Contrary to adult patients, expression of the multidrug resistance gene (MDR1) fails to define a poor prognostic group in childhood AML.
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Adult↗
Biomedical subjects
A Sauerbrey
Publications and source records attributed to A Sauerbrey.
BCRP gene expression is associated with a poor response to remission induction therapy in childhood acute myeloid leukemia.
Breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MRX) or placenta ABC protein (ABC-P), is the second member of the ABCG subfamily of ABC transport proteins (gene symbol ABCG2). Transfection and enforced expression of BCRP in drug-sensitive cells confers resistance to mitoxantrone, doxorubicin, daunorubicin and topotecan. In this study the expression of BCRP gene was measured using TaqMan real-time PCR in 59 children with newly diagnosed AML. Nine patients were also analyzed in relapse. The median of BCRP gene expression was more than 10 times higher in patients who did not achieve remission after the first phase of chemotherapy (n = 24) as compared to patients who did achieve remission at this stage (n = 21; P = 0.012). In first relapse the expression of the BCRP gene was higher than at diagnosis (P = 0.038). Although high levels of BCRP gene expression were more frequent in subtypes of AML with a favorable prognosis, we found that within both risk groups (high and low risk), patients who expressed high levels of BCRP had a worse prognosis (P = 0.023). Our results strongly suggest that the expression of the BCRP gene reduces the response to chemotherapy in AML and that BCRP expression is higher at the time of relapse.
ATP Binding Cassette Transporter, Subfamily G, Mem↗
High-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (ASCT) as salvage therapy for relapsed osteosarcoma.
In this report, we describe our experience with high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) in 15 children with relapsed osteosarcoma who were treated by members of the Cooperative Osteosarcoma Study Group. Eight patients received HDC after the first relapse, six patients after the second relapse and one after the sixth relapse. Thirteen patients underwent HDC and ASCT in complete remission and two patients had macroscopic tumor residues. Seven patients received HDC based on melphalan and etoposide. Four of these patients were treated with additional carboplatinum. Two patients received carboplatinum, etoposide, and thiotepa or cyclophosphamide. In six patients double HDC was performed. In all six of these, the first HDC consisted of thiotepa/ cyclophosphamide. The second regimens included melphalan/etposide (two patients), melphalan/etposide/ carboplatinum (one patient), and melphalan/busulfan (one patient). Three of the 15 patients died of toxic complications. Eight patients developed further relapses, two patients showed persistent disease, and two patients are presently in continuous complete remission. The probability of relapse-free survival was 0.20 +/- 0.12 within a median follow-up (MFU) of 8 months and the probability of overall survival was 0.29 +/- 0.12 after a MFU of 16 months. In conclusion, utilization of HDC and ASCT in this patient group did not significantly improve the treatment outcome compared to conventional relapse therapy.
Adolescent↗
The anti-malarial artesunate is also active against cancer.
Artesunate (ART) is a semi-synthetic derivative of artemisinin, the active principle of the Chinese herb Artemisia annua. ART reveals remarkable activity against otherwise multidrug-resistant Plasmodium falciparum and P. vivax malaria. ART has now been analyzed for its anti-cancer activity against 55 cell lines of the Developmental Therapeutics Program of the National Cancer Institute, USA. ART was most active against leukemia and colon cancer cell lines (mean GI50 values: 1.11+/-0.56 microM and 2.13+/-0.74 microM , respectively). Non-small cell lung cancer cell lines showed the highest mean GI50 value (25.62+/-14.95 microM) indicating the lowest sensitivity towards ART in this test panel. Intermediate GI50 values were obtained for melanomas, breast, ovarian, prostate, CNS, and renal cancer cell lines. Importantly, a comparison of ART's cytotoxicity with those of other standard cytostatic drugs showed that ART was active in molar ranges comparable to those of established anti-tumor drugs. Furthermore, we tested CEM leukemia sub-lines resistant to either doxorubicin, vincristine, methotrexate, or hydroxyurea which do not belong to the N.C.I. screening panel. None of these drug-resistant cell lines showed cross resistance to ART. To gain insight into the molecular mechanisms of ART's cytotoxicity, we used a panel of isogenic Saccaromyces cerevisiae strains with defined genetic mutations in DNA repair, DNA checkpoint and cell proliferation genes. A yeast strain with a defective mitosis regulating BUB3 gene showed increased ART sensitivity and another strain with a defective proliferation-regulating CLN2 gene showed increased ART resistance over the wild-type strain, wt644. None of the other DNA repair or DNA check-point deficient isogenic strains were different from the wild-type. These results and the known low toxicity of ART are clues that ART may be a promising novel candidate for cancer chemotherapy.
Antimalarials↗
Vascular endothelial growth factor in newly diagnosed and recurrent childhood acute lymphoblastic leukemia as measured by real-time quantitative polymerase chain reaction.
PURPOSE: Overexpression of vascular endothelial growth factor (VEGF) is associated with increased angiogenesis, growth, and metastasis in solid tumors, but to date the significance of VEGF in leukemia has received only limited attention. Therefore, this study examined the cellular VEGF levels in 31 newly diagnosed and 22 recurrent cases of childhood acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: VEGF was determined with real-time quantitative PCR methods. Kaplan-Meier statistical analyses were conducted for the relapse-free intervals and the overall survival times. The groups were compared by log-rank and rank-sum tests. RESULTS: The VEGF levels were significantly higher in recurrent ALL compared with newly diagnosed ALL (28.0 versus 3.1 units; P = 0.001). Kaplan-Meier estimates were conducted to analyze the prognostic value of VEGF levels in newly diagnosed ALL with regard to the relapse-free intervals and the overall survival times. In this analysis, the median relapse-free interval of patients with low VEGF levels was more than 10 years, whereas the relapse-free interval of patients with high VEGF expression was only 1.2 years. The median overall survival time for the collective with low VEGF levels was >10 years, whereas the survival of the group of patients with high VEGF levels was 3.9 years. This difference was not statistically significant. This may be attributable to the small number of patients involved. CONCLUSION: Our data suggest that VEGF may play an important role in the pathophysiology of ALL. The expression of VEGF raises the possibility of using angiogenesis inhibitors as a novel therapeutic strategy in childhood ALL.
Adolescent↗
A Meckel's diverticulum containing pancreatic tissue and nesidioblastosis in a patient with Beckwith-Wiedemann syndrome.
A 30-month-old twin with Beckwith-Wiedemann syndrome underwent exstirpation of a nephroblastoma from the right kidney. A Meckel's diverticulum (MD), an incidental finding intraoperatively, was resected because it was indurated and enlarged. Histologically, the MD contained ectopic gastric and pancreatic mucosa. Nesidioblastosis was identified within the pancreatic tissue. This is probably the first description of ectopic nesidioblastosis within a MD.
Beckwith-Wiedemann Syndrome↗
Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): experience from the BFM trials.
BACKGROUND: Lymphoma and leukemia are the commonest malignant diseases in patients with chromosomal breakage syndromes and immunodeficiency (Ataxia teleangiectasia (AT) and Nijmegen breakage syndrome (NBS)). With improved management of infections, malignant disease is more frequently diagnosed and has become one of the commonest causes of death in pediatric AT and NBS. PATIENTS AND METHODS: In three consecutive multicenter therapy trials for pediatric non-Hodgkin's lymphoma (NHL) (NHL-BFM), 1569 patients with newly diagnosed NHL have been registered between 1986 and 1997. Nine patients with AT (n = 5) and NBS (n = 4) were identified and analysed. RESULTS: Median age of patients with AT and NBS at diagnosis of NHL was nine years. NHL-entities differed from non-AT/NBS-patients: diffuse large B-cell lymphomas, n = 7 (78%); ALCL, n = 1; lymphoblastic T-cell lymphoma, n = 1. Cervical nodes, paranasal sinuses and epipharynx were the sites most frequently involved. Stages were: I and II in three patients, III in five and IV in one patient. All patients received polychemotherapy according to tumor-entity and stage, none received radiation. Dose reductions according to individual tolerance concerned mainly ethotrexate, alkylating agents and epipodophyllotoxines. One patient died of toxic complications, two patients relapsed and died, one patient suffered from second malignancy. Five of nine patients are in 1. CCR after a median follow-up of five years. CONCLUSIONS: Patients with AT and NBS suffer from rare entities of pediatric NHL. Curative treatment is possible and should be attempted. Intensity of therapy should be adjusted to individual risk factors and tolerance. Alkylating agents, epipodophyllotoxines should be omitted, dose of MTX should be limited to 1 g/m2. Further cooperative trials using standardized approaches are required.
Adolescent↗
Expression of a novel double-mutant dihydrofolate reductase-cytidine deaminase fusion gene confers resistance to both methotrexate and cytosine arabinoside.
A novel fusion gene consisting of the open reading frame of a double-mutant (Phe22-Ser31) dihydrofolate reductase (dmDHFR) cDNA fused to the open reading frame of cytidine deaminase (CD) was constructed and characterized for the purpose of conferring simultaneous resistance to methotrexate (MTX) and cytosine arabinoside (ara-C). The kinetic properties of purified recombinant dmDHFR-CD fusion protein were compared with those of purified CD and dmDHFR. The fusion protein was found to retain enzymatic properties of both dmDHFR and CD, in that the Km and Kcat values of purified dmDHFR-CD protein were found to be virtually identical to those of CD and dmDHFR alone. Retrovirus-mediated expression of dmDHFR-CD in NIH 3T3 cells conferred significant resistance (10- to 12-fold) against MTX and ara-C, compared with mock- and single gene-infected cells and the level of resistance obtained was similar to that of cells expressing both CD and dmDHFR from a retroviral bicistronic vector. Infection of mouse bone marrow cells with the dmDHFR-CD construct also showed high levels of resistance to MTX and ara-C in a CFU-GM assay. This fusion protein confers resistance to two antineoplastic agents that differ in their mechanism of action, and may be useful in the design of gene transfer strategies for protection of target cells against multiple drugs. Since high-dose ara-C and MTX are used in the treatment of lymphomas, this vector may be of value in protecting human hematopoietic progenitor cells from the toxicity of these antimetabolites.
3T3 Cells↗
Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials.
BACKGROUND: Non-Hodgkin lymphomas (NHL) represent an important complication of primary immunodeficiency (ID), posing new therapeutic challenges in this patient population. This study analyzes clinical data and therapy results of pediatric patients with primary ID and NHL in three consecutive NHL-BFM trials. PROCEDURE: Retrospective analysis of children with primary ID and NHL, treated according to protocol NHL-BFM, was performed regarding clinical presentation, diagnostic features, therapy, and outcome. RESULTS: From October, 1986, to April, 1997, 19 of 1,413 newly diagnosed patients with NHL were registered as suffering from primary ID. Age at diagnosis of NHL was lower in patients with ID. Six patients suffered from humoral ID, 13 patients from combined ID (ataxia teleangiectasia n = 3; Nijmegen breakage syndrome n = 4; PNP deficiency n = 1; IL2 receptor defect n = 1, other combined ID n = 4). Thirteen lymphomas were of B-cell and six of T-cell-lineage. Four of thirteen patients with combined ID were diagnosed with T-NHL, nine with B-NHL. Two of six patients with humoral ID presented with T-NHL and four with B-NHL. NHL entities differed significantly between ID and non-ID patients (P < or = 0.01): centroblastic and immunoblastic lymphomas (31.6% vs. 8.1%), anaplastic large cell lymphoma (26.3% vs. 10.7%), Burkitt lymphoma and B-ALL (21% vs. 47. 8%). Seventeen patients received polychemotherapy. Therapy-related toxicity was increased in ID- compared to non-ID-patients. Three patients died of sepsis; three died of tumor progression; one patient relapsed; one died of BMT-related toxicity; one died of second malignancy. Ten patients are in first continuous remission after a median follow-up of 4 years. CONCLUSIONS: Curative treatment of NHL in the presence of primary ID is possible and should be attempted.
Adolescent↗
Successful treatment of essential thrombocythemia with anagrelide in a child.
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Child↗
Expression of the retinoblastoma tumor suppressor gene (RB-1) in acute leukemia.
In this report we review current studies concerning the RB-1 gene expression in acute leukemias. The RB-1 gene was analyzed in several studies by protein-, RNA and DNA-techniques in acute lymphoblastic leukemia (ALL) as well as in acute myelogenous leukemia (AML). The frequency of RB-1 inactivation in ALL-patients ranged between 30% and 64% in several studies. Structural abnormalities of the RB-1 gene were reported in 18% of ALL-patients and in 27% of Philadelphia chromosome-positive ALL, respectively. The proportion of AML-patients with absent RB-1 protein expression ranged between 19% and 55%. Structural RB-1-abnormalities in AML were predominantly reported in leukemias with monocytic differentiation. Furthermore, the prognostic value of an abnormal RB-1 gene expression was also estimated in some studies. In childhood ALL RB-1 inactivation was reported to have prognostic significance while in contrast, in another study on adults no prognostic value of RB-1 was found. In 4 out of 5 documented studies AML-patients with RB-1 inactivation generally had a poorer prognosis. In conclusion, RB-1 inactivation is frequently observed in acute leukemia. The prognostic value of low RB-1 expression is controversial but the majority of published studies found low RB-1 expression to be a negative prognostic predictor, in acute leukemia.
Adult↗
Prognostic implications of cyclins (D1, E, A), cyclin-dependent kinases (CDK2, CDK4) and tumor-suppressor genes (pRB, p16INK4A) in childhood acute lymphoblastic leukemia.
Immunohistochemistry was used to analyze samples of 40 newly diagnosed childhood acute lymphoblastic leukemias (ALL) for their expression of cyclins (D1, E, A), cyclin-dependent kinases (cdk2, cdk4) and tumor-suppressor genes (pRb, p16INK4A), in order to discover whether or not the expression of these various proteins may be of prognostic relevance for the survival of children with ALL. Patients with ALL who were strongly positive for cyclin D1 had a lower probability of remaining in first continuous remission than ALL patients who were negative or weakly positive for this trait. There was also a significant correlation between expression of cyclin D1 and frequency of recurrence. For cyclin E and cyclin A, in contrast, there was no difference in the duration of relapse-free-intervals or the frequency of recurrence in patients. Children with cdk4-positive ALL had a lower probability of remaining in first continuous remission than children with cdk4-negative ALL. No prognostic relevance was found for cdk2. Patients with ALL who expressed pRb had a higher probability and patients who expressed p16 a lower probability of remaining in first continuous remission, but the results were not statistically significant. This investigation demonstrated that cyclin D1 and cdk4 were the most important prognostic factors for children with ALL, and that the combination of them showed the strongest prognostic relevance.
Adolescent↗
Prognostic value of protein kinase C, proto-oncogene products and resistance-related proteins in newly diagnosed childhood acute lymphoblastic leukemia.
In this investigation, untreated non-B-type acute lymphoblastic leukemia (ALL) of 104 children was analyzed using immunocytochemistry for expression of protein kinase C, proto-oncogene products (Fos, Jun, Ras) and resistance-related proteins (topoisomerase II, P-glycoprotein, glutathione S-transferase-pi, metallothionein, dihydrofolate-reductase, thymidylate-synthase). The aim of the analysis was to find out whether combining those factors with the most important clinical prognostic factor (blast cell count) can improve the prognostic value (relapse-free interval). Univariate analysis shows that protein kinase D (PKC), Fos, P-glycoprotein (P-170) and glutathione S-transferase-pi (GST-pi) are significant prognostic factors independent of blast cell count (PBC) for the relapse-free intervals of children with ALL. The presence of the proteins Fos, PKC, P-170 and GST-pi was not independent within the patient population. The multivariate analysis showed that in combination with PBC and PKC, both P-170 and GST-pi have only limited prognostic influence. Combining the factors PKC, Fos and GST-pi as a categorical variable showed that this variable is a strong prognostic factor in addition to PBC.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Apoptotic index, Fas and bcl-2 in initial and relapsed childhood acute lymphoblastic leukaemia.
Seventy-two samples with initial and 23 samples with relapsed childhood acute lymphoblastic leukaemia (ALL) were investigated for apoptotic index (AI) and for Fas expression. AI was determined by DNA-fragmentation using deoxynucleotidyl terminal transferase and Fas expression by immunocytochemistry. bcl-2 mRNA expression was measured in 50 initial and 20 relapsed ALL. The patients were discriminated in groups with low and high AI, Fas-protein expression and bcl-2mRNA expression by the mean value. AI was higher in relapsed than in initial ALL. The mean survival was significantly higher in patients with low AI (p= 0.034). This was also true for the relapse-free interval, however, this result was borderline significant (p= 0.064). AI was directly correlated with expression of Fas and inversely correlated with bcl-2 mRNA expression. These results suggest that Fas and - with limitations - bcl-2 may influence the apoptotic process in childhood ALL and that enhanced apoptotic activity predicts poor prognosis.
Journal Article↗
Deoxycytidine kinase mRNA expression in childhood acute lymphoblastic leukemia.
Initial and relapsed childhood acute lymphoblastic leukemias (ALL) were investigated for mutations and expression of deoxycytidine kinase (dCK). dCK mediating toxicity of 1-beta-D-arabinofuranosylcytosine was analyzed semiquantitatively by RT-PCR and by single-strand conformation polymorphism. We found that patients with initial ALL experienced more frequently a relapse if dCK expression was low or absent. No mutations were found in initial and relapsed ALL.
Antineoplastic Combined Chemotherapy Protocols↗
Expression of lung resistance-related protein (LRP) in initial and relapsed childhood acute lymphoblastic leukemia.
Thirty-eight children with initial and 25 children with relapsed lymphoblastic leukemia (ALL) were analyzed for the expression of LRP (lung resistance protein or p110 major vault protein) using immunocytochemistry. LRP expression was found in 18 of 38 (47%) children with initial ALL and in 17 of 25 (68%) children with relapsed ALL. Children with initial ALL and without LRP expression had significantly longer relapse-free intervals than patients with LRP expression.
Child↗
Expression and prognostic value of the retinoblastoma tumour suppressor gene (RB-1) in childhood acute lymphoblastic leukaemia.
In a retrospective analysis, acute lymphoblastic leukaemia (ALL) blast cells of 102 children were investigated for the expression of the retinoblastoma susceptibility (RB)-1 gene at mRNA level by dot blot hybridization and semiquantitative RT-PCR. 56 patients were analysed by dot blot hybridization and 35 representative patients out of this group by semiquantitative RT-PCR. Two additional groups of patients (23 patients with initial and 23 patients with relapsed ALL) were also investigated by semiquantitative RT-PCR. RB-1 gene expression was detectable in all investigated ALL at different levels. According to the relative mRNA expression the patients were discriminated by the median value in groups with low or high RB-1 expression. The Kaplan-Meier estimates showed that patients with low RB-1 expression had a lower probability of remaining in first remission (P = 0.03) and a significantly higher risk to succumb to their disease (P = 0.03). Furthermore, the comparison of the results between initial and relapsed ALL showed that the relapses had significantly lower RB-1 mRNA expression (P = 0.02). The overall survival of the patients was shorter in both groups when RB-1 gene expression was low. A multivariate analysis, including age, sex, immunological subtype, initial white blood cell count and RB-1 expression, identified RB-1 as an independent prognostic predictor (P = 0.017) in addition to the initial white blood cell count (P = 0.00001). In conclusion, low RB-1 expression is an unfavourable prognostic predictor in initial and relapsed childhood ALL. The RB-1 gene expression in relapsed ALL is significantly lower than in initial ALL.
Adolescent↗
Predictive value of statin, a G0-associated cell cycle protein, in childhood acute lymphoblastic leukemia.
Blast cells of 71 children with newly diagnosed acute lymphoblastic leukemia (ALL) were examined with a novel monoclonal antibody (MAb), S-44, immunoreactive to statin, a nuclear protein specifically expressed in non-proliferating cells. The statin labeling index (LI) varied greatly from case to case and ranged from 0.3% to 86%, with a mean value of 10%. The degree of statin LI correlated inversely with the expression of Ki-67. When patients were subdivided according to whether the statin LI was higher or lower than the mean value, patients with higher statin LI did not respond to chemotherapy and survived for a shorter period of time. Our results suggest that labeling of statin with the S-44 MAb is a useful prognostic marker of the cytotoxic effects of anti-cancer drugs in patients with ALL.
Adolescent↗