Low-dose chemotherapy with vinblastine and methotrexate in childhood desmoid tumors.
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Adolescent↗
Biomedical subjects
G Henze
Publications and source records attributed to G Henze.
Relationship between major vault protein/lung resistance protein, multidrug resistance-associated protein, P-glycoprotein expression, and drug resistance in childhood leukemia.
Cellular drug resistance is related to a poor prognosis in childhood leukemia, but little is known about the underlying mechanisms. We studied the expression of P-glycoprotein (P-gp), multidrug resistance (MDR)-associated protein (MRP), and major vault protein/lung resistance protein (LRP) in 141 children with acute lymphoblastic leukemia (ALL) and 27 with acute myeloid leukemia (AML) by flow cytometry. The expression was compared between different types of leukemia and was studied in relation with clinical risk indicators and in vitro cytotoxicity of the MDR-related drugs daunorubicin (DNR), vincristine (VCR), and etoposide (VP16) and the non-MDR-related drugs prednisolone (PRD) and L-asparaginase (ASP). In ALL, P-gp, MRP, and LRP expression did not differ between 112 initial and 29 unrelated relapse samples nor between paired initial and relapse samples from 9 patients. In multiple relapse samples, LRP expression was 1.6-fold higher compared with both initial (P = .026) and first relapse samples (P = .050), which was not observed for P-gp and MRP. LRP expression was weakly but significantly related to in vitro resistance to DNR (Spearman's rank correlation coefficient 0.25, P = .016) but not to VCR, VP16, PRD, and ASP. No significant correlations were found between P-gp or MRP expression and in vitro drug resistance. Samples with a marked expression of two or three resistance proteins did not show increased resistance to the tested drugs compared with the remaining samples. The expression of P-gp, MRP, and LRP was not higher in initial ALL patients with prognostically unfavorable immunophenotype, white blood cell count, or age. The expression of P-gp and MRP in 20 initial AML samples did not differ or was even lower compared with 112 initial ALL samples. However, LRP expression was twofold higher in the AML samples (P < .001), which are more resistant to a variety of drugs compared with ALL samples. In conclusion, P-gp and MRP are unlikely to be involved in drug resistance in childhood leukemia. LRP might contribute to drug resistance but only in specific subsets of children with leukemia.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
TEL-AML1 fusion transcript in relapsed childhood acute lymphoblastic leukemia. The Berlin-Frankfurt-Münster Study Group.
The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1-positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph)-positive leukemia. Thus, the incidence of TEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1-positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = . 0001) and age at initial diagnosis (53.5 v 74 months; P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference. TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.
Adolescent↗
Clinicopathologic features of retinoblastoma after primary chemoreduction.
BACKGROUND: Primary chemotherapy is a new treatment approach in retinoblastoma, aiming to avoid radiogenic adverse effects, such as second tumor-associated mortality, as observed following external beam irradiation. OBJECTIVE: To describe the clinical and histopathologic regression pattern after primary chemotherapy in retinoblastoma. METHODS: Five patients with sporadic bilateral retinoblastoma underwent planned enucleation of their functionally blind eye after 2, 3 (in 2 patients), 4, and 6 courses of primary chemotherapy with carboplatin, etoposide, cyclophosphamide, and vincristine. The eyes were examined histopathologically, using light microscopy and immunohistochemical analysis with proliferation markers. RESULTS: One patient had a type 1 (cottage cheese) regression and 4 patients had either a type 2 (fish flesh) or a type 3 (combined) regression pattern. Histopathologic examination revealed a complete tumor necrosis in 1 patient with type 1 regression after 3 courses of chemotherapy and in 1 patient with type 3 regression after 4 courses of chemotherapy. The remaining 3 patients with type 2 or type 3 regression had histologically still active proliferative tumor cells after 2, 3, and 6 courses of chemotherapy. CONCLUSION: This article correlates histopathologically the clinically described efficacy of primary chemotherapy in the treatment of retinoblastoma, underlining, however, the necessity of careful observation and the use of ancillary treatment whenever there is no complete tumor regression.
Antineoplastic Combined Chemotherapy Protocols↗
Immunotherapy of acute lymphoblastic leukemia by vaccination with autologous leukemic cells transfected with a cDNA expression plasmid coding for an allogeneic HLA class I antigen combined with interleukin-2 treatment.
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Adolescent↗
Recommendations on the use of colony-stimulating factors in children: conclusions of a European panel.
UNLABELLED: During 1996 and 1997 a panel of European haematologists, oncologists, and neonatologists developed specific paediatric guidelines for the use of colony stimulating factors based on published literature and the clinical experience of these specialists within each of 13 countries. Well established indications for use comprise intervention in patients with life-threatening infection, adjunctive therapy post autologous bone marrow transplantation (BMT), mobilization of peripheral blood progenitor cells for autologous BMT, patients with acquired aplastic anaemia on anti-lymphocyte globulin and cyclosporin regimen, and severe congenital neutropenia. Less clear indications include primary prophylaxis to support dose intensification in children with high risk/advanced malignancies, secondary prophylaxis to prevent neutropenia in patients with a history of severe neutropenia, support therapy in cases of poor marrow function following BMT and for deteriorating marrow function following successful BMT, in neonatal sepsis and non infectious neonatal neutropenia, in drug induced neutropenia and in HIV-positive patients. Treatment is generally well tolerated and granulocyte colony stimulating factor appears better tolerated than granulocyte and macrophage colony stimulating factor. Economically colony stimulating factors have not been shown to induce excessive costs for a given patient. CONCLUSION: In general the adult guidelines are applicable to children but additional considerations (aggressive or very progressive childhood neoplasms, specific indications, neonatal use, congenital disorders) must be taken into account.
Bone Marrow Transplantation↗
The modulating effect of PSC 833, cyclosporin A, verapamil and genistein on in vitro cytotoxicity and intracellular content of daunorubicin in childhood acute lymphoblastic leukemia.
Resistance to anthracyclines is related to a poor prognosis in childhood acute lymphoblastic leukemia (ALL). Resistance to this class of drugs may (partly) be reversed by modulating agents, as has been demonstrated in a variety of cell lines. However, it is unknown which modulators may be of clinical benefit in childhood ALL. Therefore, we studied the modulating effect of PSC 833, cyclosporin A (CsA), verapamil (Vp) and genistein on daunorubicin (DNR) cytotoxicity, accumulation and retention in childhood ALL cells. DNR cytotoxicity was determined using the MTT assay; DNR accumulation, DNR retention and the expression of P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and major vault protein/lung resistance protein (LRP) were determined by flow cytometry. In the majority of samples PSC 833 (19/26), CsA (22/26) and Vp (15/18) sensitized the cells to DNR whereas genistein made 25 out of 26 samples more resistant to DNR. The sensitizing effect on the cytotoxicity of DNR was median 1.2-fold using 2 microM PSC 833 (P = 0.025), 1.5-fold using 4 microM CsA (P = 0.003) and 1.6-fold using 6 microM Vp (P = 0.012) whereas the adverse effect of 25 microM genistein was median 1.8-fold (P < 0.0001). No relationship was found between the sensitizing effect of PSC 833, CsA or Vp and the degree of DNR resistance. In contrast, the adverse effect of genistein was largest in DNR sensitive samples (P = 0.003). The effect of each modulator on the cytotoxicity of DNR did not differ between initial and relapse ALL samples although the latter were median 1.4-fold more resistant to DNR (P = 0.005). Modulation of DNR cytotoxicity was not correlated with changes in the accumulated and retained intracellular DNR content or with the expression of P-gp, MRP and LRP. Besides genistein, PSC 833, CsA and Vp incidentally made ALL cells more resistant to DNR. CsA stimulated the leukemic cell survival in seven out of 26 samples, a phenomenon that was not related to the degree of DNR resistance. In conclusion, PSC 833, CsA and Vp but not genistein may be used to sensitize cells to DNR in childhood ALL. The data also indicate that not all patients may have a therapeutic benefit from these modulators. Therefore, an in vitro culture assay may be necessary to screen for patients who may benefit by a modulator in their therapy.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Advantages of a new Taq DNA polymerase in multiplex PCR and time-release PCR.
Extensive diagnostic and scientific investigations are often restricted by limited availability of material. Therefore, methods like multiplex PCR strategies are needed to conserve as much sample as possible. Unfortunately, the establishment of such procedures poses several difficulties. Here we describe the advantages of a new enzyme, AmpliTaq Gold DNA Polymerase, in multiplex and time-release PCR. The application of this thermostable recombinant Taq DNA polymerase allows the specific amplification of DNA/cDNA targets with very high sensitivity. With our protocol, the specific amplification of 13 different cDNAs of cytokines and cytokine receptors can be realized in three multiplex PCRs (IL-2R alpha, IL-2/15R beta, gamma c-chain, IL-4 and IL-4R alpha; IL-10, IL-15 and IL-15R alpha; and IL-2, IFN gamma, IL-7, IL-7R alpha and IL-9R alpha). The novel application of AmpliTaq Gold DNA Polymerase in a time-release PCR protocol allows specific amplification of target DNA/cDNA when only limited amounts of material are available or only low-copy-number DNA/cDNA is suspected. No IL-9 cDNA can be detected in peripheral blood mononuclear cells (PBMC) in the absence of any stimulation, thus it was difficult to amplify this target with routine PCR protocols. Here we demonstrate the reliable and reproducible amplification of IL-9 cDNA in the Hodgkin's lymphoma cell line KM-H2, in PBMC and in stimulated PBMC. Results with AmpliTaq Gold DNA Polymerase were more sensitive and specific compared with AmpliTaq DNA Polymerase, with and without manual hot-start procedure.
DNA, Complementary↗
Incidence of TEL/AML1 fusion gene analyzed consecutively in children with acute lymphoblastic leukemia in relapse.
The translocation t(12; 21)(p13; q22) is difficult to detect by classic cytogenetics. However, using fluorescence in situ hybridization (FISH) and by screening for the TEL/AML1 rearrangement by the polymerase chain reaction (PCR), it has been demonstrated to be the most frequent known structural chromosomal abnormality in childhood acute lymphoblastic leukemia (ALL). It is closely correlated with a B-cell precursor (BCP) phenotype and is considered a favorable prognostic factor. However, little is known about the incidence of the translocation in relapsed patients and the duration of complete remission (CR) in children expressing the TEL/AML1 fusion gene. We therefore examined 49 bone marrow samples from children with ALL at first or second relapse that were consecutively mailed to our laboratory to test for the presence of t(12; 21) using reverse transcriptase (RT)-PCR. The TEL/AML1 rearrangement could be identified in nine of 44 (20%) of the patients, a result similar to the reported incidence at diagnosis. Most of the TEL/AML1-positive children showed no adverse clinical features at diagnosis (eg, white blood cell [WBC] count <100 x 10(9)/L or age <10 years), and regarding these data, there were no differences versus children who were negative for the fusion gene. However, the period of remission was about 1 year longer in children expressing TEL/AML1 (P = .046), and the majority of relapses in this group appeared late (<2 years after diagnosis). Our findings therefore reinforce the urgent need for further prospective studies with a long follow-up period to determine the true prognostic significance of t(12; 21) and to avoid premature changes of treatment strategies.
Adolescent↗
Childhood acute lymphoblastic leukaemia.
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Child↗
Bronchiolitis obliterans organizing pneumonia and chronic graft-versus-host disease in a child after allogeneic bone marrow transplantation.
We report an 8-year-old boy who developed cough and respiratory failure 7 months after bone marrow transplantation (BMT) coinciding with the onset of chronic graft-versus-host disease (GVHD). Lung function data, imaging studies, lung biopsy and bronchoalveolar lavage were consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia. While this has been reported in association with chronic graft-versus-host disease in one adult case previously, we report the simultaneous occurrence of BOOP and chronic GVHD in a child after bone marrow transplantation for the first time.
Adult↗
Allogeneic bone marrow transplantation for a subset of children with acute lymphoblastic leukemia in third remission: a conceivable alternative?
In the BFM Relapse Study registry we retrospectively identified 136 patients with a first marrow relapse who had undergone BMT in second complete remission (CR2) (group A) and 33 patients who received transplants only after a 2nd bone marrow (BM) relapse had occurred (group B). Event-free survival (EFS) rates at 6 years after BMT were 0.49 +/- 0.05 and 0.48 +/- 0.09 for patients transplanted in CR2 and CR3, respectively. In context with the BFM chemotherapy trials for relapsed childhood ALL there is a clear benefit from BMT in 2nd CR for children with unfavorable prognostic features (isolated early BM relapse, very early BM relapse or BM relapse of T cell ALL). Similar control of leukemia can be achieved with either chemotherapy or BMT in late BM relapse of ALL. Assuming a 60% failure rate with chemotherapy for patients in second relapse, a third remission can be achieved in about 60% of patients who have received chemotherapy, rendering them eligible for BMT in 3rd CR. With this strategy 58% of these patients would survive and late sequelae of BMT be restricted to a minority. To withhold BMT in CR2 and not perform BMT before a 2nd BM relapse has occurred, may be a conceivable alternative for children with late ALL BM relapse, at least if no related donor is available.
Adolescent↗
Multiplex PCR for simultaneous detection of the most frequent T cell receptor-delta gene rearrangements in childhood ALL.
A rapid and simple multiplex polymerase chain reaction (PCR) is described that is capable of identifying the six most frequent rearrangements of the T cell receptor (TCR)-delta gene segments in childhood acute lymphoblastic leukemia (ALL). The PCR products amplified in a single reaction are of different size for each TCR-delta gene rearrangement. Therefore, they are readily and unambiguously distinguished after agarose gel electrophoresis and assigned to a specific V-D-J gene rearrangement. There is no need for labor-intensive and time-consuming Southern blot hybridization or nested PCR. To evaluate the multiplex assay we chose 45 DNA samples of childhood ALL analyzed beforehand for TCR-delta gene rearrangements by Southern blot and single PCR of which 30 showed TCR-delta gene rearrangements. The multiplex PCR results corresponded to the Southern blot and single PCR analyses. The described multiplex PCR enables the detection of clonal markers in about 50% of patients in order to monitor minimal residual disease (MRD) in prospective studies with a high turnover of samples.
Blotting, Southern↗
Acute toxicity and effectiveness of idarubicin in childhood acute lymphoblastic leukemia.
Anthracyclines have become important components of multi-agent remission induction and continuation therapy of acute lymphoblastic leukemia (ALL). New anthracycline derivatives are being investigated in an attempt to shift the balance of side effects and antileukemic potency. To evaluate the toxicity and efficacy of idarubicin (IDA) in childhood ALL, a prospective multicenter phase-II study was performed. A total of 51 children with prognostically poor recurrences of ALL were enrolled, all of whom had been exposed to anthracyclines during front-line treatment. A single 48-h continuous infusion of IDA at 24 mg/m2 was started on the first day of salvage treatment without concomitant systemic cytostatic agents. The response was assessed by reduction of leukemic blasts in the bone marrow and other compartments 2 wk later. IDA monotherapy caused complete and partial remissions in 5 and 20 patients, respectively (49%). Delays of treatment with subsequent polychemotherapy courses were frequent and mainly caused by prolonged intervals of myelosuppression and high rates of systemic infection. Non-hematological toxicities including acute cardiac reactions were transient and moderate. Our findings suggest that IDA is an effective drug for remission induction in children with ALL, with acute hematological toxicity being dose-limiting.
Adolescent↗
Serum S100--a marker for disease monitoring in metastatic melanoma.
BACKGROUND: S100 proteins are low-molecular-weight calcium-binding proteins and appear to play an important role in various cellular processes such as cell division and differentiation. In histopathology, S100 is widely accepted as the marker of choice for immunohistochemical identification of malignant melanoma. When S100 was detected in the serum of patients with malignant melanoma, it was suggested that serum S100 may be a useful marker for the stage of disease. OBJECTIVE: The aim of this study was to examine serum S100 concentrations of patients with different stages of malignant melanoma and to determine the value of serum S100 in the follow-up of melanoma patients during treatment. METHODS: Sera were obtained from 73 melanoma patients in different stages of the disease. The control group consisted of 130 healthy subjects. In 4 patients with metastatic melanoma, serum S100 was measured serially. Serum levels were measured by a commercially available immunoradiometric assay. RESULTS: While only 1 out of 25 stage I/II patients and 3 of 14 patients with lymph node metastases (stage III, 21.4%) showed detectable serum S100 levels, 27 of 34 patients with disseminated disease (stage IV, 79.4%) had elevated serum S100. Interestingly, rising levels of serum S100 in the serial measurement indicated progression of the disease, and a complete decline reflected 2 patient remissions. CONCLUSION: The data support the value of serum S100 as a clinical marker for progression of metastatic melanoma and serological monitoring during systemic therapies.
Adult↗
Philadelphia chromosome in relapsed childhood acute lymphoblastic leukemia: a matched-pair analysis. Berlin-Frankfurt-Münster Study Group.
PURPOSE: The translocation t(9;22)(q34;q11), known as Philadelphia chromosome (Ph1) or its molecular equivalent the expression of BCR-ABL-mRNA, is one of the most striking and well-characterized cytogenetic abnormalities in leukemia. Although investigated for more than 30 years, it remains unclear whether the Ph1 is an independent risk factor for outcome of leukemia or not. METHODS: A matched-pair analysis was performed within a homogeneous group of patients, which consisted of children who presented with a first relapse of acute lymphoblastic leukemia (ALL) who were treated according to ALL relapse trials (ALL-REZ BFM) protocols. A total of 307 patients were eligible for this analysis: 30 positive and 277 negative for Ph1. Positive patients were matched exactly for time point of relapse (on [during] or off [after cessation of] front-line therapy), site, and immunophenotype, and as close as possible for duration of first remission, peripheral blast-cell count, WBC count, and year of relapse diagnosis. RESULTS: The probability of event-free survival is 0.46 at 5 years for negative and 0.11 for positive patients, respectively (P = .0006). Multivariate analysis showed risk ratios of 4.229 for relapse on therapy, 3.561 for Ph1 and/or expression of BCR-ABL- mRNA, 1.691 for high peripheral blast-cell count, and 0.232 for bone marrow transplantation. CONCLUSION: It was shown that the Ph1 is indeed an independent risk factor in childhood relapsed ALL. There are striking similarities between these patients and children at initial diagnosis, as well as adult patients. Therefore, it is highly suggestive that the Ph1 is also an independent risk factor under all of these circumstances.
Adult↗
Regarding Kumar et al. IJROBP 31(3):477-483; 1995.
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Data Interpretation, Statistical↗
Clinical features and outcome of children with first marrow relapse of acute lymphoblastic leukemia expressing BCR-ABL fusion transcripts. BFM Relapse Study Group.
Although the Philadelphia chromosome (Ph1) has been identified as an adverse prognostic factor in acute lymphoblastic leukemia (ALL), little is known about the incidence and clinical course of relapsed Ph1-positive ALL in children. The incidence was determined by screening of 170 consecutive children with first bone marrow relapse of ALL using the reverse transcriptase-polymerase chain reaction (RT-PCR) and comparison, with cytogenetic analysis. Among these 170 children, 20 (12%) were found to be BCR-ABL-positive, representing a rate that is about three times higher than that reported for newly diagnosed ALL. Ten of the cases were identified by RT-PCR only. In none of the 21 patients with T-cell immunophenotypes could an expression of the BCR-ABL mRNA be detected. BCR-ABL positivity was associated with a significantly shorter duration of first remission (P = .0086) and higher white blood cell (P = .0157) and blast cell counts (P = .0304) at relapse diagnosis. All patients were treated according to the ALL-REZ BFM 87 and 90 relapse trials of the BFM Relapse Study Group. The intensive multiagent chemotherapy induced a second complete remission in only 60% of children with BCR-ABL-positive ALL compared with in 91% of those without BCR-ABL expression (P = .0023). The prognosis of BCR-ABL-positive ALL in children is poor, with a probability of event-free survival at 2 years of 8% versus 50% in those without BCR-ABL mRNA or cytogenetic analysis should become part of the routine diagnostic panel for children with newly diagnosed ALL and is fundamental for children presenting with an early bone marrow relapse.
Adolescent↗