Stem cell transplantation (SCT) has established itself as a very successful therapy in often otherwise unbeatable disorders. In a subset of children and adolescents there are, however, late effects, ...often as a combination of the underlying disorder, its primary treatment and subsequent SCT. In children and adolescents, disorders of growth and the endocrine system have been observed to occur frequently. The assurance of normal growth, puberty, fertility and thyroid function--including the prevention of secondary malignancies--is of utmost importance for the overall success of treatment and the maintenance of quality of life. This, however, requires a systematic and structured follow-up programme for patients after SCT. Patients and their families need to be made familiar with this concept early and physicians need to understand that such a system must be implemented as part of a comprehensive care.
Inhalant tobramycin is established in the treatment of cystic fibrosis patients. Conventional nebulizers require a large amount of the expensive compound, because only a small fraction is deposited ...in the targeted lung region. In contrast, techniques based on controlled inhalation allow a high and reproducible deposition of the drug in specific lung regions. In our study we compared the efficiency of two techniques based on conventional and controlled inhalation in 16 cystic fibrosis patients aged 13-39 years. Inhalations with the doses of tobramycin of 300 mg and 150 mg were performed twice daily for three days. The efficiency of the drug deposition was measured by the determination of its serum concentration 1 h after the end of the inhalation. The mean FEV1 value in our patients was 61% of predicted, range 36%-116%. There were no differences in tobramycin serum concentrations among the three study days in both methods (controlled inhalation: 0.983 +/-0.381(+/-SD) mg/l, 1.119+/-0.448 mg/l, 1.194+/-0.568 mg/l; conventional inhalation: 1.075+/-0.798 mg/l, 1.294 0.839 mg/l and 1.269+/-0.767 mg/l, on Day 1, Day 2, and Day 3, respectively). Even though the drug amount was double in the conventional technique, there was no significant difference in its overall serum concentration from the three study days (conventional inhalation: 1.210+/-0.783 mg/l, controlled inhalation: 1.092+/-0.461 mg/l). In addition, the coefficient of variation and the required inhalation time were shorter in controlled inhalation than in conventional inhalation (42% vs. 65% and 7-8 min vs. 20 min, respectively). Our data suggest that controlled inhalation can significantly reduce the amount of a drug required for therapy, the inhalation time required for drug deposition, and the variability of pulmonary dosage. It seems probable that controlled inhalation can improve the antibiotic prevention of pulmonary infection.
9 patients with stage IV neuroblastoma were treated with 19 courses of human/mouse chimeric monoclonal antiganglioside GD2 antibody ch14.18 at dose levels of 30,40 and 50 mg/m
2/day for 5 days per ...course. The maximum tolerated dose (MTD) per injection was 50 mg/m
2/day. 7 patients received more than one course of treatment, and none revealed any human anti-mouse antibody (HAMA) response. Clinical side-effects of patients treated with chi4.18 were abdominal and joint pains, pruritus and urticaria. One patient presented with a transient pupillatonia, while 2 others showed a unilateral atrophy of the optical nerve that was probably attributable to prior therapies. A complete remission was seen in 2 patients, partial remission in 2 patients, a minor response in 1 patient and stable disease in 1 patient. 3 patients showed tumour progression. Thus, our results indicate that treatment with chimeric: MAb ch14.18 can elicit some complete and partial tumour responses in neuroblastoma patients.
To prove prospectively the efficacy of a short-pulse chemotherapy for treatment of Ki-1 anaplastic large-cell lymphoma (ALCL) of childhood.
From October 1983 to December 1992, 62 patients (median ...age, 9.7 years) with newly diagnosed Ki-1 ALCL were enrolled onto Non-Hodgkin's Lymphoma-Berlin-Frankfurt-Munster (NHL-BFM) studies 83, 86, and 90. The most frequent immunophenotype was T cell. Ki-1 ALCL differed from other subsets of NHL of childhood by the more frequent involvement of bone, soft tissue, and skin, and by the lack of bone marrow (BM) disease. A 5-day prephase course (prednisone/cyclophosphamide) was followed by two different 5-day courses of chemotherapy: course A consisted of dexamethasone, methotrexate (MTX) 0.5 g/m2 (24-hour infusion), intrathecal chemotherapy, ifosfamide, cytarabine (Ara-C), and etoposide (VP-16); course B consisted of cyclophosphamide and doxorubicin instead of ifosfamide, and Ara-C/VP-16, respectively. Treatment was stratified into three branches. Branch 1 (stage I and stage II resected) received three courses; branch 2 (stage II not resected, stage III), six courses; and branch 3 (stage IV), six intensified courses containing MTX 5 g/m2, and Ara-C 2 g/m2. Local radiotherapy was not performed.
Four patients failed to enter remission, and one died of infection. Seven patients relapsed within 9 months after diagnosis; two patients had isolated local relapses, but BM and CNS were never involved. Fifty patients have been in first continuous complete remission (CR) for 0.6 to 9.7 years (median, 2.5), and 56 are alive. The probabilities for survival and event-free survival (EFS) at 9 years are 83% +/- 7% (SE) and 81% +/- 5%. Skin involvement was the only negative prognostic parameter.
Short-pulse chemotherapy over 2 to 5 months without local therapy modalities is effective in the treatment of Ki-1 ALCL.
Zusammenfassung
Onkologische und hämatologische Erkrankungen im Kindesalter betreffen nicht nur den Patienten, sondern haben auf das gesamte familiäre System weit reichende Einflüsse. Deshalb ist die ...Behandlung der Erkrankung mit der Akuttherapie nicht abgeschlossen. Eine Rehabilitation der Gesamtfamilie im Rahmen einer familienorientierten Rehabilitation (FOR) ist integraler Bestandteil des Behandlungskonzepts. Die FOR gibt es als Therapiemaßnahme bisher nur in der Bundesrepublik Deutschland. Sie wird in wenigen dafür spezialisierten Kliniken durchgeführt und von den Kostenträgern Rentenversicherung und Krankenversicherung für onkologische Erkrankungen, Mukoviszidose und kardiologische Erkrankungen im Kindesalter akzeptiert und für die gesamte Familie finanziert.
In a series of 60 ALL samples drawn during different stages of the disease we used a cDNA-PCR approach to analyse the relative mRNA levels of the MDR-associated genes encoding mdr1/P-glycoprotein, ...mrp, and the topoisomerase II isozymes alpha and beta. Expression analysis of the cyclin A gene was included to examine cellular proliferation activity. The expression of gapdh served as an internal standard. Calculating the mean values we found: (i) a distinctly lower mdr1 gene expression in primary ALL and first relapses compared to bone marrow from healthy donors, (ii) no change in mdr1 and mrp, but a decreased topoisomerase II alpha gene expression in first relapses of ALL compared to the primary leukaemia, and (iii) increased mdr1 and mrp levels combined to decreased topoisomerase II alpha levels in recurrent relapses of ALL showing significant correlations (mdr1/mrp: rs = +0.6833, P < 0.05; mdr1/topoII alpha: rs = -0.6727, P < 0.05). The expression of the topoisomerase II alpha gene was correlated to that of cyclin A, indicating a link of its expression to cellular proliferation. Our findings suggest that a multifactorial MDR including mrp appears particularly in recurrent relapses of ALL, which often do not respond to chemotherapy. Nonetheless, some individual samples showed gene expression levels very different from the mean values calculated for a particular state of the leukaemia, indicating the need of an individual expression analysis of MDR-associated genes.
To investigate the prevalence and potential risk factors of obesity after therapy for childhood acute lymphoblastic leukemia (ALL).
39 ALL patients (age 10.7-20.5 years) who were in first remission ...for 3.4-14.6 years after standardized treatment with chemotherapy plus cranial irradiation (n = 25) or with chemotherapy alone (n = 14) were examined. After fasting overnight, the following parameters were investigated: body mass index (BMI) of patients and their parents; patients' BMI before ALL therapy; serum free thyroxin, growth hormone-dependent factors, estradiol, testosterone, cortisol, leptin and c-peptide; fat-free mass (bioelectrical impedance); resting metabolic rate (RMR, indirect calorimetry); caloric intake (24-hour recall); and physical activity (questionnaire). RMR data were applied to the fat-free mass and compared with 83 controls.
The prevalence of obesity (criterion: BMI > 2 SDS) was significantly (p < 0.05) higher after ALL therapy (38%; irradiated patients 48%, non-irradiated patients 21%) than before therapy (3%). Compared to non-irradiated patients, irradiated patients had significantly lower RMRs (-1.07 +/- 0.24 vs. -0.32 +/- 0.21 SDS; p < 0.05), reduced physical activity levels (1.41 +/- 0.03 vs. 1.52 +/- 0.03; p < 0.05), and lower concentrations of insulin-like growth factor-binding protein-3 (-0.65 +/- 0.17 vs. 0.25 +/- 0.33 SDS; p < 0.05) and of free thyroxin (1.17 +/- 0.06 vs. 1.38 +/- 0.08 ng/dl; p < 0.05). Caloric intake was adequate.
After ALL during childhood, patients face a higher risk of obesity. In the cranially irradiated patients, the likely causes are low physical activity, RMRs and hormonal insufficiency.
Fifty-one children between 26 and 214 months of age (median, 100 months) with acute lymphoblastic leukemia (ALL) were grafted in second remission from HLA-identical sibling donors (except for two ...patients who were grafted with a marrow with 1 antigen-mismatch). Initial treatment and relapse therapy were similar in all patients according to the BFM- and CoALL-protocols (front line: 38 patients according to BFM-protocols and 13 patients according to CoALL-protocols; relapse: 12 patients in study ALL-REZ-BFM 83, 17 in ALL-REZ-BFM 85, 20 in ALL-REZ-BFM 87, and two in ALL-REZ-BFM 90). The conditioning regimens were different, consisting of cyclophosphamide (CY) total body irradiation (TBI) plus (n = 27), VP-16-TBI (n = 23), and CY-TBI and ARA-C (n = 1). Three patients had a second graft after conditioning with CY-TBI for the first transplantation. The second ablative regimen consisted of CY plus VP-16 in the first patient and CY plus busulfan in the two other patients, one of whom relapsed again. All patients but three had bone marrow (BM), either isolated or combined, relapses. Twenty-nine of the patients are in continuous complete remission (CCR), ranging from 1 to 67 months after transplantation with a median time of 30 months. One patient was lost to follow-up in continuous remission. Nine patients died from treatment-related complications (infections and graft-versus-host disease) and 12 patients suffered a leukemic relapse; three of them received a second graft and two are in CCR. Kaplan-Meier analysis yields an event-free survival (EFS) of 0.52 +/- 0.08. The probability of a 7-year relapse-free interval (RFI) is 0.68 +/- 0.08. EFS for patients with late relapses is 0.47 +/- 0.12 and for patients with early relapses 0.56 +/- 0.1. The RFI for patients with late relapses is 0.65 +/- 0.12 and for patients with early relapses 0.69 +/- 0.11. There is a nonsignificant trend towards superior results for patients grafted after conditioning with VP-16 plus TBI. When all patients who are not in CCR at day +125 (which is the median interval between relapse diagnosis and BM transplantation BMT) are excluded from the chemotherapy results, there is no significant difference between the results of BMT and chemotherapy for late relapses. On the other hand, there is a significant advantage between chemotherapy and BMT for early relapses over chemotherapy (P less than or equal to .01).
For investigation of relative differences in mRNA expression levels and of correlations in the expression of genes possibly involved in multidrug resistance (MDR) of acute myelogenous leukemias ...(AML), a complementary DNA polymerase chain reaction (cDNA-PCR) analysis was established for the genes encoding MDR1/P-glycoprotein, the multidrug resistance-associated protein (MRP), topoisomerase II alpha, topoisomerase II beta, topoisomerase I, glutathione S-transferase pi, protein kinase C (PKC) isozymes alpha, beta 1, beta 2, epsilon, eta, theta and cyclin A. In a first descriptive study comprising samples of childhood or adult AML we calculated the mean values from primary (n=14) or relapsed (n=23) states of the diseases, respectively. We found in the latter significant increases of MDR1, MRP, gst pi, and PKC theta gene expression. MDR1 and MRP gene expression levels were generally correlated (rs= +0.4128, P<0.02, n=37), as well as topoisomerase II alpha and cyclin A gene expression levels (rs= +0.8727, P<0.0001, n=35). Within the group of relapsed state AML a significant negative correlation between the gene expression levels of MDR1 and topoisomerase II alpha (rs= -0.5500, P<0.01, n=22) was observed. Remarkably, highly significant positive correlations were found for MDR1/PKC eta (rs= +0.5560, P<0.001, n=32), MRP/PKC theta (rs= +0.6573, P<0.0001, n=34) and MRP/PKC eta (rs= +0.5241, P<0.005, n=32).
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