Comprehensive genetic analyses of childhood acute leukemia in Iraq using next-generation sequencing.

Background: Molecular analyses in hematological malignancies provide insights about genetic makeup. Probable etiological factors in leukemogenesis could also be disclosed. Since genetic analyses are still primitive in Iraq, a country of repeated wars, we conceived of performing next-generation sequencing (NGS), to disclose the genomic landscape of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) among a cohort of Iraqi children. Methods: Dried blood samples were collected from Iraqi children with ALL (n=55), or AML (n=11), and transferred to Japan where NGS was done. Whole-exome, whole-genome, and targeted gene sequencings were performed. Results: Somatic point mutations and the copy number variations among Iraqi children with acute leukemia were comparable with those in other countries, and cytosine-to-thymine nucleotide alterations were dominant. Strikingly, TCF3-PBX1 was the most recurrent fusion gene (22.4%) in B-cell precursor ALL (B-ALL), and acute promyelocytic leukemia (AML-M3) was subtyped in 5 AML cases. Additionally, a high frequency of RAS signaling pathway mutations was detected in children with B-ALL (38.8%), along with 3 AML cases that carried oncogenic RAS. Conclusions: Apart from disclosing the high frequency of TCF3-PBX1, NGS confirmed our previous finding of recurrent RAS mutations in Iraqi childhood acute leukemia. Our results suggest that the biology of Iraqi childhood acute leukemia is in part characteristic, where the war-aftermath environment or geography might play a role.

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.

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.

Evaluating Pain Management Practices for Cancer Patients among Health Professionals: A Global Survey.

Background: Cancer incidence in the world is predicted to increase in the next decade. While progress has been in diagnosis and treatment, much still remains to be done to improve cancer pain therapy, mainly in underserved communities in low-income countries. Objective: To determine knowledge, beliefs, and barriers regarding pain management in both high- and low-income countries (according to the WHO classification); and to learn about ways to improve the current state of affairs. Design: Descriptive survey. Setting/Subjects: Fifty-six countries worldwide; convenience sample of 1639 consisted of 36.8% physicians; 45.1% nurses, and 4.5% pharmacists employed in varied settings. Results: Improved pain management services are key elements. Top barriers include religion factors, lack of appropriate education and training at all levels, nonadherence to guidelines, patients' reluctance to report on pains, over regulation associated with prescribing and access to opioid analgesics, fear of addiction to opioids, and lack of discussions around prognosis and treatment planning. Conclusion: The majority of patients with cancer in low-income countries are undertreated for their pain. Promoting cancer pain accredited program of training and education on pain management for physicians and nurses is crucial, as well as advocating policymakers and the public at large.

Effectiveness of sofosbuvir/ledipasvir in hepatitis C virus infection in children and adolescents with malignancy: tertiary center experience.

Aim of the study: To determine the outcome of concomitant treatment of chronic hepatitis C virus (HCV) in children with malignant disease. Material and methods: This was a prospective cohort study conducted at a gastroenterology and hepatology outpatient clinic in a children's welfare teaching hospital/medical city complex, Baghdad, from January 2018 to October 2020 and included 30 child and adolescent patients who contracted HCV while receiving treatment for malignant diseases. Data collected included those of medical history, physical examination, and periodic clinical and laboratory evaluation during their follow-up. Their age (at the time of diagnosis of HCV) ranged between 3.2 and 15.3 years, the mean age was 8.3 years, with male predominance of 60%. Results: Sustained virologic response at post-treatment week 12 (SVR12) was obtained in all patients, 30/30 (100%), with gradual dramatic improvements of the liver enzymes, TSB, serum creatinine, and serum albumin. No serious side effects were registered, nor was there any treatment discontinuation or death. Tiredness was the most common side effect 10/30 (33.3%) in all patients. Conclusions: A combination of the ledipasvir plus sofosbuvir regimen for 12 weeks is effective and well tolerated, and can be used safely in treating children older than 3 years and adolescent patients with chronic hepatitis C.

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.

Correction to: Human Development Index and its association with staff spiritual care provision: a Middle Eastern oncology study.

Incorrect family name of Layth Mula-Hussain.

Human Development Index and its association with staff spiritual care provision: a Middle Eastern oncology study.

BACKGROUND: Although staff spiritual care provision plays a key role in patient-centered care, there is insufficient information on international variance in attitudes toward spiritual care and its actual provision. METHODS: A cross-sectional survey of the attitudes of Middle Eastern oncology physicians and nurses toward eight examples of staff provision of spiritual care: two questionnaire items concerned prayer, while six items related to applied information gathering, such as spiritual history taking, referrals, and encouraging patients in their spirituality. In addition, respondents reported on spiritual care provision for their last three advanced cancer patients. RESULTS: Seven hundred seventy responses were received from 14 countries (25% from countries with very high Human Development Index (HDI), 41% high, 29% medium, 5% low). Over 63% of respondents positively viewed the six applied information gathering items, while significantly more, over 76%, did so among respondents from very high HDI countries (p value range, p < 0.001 to p = 0.01). Even though only 42-45% overall were positively inclined toward praying with patients, respondents in lower HDI countries expressed more positive views (p < 0.001). In interaction analysis, HDI proved to be the single strongest factor associated with five of eight spiritual care examples (p < 0.001 for all). Significantly, the Middle Eastern respondents in our study actually provided actual spiritual care to 47% of their most recent advanced cancer patients, compared to only 27% in a parallel American study, with the key difference identified being HDI. CONCLUSIONS: A country's development level is a key factor influencing attitudes toward spiritual care and its actual provision. Respondents from lower ranking HDI countries proved relatively more likely to provide spiritual care and to have positive attitudes toward praying with patients. In contrast, respondents from countries with higher HDI levels had relatively more positive attitudes toward spiritual care interventions that involved gathering information applicable to patient care.

Training for awareness of one's own spirituality: A key factor in overcoming barriers to the provision of spiritual care to advanced cancer patients by doctors and nurses.

OBJECTIVE: When patients feel spiritually supported by staff, we find increased use of hospice and reduced use of aggressive treatments at end of life, yet substantial barriers to staff spiritual care provision still exist. We aimed to study these barriers in a new cultural context and analyzed a new subgroup with "unrealized potential" for improved spiritual care provision: those who are positively inclined toward spiritual care yet do not themselves provide it. METHOD: We distributed the Religion and Spirituality in Cancer Care Study via the Middle East Cancer Consortium to physicians and nurses caring for advanced cancer patients. Survey items included how often spiritual care should be provided, how often respondents themselves provide it, and perceived barriers to spiritual care provision.ResultWe had 770 respondents (40% physicians, 60% nurses) from 14 Middle Eastern countries. The results showed that 82% of respondents think staff should provide spiritual care at least occasionally, but 44% provide spiritual care less often than they think they should. In multivariable analysis of respondents who valued spiritual care yet did not themselves provide it to their most recent patients, predictors included low personal sense of being spiritual (p < 0.001) and not having received training (p = 0.02; only 22% received training). How "developed" a country is negatively predicted spiritual care provision (p < 0.001). Self-perceived barriers were quite similar across cultures.Significance of resultsDespite relatively high levels of spiritual care provision, we see a gap between desirability and actual provision. Seeing oneself as not spiritual or only slightly spiritual is a key factor demonstrably associated with not providing spiritual care. Efforts to increase spiritual care provision should target those in favor of spiritual care provision, promoting training that helps participants consider their own spirituality and the role that it plays in their personal and professional lives.

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.

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.