Retinoblastoma in Asia: Clinical Presentation and Treatment Outcomes in 2112 Patients from 33 Countries.

PURPOSE: To describe the clinical presentation and treatment outcomes of children who received a diagnosis of retinoblastoma in 2017 throughout Asia. DESIGN: Multinational, prospective study including treatment-naïve patients in Asia who received a diagnosis of retinoblastoma in 2017 and were followed up thereafter. PARTICIPANTS: A total of 2112 patients (2797 eyes) from 96 retinoblastoma treatment centers in 33 Asian countries. INTERVENTIONS: Chemotherapy, radiotherapy, enucleation, and orbital exenteration. MAIN OUTCOME MEASURES: Enucleation and death. RESULTS: Within the cohort, 1021 patients (48%) were from South Asia (SA), 503 patients (24%) were from East Asia (EA), 310 patients (15%) were from Southeast Asia (SEA), 218 patients (10%) were from West Asia (WA), and 60 patients (3%) were from Central Asia (CA). Mean age at presentation was 27 months (median, 23 months; range, < 1-261 months). The cohort included 1195 male patients (57%) and 917 female patients (43%). The most common presenting symptoms were leukocoria (72%) and strabismus (13%). Using the American Joint Committee on Cancer Staging Manual, Eighth Edition, classification, tumors were staged as cT1 (n = 441 [16%]), cT2 (n = 951 [34%]), cT3 (n = 1136 [41%]), cT4 (n = 267 [10%]), N1 (n = 48 [2%]), and M1 (n = 129 [6%]) at presentation. Retinoblastoma was treated with intravenous chemotherapy in 1450 eyes (52%) and 857 eyes (31%) underwent primary enucleation. Three-year Kaplan-Meier estimates for enucleation and death were 33% and 13% for CA, 18% and 4% for EA, 27% and 15% for SA, 32% and 22% for SEA, and 20% and 11% for WA (P < 0.0001 and P < 0.0001), respectively. CONCLUSIONS: At the conclusion of this study, significant heterogeneity was found in treatment outcomes of retinoblastoma among the regions of Asia. East Asia displayed better outcomes with higher rates of globe and life salvage, whereas Southeast Asia showed poorer outcomes compared with the rest of Asia. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Pediatric oncology infrastructure and workforce training needs: a report from the Pediatric Oncology East and Mediterranean (POEM) Group.

BACKGROUND: Inadequate numbers of trained healthcare providers (HCPs), contribute to poor pediatric oncology (PO) outcomes, particularly in low- and lower middle-income countries (L/LMICs). An understanding of the characteristics of the workforce challenges are vital for addressing these problems. METHODS: The Pediatric Oncology East and Mediterranean (POEM) Group surveyed PO centers in countries of the North Africa, Middle East, Central Asia and Indian subcontinent on infrastructure and workforce capacity, service availability, and training opportunities for HCPs. Participating centers were categorized by the World Bank income levels for their countries and correlated with services, workload and staffing characteristics, and training needs. RESULTS: Fifty of 82 member-centers (61%) from 21 countries responded to the survey. 299 pediatric oncologists and 1,176 nurses treated 12,496 new PO patients/year, with a 1,451 beds utilization. The majority (71%) of new cases occurred in L/LMICs. The availability of HCPs correlated with country income level, as did pediatric subspecialty access, while availability of support services was unrelated. Twenty-five centers in 11 countries offered PO fellowship training for physicians, whereas 13 PO nurse training centers in 9 countries had the capacity to train 273 nurses annually. The survey respondents indicated that, among their existing workforce, an average of 3·5 physicians and 14 nurses per institution would benefit from additional PO training opportunities. CONCLUSIONS: The participating centers exhibited intra-regional heterogeneity in financial resources, infrastructure, workload, workforce, and medical services. Our findings provide insight into the disparities and regional resources available to POEM, which can be mobilized to rectify specific deficiencies. This article is protected by copyright. All rights reserved.

Pediatric oncology infrastructure and workforce training needs: A report from the Pediatric Oncology East and Mediterranean (POEM) Group.

BACKGROUND: Inadequate numbers of trained health care providers (HCPs) contribute to poor pediatric oncology (PO) outcomes, particularly in low- and lower middle-income countries (L/LMICs). An understanding of the characteristics of the workforce challenges is vital for addressing these problems. METHODS: The Pediatric Oncology East and Mediterranean (POEM) Group surveyed PO centers in countries of North Africa, Middle East, Central Asia, and Indian subcontinent on infrastructure and workforce capacity, service availability, and training opportunities for HCPs. Participating centers were categorized by the World Bank income levels for their countries and correlated with services, workload and staffing characteristics, and training needs. RESULTS: Fifty of 82 member centers (61%) from 21 countries responded to the survey. Two hundred ninety-nine pediatric oncologists and 1176 nurses treated 12 496 new PO patients/year, with a 1451-bed utilization. The majority (71%) of new cases occurred in L/LMICs. The availability of HCPs correlated with country income level, as did pediatric subspecialty access, while availability of support services was unrelated. Twenty-five centers in 11 countries offered PO fellowship training for physicians, whereas 13 PO nurse training centers in nine countries had the capacity to train 273 nurses annually. The survey respondents indicated that, among their existing workforce, an average of 3.5 physicians and 14 nurses per institution would benefit from additional PO training opportunities. CONCLUSIONS: The participating centers exhibited intraregional heterogeneity in financial resources, infrastructure, workload, workforce, and medical services. Our findings provide insight into the disparities and regional resources available to POEM, which can be mobilized to rectify specific deficiencies.

Analysis of KRAS and NRAS Gene Mutations in Arab Asian Children With Acute Leukemia: High Frequency of RAS Mutations in Acute Lymphoblastic Leukemia.

BACKGROUND: KRAS and NRAS gene mutations are frequently observed in childhood leukemia. The objective of this study was to determine the frequency of RAS mutations and the association between RAS mutations and other genetic aberrations in Arab Asian children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). METHODS: Diagnostic samples of 485 patients (<18 years) with acute leukemia from Iraq and Jordan were obtained, using Flinders Technology Associates filter papers. Polymerase chain reaction and direct sequencing were performed in Japan. RESULTS: RAS mutations were detected in 86/318 (27%) of ALL cases and 35/167 (21%) of AML cases. The frequency of NRAS mutation was similar to that of KRAS mutation in ALL. Two RAS mutations were detected in nine patients. Among 264 Iraqi patients with ALL, RAS mutation was significantly associated with lower initial white blood cell count. Of 57 patients with chimeric transcripts, only two patients with either TEL-AML1 or E2A-PBX1 had KRAS mutation. The frequency of NRAS mutation was four times higher than that of KRAS mutation in AML. FAB-M4 and M5 subsets were associated with RAS mutation. Among 134 Iraqi patients with AML, 18 patients had RAS mutations and other genetic aberrations. In particular, 9 of 25 (36%) with MLL-rearrangement had RAS mutations. CONCLUSION: The prevalence of oncogenic RAS mutations was higher among Arab Asian children than in other countries. RAS mutations in AML were found to coexist with other genetic aberrations, particularly MLL rearrangement.

Analysis of class I and II aberrations in Iraqi childhood acute myeloid leukemia using filter paper cards.

The lack of molecular diagnosis in the field of cancer in Iraq has motivated us to perform a genetic analysis of pediatric acute myelogenous leukemia (AML), including class I and II aberrations. Peripheral blood or bone marrow cells were collected from 134 AML children aged ≤15 years. Flinders Technology Associates (FTA) filter paper cards were used to transfer dried blood samples from five Iraqi hospitals to Japan. DNA sequencing was performed to identify class I mutations. Nested RT-PCR was used to detect class II aberrations, except that MLL rearrangement was detected according to long distance inverse-PCR. NPM1 and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations were analyzed by GeneScan using DNA template. Among 134 Iraqi pediatric AML samples, the most prevalent FAB subtype was M2 (33.6 %) followed by M3 (17.9 %). Class I mutations: 20 (14.9 %), 8 (6.0 %), and 8 (6.0 %) patients had FLT3-ITD, FLT3-TKD, and KIT mutations, respectively. Class II mutations: 24 (17.9 %), 19 (14.2 %), and 9 (6.7 %) children had PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 transcripts, respectively. MLL rearrangements were detected in 25 (18.7 %) patients. NPM1 mutation was detected in seven (5.2 %) cases. Collectively, approximately 30 % of AML children were proved to carry favorable prognostic genetic abnormalities, whereas approximately 10 % had high FLT3-ITD allelic burden and needed a special treatment plan including allogeneic hematopoietic stem cell transplantation. Acute promyelocytic leukemia (APL) was frequent among Iraqi pediatric AML. It is likely that molecular diagnosis using FTA cards in underdeveloped countries could guide doctors towards an appropriate treatment strategy.

Frequent coexistence of RAS mutations in RUNX1-mutated acute myeloid leukemia in Arab Asian children.

BACKGROUND: RUNX1 mutation plays an important role in adult leukemic transformation. However, its contribution to the development of childhood leukemia remains unclear. In the present study, we analyzed point mutations of RUNX1 gene in children and adolescents with acute myeloid leukemia (AML) from Iraq and Jordan. PROCEDURE: Bone marrow and/or peripheral blood samples were collected from 178 patients of Arab Asian ethnicity (aged ≤17 years) newly diagnosed with AML: 145 samples from Iraq and 33 samples from Jordan. Direct DNA sequencing was performed on six genes including RUNX1 gene (exons 3-8). RESULTS: RUNX1 point mutations were identified in 10 (5.6%) of 178 patients. One patient possessed biallelic mutations of RUNX1 gene. C-terminal area was the predominant site of RUNX1 mutations (eight in C-terminal and two in N-terminal). Patients with RUNX1 mutations were significantly older than those with wild-type of the gene. Additionally, AML M0 subtype was more frequently found in patients with RUNX1 mutations. Both RUNX1 mutations and RAS mutations were identified in 4 of 10 children. Three patients with RUNX1 mutation had FLT3-ITD. On the other hand, 36 (21.4%) and 25 (14.9%) of 168 patients with wild-type of the gene had a RAS mutation and FLT3-ITD, respectively. Eight of 10 patients with RUNX1 mutations died of hematological relapse. CONCLUSION: The incidence of RUNX1 mutations in Arab Asian children and adolescents with AML was 5.6%. Further studies are required to clarify whether RAS mutations contribute to the development of pediatric AML associated with RUNX1 mutations.

Comprehensive global collaboration in the care of 1182 pediatric oncology patients over 12 years: The Iraqi-Italian experience.

BACKGROUND: Iraq's health care system has gradually declined after several decades of wars, terrorism, and UN economic sanctions. The Oncology Unit at Children's Welfare Teaching Hospital (CWTH) in Baghdad was lacking basic facilities and support. To address this shortcoming, a humanitarian and educational partnership was established between CWTH and Sapienza University of Rome (SUR). METHODS: We investigated the outcomes of 80 online and 16 onsite educational sessions and 142 teleconsultation sessions from 2006 to 2014. We also determined the outcomes of pathology reviews by SUR of 1216 tissue specimens submitted by CWTH from 2007 until 2019 for second opinions. The primary outcomes were discordance, concordance, and changes among clinical diagnoses and pathology review findings. The measures included the frequency of teleconsultation and tele-education sessions, the topics discussed in these sessions, and the number of pathology samples requiring second opinions. FINDINGS: A total of 500 cases were discussed via teleconsultations during the study period. The median patient age was 7 years (range, 24 days to 16·4 years), and the cases comprised 79 benign tumors, 299 leukemias, 120 lymphomas, and 97 solid tumors. The teleconsultation sessions yielded 27 diagnostic changes, 123 confirmed diagnoses, and 13 equivocal impacts. The pathology reviews by SUR were concordant for 996 (81·9%) cases, discordant for 186 (15·3%), and inconclusive for 34 (2·8%). The major cause of discordance was inadequate immunohistochemical staining. The percentage of discordance markedly decreased over time (from 40% to 10%). The cause of the improvement is multifactorial: training of two CWTH pathologists at SUR, better immunohistochemical staining, and the ongoing clinical and pathologic telemedicine activities. The partnership yielded 12 publications, six posters, and three oral presentations by CWTH investigators. INTERPRETATION: The exchange of knowledge and expertise across continental boundaries meaningfully improved the diagnoses and management of pediatric cancer at CWTH.

Genetic evaluation of childhood acute lymphoblastic leukemia in Iraq using FTA cards.

BACKGROUND: Genetic examination of childhood leukemia has not been available in Iraq. We here report the frequency of TEL-AML1, E2A-PBX1, MLL-AF4, and BCR-ABL chimeric transcripts in 264 Iraqi children newly diagnosed with acute lymphoblastic leukemia (ALL), using FTA cards impregnated with bone marrow aspirate or whole blood. PATIENTS AND METHODS: The diagnosis of ALL was made according to standard French-American-British morphologic criteria. Based on the results of storage temperature and duration, most of the FTA samples were preserved at 4°C for up to 6 weeks in five Iraqi hospitals and then transferred to Japan for molecular analysis. Nested reverse transcription-polymerase chain reaction was adopted for the analysis. RESULTS: TEL-AML1 chimeric transcript product was found in 32 (12.1%) of 264 ALL patients. Eleven (4.2%) patients, 4 (1.5%) patients, and 11 (4.2%) patients had E2A-PBX1 mRNA, MLL-AF4 mRNA, and BCR-ABL mRNA, respectively. One patient had both TEL-AML1 and E2A-PBX1 fusion genes. The incidence of TEL-AML1 in Iraqi ALL children appears to be similar to or slightly higher than those of Jordan (12%) and Kuwait (7%). The prevalence and clinical findings of ALL patients with either E2A-PBX1 or BCR-ABL were comparable to the data reported elsewhere. CONCLUSION: International collaboration via FTA cards may be helpful to improve diagnosis and management of patients with hematological malignancies in low-income and underdeveloped countries.

Future planning to upgrade the pediatric oncology service in the Baghdad children welfare teaching hospital.

In Iraq; the community has suffered considerably in the past 40 years that makes any attempt of repair very difficult. Our hospital operates below the standard on all levels, the pediatric oncology unit, which has a capacity of 30 single beds, is occupied by double or triples. In 2010; new patients with cancer reached 366. Drug shortages, limitation of diagnostic facilities, lack of infection control and pain management have major impact on the management of children with cancer. Telemedicine program has an impact to improve the service; we have just ourselves and feelings of responsibility to keep motivation and looking forward for any help to continue.

Childhood acute promyelocytic leukemia in a pediatric cancer referral center in Baghdad, Iraq. Improved results with ATRA extended consolidation.

Modern treatments have dramatically improved the prognosis of childhood acute promyelocytic leukemia (APL). This progress has not yielded equivalent benefit in developing countries, where biological studies and supportive cares are insufficient and often unavailable. Since 2003, an all-trans retinoic (ATRA)-based, risk-adapted protocol was initiated in Baghdad. Patients were defined: high-risk with WBC ≥10 × 109/L and standard-risk with WBC <10 × 109/L. ATRA was included in induction and maintenance and, from 2010, in consolidation. Of 429 pediatric acute myeloid leukemia (September 2003-August 2019), 118 (27.5%) were APL. Six children died before therapy, 4 refused; 94/108 (87%) achieved a remission; 12 (11%) died early and 2 abandoned. The 5-year overall survival and event-free survival are 61.8% and 55.5% for all patients, 51.7% and 43.6% for first protocol, 68.4% and 63.9% for second one. Baseline WBC count was a risk factor for induction mortality; early hemorrhagic death remains a major cause of failure. ATRA extended consolidation improved results.

Treatment of children with B-cell non-Hodgkin lymphoma in a low-income country.

BACKGROUND: An adapted LMB 96 derived protocol for B-cell non-Hodgkin lymphoma (NHL) was implemented at the pediatric oncology unit of the Children Welfare Teaching Hospital in Baghdad (Iraq) from 2000 to present. The purpose was to evaluate the feasibility and efficacy of this intensive therapeutic regimen in a limited resource country. METHODS: Patients <15 years of age with high grade B-cell NHL were included. A modified LMB 96 regimen was employed with a reduction of cyclophosphamide and methotrexate dosages due to inadequate laboratory facilities and supportive care. RESULTS: Between 2000 and 2005, 261 children with non-lymphoblastic NHL were registered; 239 were eligible for the analysis. Two patients had stage I disease, 20 stage II, 179 stage III, and 38 stage IV. Fifty-two patients (22%) had bulky disease. Twelve children were assigned to therapeutic group A (low risk), 184 to group B (intermediate risk), and 43 to group C (high risk). One hundred and eighty-four patients (77%) had a complete response after the COP pre-phase. Sixty-nine patients (29%) died during treatment. Twenty-nine patients abandoned treatment. At 24 months, the overall survival rate of the entire patient population was 66% (CI 95%: 62.2-70.6) and the event-free survival rate 53.3% (CI 95%: 50.0-56.8). CONCLUSIONS: The treatment schedule proved effective, but the treatment-related mortality due to infections and metabolic complications was very high owing to the limited supportive care available. The high rate of treatment abandonment was also an important cause of failure, especially for children living far away from the hospital.

Reality of pediatric cancer in Iraq.

This brief report displays comprehensive details of health services provided by Children's Welfare Teaching Hospital, medical city, Baghdad. In 2010; 366 children with newly diagnosed cancer were admitted for treatment, two thirds were leukemia and lymphoma cases followed by other solid tumors except brain tumors. With this large number of patients; there are shortcomings in provision of health services in many aspects including professional manpower, infrastructure, diagnostic and therapeutic facilities, supportive and palliative care. The previous wars and sanction and the current instability of the country added to the socioeconomic difficulties of the families jeopardizing the appropriate therapy and ultimately the poor treatment outcome. Since 2003 an international collaboration had a major contribution in many aspects like provision of drugs and medical supplies, attendance of scientific workshops, and updating doctor's knowledge and experience through telemedicine programs which resulted in decreasing the induction mortality in acute lymphoblastic leukemia from 24% in the year 2007% to 10% in 2010 after introduction of pre-phase steroids and in acute promyelocytic leukemia from 95% to 5% after introduction of all trans-retinoic acid. A collaborative work with Rome University resulted in changing diagnosis of 20% of pathological samples sent there for reevaluation. Iraqi pediatric oncologists still need real attempts to improve infrastructure and human resources in addition to twinning programs with internationally recognized cancer centers to face these management challenges.

Treatment of childhood acute lymphoblastic leukemia in Iraq: a 17-year experience from a single center.

We performed a retrospective analysis of 1415 acute lymphoblastic leukemia children diagnosed between January 2000 and December 2016 at Children Welfare Teaching Hospital, Baghdad, Iraq. Patients were divided into three cohorts according to treatment period (2000-2005; 2006-2011; 2012-2016). Treatments were based on modified-UKALL protocols; a steroid-pre-phase was introduced from September 2008. The overall complete remission was 86%, increased from 80% to 91% in the last period. Early deaths occurred in 10%, decreasing to 6%, overtime. Relapses were 23%; toxic deaths and abandonment 8% and 13%, respectively. At a median follow-up of 65.3 months, with abandonment considered as an event, the 5-year overall survival (OS) and event-free survival were 62.2% and 46.3%, statistically influenced by treatment period (5-year OS 62.6%, 59.1%, 66.3%; p=.057, respectively). Though pediatric ALL survival in Iraq is still below that observed in high income countries, survival rates progressively improved. Toxic deaths remain an important cause of failure.

Long-term results with the adapted LMB 96 protocol in children with B-cell non Hodgkin lymphoma treated in Iraq: comparison in two subsequent cohorts of patients.

Since 2000, an adapted LMB 96 protocol was implemented at the Children-Welfare-Teaching-Hospital in Baghdad for the treatment of childhood B-cell non-Hodgkin lymphoma. The first experience (2000-2005) demonstrated efficacy and feasibility of this protocol in Iraq. In 2006, further adjustments were made in an attempt to reduce therapy-related toxicities. The outcome of the second cohort of 190 children (2006-2010) and the comparison with the previous study are hereby reported. Out of the 180 treated patients, 120 achieved a complete response; during treatment 51 died and 9 abandoned. The 60-month overall survival (OS) and event-free survival (EFS) were 64.7 and 56.3%, respectively. No differences were observed in the 24-month OS and EFS between the 2000-2005 and 2006-2010 cohorts (66.3% vs. 65.1%; p = .89 and 53.3% vs. 57.3%; p = .28, respectively). Therapeutic group-B in the second cohort showed better outcome, although not significant, compared to the first one (EFS 62.9% vs. 53.8%; p = .088). Therapy-related mortality remained high.

Impact of international collaboration on the prognosis of childhood acute promyelocytic leukemia in Iraq.

The promotion of an operational network between hospitals and medical schools in Iraq and in Western countries is a primary humanitarian objective of international collaboration. As a consequence of a collaborative project between the Al Mansour Hospital for Pediatrics in Baghdad and the Pediatric Unit of Hematology of "La Sapienza" University, in Rome, in October 2003 a specific all-trans-retinoic acid-based protocol was designed in order to offer a modern therapeutic program for the management of Iraqi children with acute promyelocytic leukemia, adapted to the severe local difficulties. The preliminary encouraging results represent a substantial improvement over the earlier experience in childhood acute promyelocytic leukemia in Iraq.

Paediatric cancer care in a limited-resource setting: Children's Welfare Teaching Hospital, Medical City, Baghdad.

There has been a lot of news coming out of Iraq in recent decades, but most of it ignores the situation for people on the ground: ordinary men, women and children who continue trying to live their lives in spite of wars, economic sanctions, violence, and social, political and cultural collapse. The challenges of maintaining and sustaining health in an environment where everything-the human spirit, education and health care systems and the health-sustaining infrastructures of housing, water purification and the electric grid-is damaged or broken are enormous.