Evaluating the Frequencies of CNOT3, GRIA1, NFATC2, and PNPLA3 Variant Alleles and Their Association with L-Asparaginase Hypersensitivity in Pediatric Acute Lymphoblastic Leukemia in Addis Ababa, Ethiopia.

Introduction: L-asparaginase is a vital component for the treatment of childhood acute lymphoblastic leukemia (ALL); however, hypersensitivity reactions and hepatotoxicity hinder its anti-neoplastic efficacy. Previous reports indicated that genetic variants in CNOT3, GRIA1, and NFATC2 genes might be associated with hypersensitivity reactions and PNPLA3 with liver function. Objective: In this study, it was investigated whether this association also exists in a pediatric ALL cohort from Ethiopia. Methods: Three variants GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were genotyped in a cohort of 160 patients. Association analysis to investigate the association with hypersensitivity reactions was performed using logistic regression analyses. Besides these variants, a variant in PNPLA3 (rs738409) was genotyped to assess the association with liver function. Results: Genotype frequencies of GRIA1 rs4958351, CNOT3 rs73062673, and NFATC2 rs6021191 were higher/lower than previously reported. One hundred and forty-four patients were included in the association analysis of which, 18 (12.5%) developed L-ASP hypersensitivity. Though the frequency of hypersensitivity was higher in patients that carried the risk alleles of the three investigated genes, no statistically significant differences were observed. Association analysis between PNPLA3 rs738409 and liver function could not be investigated due to a lack of clinical information. Conclusion: In conclusion, none of the tested genes did predict L-asparaginase hypersensitivity in an Ethiopian pediatric ALL patients.

Beckwith-Wiedemann syndrome in a child with multifocal Wilms tumor and lateralized overgrowth: A case report.

Beckwith-Wiedemann syndrome (BWS) is a rare imprinting disorder and overgrowth syndrome with a prevalence of 1 in 10,000 live births. It is characterized by predilection for embryonal tumor growth, especially Wilms tumor (WT), and manifestations like lateralized overgrowth/hemihypertrophy, macroglossia, macrosomia, anterior abdominal wall defects, and hyperinsulinism. Our case is a 1 year of female child who presented with abdominal swelling and limb length discrepancies. A clinical diagnosis of BWS was made based on multifocal WT and hepatomegaly and nephromegaly detected on contrast-enhanced abdominal computed tomography and physical examination findings of lateralized overgrowth and umbilical hernia. A molecular genetic test was not available. The patient was started on preoperative chemotherapy with good tolerance. Clinical criteria can be used to diagnose WBS in a setting where confirmatory molecular testing is unavailable. This will considerably change approaches to management of presenting complications such as WT .

Cost of childhood cancer treatment in Ethiopia.

BACKGROUND: Despite the recent interest in expanding pediatric oncology units in Ethiopia, reflected in the National Childhood and Adolescent Cancer Control Plan (NCACCP), little is known about the cost of running a pediatric oncology unit and treating childhood cancers. METHODS: We collected historical cost data and quantity of services provided for the pediatric oncology unit and all other departments in Tikur Anbessa Specialized Hospital (TASH) from 8 July 2018 to 7 July 2019, using a provider perspective and mixed (top-down and bottom-up) costing approaches. Direct costs (human resources, drugs, supplies, medical equipment) of the pediatric oncology unit, costs at other relevant clinical departments, and overhead cost share are summed up to estimate the total annual cost of running the unit. Further, unit costs were estimated at specific childhood cancer levels. RESULTS: The estimated annual total cost of running a pediatric oncology unit was USD 776,060 (equivalent to USD 577 per treated child). The cost of running a pediatric oncology unit per treated child ranged from USD 469 to USD 1,085, on the scenario-based sensitivity analysis. Drugs and supplies, and human resources accounted for 33% and 27% of the total cost, respectively. Outpatient department and inpatient department shared 37% and 63% of the cost, respectively. For the pediatric oncology unit, the cost per OPD visit, cost per bed day, and cost per episode of hospital admission were USD 36.9, 39.9, and 373.3, respectively. The annual cost per treated child ranged from USD 322 to USD 1,313 for the specific childhood cancers. CONCLUSION: Running a pediatric oncology unit in Ethiopia is likely to be affordable. Further analysis of cost effectiveness, equity, and financial risk protection impacts of investing in childhood cancer programs could better inform the prioritization of childhood cancer control interventions in the Ethiopia Essential Health Service Package.

Incidence and determinants of hematotoxicity in acute lymphoblastic leukemia children who received 6-mercaptopurine based maintenance therapy in Addis Ababa, Ethiopia.

INTRODUCTION: The maintenance phase of acute lymphoblastic leukemia treatment is the final and longest stage of treatment, mainly focused on antimetabolite therapy. This phase is essential to eliminate residual leukemic clones and prevent relapse. However, dose-limiting hematotoxicity is a major problem during this phase resulting in dose reduction or treatment discontinuation. OBJECTIVE: In this cohort study, the clinical features and risk factors of hematological toxicity during the maintenance phase of treatment were analyzed in pediatric patients from Ethiopia. METHODS: A total of 160 patients from Tikur Anbessa specialized hospital were included in the study of which 142 had sufficient data available for analysis. Patient characteristics as well as information about the care-givers, sides-effects as reported by the care-givers and clinical factors were collected. Bivariable followed by multivariable analysis was performed to investigate which factors were associated with hematological toxicity during the maintenance phase. RESULTS: During the first six months of maintenance phase treatment grade 4 neutropenia was detected in 52.8% of the patients. The risk of developing grade 4 neutropenia was increased by about two fold in children with the age of 6 years and less compared to those with the age of more than 6 years. Similarly, the rate of developing grade 4 neutropenia among children with less than 4,500 maintenance day 1 white blood cell counts was significantly higher than that of children with normal maintenance day 1 white blood cell counts (AHR 2.477, 95% CI = 1.461-4.200, p = 0.001). CONCLUSION: In conclusion, child's age and day 1 maintenance white blood cell/absolute neutrophil counts significantly affected the occurrence of grade 4 hematotoxicity. Close monitoring for white blood cell and absolute neutrophil counts during maintenance phase treatment is recommended for early diagnosis of hematotoxicity.

A retrospective review on the histopathological pattern of childhood malignant solid tumors in Ethiopia.

In low- and middle-income countries (LMICs), malignancies remain underreported due to lack of quality data. This study outlines the histopathological pattern of pediatric solid malignancies in children aged 0-15 years at the largest referral hospital in Ethiopia. A total of 432 solid malignancies were evaluated. The most common malignancies were lymphoma (21.8%), retinoblastoma (19.4%), and Wilms tumor (13.9%). Burkitt lymphoma accounted for 2.1%, despite being the most reported pediatric malignancy in sub-Saharan Africa in published literature. Definitive diagnosis could not be made in 7% of cases, related to the lack of confirmatory testing. The study highlights the need for improvement in diagnostic capabilities in LMICs.

Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.

Introduction: Genetic variation in the thiopurine S-methyltransferase (TPMT) gene by and large predicts variability in 6-mercaptopurine (6-MP) related toxicities. However, some individuals without genetic variants in TPMT still develop toxicity that necessitates 6-MP dose reduction or interruption. Genetic variants of other genes in the thiopurine pathway have been linked to 6-MP related toxicities previously. Objective: The aim of this study was to evaluate the effect of genetic variants in ITPA, TPMT, NUDT15, XDH, and ABCB1 on 6-MP related toxicities in patients with acute lymphoblastic leukemia (ALL) from Ethiopia. Methods: Genotyping of ITPA, and XDH was performed using KASP genotyping assay, while that of TPMT, NUDT15, and ABCB1 with TaqMan® SNP genotyping assays. Clinical profile of the patients was collected for the first 6 months of the maintenance phase treatment. The primary outcome was the incidence of grade 4 neutropenia. Bivariable followed by multivariable cox regression analysis was performed to identify genetic variants associated with the development of grade 4 neutropenia within the first 6 months of maintenance treatment. Results: In this study, genetic variants in XDH and ITPA were associated with 6-MP related grade 4 neutropenia and neutropenic fever, respectively. Multivariable analysis revealed that patients who are homozygous (CC) for XDH rs2281547 were 2.956 times (AHR 2.956, 95% CI = 1.494-5.849, p = 0.002) more likely to develop grade 4 neutropenia than those with the TT genotype. Conclusion: In conclusion, in this cohort, XDH rs2281547 was identified as a genetic risk factor for grade 4 hematologic toxicities in ALL patients treated with 6-MP. Genetic polymorphisms in enzymes other than TPMT involved in the 6-mercaptopurine pathway should be considered during its use to avoid hematological toxicity.

Impact of Delay Prior to Treatment in Ethiopian Children with Acute Lymphoblastic Leukemia.

Introduction: More than 85% of childhood malignancies occur in developing countries with less than a 30% cure rate as opposed to more than 80% cure rate in developed countries. This disproportionately significant difference might be due to delays in diagnosis, treatment initiation, lack of adequate supportive care, and treatment abandonment. We aimed to determine the impact of overall treatment delay on induction mortality of children with acute lymphoblastic leukemia treated at Tikur Anbessa specialized hospital (TASH). Methods: A cross-sectional study was conducted among children who were treated from 2016 to 2019. Children with Down syndrome and relapsed leukemia were excluded from this study. Results: A total of 166 children were included; most patients were males (71.7%). The mean age at diagnosis was 5.9 years. The median time interval from the onset of symptoms to the first TASH visit was 30 days and the median period from TASH's first clinic visit to diagnosis was 11 days. The median time to initiate chemotherapy after diagnosis was 8 days. The total median time from the first onset of symptoms to chemotherapy initiation was 53.5 days. Induction mortality was 31.3%. High-risk ALL and patients with an overall delay between 30 and 90 days were more likely to experience induction mortality. Discussion: Patient and healthcare system delay is high compared to most studies done and a significant association has been noted with induction mortality. Efforts to expand the pediatric oncology service in the country and efficient diagnostic and treatment approach need to be established to reduce mortality associated with overall delay.

Cost-effectiveness of running a paediatric oncology unit in Ethiopia.

OBJECTIVE: To estimate the cost-effectiveness of running a paediatric oncology unit in Ethiopia to inform the revision of the Ethiopia Essential Health Service Package (EEHSP), which ranks the treatment of childhood cancers at a low and medium priority. METHODS: We built a decision analytical model-a decision tree-to estimate the cost-effectiveness of running a paediatric oncology unit compared with a do-nothing scenario (no paediatric oncology care) from a healthcare provider perspective. We used the recently (2018-2019) conducted costing estimate for running the paediatric oncology unit at Tikur Anbessa Specialized Hospital (TASH) and employed a mixed costing approach (top-down and bottom-up). We used data on health outcomes from other studies in similar settings to estimate the disability-adjusted life years (DALYs) averted of running a paediatric oncology unit compared with a do-nothing scenario over a lifetime horizon. Both costs and effects were discounted (3%) to the present value. The primary outcome was incremental cost in US dollars (USDs) per DALY averted, and we used a willingness-to-pay (WTP) threshold of 50% of the Ethiopian gross domestic product per capita (USD 477 in 2019). Uncertainty was tested using one-way and probabilistic sensitivity analyses. RESULTS: The incremental cost and DALYs averted per child treated in the paediatric oncology unit at TASH were USD 876 and 2.4, respectively, compared with no paediatric oncology care. The incremental cost-effectiveness ratio of running a paediatric oncology unit was USD 361 per DALY averted, and it was cost-effective in 90% of 100 000 Monte Carlo iterations at a USD 477 WTP threshold. CONCLUSIONS: The provision of paediatric cancer services using a specialised oncology unit is most likely cost-effective in Ethiopia, at least for easily treatable cancer types in centres with minimal to moderate capability. We recommend reassessing the priority-level decision of childhood cancer treatment in the current EEHSP.

Sonographic and Clinical Features of Typhlitis in Pediatric Cancer Patients on Chemotheaphy at Tikur Anbessa Specialized Hospital, Ethiopia, 2021.

Background: Typhlitis, (neutropenic enterocolitis), is a necrotizing enteropathy of the right colon, and is characterized by the clinical triad of fever, abdominal pain, neutropenia and imaging findings of right-side colonic inflammation. It is seen in the setting of severe neutropenia in immune suppressed patients who undergo treatment for malignancies, in those who have organ transplant(s) or congenital or other acquired immunosuppression. We report the clinical and imaging findings of typhlitis in pediatric cancer patients who had received chemotherapy in the largest tertiary center in Addis Ababa, Ethiopia over a period of 20 months. Methods: The medical records of hospitalized cancer patients on treatment and with suspected typhlitis and with ultrasound reports were screened (November 2018- July 2020). Retrospective analysis of the clinical and sonographic data of those with typhlitis was done. Results: Typhlitis was identified in 4.2% (12/286) of the patients on chemotherapy. 11 (91.7%) had hematologic malignancies (leukemia, lymphoma), one had a solid tumor (Head and neck embryonal RMS). Most (83.3%) had abdominal pain, diarrhea and neutropenia. Fever was identified in 67.7%. All had ultrasound evidence of typhlitis. and treated with IV antibiotics. Neither complications requiring surgical intervention nor death were seen. Conclusion: The magnitude of disease was comparable to what had previously been reported in other studies. While the presence of clinical a triad should prompt suspicion for the diagnosis, sonography can be used for confirmation and follow up obviating radiation, with good access in a resource limited setting.

The magnitude and perceived reasons for childhood cancer treatment abandonment in Ethiopia: from health care providers' perspective.

BACKGROUND: Treatment abandonment is one of major reasons for childhood cancer treatment failure and low survival rate in low- and middle-income countries. Ethiopia plans to reduce abandonment rate by 60% (2019-2023), but baseline data and information about the contextual risk factors that influence treatment abandonment are scarce. METHODS: This cross-sectional study was conducted from September 5 to 22, 2021, on the three major pediatric oncology centers in Ethiopia. Data on the incidence and reasons for treatment abandonment were obtained from healthcare professionals. We were unable to obtain data about the patients' or guardians' perspective because the information available in the cancer registry was incomplete to contact adequate number of respondents. We used a validated, semi-structured questionnaire developed by the International Society of Pediatric Oncology Abandonment Technical Working Group. We included all (N = 38) health care professionals (physicians, nurses, and social workers) working at these centers who had more than one year of experience in childhood cancer service provision (a universal sampling and 100% response rate). RESULTS: The perceived mean abandonment rate in Ethiopia is 34% (SE 2.5%). The risk of treatment abandonment is dependent on the type of cancer (high for bone sarcoma and brain tumor), the phase of treatment and treatment outcome. The highest risk is during maintenance and treatment failure or relapse for acute lymphoblastic leukemia, and during pre- or post-surgical phase for Wilms tumor and bone sarcoma. The major influencing risk factors in Ethiopia includes high cost of care, low economic status, long travel time to treatment centers, long waiting time, belief in the incurability of cancer and poor public awareness about childhood cancer. CONCLUSIONS: The perceived abandonment rate in Ethiopia is high, and the risk of abandonment varies according to the type of cancer, phase of treatment or treatment outcome. Therefore, mitigation strategies to reduce the abandonment rate should include identifying specific risk factors and prioritizing strategies based on their level of influence, effectiveness, feasibility, and affordability.

Results of a pre-implementation analysis of Ethiopia's National Pediatric Cancer Registry.

In Ethiopia, cancer accounts for about 5.8% of total national mortality, with an estimated annual incidence of cancer of approximately 60,960 cases and an annual mortality of over 44,000 persons. This is likely an underestimation. Survival rates for pediatric malignancies are likewise suboptimal although exact figures are unknown since a national cancer registry is unavailable. The World Health Organization (WHO) provides recommendations for the creation of cancer registries to track such data. Here we describe our pharmacist-led, pre-implementation assessment of introducing an enhanced national pediatric cancer registry in Ethiopia. Our assessment project had three specific aims around which the methods were designed: 1) characterization of the current spreadsheet-based tool across participating sites, including which variables were being collected, how these variables compared to standards set by the WHO, and a description of how the data were entered and its completeness; 2) assessment of the perceptions of an enhanced registry from hospital staff; and 3) evaluation of workflow gaps regarding documentation. The hospital staff and leadership have generally positive perceptions of an enhanced pediatric cancer registry, which were further improved by our interactions. The workflow assessment revealed several gaps, which were addressed systematically using a three-phase implementation science approach. The assessment also demonstrated that the existing spreadsheet-based tool was missing WHO-recommended variables and had inconsistent completion due to the workflow gaps. A pediatric oncology summary sheet will be implemented in upcoming trips in patient charts to better summarize the patients' journey starting from diagnosis. This document will be used by the data clerks in an enhanced-spreadsheet to have a more complete data set.

Training pediatric hematologist/oncologists for capacity building in Ethiopia.

PURPOSE: A considerable barrier to global pediatric oncology efforts has been the scarcity and even absence of trained professionals in many low- and middle-income countries, where the majority of children with cancer reside. In 2013, no dedicated pediatric hematology-oncology (PHO) programs existed in Ethiopia despite the estimated annual incidence of 6000-12000 cases. The Aslan Project initiative was established to fill this gap in order to improve pediatric cancer care in Ethiopia. A major objective was to increase subspecialty PHO-trained physicians who were committed to practicing locally and empowered to lead programmatic development. METHODS: We designed and implemented a PHO training curriculum to provide a robust educational and clinical experience within the existing resource-constrained environment in Ethiopia. Education relied on visiting PHO faculty, a training attachment abroad, and extraordinary initiative from trainees. RESULTS: Four physicians have completed comprehensive PHO subspecialty training based primarily in Ethiopia, and all have remained local. Former fellows are now leading two PHO centers in Ethiopia with a combined capacity of 64 inpatient beds and over 800 new diagnoses per year; an additional former fellow is developing a pediatric cancer program in Nairobi, Kenya. Two fellows currently are in training. Program leadership, teaching, and advocacy are being transitioned to these physicians. CONCLUSIONS: Despite myriad challenges, a subspecialty PHO training program was successfully implemented in a low-income country. PHO training in Ethiopia is approaching sustainability through human resource development, and is accelerating the growth of dedicated PHO services where none existed 7 years ago.

Hepatocellular carcinoma with vertebral metastasis in a child with hepatitis B virus infection: a case report.

BACKGROUND: Hepatocellular carcinoma in children with hepatitis B virus infection is rarely reported. Metastases to the vertebrae are an even more unusual phenomenon. CASE PRESENTATION: We report on a case of a 10-year-old Ethiopian boy with hepatitis B infection presenting with paraplegia and incontinence of 10 days' duration. A diagnosis of hepatocellular carcinoma with vertebral metastases was confirmed with serum α-fetoprotein, fine-needle aspirate cytology, and abdominal imaging. CONCLUSION: Surveillance of children not immunized against hepatitis B virus prevents infection and its complications, such as hepatocellular carcinoma. Among children in endemic countries prone to development of hepatocellular carcinoma, metastatic disease can present as sudden weakness of extremities with radiologic findings of vertebral body collapse.

Evaluation and characterization of tumor lysis syndrome before and after chemotherapy among pediatric oncology patients in Tikur Anbessa specialized hospital, Addis Ababa, Ethiopia.

BACKGROUND: Tumor lysis syndrome (TLS) is a life-threatening emergency disorder, caused by an abrupt release of intracellular metabolites after tumor cell death. It is characterized by a series of metabolic manifestations, especially hyperuricemia, hyperkalemia, hyperphosphatemia and hypocalcemia. The aim of this study was to evaluate and characterize the incidence of tumor lysis syndrome among pediatric oncology patients before and after treatment. METHODS: Hospital based prospective cohort study was conducted for 6 months on 61 newly diagnosed pediatric oncology patients. Socio-demographic data was collected by interview administered questionnaire. Patients were followed and the physical diagnosis, imaging and laboratory results were interpreted by senior physicians. Data was entered to and analyzed by SPSS version 23. RESULTS: Among 61 pediatric oncology patients 39(63.9%) were males. The mean (±SD) age of the pediatric patients was 6.39 (± 3.67) years ranging from 2 months to 14 years. 29.5% of patients were found to have TLS. There were 11.5% and 18.0% of laboratory TLS (LTLS) and clinical TLS (CTLS) cases respectively. There were72.2% spontaneous and 27.8% treatment induced TLS cases with 23% and 21.3% cases of hyperuricemia and 4.9% and 6.6% cases of hyperkalemia incidence before and after treatment respectively. Only two patients died, in the study period, due to TLS. CONCLUSION: There was high incidence of TLS irrespective of socio-demographic variation among study participants, suggesting that children with cancer are at risk of developing TLS. As TLS is a life-threatening complication of malignancies, early identification of patients at risk and reducing morbidity and mortality is crucially important.

Fibroplasia Ossificans Progressiva: A Case Report of a Rare Disease Entity.

BACKGROUND: Fibrodysplasia ossificans progressiva (FOP), also known as Myositis ossificans progressiva or Munchmeyer's disease, is an extremely rare and disabling genetic condition of congenital skeletal malformations and progressive heterotopic ossification (HO). The disease is characterized by congenital skeletal anomalies and progressive ectopic bone formation in connective tissues such as ligaments, muscles and tendons. The disease has an incidence of about 1 in 2 million population. CASE DETAILS: We report a case of a 2-year and 8-month old male child with an initial diagnosis of soft tissue sarcoma based on fine needle aspiration (FNAC) of neck swelling. CONCLUSION: Fibroplasia ossificans progressive (FOP) characteristically manifests with bilateral malformation of the great toe and progressive heterotopic ossification (HO). Clinicians and radiologists should be aware of these to prevent permanent disability.

Birth trauma among live born term neonates at a referral hospital in Addis Ababa, Ethiopia.

OBJECTIVE: To assess the occurrence, risk factors and outcomes of mechanical birth injuries among live term neonates. METHODS: A two-year retrospective case control study (September 2000-August 2002) was conducted in a referral hospital in Addis Ababa. RESULTS: One hundred and fifty cases and 358 controls were studied. Subgaleal hemorrhage was the commonest birth injury (61%). Primiparity, vacuum delivery, forceps delivery and birth weight > 3.5 kilograms were found to be strongly associated with birth trauma. Infants with subgaleal hemorrhage were more likely to be complicated than infants with other mechanical birth injuries. CONCLUSION: Indications and benefits of instrumntal delivery should be revised in our circumstances and prim gravid mothers should be evaluated carefully during ANC follow-up.