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Biomedical subjects

Tomasz Szczepański

Publications and source records attributed to Tomasz Szczepański.

At least 19 recordsLinked to original sources
PubMed2006

ALK-positive diffuse large B-cell lymphoma.

Anaplastic lymphoma kinase (ALK) positive diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non-Hodgkins lymphoma. Five such cases have been described in children. We present a 9-year-old boy, in whom diagnosis of DLBCL has been established in addition to congenital multiple enchondromatosis. Immunohistopathological evaluation of tumor biopsy established the final diagnosis of ALK + DLBCL. The clathrin gene (CLTC)-ALK fusion underlying aberrant expression of ALK in the present case was demonstrated by interphase fluorescence in situ hybridization (FISH) using break-apart rearrangement probes for ALK and CLTC. The disease in this patient was highly resistant to applied chemotherapy regimens and to radiotherapy. Analysis of the disease course in our patient and review of other cases reported previously show that ALK + DLBCL can be an aggressive malignancy that can be cured with conventional chemotherapy protocols only at stage of localized disease.

Anaplastic Lymphoma Kinase↗
PubMed2006

Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies.

Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency = 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence.

Adolescent↗
PubMed2006

Pattern of immunoglobulin and T-cell receptor (Ig/TCR) gene rearrangements in Polish pediatric acute lymphoblastic leukemia patients--implications for RQ-PCR-based assessment of minimal residual disease.

We studied 23 Polish children with precursor-B-ALL, using PCR-heteroduplex analysis and DNA sequencing, to determine the availability of Ig/TCR gene rearrangements as patient-specific MRD-RQ-PCR targets. We found IGH, IGK-Kde, incomplete TCRD, Vdelta2-Jalpha, TCRG and TCRB rearrangements in 83%, 39%, 61%, 35%, 61% and 13% of patients, respectively. Comparison of Ig/TCR gene rearrangements pattern (frequency and characteristics of rearrangements) in Polish patients with those reported for patients of other European nationalities did not show major differences. These results are the first promising step for further development of MRD study in Polish patients according to current diagnostic standards.

Adolescent↗
PubMed2006

Flow-cytometric immunophenotyping of normal and malignant lymphocytes.

During the past two decades, flow-cytometric immunophenotyping of lymphocytes has evolved from a research technique into a routine laboratory diagnostic test. Extensive studies in healthy individuals resulted in detailed age-related reference values for different lymphocyte subpopulations in peripheral blood. This is an important tool for the diagnosis of hematological and immunological disorders. Similar, albeit less detailed, information is now available for other lymphoid organs, e.g., normal bone marrow, lymph nodes, tonsils, thymus and spleen. Flow-cytometric immunophenotyping forms the basis of modern classification of acute and chronic leukemias and is increasingly applied for initial diagnostic work-up of non-Hodgkin's lymphomas. Finally, with multiparameter flow cytometry, it is now possible to identify routinely and reliably low numbers of leukemia and lymphoma cells (minimal residual disease).

Animals↗
PubMed2005

Decreased numbers of CD4+ T lymphocytes in peripheral blood after treatment of childhood acute lymphoblastic leukemia.

Treatment-related immunosuppression in patients with acute lymphoblastic leukemia (ALL) is associated with increased susceptibility to infectious diseases, also after the treatment. The aim of the present study was the detailed evaluation of T lymphocyte subsets in peripheral blood in children after treatment of ALL. All children were treated according to the BFM 90 protocol. The patients were divided into 5 groups of 30 children in each, depending on the time from cessation of the ALL treatment. A control group consisted of 30 healthy children subjected to elective "1-day" surgery. The children's age ranged from 6 to 18 years. The examinations were performed in FACScan flow cytometer with the use of wide set of monoclonal antibodies: CD3, CD4, CD8, TCRalphabeta, TCRgammadelta, CD19, CD25, CD45RA, CD45RO, CD69, HLA-DR, CD16 and CD56, which particularly allowed detailed analysis of T lymphocytes. The results showed that most parameters in children 1 year after ALL treatment completion were similar to healthy children. However, we observed persistently low CD4+ T cell numbers, both CD45RA+ as well as CD45RO+ subsets as compared to the control group. This might reflect decreased regenerative potential of immunological system in children 1 year after ALL treatment.

Adolescent↗
PubMed2005

Aberrant methylation in promoter-associated CpG islands of multiple genes in acute lymphoblastic leukemia.

Methylation profile was analyzed in 10 childhood acute lymphoblastic leukemia (ALL) and nine adult ALL cases. Four genes (p15, p16, RARbeta, FHIT) had methylation in both diseases, four genes (p14, Rb, MLH1, DAPK) showed no methylation in both diseases, and the two genes (APC, RIZ) demonstrated methylation only in adult ALL. Methylation of the RARbeta was more frequent in adult ALL than that in childhood ALL (p=0.01). The number of patients with methylation of multiple genes was higher in adult ALL than that in childhood ALL (p=0.006). Moreover, overall frequency of methylation was higher in adult ALL than that in childhood ALL (p=0.01).

Adolescent↗
PubMed2004

Concentration of IL-2, IL-6, IL-8, IL-10 and TNF-alpha in children with acute lymphoblastic leukemia after cessation of chemotherapy.

The immunosuppressive effect of cytotoxic drugs, basic therapeutic agents in the treatment of childhood acute leukemias, requires monitoring of the immune system following cessation of therapy. The cytokines are soluble proteins that play a key role in the immunoregulation of the lymphocyte function. The cytokines regulate growth, differentiation and function of various cells in normal conditions. The aim of our study was to estimate serum levels of IL-2, IL-6, IL-8, IL-10 and TNF-alpha in children with acute lymphoblastic leukemia (ALL) after cessation of chemotherapy. The study involved 150 children with ALL. This group consisted of: 30 children 1 month after treatment cessation; 30 children, 3 months later; 30 children 6 months later; 30 children, 9 months later and 30 children, 12 months later. The control group consisted of 30 healthy children. The levels of the cytokines under study were assayed using the immunoassay kits (R&D Systems, USA). During the study significant differences in TNF-alpha, IL-2 and IL-8 serum concentrations were observed among treated children and controls. However there were no differences in IL-6 and IL-10 concentrations.

Adolescent↗
PubMed2004

Acute lymphoblastic leukemia followed by a clonally-unrelated EBV-positive non-Hodgkin lymphoma and a clonally-related myelomonocytic leukemia cutis.

BACKGROUND: Complicating malignant hematopoietic proliferations might severely hamper the course of acute lymphoblastic leukemia (ALL) in patients with an otherwise good prognosis. It is important to distinguish whether such neoplastic proliferations represent ALL relapses or secondary treatment-related malignancies. PROCEDURE: We present an 11-year-old girl with precursor-B-ALL in whom maintenance treatment was complicated by an isolated ALL relapse in the brain, nodular lymphoproliferations in the liver, and an isolated myelo-monocytic leukemia cutis. All these hemato-oncologic malignancies occurred in the background of a secondary immunodeficiency, most likely caused by cytotoxic treatment. RESULTS AND CONCLUSIONS: Using a stepwise molecular approach, we were able to demonstrate that the liver infiltrates were Epstein-Barr virus (EBV)-positive, contained monoclonal mature B-cells with immunoglobulin heavy chain gene (IGH) gene rearrangements unrelated to the primary ALL, and thus represented a true secondary non-Hodgkin lymphoma (NHL). In contrast, the skin infiltrates consisted of myelo-monocytic cells with clonal IGH and T-cell receptor gamma gene rearrangements, identical to the precursor-B-ALL blasts at diagnosis. Thus, the disease course of the precursor-B-ALL patient was complicated by two different isolated extramedullary relapses (brain and skin) and a secondary EBV(+) B-NHL.

Child↗
PubMed2004

[Acute lymphoblastic leukemia in a 3-week-old neonate].

We present a case of 3-week-old infant, in whom we established the diagnosis of congenital acute lymphoblastic leukemia (ALL), characterized by the immunophenotype of the most immature B-cell precursors (pro-B-ALL) and chromosomal translocation t(4;11) associated with the rearrangement of MLL and AF4 genes. The clinical course of this leukemia deserves particular attention, because it was different from classical presentation: diagnosis--not immediately after birth--but at the age of 3 weeks, no signs of hemorrhagic diathesis, lack of nodular skin infiltrates, and no central nervous system involvement. Exchange blood transfusions performed during the remission induction treatment saved the child from life-threatening symptoms of leukostasis at the initial stage of leukemia. Despite successful remission induction in bone marrow, the infant relapsed during the fifth month of treatment. After subsequent chemotherapy course the child died owing to fatal infectious complications. Despite enormous progress in treatment of childhood ALL, this type of leukemia in infants below 6 months of age, and particularly in cases of congenital leukemia is still associated with a very poor prognosis.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

[Leukapheresis in children with chronic myeloid leukemia and pulmonary leukostasis].

We present two patients with chronic myeloid leukemia and hyperleukocytosis above 350 x 10(9)/l causing the symptoms of pulmonary leukostasis. Therapeutic leukapheresis procedures with concomitant chemotherapy were initiated within 12 hours from the diagnosis. After the therapy commencement the general condition of the patients systematically improved and leukocytosis gradually decreased from the second day of treatment with disappearance of pulmonary leukostasis symptoms. Thanks to application of such treatment procedures during the cytoreductive period, severe complications related to leukostasis could be prevented.

Adolescent↗
PubMed2003

Allelotype analysis in relapsed childhood acute lymphoblastic leukemia.

We performed for the first time the allelotype of relapsed childhood acute lymphoblastic leukemia (ALL). A total of 38 cases were screened for loss of heterozygosity (LOH) using 71 markers. In all, 26 (68%) patients showed LOH on at least one chromosomal arm, indicating that LOH is a frequent event at relapse. The most frequent loss was found on chromosomal arm 9p at the p16/INK4a locus (39%). LOH at the TEL gene locus on chromosomal arm 12p also occurred often (25%). Frequent loss was observed on chromosome arms 4q (20%), 6q (21%), and 17q (20%). Sequential analysis (i.e. samples obtained from both initial diagnosis and relapse) shows that some patients (63%) have the identical LOH status at both phases, suggesting the presence of the same clone. Other samples (37%) showed distinct LOH alterations, indicating clonal evolution at relapse. Despite the heterogeneous and complex changes, some shared LOH loci occurred in these matched samples, suggesting that many of the same tumor-suppressor genes are aberrant at both phases. In summary, novel tumor-suppressor genes on chromosome arms 4q, 6q, and 17q, as well as the p16 and TEL genes, have an important role in the relapse of childhood ALL.

Adolescent↗
PubMed2003

Classification systems for acute and chronic leukaemias.

Modern classification systems for acute and chronic leukaemias are based on cytomorphology, cytochemistry, immunophenotyping, immunogenetics and molecular cytogenetics. Morphology forms the initial diagnosis of leukaemia, but generally is not sufficient to identify biologically and clinically relevant subsets within the main categories of leukaemia. Immunophenotyping precisely defines the lineage and stage of differentiation of malignantly transformed haematopoietic cells. This is usually sufficient for precise classification of mature lymphoid malignancies, although immunogenetic and (molecular) cytogenetic studies might be helpful to confirm the diagnosis of disseminated non-Hodgkin's lymphomas. However, certain categories of disease that are clearly defined by cytomorphology and immunophenotyping, particularly acute leukaemias, are still heterogeneous, mainly owing to different underlying leukaemogenic events. Immunophenotyping can reveal subgroups highly suggestive of certain chromosome aberrations but reliable identification of such aberrations requires cytogenetic or molecular studies. Such combined diagnostic information forms the basis of current WHO classification of tumours of haematopoietic and lymphoid tissues. This will be complemented in the near future with novel criteria revealed by microarray gene expression profiling. This chapter summarizes and comments on the currently used immunophenotypic classification systems of acute and chronic leukaemias and on the added value of molecular diagnostics.

Humans↗
PubMed2003

[Minimal residual disease in childhood acute lymphoblastic leukemia: diagnosis of the 21 century].

The detection of very low numbers of leukemic cells persisting after treatment, i.e. the monitoring of minimal residual disease (MRD) is of significant clinical value for children with acute lymphoblastic leukemia (ALL). Particularly, the assessment of early response to remission induction treatment has high prognostic value and enables more reliable definition of low-risk and high-risk patient groups. This forms the basis for treatment modification in new treatment protocols. The predictive value of MRD monitoring is particularly clear after first relapse. It enables recognition of low-risk patients with low MRD levels (probability of relapse-free survival (RFS) of 86%), whereas high MRD levels in high-risk patients are predictive of dismal outcome (probability of RFS of 0%). Moreover high MRD positivity before stem cell transplantation is strongly prognostic of relapse after transplantation.

Antineoplastic Agents↗
PubMed2003

[Leukemia in neonates and infants].

Leukemia diagnosed during the first year of life is a rare but highly malignant disease of hematopoietic system. In contrast to leukemias diagnosed after the first year of life, infant leukemia is characterized by distinct biological and genetic features, which influence the clinical course and disease outcome. Approximately 60% of acute leukemias in infants are associated with aberrations of chromosome 11q23 with the rearrangement of the MLL gene. Despite major progress in treatment of childhood leukemias, prognosis of infant leukemia (particularly in acute lymphoblastic leukemia--ALL) remains poor. The most unfavorable prognostic factors in infant ALL are age at diagnosis below 6 months, CD10 negativity, myeloid antigen co-expression, presence of MLL gene rearrangements and in particular poor response to steroids. Long-term event free survival (EFS) in infant ALL ranges from 20 to 40%, depending on treatment protocol. Slightly better results are achieved in infant acute myeloid leukemia.

Acute Disease↗
PubMed2002

Comparative analysis of Ig and TCR gene rearrangements at diagnosis and at relapse of childhood precursor-B-ALL provides improved strategies for selection of stable PCR targets for monitoring of minimal residual disease.

Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements are excellent patient-specific polymerase chain reaction (PCR) targets for detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL), but they might be unstable during the disease course. Therefore, we performed detailed molecular studies in 96 childhood precursor-B-ALL at diagnosis and at relapse (n = 91) or at presumably secondary acute myeloid leukemia (n = 5). Clonal Ig and TCR targets for MRD detection were identified in 94 patients, with 71% of these targets being preserved at relapse. The best stability was found for IGK-Kde rearrangements (90%), followed by TCRG (75%), IGH (64%), and incomplete TCRD rearrangements (63%). Combined Southern blot and PCR data for IGH, IGK-Kde, and TCRD genes showed significant differences in stability at relapse between monoclonal and oligoclonal rearrangements: 89% versus 40%, respectively. In 38% of patients all MRD-PCR targets were preserved at relapse, and in 40% most of the targets (> or = 50%) were preserved. In 22% of patients most targets (10 cases) or all targets (10 cases) were lost at relapse. The latter 10 cases included 4 patients with secondary acute myeloid leukemia with germline Ig/TCR genes. In 5 other patients additional analyses proved the clonal relationship between both disease stages. Finally, in 1 patient all Ig/TCR gene rearrangements were completely different between diagnosis and relapse, which is suggestive of secondary ALL. Based on the presented data, we propose stepwise strategies for selection of stable PCR targets for MRD monitoring, which should enable successful detection of relapse in most (95%) of childhood precursor-B-ALL.

Bone Marrow↗
PubMed2002

Molecular monitoring of residual disease using antigen receptor genes in childhood acute lymphoblastic leukaemia.

Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements are assumed to be unique 'fingerprint-like' sequences for each acute lymphoblastic leukaemia (ALL). Various clonal Ig/TCR gene rearrangements can be identified at diagnosis in virtually all childhood ALL patients, representing molecular targets for detection of minimal residual disease (MRD) during follow-up analysis. The usage of at least two MRD-PCR targets per patient generally ensures high sensitivity (</=1:10(4) normal cells) and prevents false-negative results owing to ongoing or secondary rearrangements.MRD monitoring in childhood ALL employing Ig/TCR gene rearrangements as PCR targets has significant prognostic value. This is particularly powerful for evaluation of early treatment response and consequently can be used for improved therapy stratification. Prolonged continuous MRD monitoring might be important for patients at intermediate or high risk of relapse. MRD monitoring in second complete remission identifies patients with excellent drug sensitivity and predicts outcome after stem cell transplantation.

Child↗
PubMed2002

Acute lymphoblastic leukemia.

This is a comprehensive overview on the most recent developments in diagnosis and treatment of acute lymphoblastic leukemia (ALL). Dr. Dieter Hoelzer and colleagues give an overview of current chemotherapy approaches, prognostic factors, risk stratification, and new treatment options such as tyrosine kinase inhibitors and monoclonal antibodies. Furthermore the role of minimal residual disease (MRD) for individual treatment decisions in prospective clinical studies in adult ALL is reviewed. Drs. Ching-Hon Pui and Mary Relling discuss late treatment sequelae in childhood ALL. The relation between the risk of second cancer and treatment schedule, pharmacogenetics, and gene expression profile studies is described. Also pathogenesis, risk factors, and management of other complications such as endocrinopathy, bone demineralization, obesity, and avascular necrosis of bone is reviewed. Dr. Fred Appelbaum addresses long-term results, late sequelae and quality of life in ALL patients after stem cell transplantation. New options for reduction of relapse risk, e.g., by intensified conditioning regimens or donor lymphocyte infusions, for reduction of mortality and new approaches such as nonmyeloablative transplantation in ALL are discussed. Drs. Jacques van Dongen and Tomasz Szczepanski demonstrate the prognostic value of MRD detection via flow cytometry or PCR analysis in childhood ALL. They discuss the relation between MRD results and type of treatment protocol, timing of the follow-up samples, and the applied technique and underline the importance of standardization and quality control. They also review MRD-based risk group definition and clinical consequences.

Adult↗