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- Djos, Anna, 1983, et al.
(författare)
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Telomere Maintenance Mechanisms in a Cohort of High-Risk Neuroblastoma Tumors and Its Relation to Genomic Variants in the TERT and ATRX Genes
- 2023
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Ingår i: CANCERS. - 2072-6694. ; 15:24
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Tidskriftsartikel (refereegranskat)abstract
- Tumor cells are hallmarked by their capacity to undergo unlimited cell divisions, commonly accomplished either by mechanisms that activate TERT or through the alternative lengthening of telomeres pathway. Neuroblastoma is a heterogeneous pediatric cancer, and the aim of this study was to characterize telomere maintenance mechanisms in a high-risk neuroblastoma cohort. All tumor samples were profiled with SNP microarrays and, when material was available, subjected to whole genome sequencing (WGS). Telomere length was estimated from WGS data, samples were assayed for the ALT biomarker c-circles, and selected samples were subjected to methylation array analysis. Samples with ATRX aberration in this study were positive for c-circles, whereas samples with either MYCN amplification or TERT re-arrangement were negative for c-circles. Both ATRX aberrations and TERT re-arrangement were enriched in 11q-deleted samples. An association between older age at diagnosis and 1q-deletion was found in the ALT-positive group. TERT was frequently placed in juxtaposition to a previously established gene in neuroblastoma tumorigenesis or cancer in general. Given the importance of high-risk neuroblastoma, means for mitigating active telomere maintenance must be therapeutically explored.
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| 4. |
- Ek, Torben, 1963, et al.
(författare)
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Ara-C fever and infections after high-dose ara-C treatment in pediatric lymphoid malignancies
- 2005
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Ingår i: J Pediatr Hematol Oncol. - 1077-4114. ; 27:7, s. 364-9
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Tidskriftsartikel (refereegranskat)abstract
- The objective of this study was to examine the incidence and characteristics of Ara-C-related fever and the frequency and severity of infections after single-drug, high-dose Ara-C treatment (HDAC) in children treated for acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). A retrospective review was performed of 169 courses of HDAC administered to 57 patients (age 1.8-17.8 years). Procalcitonin values (PCT) were analyzed in a subgroup of 16 patients. Fever during HDAC occurred in 113 of 169 (67%) cases. C-reactive protein (CRP) was elevated in the febrile patients (median 38 mg/L [range 3-150]). PCT was elevated (>0.5 ng/mL) during HDAC in 4 of the 16 evaluated patients. Corticosteroids could inhibit fever (P < 0.001). Myelosuppression after HDAC was prominent: 99% developed neutropenia (<0.5 x 10/L) and 92% thrombocytopenia (<25 x 10/L). An early lymphopenia (median 0.1 x 10/L [range 0.01-0.68]) was seen during the first week. G-CSF was used after 12 of the 169 HDAC courses. A febrile episode occurred after 93 of the 169 (55%) HDAC courses, with no need for intensive care and no deaths. The incidence of viridans streptococcal septicemia was 2 of the 169 cases. Ara-C fever is common, and evaluation with inflammation markers is complicated by the fact that HDAC can induce a moderate release of both CRP and PCT. Profound neutropenia and lymphopenia are causative factors for the high incidence of infections, but the risk of life-threatening complications after HDAC in children in remission of lymphoid malignancies is low, even without prophylactic use of colony-stimulating factors.
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| 6. |
- Ek, Torben, 1963, et al.
(författare)
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Immune reconstitution after childhood acute lymphoblastic leukemia is most severely affected in the high risk group
- 2005
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Ingår i: Pediatr Blood Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 44:5, s. 461-8
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim was to examine the immune reconstitution after current chemotherapy for childhood ALL, with a special focus on finding immunologic variables that predict a poor immune response to vaccinations. PROCEDURE: In a cross-sectional study of 31 children after treatment with the NOPHO ALL-1992 protocol peripheral blood lymphocyte subsets, T- and B-cell function in vitro and serum immunoglobulins (Ig) were measured. All patients were examined once, at 1 or at 6 months after cessation of chemotherapy, immediately before vaccination with DT and Hib. RESULTS: Lymphocytes, T-cells, and CD4+ T-cells were low at 6 months after treatment. Naive T-cell subsets were more reduced than memory subsets. In the high risk (HR) ALL group, CD8+ T-cells were reduced at 6 months. NK-cells were low at 1 month, but normal at 6 months; however, the CD3+CD56+ (NKT) subset was reduced at both time points. Total B-cell number was low at 1 month, but normal at 6 months. A relative increase of CD5+ B-cells (B-1 cells) was evident, particularly in the HR group. Antigen-independent T- and B-cell function in vitro were affected at 1 month, but virtually normalized at 6 months. Serum IgM level was decreased at 1 month and IgG3 level was increased at 1 and 6 months. CONCLUSIONS: This study shows that immune reconstitution after childhood ALL is slower than previously reported and emphasizes the influence of treatment intensity. The most intensively treated patients still have persistent abnormalities in T-, B-, and NK-cell subsets at 6 months post therapy and show a poor response to immunization with T-cell dependent antigens. In the HR group, routine re-immunizations before this time point are of limited benefit, and the effect of repeated vaccinations should be evaluated.
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| 7. |
- Ek, Torben, 1963
(författare)
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Immune reconstitution after childhood leukemia. Aspects on immunizations and effects of Ara-C on the innate immune system
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Children with acute lymphoblastic leukemia (ALL) can be cured with cytotoxic chemotherapy, but myelosuppression and immunosuppression are major side effects causing morbidity and even mortality from infections. Vaccinations with diphtheria toxoid (DT), tetanus toxoid (TT) and protein conjugated Haemophilus influenzae type B (Hib) capsular polysaccharide were used to investigate the adaptive immune system in a controlled study of 31 children after treatment for ALL. Subprotective antibody levels were found in 83% of the patients against diphtheria and 67% against tetanus, whereas all had protective levels of Hib antibodies. All standard and intermediate risk patients had protective antibody levels after immunization. The memory response was weak in the high risk (HR) group, with subprotective antibody levels in a substantial proportion after immunization. Antibody avidity after immunization was low for anti-TT, but not for anti-Hib, in the HR group. The poor antibody production in the HR group correlated to low numbers of specific antibody secreting cells after immunization. No difference in the immune response was detected between patients vaccinated at one month (N=12) or six months (N=19) after treatment. To examine immune reconstitution after childhood ALL, lymphocyte populations and in vitro function of T and B cells was measured in the vaccine recipients. At 6 months after treatment T cells were subnormal due to low CD4+ and CD4+45RA+ T cells. During reconstitution the CD5+ B cells were increased, most marked in the HR group. These findings clearly suggest a relationship between treatment intensity and immunosuppression in children with ALL, which should influence the policy for immunizations. Inactivated vaccines are effective in patients from the lower risk group already at 1 month after treatment. The effect of repeated immunizations after 6 months in the HR group should be examined.Ara-C is an important, but highly myelosuppressive drug for ALL. To investigate the inflammatory reaction named the Ara-C syndrome a retrospective study of 57 patients in first complete remission (ALL=49, NHL=8) treated with 169 courses of high dose ara-C (HDAC) was performed. Ara-C fever occurred in 113/169 (67%) of the courses, and was associated with elevated plasma levels of the inflammation markers CRP and procalcitonin. An association between fever and release of proinflammatory cytokines (TNF-alpha, IL-6 and IFN-gamma) was found. This was counterbalanced by elevations of the anti-inflammatory cytokines IL1-ra and IL-10. The syndrome was self limiting, but could be inhibited by administration of corticosteroids. Myelosuppression, including lymphopenia, was profound after HDAC, and neutropenic fever occurred after 55% of the courses. The incidence of viridans streptococcal sepsis was low (2/169) and no mortality occurred, despite that 93% of all HDAC was administered without the use of colony stimulating factors. This study demonstrates that ara-C has strong effects on the innate immune system leading to an exceptionally high incidence of both drug fever and infections.
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| 9. |
- Ek, Torben, 1963, et al.
(författare)
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Intensive treatment for childhood acute lymphoblastic leukemia reduces immune responses to diphtheria, tetanus, and Haemophilus influenzae type b
- 2004
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Ingår i: J Pediatr Hematol Oncol. - 1077-4114. ; 26:11, s. 727-34
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Immunity to diphtheria toxoid (D), tetanus toxoid (T), and Haemophilus influenzae type b (Hib) is affected in children with acute lymphoblastic leukemia (ALL). The aims were to examine immunity and to compare the response to immunization at 1 or 6 months after treatment. METHODS: Thirty-one patients were immunized with DT and conjugated Hib vaccine (ActHib) at 1 month or 6 months after treatment of ALL with the NOPHO 92 protocol. Antibody levels were determined before and 3 weeks after vaccination. Specific T and Hib antibody-secreting cells of IgG/IgA/IgM isotypes were analyzed in peripheral blood using an ELISPOT technique. RESULTS: All specific antibody levels decreased during ALL treatment, and protective levels after treatment were noted for 17% against D, 33% against T, and 100% against Hib. No high-risk patient had full D or T protection after treatment. After vaccination all the standard- and intermediate-risk patients achieved full protection against D, T, and Hib. The high-risk group showed insufficient immune response (full protection after vaccination: D 56%, T 22%, Hib 78%). No difference was found between vaccination at 1 month or 6 months after treatment. The poor antibody production in the high-risk group correlated to low numbers of antibody-secreting cells. CONCLUSIONS: Nonprotective antibody levels against D, T, and Hib after childhood ALL are more common than previously thought. Insufficient immune response was restricted to the high-risk group and was related to a low number of memory B cells in this study. Immunizations should be included in follow-up after childhood ALL, and the policy should be adapted to treatment intensity.
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| 10. |
- Ek, Torben, 1963, et al.
(författare)
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Interferon gamma and tumour necrosis factor alpha in relation to anaemia and prognosis in childhood cancer
- 2005
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Ingår i: Acta Paediatr. - 0803-5253. ; 94:4, s. 435-7
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Tidskriftsartikel (refereegranskat)abstract
- This study examined whether the initial plasma levels of tumour necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) in 131 children with newly diagnosed cancer were associated with haematopoietic suppression, and whether plasma levels of TNFalpha or haemoglobin at diagnosis affects long-term prognosis in childhood acute lymphoblastic leukaemia (ALL). Conclusions: IFNgamma, and possibly also TNFalpha, were related to anaemia in children with solid tumours. Neither TNFalpha levels nor Hb levels were associated with increased risk of ALL relapse.
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