ser sistematicamente analisada nos centros especializados no tratamento da LLA que adotam diferentes protocolos de tratamento, visando não somente contribuir com a análise do grau de toxicidade das drogas quimioterápicas, mas principalmente, melhorar a qualidade de vida do paciente com base em condutas terapêuticas e profiláticas mais efetivas na prevenção de sua ocorrência.Oral mucositis is one of the main complications secondary to antineoplastic treatment in patients with acute lymphoblastic leukemia (ALL). The risk factors for its occurrence include age, gender and initial leukocyte count, besides chemotherapeutic drugs with known stomatotoxic action. This study investigated the prevalence and risk factors to oral mucositis in patients with ALL submitted to different chemotherapeutic treatment protocols. A total of 169 clinical records of pediatric oncology patients submitted to different treatment protocols for ALL at the Pediatric Oncology Sector of the Child Hospital Darcy Vargas, in the city of São Paulo, in the period 1994 to 2005 were retrospectively evaluated. Demographic (age and gender) and clinical data (initial leukocyte count, treatment protocol adopted, evolution, occurrence of mucositis and other oral lesions) were recorded. The association of oral mucositis with the clinical and demographic variables was assessed by the chi-square test and multivariate logistic regression analysis. The results demonstrated occurrence of oral mucositis in 46% of pediatric oncology patients with ALL, without statistically significant correlation between its occurrence and gender (p=0.08), age (p=0.33) and initial leukocyte count (p=0.34). Multivariate analysis revealed that the Berlin-Frankfurt-Munich protocol of 1995 (ALL-BFM 95) was the most significant factor (p=0.009) to the occurrence of oral mucositis according to the variables evaluated in this study. These results strongly suggest the greater stomatotoxic effect of the ALL-BFM 95 protocol, as demonstrated by the higher frequency of oral mucositis in pediatric oncology patients with ALL. Thus, it may be concluded that oral mucositis should be systematically analyzed in centers specialized in the treatment of ALL adopting different treatment protocols, with a view to contribute to analysis of the degree of toxicity of chemotherapeutic drugs and mainly to improve the quality of life of patients on the basis of more effective therapeutic and prophylactic approaches for prevention of its occurrence.
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Kizhakkekkara, Vadukoot Anish. „Targeting the Stress Response to ROS: Design and Development of Novel and Selective Anti-cancer Agents“. University of Cincinnati / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1460652535.
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Löfgren, Christina. „Pharmacological and clinical studies of new ways to improve cytostatic treatment of acute myelocytic leukemia : in vitro and in vivo studies /“. Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-183-0/.
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Grohmann, Theresa, Melanie Penke, Stefanie Petzold-Quinque, Susanne Schuster, Sandy Richter, Wieland Kiess und Antje Garten. „Inhibition of NAMPT sensitizes MOLT4 leukemia cells for etoposide treatment through the SIRT2-p53 pathway“. Elsevier, 2018. https://ul.qucosa.de/id/qucosa%3A38590.
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NAMPT (Nicotinamide phosphoribosyltransferase) catalyses the rate-limiting step in the NAD biosynthesis from nicotinamide and thereby regulates the activity of NAD-dependent enzymes. Cancer cells are highly dependent on NAD for energy and DNA repair processes and are assumed to be more susceptible to an inhibition of NAD synthesis than non-transformed cells. We aimed to investigate whether or not inhibition of NAMPT with its specific inhibitor FK866 can sensitize leukemia cells for chemotherapeutic agents.
NAMPT protein abundance, enzymatic activity and NAD concentrations were significantly higher in Jurkat and Molt-4 leukemia cell lines compared to normal peripheral blood mononuclear cells. Combination of etoposide and FK866 caused increased cell death in leukemia cell lines compared to etoposide alone. Etoposide decreased protein abundance of NAD-dependent deacetylases SIRTUIN1. After combining etoposide and FK866 treatment SIRTUIN2 was further decreased and accumulation and acetylation of the downstream target p53 was further enhanced in MOLT4 cells. Concomitantly, protein abundance of p21 and cleaved BAX was increased.
Targeting NAMPT could be a novel therapeutic strategy to enhance the efficacy of chemotherapeutic agents such as etoposide against leukemia.
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Javier, Jose Emmanuel F. „Increased TGF-beta Signaling Drives Different Hematopoietic Disease Outcomes following Stress Hematopoiesis“. University of Cincinnati / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1617109578665394.
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Soares, Andrea Ferreira. „Avalia??o cl?nica e microbiol?gica da mucosa oral de crian?as com leucemia linfobl?stica aguda, submetidas ? a??o profil?tica do gluconato de clorexidina A 0,12%“. Universidade Federal do Rio Grande do Norte, 2004. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17106.
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Regarding the morbidity potential of oral complications in patients with leukemia, it evaluated the cl?nical and microbiologic changes of oral mucosal in children with LLA, with age range of O to 15 years old, undergone the chemotherapy antineoplastic and for the use prophylactic of chlorhexidine gluconate 0,12% during ten days, that was utilized in each chemotherapy treatment stage. The collect for rnicrobiological study was obtained preferentiality in intensification stage at the end prophylatic treatment. The study grouup had 20 children, where it observed clinically decrease in frequency of mucositis, with 8 cases (40%) only. In microbiological examination observed one reduced incidence of pathogenic microorganisms with Staphylococcus coagulase- negative (40%), Klebsiella pneumoniae (5%), Escherichia coZi enteropathogenic (15%), Stenotrophomonas maltophilia (5%) e Candida albicans (35%). The findings obtained in the present trial suggest that the use of chlorhexidine gluconate 0,12% can be responsible for incidence reduced of mucositis, but it wasn t possible to make correlation between isolated pathogenic microorganisms and mucositis development
Considerando o potencial de morbidade das complica??es orais em pacientes com leucemia, procurou-se avaliar as altera??es clinicas e microbiol?gicas da mucosa, em crian?as com LLA. na faixa et?ria de O a 15 OOos, submetidas a quimioterapia antineopl?sica e ao uso profil?tico do gluconato de clorexidina a 0,12%, durante dez dias, o qual era administrado em todas as fases do tratamento quimioter?pico. A coleta para o estudo microbiol?gico foi obtida, preferencialmente, na fase de intensifica??o, ao t?rmino do tratamento profil?tico. A amostra foi constituida por 20 crian?as, na qual evidenciou-se em nivel clinico, uma freq??ncia reduzida de mucosite, com 8 ocorr?ncias (40%) apenas. No exame microbiol?gico, constatou-se a presen?a de reduzido n?mero de microrganismos patog?nicos, como Staphylococcus coagulase-negativo (40%), Klebsiella pneumoniae (5%), Escherichia coli-enteropatog?nica (15%), Stenotrophomonas maltophilia (5%) e Candida albicans (35%). Diante dos resultados, sugeriu-se que o uso do referido antiss?ptico contribuiu para a reduzida ocorr?ncia de mucosite, no entanto, n?o foi possivel estabelecer correla??o entre os microrganimos isolados e o desenvolvimento da mucosite
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Pillay, Looventharee. „The development of a nutrition support protocol for children with Acute Lymphoblastic Leukemia (ALL) : twenty case studies from Sheikh Khalifa Medical City, Abu Dhabi, UAE“. University of the Western Cape, 2017. http://hdl.handle.net/11394/5636.
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Magister Scientiae (Nutrition Management) - MSc(NM)Acute lymphocytic leukemia (ALL) is the most common type of childhood cancer accounting for approximately 25% of cancers diagnosed in children less than 20 years of age. It originates in the bone marrow and prevents the normal manufacture of red blood cells, white blood cells and platelets. A poor nutritional status is frequently observed in children with ALL at the time of diagnosis and during treatment which may result in protein energy malnutrition if nutrition intervention is delayed. This retrospective study aims to assess the nutritional status of children newly diagnosed with Acute Lymphoblastic Leukemia (ALL) using 20 case studies between 1 January 2013 and 31 December 2014 from Sheikh Khalifa Medical City (Abu Dhabi, UAE), in order to develop an appropriate nutritional support protocol for pediatric ALL patients treated at this institution. Study Design: A retrospective descriptive case study design was used. The study population consisted of 20 electronic medical records of patients aged between 1-14 years who were newly diagnosed with Acute Lymphoblastic Leukemia (ALL) and admitted to Sheikh Khalifa Medical City for treatment during the period 1 January 2012 and 31 Dec 2014. Data Collection: Identification of suitable participants began through a review of each potential study participant`s electronic medical record. Data was collected and recorded on a data collection form (Appendix III) from the electronic medical record for each suitable participant for the following at admission and during the full duration of all phases of cancer treatment namely induction, consolidation, interim maintenance, delayed intensification and maintenance. The data collected comprised of the following: age, gender, date of diagnosis, symptoms on diagnosis, the cancer diagnosis (type and subtype), anthropometric measurements (weight, length/ height, head circumference), biochemical values (visceral proteins, blood glucose levels, hemoglobin, hematocrit, lymphocyte count), clinical assessment (stomatitis, anemia, mucositis), diet history (home feeding regimes; consumption of daily requirements; food preferences – types, textures; food allergies, food intolerances; food aversions; use of oral nutritional supplements; treatment-related side-effects; systemic related side-effects (nausea; vomiting; diarrhea; anorexia; appetite changes; taste changes; physical activity level; depression), dietary requirements (age and gender related nutritional requirements for energy, protein, fat and fluids) and indications for nutritional support (oral feeding; enteral feeding; parenteral feeding). Analysis of Results: The weights and length/ heights of participants recorded in the electronic medical records were converted to z-scores on the World Health Organization growth charts. The diet prescription of nutritional intervention was interpreted in comparison to the biochemical indices, anthropometric status and dietary intake of each participant. All the data involving changes in anthropometrics, biochemistry, diet history and nutritional interventions from each case study (from diagnosis and through all stages of treatment) was screened and compared with reference values in the context of the age and sex of the child. Evidence based nutritional guidelines were used to document the outcomes of the medical nutrition treatment provided in order to develop a nutrition support protocol for children with Acute Lymphoblastic Leukemia at Sheikh Khalifa Medical City. Results: The results showed that weight loss expressed as a percentage of body weight provided a more accurate estimate of the true significance of weight loss in subjects undergoing cancer treatment (chemotherapy) for ALL. A weight loss of greater than 5% of body weight over a period of one month is considered a sign of nutritional deprivation even if the subject is not classified as undernourished by anthropometric parameters. Subjects experienced the highest weight loss during the consolidation phase and interim maintenance phases of treatment. Conclusion: It can therefore be concluded that pediatric subjects on cancer treatment for ALL at SKMC and receiving nutritional support underwent changes in nutritional status as manifest by a reduction in more than 5% of their body weight during three phases of treatment namely induction, consolidation and interim maintenance. An appropriate nutrition support protocol was developed based on the results and experience obtained from this study for pediatric ALL patients treated at SKMC.
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Viana, Simone Santana. „Anticorpos vacinais virais em crianças portadoras de Leucemia Linfóide Aguda após quimioterapia“. Universidade Federal de Sergipe, 2009. https://ri.ufs.br/handle/riufs/3681.
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The role of vaccination in children, who received chemotherapy for malignancies, including acute lymphoblastic leukemia (ALL), remains controversial. Both the disease and treatment affect the immune system. Changes may occur by
neutropenia, leading to immediate risk of bacterial and fungal infections, loss protective levels of antibody by previous immunizations, as well as the questionable efficacy of revaccination. Therefore, different approaches are applied in several countries and the best vaccination schedule is not well defined yet. Moreover, the existing recommendations, mainly built on low levels of evidence, are not always followed by oncologists in clinical practice and there are still few references to literature on the subject. The paucity of data from controlled trials on both residual immunity against vaccine antigens at the end of treatment of children with ALL and the ability of the patients to respond to vaccine boosters does not allow the development of guidelines, and then further evaluation are required. We conducted a study using open controlled clinical trial to assess the levels of protection against viral vaccine antigens in children treated for leukemia after completion of chemotherapy, and implementation of a booster dose vaccine. Serum antibody levels were evaluated for hepatitis B, measles, rubella and mumps in 33 patients and compared with a control group. Statistical analysis was performed using the Chi-square and Fisher exact tests for categorical variables and Mann-Whitney test for continuous
variables. As a result, there was a high proportion of individuals not immune to measles (75.9%), to rubella (51.7%) and hepatitis B (59.3%) at the end of chemotherapy for ALL. After administration of one booster dose of vaccine, had a
recovery for all antigens tested was statistically significant for measles (p = 0, 0422) and hepatitis B (p = 0.0357). It is recommended, therefore, administration of one dose of the MMR and evaluate vaccine antibody titers for individual interventions.O papel da vacinação em crianças que receberam quimioterapia (QT) para neoplasias malignas, inclusive leucemia linfóide aguda (LLA), continua controverso. Tanto a doença quanto o tratamento afetam o sistema imune. As alterações podem ocorrer pela neutropenia, que leva ao risco imediato de infecções bacterianas e fúngicas, pela perda dos níveis protetores de anticorpos adquiridos por imunizações prévias, como também pela eficácia duvidosa das reimunizações. Por isso, diferentes abordagens são aplicadas em vários países e o melhor esquema de vacinação não está bem definido. Além disso, as recomendações existentes, construídas principalmente com baixos níveis de evidência, nem sempre são seguidas pelos oncologistas na prática clínica e as referências de literatura quanto ao tema são poucas. A escassez de dados de ensaios controlados, tanto para a imunidade residual contra antígenos vacinais no final do tratamento de crianças com LLA, como para a capacidade desses pacientes responderem aos reforços vacinais, não permitiu até o momento o desenvolvimento de diretrizes, sendo, então, necessárias novas avaliações. Foi realizado um estudo do tipo ensaio clínico controlado aberto, para avaliar as taxas de proteção contra antígenos vacinais virais em crianças tratadas para LLA após término da QT, e da aplicação de uma dose de reforço vacinal. O estado imunológico contra hepatite B, sarampo, rubéola e caxumba foi avaliado em 33 pacientes e comparado com um grupo controle. Para análise estatística foram utilizados o teste do qui-quadrado e exato de Fisher para variáveis categóricas e teste de Mann-Whitney para variáveis contínuas. Observouse uma elevada proporção de indivíduos não imunes ao sarampo (75,9%) à rubéola (51,7%) e à hepatite B (59,3%) ao final da QT para LLA. Após a administração de uma dose vacinal de reforço, ocorreu a recuperação para todos os antígenos testados sendo estatisticamente significante para sarampo (p = 0,0422) e hepatite B (p = 0,0357). Recomenda-se, portanto, uma dose das vacinas tríplice viral e hepatite B após recuperação hematológica e posterior avaliação dos títulos de anticorpos vacinais para intervenções individualizadas.
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Melo, Carolina Pereira de Souza 1979. „Padronização da RMN para determinação precoce da resistência à quimioterapia na leucemia linfóide aguda infantil“. [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316897.
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Orientadores: José Andrés Yunes, Ana Carolina de Mattos ZeriTese (doutorado) - Universidade Estadual de Campinas, Instituo de Biologis
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Resumo: O uso intensivo e combinado de diferentes quimioterápicos tem permitido a cura de 70-80% das leucemias linfóides agudas (LLA) da infância. A intensidade e o uso das drogas são adaptados ao risco de recaída dos pacientes, aferido ao diagnóstico e nas primeiras semanas do tratamento. Embora existam diferenças, os principais critérios utilizados na estratificação dos pacientes nos grupos de risco são idade, contagem leucocitária, imunofenotipagem e a resposta inicial ao tratamento, mensurada pela citoredução na medula óssea e/ou sangue periférico. Este último, tem se mostrado um fator prognóstico poderoso, independente, que permite identificar pacientes com maior ou menor risco de recaída. Ao mensurar a citoredução, faz-se, indiretamente, uma avaliação in loco, da sensibilidade intrínseca da leucemia à quimioterapia. A proposta deste trabalho foi a implementação do uso da metodologia de Ressonância Magnética Nuclear (RMN) para futura identificação de pacientes de LLA com resistência aos quimioterápicos usados na fase de indução. A implementação do método de RMN foi feito com células (linhagens celulares e células primárias de LLA) em cultura com doses de dois quimioterápicos: Prednisolona (PRED) e L-asparaginase (ASNase). O perfil dos metabólitos presentes no meio de cultura das células tratadas com as drogas foi obtido por meio da análise de espectros de RMN, e buscou-se associá-lo à resistência das células aos quimioterápicos. Os biomarcadores identificados neste trabalho permitiram distinguir tanto as linhagens sensíveis das resistentes quanto pacientes que recaíram dos que entraram em remissão, utilizando a técnica da metabolômica. Além disso, a análise do perfil metabólico permitiu formular algumas hipóteses sobre as vias metabólicas implicadas na resistência às drogas. Experimentos complementares com um maior número de pacientes se fazem necessários. Porém, nossos resultados indicam que este método poderá ser futuramente usado para análise de células de pacientes em tratamento, subsidiando, com maior precisão do que os métodos atuais, a alocação dos pacientes nos grupos de risco
Abstract: Intensive and combined use of different chemotherapic drugs has improved the cure rate of childhood Acute Lymphoblastic Leukemia (ALL) to 70-80%. Drugs use and intensity are determined based on patient relapse risk, which is measured at diagnosis and during the first weeks of treatment. Although differences may exist, the main criteria used to stratify patients in risk groups are age, leukocyte count, immunophenotyping and initial response to treatment, measured by cytoreduction in bone marrow and / or peripheral blood. The latter has proved to be a powerful independent prognostic factor, which allows identification of patients at higher or lower risk of relapse. By measuring cytoreduction, an in situ evaluation of the leukemia intrinsic sensitivity to chemotherapy is done indirectly. The aim of this study was to implement the use of Nuclear Magnetic Resonance (NMR) methodology for future identification of ALL patients resistance to chemotherapeutic agents used in the induction phase. NMR method implementation was done with cells (cell lines and primary ALL cells) kept in culture with two chemotherapic drugs: prednisolone (PRED) and L-asparaginase (ASNase). NMR spectra analysis provided information about the metabolic profile of drug treated cells culture medium, which was associated with the cells resistance to chemotherapic drugs. The biomarkers identified in this study allowed distinguishing, not only between the resistant and sensitive strains, but also between relapsed patients and those ones who remained in remission, using the metabolomics technique. Furthermore, analysis of the metabolic profile allowed the formulation of some hypotheses about the metabolic pathways involved in drug resistance. Further experiments with larger numbers of patients are needed. However, our results indicate that this method can be used for future analysis of patients treated cells, supporting, with greater precision than current methods, the allocation of patients into risk groups
Doutorado
Genetica Animal e Evolução
Doutor em Genetica e Biologia Molecular
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Abreu, Ana Isabel Alves. „Manifestações orais em crianças em tratamento oncológico“. Master's thesis, [s.n.], 2015. http://hdl.handle.net/10284/5130.
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Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Medicina DentáriaDados da Organização Mundial de Saúde (OMS) de 2012 demonstram que a incidência de cancro a nível mundial tem vindo a aumentar, e referem cerca de 14 milhões de novos casos por ano. O cancro infantil representa 0,5% a 4,6% de todos os cancros, variando a sua taxa de incidência entre 50 a 200 novos casos, por milhão de crianças, em todo o mundo. Nos países ocidentais, os protocolos terapêuticos antineoplásicos atualmente empregues melhoram de forma significativa as taxas de sobrevivência do cancro, agravando contudo a morbidade nos pacientes. Na cavidade oral, a terapia oncológica é responsável por efeitos adversos agudos e também por complicações a longo prazo. Nas crianças estas manifestações orais são ainda mais prevalentes que nos adultos e contribuem para a morbilidade e até mesmo para a mortalidade destes doentes. Pretendeu-se assim, com este trabalho, realizar uma revisão sistemática de literatura científica, publicada nos últimos 15 anos, acerca das complicações orais do tratamento oncológico em crianças. Bem como, compilar diretrizes de atuação clínica para orientar o médico dentista no atendimento destes doentes. Durante os meses de Janeiro a Maio de 2015, procedeu-se a uma ;pesquisa bibliográfica nas bases de dados PubMed e B-on, sendo consultados também outros bancos de dados como LILACS – BIREME, SciELO, utilizando as seguintes palavras chave: cancer, children, leukemia, limphoma, “oral manifestations”, radiotherapy, chemotherapy; separadas ou associadas pelo operador de pesquisa, booleano AND. Na pesquisa foram empregues os seguintes limites: artigos publicados nos últimos 15 anos, abstract disponível, estudos em humanos e artigos e língua inglesa, portuguesa e espanhola. Desta pesquisa resultou um total de 116 artigos que foram selecionados primeiramente pelos títulos, seguidamente pela leitura dos abstracts e, finalmente, do artigo por inteiro, obtendo-se assim 68 artigos, para revisão. Foram ainda considerados artigos de referência publicados em anos anteriores, livros de texto médicos e publicações portuguesas com dados epidemiológicos sobre cancro infantil em Portugal. Os efeitos colaterais agudos e crónicos, da terapia antineoplásica, mais frequentemente observados na cavidade oral são então: mucosite, hemorragia oral, disgeusia, infeções oportunistas, disfunção das glândulas salivares, cárie dentária, neurotoxicidade, osteorradionecrose, disfunção na articulação temporomandibular e anomalias do desenvolvimento dentário e craniofacial. O médico dentista desempenha portanto um papel fundamental na prevenção diagnóstico e tratamento dessas complicações. Logo, estas crianças deverão ser incluídas, antes mesmo de iniciar a oncoterapia, num rigoroso programa de acompanhamento médico-dentário, que deve prolongar-se mesmo depois de terminado o tratamento do cancro. Idealmente, estes programas deverão ter lugar nas próprias instituições de cuidados de saúde oncológicos, para promover a estreita colaboração do médico dentista com os restantes membros da equipa oncológica, e assim garantir cuidados orais e aconselhamento especializado, que contribuirão para melhorar a sua qualidade de vida e para a diminuir a morbilidade e mortalidade. World Health Organization (WHO) data from 2012 show that cancer`s incidence has been globally increasing, and mentions around 14 million new cases a year. Childhood cancer represents from 0.5% to 4.6% of all cancer, with an incidence rate between 50 to 200 new cases per million children worldwide. In western countries, currently used antineoplastic therapeutic protocols have improved significantly cancer surviving rates, yet increasing, patients’ morbidity. Oncological therapy is responsible for acute adverse effects and long-term complications in the oral cavity. In children, these oral manifestations are even more prevalent than in adults and contribute to their morbidity and mortality. Therefore, this works objective was to conduct a systematic review of scientific literature published in the last 15 years, about the oral complications of oncological treatment in children. Furthermore, it was intended to gather guidelines on clinical procedures to guide the dentist in the care of pediatric oncological patients. During the months of January until March 2015, PubMed and B-on databases were sceened for Portuguese, Spanish and English abstact-free articles, published in the last 15 years, using the words: cancer, children, leukemia, lymphoma, ”oral manifestation”, radiotherapy, chemotherapy; separated or associated by the Boolean operator ”AND”. Other databases such as LILACS – BIREME, and SciELO were also used for the research aplling the same limitations and key words. 116 articles were found. Article selection was accomplished firstly by the title and abstract reading and finally, by full article analysis. A total of 68 articles were reviewed. For better understanding of the theme to develop, reference articles from previous years were also reviewed; Medical textbooks and epidemiological data on pediatric cancers in Portugal were also consulted. The acute and chronical side effects of anti-neoplastic therapy, more frequently observed in the oral cavity are: mucositis, oral bleeding, dysgeusia, opportunistic infections, salivary gland dysfunction, dental caries, neurotoxicity, osteoradionecrosis, temporomandibular joint dysfunction and dental and craniofacial growth anormalities. So, it is unquestionable the dentist`s malor role in the diagnosis, prevention and treatment of these complications. Therefore, before starting the oncological therapy, children should enter a strict dental monitoring program, that must be extended even after completing cancer treatment. Ideally, these dental programs should take place in the oncologic healthcare institutions, in order to promote dentist and oncological team close cooperation and ensure professional oral care and expert advice. Implementing these measures will be a strong asset towars improving pediatric oncological patients` quality of life and in decreasing their morbidity and mortality.
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Silva, D?bora Sunaly Leite da. „Avalia??o das habilidades neurocognitivas em crian?as e adolescentes sobreviventes da Leucemia Linfoide Aguda - LLA“. Universidade Federal do Rio Grande do Norte, 2014. http://repositorio.ufrn.br:8080/jspui/handle/123456789/17557.
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The present study investigated the impact of the treatment modalities of Acute Lymphoblastic Leukemia on neurocognitive abilities of children and adolescents survivors, aged between 6 and 16 years of age, accompanied in pediatric oncology sectors of public health services in the cities of Campina Grande-PB and Natal-RN. The study included 52 children, 13 of these being children and adolescents diagnosed with leukemia and 39 healthy children matched in relation to the study group considering gender, age, school type and level of maternal education. Later the group of children with leukemia was subdivided into two subgroups depending on treatment modality which were submitted: Group 1A (only chemotherapy) and 1B (chemotherapy and radiotherapy). All participants were subjected to a battery of neuropsychological tests that investigated the following neurocognitive abilities: intellectual ability, memory system, attention, visuospatiality and visuoconstruction, processing speed and executive functions. Data were analyzed using descriptive and inferential measurements with the aid of the U test of Mann-Whitney and T test, considering the influence of the variables: sex, age at diagnosis, time since completion of treatment and level of schooling mothers, on the performance of children. Overall, it is concluded that the illness and the treatment of acute lymphoblastic leukemia significantly favors the emergence of cognitive deficits, particularly in terms of visuospatial skills, and executive skills visoconstrutivas. In turn, the treatment modality of radiotherapy is associated with the presence of more severe deficits, highlighting the significant impact on the speed of information processing. It is hoped that the results presented here will contribute to a better understanding of the nature and extent of neurocognitive effects arising ALL treatment
O presente estudo investigou o impacto das modalidades de tratamento da Leucemia Linf?ide Aguda sobre as habilidades neurocognitivas de crian?as e adolescentes sobreviventes, com faixa et?ria entre 6 e 16 anos de idade, acompanhados nos setores de oncologia pedi?trica de servi?os p?blicos de sa?de das cidades de Campina Grande- PB e Natal-RN. Participaram deste estudo 52 crian?as, sendo destas 13 crian?as e adolescentes diagnosticados com leucemia e 39 crian?as saud?veis pareadas em rela??o ao grupo de estudo considerando-se o sexo, idade, tipo de escola e n?vel de escolaridade materna. Posteriormente o grupo de crian?as com leucemia foi subdividido em dois subgrupos em fun??o da modalidade de tratamento as quais foram submetidos: Grupo 1A (exclusivamente tratamento quimioter?pico) e 1B (tratamento quimioter?pico e radioter?pico). Todos os participantes foram submetidos ? bateria de testes neuropsicol?gicos que investigou as seguintes habilidades neurocognitivas: capacidade intelectiva, sistema mnem?nico, aten??o, visoespacialidade e visoconstru??o, velocidade de processamento e fun??es executivas. Os dados foram analisados atrav?s de medidas descritivas e inferenciais com o aux?lio do Teste U de Mann-Whitney e do Teste t, considerando-se a influ?ncia das vari?veis: sexo, idade ao diagn?stico, tempo decorrido desde o t?rmino do tratamento e n?vel de escolariza??o das m?es, sobre o desempenho das crian?as. De forma geral, conclui-se que o adoecimento e o tratamento da leucemia linfoide aguda favorece significativamente o surgimento de d?ficits cognitivos, em especial em termos de habilidades visoespaciais, visoconstrutivas e habilidades executivas. Por sua vez, a modalidade de tratamento da radioterapia est? associada ? presen?a de d?ficits mais severos, com destaque para o impacto significativo sobre a velocidade no processamento da informa??o. Espera-se que os resultados ora apresentados venham a contribuir para uma melhor compreens?o acerca da natureza e da extens?o dos efeitos neurocognitivos advindos do tratamento da LLA
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Rech, Ângela. „Influência da punção lombar traumática e da quimioterapia intratecal na sobrevida de pacientes pediátricos com leucemia linfocítica aguda“. reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2005. http://hdl.handle.net/10183/4146.
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Introdução e Objetivos: O sistema nervoso central (SNC) é o um sítio freqüente de recaída na criança com leucemia linfocítica aguda (LLA). Existe evidência de que a punção lombar traumática (PLT) pode representar um risco adicional de recaída no SNC quando ocorre inoculação de blastos no liqüido céfalorraquidiano (LCR). Este estudo tem por objetivo determinar se a ocorrência da PLT ao diagnóstico afeta o prognóstico de pacientes com essa patologia. Material e Métodos: Setenta e sete pacientes com diagnóstico de LLA, tratados entre 1992 a 2002, foram incluídos na análise. Quimioterapia intratecal (QIT) foi instilada imediatamente após a PL inicial (precoce), ou na segunda PL (tardia), realizada no período de 24 a 48 horas após a realização da PL inicial. Foi feita análise da influência da PLT e do momento (precoce x tardia) de administração da QIT em relação a recaída no SNC. Resultados: Entre os 19 pacientes que apresentaram PLT ao diagnóstico e receberam QIT tardia, seis tiveram recaída isolada no SNC e dois recaída combinada em SNC e medula óssea (MO). Entre os nove pacientes que tiveram PLT e receberam QIT precoce, somente um apresentou recaída combinada em SNC e MO (P=0,20); não houve, portanto, influência estatisticamente significativa da PLT na sobrevida livre de eventos (SLE) (55% para QIT precoce x 49% para QIT tardia) (P=0,37). Entretanto, em análise estratificada, de acordo com grupos de risco, observamos que para pacientes de baixo ou médio risco o OR foi de 0,8 quando recebiam QIT tardia (P=0,99) e 0,17 quando recebiam QIT precoce (P=0,47). Por outro lado, entre pacientes de alto risco o OR para recaída foi de 21,0 para aqueles que recebiam QIT tardia (P=0,09) e 1,5 para o grupo que recebia Q IT precoce (P=0,99). Conclusão: Os resultados do presente estudo são sugestivos de que a ocorrência da PLT tem uma influência adversa no prognóstico de pacientes com LLA de alto risco de recaída. Como estes resultados são decorrentes de um estudo retrospectivo, recomenda-se que sejam confirmados em estudos prospectivos randomizados.Introduction and Objectives: The Central Nervous System (CNS) is a frequent site of relapse in childhood acute lymphoblastic leukemia (ALL). Traumatic lumbar puncture (TLP) is thought to increase the risk of relapse in the CNS. This study sought to determine if TLP at the time of diagnosis affected the outcome of patients. Matherial and Methods: Seventy-seven newly diagnosed patients treated from 1992 to 2002 were included in the analysis. Intrathecal therapy (IT) was instilled either immediately after the diagnostic LP (early) or at a second LP (delayed) 24 to 48 hours following the diagnostic LP procedure. The authors carried out an analysis of the influence of TLP and the timing (early versus late) of administration of IT therapy on CNS relapse. Results: Among the 19 patients who had a TLP at diagnosis and received late IT therapy, six had isolated CNS relapse and two had combined CNS and bone marrow (BM) relapse. Among the nine patients who had TLP and received early IT therapy, only one had a combined CNS and BM relapse (P=0.20); the influence of TLP was not statistically significant on the event-free survival (EFS) (55% for early IT versus 49% for delayed IT) ( P =0.37). However, when we carried out a stratified analysis according to risk categories we found that for low and standard risk patients the odds ratio (OR) for relapse was 0.8 for delayed IT therapy (P=0.99) and 0.17 for early IT (P=0.47). On the other hand, among high risk (HR) patients the OR for relapse was 21.0 for delayed IT therapy (P=0.09) and 1.5 for early IT (P=0.99). Conclusion: The occurrence of TLP impacts adversely on prognosis of HR ALL patients. As these results are based in a retrospective study with a low number of patients, the authors recommend future trials using prospective randomized studies to confirm these findings.
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Silveira, André Bortolini 1987. „Inibição da via PI3K na leucemia linfoide aguda T pediátrica = resposta à quimioterapia e implicações clínicas = PI3K inhibition in childhood T-cell acute lymphoblastic leukemia: response to chemotherapy and clinical implications“. [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317454.
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Orientadores: José Andrés Yunes, Nilson Ivo Tonin ZanchinTese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: A via PI3K está frequentemente hiperativada em células primárias de leucemia linfoide aguda T (LLA-T) pediátrica, característica previamente associada à resistência a glucocorticoides. Pacientes cujas células leucêmicas apresentam mutações em PTEN, o principal regulador negativo de PI3K, podem apresentar maior risco de falha na terapia de indução e recaída. Neste estudo, uma assinatura baseada em expressão gênica foi utilizada para acessar o nível de ativação da via PI3K em amostras diagnósticas de LLA-T. Nós identificamos Myc como um importante integrador da atividade de sinalização por PI3K e observamos que maior atividade da via está associada à resistência a glucocorticoides e pior prognóstico. O inibidor de PI3K AS605240 mostrou atividade antileucêmica e forte sinergismo com glucocorticoides tanto in vitro como em um modelo xenográfico de LLA-T em camundongos NOD/SCID. Em contraste, a inibição de PI3K resultou em antagonismo com metotrexato e daunorrubicina, drogas que atuam preferencialmente em células em divisão. Esta interação antagonística, no entanto, pôde ser revertida pelo uso de um esquema temporal específico de administração das drogas. Nossos dados indicam os potenciais benefícios e limitações para a incorporação de inibidores de PI3K na terapia da LLA-T
Abstract: The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. In this study, a PI3K gene expression signature was used as readout of PI3K activity in diagnostic T-ALL samples. We identified Myc as an important downstream integrator of PI3K pathway activity in T-ALL and found that higher PI3K activity is associated with glucocorticoid resistance and worse clinical outcome. The PI3K inhibitor AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy. OBSERVAÇÃOArquivo pdf com capa, página de rosto, folha de assinatura da banca examinadora, resumo e abstract foi editado segundo informação CCPG/002/2013
Doutorado
Genetica Animal e Evolução
Doutor em Genetica e Biologia Molecular
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Alcanfôr, Brasília Mendes de Melo. „Anticorpos contra sarampo e rubéola em crianças portadoras de Leucemia Linfóide Aguda“. Universidade Federal de Sergipe, 2009. https://ri.ufs.br/handle/riufs/3676.
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The Acute Linfoid Leukemias (ALL) represent one third of oncologic disease in childhood. Children, at the end of treatment, can present endangerment of immune response, secondary to the illness itself and the chemotherapy, so that it is important the evaluation of humoral immunity against vaccine antigens, with the purpose to establish suitable vaccination protocols. Despite being controlled by vaccination, there are registers of imported cases of measles in Brazil, originating of Europe and Asia, with risk of re-introduction of the illness, as well as recent outbreak of rubella in brazilian territory. With the objective to evaluate the persistence of the protection against measles and rubella in children with ALL previously immunized, as well as the response to one dose of reinforcement vaccine after the end of the chemotherapy, it was realized an study of transversal cut in patients with younger than 19 years, assisted by a service of Pediatric Oncology of reference in state of Sergipe. It was studied 83 patients carriers of ALL, of both genders, of which 30 were on chemotherapy treatment (maintenance phase), 29 had ended the treatment, presented hematologic recuperation, but had received any additional vaccine dose yet, and 24 had concluded the treatment and received a reinforcement dose of vaccine MMR there were at least 4 weeks. There were either evaluated 30 healthy children and with complete vaccination. Antibodies of IgG class against measles and rubella were dosed, considering protected those that present higher or equal values than 0,275 UI/mL and higher or equal than 10 UI/mL respectively for measles and rubella. Results showed that the minor frequency of patients protected against measles occurred at group of patients after the end of treatment and that had not received vaccine reforce (41,4%), while the highest frequency was in the group that received addicional dose (79,2%; p=0.005), similar percentage of the control group (73%; p=0,01). It was observed similar situation for rubella, but the difference was not statistically significant. Antibodies levels against measles and rubella of patients that ended the treatment and did not receive enforcement vaccination were significantly lower than the other 3 groups. For patients that ended the chemotherapy treatment for ALL the critic phase is immediately after the final of treatment, suggesting that patients are supposed to receive a dose of enforcement of the vaccine for measles and rubella as soon as highest hematologic recovery occurs. The vaccination enforcement dose seems to have been capable of re-activate the immunologic memory, suggesting that the same was not compromised for the illness or treatment.As Leucemias Linfóides Agudas (LLA) correspondem a um terço das doenças oncológicas na infância. As crianças, ao final do tratamento, podem apresentar comprometimento da resposta imune, secundário à própria doença e à quimioterapia, sendo importante a avaliação da imunidade humoral contra antígenos vacinais, com a finalidade de estabelecerem-se protocolos de vacinação adequados. Ainda que sob controle com vacinação, há registros de casos importados de sarampo no Brasil, procedentes da Europa e Ásia, com risco de reintrodução da doença, bem como recente surto de rubéola em território brasileiro. Com o objetivo de avaliar a persistência da proteção contra sarampo e rubéola em crianças com LLA previamente imunizadas, bem como a resposta a uma dose de vacina de reforço após o término da quimioterapia, foi realizado um estudo de corte transversal em pacientes com idade inferior a 19 anos, atendidos em serviço de Oncologia Pediátrica de referência do estado de Sergipe. Foram estudados 83 pacientes portadores de LLA, de ambos os gêneros, dos quais 30 encontravam-se em tratamento quimioterápico (fase de manutenção), 29 haviam terminado o tratamento, apresentavam recuperação hematológica, mas ainda não haviam recebido nenhuma dose adicional de vacina, e 24 haviam concluído o tratamento e recebido uma dose de reforço de vacina tríplice viral há pelo menos quatro semanas. Foram também avaliadas 30 crianças saudáveis e com vacinação completa. Foram dosados anticorpos de classe IgG contra sarampo e rubéola, sendo considerados protegidos os que apresentavam valores superiores ou igual a 0,275 UI/mL e maiores ou igual a 10 UI/ml, respectivamente para sarampo e rubéola. Os resultados mostraram que a menor freqüência de pacientes protegidos contra sarampo ocorreu no grupo de pacientes após o término do tratamento e que não recebeu vacinação de reforço (41,4%), enquanto que a maior freqüência foi no grupo que recebeu dose adicional (79,2%; p=0,005), porcentagem semelhante ao grupo controle (73%; p=0,01). Observou-se situação semelhante para rubéola, porém a diferença não foi estatisticamente significativa. Os níveis de anticorpos contra sarampo e rubéola dos pacientes que terminaram o tratamento e não receberam vacinação de reforço foram significativamente inferiores aos dos outros três grupos. Para os pacientes que terminaram o tratamento quimioterápico para LLA a fase crítica é imediatamente após o final do tratamento, sugerindo que os pacientes devem receber uma dose de reforço das vacinas para sarampo e rubéola assim que ocorra a recuperação hematológica. A dose vacinal de reforço parece ter sido capaz de reativar a memória imunológica, sugerindo que a mesma não foi comprometida pela doença ou tratamento.
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Mendonça, Cristiano de Queiroz. „Comportamento da pressão ocular em pacientes pediátricos tratados para Leucemia Linfoblástica Aguda e Linfoma não Hodgkin“. Universidade Federal de Sergipe, 2014. https://ri.ufs.br/handle/riufs/3885.
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Introduction:Acute Lymphoid Leukemia (ALL) is the most frequent cancer in young people and, if analyzed together with Non-Hodgkin Lymphoma (NHL), we find that they are responsible for at least one third of all cases of childhood cancer. Present-day therapeutic protocols include high doses of glucocorticoids (GC), drugs associate with high potential for elevating intraocular pressure (IOP) and, consequently provoking damage to the fibers of the optic nerve fibers, a pathology classified as cortisone glaucoma. In genetically susceptible patients, ocular hypertension normally occurs some weeks into the use of a steroid but is generally reversible with the suspension of its use. However, depending on the levels of ocular pressure and the duration of ocular hypertension, it can result in optic neuropathology and, in extreme cases, blindness. Since ALL and NHL are oncological disorders with elevated potential for cure of young people with have high life expectancy, the identification of eventual long-term treatment complications could give support to a delineation still lacking in scientific literature, that is, an ophthalmological protocol for these cases. Objective: The aim of this study was to evaluate the behavior of intraocular pressure in pediatric patients treated with GC for the acute lymphoproliferative neoplasias that are most common during childhood and adolescence.Methods: A systematic review of the theme was carried out, followed by a descriptive, prospective study of children and adolescents of both sexes who were diagnosed with ALL and NHL, and who were registered for beginning chemotherapeutic treatment at the Dr. Oswaldo Leite Oncology Center of Sergipe. The inclusion criteria were: diagnosis of ALL or NHL-T confirmed by immunophenotyping of bone marrow or peripheral blood samples (ALL), or immunohistochemistry of material obtained by open biopsy (NHL); age less than 19; no previous chemotherapy; absence of previous diagnosis compatible with glaucoma or any other disorder envolving change in intraocular pressure; no systemic use of GC in the six months preceding diagnosis of ALL or NHL. Patients whose evaluation of IOP might not have been technically adequate, as well as those who expired during the follow-up period, were excluded. Intraocular pressure was measured before treatment (D0), on the eighth (D8), the fourteenth (D14) and twentieth (D28) treatment day. The IOP results above 21 mm Hg were considered to be ocular hypertension. Results: Results of the systematic review indicate the need for new studies, for the review found a total of only three published articles whose results varied between total control of ocular pressure and visual function, to irreversible blindness. The results of our field research involved 15 patients, two of them with ocular hypertension, and with a statistically significant difference of measurements of IOP between D0 vs D8 and D0 vs D14 (p=0.013). Conclusion: The possibility of silent ocular hypertension, with the consequent risk of irreversible blindness, indicates the need to assess the introduction of a protocol for verification of IOP in patients recently diagnosed with ALL and NHL, including weekly exams, at least until the complete cessation of GC use.Introdução: Leucemia Linfóide Aguda (ALL) é o câncer mais comumente encontrado entre os jovens e, se analisada em conjunto com o Linfoma não-Hodgkin (NHL), são responsáveis por pelo menos um terço dos casos de câncer infantil. Protocolos terapêuticos atuais incluem altas doses de glicocorticóides (GC), droga associada com alto potencial para elevar a pressão intraocular (IOP) e, consequentemente, provocar danos às fibras do nervo óptico, patologia classificada como glaucoma cortisônico. A hipertensão ocular geralmente ocorre com algumas semanas de uso de GC em pacientes geneticamente susceptíveis, mas é geralmente reversível com a descontinuação do tratamento. Entretanto, dependendo dos níveis pressóricos oculares e do tempo de elevação, pode resultar em neuropatia óptica e, em situações extremas, em cegueira. Por serem a ALL e o NHL doenças oncológicas com potencial elevado de cura, em indivíduos jovens com elevada expectativa de vida, a identificação de eventuais complicações de longo prazo decorrentes do tratamento poderá subsidiar o delineamento de um protocolo oftalmológico para esses casos, ainda inexistente na literatura científica. Objetivo: O objetivo deste estudo foi avaliar o comportamento da pressão intraocular em pacientes pediátricos portadores das mais frequentes neoplasias linfoproliferativas agudas da infância e adolescência, e que são tratados com GC. Métodos: Foi feita uma revisão sistemática sobre o tema estudado, seguida por um estudo descritivo, prospectivo, em crianças e adolescentes de ambos os sexos, com diagnóstico de ALL e NHL, matriculados para início de tratamento quimioterápico no Centro de Oncologia de Sergipe Dr. Oswaldo Leite. Os critérios de inclusão foram: diagnóstico de ALL ou NHL-T, confirmada por imunofenotipagem de amostra de medula óssea ou sangue periférico (ALL) ou imuno-histoquímica de material obtido por biópsia aberta (NHL); idade menor de 19 anos; sem quimioterapia anterior; ausência de diagnóstico prévio compatível com glaucoma ou doença anterior relacionada a qualquer mudança na pressão intra-ocular; não uso sistêmico de GC nos seis meses anteriores ao diagnóstico da ALL ou NHL. Pacientes cuja avaliação da pressão intraocular (PIO) pode não ter sido tecnicamente adequada e os que faleceram durante o período de seguimento foram excluídos. Realizaram-se medidas de pressão intraocular antes do tratamento (D0), no oitavo (D8), décimo quarto (D14) e vigésimo (D28) dias de tratamento. Os resultados da PIO acima de 21 mm de Hg foram considerados como hipertensão ocular Resultados: Os resultados da revisão sistemática apontaram para necessidade de novos estudos, limitando-se a um total de três publicações de relatos de casos envolvendo sete pacientes, com resultados variando de total controle da pressão ocular e conservação da função visual, até cegueira irreversível. Os resultados da pesquisa de campo envolveram 15 pacientes, com dois casos de hipertensão ocular e com diferença estatisticamente significativa entre as médias de PIO entre D0 vs D8 e D0 vs D14 (p = 0,013). Conclusão: A possibilidade de hipertensão ocular silenciosa, com o consequente risco de cegueira irreversível, indica a necessidade de se avaliar a introdução de um protocolo para verificação da IOP em pacientes jovens recentemente diagnosticados com ALL e NHL, incluindo exames semanais, pelo menos até a retirada completa do GC.
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Pereira, Michelle Miranda. „Avaliação da fluência verbal e da memória verbal em pacientes pediátricos com leucemia“. Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/5/5170/tde-01112018-124708/.
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Objetivo: avaliar as habilidades cognitivo-linguísticas de crianças diagnosticadas com leucemia linfoide aguda durante o tratamento quimioterápico. Método: estudo clínico transversal observacional. Formaram o grupo pesquisa (GLL) 18 crianças com idades entre 7 anos e 10 anos e 11 meses, com diagnóstico de leucemia linfoide aguda e em tratamento quimioterápico, que não apresentavam síndromes genéticas, alterações neurológicas e/ou auditivas, não haviam realizado radioterapia e/ou transplante de medula óssea. Foi coletado grupo controle (GC), formado por 18 crianças hígidas, pareadas ao grupo pesquisa por idade, gênero e escolaridade materna. Foram aplicadas provas de avaliação da inteligência não-verbal, fonologia, vocabulário expressivo, fluência verbal, memória verbal de curto prazo e memória verbal operacional. Os dados coletados foram submetidos à análise estatística. Resultados: não houve diferenças estatísticas entre os grupos nas provas de inteligência e vocabulário expressivo. O grupo GLL apresentou desempenho inferior nas demais provas, com diferença significante apenas em memória operacional e na categoria \"partes do corpo\" da prova de fluência verbal. Conclusão: Esse estudo possibilitou uma primeira análise dos efeitos do tratamento quimioterápico em crianças com leucemia nas habilidades cognitivo-linguísticas. Não houve diferença no vocabulário expressivo, mas as habilidades de fluência verbal e memória parecem ser prejudicadas nessas crianças, quando comparadas ao grupo controle, apesar de não haver significância estatística em todas as variáveisObjective: to evaluate the cognitive-linguistic abilities of children diagnosed with acute lymphoid leukemia during chemotherapy treatment. Methods: observational cross-sectional clinical study. The research group (GLL) was composed by 18 children aged between 7 years and 10 years and 11 months, with diagnosis of acute lymphoid leukemia receiving chemotherapeutic treatment, who did not present genetic syndromes, neurological and/or auditory alterations, had not undergone radiotherapy and/or bone marrow transplantation. A control group (GC) was collected, comprising eighteen healthy children, matched to the research group by age, gender and maternal schooling. Non-verbal intelligence, phonology, expressive vocabulary, verbal fluency, short-term verbal memory, and operational verbal memory were evaluated. The collected data were submitted to statistical analysis. Results: There were no statistical differences between groups in the intelligence and expressive vocabulary tests. The GLL group presented a worse performance in the other tests, but with significant difference only in operational memory and in the \"body parts\" category of the verbal fluency test. Conclusion: This study enabled a first analysis of the effects of chemotherapy treatment in children with leukemia on cognitive-linguistic abilities. There was no difference in expressive vocabulary, but verbal fluency and memory skills appear to be impaired in these children, when compared to the control group, although there was no statistical significance in all variables
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Delgado, Irene. „Neurocognitive Sequelae of Pediatric Cancers: A Prospective Study of Late Effects“. Scholarly Repository, 2009. http://scholarlyrepository.miami.edu/oa_dissertations/280.
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Nearly 80% of children treated for cancer are expected to survive, but not without cost. Survivors face unprecedented challenges associated with long-term consequences of treatment, also called late effects. Approximately half of children treated for cancer are at risk for experiencing cognitive late effects, which typically emerge several years post diagnosis. The nature and extent of cognitive late effects appear to be developmental and related to patient, disease, and treatment variables. However, the relationships between these variables is not well understood because there have been few prospective and longitudinal studies that report on the contributions of these variables over time. This dissertation examined the effects of patient, disease, and treatment variables, as well as their interactions over time on neurocognitive functioning in childhood cancer survivors. It comprises part of a large prospective, randomized clinical trial designed to examine changes in cognitive function over three years as a function of different levels of monitoring of school-based intervention based on individual educational plans (IEPs). This dissertation uniquely contributed a new measure (the Treatment Intensity Rating Scale) that was used to systematically classify treatment severity across different types of cancer and cancer treatments. Participants included 61 children ages 7 to 12 years at enrollment who were two to five years from completion of treatment for a brain tumor, leukemia, or lymphoma. Participants received yearly neuropsychological evaluations for a follow-up period of 3 years. Results of these evaluations were used to develop IEPs. Participants were randomized to have their IEPs monitored on a quarterly or annual basis for the duration of the study. Contrary to the progressive decline in neurocognitive functioning that is typically anticipated in pediatric cancer survivors, analyses revealed relative stability of performance on neurocognitive measures over time. Higher neurocognitive performance was noted in children whose IEPs were monitored more frequently versus less frequently. Results also supported gender-specific risk for late effects, with lower performance on select neurocognitive measures in females compared to males. Results of this study provide encouraging evidence of the positive effects of school-based interventions and their close monitoring. This has important implications for quality of life as these children survive well beyond childhood into adulthood.
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Abrisqueta, Costa Pau. „Tratamiento de primera línea con rituximab combinado con fludarabina, ciclofosfamida y mitoxantrone (RFCM) y mantenimiento con rituximab en pacientes con leucemia linfática crónica“. Doctoral thesis, Universitat de Barcelona, 2014. http://hdl.handle.net/10803/283529.
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La leucemia linfática crónica (LLC) es la leucemia más frecuente en la edad adulta en los países occidentales, y se caracteriza por la acumulación y proliferación de linfocitos clonales B maduros CD5+ en la sangre, médula ósea, y ganglios linfáticos. La mediana de supervivencia de los pacientes es de alrededor de 10 años aunque su curso clínico es heterogéneo. Durante varias décadas el tratamiento de esta enfermedad se había basado en el empleo de agentes alquilantes como el clorambucilo, en los análogos de la purinas, o en la asociación de ambos, como la combinación de fludarabina y ciclofosfamida (FC). Posteriormente las combinaciones de rituximab, un anticuerpo monoclonal anti-CD20, con quimioterapia, en general FC, lo que ha pasado a denominarse tratamiento inmunoquimioterápico, revolucionaron el tratamiento de esta enfermedad al alcanzar intervalos de supervivencia libre de progresión (SLP) superiores a cinco años, lo que se tradujo en una mayor supervivencia de los enfermos. Sin embargo, a pesar de estos buenos resultados, los pacientes siguen recayendo de su enfermedad y la LLC continúa siendo incurable más allá del trasplante de progenitores hematopoyéticos. Con el fin de mejorar estos resultados se han diseñado nuevas combinaciones de quimioterapia como la asociación de FC con mitoxantrone (FCM), una anthracenedione con capacidad de inhibir la topoisomerasa II. Por otro lado, las estrategias de mantenimiento o las terapias de consolidación dirigidas a controlar la enfermedad mínima residual (EMR) persistente tras el tratamiento inicial, podrían derivar en una mejora en la evolución de los pacientes con LLC.
Con estos antecedentes, diseñamos un ensayo clínico multicéntrico fase II en pacientes jóvenes (= 70 años) con LLC previamente no tratados que consistió en un tratamiento inicial con rituximab 500 mg/m2 (día 1) (375mg/m2 en el primer ciclo), fludarabina 25mg/m2 (días 1-3), ciclofosfamida 200mg/m2 (días 1-3), y mitoxantrone 6mg/m2 (día 1), (R-FCM), cada cuatro semanas, hasta un total de seis ciclos. Posteriormente, aquellos pacientes que obtuvieron al menos una respuesta parcial (RP) tras el tratamiento inicial fueron elegibles para la fase de mantenimiento, que consistió en 375mg/m2 de rituximab cada tres meses durante dos años. Además, se analizó la EMR mediante citometría de flujo de forma simultánea en sangre periférica y médula ósea. El objetivo principal del estudio fue el determinar la eficacia de R-FCM medida a través de la tasa de respuestas, incluyendo la tasa de respuestas con EMR negativa. Como objetivos secundarios se planteó el determinar la duración de la respuesta y la SLP, el análisis de las variables clínico-biológicas que influyen en la respuesta, y el perfil de toxicidad del tratamiento. Se incluyeron 81 pacientes en el estudio, con una mediana de edad de 60 años (rango, 40 a 70 años). La tasa de respuesta global obtenida tras el tratamiento inicial con R-FCM fue del 93%, con una tasa de respuesta completa (RC) con EMR negativa, tasa de RC con EMR positiva y de RP del 46%, 36% y 11%, respectivamente. Los factores que se correlacionaron con una menor tasa de RC fueron el estadio clínico avanzado al inicio del tratamiento, la deleción de 17p, y un valor elevado de ß2-microglobulina. En general, el tratamiento con R-FCM fue bien tolerado y aunque se observó algún grado de neutropenia en un 41% de los ciclos administrados, ésta fue grave únicamente en una 13% de los ciclos. En cuanto a la toxicidad infecciosa, se observó un evento infeccioso mayor en un 8% de los ciclos administrados. Sesenta y siete pacientes recibieron el tratamiento de mantenimiento con rituximab. Al finalizar el mantenimiento, un 40.6% de los pacientes presentaban una RC con EMR negativa, un 40.6% una RC con EMR positiva, un 4.8% un RP, y un 14% se consideraron como fallo de tratamiento. Seis de los 29 pacientes (21%) que se hallaban en RC con EMR positiva o en RP tras R-FCM mejoraron su respuesta mediante el tratamiento de mantenimiento. La SLP y la supervivencia global estimada a los cuatro años fueron del 74.8% y 93.7%, respectivamente. El nivel de EMR obtenido tras el tratamiento con R-FCM fue la variable con mayor poder predictivo de la SLP. Se observó neutropenia grave en el 8.5% de los ciclos de mantenimiento y 16 pacientes tuvieron un episodio infeccioso grado 3–4. En conclusión, la combinación de R-FCM es un tratamiento de primera línea altamente eficaz en pacientes jóvenes con LLC. Esta combinación obtuvo una alta tasa de RC, consiguiendo en gran parte de ellas la negativización de la EMR. El tratamiento de mantenimiento con rituximab tras R-FCM consiguió una SLP prolongada y mejoró la calidad de las respuestas en un porcentaje de pacientes, particularmente en aquellos con persistencia de enfermedad detectable tras R-FCM.Chronic lymphocytic leukemia (CLL) is a frequent malignancy composed of CD5+ B-lymphocytes, is predominant in older people, and has a variable clinical course. The median survival of patients with CLL is approximately 10 years, but the individual prognosis is extremely variable. The addition of monoclonal antibodies to chemotherapy has significantly improved treatment of CLL. Based on excellent results with the chemotherapy-only regimen fludarabine, cyclophosphamide, and mitoxantrone (FCM), we built a new chemoimmunotherapy combination—rituximab plus FCM (R-FCM). The effectiveness of R-FCM followed by rituximab maintenance therapy as first-line treatment for younger patients with CLL (age = 70) has been investigated in a phase 2 clinical trial that included an initial treatment with rituximab 500 mg/m2 on day 1 (375 mg/m2 the first cycle), fludarabine 25 mg/m2 on days 1 to 3, cyclophosphamide 200 mg/m2 on days 1 to 3, and mitoxantrone 6 mg/m2 on day 1 (R-FCM), for 6 cycles. Patients achieving response received maintenance with rituximab 375 mg/m2 every 3 months for 2 years. Eighty-one patients (median age, 60 years; range, 40 to 70 years) were enrolled in the study. The overall response, minimal residual disease (MRD)–negative complete response (CR), MRD positive CR, and partial response (PR) rates were 93%, 46%, 36%, and 11%, respectively. Severe neutropenia developed in 13% of patients. Major and minor infections were reported in 8% and 5% of cycles, respectively. Advanced clinical stage, del(17p), or increased serum ß2-microglobulin levels correlated with a lower CR rate. Sixty-seven patients having achieved CR or PR with R-FCM were given maintenance therapy. At the end of maintenance, 40.6% of patients were in CR MRD-negative, 40.6% were in CR MRD-positive, 4.8% remained in PR, and 14% were considered failures. Six of 29 patients (21%) who were in CR MRD-positive or in PR after R-FCM improved their response upon rituximab maintenance. The 4-year progression-free survival (PFS) and overall survival rates were 74.8% and 93.7%, respectively. MRD status after R-FCM induction was the strongest predictor of PFS. R-FCM is highly effective in previously untreated CLL, with an 82% CR rate and a high proportion of MRD-negative CRs (46%). Treatment toxicity is acceptable. Maintenance with rituximab after R-FCM improved the quality of the response, particularly in patients MRD-positive after initial treatment, and obtained a prolonged PFS.
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Fernandez, Solène. „Microenvironnement médullaire et résistance à la Midostaurine dans les leucémies aiguës myéloïdes FLT3-ITD Identification de cibles thérapeutiques par criblage génomique fonctionnel“. Thesis, Bordeaux, 2020. http://www.theses.fr/2020BORD0281.
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Les leucémies aiguës myéloïdes (LAM) sont des hémopathies malignes agressives. Environ 30% des patients présentent des mutations ITD (Internal tandem reapeat) affectant le récepteur tyrosine kinase FLT3. Ces mutations sont associées à des résistances et à un taux de rechute important au cours des chimiothérapies (Aracytine + Anthracyclines). Des thérapies ciblées utilisant des inhibiteurs de tyrosine kinase (ITK) tels que la Midostaurine ont permis d’améliorer la survie des patients. Malgré cela, le traitement des LAM, reste un véritable défi en raison des rechutes persistantes. Caractériser les mécanismes moléculaires intervenant dans la résistance à ces traitements ciblés est devenu un enjeu majeur. Afin d’identifier dans les LAM FLT3-ITD les gènes impliqués dans la résistance à la Midostaurine, nous avons effectué un criblage génomique fonctionnel par CRISPR-Cas9. Ce criblage a été réalisé dans la lignée MV4 ;11 (positive pour FLT3-ITD) dans des conditions de culture mimant le microenvironnement médullaire. Ce dernier est impliqué dans les mécanismes de résistances. Parmi les cibles identifiées, deux gènes candidats ont été évalué individuellement : SLC4A2 et ADAM22. Leur invalidation génomique dans la lignée MV4 ;11 a conduit à une augmentation de la sensibilité à la Midostaurine. Leur rôle fonctionnel sera confirmé ex vivo et in vivo. Ces travaux ont pour objectif d’identifier des cibles thérapeutiques potentielles afin de développer de nouvelles thérapies ciblées ou de mettre en évidence des repositionnements de médicaments. L’utilisation synergique de ces diverses thérapies permettra de surmonter les résistances et d’améliorer la prise en charge des patients atteints de LAM FLT3-ITDAcute myeloid leukemia (AML) is an aggressive hematological malignancy. Approximately 30% of patients have ITD (Internal tandem reapeat) mutations affecting the FLT3 tyrosine kinase receptor. These mutations are associated with resistance and a high relapse rate during chemotherapy (Aracytine + Anthracyclines). Targeted therapies using tyrosine kinase inhibitors (TKIs) such as Midostaurine have improved patient survival. Despite this, the treatment of AML remains a real challenge due to persistent relapses. Characterizing the molecular mechanisms involved in resistance to these targeted therapies has become a major challenge. In order to identify in FLT3-ITD AMLs the genes involved in Midostaurin resistance, we performed a functional genomic screening by CRISPR-Cas9. This screening was performed in the MV4;11 line (positive for FLT3-ITD) under culture conditions mimicking the medullary microenvironment. The latter is involved in resistance mechanisms. Among the identified targets, two candidate genes were evaluated individually: SLC4A2 and ADAM22. Their genomic invalidation in the MV4;11 lineage led to an increase in sensitivity to midostaurin. Their functional role will be confirmed ex vivo and in vivo. The objective of this work is to identify potential therapeutic targets in order to develop new targeted therapies or to highlight drug repositioning. The synergistic use of these various therapies will make it possible to overcome resistance and improve the management of patients with FLT3-ITD AML
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Marchioro, Mariana Kliemann. „Estudo de utilização de medicamentos em uma unidade de oncologia pediátrica de um hospital universitário de Porto Alegre“. reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/101511.
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O câncer pediátrico é raro em números absolutos, porém quando comparado às incidências em adultos vem apresentando aumento nas taxas de incidência, exigindo um preparo do sistema de saúde para acompanhamento. Este acompanhamento não pode ser igual ao do adulto, visto que crianças possuem diferenças fisiológicas nas diferentes faixas etárias pediátricas. Sendo assim, estudos de utilização de medicamentos são importantes nesta população, a fim de promover o uso racional dos mesmos, bem como, garantir seu uso seguro e uma terapêutica eficaz. O presente estudo tem por objetivo avaliar as prescrições de antineoplásicos, na unidade de oncologia pediátrica de um hospital universitário de Porto Alegre, identificando os protocolos mais utilizados, e posteriormente contextualizando-os com o preconizado no referencial teórico. Foi realizado um estudo transversal prospectivo envolvendo internações realizadas na unidade de oncologia pediátrica do Hospital de Clínicas de Porto Alegre (HCPA). Foram analisadas 274 internações, das quais 40 eram primeira internação e 234 reinternações. A maioria dos pacientes tinha idade de 0 a 10 anos, uma discreta prevalência do sexo masculino, de raça/cor branca, residentes na mesorregião metropolitana. A principal forma de financiamento das internações foi o público, e a principal causa de internação foi o tratamento, sendo o mais frequente o quimioterápico. Foram analisados os protocolos utilizados durante as internações de pacientes com diagnóstico de Leucemia Linfocítica Aguda, Retinoblastoma e Sarcoma de Ewing. Os protocolos são conjunto de regras criadas a partir de grupos cooperativos ou da indústria farmacêutica, permitindo um maior conhecimento sobre os medicamentos utilizados na pediatria. A oncologia pediátrica com sua particularidade de ser uma doença culturalmente ligada ao óbito possui maior facilidade de estudos deste porte. Porém, ainda são necessários mais estudos de utilização destes medicamentos, a fim de agregar conhecimento aos protocolos de tratamento.Pediatric cancer is rare in absolute numbers, but when compared to the incidence in adults has shown an increase in incidence rates, requiring a prepared system health for following. Pediatrics treatment can’t be the same as that of adults, because children have different physiological differences in pediatric age groups. Studies of medication use in this population are very important in order to promote the rational use of drugs, as well as to guarantee their safe use and effective therapy. The present study aims to evaluate the anticancer prescriptions in pediatric oncology unit of a university hospital in Porto Alegre, identifying the most used protocols, and contextualizing them later with the recommendations in the theoretical framework. A prospective cross-sectional study involving hospital admissions in the pediatric oncology unit of the Hospital de Clínicas de Porto Alegre (HCPA) was performed. We analyzed 274 admissions, which 40 were first admission and 234 were readmissions. These admissions most patients were aged 0 to 10 years, white race, a slight male prevalence, residing in Metropolitan Mesoregion. The financing the hospital admissions was public, and the maining cause of hospitalization was treatment, the most frequent being the chemotherapy. We analyzed the protocols used during the admissions of patients diagnosed with Acute Lymphocytic Leukemia, Retinoblastoma and Ewing's Sarcoma. Protocols are studies that allow a greater knowledge about medicines for pediatric use. The pediatric oncology with its characteristic of being a disease has culturally linked with death ease of studies of this size. However, more studies of medication use are still needed to use these drugs in order to knowledge to the treatment protocols.
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Labiad, Yasmine. „Contribution de l’approche transcriptomique dans la physiopathologie et le traitement des hémopathies malignes“. Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4068.
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L’objectif général de cette thèse a été de mettre en évidence la contribution de l’approche transcriptomique dans la physiopathologie et le traitement des hémopathies malignes. En particulier, comment la technologie des microarrays nous a aidée à étudier diverses problématiques en onco-hématologie.Dans la première partie, notre objectif était d’étudier les cellules Natural killer (Nk) chez les patients atteints de leucémie aiguë myéloïde (LAM). Nous avons comparé la signature transcriptomique des cellules Nk de patients LAM à celle des cellules Nk de sujet sains et suggéré que le facteur de transcription ETS-1 est un bon candidat capable de réguler les récepteurs activateurs NCR (natural cytotoxicity receptors) dont les gènes sont situés sur deux chromosomes différents, même si leur expression reste fortement cordonnée.Dans la seconde partie, nous nous sommes intéressés à la prédiction du sepsis en utilisant une approche transcriptomique dans le cadre de l’autogreffe de cellules souches hématopoïétiques (auto-CSH). En utilisant le même modèle, dans la troisième partie, nous avons mis en évidence l’effet du melphalan en tant que chimiothérapie de conditionnement sur les cellules mononuclées du sang périphérique et identifié un marqueur potentiel de rechute précoce chez les patients atteints de myélome dans le cas de l’auto-CSH. Enfin, dans la dernière partie, notre objectif a été d’analyser le profil d’expression génique des lymphomes B diffus à grandes cellules liés à l’infection par le VIH afin de vérifier ou pas l’existence des sous-types décrits chez les patients immunocompétentsThe aim of this research is to demonstrate transcriptomic approach contribution in the physiopathology and treatment of hematological malignancies. In particular, how microarrays technology is used to study several oncohematology difficulties; which remain deaths-related infection, as well as the failure to obtain remission and death related relapse. In the first part, our focus was to study natural killer cells (Nks) in patients affected with acute myeloid leukemia (AML). We compared transcriptomic AML-NKs signature with healthy donors-NKs signature and suggested that ETS-1 transcription factor is a good candidate able to regulate the natural cytotoxicity receptors (NCRs), whose coding genes, are located on two different chromosomes even if their expression remain strongly coordinated.Our second part, aimed to predict sepsis using a transcriptomic approach in the case of autologous stem cell transplantation (auto-HSCT). Using the same model, in the third part, we highlighted the melphalan high-dose chemotherapy effect on peripheral blood mononuclear cells and identified a potential good biomarker of early relapse in patients affected by myeloma in the case of auto-HSCT.Our final focus was to analyze gene expression profile of HIV-related large diffuse B-cell lymphoma type in order to verify the existence of subgroups described in immune-competent patients
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Morice, Pierre-Marie. „Evaluation de la déficience de la recombinaison homologue et de la réponse des tumeurs ovariennes aux inhibiteurs de PARP grâce à l'utilisation de modèles de culture 3D en vue du développement d'un test prédictif Identifying eligible patients to PARP inhibitors: from NGS-based tests to promising 3D functional assays Automated scoring for assessment of RAD51-mediated homologous recombination in patient-derived tumor organoids of ovarian cancers Risk of myelodysplastic syndrome and acute myeloid leukemia related to PARP inhibitors: a combined approach using a safety meta-analysis of placebo randomized controlled trials and the World Health Organization's pharmacovigilance database The long non-coding RNA ‘UCA1’ modulates the response to chemotherapy of ovarian cancer through direct binding to miR-27a-5p and control of UBE2N levels“. Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC414.
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Chaque année, plus de 150 000 décès sont associés aux cancers épithéliaux de l’ovaire dans le monde, notamment en raison du développement d’une résistance à la chimiothérapie. Environ la moitié de ces cancers présentent des altérations moléculaires provoquant une déficience de la réparation de l’ADN par recombinaison homologue (HRD) qui les sensibilise à l’action des inhibiteurs de la protéine PARP (PARPi). A ce jour, il n’existe pas de test capable d’appréhender le phénotype HRD dans sa globalité, limitant ainsi l’accès à ces traitements. Dans ce contexte, nous avons entrepris de mettre au point des tests fonctionnels basés sur l’utilisation d’explants tumoraux tranchés puis sur l’utilisation d’organoïdes tumoraux dérivés de tumeurs ovariennes de patientes chimio-naïves ou antérieurement traitées. La culture d’explants s’est révélée inappropriée pour la réalisation de ces tests et nous avons alors focalisé nos travaux sur les organoïdes tumoraux. Ces derniers ont été exposés au carboplatine (traitement de 1e ligne) et à deux inhibiteurs de PARP (l’olaparib et le niraparib) utilisés en traitement d’entretien. En parallèle, nous avons collecté les données cliniques des patientes (survie, intervalle sans platine, RECIST, traitements) afin d’évaluer le potentiel prédictif de ces modèles. Les organoïdes tumoraux établis ont répondu de façon hétérogène aux différents médicaments testés, et nos résultats montrent que les tests réalisés sur les organoïdes sont capables d’identifier des patientes présentant un niveau de résistance élevé au carboplatine, suggérant que ce test fonctionnel pourrait présenter un intérêt prédictif vis-à-vis de ce médicament. Concernant le potentiel prédictif des organoïdes vis-à-vis des PARPi, des profils de sensibilité variés ont été identifiés, mais la corrélation avec la réponse clinique reste à établir par des études menées sur des échantillons de tumeurs issus de patientes traitées par ces médicamentsWorldwide each year, more than 150 000 women die from epithelial ovarian cancer largely due to emergence of resistance to chemotherapy. Approximately half of these cancers display molecular alterations that cause deficiency of DNA repair via homologous recombination (HRD), which confer sensitivity to PARP protein inhibitors (PARPi). To date, there is no test capable of fully identifying the HRD phenotype, thus limiting access to these treatments. In this context, we are developing functional assays based on the use of tumor explant slices and then, on the use of tumor organoids derived from ovarian tumors of chemotherapy-naive or previously treated patients. The culture of explants was unsuitable for this application and we then focused our work on tumor organoids. Tumor organoids were exposed to carboplatin (first-line treatment) and two PARP inhibitors (olaparib and niraparib) used for maintenance therapy. In parallel, we collected clinical data from patients (survival, platinum-free interval, RECIST, treatments) to evaluate the predictive potential of these models. The established tumor organoids responded heterogeneously to different drugs, and our results show that the organoid-based assay is capable of identifying patients highly resistant to carboplatin, suggesting that this functional assay could have a predictive value for patients treated with carboplatin. Regarding the potential of organoids in predicting PARPi response, multiple sensitivity profiles have been identified, but the correlation with clinical response has yet to be determined by studies conducted on tumor samples from patients treated with these drugs
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Masters, Geoffrey John. „Unscheduled interruptions to chemotherapy and high white blood cell counts during chemotherapy increase the risk of relapse in children with acute lymphoblastic leukaemia“. Master's thesis, 2005. http://hdl.handle.net/1885/151543.
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