Patterns and Outcomes of Acute Central Nervous System Complications During Treatment of Childhood Acute Lymphoblastic Leukemia: A Single-center Experience.

Central nervous system (CNS) complications are considered adverse events during the treatment of pediatric acute lymphoblastic leukemia (ALL). This study aimed to assess the incidence, types, clinical and radiologic patterns, risk factors, and the fate of different CNS complications during the treatment of pediatric ALL. A retrospective study included 390 patients with pediatric ALL, treated according to St. Jude total XV protocol at the National Cancer Institute, Cairo University, from January 2012 to December 2017. Thirty-nine (10%) patients developed different types of CNS complications. Nineteen (4.9%) patients had cerebrovascular complications, 12 (3.1%) patients had posterior reversible encephalopathy syndrome (PRES), and 6 (1.5%) patients had leukoencephalopathy; both CNS infections and leukemic infiltrates were diagnosed in one patient each. CNS complications were significantly higher in patients older than 10 years old, patients with high-risk disease, and patients who were classified as CNS III status with a statistically significant P value of 0.040, 0.020, and 0.002, respectively. There were 31 (79.5%) cases that achieved complete recovery, 6 (15.4%) patients who died, and 2 (5.1%) patients who developed residual neurological deficits. In conclusion, pediatric patients with ALL, who presented with older age, high-risk disease initially, and had initial CNS III status, were at higher risk of developing acute CNS complications during their treatment period. Patients who developed visual disturbances were associated with unfavorable outcomes. Despite that, around 80% of patients showed complete recovery, but still, 15% of them died from these complications.

Optimizing cyclosporine A dose post allogeneic hematopoietic stem cell transplantation in paediatric cancer patients.

BACKGROUND/OBJECTIVES: Cyclosporine A (CSA) dosing has been complicated by considerable intra-patient and inter-patient variability in pharmacokinetics, which is affected by different factors. We aimed to assess the various factors that might affect the CSA dose and its plasma level. PATIENTS AND METHODS: This retrospective study included paediatric cancer patients who underwent allogeneic hematopoietic stem cell transplant at the Children's Cancer Hospital Egypt 57357 from matched related donors with CSA as graft versus host disease prophylaxis. The CSA initial dose was 1.5 mg/kg IV Q12H. Then, it was titrated according to the level and drug toxicity. Cyclosporine A trough levels were assessed two to three times per week using the Emit 2000 cyclosporine-specific assay. Moreover, factors that may affect cyclosporine levels, such as age, sex, weight and the antifungal used, were analyzed to determine their effect on CSA plasma levels. RESULTS: There were 119 patients included in the study. The median age was 10 years; and 43% of them used voriconazole as a prophylactic antifungal. The multivariate analysis revealed that female patients, those >9 years or on voriconazole reached the target level at low initial CSA doses. A higher probability (93%) of reaching the desired plasma level with doses 1.5 mg/kg IV Q12H was observed among patients >9 years, and on voriconazole. While those who were ≤9 years and not on voriconazole required doses >1.5 mg/kg IV Q12H, with an 89% probability of reaching the desired level. CONCLUSION: This study suggests that the initial CSA dose should consider the patient's age and the antifungal used. Patients >9 years and/or on voriconazole may require lower initial CSA doses and could start with 1.5 mg/kg IV Q12H.

MECOM gene overexpression in pediatric patients with acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by blocked or aberrant differentiation of hematopoietic stem cells. The MECOM gene overexpression in hematopoietic progenitors induces myeloid differentiation block, resulting in increased self-renewal and survival of these transformed progenitors. However, its exact role in AML remains unclear. We aimed to estimate the prevalence of MECOM overexpression among pediatric AML patients, and assess its impact on clinical outcome. PATIENTS AND METHODS: Real-time quantitative polymerase chain reaction and Livak method (2ΔΔCt) were used to determine relative MECOM expression level among 243 pediatric patients with AML. MECOM overexpression was considered if the cumulative relative expression was above 1 (2-ΔΔCt) and was designated as MECOMpos. RESULTS: Of 243 AML patients tested 57(23.5%) demonstrated MECOMpos. Patients with MECOMpos had significantly lower median age. The frequency of MECOMpos was significantly higher among AML patients with 11q23 abnormalities, complex karyotypes and among high- and intermediate-risk groups compared to low-risk group (p = .014). MECOMpos patients had significantly lower overall survival (OS) (38.7 vs. 78.9%, p < .001), event-free survival (EFS) (37.3% vs. 68.4%, p < .001), and had higher cumulative incidence of relapse (49.5% vs. 23.5%, p = .002) at 36 months compared to MECOMneg patients. Multivariate analysis revealed that MECOMpos was an adverse prognostic factor for OS (hazards ratio (HR) = 2.11, 95% confidence interval (CI) 1.24-3.60, p = .006) and EFS (HR= 1.71, 95% CI 1.07-2.75, p = .025). The logistic regression model showed that MECOMpos was an independent prognostic factor regardless of minimal residual disease status post first induction therapy in the intermediate-risk group (odds ratio 2.89; 95% CI 1.19-6.57, p = .018). CONCLUSION: The aberrant MECOM gene expression is an adverse prognostic factor, especially in patients without previously known cytogenetic risk factors. Our results suggest the potential benefit from pretreatment screening for MECOM gene overexpression in newly diagnosed AML patients for better risk stratification and treatment adjustment.

Temporal trends in childhood cancer survival in Egypt, 2007 to 2017: A large retrospective study of 14 808 children with cancer from the Children's Cancer Hospital Egypt.

Childhood cancer is a priority in Egypt due to large numbers of children with cancer, suboptimal care and insufficient resources. It is difficult to evaluate progress in survival because of paucity of data in National Cancer Registry. In this study, we studied survival rates and trends in survival of the largest available cohort of children with cancer (n = 15 779, aged 0-18 years) from Egypt between 2007 and 2017, treated at Children's Cancer Hospital Egypt-(CCHE), representing 40% to 50% of all childhood cancers across Egypt. We estimated 5-year overall survival (OS) for 14 808 eligible patients using Kaplan-Meier method, and determined survival trends using Cox regression by single year of diagnosis and by diagnosis periods. We compared age-standardized rates to international benchmarks in England and the United States, identified cancers with inferior survival and provided recommendations for improvement. Five-year OS was 72.1% (95% CI 71.3-72.9) for all cancers combined, and survival trends increased significantly by single year of diagnosis (P < .001) and by calendar periods from 69.6% to 74.2% (P < .0001) between 2007-2012 and 2013-2017. Survival trends improved significantly for leukemias, lymphomas, CNS tumors, neuroblastoma, hepatoblastoma and Ewing Sarcoma. Survival was significantly lower by 9% and 11.2% (P < .001) than England and the United States, respectively. Significantly inferior survival was observed for the majority of cancers. Although survival trends are improving for childhood cancers in Egypt/CCHE, survival is still inferior in high-income countries. We provide evidence-based recommendations to improve survival in Egypt by reflecting on current obstacles in care, with further implications on practice and policy.

Incidence, risk factors, and outcome of blood stream infections during the first 100 days post-pediatric allogeneic and autologous hematopoietic stem cell transplantations.

Bloodstream infections (BSI) are a frequently observed complication after hematopoietic stem cell transplant (HSCT). Retrospective analysis of clinical and microbiological data during the first 100 days from 302 consecutive pediatric patients who underwent HSCT for a malignant disease at our institute between January 2013 and June 2017. A total of 164 patients underwent autologous and 138 allogeneic HSCT. The overall incidence of BSI was 37% with 92% of infectious episodes occurring during the pre-engraftment phase. Gram-positive bacteria (GPB) accounted for 54.6% of the isolated pathogens, gram-negative bacteria (GNB) for 43.9%, and fungi for 1.4%. Coagulase-negative staphylococci and Escherichia coli were the most commonly isolated GPB and GNB, respectively. Forty-five percent of GNB were extended-spectrum beta-lactamase producers and 21% were multidrug-resistant organisms. Fluoroquinolone resistance was 92% and 68%, among GPB and GNB, respectively. Risk factors for BSI in univariate analysis were allogeneic HSCT, delayed time to engraftment more than 12 days, previous BSI before HSCT, and alternative donor. In multivariate analysis, only HSCT type (allogeneic vs autologous P = .03) and previous BSI within 6 months before HSCT (P = .016) were significant. Overall survival at day 100 was 98% and did not differ significantly between patients with and without BSI (P = .76). BSI is common in children undergoing HSCT for malignant diseases. Allogeneic HSCT recipients and previous BSI within 6 months before HSCT are associated with increased risk of post-transplant BSI. With current supportive measures, BSI does not seem to confer an increased risk for 100-day mortality.

Outcomes of allogenic hematopoietic cell transplantation for childhood chronic myeloid leukemia: Single-center experience.

BACKGROUND/OBJECTIVES: Despite the apparent efficacy and favorable toxicity profile of TKIs, allogeneic SCT remains the only curative treatment for CML especially in younger patients, but TRM should be considered. We evaluated the clinical outcomes of pediatric CML patients who had SCT in our center. METHODS: This retrospective study included children with CML, who received an allogeneic SCT at Children Cancer Hospital Egypt, 57357, from 2007 to 2017. All patients received myeloablative conditioning chemotherapy containing busulfan/cyclophosphamide followed by stem cell infusion from MRD. RESULTS: From 121 patients diagnosed with CML, 43 had available MRD and subjected to HSCT while 78 patients continued TKI therapy. The median time to transplant from diagnosis was 13 months. At initial diagnosis, there were 39 patients in CP and 4 had blastic crises. Bone marrow harvest was the stem cell source in 32 patients, while 11 cases received mobilized peripheral blood stem cells with average stem cell dose of 4.45 × 106 /kg. The probabilities of overall survival and event-free survival at 5 years were 97.4% and 79.8%, respectively. TRM at 100 days and TRM at 1-year post-transplant were 0%. The incidence of chronic GVHD was significantly higher in peripheral blood than bone marrow stem cell source (P = .004). CONCLUSION: Considering the excellent survival rates and very low TRM, HSCT is still a valid option for pediatric patients with newly diagnosed CML with best using marrow stem cell source to avoid a significant risk of cGVHD and its related complications.

Clinical features and outcome of hepatosplenic fungal infections in children with haematological malignancies.

Hepatosplenic fungal infection (HSFI) is a severe invasive fungal infection observed during neutrophil recovery in patients with acute leukaemia treated with intensive chemotherapy. Retrospective analysis including all paediatric haematological malignancies patients with HSC treated in Children Cancer Hospital Egypt (2013-2018). Twenty-five patients with acute leukaemia developed HSFI (19 patients diagnosed as hepatosplenic candidiasis). Most of the cases (92%) occurred during the induction phase. Organs affected were as follows: liver in 18 patients, renal in 13 patients, spleen in 12 patients, skin in four patients and retina in one patient. Five (20%) patients had proven HSC, 14 (56%) probable and six (24%) possible HSFI. Ten patients had a PET-CT for response assessment. Candida tropicalis was the most common isolated spp. from blood/tissue culture. Six (24%) patients developed HSFI on top of antifungal prophylaxis. Steroids were given in 12 (52%) patients with HSFI as immune reconstitution syndrome (IRS). Caspofungin was the first line of treatment in 14 (56%) patients, liposomal amphotericin B in six (24%) patients and azoles in five (20%) patients. HSFI was associated with delayed of intensification phase of chemotherapy (median 42 days). The success rate was reported in 24 patients with complete response (68%) and partial response in (28%) patients, while failure (death) seen in 1(4%) patient. HSC is still a major challenge in paediatric leukaemias patients with impact on treatment delay and survival outcome. PET scan, non-culture diagnostics and steroid role evidence in IRS are growing. Antifungal stewardship for screening, early detection for high-risk patients and better response assessment is challenging.

Outcome predictors of autologous hematopoietic stem cell transplantation in children with relapsed and refractory Hodgkin lymphoma: Single-center experience in a lower-middle-income country.

BACKGROUND: Children and adolescents with HL have excellent long-term survival exceeding 95% after combined modality treatment. However, about 20% will either relapse or have PRF. Salvage HDCT followed by AHSCT is considered to be the preferential treatment. OBJECTIVE: To describe the outcome (OS and EFS) and prognostic factors in pediatric patients with relapsed or refractory HL (r/rHL) who underwent AHSCT. METHODS: We retrospectively included 43 pediatric patients with r/rHL who underwent AHSCT from July 1, 2007, till December 31, 2016, at the Children's Cancer Hospital of Egypt. MAC regimen given was CMV. RESULTS: Of the whole cohort, 88.4% of patients achieved CR, while 11.6% had a positive PET scan prior to transplantation. The 3-year OS and EFS were 85% and 70.6%, respectively. The 3-year OS for patients > 10 years was 94% versus 65.5% for patients 10 years of age or younger (P = 0.046). There is strong tendency toward better 3-year OS for patients with negative PET scan as compared to those with positive PET scan before AHSCT, 89.4% vs 60%, respectively (P = 0.059). This tendency is also applicable when looking at the 3-year EFS for the two groups, 78.3% vs 40%, respectively (P = 0.069). CONCLUSION: Poor predictors of OS were younger age and positive PET scan before AHSCT. The latter, along with single modality treatment before AHSCT, were poor predictors of EFS.

Early Deaths in Pediatric Acute Leukemia: A Major Challenge in Developing Countries.

Children with acute leukemia may experience high treatment-related mortality, which often occurs early in the induction phase. The aim of the study was to assess the incidence and risk factors related to increased mortality during induction therapy of pediatric patients with acute leukemia. This is a retrospective study that included pediatric acute leukemia patients who presented to the National Cancer Institute, Cairo University, between January 2011 and December 2013. The study included 370 patients, 253 with acute lymphoblastic leukemia, 100 with acute myeloid leukemia, and 17 with mixed phenotype acute leukemia. The total and induction death rates were 40.5% and 19.2%, respectively. Most of the early deaths were attributed to infections (64.7%) and cerebrovascular accidents (18.3%). Using enhanced supportive care measures during 2013 had significantly reduced the overall and induction mortality rates (29% and 13.6%, respectively, in 2013 vs. 46% and 20.3% in 2011). Induction deaths in pediatric acute leukemia remain a major challenge in developing countries, and using enhanced supportive care measures is effective to improve the survival outcome in this group of patients.

Overview and outcome of mucormycosis among children with cancer: Report from the Children's Cancer Hospital Egypt.

Mucormycosis represents a real challenge in immunocompromised patients. This study aimed to describe the clinical characteristics, treatment outcome and infection-related mortality in our patients at the Children's Cancer Hospital 57357, Cairo, Egypt. This is a retrospective study during the period 2007-2017. Data analysis included demographic data, risk factors, diagnostic workup, treatment and outcome. During the study period, 45 patients developed proven mucormycosis according to EORTC/MSG criteria (2008). Ninety percentof cases were of haematological malignancies. Liposomal amphotericin B was the mainstay of treatment. Posaconazole was used as secondary prophylaxis in 35% of cases. Combination antifungal was used in three cases with progressive mucormycosis. Surgical intervention was achievable in 50% of cases. Therapy was successful in 35 patients (66%). Complications related to mucormycosis were seen in five cases with disfigurement and perforated hard palate. Chemotherapy delay with subsequent relapse of primary malignancy was reported in one case. Mucormycosis-related mortality was 33% (15 cases). Mucormycosis is a major cause of mortality among patients with haematological malignancies. Early diagnosis of Mucormycosis infection, with rapid initiation of appropriate antifungal therapy and surgical intervention, whenever feasible, is the backbone of mucormycosis treatment.

Comparison of toxicity following different conditioning regimens (busulfan/melphalan and carboplatin/etoposide/melphalan) for advanced stage neuroblastoma: Experience of two transplant centers.

The outcome for advanced neuroblastoma has improved with combined modality therapy: induction chemotherapy, surgery, and consolidation with high-dose chemotherapy/autologous HSCT, followed by local radiation, cisretinoic acid, and recently antibody therapy. In the United States, the most common conditioning regimen is CEM, while in Europe/Middle East, Bu/Mel has been widely used; it remains unclear which regimen has the best outcome. Assess renal, hepatic, and infectious toxicity through Day+100 in 2 different regimens. Retrospective comparison between CEM-DFCHCC Boston and Bu/Mel- CCHE-57357. Thirty-five patients, median age 4, in Boston (2007-2011) and 38 patients, median age 3, in Cairo (2009-2011). Renal toxicity; creatinine was significantly higher in CEM than Bu/Mel: 57% (median day+90) vs. 29% (median>day+100), p = 0.004. One CEM patient died from renal dialysis at day+19. Hepatic toxicity was significantly higher in CEM than Bu/Mel: 80% (median day+26) vs. 58% (median day+60), p = 0.04. In infectious complications with CEM 14%, bacteremia (n = 4) and fungemia (n = 1), 3 had culture-negative sepsis requiring vasopressors. With Bu/Mel 18%, bacteremia (n = 7), none required pressors, p = 0.4. Bu/Mel was associated with less acute hepatic and renal toxicity and thus may be preferable for preserving organ functions.

Prophylactic levofloxacin in pediatric neutropenic patients during autologous hematopoietic stem cell transplantation.

BACKGROUND: Using fluoroquinolone prophylaxis in pediatric neutropenic patients is a controversial issue due to the concern about emergence of resistant strains in addition to the lack of pediatric studies. This study was performed to assess the effectiveness of levofloxacin prophylaxis in pediatric patients during autologous stem cell transplantation. METHODS: This was an observational study of pediatric patients who underwent autologous stem cell transplantation, comparing patients who received levofloxacin prophylaxis to historical controls. RESULTS: A total of 96 patients were included (46 patients in the control group and 50 patients received levofloxacin). The median duration till onset of first fever was 11 d in the control group as compared to 15 d in patients who received levofloxacin (p ≤ 0.001). The incidence of infectious complications was higher in patients without levofloxacin (4/46) than those with levofloxacin (1/50). The median duration of empirical antibiotic use was 10 d in the levofloxacin group compared with 14 d in the control group (p < 0.001). CONCLUSION: Levofloxacin prophylaxis delayed first spike of fever, decreased the incidence of septic complications, and shortened the duration of empiric antibiotic use, but its impact on emergence of resistant organisms should be closely monitored.

Profiling Loss of Heterozygosity Patterns in a Cohort of Favorable Histology Nephroblastoma Egyptian Patients: What is Consistent With the Rest of the World.

According to the Fifth National Wilms Tumor Study (NWTS-5), tumor-specific loss of heterozygosity (LOH) for chromosomes 1p and 16q identifies a subset of patients with Wilms tumor (WT) who despite having favorable histology (FH) have a significantly increased risk of relapse and death. We aimed to find out 1p and 16q LOH frequencies in patients with FH-WT as well as its correlation to survival outcome and epidemiologic and clinical characteristics. Data of patients with FH-WT presenting to the National Cancer Institute, Egypt, were retrospectively analyzed. Paraffin blocks were tested for 1p and 16q LOH using polymorphic loci that span the minimal regions of LOH at this area. The study included 100 patients with a median age of 5 years. Thirty-nine patients (39%) showed LOH at 1p (n = 14), 16q (n = 13), or both (n = 12). LOH was most frequently encountered in patients above 10 years (5/5), advanced stages disease (80% of stage V and 50% of stages IV and III each). The 3-year overall survival (OS) and event-free survival (EFS) were significantly lower in patients with double LOH (75% and 50%, respectively), followed by 16q (92% and 54%), in comparison with 1p (93% each) and negative LOH (97% and 100%) cases, respectively (p = 0.001). Combined LOH (1p+16q), followed by 16q LOH alone, was predictive of poorer outcome and was associated with lower OS and EFS in patients with FH-WT. Our results showed a higher-risk disease that would suggest the need for an intensified upfront therapy in this group of patients.

Integration of measurable residual disease by WT1 gene expression and flow cytometry identifies pediatric patients with high risk of relapse in acute myeloid leukemia.

Background: Molecular testing plays a pivotal role in monitoring measurable residual disease (MRD) in acute myeloid leukemia (AML), aiding in the refinement of risk stratification and treatment guidance. Wilms tumor gene 1 (WT1) is frequently upregulated in pediatric AML and serves as a potential molecular marker for MRD. This study aimed to evaluate WT1 predictive value as an MRD marker and its impact on disease prognosis. Methods: Quantification of WT1 expression levels was analyzed using the standardized European Leukemia Network real-time quantitative polymerase chain reaction assay (qRT-PCR) among a cohort of 146 pediatric AML patients. Post-induction I and intensification I, MRD response by WT1 was assessed. Patients achieving a ≥2 log reduction in WT1MRD were categorized as good responders, while those failing to reach this threshold were classified as poor responders. Results: At diagnosis, WT1 overexpression was observed in 112 out of 146 (76.7%) patients. Significantly high levels were found in patients with M4- FAB subtype (p=0.018) and core binding fusion transcript (CBF) (RUNX1::RUNX1T1, p=0.018, CBFB::MYH11, p=0.016). Following induction treatment, good responders exhibited a reduced risk of relapse (2-year cumulative incidence of relapse [CIR] 7.9% vs 33.2%, p=0.008). Conversely, poor responders' post-intensification I showed significantly lower overall survival (OS) (51% vs 93.2%, p<0.001), event-free survival (EFS) (33.3% vs 82.6%, p<0.001), and higher CIR (66.6% vs 10.6%, p<0.001) at 24 months compared to good responders. Even after adjusting for potential confounders, it remained an independent adverse prognostic factor for OS (p=0.04) and EFS (p=0.008). High concordance rates between WT1-based MRD response and molecular MRD were observed in CBF patients. Furthermore, failure to achieve either a 3-log reduction by RT-PCR or a 2-log reduction by WT1 indicated a high risk of relapse. Combining MFC-based and WT1-based MRD results among the intermediate-risk group identified patients with unfavorable prognosis (positive predictive value [PPV] 100%, negative predictive value [NPV] 85%, and accuracy 87.5%). Conclusion: WT1MRD response post-intensification I serves as an independent prognostic factor for survival in pediatric AML. Integration of WT1 and MFC-based MRD results enhances the reliability of MRD-based prognostic stratification, particularly in patients lacking specific leukemic markers, thereby influencing treatment strategies.

Outcome and safety of colistin usage in pediatric cancer patients with carbapenem-resistant enterobacteriaceae bacteremia at children cancer hospital Egypt.

Background: Carbapenem resistant Enterobacteriacae (CRE) bloodstream infection (BSI) causes complicated infections, especially in immunocompromised patients. This study aimed to assess the renal toxicity and the efficacy of therapy with colistin in a cohort of pediatric cancer patients with BSIs due to CRE and sensitivity to colistin. Patients and Methods: This was an observational, prospective cohort study from May 2017 to October 2017 in Children's Cancer Hospital Egypt 57,357. All patients who had blood stream infections due to CRE receiving intravenous colistin were prospectively enrolled. We used a standardized case form to record patient characteristics, including age, sex, weight, underlying comorbidities, type of infection, causative organism, and antibiotic susceptibility testing. Daily doses, duration of colistin therapy, and co-administered antibiotics (aminoglycosides, vancomycin) were collected. Furthermore, clinical and microbiological responses to treatment were reported. The dosing schedule was based on a loading dose of 5 MU and a 5-MU twice-daily divided maintenance dose, titrated on renal function. Clinical cure, bacteriological clearance, and daily serum creatinine were recorded. Results: One hundred and forty-one Blood Stream infectious episodes mainly due to Klebsiella Species (pneumoniae and Oxytoca) (27%) and Escherichia coli (68%) were analyzed. All strains were susceptible to colistin with Minimum inhibitory concentration (MICs) of 0.19-1.5 mg/L. Patients were predominantly females (69%), with a mean age of 7 years. It was used as a combination therapy with carbapenems (69.2%) or aminoglycosides (80%). The median duration of treatment was 9 days (Range 1-50 days). Clinical and microbiological cure was observed in 110 cases (80%). Acute kidney injury developed during five treatment courses (4%) in which colistin was used in combination with amikacin. No renal replacement therapy was required and subsided within 7 days from colistin discontinuation. Conclusions: Our study showed that colistin had a high efficacy without significant renal toxicity in severe infections due to CRE Gram-negative bacteria.

Résumé Carbapenem-resistant Gram-negative (CRE) bloodstream infection (BSI) causes complicated infections, especially in immunocompromised patients .This study aimed to assess the renal toxicity and the efficacy of therapy with colistin in a cohort of pediatric cancer patients with BSIs due to CRE and sensitivity to colistin. colistin proved to be effective and safe in managing CRE in children with cancer Mots-clés: Colistin, cancer, children, and Carbapenem-Resistant Enterobacteriaceae.

Carbapenem-Resistant Enterobacteriaceae (CRE) among Children with Cancer: Predictors of Mortality and Treatment Outcome.

Carbapenem-resistant Enterobacteriaceae (CRE) is an important emerging threat among pediatric cancer patients, with a high mortality rate. This retrospective study included all pediatric cancer patients with (CRE) bloodstream infections (BSIs) at a children's cancer hospital in Egypt (2013-2017). Two hundred and fifty-four pediatric cancer patients with CRE BSI were identified; 74% had hematological malignancies, and 26% had solid tumors. Acute myeloid leukemia was the most common hematological malignancy (50%). The main clinical features for acquiring CRE-BSI were previous antibiotics exposure (90%), profound neutropenia (84%), prolonged steroid use (45%), previous colonization with a resistant pathogen (35%), ICU admission within 90 days (28%), and central venous catheter use (24%). E. coli was the most common isolated pathogen (56%), followed by Klebsiella pneumoniae (37%). All isolates were resistant to carbapenem with an MIC < 4-8 µg/mL in 100 (45%) and >8 µg/mL in 153 (55%). The overall mortality rate was 57%, and 30 day mortality was reported in 30%. Upon multivariate analysis, for the patients with Klebsiella pneumoniae BSI, carbapenem resistance with an MIC > 8 µg/mL and associated typhlitis or pneumonia were predictors of poor outcome. In conclusion, CRE-BSI is a major threat among pediatric cancer patients in limited resource countries with limited options for treatment. Antimicrobial stewardship for early detection through routine screening, adequate empirical treatment, and timely adequate therapy may impact the outcome for such high-risk patient groups.

Cost-effectiveness of childhood cancer treatment in Egypt: Lessons to promote high-value care in a resource-limited setting based on real-world evidence.

Background: Childhood cancer in low-and middle-income countries is a global health priority, however, the perception that treatment is unaffordable has potentially led to scarce investment in resources, contributing to inferior survival. In this study, we analysed real-world data about the cost-effectiveness of treating 8886 children with cancer at a large resource-limited paediatric oncology setting in Egypt, between 2013 and 2017, stratified by cancer type, stage/risk, and disease status. Methods: Childhood cancer costs (USD 2019) were calculated from a health-system perspective, and 5-year overall survival was used to represent clinical effectiveness. We estimated cost-effectiveness as the cost per disability-adjusted life-year (cost/DALY) averted, adjusted for utility decrement for late-effect morbidity and mortality. Findings: For all cancers combined, cost/DALY averted was $1384 (0.5 × GDP/capita), which is very cost-effective according to WHO-CHOICE thresholds. Ratio of cost/DALY averted to GDP/capita varied by cancer type/sub-type and disease severity (range: 0.1-1.6), where it was lowest for Hodgkin lymphoma, and retinoblastoma, and highest for high-risk acute leukaemia, and high-risk neuroblastoma. Treatment was cost-effective (ratio <3 × GDP/capita) for all cancer types/subtypes and risk/stage groups, except for relapsed/refractory acute leukaemia, and relapsed/progressive patients with brain tumours, hepatoblastoma, Ewing sarcoma, and neuroblastoma. Treatment cost-effectiveness was affected by the high costs and inferior survival of advanced-stage/high-risk and relapsed/progressive cancers. Interpretation: Childhood cancer treatment is cost-effective in a resource-limited setting in Egypt, except for some relapsed/progressive cancer groups. We present evidence-based recommendations and lessons to promote high-value in care delivery, with implications on practice and policy. Funding: Egypt Cancer Network; NIHR School for Primary Care Research; ALSAC.

Hematopoietic stem cell transplantation from HLA-matched sibling donors in children with acute lymphoblastic leukemia: A report from the Children's Cancer Hospital Egypt.

Introduction: Allogeneic hematopoietic stem cell transplantation (HSCT) is widely used for high-risk acute lymphoblastic leukemia (ALL) patients in their first complete remission (CR1), and for relapsed patients in second complete remission (CR2). Patients and methods: We retrospectively analyzed data for 67 children with ALL, from a cancer center in a low/middle income country, who had undergone HSCT from human leukocyte antigen (HLA)-matched sibling donors (MSDs) using myeloablative conditioning (MAC) regimens, between 2007 and 2020, describing the survival outcome and relapse probability after achieving CR1 and CR2 and determining outcome differences in relation to indications for HSCT in patients transplanted in CR1. All patients had achieved a negative minimal residual disease prior to transplant (<0.01%). Results: Forty-six patients (68.7%) were in CR1; 25 had adverse cytogenetics, including 18 patients with Philadelphia chromosome-positive ALL (Ph-positive ALL), and 21 had poor induction response. The 5-year overall survival (OS), event-free survival (EFS) and cumulative incidence of relapse (CIR) for the whole cohort were 56.1% (95% CI, 42.8%-69.4%), 49% (95% CI, 35.7%-62.3%) and 33.5% (95% CI, 21.7%-45.8%), respectively with better EFS and CIR for CR1 transplants compared to CR2 transplants (P=0.02 and P=0.03, respectively). Patients with Ph-positive ALL had better 5-year OS, EFS and non-relapse mortality (NRM) compared with other CR1 transplants (P=0.015, P=0.009 and P=0.028, respectively). Conclusion: Hematopoietic stem cell transplantation from MSD for ALL in CR1 group had superior outcomes compared to CR2 group and was apparently a curable option for Ph-positive ALL without an increased risk of non-relapse mortality. Poorer survival rates and higher relapse probabilities were associated with HSCT conducted to patients who had a poor response to induction therapy or suffered a relapse.