Metabolic Fingerprint in Childhood Acute Lymphoblastic Leukemia.

INTRODUCTION: Acute lymphoblastic leukemia (ALL) is the most prevalent childhood malignancy. Despite high cure rates, several questions remain regarding predisposition, response to treatment, and prognosis of the disease. The role of intermediary metabolism in the individualized mechanistic pathways of the disease is unclear. We have hypothesized that children with any (sub)type of ALL have a distinct metabolomic fingerprint at diagnosis when compared: (i) to a control group; (ii) to children with a different (sub)type of ALL; (iii) to the end of the induction treatment. MATERIALS AND METHODS: In this prospective case-control study (NCT03035344), plasma and urinary metabolites were analyzed in 34 children with ALL before the beginning (D0) and at the end of the induction treatment (D33). Their metabolic fingerprint was defined by targeted analysis of 106 metabolites and compared to that of an equal number of matched controls. Multivariate and univariate statistical analyses were performed using SIMCAP and scripts under the R programming language. RESULTS: Metabolomic analysis showed distinct changes in patients with ALL compared to controls on both D0 and D33. The metabolomic fingerprint within the patient group differed significantly between common B-ALL and pre-B ALL and between D0 and D33, reflecting the effect of treatment. We have further identified the major components of this metabolic dysregulation, indicating shifts in fatty acid synthesis, transfer and oxidation, in amino acid and glycerophospholipid metabolism, and in the glutaminolysis/TCA cycle. CONCLUSIONS: The disease type and time point-specific metabolic alterations observed in pediatric ALL are of particular interest as they may offer potential for the discovery of new prognostic biomarkers and therapeutic targets.

Effect of apolipoprotein E (APOE) gene polymorphisms on the lipid profile of children being treated for acute lymphoblastic leukemia.

BACKGROUND: Medications used to treat acute lymphoblastic leukemia (ALL), such as L-asparaginase, can cause blood lipid disturbances. These can also be associated with polymorphisms of the lipoprotein lipase (LpL) and apolipoprotein E (APOE) genes. PROCEDURE: We aimed to investigate the association between lipid profile, certain LpL and APOE gene polymorphisms (rs268, rs328, rs1801177 and rs7412, rs429358 respectively) as well as the risk subgroup in 30 pediatric patients being treated for ALL, compared with 30 pediatric ALL survivors and 30 healthy controls. RESULTS: The only APOE gene polymorphism with significant allelic and genotypic heterogeneity was rs429358. Further analysis of this polymorphism showed that genotype (CC, CT, or TT) was significantly associated with (1) changes in the lipid profile at the end of consolidation (total cholesterol, LDL, apo-B100, and lipoprotein a) and during re-induction (total cholesterol and apo-B100), and (2) classification in the high risk-ALL subgroup (for CC genotype/C allele presence). CONCLUSIONS: Lipid abnormalities in children being treated for ALL may be associated with the APOE genotype, which is also possibly associated with risk stratification. Further research is needed to confirm the potential prognostic value of these findings.

Hodgkin Lymphoma in Children and Adolescents of Northern Greece: 25-Year Results and Long-term Follow-up.

Aim of this study was to evaluate the long-term therapeutic outcome and treatment-related complications in Hodgkin disease. We reviewed the medical records of 93 patients diagnosed with classic Hodgkin lymphoma, treated, and followed-up during the last 25 years. The cohort study included 49 males and 44 females with median age 11.8 years old (range: 3.95 to 17.42 y). The most common subtype was nodular sclerosis in 47/93 (50.5%). B symptoms were present in 15/93 (16.1%). From January 2009 until December 2020, 55 (59%) patients diagnosed with Hodgkin lymphoma were treated according to European Network for Pediatric Hodgkin Lymphoma (EURONET)-PHL-C1 protocol. Concerning outcome, a total of 89/93 patients are alive. Relapse occurred in 7/93. Second malignancies are reported in a total of 5 patients, 3 solid tumors (thyroid cancer, breast cancer, and osteosarcoma), and 2 acute myeloid leukemias. The overall survival and event-free survival for the whole cohort were 95.7% and 83.9%, respectively. Disease-free survival was 92.5%. Although a considerable high fraction of patients with Hodgkin disease can achieve continuous complete remission, they are at a high risk of developing long-term treatment-related complications. High curative rates as well as prevention of late effects can be achieved by implementation of individualized treatment strategies and innovative treatments.

Clinical Characteristics and Risk Factors for Bloodstream Infections in Children with Cancer: A Report from a Pediatric Hematology Oncology Unit.

BACKGROUND/AIM: Infections are a major cause of morbidity and mortality in children with haematologic malignancies and solid tumors as well as those undergoing hematopoietic stem cell transplantation (HSCT). The purpose of our study was to record the epidemiological characteristics and outcomes of bacteremias, focusing on pathogens, as well as risk factors and mortality rates in patients of a pediatric hematology-oncology unit from Northern Greece. MATERIALS AND METHODS: A retrospective analysis was conducted, which included all positive blood cultures from pediatric hematology oncology patients aged from 1 to 16 years old admitted to the Pediatric and Adolescent Hematology Oncology Unit of AHEPA University Hospital of Thessaloniki between January 2014 and December 2018. Data were collected from patients' printed and electronic medical records. RESULTS: 73 episodes of bacteremias were identified (41% male and 32% female with a ratio of 1.28:1; median age 6.5 years; 13.7% solid tumor, 72.6% acute lymphoblastic leukemia, 13.7% acute myeloid leukemia, and 95.8% with an indwelling permanent catheter). 49.3% of the isolates were Gram-positive bacteria and 50.7% Gram-negative, and the ratio of Gram-negative to Grampositive was 1.02. Coagulase-negative staphylococci were most frequent (39.7%), followed by E. coli (17.8%) and Klebsiella pneumoniae (17.8%). Out of all Gram-negatives, 13.5% carbapenemase producers and 8.1% ESBL-producers were found. In relation to Gram-positive, 79.3% were identified as methicillin-resistant CoNS. During the study period, 10.9% of indwelling catheters were removed, and 2.73% of episodes resulted in ICU transfer. The 3-month mortality rate was 8.2%. CONCLUSION: This study demonstrated an almost equal distribution of Gram-positive and Gramnegative bacteremias in total in this population but with an increase in the isolation of Grampositive bacteria over the last years, which is consistent with other similar studies in this patient group. Knowledge of the local epidemiology and bacterial antimicrobial resistance is important to prevent and timely treat these life-threatening infections in immunocompromised pediatric oncology patients.

Invasive fungal infections in a pediatric hematology-oncology department: A 16-year retrospective study.

Background and Purpose: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in immunocompromised children. The purpose of our study was to evaluate the incidence of IFIs in pediatric patients with underlying hematologic malignancies and determine the patient characteristics, predisposing factors, diagnosis, treatment efficacy, and outcome of IFIs. Materials and Methods: For the purpose of the study, a retrospective analysis was performed on cases with proven and probable fungal infections from January 2001 to December 2016 (16 years). Results: During this period, 297 children with hematologic malignancies were admitted to the 2nd Pediatric Department of Aristotle University of Thessaloniki, Greece, and 24 cases of IFIs were registered. The most common underlying diseases were acute lymphoblastic leukemia (ALL; n=19,79%), followed by acute myeloid leukemia (AML; n=4, 17%) and non-Hodgkin lymphoma (NHL; n=1,4%). The crude incidence rates of IFIs in ALL, AML, and NHL were 10.5%, 18.2%, and 2.8% respectively. Based on the results, 25% (n=6) and 75% (n=18) of the patients were diagnosed as proven and probable IFI cases, respectively. The lung was the most common site of involvement in 16 (66.7%) cases. Furthermore, Aspergillus and Candida species represented 58.3% and 29.1% of the identified species, respectively. Regarding antifungal treatment, liposomal amphotericin B was the most commonly prescribed therapeutic agent (n=21), followed by voriconazole (n=9), caspofungin (n=3), posaconazole (n=3), micafungin (n=1), and fluconazole (n=1). In addition, 12 children received combined antifungal treatment. The crude mortality rate was obtained as 33.3%. Conclusion: As the findings of the present study indicated, despite the progress in the diagnosis and treatment of IFIs with the use of new antifungal agents, the mortality rate of these infections still remains high.

Urine albumin-to-creatinine ratio is associated with the severity of liver disease, renal function and survival in patients with decompensated cirrhosis.

BACKGROUND AND AIMS: To investigate if urine albumin-to-creatinine ratio (UACR) is associated with the presence of glomerular filtration rate (GFR) <60 mL/min, severity of liver disease and survival in patients with stable decompensated cirrhosis. METHODS: We evaluated prospectively 220 patients (73 % male, age 52.8 ± 12 years). In each patient, assessment of GFR was based on 51chromium-EDTA. Random urine samples were obtained for measurement of UACR. RESULTS: Thirty-eight patients (17 %, group 1) had UACR ≥30 mg/g and 182 (83 %, group 2) had UACR <30 mg/g. Group 1, compared to group 2 patients, had significantly lower levels of "true" GFR (61 vs. 71 ml/min, p = 0.035). Patients with "true" GFR <60 mL/min (n = 93), compared to those with "true" GFR ≥60 mL/min (n = 127), had higher levels of UACR (16 vs. 11.3 mg/g, p = 0.023). In multivariate analysis, serum creatinine and UACR (ΟR 0.98, 95 % CI 0.95-0.99, p = 0.04) were independently associated with the presence of GFR <60 mL/min. Based on the area under the ROC curves, the best cut-off point for UACR was >16.51 mg/g giving a sensitivity 70 %, specificity 49 %, PPV 68 % and NPV 51 %. During the follow-up period [17 (6-52) months], the patients who died or underwent LT (n = 158), compared to those who remained alive (n = 62), had higher levels of UACR (41 vs. 13 mg/g, p = 0.025). Patients with UACR ≥30 mg/g had worse outcome, compared to those with UACR <30 mg/g (log rank p = 0.053). CONCLUSIONS: We showed for the first time that UACR ≥30 mg/g was associated with more severe liver disease, lower GFR and worse LT-free survival in patients with decompensated cirrhosis. However, further studies are needed to confirm these findings.

Comparison of creatinine and cystatin formulae with 51 Chromium-ethylenediaminetetraacetic acid glomerular filtration rate in patients with decompensated cirrhosis.

BACKGROUND AND AIM: Evaluation of renal function, that is, glomerular filtration rate (GFR), has become very important, but conventional mathematical formulae for GFR assessment are inaccurate in patients with cirrhosis. The aim of the present study was to compare serum creatinine (sCr)-based and serum cystatin C (cysC)-based estimated GFR (eGFR) formulae with 51 Chromium-ethylenediaminetetraacetic acid GFR (51 Chr-GFR) in patients with stable decompensated cirrhosis. METHODS: In 129 Caucasian patients with decompensated cirrhosis, we assessed sCr-based GFRs [Modification of Diet in Renal Disease and chronic kidney disease-epidemiology (CKD-EPI)-sCr formulae], cysC-based GFRs [Hoek, Larsson, and CKD-EPI-cysC equations], and the mathematical formulae, which combined both sCr and cysC [i.e. CKD-EPI-sCr-cysC and the specific for cirrhotics formula recently proposed by Mindikoglu et al. (Mindikoglu-eGFR)]. Multivariate linear regression analysis was used for GFR predictors in our cohort. RESULTS: The correlations between 51 Chr-GFR and all mathematical formulae were good (Spearman r2 > 0.68, P < 0.001). Modification of Diet in Renal Disease and CKD-EPI-sCr had lower bias (6.6 and -4.8, respectively), compared with the other eGFRs, while Mindikoglu-eGFR and CKD-EPI-sCr-cysC formulae had greater precision (17.1 and 17.3, respectively), compared with the other eGFRs. CKD-EPI-sCr and Mindikoglu-eGFR had higher accuracy (39% and 41%, respectively), compared with the other eGFRs. The factors independently associated with the 51 Chr-GFR were age, cysC, and sCr, and the new derived formula had lower bias (0.89) and similar precision (17.2) and accuracy (41%) with Mindikoglu-eGFR formula. CONCLUSION: The specific mathematical formulae derived from patients with cirrhosis seem to provide superior assessment of renal function, compared with the conventional used sCr-based and cysC-based formulae.

Diastolic dysfunction is associated with low urinary sodium excretion in patients with decompensated cirrhosis.

BACKGROUND/AIM: The pathogenesis and the clinical impact of diastolic dysfunction (DD) in cirrhosis remain unclear. Our aim was to investigate the factors significantly associated with the presence of DD in patients with decompensated cirrhosis on the waiting list for liver transplantation. MATERIAL AND METHODS: consecutive patients with decompensated cirrhosis, who admitted for transplant assessment, were prospectively evaluated. We assessed the independent factors associated with the presence of DD, while their discriminative ability was evaluated by AUC curve. The diagnosis of DD was based on Doppler echocardiography and classified into three categories according to the current guidelines. RESULTS: we evaluated 115 consecutive patients. Sixty six patients (57.3%-group 1) had DD and 49 (42.7%-group 2) had not DD. The 2 groups had similar Child-Pugh/MELD scores and survival. In multivariable logistic regression analysis, pulse rate (OR: 1.082, 95% CI: 1.03-1.15, p = 0.004), and UNa24h (OR: 0.98, 95% CI: 0.97- 0.99, p = 0.004) were the only variables independently associated with the presence of DD. In the subgroup of consecutive patients (n = 31) with evaluation of cytokines, those (n = 22) with DD, compared to those (n = 9) without DD, had significantly higher levels of inteleukin-6 [145 (45-2000) vs. 56 (10-149)pg/mL, p = 0.043]. CONCLUSIONS: We found that DD was independently associated with lower 24-hour urine sodium. Although no correlation was found between DD and severity of liver disease or survival, further studies are needed for final conclusions.

Glomerular filtration rate is an independent factor of mortality in patients with decompensated cirrhosis.

AIM: Although serum creatinine is included in the Model for End-Stage Liver Disease (MELD) score, it is an inaccurate marker of renal function, namely, of glomerular filtration rate ("true" GFR) in patients with decompensated cirrhosis. Our aim was to investigate the impact of MELD score and "true" GFR as determinants of survival in patients with decompensated cirrhosis. METHODS: We included all consecutive patients with decompensated cirrhosis who were admitted to our department. Renal function was assessed by creatinine- and cystatin-based estimated GFR and "true" GFR using (51) Cr-ethylenediaminetetraacetic acid. The independent factors associated with survival were evaluated. The discriminative ability of the prognostic scores (MELD and modifications of MELD score) were evaluated by using the area under the receiver-operator curve (AUC). RESULTS: One hundred and ten consecutive patients (77 men, aged 56 ± 12 years); at the end of follow up (8 months; range, 6-18), 92 patients (84%) were alive and 18 (16%) had died. In multivariate analysis, serum bilirubin (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.05-1.26; P = 0.020) and "true" GFR (HR, 0.96; 95% CI, 0.93-0.98; P = 0.003) were the only independent factors significantly associated with the outcome. The derived new prognostic model had high discriminative ability (AUC, 0.90), which was confirmed in the validation sample of 77 patients. CONCLUSION: In our cohort of patients with decompensated cirrhosis, "true" GFR and bilirubin were the independent factors of the outcome.

Hashimoto thyroiditis: A "true" adenoma visualized as a hot nodule in the presence of overt hypothyroidism.

A 63 years old woman with Hashimoto's thyroiditis, on thyroxin treatment presented imaging studies concordant with a multinodular goiter, a "hot" nodule in the left lobe and partial suppression of the right lobe. After thyroxin withdrawal overt hypothyroidism developed, yet the patient's imaging studies were not altered. This is a case of hypothyroidism in a patient with Hashimoto's thyroiditis, multinodular goiter and a concomitant "hot nodule", showed on scintigraphy, as a functioning adenoma in a non functioning thyroid. This finding is quite rare as no specific percentages are mentioned in the literature. To our knowledge this is the first such case described in Greece.

Colistin administration to pediatric and neonatal patients.

Emergence of multidrug-resistant Gram-negative nosocomial pathogens has led to resurgence of colistin use. Safety and efficacy data regarding colistin use in pediatric patients are sparse, while optimal dosage has not been defined. We present a case series of neonates and children without cystic fibrosis treated with various doses of colistin intravenously. The records of patients who received colistin in a tertiary-care hospital from January 2007 to March 2009 were reviewed. Thirteen patients (median age 5 years, range 22 days to 14 years) received 19 courses of colistin as treatment of pneumonia, central nervous system infection, bacteremia, or complicated soft tissue infection. The isolated pathogens were Acinetobacter baumannii, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Daily dose of colistin (colistimethate) ranged between 40,000 and 225,000 IU/kg. Duration of administration ranged from 1 to 133 days. Other antimicrobials were co-administered in 18/19 courses. Increase of serum creatinine in one patient was associated with co-administration of colistin and gentamicin. Sixteen of 19 courses had a favorable outcome, and only two of the three deaths were infection-related. Colistin intravenous administration appears well tolerated even at higher than previously recommended doses and of prolonged duration.

Magnetization transfer ratio measurements of the brain in children with tuberous sclerosis complex.

BACKGROUND: Magnetization transfer contrast and magnetization transfer ratio (MTR) in brain are mainly related to the presence of myelin. Neuropathological studies of brain lesions in tuberous sclerosis complex (TSC) have demonstrated disordered myelin sheaths. OBJECTIVE: To evaluate the MTR of the brain in children with TSC and to compare with that in controls. MATERIALS AND METHODS: Four patients (aged 0.41-8.4 years, mean 2.5 years) with TSC and four age- and sex-matched controls were evaluated with classic MR sequences and with a three-dimensional gradient-echo sequence without and with magnetization transfer pre-pulse. The MTR was calculated as: (SI(0)-SI(m))/SI(0)x100%, where SI(m) refers to signal intensity from an image acquired with a magnetization transfer pre-pulse and SI(0) the signal intensity from the image acquired without a magnetization transfer pre-pulse. RESULTS: The MTR values of cortical tubers (44.1+/-4.1), of subependymal nodules (51.6+/-4.8) and of white matter lesions (52.4+/-1.8) were significantly lower than those of cortex (58.7+/-3.53), of basal ganglia (caudate nucleus 58.2+/-2.8, putamen 59.6+/-2.5, thalamus 61.3+/-2.4) and of white matter (64.2+/-2.5) in controls (P<0.001). The MTR of normal-appearing white matter (61.2+/-3.0) in patients was lower than that of white matter in controls (P<0.01). The MTR of cortex and basal ganglia in patients was not significantly different from that in controls. CONCLUSIONS: MTR measurements not only provide semiquantitative information for TSC lesions but also reveal more extensive disease.