Bilateral adrenal neuroblastoma: peculiar pattern of a rare pediatric presentation.

BACKGROUND: Bilateral suprarenal neuroblastoma (BSN) is a rare presentation. Few previously published literature showed BSN patients to have favorable pattern and prognosis. This study aim was to evaluate clinical and biological features in relation to outcome of Egyptian patients with BSN. METHODS: Included patients were diagnosed from 2007 to 2017, retrospectively. Tissue biopsy, imaging and bone marrow were evaluated at presentation. Clinical, demographic, biological variables and risk group were determined and analyzed in relation to overall (OS) and event-free-survival (EFS). RESULTS: BSN patients (n = 33) represented 2% of hospital patients with neuroblastoma during the 10-year study period, 17 were males and 16 were females. Twenty-four patients (72.7%) were infants, and 9 patients (27.3%) were above 1 year of age (range: 1 month to 3 years). Metachronous disease was present in only one patient. Amplified MYCN was found in 10 patients. Initially, most patients (n = 25) had distant metastasis, 6 had stage 3 versus 2 stage 2. Fifteen were high risk (HR), 15 intermediate (IR), 1 low risk (LR) and 2 were undetermined due to inadequate tissue biopsy. Three-year OS for HR and IR patients were 40.5% and 83.9% versus 23.2% and 56.6% EFS; respectively. CONCLUSION: BSN treatment is similar to unilateral disease. A more conservative surgical approach with adrenal tissue preservation on less extensive side should be considered. Biological variables and extent of disease are amongst the most important prognostic determinants. Future studies are warranted to further address the biologic profiling of BSN and highlight prognostic significance of size difference between both adrenal sides.

Apelin Association with Hepatic Fibrosis and Esophageal Varices in Patients with Chronic Hepatitis C Virus.

Portal hypertension and esophageal varices complicating hepatitis C virus (HCV)-related chronic liver diseases are some of the most devastating sequelae. Angiogenesis is the hallmark of their pathogenesis. Apelin is one of the recently identified angiogenic and fibrogenic peptides. We studied apelin gene expression, apelin (rs3761581) single-nucleotide polymorphism (SNP), and serum apelin level in patients with chronic HCV, and their association with liver fibrosis and esophageal varices in 112 patients with HCV-related chronic liver disease (40 with liver cirrhosis [LC]/low-grade varices, 33 with LC/high-grade varices, and 39 with fibrotic non-cirrhotic liver/no varices) and 80 healthy control subjects. Real-time polymerase chain reaction was used for apelin gene expression assay and apelin rs3761581 SNP analysis in peripheral blood samples. The serum apelin level was measured by ELISA. Apelin gene expression was undetectable in the studied samples. The SNP analysis revealed a greater frequency of the C (mutant) allele among patients compared with control subjects (P = 0.012; odds ratio, 3.67). The serum apelin level was significantly greater in patients with LC/varices (median, 31.6 ng/L) compared with patients without LC/varices (median, 2.9 ng/L; P < 0.001). A serum apelin level cutoff value of 16.55 ng/L predicted the presence of varices, with an area under the receiver operating characteristic curve value of 0.786. A positive correlation was found between serum apelin level and grade of liver fibrosis (r = 0.346, P < 0.001) and portal hypertension (r = 0.438, P < 0.001). In conclusion, the apelin rs3761581-C allele may be associated with the progression of HCV-related chronic liver disease and varices formation, and can be considered a potential therapeutic target to control fibrosis progression. The serum apelin level provided an accurate prediction of the presence of esophageal varices.

Clinical Characteristics, Molecular Background, and Survival of Egyptian Patients With Gaucher Disease Over a 20-Year Follow-up.

This study analyzes the general disease characteristics, impact of enzyme replacement therapy (ERT), and overall survival (OS) of 156 Egyptian patients with Gaucher disease (GD) enrolled on hormone replacement from 1998 to 2017. The mean age at diagnosis was 32.46±12.68 months. Anemia was noted at diagnosis in 50%, thrombocytopenia in 30.7%, severe splenomegaly in 58.7%, severe hepatomegaly in 11.9%, and skeletal findings were detected in 24.3% of the patients. The most prevalent GD type was type 3 (54.5%). Twenty-two of type 3 patients had no neurological manifestations at diagnosis, and 12 developed variable central nervous system manifestations during follow-up. The most common neurological features were limited eye movements, oculomotor apraxia, and squint. Of the 60 patients for whom genotypes were obtained, homozygous L444P was the most common (n=35/60, 58.3%). Treatment with ERT (imiglucerase) revealed significant improvements in blood indices, organ volumes, and growth parameters (P<0.05). Ten (11.7%) type 3 patients did not develop any neurological manifestations under ERT over 20 years. Mortality was 16%, and the 20-year OS was 73.3%. We conclude that in Egypt, type 3 is the most prevalent phenotype of GD, and homozygous L444P is the predominant GBA genotype of GD. Early age at diagnosis and treatment with ERT over 20 years revealed significant improvements in disease manifestations, with an OS of 73.3%.

Clinical Significance of MicroRNA-29a and MicroRNA-100 Gene Expression in Pediatric Acute Myeloid Leukemia.

AIM: The aim of this study was to evaluate the diagnostic and prognostic performance of miRNA-29a and miRNA-100 in pediatric acute myeloid leukemia (AML). PATIENTS AND METHODS: In all, 73 children with diagnosed pediatric AML (based on standard morphologic, cytochemical, cytogenetic, immunologic, and molecular workup, and the French-American British classification) admitted to Children's Cancer Hospital Egypt (CCHE-57357), and 9 healthy age-matched and sex-matched controls were recruited for a case-control study. Gene expression levels of miRNA-29a and miRNA-100 were assessed using real-time quantitative RT-PCR. RESULTS: When diagnosed, patients had a significantly higher expression of miRNA-100 as against controls (median [range]: 12.99 [0.92-851.38] vs. 0.26 [0.03-2.67], P<0.001), with a significantly lower expression of miRNA-29a (2.08 [0.02-19.72] vs. 24.95 [15.48-42.54], P<0.001). Likewise, high-risk patients according to cytogenetic stratification had significantly higher miRNA-100 expression and lower miRNA-29a expression. Both miRNA-100 and miRNA-29a performed well as diagnostic markers of pediatric AML with an area under the curve of 0.977 (95% confidence interval [95% CI: 0.943-1.0]) and 0.994 (0.982-1.0) for miRNA-100 and miRNA-29a, respectively. Both miRNA-29a (odds ratio [95% CI]: 0.160 [0.054-0.474], P=0.001) and miRNA-100 (odds ratio [95% CI]: 1.997 [1.994-2.001], P=0.047) were identified as significant predictors of treatment response. CONCLUSION: The miRNA-29a and miRNA-100 expression may serve as diagnostic and prognostic markers in pediatric AML.

Effect of Interleukin and Hepcidin in Anemia of Chronic Diseases.

BACKGROUND: Anemia of chronic disease (ACD) also termed as the anemia of inflammation has been found to be associated with inflammations, chronic infections, and cancers, particularly in old age. Recent studies revealed that interleukin-6 (IL-6), a proinflammatory cytokine, and hepcidin, an antimicrobial hepatic peptide, play a key role in ACD pathogenesis. Patients and Methods. The study included 40 subjects with chronic diseases and 40 normal subjects of the same age group. Red cell indices, levels of IL-6 and hepcidin, and iron profile were measured in all participants using Bayer ADVIA 120, VITROS 5600, Integrated System/2008, and ELISA assay, respectively. RESULTS: The level of hemoglobin was considerably less in patients of chronic diseases referred to as "cases" than the normal subjects or "controls" (8.7 ± 1.5 vs. 13.2 ± 0.9). Red blood corpuscle (RBC) count, hematocrit (HCT) level, serum iron, mean corpuscular hemoglobin concentration (MCHC), and serum total iron-binding capacity (TIBC) were found to be significantly lower in the cases as compared to controls (p < 0.001). Serum IL-6 and hepcidin levels were substantially higher in the cases than in the controls (p < 0.001). Serum IL-6 and hepcidin levels were substantially higher in the cases than in the controls (p < 0.001). Serum IL-6 and hepcidin levels were substantially higher in the cases than in the controls (. CONCLUSION: This study detected a significant increase in serum IL-6 and hepcidin levels in patients with ACD than the controls. These findings offer an insight into the role played by both cytokine and peptide in the pathogenesis of ACD and thus provide a rationale for future use of novel drugs inhibiting their effects on iron metabolism.

Indoleamine 2,3-dioxygenase and regulatory T cells in acute myeloid leukemia.

BACKGROUND AND OBJECTIVES: The microenvironment of acute myeloid leukemia (AML) is suppressive for immune cells. Regulatory T cells (Tregs) have been recognized to play a role in helping leukemic cells to evade immunesurveillance. The mesenchymal stem cells (MSCs) are essential contributors in immunomodulation of the microenvironment as they can promote differentiation of Tregs via the indoleamine 2,3-dioxygenase (IDO) pathway. The aim of the present work was to evaluate the expression of IDO in bone marrow derived MSCs and to study its correlation to percentage of Tregs. METHODS: Thirty-seven adult bone marrow samples were cultured in appropriate culture medium to isolate MSCs. Successful harvest of MSCs was determined by plastic adherence, morphology, and positive expression of CD271 and CD105; negative expression of CD34 and CD45 using flowcytometry. MSCs were examined for IDO expression by immunocytochemistry using anti-IDO monoclonal antibody. CD4+ CD25+ cells (Tregs) were measured in bone marrow samples by flowcytometry. RESULTS: MSCs were successfully isolated from 20 of the 37 bone marrow samples cultured. MSCs showed higher expression of IDO and Tregs percentage was higher in AML patients compared to control subjects (P = 0.002 and P < 0.001, respectively). A positive correlation was found between IDO expression and Tregs percentage (P value = 0.012, r = 0.5). CONCLUSION: In this study, we revealed an association between high IDO expression in MSCs and elevated levels of Tregs which could have an important role in the pathogenesis of AML, providing immunosuppressive microenvironment.

Early detection of right ventricular diastolic dysfunction by pulsed tissue Doppler echocardiography in iron loaded beta thalassemia patients.

Early heart iron overload in beta thalassemia major patients can be quantified through T2* cardiovascular magnetic resonance (CMR). To clarify the value of tissue Doppler imaging (TDI) in early detection of myocardial dysfunction in iron loaded thalassemia patients diagnosed by CMR. Two groups were included in the study; Group I: 69 asymptomatic thalassemia patients (28 females, 41 males), mean age 18.1 ± 7.03 years (range 6-39 years); Group II (n = 41) healthy normal controls matched for age and sex. Serum ferritin and CMR were performed to assess the cardiac siderosis (T2* < 20 ms). Group I was subdivided into two subgroups; Group Ia (n = 26) T2* < 20 ms and Group Ib (n = 43) T2* > 20 ms. Conventional and Doppler echocardiography of LV, RV dimensions and functions and pulmonary artery pressure were evaluated. Right ventricular diastolic function assessed by tricuspid annular E'/A' was positively correlated with T2* value; lower tricuspid E'/A' ratios were correlated with lower T2* values (r = 0.366, P = 0.002). Tricuspid annular A' was significantly higher in group Ia compared to group Ib (16.7 ± 5.2 vs 12.1 ± 4.0 cm/s, P < 0.001). Tricuspid E'/A' < 1 was common in group Ia compared to group Ib (19/26 (73.0) vs 3/43 (6.97%), P < 0.001). By multivariate analysis, right ventricular diastolic dysfunction (tricuspid E'/A' < 1) was associated with serum ferritin and T2* level of the thalassemia patients. TDI is a promising tool for quantitative assessment of myocardial function and early detection of right ventricular diastolic dysfunction in iron loaded beta thalassemia major patients.

Response to hydroxycarbamide in pediatric ß-thalassemia intermedia: 8 years' follow-up in Egypt.

Hydroxycarbamide (hydroxyurea or HU) has been shown to increase fetal hemoglobin (HbF) in patients with ß-thalassemia intermedia (TI). The reported effects of HU in increasing the total hemoglobin (Hb) have been inconsistent. Studies of long-term therapy with HU in pediatric TI are rather uncommon. A retrospective observational study was carried out to evaluate the clinical responses to HU in Egyptian patients with ß-TI. One hundred patients; children (n = 82, mean age 9.9 ± 4.1 years) and adults (n = 18) were studied for the mean Hb, HbF%, median serum ferritin, transfusion history, and splenic size before and after HU therapy (mean dose 20.0 ± 4.2 mg/kg/day, range 10-29 mg/kg/day) over a follow-up period 4 to 96 months (mean 35.4 ± 19.2 months). Molecular studies were also done for group of patients (n = 42). The overall response rate to HU was 79 %; 46 % were minor responders (with a reduction in transfusion rate by 50 % or more and/or an increase in their total hemoglobin level by 1-2 g/dl) and 33 % major responders (becoming transfusion-free and/or having an increase in total hemoglobin level by >2 g/dl). Mean hemoglobin increased among responders from 6.9 ± 0.9 g/dl to 8.3 ± 1.4 g/dl (p < 0.001). A significant rise in mean HbF (27.0 vs. 42.5 %; p < 0.011) and a decrease in median serum ferritin (800 vs. 644 ng/ml; p < 0.001) were also observed among responders (n = 45). Transfusions stopped in 44 % of pretreatment frequently transfused responders (n = 11/25). Splenic size decreased in 37 % of patients (n = 30/81). The predominant ß-thalassemia mutation was 1-6 (T > C) in 32/42 (76 %) of studied patients; 28/32 were responders. Bivariate analysis showed no predictors of response as regards sex, pediatric and adult age, splenic status, or genotype. Hydroxycarbamide is a good therapeutic modality in the management of pediatric as in adult TI patients. It can minimize the need for blood transfusion, concomitant iron overload, and blood-born viral transmission especially in developing countries like Egypt.

Low prevalence of cardiac siderosis in heavily iron loaded Egyptian thalassemia major patients.

Myocardial siderosis in thalassemia major remains the leading cause of death in developing countries. Once heart failure develops, the outlook is usually poor with precipitous deterioration and death. Cardiovascular magnetic resonance (CMR) can measure cardiac iron deposition directly using the magnetic relaxation time T2*. This allows earlier diagnosis and treatment and helps to reduce mortality from this cardiac affection. This study aims to determine the prevalence of cardiac siderosis in Egyptian patients who are heavily iron loaded and its relation to liver iron concentration, serum ferritin, and left ventricular ejection fraction. Eighty-nine ß-thalassemia patients receiving chelation therapy (mean age of 20.8 ± 6.4 years) were recruited in this study. Tissue iron levels were determined by CMR with cardiac T2* and liver R2*. The mean ± standard deviation (range) of cardiac T2* was 28.5 ± 11.7 ms (4.3 to 53.8 ms), the left ventricular ejection fraction (LVEF) was 67.7 ± 4.7 % (55 to 78 %), and the liver iron concentration (LIC) was 26.1 ± 13.4 mg Fe/g dry weight (dw) (1.5 to 56 mg Fe/g dw). The mean serum ferritin was 4,510 ± 2,847 ng/ml (533 to 22,360 ng/ml), and in 83.2 %, the serum ferritin was >2,500 ng/ml. The prevalence of myocardial siderosis (T2* of <20 ms) was 24.7 % (mean age 20.9 ± 7.5 years), with mean T2* of 12.7 ± 4.4 ms, mean LVEF of 68.6 ±5.8 %, mean LIC of 30.9 ± 13 mg Fe/g dw, and median serum ferritin of 4,996 ng/ml. There was no correlation between T2* and age, LVEF, LIC, and serum ferritin (P = 0.65, P = 0.085, P = 0.99, and P = 0.63, respectively). Severe cardiac siderosis (T2* of <10 ms) was present in 7.9 %, with a mean age of 18.4 ± 4.4 years. Although these patients had a mean T2* of 7.8 ± 1.7 ms, the LVEF was 65.1 ± 6.2 %, and only one patient had heart failure (T2* of 4.3 ms and LVEF of 55 %). LIC and serum ferritin results were 29.8 ± 17.0 mg/g and 7,200 ± 6,950 ng/ml, respectively. In this group of severe cardiac siderosis, T2* was also not correlated to age (P = 0.5), LVEF (P = 0.14), LIC (P = 0.97), or serum ferritin (P = 0.82). There was a low prevalence of myocardial siderosis in the Egyptian thalassemia patients in spite of very high serum ferritin and high LIC. T2* is the best test that can identify at-risk patients who can be managed with optimization of their chelation therapy. The possibility of a genetic component for the resistance to cardiac iron loading in our population should be considered.

Intrafamilial transmission of hepatitis C infection in Egyptian multitransfused thalassemia patients.

OBJECTIVE: Detecting the current prevalence of hepatitis C virus (HCV) among Egyptian multitransfused thalassemic patients and evaluating the risk of its transmission within their family members. METHODS: Multitransfused Egyptian thalassemia patients (n = 137) were tested for HCV infection. Household contacts of positive members were compared with household contacts of HCV-negative patients. Antibodies to HCV were detected by enzyme immunoassay. Antibody-positive cases were retested for viral load using reverse transcriptase polymerase chain reaction. HCV genotyping was performed on positive samples of the patients and the positive household contacts. RESULTS: In all, 34.4% of patients (n = 47) were positive for HCV antibodies and RNA. The study of 24 families of HCV-positive patients showed 14 affected family members (19.2%). In 27 families of HCV-negative patients, four family members were affected (4.9%). HCV genotyping of seven families was similar in both patients and their family members. CONCLUSION: Our results support the role of intrafamilial transmission in the spread of HCV.