Effects of COVID-19 on Pediatric Cancer Care: A Multicenter Study of 11 Middle Eastern Countries.

During the COVID-19 pandemic, major challenges are facing pediatric cancer centers regarding access to cancer centers, continuity of the anti-cancer therapy, hospital admission, and infection protection precautions. Pediatric oncologists actively treating children with cancer from 29 cancer centers at 11 countries were asked to answer a survey from May 2020 to August 2020 either directly or through the internet. COVID-19 pandemic affected the access to pediatric cancer care in the form of difficulty in reaching the center in 22 (75.9%) centers and affection of patients' flow in 21 (72.4%) centers. Health care professionals (HCP) were infected with COVID-19 in 20 (69%) surveyed centers. Eighteen centers (62%) modified the treatment guidelines. Care of follow-up patients was provided in-hospital in 8(27.6%) centers, through telemedicine in 10 (34.5%) centers, and just delayed in 11 (38%) centers. Pediatric oncologists had different expectations about the future effects of COVID-19 on pediatric cancer care. Seventy-six percent of pediatric oncologists think the COVID-19 pandemic will increase the use of telemedicine. Fifty-five percent of pediatric oncologists think if the COVID-19 pandemic persists, we will need to change chemotherapy protocols to less myelosuppressive ones. Collaborative studies are required to prioritize pediatric cancer management during COVID-19 era.

Beta Thalassemia Carrier Rate: Problem Burden among High School Children.

Background & Aim of the Work: ß-Thalassemia (ßT) is highly prevalent in some countries like Egypt. Accurate data about actual disease prevalence and heavily prevalent geographic locations are essential to help in early detection and in setting up effective preventive programs. We aim for screening ßT carriers among Egyptian high school students in the Delta region. SUBJECTS AND METHODS: A cross-sectional multicenter study was carried out on 4320 randomly selected students from four governorates of the Nile Delta region, Egypt. All patients were to be tested for their complete blood count. Those with microcytic hypochromic anemia not caused by iron deficiency were tested for ßT carrier status using high-performance liquid chromatography. RESULTS: The total prevalence of ßT carrier rate was 6.13%. The highest prevalence was detected in Al-Sharkia Governorate, reaching 7.89%, followed by 6.90% in Al-Gharbia Governorate. Al- Dakahilia and Al-Menoufia showed lower rates of 4.86% and 3.73%, respectively. CONCLUSION: Despite the premarital national screening program for ßT in Egypt, the carrier rate is still high. More effort should be done into the proper implementation of national prevention programs.

Prevalence of iron deficiency anemia and beta thalassemia carriers among relatives of beta thalassemia patients in Nile Delta region, Egypt: a multicenter study.

BACKGROUND: Screening of ß thalassemia among close relatives is more feasible in highly prevalent countries with limited resources. The purpose of this study is to determine the prevalence of ß thalassemia carriers and iron deficiency anemia among relatives of ß thalassemia patients in Mid Delta, Egypt. METHODS: This is a cross-sectional multi-center study conducted on 2118 relatives of patients with ß thalassemia from different Egyptian governorates in the Mid Delta region. They were subjected to history taking with precise determination of geographic location, general examination, and the following investigations: complete blood counts, serum ferritin for those who showed microcytic hypochromic anemia, and high-performance liquid chromatography for those who were not diagnosed as iron deficiency anemia. RESULTS: The total prevalence of iron deficiency anemia among close relatives of confirmed ß thalassemia patients in the Nile Delta region was 17.19%. The highest prevalence of iron deficiency anemia (45.05%) was reported in Al-Gharbia Governorate, followed by Al-Menoufia Governorate (21.67%), and the lowest prevalence was that of Al-Sharkia Governorate (4.91%). The differences were highly statistically significant (p < 0.001). ß thalassemia carrier prevalence rate in the studied relatives was 35.84%, with the highest prevalence detected in Al-Sharkia Governorate (51.32%), followed by Kafr-Alsheikh and Al-Dakahilia Governorates (41.78%, 37.13%) respectively, while Al-Menoufia Governorate had the lowest prevalence rate (25.00%). These differences were also highly statistically significant (p < 0.001). CONCLUSION: More than one-third of relatives of patients with ß thalassemia are carriers of the disease, while 17.19% suffer from iron deficiency anemia. This study demonstrates the importance of tracing the high number of beta thalassemia carriers among relatives of patients with ß thalassemia in Egypt.

CMV, B and C hepatitis among multi-transfused hereditary hemolytic Anemia children: an updated Egyptian experience.

BACKGROUND AND OBJECTIVES: Regular blood transfusion has improved the overall survival and quality of life for patients with hereditary hemolytic anemias. Nevertheless, it carries a real risk of acquisition of blood-borne virus infections, especially viral hepatitis. The purpose of the current study is to present an Egyptian update on blood-borne hepatitis C & B viruses (HCV & HBV) and cytomegalovirus (CMV) among multi-transfused Egyptian children with hereditary hemolytic anemias, especially after implementation of national preventive programs in Egypt. PATIENTS AND METHODS: All pediatric patients with hereditary hemolytic anemias who have regular follow-up and received frequent blood transfusion at the Pediatric Hematology Units, Menuofia and Zagazig Universities Hospitals, Egypt, during the study period, were recruited. They were tested for hepatitis B surface antigen (HBVsAg), hepatitis C antibody (HCVab), and CMV immunoglobulin M (IgM) serology. Those with positive results were confirmed by real-time polymerase chain reaction (PCR). RESULTS: Four hundred and seventy-seven hereditary hemolytic anemia patients fulfilled the study inclusion criteria. Their ages ranged from 2 to 18 years, 54.9% of them were males. Seroprevalence of HCVab and CMV-IgM were (14.7% & 6.7% respectively) and they were confirmed by PCR. None of the studied cases were HBVsAg positive. Seropositivity for HCV was significantly associated with older age of the patients, higher transfusion frequency, longer disease duration, and higher mean serum ferritin. CONCLUSION: HCV followed by CMV infections still represent a significant problem for patients with hereditary hemolytic anemias. Nationwide plans should be taken to ensure meticulous and highly sensitive methods of blood screening before transfusion. On the other hand, it seems that HBV compulsory vaccination had succeeded to eliminate HBV infection.

Evaluation of Glutathione-S-Transferase P1 Polymorphism and its Relation to Bone Mineral Density in Egyptian Children and Adolescents with Beta-Thalassemia Major.

BACKGROUND: Osteoporosis is a major complication of beta thalassemia major (TM). Increased oxidative stress and its controlling genes were linked to osteoporosis. Ile105 Val variant is a functional polymorphism of Glutathione S-transferase P1 (GSTP1), with reduced anti-oxidative property. No data are available about this variant or its association with osteoporosis among thalassemia patients yet. OBJECTIVES: To investigate Ile105Val polymorphism and its possible association with bone mineral density (BMD) values in a group of TM children. METHODS: Thirty five TM children and 30 age and sex matched healthy controls were included. Liver and renal functions, serum ferritin, calcium, phosphorous, alkaline phosphatase and osteocalcin were assayed. BMD was determined by DXA with calculation of Z-scores at lumbar spine (LS) and femoral neck (FN). Height for age Z- score (HAZ) adjusted BMD Z-scores were calculated. GSTP1 Ile105Val polymorphism was studied by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The relative frequency of 105 Val allele was significantly higher in TM patients than the controls (p<0.0001). Significant association between genotype subgroups and BMD parameters was detected. Compared to wild homozygotes, polymorphic homozygotes had lower LS-BMD (p =0.029), LS-BMD Z -score (p=0.008 ), LS- BMD haz - Z-score (p=0.011), FN- BMD (p= 0.001), FN- BMD Z -score (p=0.02) and FN-BMD haz - Z-score (p=0.001). They exhibited higher osteocalcin levels compared to heterozygotes and wild homozygotes (p=0.012, p=0.013, respectively). CONCLUSION: Ile105Val polymorphism was frequent among TM patients and could increase their susceptibility to reduced BMD. Large sample studies are required to confirm these findings.

Tissue factor-positive monocytes expression in children with sickle cell disease: clinical implication and relation to inflammatory and coagulation markers.

Hemostatic abnormalities are well documented in sickle cell disease (SCD). Nevertheless, whether these perturbations could contribute to sickle vasculopathy is still not clear. We evaluated monocytes tissue factor (TF) expression in children with SCD correlating the results with the clinical state and some inflammatory and coagulation markers. The study included 24 children with SCD in steady state, 24 in painful crisis and 20 healthy age and sex-matched children as controls. Complete blood count, prothrombin time (%), activated partial thromboplastin time, fibrinogen, D-dimer, thrombin-antithrombin complex and quantitative C-reactive protein were assayed. TF expression on monocytes was analyzed by flow cytometry. TF-positive monocytes were significantly higher in both patient groups compared with the controls, being higher in painful crisis group (2.06 ±â€Š0.64, 8.01 ±â€Š1.53, 13.5 ±â€Š4.3 for the controls, steady state and painful crisis groups, respectively). Among painful crisis group, TF expression on monocytes was positively correlated with the pain rate, reticulocytes (%) and three out of six markers of inflammation and coagulation (C-reactive protein, D-dimer and fibrinogen) with inverse correlation with hemoglobin and the red blood cells count. TF-positive monocytes were more expressed in SCD both in steady state and in painful crisis, being significantly higher in painful crisis. This expression was significantly related to the pain rate as well as to markers of hemolysis, inflammation and coagulation among patients in painful crisis. These results confirm the substantial role played by TF-positive monocytes in the pathogenesis of SCD painful crisis.

Evaluation of serum and urine fetuin-A levels in children with acute lymphoblastic leukemia during and after high-dose methotrexate therapy: Relation to toxicity.

BACKGROUND/OBJECTIVES: Fetuin-A is a multifunctional protein with its urine level was considered as a marker of acute kidney injury. We investigated the serum and urine fetuin-A in acute lymphoblastic leukemia (ALL) children during and after high-dose methotrexate (HDMTX). METHODS: Twenty-two ALL children and 20 matched healthy controls were included. Liver transaminases, serum creatinine, estimated glomular filtration rate (eGFR), creatinine clearance (CrCl), serum ß2 microglobulin (B2M), and serum and urine fetuin-A levels were assayed pre and 4 months after the consolidation. Among a subgroup of 15 patients, the investigations were performed 42 hours after the start of the second and the fourth HDMTX infusions. RESULTS: HDMTX was well tolerated. During HDMTX, there was significant decline in serum fetuin-A together with significant rise of urine fetuin-A and B2M levels compared to the control and to the pre-consolidation levels, changes that persisted 4 months after the consolidation despite recovery of the significantly altered renal functions. The second HDMTX-related serum fetuin-A level directly correlated with eGFR and CrCl (r = 0.86, P < 0.0001 and r = 0.67, P = 0.016, respectively). Four months after consolidation, urine fetuin-A directly correlated with serum creatinine (r = 0.54, P = 0.004) and inversely correlated with the eGFR (r = -0.66, P < 0.0001). CONCLUSION: Significant disturbance in serum and urinary fetuin-A levels, which was related to renal functions, had occurred during HDMTX and persisted for at least 4 months after the consolidation. Serum and urine fetuin-A could be sensitive markers for subtle renal dysfunction in ALL children.

The Diagnostic Value of Pulsed Wave Tissue Doppler Imaging in Asymptomatic Beta- Thalassemia Major Children and Young Adults; Relation to Chemical Biomarkers of Left Ventricular Function and Iron Overload.

BACKGROUND: Cardiac iron toxicity is the leading cause of death among ß-halassaemia major (TM) patients. Once heart failure becomes overt, it is difficult to reverse. OBJECTIVES: To investigate non-overt cardiac dysfunctions in TM patients using pulsed wave Tissue Doppler Imaging (TD I) and its relation to iron overload and brain natriuretic peptide (BNP). METHODS: Thorough clinical, conventional echo and pulsed wave TDI parameters were compared between asymptomatic 25 ß-TM patients and 20 age and gender matched individuals. Serum ferritin and plasma BNP levels were assayed by ELISA. RESULTS: TM patients had significant higher mitral inflow early diastolic (E) wave and non significant other conventional echo parameters. In the patient group, pulsed wave TDI revealed systolic dysfunctions, in the form of significant higher isovolumetric contraction time (ICT), and lower ejection time (E T), with diastolic dysfunction in the form of higher isovolumetric relaxation time (IRT), and lower mitral annulus early diastolic velocity E' (12.07 ±2.06 vs 15.04±2.65, P= 0.003) compared to the controls. Plasma BNP was higher in patients compared to the controls. Plasma BNP and serum ferritin had a significant correlation with each other and with pulsed wave conventional and TDI indices of systolic and diastolic functions. Patients with E/E' ≥ 8 had significant higher serum ferritin and plasma BNP levels compared to those with ratio < 8 without a difference in Hb levels. CONCLUSION: Pulsed wave TDI is an important diagnostic tool for latent cardiac dysfunction in iron-loaded TM patients and is related to iron overload and BNP.

Study of serum haptoglobin level and its relation to erythropoietic activity in Beta thalassemia children.

BACKGROUND: Serum haptoglobin (Hp) is a reliable marker for hemolysis regardless the inflammatory state. OBJECTIVE: We investigated the possible relation between Hp depletion and hemolysis severity, hepatitis C virus (HCV) infection and iron load in ß-thalassemia children. METHODS: Twenty two ß-thalassemia major (TM),20 ß-thalassemia intermedia (TI) children with 20 age and sex matched healthy controls were involved. Pre-transfusion hemoglobin level was considered. Serum ferritin, Hp and transferrin receptor levels (sTfR) (by ELISA ), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (by colorimetric method) were assayed. Markers of hepatitis C virus (HCV) were done by PCR. RESULTS: The mean Hp levels among the studied groups were as follows; 8.02 ± 0.93 (mg/dl), 8.6 ±0.72 (mg/dl) and 122 ± 18.5(mg/dl) for TM, TI and the controls respectively. Both patient groups had significantly lower Hp level compared to the controls (P<0.0001) with significant lower level in TM compared to TI children ( P= 0.034). Significant inverse correlations were found between serum Hp and sTfR levels ( reflecting the erythropoietic activity) in thalassemia children combined and in each group (TM and TI) as well as among HCV infected children. STfR was the only significant independent predictor for serum Hp level (t= -5.585, P<0.0001). Among HCV infected patients, no significant correlation was found between serum Hp and serum transaminases. CONCLUSION: Serum Hp depletion in thalassemia had significant relation to disease severity and correlated well with their erythropoietic activity, as assessed by the measurement of sTfR without significant relation to HCV infection. Extensive multicenter studies are recommended.

Lipoprotein-associated phospholipase A2 (Lp-PLA2) and tumor necrosis factor-alpha (TNF-α) and their relation to premature atherosclerosis in ß-thalassemia children.

BACKGROUND/OBJECTIVES: Beta (ß)-thalassemia adults are prone to premature atherosclerosis but data about this complication among thalassemia children are few. Lipoprotein-associated phospholipase A2 (Lp-PLA2) and tumor necrosis factor-α (TNF-α) are inflammatory markers that could be implicated in atherosclerotic process. We investigated Lp-PLA2 and TNF-α levels in ß-thalassemia children and their relation to subclinical atherosclerosis. METHODS: Twenty-two ß-thalassemia major (TM), 20 ß-thalassemia intermedia children, and 30 age- and sex-matched healthy controls were included. Lipid profile (by colorimetric assay), serum ferritin, TNF-α, and plasma Lp-PLA2 levels (by enzyme-linked immunosorbent assay technique) were estimated. Carotid intima-media thickness (cIMT) was measured by high-resolution ultrasound. RESULTS: Both patient groups exhibited anti-atherogenic lipid profile except increased serum triglycerides. They had significantly higher plasma Lp-PLA2 and serum TNF-α compared to the controls (P < 0.001). Elevated cIMT was documented in 57% of the thalassemia children and was higher among hepatitis C (HCV) positive patients. Serum ferritin, TNF-α, and plasma Lp-PLA2 levels were significantly higher in patients with premature atherosclerosis. cIMT correlated significantly with serum ferritin, TNF-α, and plasma Lp-PLA2 in both patient groups. Among TM children, serum ferritin had significant positive correlation with serum TNF-α and plasma Lp-PLA2. The elevation of both markers was not related to HCV infection. CONCLUSIONS: Premature atherosclerosis is common among young thalassemia children. Lp-PLA2 and TNF-α are significantly increased in thalassemia children and show strong correlations with cIMT, suggesting that both of them may be appreciated as modulating factors in carotid atherosclerosis pathophysiological process among these children.

Haptoglobin genotypes polymorphism as a risk factor for subclinical atherosclerosis in beta-thalassemia major children; a single center Egyptian study.

Background/Objectives Haptoglobin (Hp) is an antioxidant protein. Its genotypic polymorphism had been proposed to influence vascular complications among diabetics, but no data are available about this association among thalassemia patients so far. We have investigated the assumption of an association between Hp genotypes and subclinical atherosclerosis among beta-thalassemia major (TM) children. Methods One hundred beta-TM children and 70 matched healthy controls were included. Serum ferritin level and fasting lipid profile were assayed. Haptoglobin genotyping was determined by amplification gel electrophoresis. Carotid intima media thickness (cIMT) was measured using high resolution ultrasound. Results The relative distribution of the three Hp genotypes among thalassemia group and the control group were 18 and 14.3% for Hp1-1; 38 and 37.1% for Hp2-1; and 44 and 48.6% for Hp2-2 respectively. There was no significant difference between patients and controls regarding Hp genotypes distribution. Hp2-2 genotype TM children had significantly higher cIMT compared to other genotypes (P < 0.0001). Elevated cIMT was significantly represented in Hp2-2 genotype patients (P < 0.0001) who had higher serum ferritin compared to their counterparts (P < 0.05). Hp2-2 patients were five times more likely to suffer from subclinical atherosclerosis than Hp1-1 and six times than Hp2-1 genotype patients (P = 0.008 and 0.001, respectively); a difference that persisted significant after adjustment for some risk factors compared to Hp2-1 patients (OR 3.96; P = 0.02). Conclusions Hp2-2 genotype is a significant predictor for premature atherosclerosis in TM children and confers them an increased risk for iron overload.

P-glycoprotein-1 functional activity in CD5+CD7+ and CD20+ lymphocytes in systemic lupus erythematosus children: relation to disease activity, complications and steroid response.

The multi-drug resistance protein -1 or P-glycoprotein-1 ( P-gp1) functions as Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells. Increased P-gp1 expression in lymphocytes of patients with systemic lupus erythematosus (SLE) may influence steroid requirements for disease control. This study evaluates P-gp1 functional activity in CD5+, CD7+ and CD20+ lymphocytes in SLE children and its impact on clinical outcome. 44 SLE children and 50 healthy controls were studied. Estimation of P-gp1 function was based on the efflux of Rhodamine-123 using flow cytometry. Results were expressed as percentage of lymphocytes with high P-gp1 activity. The P-gp1 function in CD5+, CD7+ and CD20+ lymphocytes was significantly higher in patients compared to controls (with P value < 0.05 for each lymphocyte population). The expression of active P-gp1 in CD5+ and CD7+ lymphocytes correlated positively with disease activity as estimated by SLEDAI and ESR. P-gp1 expression in SLE lymphocytes was also found to correlate significantly with some disease manifestations specially lupus nephritis, thrombocytopenia and ANA positivity. Steroids low responders whose SLEDAI were > or = 11 while receiving 1 mg/Kg/day of prednisolone demonstrated higher P-gp1 functions in CD 5+ and CD 7+ lymphocytes compared to high responders whose SLEDAI were < 11 while receiving < 1 mg/Kg/day of prednisolone. CD5+ lymphocyte's P-gp1 function was found to be lower in the patients receiving cyclophosphamide in addition to steroids compared to those on steroids only. It is concluded that measuring P-gp1 function in CD5+ and CD7+ lymphocytes could be one of the prognostic and therapeutic indices in SLE.

HER2/neu expression: a predictor for differentiation and survival in children with Wilms tumor.

Wilms tumor is a mixed embroynal neoplasm of the kidney . HER2 is an onco-protein. Its over-expression could be implicated in the development of many tumors. The clinico-demographic and pathological data of 28 Wilms tumor patients were , reviewed. The tissue samples were examined by light Microscopy then immunohistochemical staining for HER2/neu expression. Additional 28 normal surrounding renal tissue specimens were included. There was significant differences between HER2/neu positive and HER2/neu negative Wilms tumors in relation to stage, histological phase and epithelial differentiation (P > 0.05 for all). The overall survival advantage was noticed if Wilms tumor was at early stages (I and II) (Log-rank = 13.23 and P > 0.001), homologous epithelial differentiation (Log-rank = 6.01 and P = 0.04), as well as HER2/neu positive tumors (Log-rank = 6.14 and P = 0.013). A statistical significant trend toward a longer recurrence free survival was, noticed if Wilms tumor was at early stages (Log-rank = 21.22, P > 0.0000) and if HER2/neu positive (Log-rank = 8.53, P = 0.004). HER2/neu expression in Wilms tumor could be a marker for epithelial and homologous differentiation and its expression could be a good predictor for overall survival and longer recurrence free survival.

Altered CD19/CD22 balance in Egyptian children and adolescents with systemic lupus erythematosus.

B cells from systemic lupus erythematosus (SLE) patients display signalling defects that may underlie disease pathogenesis activity.CD19 and CD22 play a major role as regulators of B-cell response. The aim of this study was to clarify the relationship between B cell surface markers namely CD19, CD20 and CD22 expression and clinical and laboratory indices of SLE activity. The study included 33 SLE patients and 20 healthy children and adolescents as controls. Flowcytometric assay of dual markers, CD19/CD20, and CD20/CD22 was done. SLE disease activity was assessed by SLEDAI score. CD22% was significantly higher while CD20% was significantly lower in the study compared to the control group. No significant difference was observed in both groups with respect to CD19% or CD19/CD22% ratio. The level of CD22 expression was significantly lower in high and very high active cases than in mild and moderate cases and negatively correlated with SLDEAI score and ESR. Results obtained showed that, B cell surface receptors CD20 and CD22 are significantly affected in patients with SLE, pointing to their possible involvement in the aetiopathogenesis of the disease and in the regulatory mechanisms in response to the immune disturbance.