Cardiovascular and Thyroid Late Effects in Pediatric Patients With Hodgkin Lymphoma Treated With ABVD Protocol.

BACKGROUND: Hodgkin lymphoma (HL) survivors are at risk of developing a range of therapy-related complications. The goal of this study is to investigate therapy-related late-effects in HL survivors. MATERIALS AND METHODS: We performed a cross-sectional study on 208 HL survivors who were treated at the National Cancer Institute or at the Children Cancer Hospital Egypt with doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy. RESULTS: Age at diagnosis ranged from 2.5 to 17.5 with a median of 8.7 years. The cumulative incidence of cardiac toxicity at 5 and 9 years were 18.7%±2.7% and 43.3%±4.4%, respectively. Preexisting cardiac abnormalities, cumulative anthracycline dose, and end of treatment cardiac status are strong predictors of late cardiotoxicity. Hypertension was observed in ~31% of patients. Young age and obesity at the time of treatment are important risk factors for hypertension. Thyroid abnormalities developed with a 5-year cumulative incidence of 2%±1%, whereas at 9 years the cumulative incidence was 27.9%±4.5%. Thyroid dysfunction was observed in 21.2% and thyroid tumors in 1.6% of cases. Subclinical hypothyroidism was the most common thyroid abnormality. CONCLUSIONS: Cardiotoxicity, hypertension, and thyroid dysfunction are frequent late effects after doxorubicin, bleomycin, vinblastine, and dacarbazine regimen, especially if combined with radiation therapy.

Effect of Tumor Suppressor MiR-34a Loaded on ZSM-5 Nanozeolite in Hepatocellular Carcinoma: In Vitro and In Vivo Approach.

BACKGROUND: MicroRNA modulation therapy has shown great promise to treat hepatocellular carcinoma (HCC), however Efficient tissue-specific and safe delivery remains a major challenge. OBJECTIVE: We sought to develop an inorganic-organic hybrid vehicle for the systemic delivery of the tumor suppressor miR-34a, and to investigate the efficiency of the delivered miR-34a in the treatment of HCC in vitro and in vivo. METHODS: In the present study, pEGP-miR cloning and expression vector, expressing miR-34a, was electrostatically bound to polyethyleneimine (PEI), and then loaded onto ZSM-5 zeolite nanoparticles (ZNP). Qualitative and quantitative assessment of the transfection efficiency of miR-34a construct in HepG2 cells was applied by GFP screening and qRT-PCR, respectively. The expression of miR-34a target genes was investigated by qRT-PCR in vitro and in vivo. RESULTS: ZNP/PEI/miR-34a nano-formulation could efficiently deliver into HepG2 cells with low cytotoxicity, indicating good biocompatibility of generated nanozeolite. Furthermore, five injected doses of ZNP/PEI/miR-34a nano-formulation in HCC induced male Balb-c mice, significantly inhibited tumor growth, and demonstrated improved cell structure, in addition to a significant decrease in alphafetoprotein level and liver enzymes activities, as compared to the positive control group. Moreover, injected ZNP/PEI/miR-34a nano-formulation led to a noticeable decrease in the CD44 and c-Myc levels. Results also showed that ZNP/PEI/miR-34a nano-formulation inhibited several target oncogenes including AEG-1, and SOX-9, in vitro and in vivo. CONCLUSION: Our results suggested that miR-34a is a powerful candidate in HCC treatment and that AEG-1 and SOX-9 are novel oncotargets of miR-34a in HCC. Results also demonstrated that our nano-formulation may serve as a candidate approach for miR-34a restoration for HCC therapy, and generally for safe gene delivery.

The Promise of miRNA Replacement Therapy for Hepatocellular Carcinoma.

Hepatocellular carcinoma is a devastating tumor which accounts for death mortality rate 94% globally, and about 780,000 new cases each year. Tumor suppressor miRNAs represent a class of noncoding RNAs, which exhibit decreased or inhibited expression in the case of carcinogenesis. Therefore, the replacement of these molecules leads to post-transcriptional regulation of tens to hundreds of oncogenic targets and limiting the tumor. Interestingly, there is a group of tumor silencer miRNAs that have been highlighted in HCC and herein, our review will discuss the prominent examples of these miRs in terms of their efficient delivery using vectors, nano-delivery systems, their successful models either in vitro or in vivo and pre-clinical trials. Collectively, tumor suppressor miRNAs can act as novel therapeutics for HCC and more studies should be directed towards these promising therapeutics.

Risk stratification and pattern of cardiotoxicity in pediatric Ewing sarcoma.

INTRODUCTION: Anthracycline chemotherapy contributes to improved outcomes in Ewing sarcoma; however, the most feared complication is cardiotoxicity. Echocardiograms were routinely used to monitor cardiac function after anthracycline treatment. Nevertheless, indices chosen to assess cardiac toxicity vary significantly among different centers, and no uniform protocol has been accepted as ideal. METHODS: This retrospective study included children with Ewing sarcoma treated at Children's Cancer Hospital Egypt over 4years. All echocardiograms and related clinical assessments were reviewed. RESULTS: In total, 149 patients (median age 11years; range 1-18years) were included. Although all patients had a reduced ejection fraction compared with their baseline echocardiogram, only 39 patients developed cardiotoxicity (26%): 43% acute-onset, 36% chronic early-onset, and 21% chronic late-onset. There were no statistically significant association between the frequency of myocardial dysfunction and risk factors, including age, sex, follow-up duration, cumulative doxorubicin dose, and mediastinal irradiation. Over one-third (39%) of the patients with cardiac toxicity regained normal cardiac parameters, whereas seven patients died of acute cardiac toxicity. CONCLUSION: The routine use of echocardiography to screen for anthracycline-induced cardiac toxicity before and during chemotherapy identified myocardial dysfunction. Early medical intervention can improve cardiac parameters. Improved screening techniques with better sensitivity and predictability are needed.

Forgotten Right Ventricle in Pediatric Dilated Cardiomyopathy.

To evaluate the right ventricular (RV) function in relation to that of the left ventricle (LV) in patients with dilated cardiomyopathy (DCM). Echocardiographic examination was done using tissue Doppler imaging (TDI) and two-dimensional speckle tracking echocardiography (2D-STE) for 32 pediatric patients with DCM comparing them to another 32 normal matched controls. The global longitudinal strain (GLS) derived from 2D-STE was used to reflect the LV systolic function. Tricuspid annular plan systolic excursion (TAPSE) and the following RV TDI derived indexes: peak systolic velocity (S'), peak early diastolic velocity E', peak late diastolic velocity A', isovolumic acceleration (IVA) and myocardial performance index (MPI) were measured. RV had significant systolic and diastolic dysfunction; TAPSE, S' velocity, IVA, peak early diastolic velocity (E') and peak early diastolic velocity/peak late diastolic velocity (E'/A') ratio were significantly decreased while MPI was significantly prolonged compared to controls. Moreover, TAPSE, S', IVA, E', E'/A' and RV MPI were significantly correlated to LV GLS. For prediction of LV dysfunction among patients, the area under the receiver operating characteristic curve was 0.98 for RV MPI, 0.906 for RV IVA. For identifying severe LV dysfunction; RV MPI  > 0.29 had 100% sensitivity and 93.7% specificity, while the RV IVA  ≤ 3 had 84.4% sensitivity and 90.6% specificity. In pediatric patients with DCM the RV systolic and diastolic functions are affected beside the LV dysfunction. Non-conventional echocardiographic evaluation of RV function is recommended in among this cohort.

Lysosomal Storage Disorders in Egyptian Children.

OBJECTIVE: To describe the spectrum, relative prevalence and molecular background of lysosomal storage disorders in Egypt. METHODS: The authors evaluated the selective screening program for the diagnosis of lysosomal storage disorders in Egyptian children presenting to the inherited metabolic disease unit at Cairo University Children's Hospital, the largest tertiary care pediatric hospital in Egypt, over a six-year period (April 2008 through April 2014). During this period, 1,065 suspected children were assessed clinically, biochemically and some genetically. RESULTS: Two hundred and eleven children (aged 44 ± 32 mo; 56 % boys, 82 % with consanguineous parents) were confirmed with 21 different lysosomal disorders. The diagnostic gap ranged between 2 mo and 14 y (average 25 mo). Mucopolysaccharidoses were the most common group of diseases diagnosed (44.5 %), while Maroteaux-Lamy, Gaucher and nephropathic cystinosis were the most commonly detected syndromes (17.1, 14.7 and 13.7 %, respectively). Eighty mutant alleles and 17 pathogenic mutations were detected in 48 genetically assessed confirmed patients (30 Gaucher, 16 cystinosis and two Niemann-Pick type C patients). CONCLUSIONS: This report is the first to describe relative frequency and spectrum of clinical and molecular data in a large cohort of Egyptian lysosomal patients. The crude estimate denotes that over 80 % of Egyptian lysosomal patients do not have access to optimal diagnosis. Upgrading diagnostic and genetic services for lysosomal storage disorders in Egypt is absolutely necessary.