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K Vettenranta

Publications and source records attributed to K Vettenranta.

At least 19 recordsLinked to original sources
PubMed2007

T cell regeneration in pediatric allogeneic stem cell transplantation.

Delayed and/or insufficient T cell recovery post hematopoietic stem cell transplantation (HSCT) leads to an increased risk of morbidity and mortality. We evaluated thymic function and its association with T cell regeneration post HSCT and identified factors involved in the process among pediatric stem cell transplant recipients. T cell regeneration in 66 pediatric patients was prospectively followed by naive T cell phenotyping, measuring of T cell receptor excision circles (TRECs) and expression of Foxp3 by regulatory T cells for the first 18 months post HSCT. TRECs were lower pre-HSCT in children with a malignant than non-malignant primary disease or immunosuppressed controls (P=0.001). Naive T lymphocyte reconstitution and thymic recovery were slow in the recipients of allogeneic stem cell grafts post HSCT. Infections caused by herpesviruses had a prognostic impact on mortality. Children with low TRECs had a high mortality (P=0.05) and low TRECs were also associated with extensive chronic graft-versus-host disease from 6 months onwards. Low amount of Foxp3 pre-HSCT was associated with an increased mortality post HSCT (P=0.03). Our study indicates an association between impaired T cell regeneration and thymic dysfunction and the clinical post transplant complications in pediatric allogeneic stem cell transplantation.

Adolescent↗
PubMed2005

Circulating dendritic cell subset levels after allogeneic stem cell transplantation in children correlate with time post transplant and severity of acute graft-versus-host disease.

We examined the recovery of circulating monocytoid (Lin- CD11+ HLA-DR+) and plasmacytoid (Lin- CD123+ HLA-DR+) precursor (pre) dendritic cell (DC) subsets after allogeneic stem cell transplantation (SCT) in 39 children, using age-matched healthy children as controls. The frequencies of DCs in peripheral blood samples were determined by flow cytometry. The initial recovery of DC occurred simultaneously with myeloid engraftment. However, with time, DC subset values declined, being very low 40-50 days after SCT. Low monocytoid and plasmacytoid DC values were associated significantly with the development of severe acute graft-versus-host disease (aGVHD) (P=0.042 and 0.017, respectively). Plasmacytoid DC values were lower than in the age-matched controls for the entire follow-up period (range 102-2569 days), although, with time, values approached normal levels. Normal monocytoid DC numbers were observed within 300-400 days post SCT. The severity of chronic GVHD did not correlate with quantitative recovery of DC. We conclude that in pediatric SCT, initial recovery of DC production is concurrent with that of myelopoiesis, yet with time, DC subset values decline and low counts are associated with severe aGVHD. Monocytoid DC numbers approach normal levels within a year of SCT, but plasmacytoid DC counts recover very slowly.

Acute Disease↗
PubMed2004

Dendritic cell subsets in childhood and in children with cancer: relation to age and disease prognosis.

Dendritic cells (DC) are a heterogeneous group of uniquely well-equipped bone marrow-derived antigen-presenting cells. They circulate in blood as precursor cells (preDC). In humans, two blood-borne subtypes of preDC can be distinguished by their differential expression of CD11c (CD11c+ preDC; monocytoid DC) and CD123 (CD123+ preDC; plasmacytoid DC). We studied the incidence of monocytoid and plasmacytoid DC in peripheral blood samples from 39 children of various ages (0.4-16.8 years) by flow cytometry, and found a significant negative correlation between the number of plasmacytoid DC and age (r = 0.421, P = 0.012). Monocytoid DC counts did not change significantly with age. Similarly, we analysed DC subsets in 19 children with cancer at the time of diagnosis prior to initiation of any myelosuppressive or antiproliferative treatment and compared the results with those obtained from gender- and age-matched control children. Patients with cancer had significantly less circulating monocytoid DC than controls (medians 13.2 versus 21.4 cells/ micro l, respectively, P = 0.042) at diagnosis, whereas absolute plasmacytoid DC counts did not differ significantly between the study groups. However, clinical outcome of the children with cancer (2.9-5 years follow-up after diagnosis) correlated with plasmacytoid DC count. Children with high plasmacytoid DC counts at diagnosis (above median) survived significantly worse (6/10 deceased) than those with low counts (1/9 deceased) (P = 0.034). Thus, circulating plasmacytoid DC counts are related to age during childhood, and development of cancer is associated with low number of monocytoid DC. A low circulating plasmacytoid DC count at diagnosis was a good prognostic sign.

Adolescent↗
PubMed2003

Imminent allograft rejection prevented by donor lymphocyte transfusions: report of two pediatric cases.

Gradual allograft rejection after initial good engraftment may occur with simultaneous autologous reconstitution particularly in patients receiving nonmyeloablative conditioning. Careful post-transplant follow-up of the chimerism status can reveal these cases early on, when the immunological balance may still be shifted to the donor cells. We describe two children with nonmalignant diseases, in whom imminent rejection of their sibling allografts was prevented with donor lymphocyte transfusions (DLT). DLT dosing and timing need to be individually guided by monitoring of the chimerism status.

Child↗
PubMed2002

Expression of myeloid-specific genes in childhood acute lymphoblastic leukemia - a cDNA array study.

Several specific cytogenetic changes are known to be associated with childhood acute lymphoblastic leukemia (ALL), and many of them are important prognostic factors for the disease. Little is known, however, about the changes in gene expression in ALL. Recently, the development of cDNA array technology has enabled the study of expression of hundreds to thousands of genes in a single experiment. We used the cDNA array method to study the gene expression profiles of 17 children with precursor-B ALL. Normal B cells from adenoids were used as reference material. We discuss the 25 genes that were most over-expressed compared to the reference. These included four genes that are normally expressed only in the myeloid lineages of the hematopoietic cells: RNASE2, GCSFR, PRTN3 and CLC. We also detected over-expression of S100A12, expressed in nerve cells but also in myeloid cells. In addition to the myeloid-specific genes, other over-expressed genes included AML1, LCP2 and FGF6. In conclusion, our study revealed novel information about gene expression in childhood ALL. The data obtained may contribute to further studies of the pathogenesis and prognosis of childhood ALL.

Acute Disease↗
PubMed2002

Deletion of the Ink4-locus (the p16ink4a, p14ARF and p15ink4b genes) predicts relapse in children with ALL treated according to the Nordic protocols NOPHO-86 and NOPHO-92.

Inactivation of the Ink4 gene locus locus on 9p comprising the tumour suppressor gene p16ink4a and its neighbours p14ARF and p15ink4b is common in childhood acute lymphoblastic leukaemia (ALL), but the prognostic significance is controversial. DNA from 230 patients was retrospectively analysed by Southern blotting, single strand conformation polymorphism (SSCP) and sequencing techniques. The results were correlated with clinical characteristics and outcome. One hundred and ninety-four fully analysed patients, similarly treated using the Nordic NOPHO-86 or the current NOPHO-92 protocols, were included in the outcome analysis. Deletions approached a minimally deleted region between the p16ink4a and p15ink4b genes, making the p14ARF gene the most commonly deleted coding sequence. Bi-allelic deletion was associated with high white blood cell count (WBC) (P < 0.001), T cell phenotype (P < 0.001) and mediastinal mass (P < 0.001). Patients with Ink4 locus bi-allelic deletions had an inferior pEFS (P < 0.01) and multivariate analysis indicated that bi-allelic deletion of the p16ink4a and the p14ARF genes was an independent prognostic risk factor (P < 0.05). Sub-group analysis revealed a pronounced impact of deletion status for high-risk patients, ie with high WBC. Deletion-status and clinical risk criteria (WBC) could thus be combined to further differentiate risk within the high-risk group. The analysis of the Ink4 locus adds independent prognostic information in childhood ALL treated by Nordic protocols and may help in selection of patients for alternative treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Neutrophil regeneration precedes healing of tissue destruction, as indicated by serum C-reactive protein, in children with cancer recovering from neutropenic fever.

AIM: To evaluate the relationship between absolute neutrophil count and C-reactive protein (CRP) in the recovery phase of neutropenic fever among paediatric patients with cancer. METHODS: A total of 102 paediatric oncology patients with 177 episodes of fever and neutropenia was studied prospectively in a two-centre setting. Antimicrobial therapy was discontinued 9 d (mean) post-initiation with a mean absolute neutrophil count of 1.8 x 10(9) l(-1) and CRP of 32 mg l(-1). RESULTS: The mean level of CRP below 20 mg l(-1) was reached on day 12. The level of CRP peaked on the day following the commencement of antimicrobial therapy. Throughout the episodes of fever and neutropenia higher levels of CRP were associated with a lower absolute neutrophil count. Following defervescence the pace of marrow recovery as evidenced by an increasing absolute neutrophil count to > 0.2 and > 0.5 x 10(9) l(-1) was more rapid than the normalization of serum CRP. There was a 2-3 d lag period between absolute neutrophil count exceeding the level of 200 x 10(6) l(-1) and the return of CRP to a baseline level. All episodes were treated successfully and there were no fatalities. CONCLUSION: Among patients recovering from neutropenia and fever the signs of marrow recovery remain the key criterion in evaluating the safety of discontinuing antimicrobial therapy, with serum CRP remaining more of an indicator of ongoing tissue repair.

Adolescent↗
PubMed2002

Follow-up of minimal residual disease in pediatric acute myeloblastic leukemia using metaphase-FISH.

In acute myeloblastic leukemia (AML) the follow-up of minimal residual disease (MRD) has focused on specific chromosomal aberrations (e.g. t(15;17), t(8;21), inv16/t(16;16)) mostly employing reverse transcriptase-PCR. High or increasing levels of MRD are associated with an increased risk of relapse but low levels may persist in patients with prolonged or even durable remission. In adult patients with AML the increased risk of relapse has also been demonstrated using flow cytometry and fluorescence in situ hybridization (FISH). We evaluated the presence of MRD among pediatric patients with AML during and after the cessation of therapy. We were able to establish a clonal marker for the follow-up in 80% of our cases; 11 of the 15 with a clonal marker had detectable MRD at some point during follow-up while 4/15 relapsed 12-14 months after diagnosis. In two there was hematological relapse preceded by an increase in their FISH-detectable number of clonal cells. In 7 of the 11 remaining in CR1 there were small (< 1%) numbers of clonal cells detectable at one or more time-points. Out of the group of 15 pediatric patients with AML, 12 are currently alive in CCR with a median follow-up of 44 months (range 7-63 months). Our data establish the role of metaphase-FISH in the follow-up of AML in children and emphasize the importance of an increasing level of MRD in predicting a relapse. Yet, low and stable levels of marrow MRD a ppear compatible with CCR.

Acute Disease↗
PubMed2001

Hematopoietic stem cell transplantation in infantile neuronal ceroid lipofuscinosis.

OBJECTIVE: To study the effect of allogeneic hematopoietic stem cell transplantation (SCT) on the clinical course of infantile neuronal ceroid lipofuscinosis (INCL), a lysosomal storage disease. BACKGROUND: INCL is a progressive encephalopathy with severe neuronal loss, especially in the cerebral and cerebellar cortex and retina. Autofluorescent lipopigments constitute the typical storage material in INCL. The disease is caused by recessive mutations in the palmitoyl protein thioesterase 1 (PPT1) gene. PPT1 is a depalmitoylating enzyme, which is transported to lysosomes through the mannose-6-phosphate receptor-mediated pathway, and participates in the lysosomal degradation of fatty acylated proteins. METHODS: Three patients with INCL received transplants and were followed up after SCT at the Hospital for Children and Adolescents at the University of Helsinki. The first patient rejected the first graft at the age of 7 months and had mild symptoms of INCL at the second transplantation at 11 months. The two other patients were asymptomatic when they received their transplants at the age of 4 months. RESULTS: PPT1 enzyme activity was normalized in peripheral leukocytes, but remained low in the CSF and resulted only in a mild and transient amelioration of the classic INCL. All patients who received transplants developed INCL by the age of 2 or 3 years. CONCLUSIONS: More experimental animal and cell culture studies are needed to determine the in vivo function of PPT1. SCT currently cannot be recommended as therapy for INCL.

Child, Preschool↗
PubMed2001

Loss at 12p detected by comparative genomic hybridization (CGH): association with TEL-AML1 fusion and favorable prognostic features in childhood acute lymphoblastic leukemia (ALL). A multi-institutional study.

BACKGROUND: Genetic aberrations provide prognostic information in childhood ALL. The proportion of patients with detectable aberrations can be increased by combining G-banding with comparative genomic hybridization (CGH). PROCEDURE: We studied 79 children with ALL by CGH and G-banding, and explored the relationship of these findings to clinical features and outcome. RESULTS: CGH revealed DNA copy number changes in 57 patients (72%), 9 of whom had normal karyotype by G-banding. Gains were more frequent than losses, and changes of whole chromosomes more frequent than partial aberrations. Two frequent partial losses were found; at 9p and 12p. The 9 patients with loss at 12p were studied for the deletion of TEL (ETV6) gene and the fusion of TEL and AML1 genes by fluorescent in situ hybridization (FISH). Eight out of the 9 children with loss at 12p harbored the TEL-AML1 translocation and all 9 had the deletion of a nontranslocated TEL allele. All 9 had precursor-B phenotype and L1 morphology, and 8/9 had WBC below 50 x 10(9)/liter. All children were treated according to Nordic ALL protocols, had a good response to treatment based on day 15 bone marrow morphology, and 7 out of the 9 survived in continuous complete remission (median follow-up 74 months). CONCLUSIONS: CGH is a valuable tool in screening for genetic aberrations in childhood ALL. DNA copy number losses detected at 12p associate with TEL-AML1 fusion as well as with favorable prognostic features.

Adolescent↗
PubMed2001

Comparative genomic hybridization reveals changes in DNA-copy number in poor-risk neuroblastoma.

Aggressive neuroblastoma remains a therapeutic challenge, and additional understanding of its biology is of paramount importance. Changes in DNA-copy number were analysed in the neuroblastoma cells of 27 patients using comparative genomic hybridization (CGH). Eighteen of the patients had a poor risk disease (16/18 stage IV) and 9 had a non-poor-risk disease (3/9 stage I-II, 2/9 stage III, and 4/9 stage IVS). Changes in DNA-copy number were detected in 72% of the poor-risk and 22% of the non-poor-risk tumors with gains of chromosomal material being more prevalent than losses. Gains were most common in chromosomes 2, 7, and 17 and losses in chromosome 11. Changes in DNA-copy number were multiple in all but one of the patients with poor-risk disease. The applicability of CGH in studies on the genomic changes in pediatric malignancies is demonstrated by our data also adding weight to the argument of multiple elements with oncogenic and/or tumor suppressor potential being involved in the aggressive phenotype of poor-risk neuroblastoma.

Aneuploidy↗
PubMed2001

Poor yield of dendritic cell precursors from untreated pediatric cancer.

We have studied the generation of dendritic cells (DC) in vitro from healthy children and children with newly diagnosed cancer. Peripheral blood derived adherent cells were harvested and cultured in the presence of granulocyte-macrophage colony-stimulating-factor (GM-CSF) and interleukin-4 (IL-4). Differentiated DC were characterized morphologically and analyzed by flow cytometry and allogenic mixed lymphocyte reaction (MLR). The numbers of adherent cells were two-fold higher in healthy children than in those with malignant tumors: 1.5 x 10(5)/ml of blood (mean) versus 0.7 x 10(5)/ml, respectively (p = 0.025). No significant differences were found in the cell survival or yield after the in vitro cultivation of adherent cells. Cytological examination of cultured cells showed that they were similar to DC in adults, being large, irregularly shaped, with several thin membrane protrusions, and bean-shaped nuclei. Differentiated DC from healthy controls expressed CD86 and HLA-DR, but did not express monocyte markers CD14 and CD64 (FcgammaRI). The phenotype of DC from cancer patients was otherwise similar, except that a substantial proportion (24-85%) continued to express CD64 (p = 0.001). DC derived both from cancer patients and controls were strong stimulators in allogeneic MLR. We conclude that functionally capable DC can be generated in vitro from blood-derived adherent cells in children, but children with untreated cancer yield lower numbers of DC than healthy children. The continued expression of CD64 on DC derived from cancer patients may indicate that adherent cells from cancer patients are more resistant to signals inducing differentiation into DC.

Adolescent↗
PubMed2000

Granulocyte-macrophage colony-stimulating factor support in therapy of high-risk acute lymphoblastic leukemia in children.

BACKGROUND: Our purpose was to increase the dose intensity of chemotherapy and reduce the days with neutropenic fever in childhood high-risk (HR) acute lymphoblastic leukemia (ALL) by systematic use of granulocyte-macrophage colony-stimulating factor (GM-CSF). PROCEDURE: All children with HR-ALL in Finland during 1990-1996 were included. Two open-label study groups were formed: 1) 34 children diagnosed between January, 1992, and December, 1996, received seven or nine courses (depending on cranial RT or no cranial RT) of GM-CSF at 5 microg/kg s.c. daily until an absolute neutrophil count (ANC) of 1,000 x 10(6)/liter at scheduled places in the protocol and 2) 80 control children, those diagnosed between January, 1990, and December, 1991, plus all with significant coexpression of myeloid markers, did not receive GM-CSF. RESULTS: Dose intensity increased in patients who received regular GM-CSF support. The intensive phase of therapy, including induction, consolidation courses, and delayed intensification, was 33 days shorter (P < 0.001) in children with seven courses and 26 days shorter (P < 0.01) in those with nine courses of GM-CSF compared to controls. The number of infections during the whole ALL therapy was reduced by use of GM-CSF in children aged >5 years (P < 0.001), but not in those aged <5 years. The mean total duration of intravenous antibiotics per child was 39 days in the GM-CSF group and 48 days in the control group (P < 0. 001). Systematic use of GM-CSF was cost-effective. CONCLUSIONS: Systematic use of GM-CSF improved dose intensity by shortening the intensive treatment period by about 4 weeks. Use of GM-CSF reduced the days for inpatient antibiotics by about 1 week per child, which translates into reduced costs.

Age Factors↗
PubMed2000

T cell-depleted unrelated donor bone marrow transplantation for acute myeloid leukemia.

The outcome for 39 patients with acute myeloid leukemia (AML) in remission who had CAMPATH 1M T cell-depleted unrelated donor bone marrow transplantations (BMTs) is described. Conditioning was mainly with cyclophosphamide (120 mg/kg) and total body irradiation (TBI) (14.4 Gy), but 5 patients received busulfan in place of TBI and 200 mg/kg cyclophosphamide. All patients received cyclosporin, and short-course methotrexate was given to recipients of mismatched grafts. The patient population was predominantly pediatric (median age, 10 years), but one third of the patients was aged 15 years or above. Twenty-five patients were in second complete remission (CR2), and 14 had high-risk CR1 disease (primarily failed remission induction or antecedent myelodysplastic syndrome, often with complex cytogenetic abnormalities). Both recipient and donor were cytomegalovirus seronegative in 15 of 37 cases (38%); 51% of patients were matched for HLA class I and II. Grade II to IV acute graft-versus-host disease (GVHD) occurred in 24% of patients; chronic GVHD occurred in 5 of 31 evaluable patients (16%), 4 extensive and 1 limited. Relapse occurred in 5 cases (13%); 1 of these 5 patients survives, 24 months after a second unrelated donor transplantation. Two of these relapses were associated with secondary graft failure (incidence rate, 5%). All patients engrafted primarily. Severe viral infection was the major transplant-associated complication, with 12 episodes in 9 patients, 5 of them lethal. Twenty-five patients survive at a median follow-up of 44 months (range, 2-102 months), with estimated actuarial overall and disease-free survival rates at 44 months of 61% (SE 8%) and 57% (SE 8%), respectively. Nineteen patients are more than 2 years post-BMT and may be cured. The functional status of long-term survivors is excellent, with 19 of 21 patients who survive 6 months or more in full-time employment or full-time students. These encouraging results suggest that in patients lacking a sibling donor, unrelated donor BMT for AML in remission achieves survival figures as good as or better than those reported on patients with autologous stem cell transplantation, and that T-cell depletion of grafts is associated with a low relapse rate and an excellent functional status. However, only a randomized study comparing unrelated donor BMT and auto-grafting will resolve which of these treatment strategies is better for patients with AML.

Acute Disease↗
PubMed2000

Allograft with unrelated donor accentuates the gastrointestinal toxicity associated with high-dose melphalan and total body irradiation preparative for bone marrow transplantation in children.

The use of high-dose melphalan (L-phenyalalanine mustard or L-PAM) has been shown to be associated with both hematological and non-hematological toxicity. It has been employed in the conditioning for allogeneic stem cell transplants from related donors but experience on its use in the unrelated setting has not been reported. As an attempt to elucidate the role of high-dose L-PAM (210 mg/m2) and total body irradiation (TBI) as a preparative regimen for allogeneic marrow transplantation from matched unrelated donors, they were employed in an institutional pilot series of seven pediatric patients. When compared with recipients of unrelated marrow grafts conditioned using other regimens, those treated with high-dose L-PAM experienced a markedly more severe acute graft-vs.-host disease (GvHD). The overall incidence of grade III-IV acute GvHD was higher (86% vs. 14%) among those treated with L-PAM. As judged by gastrointestinal (GI) symptoms, clinically significant (stages +2 to +4) gut GvHD was strikingly more prevalent among those treated with L-PAM (86% vs. 9%, p < 0.005). Toxic mortality prior to day + 100 was 29% in the L-PAM group and 9% in the non-L-PAM group of patients. With a mean follow-up of 21 months no increase in the incidence of chronic GvHD has been encountered among those conditioned with L-PAM. We conclude that the use of preparative L-PAM for allogeneic transplants from unrelated donors is associated with considerable procedure-related toxicity. We strongly suggest its use in this setting to be viewed with caution.

Antineoplastic Agents, Alkylating↗
PubMed2000

Pediatric marrow transplantation for acute leukemia using unrelated donors and T-replete or -depleted grafts: a case-matched analysis.

A retrospective, case-matched analysis of the short-term toxicity, risk of GVHD and relapse as well as outcome in pediatric unrelated marrow transplantation was conducted by comparing recipients of T-replete and -depleted grafts in a two-center setting. Both groups contained 30 patients with acute leukemia matched by age at transplant, gender, primary diagnosis and disease status. Acute (90% vs 53%) and chronic (48% vs 0%) GVHD were more common among recipients of T-replete grafts. No significant differences in graft rejection/failure or viral infections were encountered between the two groups. Relapses were more prevalent (37% vs 15%) among recipients of T-depleted grafts. Outcome (EFS) was similar in the two groups. Consequently, in the analysis of transplant outcome, the higher risk of procedure-related, toxic complications among pediatric recipients of T-replete marrow grafts appears to be balanced by an increased risk of relapse among the recipients of T-depleted grafts.

Acute Disease↗
PubMed2000

Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years.

Invasive fungal infections (IFI) with substantial mortality constitute an increasing problem among BMT patients. From 1986 to 1996 148 children underwent BMT, and are included in a retrospective analysis of the incidence, risk factors and outcome of IFI. By histopathology or culture-proven IFI (Candida, 10; Aspergillus, 8) was documented in 12/73 (16%) allogeneic and in 6/75 (8%) autologous BMT patients. Of these 18 patients, 15 subsequently died, and in 12 (66%) IFI was regarded as the main cause of death. In addition to the patients with documented IFI, 48 had suspected and 82 no fungal infection. Invasive candidal infections were more frequent in patients with semiquantitatively estimated abundant candidal colonization as compared with those with no colonization (18% vs 3%, P = 0.015). In the allogeneic group, 50% of those with severe (grades III-IV) aGVHD had IFI as opposed to 8% of those with no or mild aGVHD (P < 0.001). Regarding cGVHD, 57% of those with extensive cGVHD vs 5% of those with absent or limited cGVHD had IFI (P < 0.001). The dose of steroids was associated with IFI: 77% of those who received high-dose steroids (methylprednisolone 0.25-1 g/day for 5 days) vs 5% of those with conventional-dose (prednisone 2 mg/kg/day) had IFI (P < 0.001). Particularly for BMT patients at risk, new, quicker and better diagnostic tests and more effective anti-fungal agents, both for prophylaxis and treatment, are needed.

Acute Disease↗