Multidrug Resistance Studies in Patients with Acute Myeloid Leukemia

In the bone marrow, a continuous, strictly organized process of blood cell production or hematopoiesis takes place. The human hematopoietic system is capable of replacing the normal daily turnover of blood cells and is capable of maintaining a balance between the blood cell formation and increased blood cell demands such as in bleeding or infection. The different types of cells that are normally present in the peripheral blood are all derived from committed progenitor cells. The comparttnent of these committed progenitor cells is maintained by a small number of pluripotent stem cells. The process of proliferation and differentiation is regulated by cellular interaction, the microenvironment of the bone marrow, several regulatory glycoproteins and hematopoietic growth factors. Leukemia is the condition of malignant transfonnation of hematopoietic cells leading to the accumulation of immature abnonnal cells in blood and bone marrow. According to the clinical presentation, the leukemias are divided in acute and chronic leukemias. Depending on the cell1ineage involved, a further distinction can be made in myeloid and lymphoid leukemias. The focus of this thesis is on "acute myeloid leukemia" (AML). AML is a clonal disease, characterized by a maturation arrest during the differentiation of the hematopoietic cells to mature blood cells, leading to accumulation of a population of immature abnormal myeloid cells, ultimately resulting in suppression of normal hematopoeisis. Clinically, the replacement of normal functional blood cells by leukemic blasts in bone marrow and peripheral blood will result in anemia, granulocytopenia and thrombocytopenia

Impaired dexamethasone-related increase of anticoagulants is associated with the development of osteonecrosis in childhood acute lymphoblastic leukemia

Coagulation alterations may be involved in osteonecrosis in childhood acute lymphoblastic leukemia. Retrospectively, we evaluated the available coagulation parameters at diagnosis and during induction treatment of 161 acute lymphoblastic leukemia patients: 24 with symptomatic osteonecrosis (median age: 13.8 years, range 4.0-17.2) and 137 without osteonecrosis (median age: 4.9 years, range 1.0-16.7). Coagulation parameters of both groups were similar at diagnosis. After four weeks of treatment including dexamethasone, levels of antithrombin and protein S were significantly less in osteonecrosis-positive than in osteonecrosis-negative patients. Subsequently, after four doses of asparaginase and tapering dexamethasone, these coagulation parameters equally decreased in both groups. Consequently, nadirs of antithrombin and protein S were significantly lower in osteonecrosis-positive than in osteonecrosis- negative patients, even reaching levels below lower normal limits in the osteonecrosis-positive group. A reduced dexamethasone related increase of antithrombin and protein S, and subsequent decline below normal levels after introduction of asparaginase, may result in a hypercoagulable state, contributing to development of symptomatic osteonecrosis

Subtype prediction in pediatric acute myeloid leukemia: Classification using differential network rank conservation revisited

Background: One of the most important application spectrums of transcriptomic data is cancer phenotype classification. Many characteristics of transcriptomic data, such as redundant features and technical artifacts, make over-fitting commonplace. Promising classification results often fail to generalize across datasets with different sources, platforms, or preprocessing. Recently a novel differential network rank conservation (DIRAC) algorithm to characterize cancer phenotypes using transcriptomic data. DIRAC is a member of a family of algorithms that have shown useful for disease classification based on the relative expression of genes. Combining the robustness of this family's simple decision rules with known biological relationships, this systems approach identifies interpretable, yet highly discriminate networks. While DIRAC has been briefly employed for several classification problems in the original paper, the potentials of DIRAC in cancer phenotype classification, and especially robustness against artifacts in transcriptomic data have not been fully characterized yet. Results: In this study we thoroughly investigate the potentials of DIRAC by applying it to multiple datasets, and examine the variations in classification performances when datasets are (i) treated and untreated for batch effect; (ii) preprocessed with different techniques. We also propose the first DIRAC-based classifier to integrate multiple networks. We show that the DIRAC-based classifier is very robust in the examined scenarios. To our surprise, the trained DIRAC-based classifier even translated well to a dataset with different biological characteristics in the presence of substantial batch effects that, as shown here, plagued the standard expression value based classifier. In addition, the DIRAC-based classifier, because of the integrated biological information, also suggests pathways to target in specific subtypes, which may enhance the establishment of personalized therapy in diseases such as pediatric AML. In order to better comprehend the prediction power of the DIRAC-based classifier in general, we also performed classifications using publicly available datasets from breast and lung cancer. Furthermore, multiple well-known classification algorithms were utilized to create an ideal test bed for comparing the DIRAC-based classifier with the standard gene expression value based classifier. We observed that the DIRAC-based classifier greatly outperforms its rival. Conclusions: Based on our experiments with multiple datasets, we propose that DIRAC is a promising solution to the lack of generalizability in classification efforts that uses transcriptomic data. We believe that superior performances presented in this study may motivate other to initiate a new aline of research to explore the untapped power of DIRAC in a broad range of cancer types

Biology and treatment of renal tumours in childhood

In Europe, almost 1000 children are diagnosed with a malignant renal tumour each year. The vast majority of cases are nephroblastoma, also known as Wilms' tumour (WT). Most children are treated according to Société Internationale d'Oncologie Pédiatrique Renal Tumour Study Group (SIOP-RTSG) protocols with pre-operative chemotherapy, surgery, and post-operative treatment dependent on stage and histology. Overall survival approaches 90%, but a subgroup of WT, with high-risk histology and/or relapsed disease, still have a much poorer prognosis. Outcome is similarly poor for the rare non-WT, particularly for malignant rhabdoid tumour of the kidney, metastatic clear cell sarcoma of the kidney (CCSK), and metastatic renal cell carcinoma (RCC). Improving outcome and long-term quality of life requires more accurate risk stratification through biological insights. Biomarkers are also needed to signpost potential targeted therapies for high-risk subgroups. Our understanding of Wilms' tumourigenesis is evolving and several signalling pathways, microRNA processing and epigenetics are now known to play pivotal roles. Most rhabdoid tumours display somatic and/or germline mutations in the SMARCB1 gene, whereas CCSK and paediatric RCC reveal a more varied genetic basis, including characteristic translocations. Conducting early-phase trials of targeted therapies is challenging due to the scarcity of patients with refractory or relapsed disease, the rapid progression of relapse and the genetic heterogeneity of the tumours with a low prevalence of individual somatic mutations. A further consideration in improving population survival rates is the geographical variation in outcomes across Europe. This review provides a comprehensive overview of the current biological knowledge of childhood renal tumours alongside the progress achieved through international collaboration. Ongoing collaboration is needed to ensure consistency of outcomes through standardised diagnostics and treatment and incorporation of biomarker research. Together, these objectives constitute the rationale for the forthcoming SIOP-RTSG ‘UMBRELLA’ study

Topotecan distribution in an anephric infant with therapy resistant bilateral Wilms tumor with a novel germline WT1 gene mutation

The therapeutic strategy for bilateral Wilms tumor (WT) remains a challenge. Especially in cases with chemotherapy resistant disease, bilateral nephrectomy is sometimes inevitable. For optimal cure rates stage V WT patients benefit from adjuvant treatment; however, there are limited data available on chemotherapy pharmacokinetics in anephric children. In this report, we describe a 10-month old girl with bilateral Wilms tumor and a novel germline WT1 gene mutation. This patient hardly showed any response on preoperative chemotherapy, and ultimately, underwent sequential bilateral tumor-nephrectomy. Subsequently, during peritoneal dialysis, she received topotecan as adjuvant chemotherapy based on plasma levels, indicating that this is a reasonable option as adjuvant treatment in therapy-resistant Wilms tumor patients after bilateral nephrectomy. This case showed a novel germline WT1 gene mutation of which the correlation with resistant phenotype has to be confirmed in larger cohorts of WT patients

A comparison of the Muenster, SIOP Boston, Brock, Chang and CTCAEv4.03 ototoxicity grading scales applied to 3,799 audiograms of childhood cancer patients treated with platinum-based chemotherapy

Childhood cancer patients treated with platinums often develop hearing loss and the degree is classified accord

The effect of leucovorin rescue therapy on methotrexate-induced oral mucositis in the treatment of paediatric ALL: A systematic review

Introduction: This study aimed to determine the efficacy of different Leucovorin regimens to reduce oral mucositis in children with acute lymphoblastic leukemia after high-dose Methotrexate (HD-MTX). Methods: Twelve articles were included in a systematic literature review. Articles were categorized into low/medium/high risk of bias. Results: As no randomized controlled trial assessing the effect of Leucovorin has been performed, the efficacy of Leucovorin to reduce oral mucositis remains unknown. Leucovorin was initiated at 24, 36 or 42 h after HD-MTX at a dose of 15 or 30 mg/m2. No meta-analysis could be performed as treatment regimens differed. When comparing studies with similar HD-MTX doses, we observed lower oral mucositis rates in regimens with higher cumulative doses of Leucovorin and early initiation of Leucovorin after MTX. Conclusion: Even though future studies are necessary, higher cumulative Leucovorin doses and early initiation of Leucovorin after start of MTX seem to reduce oral mucositis

MDR1 gene-related clonal selection and P-glycoprotein function and expression in relapsed or refractory acute myeloid leukemia

The expression of P-glycoprotein (P-gp), encoded by the MDR1 gene, is an independent adverse prognostic factor for response and survival in de novo acute myeloid leukemia (AML). Little is known about MDR1 expression during the development of disease. The present study investigated whether MDR1 gene- related clonal selection occurs in the development from diagnosis to relapsed AML, using a genetic polymorphism of the MDR1 gene at position 2677. Expression and function of P-gp were studied using monoclonal antibodies MRK16 and UIC2 and the Rhodamine 123 retention assay with or without PSC 833. No difference was found in the levels of P-gp function and expression between diagnosis and relapse in purified paired blast samples from 30 patients with AML. Thirteen patients were homozygous for the genetic polymorphism of MDR1 (n = 7 for guanine, n = 6 for thymidine), whereas 17 patients were heterozygous (GT). In the heterozygous patients, no selective loss of one allele was observed at relapse. Homozygosity for the MDR1 gene (GG or TT) was associated with shorter relapse-free intervals (P =.002) and poor survival rates (P =.02), compared with heterozygous patients. No difference was found in P-gp expression or function in patients with AML with either of the allelic variants of the MDR1 gene. It was concluded that P-gp function or expression is not upregulated at relapse/refractory disease and expression of one of the allelic variants is not associated with altered P-gp expression or function in AML, consistent with the fact that MDR1 gene-related clonal selection does not occur when AML evolves to recurrent disease. (Blood. 2001;97:3605-3611

Obesity is underestimated using body mass index and waist-hip ratio in long-term adult survivors of childhood cancer

Objective: Obesity, represented by high body mass index (BMI), is a major complication after treatment for childhood cancer. However, it has been shown that high total fat percentage and low lean body mass are more reliable predictors of cardio