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Biomedical subjects

G Lönnerholm

Publications and source records attributed to G Lönnerholm.

At least 19 recordsLinked to original sources
PubMed2005

Cellular drug sensitivity in MLL-rearranged childhood acute leukaemia is correlated to partner genes and cell lineage.

Rearrangements in the 11q23 region, the site of the mixed lineage leukaemia (MLL) gene, are found in both childhood acute myeloid (AML) and lymphoblastic (ALL) leukaemia. We studied the in vitro drug resistance by the fluorometric microculture cytotoxicity assay (FMCA) in 132 children with AML and 178 children with ALL (aged 0-17 years). In AML, children with t(9;11) (n = 10) were significantly more sensitive to cytarabine (P < 0.001) and doxorubicin (P = 0.005) than non-11q23 rearranged patients (n = 108). Children with other 11q23 rearrangements (n = 14) differed less from non-rearranged children. The 'AML-profile' common to all three groups included relative resistance to glucocorticoids and vincristine. In ALL, children with 11q23 rearrangement (n = 22) were significantly more sensitive to cytarabine (P = 0.026) than children without 11q23 rearrangement (n = 156), also after stratification for white blood cell count. In conclusion, the findings indicate that the cellular drug resistance is correlated to both the cell lineage and the type of 11q23 rearrangement. High cellular sensitivity to cytarabine and doxorubicin might explain the excellent treatment results in children with AML and t(9;11). The present study supports the strategy of contemporary protocols to include high-dose cytarabine in the treatment of 11q23-positive patients both in AML and ALL.

Acute Disease↗
PubMed2004

Pubertal development and final height after autologous bone marrow transplantation for acute lymphoblastic leukemia.

We describe pubertal development and growth in 17 children who underwent bone marrow transplantation (BMT), including total body irradiation (TBI) for ALL. Seven children also received cranial irradiation (CI) and five boys testicular irradiation. All underwent transplantation before (n=15) or at the beginning of (n=2) puberty and reached a final height (FH). Puberty started spontaneously in all boys not given testicular irradiation. All boys who received testicular irradiation developed hypergonadotrophic hypogonadism. Puberty started spontaneously in two girls and was induced with increasing doses of ethinylestradiol in two girls. In two girls, a low dose of ethinylestradiol was given until menarche. In one girl with early onset of puberty and short stature, puberty was blocked with a GnRH analogue. The standard deviation score for height decreased significantly from BMT to FH, both in the children who received TBI only (-1.1, P=0.005) as well as in those given additional CI (-1.7, P=0.027). Most of the loss occurred during puberty. In all, 10 children received growth hormone (GH) treatment. CI, young age at BMT, and short duration of GH treatment were predictors of height loss after BMT. Although limited by the small and heterogeneous sample, our study supports the use of early GH treatment in children with decelerating growth rate and low GH levels.

Adolescent↗
PubMed2004

Pulmonary function after autologous bone marrow transplantation in children: a long-term prospective study.

We performed serial pulmonary function tests (PFTs) consisting of spirometry and diffusing capacity in 26 children after BMT. The median follow-up was 10 years. The influence of total body irradiation (TBI) on long-term pulmonary function was of particular interest. In the 20 children who had received TBI, after an initial decrease the PFTs showed recovery, but the mean lung volumes were still significantly decreased 5 years after BMT at 10% below baseline. The proportions of children with restrictive impairment 5 and 10 years after BMT were 20 and 21%, respectively. Only one child was diagnosed with obstructive impairment. The proportions of children with isolated diffusing impairment at 5 and 10 years were 7/20 (35%) and 7/13 (54%), respectively. Six children had received chemotherapy only and showed isolated diffusing impairment as the only long-term sequela in 4/5 and 1/3 at 5 and 10 years. Our main finding was that there was little change in PFTs 1-10 years after BMT. TBI was associated with persistently decreased lung volumes in a proportion of patients, whereas chemotherapy also might have been of importance for the development of impaired gas exchange.

Adolescent↗
PubMed2003

High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL).

PURPOSE: The objectives of the present study were to determine the relationship between methotrexate (MTX) elimination time and various aspects of renal function and to evaluate the prognostic value of elevated serum MTX and creatinine for delayed MTX elimination. PATIENTS AND METHODS: The majority of the 264 children were being treated for ALL. According to the NOPHO-92 protocol, 5 or 8 g MTX/m(2) was administered over 24 h. Serum creatinine was assessed daily. In 11 patients from one centre, renal function was studied in more detail using serum cystatin C, iohexol clearance, and urinary albumin, IgG and protein HC. RESULTS: Increased serum creatinine correlated significantly with the elimination time of MTX, whereas no indications were found of tubular or barrier function damage. Of the 1164 courses, 44 had delayed elimination of MTX (>/=120 h). Serum MTX >150 microM at the end of infusion had a sensitivity of 0.27 and a specificity of 0.94 to predict delayed MTX elimination, and >/=50% increase in serum creatinine during the first treatment day (creatinine ratio) had a sensitivity of 0.32 and a specificity of 0.99. The corresponding risk ratios were 5 and 19 for MTX >150 micro M and creatinine ratio, respectively. In courses with a normal elimination time (<72 h), 99% of the courses had a rise in serum creatinine of less than 50%. CONCLUSIONS: Elevation of serum creatinine by more than 50% is a better predictor of delayed elimination than the level of serum MTX at the end of MTX infusion, especially if information on previous creatinine measurements is used to reduce the impact of an occasionally low serum creatinine value before the start of the MTX infusion.

Adolescent↗
PubMed2003

Vincristine in childhood leukaemia: no pharmacokinetic rationale for dose reduction in adolescents.

AIM: To investigate whether there is any pharmacokinetic rationale for the common practice of administering vincristine to adolescents at relatively lower doses than those to younger children. METHODS: A total of 98 children, aged 1.3-17.3 y, with acute lymphoblastic leukaemia (ALL) were studied on day 1 of induction therapy. Plasma samples were drawn before and 10, 30, 360 and 1380 min after injection of vincristine 2.0 mg/m2 (maximum dose 2.0 mg) and analysed by high-performance liquid chromatography. RESULTS: The median value (and range) for distribution half-life was 6.4 min (0.8-11.8), elimination half-life 1014 min (258-2570), volume of distribution 445 L/m2 (137-1241) and total body clearance 362 ml/min/m2 (134-2553). No correlation was found between age and any of these pharmacokinetic parameters. The area under the concentration time curve (AUC) was significantly correlated to age (p = 0.002; p - 0.31), as expected from the dosage of vincristine. The lower AUC in children with a body surface area > 1 m2, which is reached at 8-9 y of age, indicates that they received a less intense treatment because of the capping of the vincristine dose at 2.0 mg. CONCLUSIONS: Vincristine pharmacokinetics were not age dependent in this paediatric population. Thus, we found no pharmacokinetic rationale for dose reduction in adolescents. The common practice of limiting the vincristine dose to 2.0 mg should be carefully reconsidered.

Adolescent↗
PubMed2002

Pharmacokinetics of doxorubicin in children with acute lymphoblastic leukemia: multi-institutional collaborative study.

BACKGROUND: In adults, it has been shown that the pharmacokinetics of doxorubicin are highly variable, despite standardization of the dose based on body surface area (BSA). The purpose of this study was to determine the plasma concentrations of doxorubicin and its active metabolite doxorubicinol in children treated for acute lymphoblastic leukemia (ALL). PROCEDURE: Children, 107 in number, aged 1.3-17.3 years, were studied at Day 1 of induction therapy according to the current Nordic protocol. Five infants, 3-9 months old, were also included. Plasma samples were drawn 23 hr after the start of a 24-hr infusion of doxorubicin 40 mg/m(2), and analyzed by reversed-phase liquid chromatography. RESULTS: There was a more than 10-fold difference between patients in dose normalized plasma concentration of doxorubicin, median 62.8 ng/ml, range 22.6-334 ng/ml. The doxorubicin concentrations differed significantly between age groups (P = 0.003). Children aged 4-6 years had the highest doxorubicin concentrations, median 77.9 ng/ml, followed by 2-4-year-old children, median 64.3 ng/ml. Both younger and older children had median values of about 50 ng/ml. Patients with white blood cell (WBC) count > 50 x 10(9)/L at diagnosis had significantly lower doxorubicin concentrations, median 55.3 ng/ml, than those with WBC count < 10 x 10(9)/L, median 64.4 ng/ml (P = 0.015). There was no difference in doxorubicin concentration between boys and girls. No correlation was found between doxorubicin levels and serum aminotransferases or serum creatinine. The concentration of doxorubicinol was 13% (median value) of that of doxorubicin. Four infants, 7-9 months old, had plasma clearance between 350-431 ml/min/m(2), which is in the same range as in older children. A 3-month-old infant had a clearance of 181 ml/min/m(2). CONCLUSIONS: The age groups who had the highest doxorubicin concentrations, (2-) 4-6-year-old children, are known to make up a large proportion of standard risk ALL cases with good prognosis. The correlation between doxorubicin plasma levels and clinical effect needs further study. The influence of age, body composition, and tumor burden on the pharmacokinetics of antineoplastic drugs should also be further explored, aiming at improvements in the current dosing regimen based on BSA.

Adolescent↗
PubMed2002

Renal function after autologous bone marrow transplantation in children: a long-term prospective study.

We measured glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and the concentrating capacity of the kidneys in children after autologous BMT. Twenty-six patients had received TBI in their conditioning regimen and 14 patients had received chemotherapy only. Median follow-up was 10 years. Mean GFR before BMT was close to normal in both groups. Mean GFR decreased from 124 [CI 114,134] ml/min/1.73 m(2) before BMT to 99 [CI 82,115] ml/min/1.73 m(2) 6 months after BMT in the + TBI group (P < 0.001). There was no significant change in the -TBI group. Mean ERPF before BMT was high: 1110 [95% CI 830,1390] ml/min/1.73 m(2) in the + TBI group and 910 [CI 570,1250] ml/min/1.73 m(2) in the - TBI group. Six months after BMT, there was a tendency to a decrease in ERPF in the +TBI group, to 760 [CI 580,940] ml/min/1.73 m(2) (P = 0.064). After this initial decrease, GFR and ERPF remained essentially unchanged in both groups. The mean concentrating capacity of the kidneys was normal before and after BMT. In seven patients chronic renal impairment developed after BMT (GFR <70 ml/min/1.73 m(2)). All had received TBI. They had also received more nephrotoxic antibiotics than the other patients. We conclude that TBI was the principal cause of deterioration of renal function after BMT, possibly by limiting compensatory hyperperfusion and resulting in a fall in GFR. Antibiotic treatment may have contributed.

Acute Kidney Injury↗
PubMed2002

In vitro activity of the novel cytotoxic agent CHS 828 in childhood acute leukemia.

CHS 828, a pyridyl cyanoguanidine, is a new drug candidate now in phase I/II trials, that has shown promising anticancer activity in experimental tumor models and primary cultures of cancer cells from patients. In this study the fluorometric microculture cytotoxicity assay was used for evaluation of CHS 828 in primary cell cultures from children with acute leukemia. The activity of and interaction with the standard drugs, doxorubicin, melphalan, etoposide and cytosine arabinoside (Ara-C), were also assessed. Samples from 65 patients, 42 with acute lymphocytic leukemia (ALL) and 23 with acute myelocytic leukemia (AML) were tested with 72-h continuous drug exposure. There was 50% cell kill at very low CHS 828 concentrations; median IC50 was 0.01 microM in ALL and 0.03 in AML samples (NS) with large interindividual variability in both groups. ALL samples were significantly more sensitive than AML samples to melphalan, doxorubicin and etoposide, but not to Ara-C. In AML samples, combinations between CHS 828 and each of the four standard drugs resulted in significantly lower cell survival than either drug alone. This was also observed in ALL samples, except for Ara-C. Using the additive interaction model, CHS 828 showed a synergistic effect with melphalan in 67%, doxorubicin in 47%, etoposide in 38% and Ara-C in 14% of AML samples. In most ALL samples subadditive effects were found. Further exploration of CHS 828 in childhood leukemia is warranted, especially in AML.

Acute Disease↗
PubMed2001

No disadvantage in outcome of using matched unrelated donors as compared with matched sibling donors for bone marrow transplantation in children with acute lymphoblastic leukemia in second remission.

PURPOSE: We evaluated the outcome of children with acute lymphoblastic leukemia (ALL) in second remission (2CR), comparing bone marrow transplantation (BMT) using either matched sibling donors or unrelated donors (URDs). PATIENTS AND METHODS: A total of 65 patients, aged 2 months to 20 years at BMT, with ALL in 2CR underwent allogeneic BMT at seven Nordic centers during 1990 to 1997. Of the first relapses, 85% were in bone marrow; 46% occurred on therapy, and 54%, off therapy. The preparative regimens were cyclophosphamide plus total-body irradiation +/- antithymocyte/antilymphocyte globulin, busulfan plus cyclophosphamide +/- antithymocyte/antilymphocyte globulin, or cytarabine plus total-body irradiation. Of the allografts, 37 were from HLA-matched siblings and 28 were from URDs. RESULTS: In the sibling versus URD graft recipient groups, the posttransplantation 5-year event-free survival was 39% versus 54% (P =.4), the estimated posttransplantation relapse rate was 76% versus 40% (P = not significant [NS]), and the toxic death rate was 19% versus 11% (P = NS). The incidence of significant (grade 2 to 4) acute graft-versus-host disease (GVHD) was 38% versus 64% (P <.05) and was 14% versus 32% (P <.10) for severe (grade 3 to 4) acute GVHD; the incidence of chronic GVHD was 26% versus 57% (P <.05) and was 13% versus 22% (P = NS) for extensive chronic GVHD in the sibling and URD groups. CONCLUSION: BMT with matched URD allografts offers at least equal survival for children with ALL in 2CR, as compared with allografts from matched sibling donors. URD allografts were not associated with a higher toxic mortality rate, although both acute and chronic GVHD were more frequent with URD. Indications for using matched URD allografts in ALL 2CR can be considered the same as for using matched sibling donors.

Adolescent↗
PubMed2001

Androgen-linked control of carbonic anhydrase III expression occurs in rat perivenous hepatocytes; an immunocytochemical study.

Carbonic anhydrase (CA) isozymes CAII and CAIII were assayed by a radioimmunosorbent technique in liver cytosolic fractions and in isolated hepatocytes of adult male and female rats. Male livers contained 0.16 mg of CAII and 57 mg of CAIII per g cytosolic protein. Corresponding values for female livers were 0.34 mg CAII and 4 mg CAIII. Similar values and differences between CAII and III were found in isolated hepatocytes. Neonatal and adult castration of males reduced the CAIII levels to those of the females. Treatment with testosterone for three weeks restored the copulatory behaviour in the males castrated at adult age, but restored only partially the levels of CAIII. No significant effects of the endocrine manipulations were seen on CAII. Oophorectomy, with or without testosterone substitution, had no significant effect on CAII and CAIII levels in female rats. Immunohistochemistry and histochemistry showed that the regulation of CAIII is confined to perivenous hepatocytes. CAIII can therefore serve as a useful marker in the separation of these cells. CAIII appears to belong to the proteins and enzymes of the rat liver, known to be regulated via the hypothalamo-pituitary-liver axis. It may be used as a model of gene regulation in perivenous hepatocytes.

Androgens↗
PubMed2000

Prepubertal growth and growth hormone secretion in children after treatment for hematological malignancies, including autologous bone marrow transplantation.

Prepubertal growth standards were used to assess growth in 20 children who had undergone autologous bone marrow transplantation (ABMT) as part of their treatment for hematological malignancy. Most of the patients (16 of 20) were transplanted after a relapse of their disease. A negative change in height standard deviation score (H-SDS) was seen only in the group of patients (n = 7) who had received both cranial irradiation therapy (CRT) and 7.5-Gy single-fraction total body irradiation (TBI). Height changes in this group were observed from the time of diagnosis. In contrast, the groups of patients conditioned with chemotherapy only (n = 3) or both chemotherapy and TBI, without preceding CRT (n = 10), did not demonstrate a significant loss in H-SDS. Weight related to height demonstrated large individual differences over time. Spontaneous growth hormone (GH) secretion, as measured by a four-point sleep curve, was followed longitudinally and an increasing proportion of patients with low peak levels was seen in all patient groups. In summary, prepubertal growth was suppressed only in patients who received cranial irradiation before ABMT. Despite low GH peak levels, normal prepubertal growth was found in patients with no CRT before ABMT.

Adolescent↗
PubMed2000

Cataracts after autologous bone marrow transplantation in children.

We recorded the incidence and degree of posterior subcapsular cataract (PSC) in 29 children who had undergone autologous (n = 28) or syngeneic (n = 1) bone marrow transplantation (BMT) due to haematologic or lymphoid malignancy. Conditioning prior to transplantation consisted either of a combination of chemotherapy and total body irradiation (TBI) (n = 21) or of chemotherapy only (n = 8). TBI was given in one fraction of 7.5 Gy. Nine patients had received previous cranial irradiation. The patients were followed for 4-10y (median 8 y) after transplantation. Of 29 patients, 22 developed PSC, all within 4 y after BMT. With the exception of one patient who developed unilateral PSC, all had received TBI. Conversely, 100% of those who received TBI developed PSC. In this group (+TBI), eight patients (38%) developed significant PSC, defined as best corrected visual acuity <0.8 in either eye. Six patients (10 eyes) have since needed surgical repair consisting of extracapsular cataract extraction and intraocular lens implantation. There was no clear relationship between previous cranial irradiation and cataract development, nor any other obvious baseline differences between those in the +TBI group who developed significant PSC and those who did not. Although effects of previous therapy cannot be ruled out, TBI appears to be the main cause of PSC in this group of patients. Twelve patients in the +TBI group had well-preserved visual acuity throughout the study, reflecting a slow progression of PSC. This compares favourably with previous reports of allogeneic BMT, possibly owing to less need for corticosteroids after autologous BMT. We conclude that the incidence of PSC was high after autologous BMT where the conditioning regimen included total body irradiation.

Adolescent↗
PubMed1999

[Umbilical cord blood from unrelated donor. An alternative to bone marrow transplantation].

Unrelated umbilical cord blood (UCB) as a source of haematopoietic stem/progenitor cells has been used for the first time in Sweden for allografting two boys (6 and 11 1/2 years old) with acute leukaemia in complete remission. Double class-II HLA-mismatch UCB units, from the Milan and New York cord blood banks, respectively, were used. Pre-transplant preparation consisted in fractionated total body irradiation in both cases, followed by cytoreductive high-dose cyclophosphamide for the 6-year-old with acute lymphocytic leukaemia (ALL) and fludarabine-melphalan for the 11 1/2-year-old with acute non-lymphocytic leukaemia (ANLL). Despite delayed haematopoietic recovery (probably due to HLA disparity) or reactivated cytomegalovirus infection in one boy, the immediate post-graft course was uneventful and extramedullary toxicity mild in both cases. Only transient acute graft-versus-host disease occurred, and complete donor chimerism was confirmed. Unfortunately, the out-come was unfavourable in both cases, the ANLL patient succumbing on day 96 due to pneumonia followed by multiorgan failure, and the ALL patient on day 140 due to combined medullar and central nervous system relapse. Although UCB transplantation needs further evaluation, it may contribute substantially to successful salvage procedures. Thus the introduction of cord blood banking in Sweden merits consideration.

Blood Banks↗
PubMed1999

Is in vitro sensitivity of blast cells correlated to therapeutic effect in childhood acute lymphoblastic leukemia?

Our aim is to study whether or not in vitro sensitivity of leukemic cells correlates with clinical effect; if so, in vitro testing might used for stratification of treatment. During 1995-1997 bone marrow samples from 145 Swedish children with newly diagnosed acute lymphoblastic leukemia were analysed by the automated fluorometric microculture cytotoxicity assay. Therapeutic effect was evaluated by bone marrow morphology day 15 and 29. Preliminary results indicate that marrow samples from patients with poor response to induction therapy show a higher degree of in vitro resistance to several cytotoxic drugs at diagnosis than good responders.

Antineoplastic Agents↗
PubMed1999

In vitro cytotoxic drug activity and in vivo pharmacokinetics in childhood acute myeloid leukemia.

Since May 1996 all Nordic countries have been participating in a study of childhood acute myeloid leukemia (AML). The aim is to correlate the in vitro sensitivity of leukemic cells and individual plasma concentrations of cytotoxic drugs with clinical effect. Blast cells from bone marrow and/or peripheral blood are tested against a panel of cytotoxic agents using the fluorometric microculture cytotoxicity assay (FMCA). Plasma concentrations of cytotoxic drugs are analysed during induction therapy. Bone marrow samples from the participating centres generally reached the analysing laboratory within 24 hours. 61 out of 71 (86%) samples were successfully analysed, 47 de novo AML and 14 relapses. Relapsing patients tended to have a more resistant test profile than newly diagnosed patients. Steady state plasma levels of doxorubicin, etoposide and 6-thioguanine nucleotide varied about 10-fold between patients. The intra-individual variation was much less, suggesting that dose adjustment based on pharmacokinetic data might be useful in the future.

Amsacrine↗