Individualized tumor response testing profile has a prognostic value in childhood acute leukemias: multicenter non-interventional long-term follow-up study.

A total number of 817 children with acute lymphoblastic leukemia (ALL) and 181 with acute myeloblastic leukemia (AML) were assessed for individualized tumor response testing (ITRT) profile as a prognostic factor in long-term follow-up. For each patient, ITRT, initial response to therapy and long-term outcome were assessed. In initial ALL, an impact on long-term response was shown in ITRT for 13 drugs, while in initial AML only for cytarabine. For patients with ALL, a combined five-drug ITRT profile for prednisolone, l-asparaginase, vincristine, cytarabine and daunorubicin or doxorubicin had predictive value for probability of disease-free survival (pDFS) in univariate analysis, whereas in multivariate analysis, bone marrow response by day 33 was the only prognostic factor. For patients with AML, no factor had prognostic value for pDFS in univariate analysis, while ITRT to cytarabine almost reached significance. In conclusion, ITRT can possibly be regarded as a risk factor in childhood acute leukemias.

[Plasma matrix metalloproteinases MMP-2 and MMP-9 and tissue inhibitors TIMP-1 and TIMP-2 in children treated for acute lymphoblastic leukemia]. / Metaloproteinazy macierzy zewnatrzkomórkowej MMP-2 i MMP-9 oraz tkankowe inhibitory TIMP-1 i TIMP-2 w osoczu dzieci chorych na ostra bialaczke limfoblastyczna.

THE AIM OF THE STUDY: An analysis of changes in plasma levels of MMP-2 and MMP-9 as well as the tissue inhibitors TIMP-1 and TIMP-2 in children diagnosed for acute lymphoblastic leukemia (ALL). MATERIAL AND METHODS: In 21 children aged from 1 to 15 with ALL (17 with pre-B ALL and 4 with T-ALL) we made the analysis: at diagnosis (point I), after induction remission (point II) and after the end of intensive treatment (point III). Control group was composed of 47 healthy persons. RESULTS: At diagnosis, the mean plasma values of MMP-2, MMP-9, TIMP-2 were lower than in control group, whereas TIMP-1 levels were similar. During and after the treatment we found the increase of MMP-2 comparing to the values at diagnosis (relatively p = 0.003 and p = 0.008). Plasma MMP-9 was higher at point III of analysis than at point II. The levels of TIMP-2 increased in following points of the study We did not found the influence of immunophenotype, initial LDH levels and leukocytosis on MMPs and TIMPs values. At diagnosis, the ratio MMP-2/TIMP-1 was at the same level as in the control but it was higher during and after the intensive treatment. At diagnosis as well as during the treatment the ratios MMP-9/TIMP-2 and MMP-9/TIMP-1 were lower than in control. At diagnosis we found a positive correlation between MMP-2 and TIMP-2 (r = 0.679, p = 0.001) and between TIMP-1 and TIMP-2 (r = 0.482, p = 0.027), whereas during the treatment--only a positive correlation between MMP-2 and TIMP-2 was observed (r = 0.766, p = 0.001). CONCLUSIONS: The differences in plasma matrix metalloproteinases and their tissue inhibitors between leukemic patients and control group, as well as in patients during the treatment, suggest their probable role in the development of leukemic process. The analysis conducted in the bigger group of patients, establishing simultaneously levels of these markers in plasma and in leukemic cells, would be advisable.

Differential ex vivo activity of bortezomib in newly diagnosed paediatric acute lymphoblastic and myeloblastic leukaemia.

The proteasome inhibitor, bortezomib, is known to be effective in the therapy of various neoplasms. The objective of this study was the analysis of the ex vivo activity of bortezomib in paediatric acute lymphoblastic leukaemia (ALL), in comparison to paediatric acute myeloid leukaemia (AML). A total of 159 patients entered the study, including 106 ALL (including 86 precursor-B-cell ALL, and 20 T-cell ALL) and 53 AML children. The ex vivo sensitivity to bortezomib and 16 other drugs was studied by MTT assay. Paediatric AML samples were more resistant than paediatric ALL samples to most of the tested drugs, except for cytarabine and thioguanine. With respect to immunophenotype, ex vivo drug resistance in T-cell ALL (T-ALL) was higher for most of the drugs. No differences in drug resistance between T-ALL and common/pre-B-cell-ALL were found for daunorubicin, mitoxantrone and 6-thioguanine. Bortezomib was the only compound which was more active in T-ALL than in common/pre-B-ALL paediatric samples. In conclusion, bortezomib had good ex vivo activity in paediatric T-ALL samples.

Prognostic impact of combined fludarabine, treosulfan and mitoxantrone resistance profile in childhood acute myeloid leukemia.

BACKGROUND: The role of cellular drug resistance in childhood acute myeloid leukemia (AML) has not yet been established. The aim of the study was the analysis of the clinical value of ex vivo drug resistance in pediatric AML. PATIENTS AND METHODS: A cohort of 90 children with de novo AML were assayed for drug resistance profile by the 3-4,5-dimethylthiazol-2-yl-2,5-difenyl tetrazolium bromide (MTT) assay and prognostic model of in vitro drug sensitivity was analyzed. RESULTS: Children who relapsed during follow-up showed higher in vitro resistance of leukemic blasts to most of the drugs tested, except for cytarabine, cladribine, vincristine, mercaptopurine and thioguanine. A combined in vitro drug resistance profile to fludarabine, treosulfan and mitoxantrone (FTM score) was defined and it had an independent prognostic significance for disease free survival in pediatric AML. CONCLUSION: The combined fludarabine, treosulfan and mitoxantrone resistance profile to possibly may be used for better stratification of children with AML or indicate the necessity for additional therapy.

Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia.

PURPOSE: Cellular resistance in childhood acute leukemias might be related to profile and function of multidrug resistance proteins and apoptosis regulating proteins. The aims of the study were: (1) analysis of expression of MRP1, PGP1, LRP, BCL-2 and p53 proteins; (2) correlation with ex vivo drug resistance, and (3) analysis of their prognostic impact on clinical outcome in childhood acute lymphoblastic (ALL) and acute myeloid (AML) leukemia. METHODS: Total number of 787 children diagnosed for initial ALL (n = 527), relapsed ALL (n = 104), initial AML (n = 133) and relapsed AML (n = 23) were included into the study. Mean follow-up period was 3.5 years. Drug resistance for up to 30 anticancer agents was performed by the MTT assay. Expression of all proteins was tested by flow cytometry. RESULTS: Both initial AML and relapsed ALL samples showed higher drug resistance than initial ALL samples. No significant differences were found in drug resistance between initial and relapsed AML samples. The presence of multidrug resistance and apoptosis proteins had no impact on pDFS in iALL and iAML, however strong trend towards adverse prognostic impact of MRP1, PGP and LRP on pDFS in rALL was observed. The same trend was observed for each of analyzed co-expressions of tested multidrug resistance proteins. CONCLUSIONS: The phenomenon of cellular drug resistance in childhood acute leukemias is multifactorial and plays an important role in response to therapy. Expression of MRP1, PGP and LRP proteins, as well as their co-expression play possible role in childhood relapsed ALL.

Carrier frequency of mutation 657del5 in the NBS1 gene in a population of Polish pediatric patients with sporadic lymphoid malignancies.

Nijmegen breakage syndrome (NBS) is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition, in particular to lymphoma and leukemia. Recently, significantly higher frequencies of heterozygous carriers of the Slavic founder NBS1 mutation, 657del5, were found in Russian children with sporadic lymphoid malignancies, and in Polish adults with non-Hodgkin lymphoma (NHL). In addition, the substitution 643C>T (R215W) has also been found in excess among children with acute lymphoblastic leukemia (ALL). In an attempt to asses the contribution of both mutations to the development of sporadic lymphoid malignancies, we analyzed DNA samples from a large group of Polish pediatric patients. The NBS1 mutation 657del5 on one allele was found in 3 of 270 patients with ALL and 2 of 212 children and adolescents with NHL; no carrier was found among 63 patients with Hodgkin lymphoma (HL). No carriers of the variant R215W were detected in any studied group. The relative frequency of the 657del5 mutation was calculated from a total of 6,984 controls matched by place of patient residence, of whom 42 were found to be carriers (frequency = 0.006). In the analyzed population with malignancies, an increased odds ratio for the occurrence of mutation 657del5 was found in comparison with the control Polish population (OR range 1.48-1.85, 95% confidence interval 1.18-2.65). This finding indicates that the frequency of the mutation carriers was indeed increased in patients with ALL and NHL (p < 0.05). Nonetheless, NBS1 gene heterozygosity is not a major risk factor for lymphoid malignancies in childhood and adolescence.

Renal function during and after treatment for acute lymphoblastic leukemia in children.

Renal function tests (cystatin C, serum and urine creatinine, creatinine clearance, serum and urine beta(2)-microglobulin, microalbuminuria, osmolality) were performed in 21 children at the diagnosis and during the treatment for acute lymphoblastic leukemia (ALL) (group I) and in 37 children (group II) treated for ALL 3.9+/-3.7 years before the study. The results were compared to 20 healthy children. Mean values of renal tests were in normal range at all points of analysis in groups I and II compared to the control group. Transitory higher cystatin C values (but in normal range) were observed after methotrexate administration and after the end of treatment. Deteriorated renal function was observed in one child during the treatment (after each protocol) and in five children treated previously for ALL. In conclusion, combined treatment for ALL is not associated with severe or long-term impairment of renal function.

[Rare tumours--are they really rare in the Polish children population?]. / Nowotwory rzadkie--czy rzeczywiscie rzadkie w populacji polskich dzieci?

Clear statement that pediatric neoplasms are really rare is not easy. Thus the incidence of rare tumours in children has not been defined so far. The paper efforts to assess the topic of rare tumours of childhood in the Polish population. Following two categories are proposed: tumours typical for adults, but possible in children (neoplasms of epithelial origin--mainly carcinomas, melanomas, carcinoids) and paediatric tumours consisting less than 10% of cases in corresponding clinical groups according to the ICCC classification. Data on 317 patients aged 0-18 years treated in centres associated in the Polish Paediatric Group for Solid Tumours (PPGST) were analysed. Classical adult malignancies were registered in 130 patients: carcinomas in 90 (mean age 12.6 +/- 4.5 years), melanomas in 25 (mean age 9.4 +/- 4.9) and carcinoids in 9 (mean age 14.5 +/- 1.2 years). Non epithelial neoplasms were registered in 187 patients (mean age 10.4 +/- 5.5). That group included rare tumours of soft tissue, CNS, bones and other organs. Treatments of certain groups were specified by separate therapeutic protocols within PPGST. Rare malignancies of adult-type among children under 18 years of age in Poland comprised 1.5% of all pediatric neoplasms. The incidence of adult-type neoplasms increased with age until 14 years. In patients over 15 years of age the number of registered cases decreased. It may suggest a first peak of incidence in early adolescence or an underestimation of number of patients with carcinoma aged over 15 years. In the analyzed group, the mean age of patients with carcinomas and other epithelial and unspecified tumours significantly exceeded the age of children with rare neoplasms of non-epithelial origin (12.1 +/- 4.7 vs 10.4 +/- 5.5 years; p<0.05). A very young age at diagnosis of malignant melanomas (mean 9.4 years) and numerous cases of carcinomas affecting the digestive tract (n=24; 27% of all carcinomas), especially those located in colorectal region (n=10), seem surprising. The preliminary analysis of the collected data on rare neoplasms in Poland encourage to undertake a prospective study, meant to link the epidemiology and characteristics of rare epithelial tumours in childhood with diagnostic and therapeutic suggestions for these types that are not coordinated within Polish Paediatric Group of Solid Tumours.

[Renal function and size after complex treatment of Wilms' tumour]. / Czynnosc i wymiary nerki po kompleksowym leczeniu guza Wilmsa.

The aim of our study was to measure renal function and growth in survivors of unilateral Wilms' tumour in 21 children and young adults (7 female). The mean age was 12.6 +/- 4.8 years, mean follow-up time was 7.01 +/- 4.25 years: seven of the group received irradiation (35 Gy). Blood pressure was normal in all patients. Three of them had elevated cystatin C and clearance of cystatin C below referenced normal value. The others had normal renal function tests (cystatin C, creatinine and cystatin clearance, B2 microglobulin, microalbuminuria, osmolality). Compared to the control we found higher cystatin C values in children treated before the age 3 years old (p=0.03) and in children treated more than 5 years before (p=0.03), and lower cystatin clearance in group treated before the age 3 years old (p=0,03). No difference between the irradiated and non-irradiated group was found. We observed a greater increase in volume (155.9% +/- 33.4) than in length (127.9% +/- 6.3). The highest rise of renal volume was in children treated more than 5 years before (174.6% +/- 22.3). In conclusion, our data suggest that after combined treatment for Wilms' tumour compensatory renal hypertrophy and a tendency progressive renal dysfunction takes place.