Late effects of childhood cancer treatment in long-term survivors diagnosed before the age of 3 years - A multicenter, nationwide study.

BACKGROUND: The effect of age on the incidence of late sequelae that occur after anticancer treatment in childhood is still not fully elucidated. In this multicenter study of long-term survivors diagnosed before age of three, we investigated the prevalence of late effects many years after treatment. METHODS: The study group (n = 561) was selected from the Polish National Childhood Cancer Survivors Registry (n = 1761) created in 2007. A survivor was defined as an individual who has survived at least 5 years after completion of anticancer treatment. All children were diagnosed between 1991 and 2016, mean age at diagnosis was 1.82 years (range 0.03-2.99) and median follow up time - 9.85 years (range 5.0-23.6). They were treated in accordance with international protocols approved by the Polish Pediatric Leukemia and Lymphoma Group and Polish Solid Tumor Group. Chemotherapy alone was used in 192 (34.2%), chemotherapy and radiotherapy - 56 (10%), chemotherapy and surgery - 176 (31.4%), chemotherapy, radiotherapy, and surgery - 79 (14.1%), and surgery alone in 58 patients (10.3%). RESULTS: Of all patients enrolled to the study, only 94 (16.8%) had normal function of all organs. Seventy-six (13.5%) children developed dysfunction in one organ, another 83 (14.8%) had symptoms or complaints suggestive of dysfunction in two organs or systems, 88 (15.7%) had abnormalities in three organs, and 220 (39.2%) had at least four or more dysfunctions. In the entire study group, dysfunctions most frequently (> 20% of cases) involved the following organs/systems: circulatory - 21.8%, urinary - 30.8%, gastrointestinal - 20.8%, immune - 23.5%, vision - 20.7%, hearing - 21.8%, and oral and masticatory dysfunction - 26.9%. We did not find any significant differences in organ dysfunction between children diagnosed under the age of 1 and those diagnosed at the age of 1-3, except for a lower incidence of thyroid abnormalities (p = 0.007) and the higher prevalence of liver dysfunction in youngest patients. In the subset with longer follow-up period (> 10 years) more frequent thyroid abnormalities (p = 0.019), male (p = 0.002) and female (p = 0.026) gonads dysfunction, as well as musculoskeletal problems (p < 0.001) were observed. Among subjects who received radiotherapy compared to those who did not, short stature (p = 0.001), and dysfunction of the following systems/organs - circulatory (p = 0.049), urinary (p = 0.012), thyroid gland (p < 0.0001), nervous (p = 0.007), immunological (p = 0.002), liver (p = 0.03), dental or chewing difficulties (p = 0.001), hearing (p = 0.001) and musculoskeletal (p = 0.026) were more frequently reported. When multimodal therapy was applied (chemotherapy, radiotherapy, and surgery) a higher incidence of short stature (p = 0.007), urinary system disorders (p < 0.0001), thyroid dysfunction (p < 0.0001), hearing loss (p < 0.0001), and skin problems (p = 0.031) were observed. CONCLUSION: This study confirms that radiotherapy and some specific toxicity of cytostatics are the most important factors affecting organ function. Apart from a higher incidence of liver dysfunction in the youngest patients, there were no significant differences in organ and system toxicities between children diagnosed under the age of 1 and those diagnosed at the age of 1-3. We have shown that this group requires systematic, careful and long-term follow-up.

Comparative Study of Malocclusions between Cancer Patients and Healthy Peers.

Background. There is lack of data related to dental occlusion among children cured from cancer. The aim of our study was to compare the prevalence of malocclusion in cancer survivors and in healthy peers. Methods. A cross-sectional study was conducted on 225 children aged between 4 and 18 years, including 75 cancer survivors, and 150 sex and age-matched controls. All patients were orthodontically examined and malocclusion traits were recorded. In the cancer group, 75 panoramic radiographs were used to evaluate the prevalence of dental anomalies and dental age using the Demirjian scale. Data were analyzed by univariate statistical analysis with p-values p < 0.05 considered as statistically significant. Results. Malocclusion was found in 49 (65.33%) cancer survivors and 99 (65.56%) controls (p > 0.05). The cancer group demonstrated significantly higher likelihood of crossbite (p < 0.01) and malalignment of teeth (p = 0.031). The healthy controls were more likely to demonstrate open bite (p = 0.038). Cancer patients with posterior crossbite (p = 0.023) or dental malalignment had a more advanced dental age (p = 0.022). Survivors with crossbite had more teeth with short roots (p = 0.016). Those who were older when they started their cancer therapy were more likely to suffer from tooth disturbances (p = 0.019). Conclusion. Oncological treatment can alter the development of occlusion in cancer patients.

The Broad Variability in Dental Age Observed among Childhood Survivors Is Cancer Specific.

PURPOSE: The study aimed to assess the differences in dental maturation between childhood cancer survivors and healthy children. MATERIALS AND METHODS: Fifty-nine cancer patients including 16 (27.1%) girls and 43 (72.8%) boys, aged between 4 and 16 years, underwent dental and radiographic examinations. The mean duration of anticancer therapy was 16.8 months (range, 1 to 47 months), and 4.6 years (range, 8 to 123 months) had passed since the termination of disease. The control group consisted of 177 panoramic radiographs of age- and sex-matched healthy individuals. Dental age (DA) was estimated with Demirjian's scale and delta age, i.e., DA-chronological age (CA), was used to compare groups. RESULTS: The DA of cancer survivors was accelerated by almost 1 year compared to their CA (9.9±3.1 vs. 8.9±2.8, p=0.040). The greatest difference was observed among patients with brain tumor: delta (DA-CA) was 2.2±1.1 years. Among all cancer patients, only children with familial adenomatous polyposis (FAP)-associated hepatoblastoma (HP) demonstrated delayed DA, with regard to both other cancer survivors (p=0.011) and healthy patients (p=0.037). All four patients with HP suffered from FAP, and three of them had documented adenomatous polyposis coli (APC) genes mutation. The DA of cancer patients having teeth with short roots was significantly greater than that of the cancer survivors without this anomaly (12.8±3.2 vs. 9.0±2.4, p < 0.001). CONCLUSION: DA in children may be altered by cancer disease.

Evaluation of Changes to the Oral Microbiome Based on 16S rRNA Sequencing among Children Treated for Cancer.

A child's mouth is the gateway to many species of bacteria. Changes in the oral microbiome may affect the health of the entire body. The aim of the study was to evaluate the changes in the oral microbiome of childhood cancer survivors. Saliva samples before and after anti-cancer treatment were collected from 20 patients aged 6-18 years, diagnosed de novo with cancer in 2018-2019 (7 girls and 13 boys, 7.5-19 years old at the second time point). Bacterial DNA was extracted, and the microbial community profiles were assessed by 16S rRNA sequencing. The relative abundances of Cellulosilyticum and Tannerella genera were found to significantly change throughout therapy (p = 0.043 and p = 0.036, respectively). However, no differences in the alpha-diversity were observed (p = 0.817). The unsupervised classification revealed two clusters of patients: the first with significant changes in Campylobacter and Fusobacterium abundance, and the other with change in Neisseria. These two groups of patients differed in median age (10.25 vs. 16.16 years; p = 0.004) and the length of anti-cancer therapy (19 vs. 4 months; p = 0.003), but not cancer type or antibiotic treatment.

Salivary immunoglobulin A level during steroids and chemotherapy treatment administered in remission induction phase among pediatric patients with acute lymphoblastic leukemia.

The agents used in the treatment of acute lymphoblastic leukaemia (ALL) might affect the oral health of cancer patients.The study aims to assess the changes in the levels of immunoglobulin A (IgA) in saliva and blood, during first 22 days of intensive chemotherapy of ALL in children.Saliva and blood samples were taken from 24 patients, including 13 boys and 11 girls (age range: 4 - 17 years) on days 1, 8 and 22 of treatment. The levels of immunoglobulin A and total protein were estimated in samples at each time-point. The distribution of the quantitative variables was assessed using the Shapiro-Wilk test. Non-parametric statistics were used to compare the levels of repeated measurements and post hoc non-parametric analysis was applied for between time-point comparisons.A constant relationship was found between the levels of Ig A in blood and saliva (r = 0.28; P = .031). No change in salivary IgA level was observed in the prednisone-only prephase, but it dropped significantly on day 22 (10.7+/-4.8 vs 9.6+/-6.4 vs 5.7+/-3.9 ng/mL; P = .04), when chemotherapy was given (anthracycline, vincristine, L-asparaginase).In blood, the total protein level decreased significantly between day 1 and 22 (6.2+/-0.4 vs 5.1+/-0.3 g/dL; P = .001). Lymphocyte count (per microliter) also decreased (2.12+/-0.8 vs 0.41+/-0.1 vs 1.08+/-0.5; P = .002). Four children suffered from oral mucositis graded 1 or higher between days 8 and 22.Chemotherapy given during the treatment of childhood ALL is associated with a reduction in the level of salivary immunoglobulin A. Prevention of the drop of salivary IgA may diminish the risk of occurrence of acute mucosal complications.

Dental caries among childhood cancer survivors.

One of many possible complications of cancer therapy in children is enamel demineralization and such changes in the ion content of dental hard tissues may increase susceptibility to caries. The study aims to assess the prevalence of dental caries among childhood cancer survivors.A cross-sectional study was conducted on 225 children aged between 4 and 18 years, including 75 cancer patients and 150 sex- and age-matched controls. The cancer survivors were recruited from single pediatric oncology center. The control group was formed from students of randomly selected kindergartens and schools. Dental investigation was held between July 2013 and January 2016, approximately 5 years after the cessation of anticancer treatment (range: 6-155 months). The occurrence of dental caries was assessed with DMF/dmf index (showing the mean number of decayed, missing and filled permanent/deciduous teeth). Univariate statistical approach was performed and P-values < .05 were considered as statistically significant.The frequency of dental caries was comparable in both groups (85.4% vs 84%). However, the DMF index was higher in cancer patients than in controls: the median and interquartile ranges were 2 (0-4) vs 0 (0-2); P < .01. This correlates with duration of anticancer therapy (r = 0.26; P < .05). Moreover, children who had radiotherapy of the head and neck regions had significantly higher DMF scores than the ones who did not: 4.5 (1-6) vs 2 (0-4); P < .05. Socioeconomic and education status within family also has a significant impact on DMF scores in the cancer group. In conclusion, cancer patients, particularly those with a poor social background, should receive professional dental care as their caries process is more active than that of healthy peers.

Correction to: Health status of Polish children and adolescents after cancer treatment.

The first and family names of the authors were interchanged. The correct author names are now correctly presented in this article.

Health status of Polish children and adolescents after cancer treatment.

In the last 40 years, considerable progress was made in the treatment of childhood cancer. Nearly 80% of children achieve long-term clinical remission or are permanently cured. This improvement is however not without sacrifice. This is the first Polish study analyzing the general health status and epidemiology of organ late effects in the cohort of Polish childhood and adolescent cancer survivors monitored by doctors and registered in the on-line national database for late effects (N = 1761). This tool collects information on previous therapy and current health status (medical history, physical examination, laboratory tests) of cancer survivors. The survivors are invited to take part in the follow-up examination 5 years after the end of treatment. In the study group, 207 survivors (11.75%) had no complaints; whereas in 1554 cases (88.25%), one or more symptoms/complaints suggesting organ dysfunction were reported. In the whole group, the circulatory problems were most common (31.7%); more than 20% of survivors presented complaints or abnormal function of the urinary tract and had skin, dental, skeletal/muscular problems, or difficulty with chewing. Obesity or short stature alone (21.4%) and a variety of endocrine problems (short stature, obesity, thyroid dysfunction, and gonads toxicity) were present in 323 patients (118 females 15.0% and 205 males 21.0%). Gonadal dysfunction, as the only problem, occurred in 75 girls (9.6%) and 131 boys (13.4%). In our cohort, severe or life-threatening health conditions (3 and 4 grade according to toxicity criteria) were present in low percentage, i.e., 0.2% in the circulatory system, 0.3% in the respiratory tract and, 0.7% in kidney insufficiency. CONCLUSION: Our findings indicate that many childhood cancer survivors demonstrate numerous complaints, even a short time after treatment, suggesting the importance of regular follow-up examinations in subsequent years. What is Known: • Contemporary studies indicate that a significant number of childhood cancer survivors present different long-term side effects which influence their quality of life. What is New: • This is the first nationwide study performed in the largest cohort of Polish childhood cancer survivors concerning general health status and frequency of organ dysfunction.

Dental Anomalies as Late Adverse Effect among Young Children Treated for Cancer.

PURPOSE: The aim of this study was to compare the incidence of dental complications in childhood cancer survivors with that of healthy control subjects, and to determine the possible influence of various factors associated with patient and treatment. MATERIALS AND METHODS: Sixty-one panoramic radiographs of the dentition of cancer survivors were compared with 521 radiographs of healthy patients at a similar age, between 5 and 18 years. The mean period from termination of therapy was 4.9 years (58.9 ± 34.3 months), and 51 children (83.60%) were under age 5 when therapy began. RESULTS: Dental anomalies were found in 38 cancer survivors (62.29%) and 69 control subjects (13.24%) (p < 0.001). Agenesis of teeth was found in 19 cancer patients (31.14%) and in 48 control subjects (9.21%). Microdontic teeth were found in 22 cancer survivors (36.06%) and 15 control subjects (2.87%) (p < 0.001), whereas teeth with short roots were found in seven cancer patients (11.47%) and 15 control subjects (2.87%) (p < 0.01). Dental anomalies in cancer patients were more common in some tooth groups and were not observed in others. The frequency of dental anomalies did not show correlation with age at the beginning or termination or time of therapy. CONCLUSION: Children under the age of 5 are in a high risk group for dental complications after anticancer treatment. Rudimentary chemotherapy has a considerable impact on the occurrence of dental anomalies.

Clinical factors in relapses of Wilms' tumor--results for the Polish Pediatric Solid Tumors Study Group.

BACKGROUND: The risk factors responsible for recurrences of Wilms' tumor (nephroblastoma) are still under discussion. The aim of the study was to analyze the relationship between relapses of Wilms' tumor and the patients' clinical history. MATERIAL AND METHODS: Clinical data from children registered in the Polish Pediatric Solid Tumors Study Group were analyzed. The clinical stages (CS), pathology variants (high risk: HR, intermediate risk: INT, and low risk: LOW) and chemotherapy regimens were correlated with the outcomes. RESULTS: Recurrences developed in 34 out of 288 (11.8%) patients with Wilms' tumor treated in accordance with International Society for Pediatric Oncology 2001 (SIOP 2001) protocols. Of these 34 patients, 11 initially had CS I, seven were at CS II, four were at CS III, 11 were at CS IV and one had CS V. There were eight patients with second recurrences; of these, seven were in the INT risk group and one in the high histological risk group. There was no correlation between age (p=0.256) or gender (p=0.538) and the risk of tumor recurrence. In the study group, seven out of 10 patients with local recurrences are alive; as are 13 out of 22 patients with distant recurrences (p=0.703). Those who died due to disease progression comprised six out of 26 patients with a first recurrence (four HR, two INT), and seven out of eight with a second recurrence (one HR, six INT). CONCLUSIONS: The prognosis after relapse in initially metastatic patients did not differ from that in patients who had primarily localized disease. The pathology variants probably had more significance.

Interleukin 18 as a marker of chronic nephropathy in children after anticancer treatment.

Novel markers of nephrotoxicity, including kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18), and beta-2 microglobulin, were used in the detection of acute renal injury. The aim of the study was to establish the frequency of postchemotherapy chronic kidney dysfunction in children and to assess the efficacy of IL-18, KIM-1, and beta-2 microglobulin in the detection of chronic nephropathy. We examined eighty-five patients after chemotherapy (median age of twelve years). The median age at the point of diagnosis was 4.2 years, and the median follow-up time was 4.6 years. We performed classic laboratory tests assessing kidney function and compared the results with novel markers (KIM-1, beta-2 microglobulin, and IL-18). Features of subclinical renal injury were identified in forty-eight children (56.3% of the examined group). Nephropathy, especially tubulopathy, appeared more frequently in patients treated with ifosfamide, cisplatin, and/or carboplatin, following nephrectomy or abdominal radiotherapy (P = 0.14, P = 0.11, and P = 0.08, resp.). Concentrations of IL-18 and beta-2 microglobulin were comparable with classic signs of tubulopathy (P = 0.0001 and P = 0.05). Concentrations of IL-18 were also significantly higher in children treated with highly nephrotoxic drugs (P = 0.0004) following nephrectomy (P = 0.0007) and abdominal radiotherapy (P = 0.01). Concentrations of beta-2 microglobulin were higher after highly toxic chemotherapy (P = 0.004) and after radiotherapy (P = 0.02). ROC curves created utilizing IL-18 data allowed us to distinguish between children with nephropathy (value 28.8 pg/mL) and tubulopathy (37.1 pg/mL). Beta-2 microglobulin and IL-18 seem to be promising markers of chronic renal injury in children after chemotherapy.

Role of GSTM1, GSTP1, and GSTT1 gene polymorphism in ifosfamide metabolism affecting neurotoxicity and nephrotoxicity in children.

The aim of this study was to evaluate the impact of GSTM1, GSTT1, and GSTP1 gene polymorphism on urinary excretion of unchanged ifosfamide, 2-dechloroethylifosfamide (2DCIF), and 3-dechloroethylifosfamide (3DCIF) with regard to the incidence of ifosfamide-related nephrotoxicity and neurotoxicity in children. The study comprised 76 children (38 girls, 38 boys) ages 9.84 to 210 months who were being treated for various malignant diseases with ifosfamide. The children were enrolled after identification of genotype coding for three classes of glutathione S-transferases (GSTM1, GSTT1, and GSTP1) at the initial stage of diagnosis. (P) nuclear magnetic resonance spectroscopy was used to analyze the urinary excretion of unchanged ifosfamide, 2DCIF, and 3DCIF metabolites on consecutive days after the end of the 3-hour infusion of ifosfamide. In children with polymorphic locus of the GSTP1 gene compared with children with homozygous wild alleles, increased urinary excretion of 3DCIF (P=0.029) and decreased creatinine clearance was found (Mann-Whitney P=0.03; median 81.1 mL/min/1.73 m vs. 105.0 mL/min/1.73 m, respectively). The authors' multidimensional analysis model revealed that besides the total ifosfamide dose and co-administration of other toxic drugs, polymorphic locus of GSTP1 gene may be one of the factors determining a higher toxicity of the cytostatic agent. The model was construed at P=0.029. Moreover, no correlation was found between the GSTM1 or GSTT1 genotype and ifosfamide toxicity and the urinary excretion of its metabolites. The results of this analysis indicate that individual reactions to ifosfamide can depend on inherited genetic polymorphisms, especially associated with the GSTP1 gene coding detoxifying enzyme.

[Increased urinary excretion of the neurotoxic side-chain metabolites of ifosphamide in children with polymorphism of the glutathione S-transferases genes]. / Zwiekszone dobowe wydalanie neurotoksycznych metabolitów ifosfamidu u dzieci z dziedziczonym polimorfizmem genów kodujacych transferazy S-glutationu.

UNLABELLED: From 5% to 30% of children treated with ifosphamide (IF) develop symptoms of neurotoxicity due to toxic metabolites of the drug: 2- and 3- dechloroifosphamide (2- and 3-DCIF) and chloracetaldehyde (CAA), which cause glutathione depletion in cells. The aim of the study is to establish the influence of polymorphism of genes encoding for glutathione S-transferases classes pi (GSTP1), mi (GSTM1) and theta (GSTT1) on frequency of neurotoxicity of IF and amounts of toxic metabolites of the drug excreted in urine. MATERIAL AND METHODS: Neurotoxicity of IF was assessed in 76 children (38 girls and 38 boys), aged 9 to 210 months with diffrent kinds of neoplasms. They were treated with IF in 3-hours infusion in doses from 1.5 g/m2 to 3 g/m2 for 3 to 5 days. Before chemotherapy, deletions of GSTT1, GSTM1 genes and transition at +313 A-G in GSTP1 gene were identified with PCR and PCR-FRLP method, respectively. Daily urine excretion of 2-DCIF, 3-DCIF and unmetabolised IF was assessed with nuclear magnetic resonance (31P NMR). RESULTS: Symptoms of neurotoxicity were observed in 14 (18%) of 76 examined children treated with IF Comparing to children without neurological symptoms, in children with encephalopathy urinary excretion of unchanged ifosphamide was lower (p=0.055) and 2DCIF and 3DCIF was increased. Concomitantly, in children with transition at 313 A-->G GSTP1 gene concentrations of 2DCIF and 3DCIF were increased. Excretion of unmetabolised IF was statistically significantly higher in children with deletion of GSTT1 gene (p=0.02). Moreover, no correlation was found between the GSTM1 genotype and the excretion of ifosphamide and its metabolites. CONCLUSION: The results suggest that ifosphamide can be the substrate for glutathione S-transferases. Polymorphism of genes coding for glutathione S-transferases can influence individual reactions to iphosphamide.

Polymorphism within the glutathione S-transferase P1 gene is associated with increased susceptibility to childhood malignant diseases.

BACKGROUND: Glutathione S-transferases (GSTs) are involved in the metabolism of carcinogens and anticancer drugs. Functional polymorphisms exist in at least three genes that code for the GSTs, such as the GSTM1 and GSTT1 gene deletions or the A-G transition within the GSTP1 gene, which represents distinct GSTP1a and GSTP1b alleles. In the present case-control study, we aimed at estimation of the relationship between the GSTM1, GSTT1, and GSTP1 genotypes and the susceptibility to various types of childhood malignancies and the early relapses of diseases. PROCEDURE: Using the polymerase chain reaction on the DNA extracted from peripheral blood leukocytes, we identified the GSTM1, GSTT1, and GSTP1 genotypes in 234 children at the initial stage of a childhood malignancy as well as in 460 age-and sex-matched healthy subjects who served as controls. The follow-up period for the effects of the anticancer therapy ranged from 11 to 43 months. RESULTS: Compared to the controls, a significant increase in the frequency of the GSTP1b/GSTP1b genotype (odds ratio (OR) 5.7; 95% confidence limit (CL) from 2.4 to 13.8; Pearsons Chi-square P = 0.0001) was detected in the children with neoplasms. The GSTM1 and GSTT1 genotypes did not show any correlation with the risk of the de novo diagnosed neoplasms. During the observation, 62 children (26%) were found to be present with a local or disseminated recurrence of the diseases. The analysis indicated a trend in increasing risk of relapse for carriers of the GSTP1a allele (OR = 3.29; 95% CL from 0.73 to 14.67 P = 0.03). CONCLUSIONS: Our results support the hypothesis that GST genotype affects etiology and outcome of a variety of childhood malignancies.

[Increased frequency of A-G transition at exon 5 of GSTP1 as a genetic risk factor for acute childhood leukaemia]. / Zwiekszona czestosc tranzycji A-G eksonu genu GSTP1 jako genetyczny cynnik ryzyka podatnosci na ostre bialaczki wieku dzieciecego. Doniesienie I.

UNLABELLED: Polymorphism of genes encoding glutathione S-transferases GSTM1, GSTT1 GSTP1 is one of the genetic predictors of susceptibility to cancers in the adults. The frequency of deletions of GSTM1. GSTT1 genes and transition A-G in GSTP1 gene were taken into consideration. THE AIM of this study was to investigate the role of GST genes polymorphisms as a genetic risk factor for acute lymphoblastic leukaemia (ALL), and to study the relationship of these polymorphisms with clinical outcome in childhood leukaemias. MATERIAL AND METHODS: 86 children with newly diagnosed acute leukaemia (female: male ratio = 37:49. median age = 7.8 years) and 460 healthy controls were examined using the PCR and PCR-RFLP methods to identify polymorphisms within GSTM1, GSTT1 and GSTP1 genes. In the group of children with ALL. the frequency of relapses, deaths, clinical course, immunophenotype of blasts and the initial response to prednisone were also analyzed. RESULTS: the higher frequency of A-G transition in the GSTP1 gene was identified in the group of children with ALL in comparison to healthy controls (OR=3.13, 95%CI=1.4-7). We also found that the combination of GSTPl (Val/Val) and GSTM1 null genotypes further increased the risk of ALL (OR= 10.63, 95%CI=3.47 - 32.58; p =0.0001). No differences in the frequency of GSTM1 and GSTTI genes between both groups (OR=1; 95%CI=0,59-1,74 and OR=0, 71; 95%CI=0.45-1.13 respectively) were observed. Statistical analysis has not revealed any connections between polymorphisms within glutathione S-transferases genes and the frequency of relapses and death or poor initial response to prednisone. However, the biphenotypic immunophenotype or B-line blasts were the risk factors of relapse or death of progression in ALL (p=0.03). CONCLUSION: transition in exon 5 of GSTP1 gene (alone or combined with GSTM1 deletion) may be one of the molecular predictors of higher susceptibility to acute leukaemia in children. but not of the clinical course of this disease.

Analysis of the urinary excretion of ifosfamide and its N-dechloroethylated metabolites in children using 31P-NMR spectroscopy.

Amounts of ifosfamide (CAS 3778-73-2) and its N-dechloroethylated metabolites excreted in the urine were measured using 31P-NMR spectroscopy in 26 cancer children treated with this drug. Strong inter-patient variation in levels of these compounds were found. These differences were independent from patients age, body surface area, and sex, the dose of the drug, suggesting genetic base of observed variations in ifosfamide metabolism.

[Polymorphism at the glutathione S-transferase pi locus as a risk factor for ifosfamide nephrotoxicity in children]. / Polimorfizm genu kodujacego transferaze S-glutationowa klasy P1 jako czynnik ryzyka nefrotoksycznego dzialania ifosfamidu u dzieci.

The aim of the study was an assessment of various risk factors for nephrotoxicity of ifosfamide (IF) in children taking into account the importance of the concentrations of toxic metabolites of the drug excreted with urine and the polymorphism of genes encoding S-glutathione transferases of mi, pi, and theta classes (GSTM1, GSTP1 and GSTT1). The study was carried out in 37 children aged 2-17 years (mean age 8.9 +/- 4.5 years) treated with IF in 3 g/m2 dose for various malignant diseases. For the assessment of the incidence of deletion of GSTM1 and GSTT1 genes PCR method was applied while in the case of GSTP1 gene the polymorphism of A-G codon 105 was detected by the PCR-RFLP method. Before and after each treatment cycle the cumulative ifosfamide dose was calculated and the biochemical indices of renal canalicular and glomerular function were assessed which were graduated according to extended WHO criteria. Additionally, nuclear magnetic resonance 31P NMR method was applied for calculation of the concentrations of ifosfamide nephrotoxic metabolites and of the unchanged drug excreted with urine. The analysis performed demonstrated that in children with GSTP1 gene A-G codon 105 transition, a statistically significantly (p = 0.01) higher urinary excretion of toxic ifosfamide metabolites occurred, that increased with the cumulative drug dose. The age, sex and deletions of GSTM1 and GSTT1 genes exerted no effect on the concentrations of the toxic metabolites excreted with urine. The results of the studies demonstrate that GSTP1 gene mutations are the genetic risk factor for nephrotoxic complications of ifosfamide use.