Assessment of Metabolic Syndrome and Kidney and Heart Function in Childhood Cancer Survivors.

BACKGROUND: The survivors of childhood cancer suffer from a number of long-term side effects. These include atherosclerosis and cardiovascular diseases (CVDs) that develop earlier in adulthood than in the rest of the population. The aim of this study was to identify prognostic factors of developing atherosclerosis before the development of symptomatic CVD. METHODS: A total of 141 children that were 7-18 years old were examined; there were 116 survivors of childhood malignancies (hematopoietic and lymphoproliferative malignancies-52; neuroblastoma-22; Wilms tumor-24; other solid tumors-18) and 25 healthy controls. Anthropometric measurements, blood pressure measurements, ultrasonography of the abdomen, echocardiography, and laboratory tests were performed. RESULTS: There were no significant differences in gender distribution, time from the end of the treatment, weight, BMI, prevalence of central obesity, blood pressure and resistive index of the renal arteries, lipid profile, or glucose and fibrinogen levels. Patients with solid tumors had a significantly lower height and worse renal function. Patients with hematological malignancies significantly presented the lowest shortening fraction of the left ventricle. The salusin ß levels were significantly higher in the control group than among the patients. CONCLUSIONS: The type and severity of side effects are closely related to the type of neoplasm and the treatment that has been undergone. Careful observation and regular follow-up are necessary.

Cytokine IL6, but not IL-1ß, TNF-α and NF-κB is increased in paediatric cancer patients.

Cytokines are responsible for maintaining homeostasis as cell growth, differentiation, migration and apoptosis mediators. They play a pivotal role in immune responses to inflammatory reactions. In oncological diseases, the cross-talk between cells of the immunological system and cells of the tumour microenvironment is led by cytokines. Also, the overproduction of cytokines may change the tumour microenvironment and stimulate tumour development and growth. To test whether pro-inflammatory cytokines or associated with them transcription factor levels are changed in a group of 53 paediatric cancer patients, serum levels of IL-1ß, IL-6, TNF-α and NF-κB were assessed and compared to measures in 25 healthy controls. Increased levels of IL-6 were found among patients in active oncological treatment (P=0.002) but not among patients whose treatment was completed. Our data suggest that IL6, but not IL-1ß, TNF-α and NF-κB, is elevated as a result of the immune response in the microenvironment around the tumour and in blood cancers, among patients who were not infected at the time of blood collection. Thus, IL6 levels might serve as a potential biomarker of oncohematological diseases.

Dimethylarginines in Children after Anti-Neoplastic Treatment.

Background and Objectives: According to a recent Cochrane systematic review, renal impairment can develop in 0-84% of childhood cancer survivors in the future. The renal function impairment in this patient group can be related to nephrectomy, nephrotoxic agents therapy, abdominal radiotherapy, and combinations of these treatment methods. In this study, in a population of patients after anti-neoplastic therapy, with particular emphasis on patients after Wilms' tumour treatment, we compared new substances which play role in the chronic kidney disease (CKD) pathogenesis (asymmetric dimethylarginine-ADMA, symmetric dimethylarginine-SDMA) with standard renal function markers (e.g., creatinine and cystatin C in serum, creatinine in urine, etc.) to assess the usefulness of the former. Materials and Methods: Eighty-four children, without CKD, bilateral kidney tumours, congenital kidney defects, or urinary tract infections, with a minimum time of 1 year after ending anti-neoplastic treatment, aged between 17 and 215 months, were divided into three groups: group 1-patients after nephroblastoma treatment (n = 21), group 2-after other solid tumours treatment (n = 44), and group 3-after lymphoproliferative neoplasms treatment (n = 19). The patients' medical histories were taken and physical examinations were performed. Concentrations of blood urea nitrogen (BUN), creatinine, cystatin C, C-reactive protein (CRP), ADMA, and SDMA in blood and albumin in urine were measured, and a general urine analysis was performed. The SDMA/ADMA ratio, albumin-creatine ratio, and estimated glomerular filtration rate (eGFR) were calculated. eGFR was estimated by three equations recommended to the paediatric population by the KDIGO from 2012: the Schwartz equation (eGFR1), equation with creatinine and urea nitrogen (eGFR2), and equation with cystatin C (eGFR3). Results: Both the eGFR1 and eGFR2 values were significantly lower in group 1 than in group 3 (eGFR1: 93.3 (83.1-102.3) vs. 116.5 (96.8-126.9) mL/min/1.73 m2, p = 0.02; eGFR2: 82.7 (±14.4) vs. 94.4 (±11.9) mL/min/1.73 m2, p = 0.02). Additionally, there were weak positive correlations between SDMA and creatinine (p < 0.05, r = 0.24), and cystatin C (p < 0.05, r = 0.32) and weak negative correlations between SDMA and eGFR1 (p < 0.05, r = -0.25), eGFR2 (p < 0.05, r = -0.24), and eGFR3 (p < 0.05, r = -0.32). Conclusions: The usefulness of ADMA and SDMA in the diagnosis of renal functional impairment should be assessed in further studies. eGFR, calculated according to equations recommended for children, should be used in routine paediatric practice.

The effect of l-arginine supplementation and surgical trauma on the frequency of myeloid-derived suppressor cells and T lymphocytes in tumour and blood of colorectal cancer patients.

PURPOSE: l-arginine (L-arg) deficiency causes immunosuppression, but it is unknown if L-arg supplementation in colorectal cancer (CRC) patients restores immune system activity. Our objective was to investigate the effect of L-arg supplementation on the frequency of monocytic (M) and polymorphonuclear (PNM) myeloid-derived suppressor cells (M-MDSCs and PMN-MDSCs, respectively). METHODS: We enrolled 65 CRC patients (34 males, 31 females) aged 69 â€‹± â€‹10 years into a prospective, randomised, double-blind study. Twenty-eight patients received L-arg and 37 received placebo for 9 days at a dose of 10 â€‹g/day. The frequency changes in MDSC, CD4+ cells and the concentration of C-reactive protein (CRP) were assessed before supplementation with L-arg (test 1), after 9 days of supplementation (test 2), and after surgery on day 11 (test 3). RESULTS: The frequency of M-MDSC in the tumours of patients receiving L-arg supplementation was higher than in placebo-treated patients, as was the frequency of PMN-MDSC and M-MDSC in the mucosa. CRP concentration in the serum of placebo-treated patients in test 2 was higher than in test 1, and the concentration in the serum of patients with L-arg supplementation in test 2 was lower than in test 1. Moreover, the expression pattern of the argininosuccinate synthase 1 (ASS1) suggests that CRC is not auxotrophic for L-arg. CONCLUSIONS: The results of this study do not support the hypothesis that L-arg supplementation in CRC patients can reduce immunosuppression by decreasing the frequency of suppressor cells and increasing the frequency of effector CD4+ T cells.

Plasma free amino acid profiling as metabolomic diagnostic and prognostic biomarker in paediatric cancer patients: a follow-up study.

Amino acids (AAs) play a crucial role in cancer cell metabolism. Levels of 22 plasma AAs at the time of diagnosis and after treatment were established among 39 pediatric cancer patients and 33 healthy children. Glutamic acid levels decreased and tryptophan levels increased during treatment. Cancer patients presented significantly lower levels of glutamine and leucine post-treatment while levels of 12 other AAs were higher comparing to controls. Results suggest that plasma free AA profile may serve as a prognostic biomarker.

Comparison of Fatty Acid Profiles in a Group of Female Patients with Chronic Kidney Diseases (CKD) and Metabolic Syndrome (MetS)⁻Similar Trends of Changes, Different Pathophysiology.

Fatty acid (FA) profiles in the plasma of patients with metabolic syndrome and chronic kidney disease (CKD) seem to be identical despite their different etiology (dietary mistakes vs. cachexia). The aim of this study was to compare both profiles and to highlight the differences that could influence the improvement of the treatment of patients in both groups. The study involved 73 women, including 24 patients with chronic kidney disease treated with haemodialysis, 19 patients with metabolic syndrome (MetS), and 30 healthy women in the control group. A total of 35 fatty acids and derivatives were identified and quantified by gas chromatography. Intensified elongation processes from acid C10:0 to C16:0 were noted in both groups (more intense in MetS), as well as an increased synthesis of arachidonic acid (C20:4n6), which was more intense in CKD. Significant correlations of oleic acid (C18:1n9), gamma linoleic acid (C18:3n6), and docosatetraenoate acid (C22:4n6) with parameters of CKD patients were observed. In the MetS group, auxiliary metabolic pathways of oleic acid were activated, which simultaneously inhibited the synthesis of eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) from alpha lipoic acid (ALA). On the other hand, in the group of female patients with CKD, the synthesis of EPA and DHA was intensified. Activation of the synthesis of oleic acid (C18: 1n9 ct) and trans-vaccinic acid (C18:1) is a protective mechanism in kidney diseases and especially in MetS due to the increased concentration of saturated fatty acid (SFA) in plasma. The cause of the increased amount of all FAs in plasma in the CKD group, especially in the case of palmitic (C16:0) and derivatives stearic (C18:0) acids, may be the decomposition of adipose tissue and the progressing devastation of the organism, whereas, in the MetS group, dietary intake seems to be the main reason for the increase in SFA. Moreover, in MetS, auxiliary metabolic pathways are activated for oleic acid, which cause the simultaneous inhibition of EPA and DHA synthesis from ALA, whereas, in the CKD group, we observe an increased synthesis of EPA and DHA. The higher increase of nervonic acid (C24:1) in CKD suggests a higher degree of demyelination and loss of axons.

Hair cortisol concentration in a population without hypothalamic-pituitary-adrenal axis disorders.

BACKGROUND: Measuring hair cortisol seems to be a good alternative to laboratory tests used thus far in routine endocrine diagnostics, primarily because it is independent of the circadian rhythm of cortisol. Due to the average hair growth of 1 cm per month, the results are related to the average blood cortisol levels over the previous weeks, months or years (depending on the length of the hair sample). OBJECTIVES: The aim of this study is an attempt to apply hair cortisol concentration (HCC) measurements to clinical endocrine diagnostics, based on reference cortisol concentrations in the blood in a population without disorders of the hypothalamic-pituitary-adrenal axis (HPA). MATERIAL AND METHODS: In the final selection process, 44 patients were enrolled in the study, all with negative interviews regarding disorders of the HPA and with reference levels of cortisol concentration obtained in routine laboratory tests. In the pre-analytic phase, we used 1 cm proximal hair strands cut from the posterior vertex area of the head, followed by the incubation of a 20 mg hair sample in methanol. The final cortisol measurement was done using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The results of HCC ranged from 2 pg/mg up to 51.63 pg/mg. The diurnal decrease in cortisol levels was significantly lower in females than in males (p = 0.031), but we do not consider that difference to be clinically significant. The difference in the HCC between males and females was not statistically significant (p = 0.767). The linear regression coefficient for age was not statistically significant (p = 0.847). Neither the regression coefficients for gender nor the gender and age interactions were statistically significant (p = 0.815). CONCLUSIONS: Hair cortisol concentration measurement, unlike other endocrinological tests, gives information about the cortisol concentration in the long-term perspective. The results obtained in this study may be used as a reference for further research aimed at determining normal values of HCC.

Amino acid profiles as potential biomarkers for pediatric cancers: a preliminary communication.

AIM: Childhood cancer remains one of the main cause of death in the pediatric population. Amino acids (AAs) level alterations in plasma are considered to play a role in carcinogenesis and further course of the disease. METHODS: Seventy-seven children with cancer, including 47 with hematological and 30 with solid tumors were enrolled in this study and compared with healthy children. Twenty-two plasma-free AAs were determined by HPLC with fluorometric detection. RESULTS: The results revealed significant decrease in glutamine levels for oncological patients and significant increase in aspartic acid, glutamic acid, asparagine, serine, citrulline, alanine, GABA, tryptophan, methionine, valine, phenylalanine and isoleucine levels in cancer children versus control. CONCLUSION: Plasma-free AA profile as a biomarker, which combines metabolic and clinical data, as an innovative and interdisciplinary approach, may allow for faster detection of tumor occurrence, and in the future for monitoring patient during treatment, and possible prediction of cancer recurrence.

Renal function and low-molecular-weight proteins (cystatin C, ß2-microglobulin, neutrophil gelatinase-associated lipocalin) in child and young adult cancer survivors.

BACKGROUND: We sought to verify the hypothesis that children and young adults with cancer who have completed treatment differ according to the type and degree of renal damage. PROCEDURE: This study included 144 children and young adults (73 female) who had completed treatment for leukemias and lymphomas (group L, n=45), Wilms tumor (group W, n=52) and other solid tumors (group S, n=47). The following parameters were evaluated: serum concentrations of creatinine, cystatin C, ß2-microglobulin, neutrophil gelatinase-associated lipocalin and urine excretion of albumin, and urinalysis with sediment. Glomerular filtration rate (eGFR) was estimated using the classic Schwartz (eGFRSch), Schwartz redux (eGFRSchred), and Filler (eGFRFiller) formulas and with the new Schwartz equation for patients with chronic kidney disease (eGFRSchCKD). RESULTS: Group S had the lowest eGFRSchCKD and eGFRFiller, the highest serum cystatin C and the highest albumin excretion compared with groups L and W. Groups S and W had lower eGFRSch and eGFRSchred and higher serum ß2-microglobulin and neutrophil gelatinase-associated lipocalin compared with group L. Group W had lower eGFRSchCKD than group L. CONCLUSIONS: Children and young adults with cancer who have completed treatment differ in the type and degree of renal damage they sustain.

Association between intestinal and antioxidant barriers in children with cancer.

OBJECTIVE: Reactive oxygen species (ROS) play a role in cancerogenesis processing and damage tissues. Furthermore, oncological treatment may impair proper function of the gut barrier. The aim of this study was to measure intestinal permeability in children in clinical remission for solid tumours and to search for a possible relationship between free radicals and the intestinal barrier. No such investigation in children has been reported so far. RESEARCH METHODS AND PROCEDURES: The prospective study consisted of 19 paediatric patients with cancer after completion of chemotherapy. 32 healthy children from the outpatients clinics were recruited for measurement of intestinal permeability and antioxidant barrier as a control group. Intestinal permeability was assessed by measurement of urinary lactulose and mannitol after oral challenge. Antioxidant enzymes: superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in erythrocytes were assessed. Ischemia modified albumin (IMA) concentration was measured in serum. RESULTS: Cancer patients excreted less mannitol and more lactulose versus controls. The ratio of lactulose to mannitol was significantly higher in oncological children vs control (mean 0.188 and 0.0453, respectively, p=0.0006,). Significantly higher IMA level in the oncological group vs control was noted (mean 123.8 and 87.3 U/ml, respectively, p=0.0037). No correlation between intestinal permeability and oxidative stress barrier was found. CONCLUSIONS: Our data shows that intestinal barrier is damaged in paediatric cancer patients after chemotherapy. IMA is believed to play a protective role in the defence against tissue damage. No correlation was found between these two barriers.

Renal function and solitary kidney disease: Wilms tumour survivors versus patients with unilateral renal agenesis.

AIMS: To test the hypothesis that Wilms tumour survivors (WTs) experience increased disturbance in renal function, even after prompt treatment, compared to patients with unilateral renal agenesis (URA). METHODS: To assess the renal function of 30 WTs and 17 individuals with URA, the estimated glomerular filtration rate (eGFR) was calculated using the Schwartz and Filler formulas as well as the new Schwartz equation for chronic kidney disease. To measure kidney damage, serum levels and urine excretion of ß(2)-microglobulin (B2M), cystatin C (Cys C), neutrophil gelatinase-associated lipocalin (NGAL) were tested, N-acetyl-ß-glucosaminidase (NAG), and albumin urine excretion and urine sediment were examined. Blood pressure was measured. RESULTS: No differences were found between the groups in terms of eGFR, serum Cys C, B2M and NGAL concentrations. The urine excretion of Cys C, NGAL and NAG was similar in both groups. URA patients had higher B2M excretion than WTs. Arterial hypertension was present in 7/30 (23%) WTs and 1/17 (6%) patients with URA. CONCLUSIONS: WTs have similar eGFR to individuals with URA and are more likely to have arterial hypertension. The patients with URA have signs of tubular damage. This study demonstrates the need for nephrological monitoring of individuals with a single kidney.

Parameters of antioxidant barrier in different histopathologic types of pediatric cancers.

AIM OF THE STUDY: The goal of this study was to evaluate the activities of erythrocyte superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), and the levels of glutathione (GSH) and ischemia-modified albumin (IMA), as potential markers in different histopathologic types of pediatric neoplasms. No studies on this subject have been reported to date. MATERIAL AND METHODS: SOD, GSH-Px, GSH, and IMA were measured before oncologic treatment in 129 children with neuroblastoma (NB), soft tissue sarcomas (STS), brain tumors, Hodgkin's disease (HD), and acute leukemias, and in 30 healthy controls. RESULTS: The statistical significance of SOD was observed in patients with brain tumors (median 1840.2 U/g Hb, p = 0.0500). The level of GSH was significantly higher in patients with NB (median 6.38 U/g Hb, p = 0.0031) and leukemias (5.16 U/g Hb, p = 0.0200). IMA was statistically significant in cases of STS, NB, and leukemias compared to healthy children (p = 0.0244, p = 0.0069, and p = 0.0000, respectively). The activity of GSH-Px was not statistically significant. CONCLUSIONS: The antioxidant barrier in all types of pediatric cancers is disturbed. None of the measured parameters was specific enough to represent a reliable marker for any particular histopathologic type of children's neoplasm.

Ischemia-modified albumin as a biochemical marker in children with neuroblastoma and soft tissue sarcomas.

In this study, the levels of ischemia-modified albumin (IMA) in pediatric oncology patients with soft tissue sarcomas (STSs) and neuroblastoma (NB) were analyzed. To date, there have been no studies concerning IMA in these groups of patients. Ninety-nine children with STSs and NB were analyzed from 2006 to 2009, and 30 healthy children were also enrolled in the study. IMA levels were measured throughout treatment in all patients. The levels of IMA in all cancer patients (mean 116.8±39.3 U/ml), in patients with STSs (mean 119.8±27.5 U/ml), and in patients with NB (mean 114.6±36.6 U/ml) were significantly higher than in the control patients (mean 87.3±38.3 U/ml; P=0.0013, 0.0066, and 0.0164, respectively). IMA levels increased before and during the treatment compared with levels in the controls. The determination of IMA levels in pediatric oncology patients with poor prognoses from STSs and NB may play an important role in predicting response to therapy and overall outcome.

The antioxidant status and response to therapy in children with soft tissue sarcomas and neuroblastoma.

BACKGROUND: Antioxidant systems in cells maintain the proper homeostasis of reactive oxygen species, which at high concentrations can induce carcinogenesis. The aim of this study was to evaluate the serum levels of ischemia-modified albumin (IMA), erythrocyte superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) as markers for prognosis in children with neuroblastoma (NB) and soft tissue sarcomas (STS), two cancer types for which reliable prognostic factors are needed. PROCEDURE: SOD, GSH-Px, and IMA were measured before and during responses to therapy assessment in 99 children with NB and STS and in 30 healthy controls. RESULTS: There were no statistically significant differences in the erythrocyte SOD and GSH-Px activities between the patients with cancer and healthy controls. The levels of IMA in patients with STS and NB were found to be significantly higher than in the controls (P = 0.0013; P = 0.0066, and 0.0164, respectively). Decreased activities of SOD and GSH-Px were found in all patients with poor-responding (PRS) cancers and decreased SOD activity was found in patients with PRS NB. An increase in GSH-Px was observed in patients with good-responding (GR) NB. All patients with GR cancers demonstrated higher SOD and GSH-Px activities than patients with PRS cancers. CONCLUSIONS: While determining the levels of specific antioxidants as antioxidant-barrier parameters in children with cancer may be valuable in predicting therapeutic responses as well as outcomes, additional studies are required.