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1. Prognostic significance of molecular subgroups in survival outcome for children with medulloblastoma in Malaysia

Author: Revathi Rajagopal, Ay Jiuan Teng, Vida Jawin, Oy Leng Wong, Hakimah Mahsin, Nor Haizura Abd Rani, Tsiao Yi Yap, Kogilavani Gunasagaran, Asohan Thevarajah, Seoh Leng Yeoh, Gek Bee Ong, Hany Ariffin, David Jones, Eric Bouffet, and Nicholas G. Gottardo
Subjects: survival outcome, medulloblastoma, Wingless, Sonic Hedgehog, Group 3, Group 4, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: IntroductionAdvancements in genomic profiling led to the discovery of four major molecular subgroups in medulloblastoma (MB), which have now been incorporated into the World Health Organization classification of central nervous system tumors. The current study aimed to determine the prognostic significance of the MB molecular subgroups among children in Malaysia.MethodsWe assembled MB samples from children
Published: 2023
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2. Manipulating the Gut Microbiome as a Therapeutic Strategy to Mitigate Late Effects in Childhood Cancer Survivors

Author: Lixian Oh PhD, Syaza Ab Rahman MBBCh, Kailey Dubinsky BSc, Mohamad Shafiq Azanan PhD, and Hany Ariffin MBBS, PhD
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Recent studies have identified causal links between altered gut microbiome, chronic inflammation, and inflammation-driven conditions such as diabetes and cardiovascular disease. Childhood cancer survivors (CCS) show late effects of therapy in the form of inflammaging-related disorders as well as microbial dysbiosis, supporting a hypothesis that the conditions are interconnected. Given the susceptibility of the gut microbiome to alteration, a number of therapeutic interventions have been investigated for the treatment of inflammatory conditions, though not within the context of cancer survivorship in children and adolescents. Here, we evaluate the potential for these interventions, which include probiotic supplementation, prebiotics/fiber-rich diet, exercise, and fecal microbiota transplantation for prevention and treatment of cancer treatment-related microbial dysbiosis in survivors. We also make recommendations to improve adherence and encourage long-term lifestyle changes for maintenance of healthy gut microbiome in CCS as a potential strategy to mitigate treatment-related late effects.
Published: 2023
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3. Transcriptional analysis highlights three distinct immune profiles of high-risk oral epithelial dysplasia

Author: Chai Phei Gan, Bernard Kok Bang Lee, Shin Hin Lau, Thomas George Kallarakkal, Zuraiza Mohamad Zaini, Bryan Kit Weng Lye, Rosnah Binti Zain, Hans Prakash Sathasivam, Joe Poh Sheng Yeong, Natalia Savelyeva, Gareth Thomas, Christian H. Ottensmeier, Hany Ariffin, Sok Ching Cheong, and Kue Peng Lim
Subjects: immune signature, non-immune reactive, immune cytotoxic, oral premalignant lesion, oral epithelial dysplasia, oral potentially malignant disorder, Immunologic diseases. Allergy, RC581-607
Abstract: Oral potentially malignant disorders (OPMD) are precursors of oral squamous cell carcinoma (OSCC), and the presence of oral epithelial dysplasia (OED) in OPMD confers an increased risk of malignant transformation. Emerging evidence has indicated a role for the immune system in OPMD disease progression; however, the underlying immune mechanisms remain elusive. In this study, we used immune signatures established from cancer to delineate the immune profiles of moderate and severe OED, which are considered high-risk OPMD. We demonstrated that moderate and severe OEDs exhibit high lymphocyte infiltration and upregulation of genes involved in both immune surveillance (major histocompatibility complex-I, T cells, B cells and cytolytic activity) and immune suppression (immune checkpoints, T regulatory cells, and tumor-associated macrophages). Notably, we identified three distinct subtypes of moderate and severe OED: immune cytotoxic, non-cytotoxic and non-immune reactive. Active immune surveillance is present in the immune cytotoxic subtype, whereas the non-cytotoxic subtype lacks CD8 immune cytotoxic response. The non-immune reactive subtype showed upregulation of genes involved in the stromal microenvironment and cell cycle. The lack of T cell infiltration and activation in the non-immune reactive subtype is due to the dysregulation of CTNNB1, PTEN and JAK2. This work suggests that moderate and severe OED that harbor the non-cytotoxic or non-immune reactive subtype are likely to progress to cancer. Overall, we showed that distinct immune responses are present in high-risk OPMD, and revealed targetable pathways that could lead to potential new approaches for non-surgical management of OED.
Published: 2022
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4. Pediatric Solid Tumor Care and Multidisciplinary Tumor Boards in Low- and Middle-Income Countries in Southeast Asia

Author: Mohd Yusran Othman, Sally Blair, Shireen A. Nah, Hany Ariffin, Chatchawin Assanasen, Shui Yen Soh, Anette S. Jacobsen, Catherine Lam, and Amos H. P. Loh
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: PURPOSEPediatric solid tumors require coordinated multidisciplinary specialist care. However, expertise and resources to conduct multidisciplinary tumor boards (MDTBs) are lacking in low- and middle-income countries (LMICs). We aimed to profile the landscape of pediatric solid tumor care and practices and perceptions on MDTBs among pediatric solid tumor units (PSTUs) in Southeast Asian LMICs.METHODSUsing online surveys, availability of specialty manpower and MDTBs among PSTUs was first determined. From the subset of PSTUs with MDTBs, one pediatric surgeon and one pediatric oncologist from each center were queried using 5-point Likert scale questions adapted from published questionnaires.RESULTSIn 37 (80.4%) of 46 identified PSTUs, availability of pediatric-trained specialists was as follows: oncologists, 94.6%; surgeons, 91.9%; radiologists, 54.1%; pathologists, 40.5%; radiation oncologists, 29.7%; nuclear medicine physicians, 13.5%; and nurses, 81.1%. Availability of pediatric-trained surgeons, radiologists, and pathologists was significantly associated with the existence of MDTBs (P = .037, .005, and .022, respectively). Among 43 (89.6%) of 48 respondents from 24 PSTUs with MDTBs, 90.5% of oncologists reported > 50% oncology-dedicated workload versus 22.7% of surgeons. Views on benefits and barriers did not significantly differ between oncologists and surgeons. The majority agreed that MDTBs helped to improve accuracy of treatment recommendations and team competence. Complex cases, insufficient radiology and pathology preparation, and need for supplementary investigations were the top barriers.CONCLUSIONThis first known profile of pediatric solid tumor care in Southeast Asia found that availability of pediatric-trained subspecialists was a significant prerequisite for pediatric MDTBs in this region. Most PSTUs lacked pediatric-trained pathologists and radiologists. Correspondingly, gaps in radiographic and pathologic diagnoses were the most common limitations for MDTBs. Greater emphasis on holistic multidisciplinary subspecialty development is needed to advance pediatric solid tumor care in Southeast Asia.
Published: 2020
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5. Malaysia-Singapore (MASPORE) leukaemia study group: From common history to successful collaboration

Author: Hany Ariffin, Syaza Ab Rahman, Sheng Hoay Leong, Edwynn Kean-Hui Chiew, Hai Peng Lin, Thuan Chong Quah, and Allen Eng-Juh Yeoh
Subjects: Pediatrics, RJ1-570
Abstract: The 1970s marked the beginning of childhood cancer services in Malaysia and Singapore, two neighbours in South-East Asia. Between 1995 and 2002, Malaysia utilized a treatment regimen based on the Dutch DCOG 7 and German BFM protocols for children with acute lymphoblastic leukaemia (ALL), whilst Singapore in collaboration with Hong Kong employed the HK-ALL 1997 protocol, based on BFM ALL 95. In 2002, the overall 6-year event-free survival (EFS) for childhood ALL in Malaysia stood at 56%, while the 5-year EFS for HK-ALL 1997 was 79%. Formal collaboration between Malaysia and Singapore for the treatment of childhood ALL began in 2003. The first collaborative trial was the seminal MASPORE ALL2003 study which utilized a single PCR-based minimal residual disease marker to risk stratify patients according to disease severity, and used a 3-drug induction regimen for non-high-risk patients. This effort resulted in an improvement in 6-year EFS for both countries, at 80%, with an overall survival of 88%. The study showed that treatment could be appropriately tailored to disease risk, and that an anthracycline-free induction strategy did not compromise outcome for the majority (86%) of patients. The follow-up study, MASPORE ALL2010 focused on delivering therapy that was more intensive for those in high-risk group while reducing intensity for standard and intermediate risk groups. The study also took into consideration patients with IKZF1 gene deletion (IKZF1del) and moved these patients into a higher risk category. Increasing treatment intensity for patients with IKZF1del resulted in a reduction in 5-year cumulative incidence of relapse (CIR) from 30 to 13%, and improved overall 5-year survival from 69 to 91%. The MASPORE ALL2010 trial also studied TPMT and NUDT15 gene variants in its patient population to optimize thiopurine dosing. As the study moves into its next phase (MASPORE ALL2020), precision medicine and risk-adapted therapy remain the cornerstone strategies for childhood ALL, especially in the era of increased recognition of late effects amongst survivors of childhood cancer. Future therapies will likely focus on further targeted treatment for childhood ALL as more molecularly distinct subtypes become known.
Published: 2020
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6. Expression of p53 N-terminal isoforms in B-cell precursor acute lymphoblastic leukemia and its correlation with clinicopathological profiles

Author: Lixian Oh, Pierre Hainaut, Sandrine Blanchet, and Hany Ariffin
Subjects: Childhood ALL, p53 tumour suppressor protein, Protein isoforms, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background TP53 mutations occur in only about 3% of primary and 10–20% of relapse B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). However, alternative mechanisms may contribute to functionally impairing the p53 pathway in the absence of a mutation. Candidate mechanisms include overexpression of p53 mRNA variants encoding either dominant-negative p53 protein isoforms such as Delta40p53 and Delta133p53, or modulatory isoforms such as p53beta, which counteract the effects of Delta133p53 on replicative senescence in T-lymphocytes. Methods We used semi-quantitative reverse-transcriptase PCR (RT-PCR) and Western blot to investigate the expression of full length p53 (TAp53), Delta40p53, Delta133p53 or p53beta in diagnostic marrow from a clinical cohort of 50 BCP-ALL patients without TP53 mutation (29 males and 21 females, age range 2–14 years) and in the bone marrow cells of 4 healthy donors (used as controls). Results Irrespective of isoforms, levels of p53 mRNA were low in controls but were increased by 2 to 20-fold in primary or relapse BCP-ALL. TAp53 was increased in primary BCP-ALL, Delta40p53 was elevated in relapse BCP-ALL, whereas Delta133p53 and p53beta were increased in both. Next, mRNA levels were used as a basis to infer the ratio between protein isoform levels. This inference suggested that, in primary BCP-ALL, p53 was predominantly in active oligomeric conformations dominated by TAp53. In contrast, p53 mostly existed in inactive quaternary conformations containing ≥2 Delta40 or Delta133p53 in relapse BCP-ALL. Western blot analysis of blasts from BCP-ALL showed a complex pattern of N-terminally truncated p53 isoforms, whereas TAp53beta was detected as a major isoform. The hypothesis that p53 is in an active form in primary B-ALL was consistent with elevated level of p53 target genes CDKN1A and MDM2 in primary cases, whereas in relapse BCP-ALL, only CDKN1A was increased as compared to controls. Conclusion Expression of p53 isoforms is deregulated in BCP-ALL in the absence of TP53 mutation, with increased expression of alternative isoforms in relapse BCP-ALL. Variations in isoform expression may contribute to functional deregulation of the p53 pathway in BCP-ALL, specifically contributing to its down-regulation in relapse forms.
Published: 2020
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7. Temporal changes in gut microbiota profile in children with acute lymphoblastic leukemia prior to commencement-, during-, and post-cessation of chemotherapy

Author: Ling Ling Chua, Reena Rajasuriar, Yvonne Ai Lian Lim, Yin Ling Woo, P’ng Loke, and Hany Ariffin
Subjects: Childhood acute lymphoblastic leukemia, Chemotherapy, Microbiome, Microbiota dysbiosis, Bacteroidetes, Bacteroides, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Abstract Background Alteration in gut microbiota has been recently linked with childhood leukemia and the use of chemotherapy. Whether the perturbed microbiota community is restored after disease remission and cessation of cancer treatment has not been evaluated. This study examines the chronological changes of gut microbiota in children with acute lymphoblastic leukemia (ALL) prior to the start-, during-, and following cessation of chemotherapy. Methodology We conducted a longitudinal observational study in gut microbiota profile in a group of paediatric patients diagnosed with ALL using 16 s ribosomal RNA sequencing and compared these patients’ microbiota pattern with age and ethnicity-matched healthy children. Temporal changes of gut microbiota in these patients with ALL were also examined at different time-points in relation to chemotherapy. Results Prior to commencement of chemotherapy, gut microbiota in children with ALL had larger inter-individual variability compared to healthy controls and was enriched with bacteria belonging to Bacteroidetes phylum and Bacteroides genus. The relative abundance of Bacteroides decreased upon commencement of chemotherapy. Restitution of gut microbiota composition to resemble that of healthy controls occurred after cessation of chemotherapy. However, the microbiota composition (beta diversity) remained distinctive and a few bacteria were different in abundance among the patients with ALL compared to controls despite completion of chemotherapy and presumed restoration of normal health. Conclusion Our findings in this pilot study is the first to suggest that gut microbiota profile in children with ALL remains marginally different from healthy controls even after cessation of chemotherapy. These persistent microbiota changes may have a role in the long-term wellbeing in childhood cancer survivors but the impact of these changes in subsequent health perturbations in these survivors remain unexplored.
Published: 2020
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8. HLA-Haploidentical Family Donors: The New Promise for Childhood Acute Lymphoblastic Leukaemia?

Author: Syaza Ab Rahman, Toni Matic, Maya Yordanova, and Hany Ariffin
Subjects: haploidentical, haematopoietic stem cell transplantation, paediatric, acute lymphoblastic leukaemia (ALL), human leukocyte antigen, Pediatrics, RJ1-570
Abstract: Allogeneic haematopoietic stem cell transplantation (HSCT) is indicated in children with high-risk, relapsed or refractory acute lymphoblastic leukaemia (ALL). HLA-matched grafts from cord blood and stem cell repositories have allowed patients without suitable sibling donors to undergo HSCT. However, challenges in procuring matched unrelated donor (MUD) grafts due to high cost, ethnic disparity and time constraints have led to the exponential rise in the use of stem cells from human leukocyte antigen (HLA)-haploidentical family donors. Whilst HLA-haploidentical HSCT (hHSCT) performed in adult patients with acute leukaemia has produced outcomes similar to MUD transplants, experience in children is limited. Over the last 5 years, more data have emerged on hHSCT in the childhood ALL setting, allowing comparisons with matched donor transplants. The feasibility of hHSCT using adult family donors in childhood ALL may also address the ethical issues related to selection of minor siblings in matched sibling donor transplants. Here, we review hHSCT in paediatric recipients with ALL and highlight the emergence of hHSCT as a promising therapeutic option for patients lacking a suitable matched donor. Recent issues related to conditioning regimens, donor selection and graft-vs.-host disease prophylaxis are discussed. We also identify areas for future research to address transplant-related complications and improve post-transplant disease-free survival.
Published: 2022
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9. Occult Kidney Dysfunction in Children With Transfusion-Dependent Thalassemia

Author: Nurwahida Mohd Zikre, Nor A. Muhamad, Caroline S. Y. Eng, Nur E. Zailanalhuddin, Charles D. Lai, Jen C. Foo, Suet L. Yap, Hany Ariffin, and Karmila Abu Bakar
Subjects: thalassemia, nephropathy, transfusion-dependent, ferritin, iron chelator, Pediatrics, RJ1-570
Abstract: Background: Thalassemia is the commonest hemoglobinopathy in Southeast Asia. Kidney dysfunction is an underreported sequelae in children with thalassemia. We conducted a retrospective study to identify the prevalence of and predisposing factors for kidney dysfunction in children with transfusion-dependent thalassemia (TDT).Method: Abnormal kidney function was defined as children with a glomerular filtration rate (GFR) of 20 ml/min/1.73 m2 or presence of nephrotic range proteinuria within 3 years of commencing regular (every ≤6 weeks) red cell transfusion. Data analyzed were age at diagnosis of thalassemia, number of transfusion-years, iron chelation therapy, serum ferritin, and pre-transfusion hemoglobin levels.Results: Eighty-one children were studied. Mean age was 11.72 ± 5.275 years. Thirty out of 81 (37%) demonstrated abnormal kidney function. Evidence of glomerular hyperfiltration was seen in 29/81 patients (25.85%) at their last clinic visit. This fraction was doubled [48/81 (59.3%)] when the cohort was tracked back by 3 years from the last clinic encounter. Age at diagnosis (RR, 1.157; 95% CI, 1.014–1.319; p = 0.03) and duration of receiving transfusions (RR, 0.984; 95% CI, 0.974–0.994; p = 0.001) were associated with increased risk of developing abnormal kidney function.Conclusion: Abnormal kidney function in children with TDT may be overlooked by medical personnel without active screening measures. Children receiving regular red cell transfusions require systematic surveillance to enable early detection of kidney dysfunction and timely implementation of appropriate therapeutic interventions.
Published: 2021
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10. 911 Immune profiling reveals enrichment of distinct immune signatures in high-risk oral potentially malignant disorders

Author: Hany Ariffin, Gareth Thomas, Joe Poh Sheng Yeong, Chai Gan, Bernard Kok Bang Lee, Shin Hin Lau, Thomas George Kallarakkal, Zuraiza Mohamad Zaini, Rosnah Binti Zain, Hans Prakash Sathasivam, Natalia Savelyeva, Christian Ottensmeier, Sok Ching Cheong, and Kue Peng Lim
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Published: 2021
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11. An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia

Author: Yoichi Tanaka, Allen Eng Juh Yeoh, Takaya Moriyama, Chi-Kong Li, Ko Kudo, Yuki Arakawa, Jassada Buaboonnam, Hui Zhang, Hsi-Che Liu, Hany Ariffin, Zhiwei Chen, Shirley K.Y. Kham, Rina Nishii, Daisuke Hasegawa, Junya Fujimura, Dai Keino, Kensuke Kondoh, Atsushi Sato, Takahiro Ueda, Masaki Yamamoto, Yuichi Taneyama, Moeko Hino, Masatoshi Takagi, Akira Ohara, Etsuro Ito, Katsuyoshi Koh, Hiroki Hori, Atsushi Manabe, Jun J. Yang, and Motohiro Kato
Subjects: Diseases of the blood and blood-forming organs, RC633-647.5
Published: 2021
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12. Challenges of Treating Childhood Medulloblastoma in a Country With Limited Resources: 20 Years of Experience at a Single Tertiary Center in Malaysia

Author: Revathi Rajagopal, Sayyidatul Abd-Ghafar, Dharmendra Ganesan, Anita Zarina Bustam Mainudin, Kum Thong Wong, Norlisah Ramli, Vida Jawin, Su Han Lum, Tsiao Yi Yap, Eric Bouffet, Ibrahim Qaddoumi, Shekhar Krishnan, Hany Ariffin, and Wan Ariffin Abdullah
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Purpose: Pediatric medulloblastoma (MB) treatment has evolved over the past few decades; however, treating children in countries with limited resources remains challenging. Until now, the literature regarding childhood MB in Malaysia has been nonexistent. Our objectives were to review the demographics and outcome of pediatric MB treated at the University Malaya Medical Center between January 1994 and December 2013 and describe the challenges encountered. Methods: Fifty-one patients with childhood MB were seen at University Malaya Medical Center. Data from 43 patients were analyzed; eight patients were excluded because their families refused treatment after surgery. Results: Headache and vomiting were the most common presenting symptoms, and the mean interval between symptom onset and diagnosis was 4 weeks. Fourteen patients presented with metastatic disease. Five-year progression-free survival (± SE) for patients ≥ 3 years old was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) in the high-risk group and 68.6% ± 18.6% (95% CI, 40.3% to 100%) in the average-risk group, and 5-year overall survival (± SE) in these two groups was 41.7% ± 14.2% (95% CI, 21.3% to 81.4%) and 58.3% ± 18.6% (95% CI, 31.3% to 100%), respectively. Children younger than 3 years old had 5-year progression-free and overall survival rates (± SE) of 47.6% ± 12.1% (95% CI, 28.9% to 78.4%) and 45.6% ± 11.7% (95% CI, 27.6% to 75.5%), respectively. Time to relapse ranged from 4 to 132 months. Most patients who experienced relapse died within 1 year. Febrile neutropenia, hearing loss, and endocrinopathy were the most common treatment-related complications. Conclusion: The survival rate of childhood MB in Malaysia is inferior to that usually reported in the literature. We postulate that the following factors contribute to this difference: lack of a multidisciplinary neuro-oncology team, limited health care facilities, inconsistent risk assessment, insufficient data in the National Cancer Registry and pathology reports, inadequate long-term follow-up, and cultural beliefs leading to treatment abandonment.
Published: 2017
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13. Working together to fight childhood cancer in Asia

Author: Hany Ariffin
Subjects: Pediatrics, RJ1-570
Published: 2020
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14. Care of adolescents and young adults with cancer in Asia: results of an ESMO/SIOPE/SIOP Asia survey

Author: Chi Kong Li, Rashmi Dalvi, Kan Yonemori, Hany Ariffin, Chuhl Joo Lyu, Mohamad Farid, Julieta Rita N Gonzales-Santos, Qing Zhou, Stefan Bielack, Laurence Brugieres, Anne Blondeel, Samira Essiaf, Fedro Alessandro Peccatori, Svetlana Jezdic, Daniel P Stark, Jean-Yves Douillard, Emmanouil Saloustros, and Giannis Mountzios
Subjects: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Background Adolescents and young adults (AYAs) with cancer require dedicated management encompassing both adult and paediatric cancer services. Following a European survey, the European Society for Medical Oncology, the European Society for Paediatric Oncology and the Asian continental branch of International Society of Paediatric Oncology undertook a similar survey to assess AYA cancer care across Asia.Methods A link to the online survey was sent to healthcare professionals (HCPs) in Asia interested in AYA cancer care. Questions covered the demographics and training of HCPs, their understanding of AYA definition, availability and access to specialised AYA services, the support and advice offered during and after treatment, and factors of treatment non-compliance.Results We received 268 responses from 22 Asian countries. There was a striking variation in the definition of AYA (median lower age 15 years, median higher age 29 years). The majority of the respondents (78%) did not have access to specialised cancer services and 73% were not aware of any research initiatives for AYA. Over two-thirds (69%) had the option to refer their patients for psychological and/or nutritional support and most advised their patients on a healthy lifestyle. Even so, 46% did not ask about smokeless tobacco habits and only half referred smokers to a smoking cessation service. Furthermore, 29% did not promote human papillomavirus vaccination for girls and 17% did not promote hepatitis B virus vaccination for high-risk individuals. In terms of funding, 69% reported governmental insurance coverage, although 65% reported that patients self-paid, at least partially. Almost half (47%) reported treatment non-compliance or abandonment as an issue, attributed to financial and family problems (72%), loss of follow-up (74%) and seeking of alternative treatments (77%).Conclusions Lack of access to and suboptimal delivery of AYA-specialised cancer care services across Asia pose major challenges and require specific interventions.
Published: 2019
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15. Survival Outcomes of Children with Relapsed or Refractory Myeloid Leukemia Associated with Down syndrome

Author: Nikhil Raghuram, Kentaro Nakashima, Syaza Ab Rahman, Evangelia Antoniou, Torjus Skajaa, Pietro Merli, Anupam Verma, Karen R. Rabin, Catherine Aftandilian, Rishi Sury Kotecha, Daniel Ka Leung Cheuk, Kirsi Jahnukainen, Alexandra Kolenova, Walentyna Balwierz, Alice Norton, Maureen M O'Brien, Sonia Cellot, Ashley Chopek, Nira Arad-Cohen, Bianca F. Goemans, Marta Rojas-Vasquez, Hany Ariffin, Jack Bartram, Edward A Kolb, Franco Locatelli, Daisuke Hasegawa, Jan-Henning Klusmann, Henrik Hasle, Bryan McGuire, Lillian Sung, and Johann K. Hitzler
Subjects: Hematology
Abstract: Children with Down syndrome (DS) are at a significantly higher risk of developing acute myeloid leukemia, also termed myeloid leukemia associated with DS (ML-DS). In contrast to the highly favorable prognosis of primary ML-DS, the limited data that are available for children who relapse or who have refractory ML-DS (r/r ML-DS) suggest a dismal prognosis. There are few clinical trials and no standardized treatment approach for this population. We conducted a retrospective analysis of international study groups and pediatric oncology centers and identified 62 patients who received treatment with curative intent for r/r ML-DS between 2000-2021. Median time from diagnosis to relapse was 6.8 (range 1.1 - 45.5) months. Three-year event-free (EFS) and overall survival (OS) were 20.9±5.3% and 22.1±5.4%, respectively. Survival was associated with receipt of hematopoietic stem cell transplantation (HSCT) (HR 0.28), duration of first complete remission (CR1) (HR 0.31 for > 12 months) and attainment of remission after relapse (HR 4.03). Patients who achieved CR prior to HSCT, had an improved OS and EFS of 56.0±11.8% and 50.5±11.9% respectively, compared to those who underwent HSCT without CR (3-year OS and EFS of 10.0±9.5%). Treatment failure after HSCT was predominantly due to disease recurrence (52%) followed by treatment related mortality (10%). The prognosis of r/r ML-DS remains dismal even in the current treatment period and serve as a reference point for current prognostication and future interventional studies. Clinical trials aimed at improving the survival of patients with r/r ML-DS are needed.
Published: 2023

16. Distinct clinical characteristics ofDUX4-andPAX5-altered childhood B-lymphoblastic leukemia

Author: Shawn Hsien Ren Lee, Grace Shimin Koh, Evelyn Huizi Lim, Bernice Ling Zhi Oh, Yi Lu, Zhenhua Li, Thuan Chong Quah, Ah Moy Tan, Allen Eng Juh Yeoh, Hany Ariffin, Nan Jiang, Zhiwei Chen, Winnie Hui Ni Chin, Hai Peng Lin, Elaine Coustan-Smith, Jun J. Yang, Shirley Kow Yin Kham, and Kean Hui Chiew
Subjects: Vincristine, medicine.medical_specialty, Neoplasm, Residual, business.industry, B lymphoblastic leukemia, Lymphoma, Non-Hodgkin, Treatment intensification, PAX5 Transcription Factor, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, Gastroenterology, Peripheral blood, DUX4, Internal medicine, Prednisolone, Humans, Medicine, PAX5, Child, business, Intermediate risk, medicine.drug
Abstract: Among the recently described subtypes in childhood B-lymphoblastic leukemia (B-ALL) were DUX4- and PAX5-altered (PAX5alt). By using whole transcriptome RNA sequencing in 377 children with B-ALL from the Malaysia-Singapore ALL 2003 (MS2003) and Malaysia-Singapore ALL 2010 (MS2010) studies, we found that, after hyperdiploid and ETV6-RUNX1, the third and fourth most common subtypes were DUX4 (n = 51; 14%) and PAX5alt (n = 36; 10%). DUX4 also formed the largest genetic subtype among patients with poor day-33 minimal residual disease (MRD; n = 12 of 44). But despite the poor MRD, outcome of DUX4 B-ALL was excellent (5-year cumulative risk of relapse [CIR], 8.9%; 95% confidence interval [CI], 2.8%-19.5% and 5-year overall survival, 97.8%; 95% CI, 85.3%-99.7%). In MS2003, 21% of patients with DUX4 B-ALL had poor peripheral blood response to prednisolone at day 8, higher than other subtypes (8%; P = .03). In MS2010, with vincristine at day 1, no day-8 poor peripheral blood response was observed in the DUX4 subtype (P = .03). The PAX5alt group had an intermediate risk of relapse (5-year CIR, 18.1%) but when IKZF1 was not deleted, outcome was excellent with no relapse among 23 patients. Compared with MS2003, outcome of PAX5alt B-ALL with IKZF1 codeletion was improved by treatment intensification in MS2010 (5-year CIR, 80.0% vs 0%; P = .05). In conclusion, despite its poor initial response, DUX4 B-ALL had a favorable overall outcome, and the prognosis of PAX5alt was strongly dependent on IKZF1 codeletion.
Published: 2021

17. Physical Inactivity as an Early Sign of Frailty in Young Adult Survivors of Childhood Acute Lymphoblastic Leukemia

Author: Ling L. Chua, Mohamad S. Azanan, Lixian Oh, and Hany Ariffin
Subjects: Oncology, Pediatrics, Perinatology and Child Health, Hematology
Published: 2022

18. Practical Considerations for Using RNA Sequencing in Management of B-Lymphoblastic Leukemia

Author: Winnie Hui Ni Chin, Evelyn Huizi Lim, Joshua Yew Suang Lim, Bernice Ling Zhi Oh, Nan Jiang, Zhenhua Li, Kean Hui Chiew, Hany Ariffin, Allen Eng Juh Yeoh, Jun J. Yang, Shirley Kow Yin Kham, Yi Lu, and Ah Moy Tan
Subjects: Oncology, Sanger sequencing, medicine.medical_specialty, Thiopurine methyltransferase, biology, business.industry, Genetic heterogeneity, Disease, medicine.disease, Pathology and Forensic Medicine, symbols.namesake, Leukemia, Workflow, Internal medicine, medicine, symbols, biology.protein, Molecular Medicine, Immunoglobulin heavy chain, Oncogene Fusion, business
Abstract: Despite the immense genetic heterogeneity of B-lymphoblastic leukemia [or precursor B-cell acute lymphoblastic leukemia (B-ALL)], RNA sequencing (RNA-Seq) could comprehensively interrogate its genetic drivers, assigning a specific molecular subtype in >90% of patients. However, study groups have only started to use RNA-Seq. For broader clinical use, technical, quality control, and appropriate performance validation are needed. We describe the development and validation of an RNA-Seq workflow for subtype classification, TPMT/NUDT15/TP53 variant discovery, and immunoglobulin heavy chain (IGH) disease clone identification for Malaysia-Singapore acute lymphoblastic leukemia (ALL) 2020. We validated this workflow in 377 patients in our preceding Malaysia-Singapore ALL 2003/Malaysia-Singapore ALL 2010 studies and proposed the quality control measures for RNA quality, library size, sequencing, and data analysis using the International Organization for Standardization 15189 quality and competence standard for medical laboratories. Compared with conventional methods, we achieved >95% accuracy in oncogene fusion identification, digital karyotyping, and TPMT and NUDT15 variant discovery. We found seven pathogenic TP53 mutations, confirmed with Sanger sequencing, which conferred a poorer outcome. Applying this workflow prospectively to the first 21 patients in Malaysia-Singapore ALL 2020, we identified the genetic drivers and IGH disease clones in >90% of patients with concordant TPMT, NUDT15, and TP53 variants using PCR-based methods. The median turnaround time was 12 days, which was clinically actionable. In conclusion, RNA-Seq workflow could be used clinically in management of B-cell ALL patients.
Published: 2021

19. Premature Ocular Aging Features in Childhood Acute Lymphoblastic Leukemia Survivors

Author: Marium Jamaluddin Ahmad, Mohamad Shafiq Azanan, Caroline Chee, Norlina Ramli, Nurul Najieha Amir, Tengku Ain Kamalden, Hany Ariffin, Sudhashini Chandrasekaran, Sayyidatul Syahirah Abd Ghafar, Rhuen Chiou Chow, and Irina Effendi
Subjects: Premature aging, Aging, Pediatrics, medicine.medical_specialty, Adolescent, business.industry, fungi, Childhood cancer, Aging, Premature, Pilot Projects, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Oncology, Case-Control Studies, Pediatrics, Perinatology and Child Health, medicine, Humans, Survivors, Young adult, business, Childhood Acute Lymphoblastic Leukemia, Organ system
Abstract: Purpose: Childhood cancer survivors (CCS) demonstrate features of premature aging in a multitude of organ systems. The aim of this pilot study is to determine the presence of premature ocular aging...
Published: 2021

20. Associations of T-Cell Receptor Repertoire Diversity with L-Asparaginase Allergy in Childhood Acute Lymphoblastic Leukemia

Author: Shawn H. R. Lee, Zhenhua Li, Evelyn H. Z. Lim, Winnie H. N. Chin, Nan Jiang, Kean Hui Chiew, Zhiwei Chen, Bernice L. Z. Oh, Ah Moy Tan, Hany Ariffin, Jun J. Yang, and Allen E. J. Yeoh
Subjects: Cancer Research, T-cell receptor repertoire, L-asparaginase, allergy, hypersensitivity, childhood acute lymphoblastic leukemia, Oncology
Abstract: Asparaginase is a critical component of therapy for childhood acute lymphoblastic leukemia (ALL), but it is commonly associated with allergy, which results in morbidity and poorer outcomes. The underlying basis of this allergy is undoubtedly immune-mediated, but the exact components of T-cell immunity have yet to be characterized. We performed longitudinal TCR sequencing of 180 bone marrow samples from 67 children with B-ALL treated as part of the Ma-Spore-ALL-2010 trial, and we evaluated the associations of TCR profile with asparaginase hypersensitivity, with functional validation of asparaginase activity in a separate cohort of 113 children. We found that a more diverse and dynamically changing TCR repertoire was associated with increased risk of clinical hypersensitivity and decreased L-asp activity. Allergic patients had a higher proportion of infrequent clonotypes, as well as a significantly lower degree of shared clonotypes amongst the cohort. Allergic patients also had significantly higher longitudinal variability of clonotypes across timepoints, where a higher dissimilarity between diagnosis and week 5 represented an 8.1-fold increased risk of an allergic event. After an allergy had occurred, there was shaping and convergence of the TCR repertoire towards a common antigen. Understanding the immunological basis of T-cell responses in allergy lays the groundwork for developing predictive biomarkers or strategies to mediate this common toxicity in childhood ALL.
Published: 2023

21. An international retrospective study for tolerability of 6-mercaptopurine on NUDT15 bi-allelic variants in children with acute lymphoblastic leukemia

Author: Akira Ohara, Ko Kudo, Etsuro Ito, Daisuke Hasegawa, Takaya Moriyama, Junya Fujimura, Moeko Hino, Dai Keino, Allen Eng Juh Yeoh, Chi Kong Li, Hui Zhang, Jun J. Yang, Yuki Arakawa, Motohiro Kato, Takahiro Ueda, Masaki Yamamoto, Yuichi Taneyama, Masatoshi Takagi, Hsi-Che Liu, Atsushi Sato, Kensuke Kondoh, Katsuyoshi Koh, Hiroki Hori, Jassada Buaboonnam, Zhiwei Chen, Yoichi Tanaka, Atsushi Manabe, Rina Nishii, Shirley Kow Yin Kham, and Hany Ariffin
Subjects: Oncology, medicine.medical_specialty, Mercaptopurine, business.industry, Lymphoblastic Leukemia, MEDLINE, Retrospective cohort study, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Tolerability, Internal medicine, medicine, Humans, Pyrophosphatases, Allele, Letters to the Editor, Child, business, Alleles, Retrospective Studies, medicine.drug
Published: 2021

22. RAS-protein activation but not mutation status is an outcome predictor and unifying therapeutic target for high-risk acute lymphoblastic leukemia

Author: Hany Ariffin, Shirley Kow-Yin Kham, Jürgen Groet, Wee Joo Chng, David Koschut, Zhenhua Li, Emanuela Giarin, Ivan Alić, Debleena Ray, David M. Weinstock, Dean Nižetić, Giuseppe Basso, and Allen Eng Juh Yeoh
Subjects: 0301 basic medicine, Cancer Research, Down syndrome, Lymphoblastic Leukemia, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Biology, medicine.disease_cause, Article, Mice, Phosphatidylinositol 3-Kinases, 03 medical and health sciences, 0302 clinical medicine, Text mining, Outcome predictor, Genetics, medicine, Animals, Humans, Receptors, Cytokine, Cytotoxicity, Molecular Biology, PI3K/AKT/mTOR pathway, Mutation, Acute lymphocytic leukaemia, business.industry, TOR Serine-Threonine Kinases, Janus Kinase 2, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, RAS, leukemia, PTPN11, 030104 developmental biology, 030220 oncology & carcinogenesis, ras Proteins, Cancer research, Cytokines, business, Signal Transduction
Abstract: Leukemias are routinely sub-typed for risk/outcome prediction and therapy choice using acquired mutations and chromosomal rearrangements. Down syndrome acute lymphoblastic leukemia (DS‐ALL) is characterized by high frequency of CRLF2‐rearrangements, JAK2‐mutations, or RAS‐pathway mutations. Intriguingly, JAK2 and RAS-mutations are mutually exclusive in leukemic sub‐clones, causing dichotomy in therapeutic target choices. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. On primary clinical DS‐ALL samples, we show that wtRAS-activation is an obligatory consequence of mutated/hyperphosphorylated JAK2. We further prove that CRLF2-ligand TSLP boosts the direct binding of active PTPN11 to wtRAS, providing the molecular mechanism for the wtRAS activation. Pre‐inhibition of RAS or PTPN11, but not of PI3K or JAK‐signaling, prevented TSLP‐induced RAS‐GTP boost. Cytotoxicity assays on primary clinical DS‐ALL samples demonstrated that, regardless of mutation status, high-risk leukemic cells could only be killed using RAS‐inhibitor or PTPN11-inhibitor, but not PI3K/JAK‐inhibitors, suggesting a unified treatment target for up to 80% of DS‐ALL. Importantly, protein activities-based principal-component-analysis multivariate clusters analyzed for independent outcome prediction using Cox proportional-hazards model showed that protein‐activity (but not mutation-status) was independently predictive of outcome, demanding a paradigm-shift in patient‐stratification strategy for precision therapy in high-risk ALL.
Published: 2020

23. Transcriptome-wide subtyping of pediatric and adult T cell acute lymphoblastic leukemia in an international study of 707 cases

Author: Yu-Ting Dai, Fan Zhang, Hai Fang, Jian-Feng Li, Gang Lu, Lu Jiang, Bing Chen, Dong-Dong Mao, Yuan-Fang Liu, Jin Wang, Li-Jun Peng, Chong Feng, Hai-Feng Chen, Jun-Xi Mu, Qun-Ling Zhang, Hao Wang, Hany Ariffin, Tan Ah Moy, Jing-Han Wang, Yin-Jun Lou, Su-Ning Chen, Qian Wang, Hong Liu, Zhe Shan, Itaru Matsumura, Yasushi Miyazaki, Takahiko Yasuda, Li-Ping Dou, Xiao-Jing Yan, Jin-Song Yan, Allen Eng-Juh Yeoh, De-Pei Wu, Hitoshi Kiyoi, Fumihiko Hayakawa, Jie Jin, Sheng-Yue Wang, Xiao-Jian Sun, Jian-Qing Mi, Zhu Chen, Jin-Yan Huang, and Sai-Juan Chen
Subjects: Multidisciplinary, Mutation, Humans, Child, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Transcriptome
Abstract: T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy of T cell progenitors, known to be a heterogeneous disease in pediatric and adult patients. Here we attempted to better understand the disease at the molecular level based on the transcriptomic landscape of 707 T-ALL patients (510 pediatric, 190 adult patients, and 7 with unknown age; 599 from published cohorts and 108 newly investigated). Leveraging the information of gene expression enabled us to identify 10 subtypes (G1–G10), including the previously undescribed one characterized by GATA3 mutations, with GATA3R276Q capable of affecting lymphocyte development in zebrafish. Through associating with T cell differentiation stages, we found that high expression of LYL1/LMO2/SPI1/HOXA (G1–G6) might represent the early T cell progenitor, pro/precortical/cortical stage with a relatively high age of disease onset, and lymphoblasts with TLX3/TLX1 high expression (G7–G8) could be blocked at the cortical/postcortical stage, while those with high expression of NKX2-1/TAL1/LMO1 (G9–G10) might correspond to cortical/postcortical/mature stages of T cell development. Notably, adult patients harbored more cooperative mutations among epigenetic regulators, and genes involved in JAK-STAT and RAS signaling pathways, with 44% of patients aged 40 y or above in G1 bearing DNMT3A/IDH2 mutations usually seen in acute myeloid leukemia, suggesting the nature of mixed phenotype acute leukemia.
Published: 2022

24. An Image Processing Application for the Localization and Segmentation of Lymphoblast Cell Using Peripheral Blood Images.

Author: Hayan T. Madhloom, Sameem Abdul Kareem, and Hany Ariffin
Published: 2012
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25. Malaysia-Singapore (MASPORE) leukaemia study group: From common history to successful collaboration

Author: Sheng Hoay Leong, Syaza Ab Rahman, Allen Eng Juh Yeoh, Hany Ariffin, Hai Peng Lin, Edwynn Kean Hui Chiew, and Thuan Chong Quah
Subjects: Pediatrics, medicine.medical_specialty, Thiopurine methyltransferase, biology, business.industry, Childhood cancer, lcsh:RJ1-570, lcsh:Pediatrics, Hematology, Precision medicine, Minimal residual disease, 03 medical and health sciences, Regimen, 0302 clinical medicine, Oncology, Disease severity, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, biology.protein, Medicine, Cumulative incidence, Dosing, business, 030215 immunology
Abstract: The 1970s marked the beginning of childhood cancer services in Malaysia and Singapore, two neighbours in South-East Asia. Between 1995 and 2002, Malaysia utilized a treatment regimen based on the Dutch DCOG 7 and German BFM protocols for children with acute lymphoblastic leukaemia (ALL), whilst Singapore in collaboration with Hong Kong employed the HK-ALL 1997 protocol, based on BFM ALL 95. In 2002, the overall 6-year event-free survival (EFS) for childhood ALL in Malaysia stood at 56%, while the 5-year EFS for HK-ALL 1997 was 79%. Formal collaboration between Malaysia and Singapore for the treatment of childhood ALL began in 2003. The first collaborative trial was the seminal MASPORE ALL2003 study which utilized a single PCR-based minimal residual disease marker to risk stratify patients according to disease severity, and used a 3-drug induction regimen for non-high-risk patients. This effort resulted in an improvement in 6-year EFS for both countries, at 80%, with an overall survival of 88%. The study showed that treatment could be appropriately tailored to disease risk, and that an anthracycline-free induction strategy did not compromise outcome for the majority (86%) of patients. The follow-up study, MASPORE ALL2010 focused on delivering therapy that was more intensive for those in high-risk group while reducing intensity for standard and intermediate risk groups. The study also took into consideration patients with IKZF1 gene deletion (IKZF1del) and moved these patients into a higher risk category. Increasing treatment intensity for patients with IKZF1del resulted in a reduction in 5-year cumulative incidence of relapse (CIR) from 30 to 13%, and improved overall 5-year survival from 69 to 91%. The MASPORE ALL2010 trial also studied TPMT and NUDT15 gene variants in its patient population to optimize thiopurine dosing. As the study moves into its next phase (MASPORE ALL2020), precision medicine and risk-adapted therapy remain the cornerstone strategies for childhood ALL, especially in the era of increased recognition of late effects amongst survivors of childhood cancer. Future therapies will likely focus on further targeted treatment for childhood ALL as more molecularly distinct subtypes become known.
Published: 2020

26. Identifying IGH disease clones for MRD monitoring in childhood B-cell acute lymphoblastic leukemia using RNA-Seq

Author: Kean Hui Chiew, Jun J. Yang, Hany Ariffin, Nan Jiang, Winnie Hui Ni Chin, Wentao Yang, Evelyn Huizi Lim, Ah Moy Tan, Shirley Kow Yin Kham, Quah Tc, Allen Eng Juh Yeoh, Hai Peng Lin, Yi Lu, and Zhenhua Li
Subjects: 0301 basic medicine, Sanger sequencing, clone (Java method), Cancer Research, biology, Sequence analysis, hemic and immune systems, chemical and pharmacologic phenomena, RNA-Seq, Hematology, Minimal residual disease, Molecular biology, 03 medical and health sciences, symbols.namesake, 030104 developmental biology, 0302 clinical medicine, Oncology, immune system diseases, hemic and lymphatic diseases, 030220 oncology & carcinogenesis, symbols, biology.protein, Antibody, Gene, Heteroduplex
Abstract: Identifying patient-specific clonal IGH/TCR junctional sequences is critical for minimal residual disease (MRD) monitoring. Conventionally these junctional sequences are identified using laborious Sanger sequencing of excised heteroduplex bands. We found that the IGH is highly expressed in our diagnostic B-cell acute lymphoblastic leukemia (B-ALL) samples using RNA-Seq. Therefore, we used RNA-Seq to identify IGH disease clone sequences in 258 childhood B-ALL samples for MRD monitoring. The amount of background IGH rearrangements uncovered by RNA-Seq followed the Zipf’s law with IGH disease clones easily identified as outliers. Four hundred and ninety-seven IGH disease clones (median 2, range 0–7 clones/patient) are identified in 90.3% of patients. High hyperdiploid patients have the most IGH disease clones (median 3) while DUX4 subtype has the least (median 1) due to the rearrangements involving the IGH locus. In all, 90.8% of IGH disease clones found by Sanger sequencing are also identified by RNA-Seq. In addition, RNA-Seq identified 43% more IGH disease clones. In 69 patients lacking sensitive IGH targets, targeted NGS IGH MRD showed high correlation (R = 0.93; P = 1.3 × 10−14), better relapse prediction than conventional RQ-PCR MRD using non-IGH targets. In conclusion, RNA-Seq can identify patient-specific clonal IGH junctional sequences for MRD monitoring, adding to its usefulness for molecular diagnosis in childhood B-ALL.
Published: 2020

27. The global burden of cancer attributable to risk factors, 2010–19 : A systematic analysis for the Global Burden of Disease Study 2019

Author: Khanh Bao Tran, Justin J Lang, Kelly Compton, Rixing Xu, Alistair R Acheson, Hannah Jacqueline Henrikson, Jonathan M Kocarnik, Louise Penberthy, Amirali Aali, Qamar Abbas, Behzad Abbasi, Mohsen Abbasi-Kangevari, Zeinab Abbasi-Kangevari, Hedayat Abbastabar, Michael Abdelmasseh, Sherief Abd-Elsalam, Ahmed Abdelwahab Abdelwahab, Gholamreza Abdoli, Hanan Abdulkadir Abdulkadir, Aidin Abedi, Kedir Hussein Abegaz, Hassan Abidi, Richard Gyan Aboagye, Hassan Abolhassani, Abdorrahim Absalan, Yonas Derso Abtew, Hiwa Abubaker Ali, Eman Abu-Gharbieh, Basavaprabhu Achappa, Juan Manuel Acuna, Daniel Addison, Isaac Yeboah Addo, Oyelola A Adegboye, Miracle Ayomikun Adesina, Mohammad Adnan, Qorinah Estiningtyas Sakilah Adnani, Shailesh M Advani, Sumia Afrin, Muhammad Sohail Afzal, Manik Aggarwal, Bright Opoku Ahinkorah, Araz Ramazan Ahmad, Rizwan Ahmad, Sajjad Ahmad, Sohail Ahmad, Sepideh Ahmadi, Haroon Ahmed, Luai A Ahmed, Muktar Beshir Ahmed, Tarik Ahmed Rashid, Wajeeha Aiman, Marjan Ajami, Gizachew Taddesse Akalu, Mostafa Akbarzadeh-Khiavi, Addis Aklilu, Maxwell Akonde, Chisom Joyqueenet Akunna, Hanadi Al Hamad, Fares Alahdab, Fahad Mashhour Alanezi, Turki M Alanzi, Saleh Ali Alessy, Abdelazeem M Algammal, Mohammed Khaled Al-Hanawi, Robert Kaba Alhassan, Beriwan Abdulqadir Ali, Liaqat Ali, Syed Shujait Ali, Yousef Alimohamadi, Vahid Alipour, Syed Mohamed Aljunid, Motasem Alkhayyat, Sadeq Ali Ali Al-Maweri, Sami Almustanyir, Nivaldo Alonso, Shehabaldin Alqalyoobi, Rajaa M Al-Raddadi, Rami H Hani Al-Rifai, Salman Khalifah Al-Sabah, Ala'a B Al-Tammemi, Haya Altawalah, Nelson Alvis-Guzman, Firehiwot Amare, Edward Kwabena Ameyaw, Javad Javad Aminian Dehkordi, Mohammad Hosein Amirzade-Iranaq, Hubert Amu, Ganiyu Adeniyi Amusa, Robert Ancuceanu, Jason A Anderson, Yaregal Animut Animut, Amir Anoushiravani, Ali Arash Anoushirvani, Alireza Ansari-Moghaddam, Mustafa Geleto Ansha, Benny Antony, Maxwell Hubert Antwi, Sumadi Lukman Anwar, Razique Anwer, Anayochukwu Edward Anyasodor, Jalal Arabloo, Morteza Arab-Zozani, Olatunde Aremu, Ayele Mamo Argaw, Hany Ariffin, Timur Aripov, Muhammad Arshad, Al Artaman, Judie Arulappan, Raphael Taiwo Aruleba, Armin Aryannejad, Malke Asaad, Mulusew A Asemahagn, Zatollah Asemi, Mohammad Asghari-Jafarabadi, Tahira Ashraf, Reza Assadi, Mohammad Athar, Seyyed Shamsadin Athari, Maha Moh'd Wahbi Atout, Sameh Attia, Avinash Aujayeb, Marcel Ausloos, Leticia Avila-Burgos, Atalel Fentahun Awedew, Mamaru Ayenew Awoke, Tewachew Awoke, Beatriz Paulina Ayala Quintanilla, Tegegn Mulatu Ayana, Solomon Shitu Ayen, Davood Azadi, Sina Azadnajafabad, Saber Azami-Aghdash, Melkalem Mamuye Azanaw, Mohammadreza Azangou-Khyavy, Amirhossein Azari Jafari, Hosein Azizi, Ahmed Y Y Azzam, Amirhesam Babajani, Muhammad Badar, Ashish D Badiye, Nayereh Baghcheghi, Nader Bagheri, Sara Bagherieh, Saeed Bahadory, Atif Amin Baig, Jennifer L Baker, Ahad Bakhtiari, Ravleen Kaur Bakshi, Maciej Banach, Indrajit Banerjee, Mainak Bardhan, Francesco Barone-Adesi, Fabio Barra, Amadou Barrow, Nasir Z Bashir, Azadeh Bashiri, Saurav Basu, Abdul-Monim Mohammad Batiha, Aeysha Begum, Alehegn Bekele Bekele, Alemayehu Sayih Belay, Melaku Ashagrie Belete, Uzma Iqbal Belgaumi, Arielle Wilder Bell, Luis Belo, Habib Benzian, Alemshet Yirga Berhie, Amiel Nazer C Bermudez, Eduardo Bernabe, Akshaya Srikanth Bhagavathula, Neeraj Bhala, Bharti Bhandari Bhandari, Nikha Bhardwaj, Pankaj Bhardwaj, Krittika Bhattacharyya, Vijayalakshmi S Bhojaraja, Soumitra S Bhuyan, Sadia Bibi, Awraris Hailu Bilchut, Bagas Suryo Bintoro, Antonio Biondi, Mesfin Geremaw Birega Birega, Habitu Eshetu Birhan, Tone Bjørge, Oleg Blyuss, Belay Boda Abule Bodicha, Srinivasa Rao Bolla, Archith Boloor, Cristina Bosetti, Dejana Braithwaite, Michael Brauer, Hermann Brenner, Andrey Nikolaevich Briko, Nikolay Ivanovich Briko, Christina Maree Buchanan, Norma B Bulamu, Maria Teresa Bustamante-Teixeira, Muhammad Hammad Butt, Nadeem Shafique Butt, Zahid A Butt, Florentino Luciano Caetano dos Santos, Luis Alberto Cámera, Chao Cao, Yin Cao, Giulia Carreras, Márcia Carvalho, Francieli Cembranel, Ester Cerin, Promit Ananyo Chakraborty, Periklis Charalampous, Vijay Kumar Chattu, Odgerel Chimed-Ochir, Jesus Lorenzo Chirinos-Caceres, Daniel Youngwhan Cho, William C S Cho, Devasahayam J Christopher, Dinh-Toi Chu, Isaac Sunday Chukwu, Aaron J Cohen, Joao Conde, Sandra Cortés, Vera Marisa Costa, Natália Cruz-Martins, Garland T Culbreth, Omid Dadras, Fentaw Teshome Dagnaw, Saad M A Dahlawi, Xiaochen Dai, Lalit Dandona, Rakhi Dandona, Parnaz Daneshpajouhnejad, Anna Danielewicz, An Thi Minh Dao, Reza Darvishi Cheshmeh Soltani, Aso Mohammad Darwesh, Saswati Das, Dragos Virgil Davitoiu, Elham Davtalab Esmaeili, Fernando Pio De la Hoz, Sisay Abebe Debela, Azizallah Dehghan, Biniyam Demisse, Fitsum Wolde Demisse, Edgar Denova-Gutiérrez, Afshin Derakhshani, Meseret Derbew Molla, Diriba Dereje, Kalkidan Solomon Deribe, Rupak Desai, Markos Desalegn Desalegn, Fikadu Nugusu Dessalegn, Samuel Abebe A Dessalegni, Gashaw Dessie, Abebaw Alemayehu Desta, Syed Masudur Rahman Dewan, Samath Dhamminda Dharmaratne, Meghnath Dhimal, Mostafa Dianatinasab, Nancy Diao, Daniel Diaz, Lankamo Ena Digesa, Shilpi Gupta Dixit, Saeid Doaei, Linh Phuong Doan, Paul Narh Doku, Deepa Dongarwar, Wendel Mombaque dos Santos, Tim Robert Driscoll, Haneil Larson Dsouza, Oyewole Christopher Durojaiye, Sareh Edalati, Fatemeh Eghbalian, Elham Ehsani-Chimeh, Ebrahim Eini, Michael Ekholuenetale, Temitope Cyrus Ekundayo, Donatus U Ekwueme, Maha El Tantawi, Mostafa Ahmed Elbahnasawy, Iffat Elbarazi, Hesham Elghazaly, Muhammed Elhadi, Waseem El-Huneidi, Mohammad Hassan Emamian, Luchuo Engelbert Bain, Daniel Berhanie Enyew, Ryenchindorj Erkhembayar, Tegegne Eshetu, Babak Eshrati, Sharareh Eskandarieh, Juan Espinosa-Montero, Farshid Etaee, Azin Etemadimanesh, Tahir Eyayu, Ifeanyi Jude Ezeonwumelu, Sayeh Ezzikouri, Adeniyi Francis Fagbamigbe, Saman Fahimi, Ildar Ravisovich Fakhradiyev, Emerito Jose A Faraon, Jawad Fares, Abbas Farmany, Umar Farooque, Hossein Farrokhpour, Abidemi Omolara Fasanmi, Ali Fatehizadeh, Wafa Fatima, Hamed Fattahi, Ginenus Fekadu, Berhanu Elfu Feleke, Allegra Allegra Ferrari, Simone Ferrero, Lorenzo Ferro Desideri, Irina Filip, Florian Fischer, Roham Foroumadi, Masoud Foroutan, Takeshi Fukumoto, Peter Andras Gaal, Mohamed M Gad, Muktar A Gadanya, Abduzhappar Gaipov, Nasrin Galehdar, Silvano Gallus, Tushar Garg, Mariana Gaspar Fonseca, Yosef Haile Gebremariam, Teferi Gebru Gebremeskel, Mathewos Alemu Gebremichael, Yohannes Fikadu Geda, Yibeltal Yismaw Gela, Belete Negese Belete Gemeda, Melaku Getachew, Motuma Erena Getachew, Kazem Ghaffari, Mansour Ghafourifard, Seyyed-Hadi Ghamari, Mohammad Ghasemi Nour, Fariba Ghassemi, Ajnish Ghimire, Nermin Ghith, Maryam Gholamalizadeh, Jamshid Gholizadeh Navashenaq, Sherief Ghozy, Syed Amir Gilani, Paramjit Singh Gill, Themba G Ginindza, Abraham Tamirat T Gizaw, James C Glasbey, Justyna Godos, Amit Goel, Mahaveer Golechha, Pouya Goleij, Davide Golinelli, Mohamad Golitaleb, Giuseppe Gorini, Bárbara Niegia Garcia Goulart, Giuseppe Grosso, Habtamu Alganeh Guadie, Mohammed Ibrahim Mohialdeen Gubari, Temesgen Worku Gudayu, Maximiliano Ribeiro Guerra, Damitha Asanga Gunawardane, Bhawna Gupta, Sapna Gupta, Veer Bala Gupta, Vivek Kumar Gupta, Mekdes Kondale Gurara, Alemu Guta, Parham Habibzadeh, Atlas Haddadi Avval, Nima Hafezi-Nejad, Adel Hajj Ali, Arvin Haj-Mirzaian, Esam S Halboub, Aram Halimi, Rabih Halwani, Randah R Hamadeh, Sajid Hameed, Samer Hamidi, Asif Hanif, Sanam Hariri, Netanja I Harlianto, Josep Maria Haro, Risky Kusuma Hartono, Ahmed I Hasaballah, S M Mahmudul Hasan, Hamidreza Hasani, Seyedeh Melika Hashemi, Abbas M Hassan, Soheil Hassanipour, Khezar Hayat, Golnaz Heidari, Mohammad Heidari, Zahra Heidarymeybodi, Brenda Yuliana Herrera-Serna, Claudiu Herteliu, Kamal Hezam, Yuta Hiraike, Mbuzeleni Mbuzeleni Hlongwa, Ramesh Holla, Marianne Holm, Nobuyuki Horita, Mohammad Hoseini, Md Mahbub Hossain, Mohammad Bellal Hossain Hossain, Mohammad-Salar Hosseini, Ali Hosseinzadeh, Mehdi Hosseinzadeh, Mihaela Hostiuc, Sorin Hostiuc, Mowafa Househ, Junjie Huang, Fernando N Hugo, Ayesha Humayun, Salman Hussain, Nawfal R Hussein, Bing-Fang Hwang, Segun Emmanuel Ibitoye, Pulwasha Maria Iftikhar, Kevin S Ikuta, Olayinka Stephen Ilesanmi, Irena M Ilic, Milena D Ilic, Mustapha Immurana, Kaire Innos, Pooya Iranpour, Lalu Muhammad Irham, Md Shariful Islam, Rakibul M Islam, Farhad Islami, Nahlah Elkudssiah Ismail, Gaetano Isola, Masao Iwagami, Linda Merin J, Abhishek Jaiswal, Mihajlo Jakovljevic, Mahsa Jalili, Shahram Jalilian, Elham Jamshidi, Sung-In Jang, Chinmay T Jani, Tahereh Javaheri, Umesh Umesh Jayarajah, Shubha Jayaram, Seyed Behzad Jazayeri, Rime Jebai, Bedru Jemal, Wonjeong Jeong, Ravi Prakash Jha, Har Ashish Jindal, Yetunde O John-Akinola, Jost B Jonas, Tamas Joo, Nitin Joseph, Farahnaz Joukar, Jacek Jerzy Jozwiak, Mikk Jürisson, Ali Kabir, Salah Eddine Oussama Kacimi, Vidya Kadashetti, Farima Kahe, Pradnya Vishal Kakodkar, Laleh R Kalankesh, Leila R Kalankesh, Rohollah Kalhor, Vineet Kumar Kamal, Farin Kamangar, Ashwin Kamath, Tanuj Kanchan, Eswar Kandaswamy, Himal Kandel, HyeJung Kang, Girum Gebremeskel Kanno, Neeti Kapoor, Sitanshu Sekhar Kar, Shama D Karanth, Ibraheem M Karaye, André Karch, Amirali Karimi, Bekalu Getnet Kassa, Patrick DMC Katoto, Joonas H Kauppila, Harkiran Kaur, Abinet Gebremickael Kebede, Leila Keikavoosi-Arani, Gemechu Gemechu Kejela, Phillip M Kemp Bohan, Maryam Keramati, Mohammad Keykhaei, Himanshu Khajuria, Abbas Khan, Abdul Aziz Khan Khan, Ejaz Ahmad Khan, Gulfaraz Khan, Md Nuruzzaman Khan, Moien AB Khan, Javad Khanali, Khaled Khatab, Moawiah Mohammad Khatatbeh, Mahalaqua Nazli Khatib, Maryam Khayamzadeh, Hamid Reza Khayat Kashani, Mohammad Amin Khazeei Tabari, Mehdi Khezeli, Mahmoud Khodadost, Min Seo Kim, Yun Jin Kim, Adnan Kisa, Sezer Kisa, Miloslav Klugar, Jitka Klugarová, Ali-Asghar Kolahi, Pavel Kolkhir, Farzad Kompani, Parvaiz A Koul, Sindhura Lakshmi Koulmane Laxminarayana, Ai Koyanagi, Kewal Krishan, Yuvaraj Krishnamoorthy, Burcu Kucuk Bicer, Nuworza Kugbey, Mukhtar Kulimbet, Akshay Kumar, G Anil Kumar, Narinder Kumar, Om P Kurmi, Ambily Kuttikkattu, Carlo La Vecchia, Arista Lahiri, Dharmesh Kumar Lal, Judit Lám, Qing Lan, Iván Landires, Bagher Larijani, Savita Lasrado, Jerrald Lau, Paolo Lauriola, Caterina Ledda, Sang-woong Lee, Shaun Wen Huey Lee, Wei-Chen Lee, Yeong Yeh Lee, Yo Han Lee, Samson Mideksa Legesse, James Leigh, Elvynna Leong, Ming-Chieh Li, Stephen S Lim, Gang Liu, Jue Liu, Chun-Han Lo, Ayush Lohiya, Platon D Lopukhov, László Lorenzovici, Mojgan Lotfi, Joana A Loureiro, Raimundas Lunevicius, Farzan Madadizadeh, Ahmad R Mafi, Sameh Magdeldin, Soleiman Mahjoub, Ata Mahmoodpoor, Morteza Mahmoudi, Marzieh Mahmoudimanesh, Rashidul Alam Mahumud, Azeem Majeed, Jamal Majidpoor, Alaa Makki, Konstantinos Christos Makris, Elaheh Malakan Rad, Mohammad-Reza Malekpour, Reza Malekzadeh, Ahmad Azam Malik, Tauqeer Hussain Mallhi, Sneha Deepak Mallya, Mohammed A Mamun, Ana Laura Manda, Fariborz Mansour-Ghanaei, Borhan Mansouri, Mohammad Ali Mansournia, Lorenzo Giovanni Mantovani, Santi Martini, Miquel Martorell, Sahar Masoudi, Seyedeh Zahra Masoumi, Clara N Matei, Elezebeth Mathews, Manu Raj Mathur, Vasundhara Mathur, Martin McKee, Jitendra Kumar Meena, Khalid Mehmood, Entezar Mehrabi Nasab, Ravi Mehrotra, Addisu Melese, Walter Mendoza, Ritesh G Menezes, SIsay Derso Mengesha, Laverne G Mensah, Alexios-Fotios A Mentis, Andry Yasmid Mera Mera-Mamián, Tuomo J Meretoja, Mehari Woldemariam Merid, Amanual Getnet Mersha, Belsity Temesgen Meselu, Mahboobeh Meshkat, Tomislav Mestrovic, Junmei Miao Jonasson, Tomasz Miazgowski, Irmina Maria Michalek, Gelana Fekadu Worku Mijena, Ted R Miller, Shabir Ahmad Mir, Seyed Kazem Mirinezhad, Seyyedmohammadsadeq Mirmoeeni, Mohammad Mirza-Aghazadeh-Attari, Hamed Mirzaei, Hamid Reza Mirzaei, Abay Sisay Misganaw, Sanjeev Misra, Karzan Abdulmuhsin Mohammad, Esmaeil Mohammadi, 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Melinda Gates Foundation, Kuwait University (Kuwait), Ministry of Higher Education (Malasia), Lega Italiana per la Lotta ai Tumori, Health Effects Institute (Estados Unidos), Unión Europea. Comisión Europea. European Research Council (ERC), Unión Europea. Comisión Europea. H2020, Fundação para a Ciência e Tecnologia (Portugal), African-German Network of Excellence in Science (AGNES), Federal Ministry of Education & Research (Alemania), Alexander von Humboldt Foundation, Novo Nordisk Foundation, National Institute for Health Research (Reino Unido), National Health and Medical Research Council (Australia), Romanian National Authority for Scientific Research and Innovation, Romanian Ministry of Research Innovation and Digitalization, Ministry of Education, Science and Technological Development (Serbia), Sigrid Jusélius Foundation, Finnish Cancer Foundation, Datta Meghe Institute of Medical Sciences (India), Xiamen University (Malasia), Manipal Academy of Higher Education (India), Panjab University (India), Sistema Nacional de Investigación (Panamá), Secretaría Nacional de Ciencia, Tecnología e Innovación (Panamá), Ministry of Science and Technology (Taiwan), Lung Foundation Australia, National Natural Science Foundation of China, Wellcome Trust, UNSW Sydney (Australia), ICMR - National Institute of Epidemiology (India), University of Tasmania (Australia), National Council for Scientific and Technological Development (Brasil), Coordenação de Aperfeicoamento de Pessoal de Nível Superior (Brasil), Institute for Advanced Studies in Basic Sciences (Irán), Ain Shams University (Egipto), International Center of Medical Sciences Research (Islamabad), National Institutes of Health (Estados Unidos), University of Oxford (Reino Unido), National Institute of Genetic Engineering and Biotechnology (Irán), Marga und Walter Boll - Stiftung, Ministero della Salute (Italia), IRCCS Materno Infantile Burlo Garofolo (Italia), King College London, Wellcome Trust/DBT India Alliance (India), Public Health, University of St Andrews. School of Medicine, and University of St Andrews. Population and Behavioural Science Division
Subjects: Male, DEATHS, DALY, cancer, risk factors, Medizin, systematic analysis, Global Health, Risk Assessment, Cancer prevention, Global Burden of Disease, RC0254, Risk-attributable cancer deaths, SDG 3 - Good Health and Well-being, RA0421, Risk Factors, RA0421 Public health. Hygiene. Preventive Medicine, Quality-Adjusted Life Year, Neoplasms, cancer, Humans, Global Burden of Disease Study, UK, Medicine(all), MCC, RC0254 Neoplasms. Tumors. Oncology (including Cancer), Risk Factor, Smoking, COVID-19, 3rd-DAS, General Medicine, Disability-adjusted life-years, SOCIAL DETERMINANTS, Risk assessments, risk factor, Cardiovascular and Metabolic Diseases, 3121 General medicine, internal medicine and other clinical medicine, OBESITY, Cancer burden, Neoplasm, Female, LIFE-STYLE, Quality-Adjusted Life Years, HEALTH, RA, Human, RC
Abstract: Background: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01-4·94) deaths and 105 million (95·0-116) DALYs for both sexes combined, representing 44·4% (41·3-48·4) of all cancer deaths and 42·0% (39·1-45·6) of all DALYs. There were 2·88 million (2·60-3·18) risk-attributable cancer deaths in males (50·6% [47·8-54·1] of all male cancer deaths) and 1·58 million (1·36-1·84) risk-attributable cancer deaths in females (36·3% [32·5-41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6-28·4) and DALYs by 16·8% (8·8-25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9-42·8] and 33·3% [25·8-42·0]). Interpretation: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. We are grateful to the surveillance systems, including cancer registries, that generated and shared observed cancer burden data. S M Aljunid acknowledges the Department of Health Policy and Management, College of Public Health, Kuwait University for the approval and support to participate in this research project. H Ariffin acknowledges support from the Ministry of Higher Education, Malaysia (grant FRGS/1/2021/SKK0/UM/01/1). F Barra acknowledges support from Lega Italiana per la Lotta contro i Tumori - LILT - Bando 5 x 1000 anno 2019. L Belo and M Carvalho acknowledge the support from FCT in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of UCIBIO and the project LA/P/0140/2020 of i4HB. A J Cohen was supported by the Health Effects Institute, Boston, MA, USA. J Conde acknowledges financial support from the European Research Council - ERC Starting Grant 848325. V M Costa acknowledges her grant (SFRH/BHD/110001/2015), received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006. T C Ekundayo was supported by the African-German Network of Excellence in Science (AGNES), the Federal Ministry of Education and Research (BMBF) and the Alexander von Humboldt Foundation (AvH). N Ghith acknowledges support from a grant from Novo Nordisk Foundation (NNF16OC0021856). J C Glasbey is support by a Doctoral Research Fellowship from the National Institute of Health Research (NIHR300175). V K Gupta and V B Gupta acknowledge funding support from National Health and Medical Research Council (NHMRC), Australia. C Herteliu, A Pana, and M Ausloos acknowledge partial support by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. C Herteliu is also partially supported by a grant of the Romanian Ministry of Research Innovation and Digitalization, MCID, project number ID-585-CTR-42-PFE-2021. S Hussain was supported from Operational Programme Research, Development and Education–Project, Postdoc2MUNI (number CZ.02.2. 69/0.0/0.0/18_053/0016952). M Jakovljevic acknowledges partial support through the grant OI 175 014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. J H Kauppila acknowledges research grants from Sigrid Jusélius Foundation and the Finnish Cancer Foundation. M N Khatib acknowledges support from Datta Meghe Institute of Medical Sciences (deemed-to-be-university). Y J Kim was supported by the Research Management Centre, Xiamen University Malaysia [XMUMRF/2020-C6/ITCM/0004]. S L Koulmane Laxminarayana acknowledges institutional assistance by Manipal Academy of Higher Education, Manipal. K Krishan is supported by the UGC Centre of Advanced Study (Phase II), awarded to the Department of Anthropology, Panjab University, Chandigarh, India. I Landires is a member of the Sistema Nacional de Investigación (SNI), which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT). M-C Li was supported by the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-003-001). G Liu acknowledges support from the CREATE Hope scientific fellowship from Lung Foundation Australia. J Liu acknowledges support from the National Natural Science Foundation (72122001). J A Loureiro was supported by Scientific Employment Stimulus (FCT; CEECINST/00049/2018). E Mathews is supported by a Clinical and Public Health Early Career Fellowship (grant number IA/CPHE/17/1/503345) from the DBT India Alliance/Wellcome Trust Department of Biotechnology, India Alliance (2018–2023). T J Meretoja was supported by an unrestricted grant from Cancer Foundation Finland sr. S Mohammed acknowledges a fellowship grant from Alexander von Humboldt Foundation, outside the submitted work. M Molokhia is supported by the National Institute for Health Research Biomedical Research Center at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London. L Monasta received support from the Italian Ministry of Health at the Institute for Maternal and Child Health IRCCS Burlo Garofolo, Trieste - Italy (RC 34/2017). U Mons is supported by the Marga and Walter Boll Foundation, Kerpen, Germany. M A Moosavi acknowledges the financial support of National Institute of Genetics Engineering and Biotechnology (NIGEB). J Musa acknowledges support from the NIH/FICK43TW011416 for research-protected time for cervical cancer research and career development at University of Jos. V Nuñez-Samudio is a member of the Sistema Nacional de Investigación (SNI), which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación (SENACYT). O O Odukoya acknowledges support by the Fogarty International Center of the National Institutes of Health under the award number K43TW010704 for research-protected time. The content is solely the responsibility of all the authors and does not necessarily represent the official views of the National Institutes of Health. A S Oguntade acknowledges funding by a doctoral scholarship from the Nuffield Department of Population Health, University of Oxford (Oxford Population Health). J R Padubidri acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal for their constant support in research collaborations. R G Pestell acknowledges support from NIH grant W81XWH1810605 Breast Cancer Research, Breakthrough Grant R21 CA235139-01. Z Z Piracha acknowledges the International Center of Medical Sciences Research (ICMSR), Islamabad (44000), Pakistan. R A Radhakrishnan acknowledges support from Wellcome Trust/DBT India Alliance - IA/CPHI/18/1/503927. U Saeed acknowledges the International Center of Medical Sciences Research (ICMSR), Islamabad, Pakistan. A M Samy acknowledges the support from Ain Shams University and the Egyptian Fulbright Mission Program. F Sha was supported by the Shenzhen Science and Technology Program (grant number KQTD20190929172835662). H R Shahsavari acknowledges the Institute for Advanced Studies in Basic Sciences (IASBS) Research Council. A Shetty acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal for all the academic support. D A S Silva acknowledges financing in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior—Brazil (CAPES)—Finance Code 001 and D A S Silva is supported in part by CNPq-Brazil (309589/2021-5). L M L R Silva was supported by project CENTRO-04-3559-FSE-000162, Fundo Social Europeu (FSE). Am Singh is supported by the International Graduate Research Scholarship, University of Tasmania. R Suliankatchi Abdulkader acknowledges support from ICMR—National Institute of Epidemiology. B Unnikrishnan acknowledges Kasturba Medical College, Mangalore, Manipal Academy of Higher Education, Manipal. H Xiao acknowledges support from the Public Health Sciences Division of the Fred Hutchinson Cancer Research Center. X Xu is supported by the University of New South Wales (Australia) Scientia Program. C Yu was supported by the National Natural Science Foundation of China (grant number 82173626) and Wuhan Medical Research Program of Joint Fund of Hubei Health Committee (grant number WJ2019H304). Sí
Published: 2022

28. The global burden of adolescent and young adult cancer in 2019: a systematic analysis for the Global Burden of Disease Study 2019

Author: Elysia M Alvarez, Lisa M Force, Rixing Xu, Kelly Compton, Dan Lu, Hannah Jacqueline Henrikson, Jonathan M Kocarnik, James D Harvey, Alyssa Pennini, Frances E Dean, Weijia Fu, Martina T Vargas, Theresa H M Keegan, Hany Ariffin, Ronald D Barr, Yana Arturovna Erdomaeva, D Sanjeeva Gunasekera, Yetunde O John-Akinola, Tyler G Ketterl, Tezer Kutluk, Marcio Henrique Malogolowkin, Prashant Mathur, Venkatraman Radhakrishnan, Lynn Ann Gloeckler Ries, Carlos Rodriguez-Galindo, Garik Barisovich Sagoyan, Iyad Sultan, Behzad Abbasi, Mohsen Abbasi-Kangevari, Zeinab Abbasi-Kangevari, Hedayat Abbastabar, Michael Abdelmasseh, Sherief Abd-Elsalam, Amir Abdoli, Haimanot Abebe, Aidin Abedi, Hassan Abidi, Hassan Abolhassani, Hiwa Abubaker Ali, Eman Abu-Gharbieh, Basavaprabhu Achappa, Juan Manuel Acuna, Isaac Akinkunmi Adedeji, Oyelola A Adegboye, Qorinah Estiningtyas Sakilah Adnani, Shailesh M Advani, Muhammad Sohail Afzal, Mohamad Aghaie Meybodi, Bahman Ahadinezhad, Bright Opoku Ahinkorah, Sajjad Ahmad, Sepideh Ahmadi, Muktar Beshir Ahmed, Tarik Ahmed Rashid, Yusra Ahmed Salih, Wajeeha Aiman, Gizachew Taddesse Akalu, Hanadi Al Hamad, Fares Alahdab, Abdulhadi A AlAmodi, Fahad Mashhour Alanezi, Turki M Alanzi, Adugnaw Zeleke Alem, Dejene Tsegaye Alem, Yosef Alemayehu, Fadwa Naji Alhalaiqa, Robert Kaba Alhassan, Saqib Ali, Gianfranco Alicandro, Vahid Alipour, Syed Mohamed Aljunid, Motasem Alkhayyat, Sunitha Alluri, Nihad A Almasri, Sadeq Ali Al-Maweri, Sami Almustanyir, Rajaa M Al-Raddadi, Nelson Alvis-Guzman, Edward Kwabena Ameyaw, Saeed Amini, Hubert Amu, Robert Ancuceanu, Catalina Liliana Andrei, Tudorel Andrei, Fereshteh Ansari, Alireza Ansari-Moghaddam, Davood Anvari, Anayochukwu Edward Anyasodor, Jalal Arabloo, Morteza Arab-Zozani, Ayele Mamo Argaw, Muhammad Arshad, Judie Arulappan, Armin Aryannejad, Zatollah Asemi, Mohammad Asghari Jafarabadi, Mohammad Reza Atashzar, Prince Atorkey, Alok Atreya, Sameh Attia, Avinash Aujayeb, Marcel Ausloos, Leticia Avila-Burgos, Atalel Fentahun Awedew, Beatriz Paulina Ayala Quintanilla, Alemu Degu Ayele, Solomon Shitu Ayen, Mohammed A Azab, Sina Azadnajafabad, Hiva Azami, Mohammadreza Azangou-Khyavy, Amirhossein Azari Jafari, Ghasem Azarian, Ahmed Y Azzam, Saeed Bahadory, Jianjun Bai, Atif Amin Baig, Jennifer L Baker, Maciej Banach, Till Winfried Bärnighausen, Francesco Barone-Adesi, Fabio Barra, Amadou Barrow, Huda Basaleem, Abdul-Monim Mohammad Batiha, Masoud Behzadifar, Niguss Cherie Bekele, Rebuma Belete, Uzma Iqbal Belgaumi, Arielle Wilder Bell, Alemshet Yirga Berhie, Devidas S Bhagat, Akshaya Srikanth Bhagavathula, Nikha Bhardwaj, Pankaj Bhardwaj, Sonu Bhaskar, Krittika Bhattacharyya, Vijayalakshmi S Bhojaraja, Sadia Bibi, Ali Bijani, Antonio Biondi, Setognal Birara, Tone Bjørge, Obasanjo Afolabi Bolarinwa, Srinivasa Rao Bolla, Archith Boloor, Dejana Braithwaite, Hermann Brenner, Norma B Bulamu, Katrin Burkart, Maria Teresa Bustamante-Teixeira, Nadeem Shafique Butt, Zahid A Butt, Florentino Luciano Caetano dos 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Mpundu-Kaambwa C., Mubarik S., Mwanri L., Nabhan A.F., Nagaraju S.P., Nagata C., Naghavi M., Naimzada M.D., Naldi L., Nangia V., Naqvi A.A., Narasimha Swamy S., Narayana A.I., Nayak B.P., Nayak V.C., Nazari J., Nduaguba S.O., Negoi I., Negru S.M., Nejadghaderi S.A., Nepal S., Neupane Kandel S., Nggada H.A., Nguyen C.T., Nnaji C.A., Nosrati H., Nouraei H., Nowroozi A., Nunez-Samudio V., Nwatah V.E., Nzoputam C.I., Oancea B., Odukoya O.O., Oguntade A.S., Oh I.-H., Olagunju A.T., Olagunju T.O., Olakunde B.O., Oluwasanu M.M., Omar E., Omar Bali A., Ong S., Onwujekwe O.E., Ortega-Altamirano D.V., Otstavnov N., Otstavnov S.S., Oumer B., Owolabi M.O., P A M., Padron-Monedero A., Padubidri J.R., Pakshir K., Pana A., Pandey A., Pardhan S., Pashazadeh Kan F., Pasovic M., Patel J.R., Pati S., Pattanshetty S.M., Paudel U., Pereira R.B., Peres M.F.P., Perianayagam A., Postma M.J., Pourjafar H., Pourshams A., Prashant A., Pulakunta T., Qadir M.M.F.F., Rabiee M., Rabiee N., Radfar A., Radhakrishnan R.A., Rafiee A., Rafiei A., Rafiei S., Rahim F., Rahimzadeh S., Rahman M., Rahman M.A., Rahmani A.M., Rajesh A., Ramezani-Doroh V., Ranabhat K., Ranasinghe P., Rao C.R., Rao S.J., Rashedi S., Rashidi M., Rashidi M.-M., Rath G.K., Rawaf D.L., Rawaf S., Rawal L., Rawassizadeh R., Razeghinia M.S., Regasa M.T., Renzaho A.M.N., Rezaei M., Rezaei N., Rezaeian M., Rezapour A., Rezazadeh-Khadem S., Riad A., Rios Lopez L.E., Rodriguez J.A.B., Ronfani L., Roshandel G., Rwegerera G.M., Saber-Ayad M.M., Sabour S., Saddik B., Sadeghi E., Sadeghian S., Saeed U., Sahebkar A., Saif-Ur-Rahman K.M., Sajadi S.M., Salahi S., Salehi S., Salem M.R., Salimzadeh H., Samy A.M., Sanabria J., Sanmarchi F., Sarveazad A., Sathian B., Sawhney M., Sawyer S.M., Saylan M., Schneider I.J.C., Seidu A.-A., Sekerija M., Sendo E.G., Sepanlou S.G., Seylani A., Seyoum K., Sha F., Shafaat O., Shaikh M.A., Shamsoddin E., Shannawaz M., Sharma R., Sheikhbahaei S., Shetty A., Shetty B.S.K., Shetty P.H., Shin J.I., Shirkoohi R., Shivakumar K.M., Shobeiri P., Siabani S., Sibhat M.M., Siddappa Malleshappa S.K., Sidemo N.B., Silva D.A.S., Silva Julian G., Singh A.D., Singh J.A., Singh J.K., Singh S., Sinke A.H., Sintayehu Y., Skryabin V.Y., Skryabina A.A., Smith L., Sofi-Mahmudi A., Soltani-Zangbar M.S., Song S., Spurlock E.E., Steiropoulos P., Straif K., Subedi R., Sufiyan M.B., Suliankatchi Abdulkader R., Sultana S., Szerencses V., Szocska M., Tabaeian S.P., Tabares-Seisdedos R., Tabary M., Tabuchi T., Tadbiri H., Taheri M., Taherkhani A., Takahashi K., Tampa M., Tan K.-K., Tat V.Y., Tavakoli A., Tbakhi A., Tehrani-Banihashemi A., Temsah M.-H., Tesfay F.H., Tesfaye B., Thakur J.S., Thapar R., Thavamani A., Thiyagarajan A., Thomas N., Tobe-Gai R., Togtmol M., Tohidast S.A., Tohidinik H.R., Tolani M.A., Tollosa D.N., Touvier M., Tovani-Palone M.R., Traini E., Tran B.X., Tran M.T.N., Tripathy J.P., Tusa B.S., Ukke G.G., Ullah I., Ullah S., Umapathi K.K., Unnikrishnan B., Upadhyay E., Ushula T.W., Vacante M., Valadan Tahbaz S., Varthya S.B., Veroux M., Villeneuve P.J., Violante F.S., Vlassov V., Vu G.T., Waheed Y., Wang N., Ward P., Weldesenbet A.B., Wen Y.F., Westerman R., Winkler A.S., Wubishet B.L., Xu S., Yahyazadeh Jabbari S.H., Yang L., Yaya S., Yazdi-Feyzabadi V., Yazie T.S., Yehualashet S.S., Yeshaneh A., Yeshaw Y., Yirdaw B.W., Yonemoto N., Younis M.Z., Yousefi Z., Yu C., Yunusa I., Zadnik V., Zahir M., Zahirian Moghadam T., Zamani M., Zamanian M., Zandian H., Zare F., Zastrozhin M.S., Zastrozhina A., Zhang J., Zhang Z.-J., Ziapour A., Zoladl M., Murray C.J.L., Fitzmaurice C., Bleyer A., Bhakta N., Real World Studies in PharmacoEpidemiology, -Genetics, -Economics and -Therapy (PEGET), Value, Affordability and Sustainability (VALUE), Microbes in Health and Disease (MHD), NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM), HUS Comprehensive Cancer Center, University of Helsinki, Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities, St. Baldrick's Foundation, NIH - National Cancer Institute (NCI) (Estados Unidos), Epidemiologie, and RS: NUTRIM - R3 - Respiratory & Age-related Health
Subjects: adolescent cancer, global burden of disease, epidemiology, Adult, Male, Adolescent, 3122 Cancers, UNITED-STATES, Disability-Adjusted Life Year, Adolescents, Socioeconomic Factor, Global Health, Global Burden of Disease, Young Adult, Life Expectancy, SDG 3 - Good Health and Well-being, Risk Factors, WORLDWIDE, Neoplasms, Cause of Death, Prevalence, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Mortality, Cancer burden analyses, Cancer, ACUTE LYMPHOBLASTIC-LEUKEMIA, disease, Global burden, OUTCOMES, CHILDHOOD-CANCER, Incidence, Risk Factor, the GBD 2019 methodology, Disability-Adjusted Life Years, GBD 2019 Adolescent Young Adult Cancer Collaborators, CARE, Cancer control efforts, Socioeconomic Factors, Oncology, Neoplasm, Female, Young adults, Human
Abstract: Funding: J A Loureiro acknowledges support from Base Funding UIDB/00511/2020 of the LEPABE funded by national funds through the FCT/MCTES (PIDDAC) and Scientific Employment Stimulus (FCT) [CEECINST/00049/2018]. Background: In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15–39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods: Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15–39 years to define adolescents and young adults. Findings: There were 1·19 million (95% UI 1·11–1·28) incident cancer cases and 396 000 (370 000–425 000) deaths due to cancer among people aged 15–39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59·6 [54·5–65·7] per 100 000 person-years) and high-middle SDI countries (53·2 [48·8–57·9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14·2 [12·9–15·6] per 100 000 person-years) and middle SDI (13·6 [12·6–14·8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23·5 million (21·9–25·2) DALYs to the global burden of disease, of which 2·7% (1·9–3·6) came from YLDs and 97·3% (96·4–98·1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation: Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Funding: Bill & Melinda Gates Foundation, American Lebanese Syrian Associated Charities, St Baldrick's Foundation, and the National Cancer Institute. publishersversion published
Published: 2022

29. Transcription factors NFIA and NFIB induce cellular differentiation in high-grade astrocytoma

Author: Bryan W. Day, Revathi Rajagopal, Jens Bunt, Brett W. Stringer, Kum Thong Wong, Linda J. Richards, Kok-Siong Chen, Jonathan W. C. Lim, Hany Ariffin, Dharmendra Ganesan, Zorana Lynton, and Caitlin Bridges
Subjects: Cancer Research, Neurogenesis, Cellular differentiation, Cell, Apoptosis, Mice, SCID, Biology, Mice, 03 medical and health sciences, Astrocyte differentiation, 0302 clinical medicine, Mice, Inbred NOD, Differentiation therapy, Biomarkers, Tumor, Tumor Cells, Cultured, medicine, Animals, Humans, neoplasms, Transcription factor, 030304 developmental biology, Cell Proliferation, 0303 health sciences, Nuclear factor I, Effector, Astrocytoma, Cell Differentiation, medicine.disease, Xenograft Model Antitumor Assays, nervous system diseases, 3. Good health, Gene Expression Regulation, Neoplastic, NFI Transcription Factors, medicine.anatomical_structure, Neurology, Oncology, NFIB, NFIA, 030220 oncology & carcinogenesis, Cancer research, Neurology (clinical), Neoplasm Grading, Glioblastoma, 030217 neurology & neurosurgery
Abstract: Malignant astrocytomas are composed of heterogeneous cell populations. Compared to grade IV glioblastoma, low-grade astrocytomas have more differentiated cells and are associated with a better prognosis. Therefore, inducing cellular differentiation to alter the behaviour of high-grade astrocytomas may serve as a therapeutic strategy. The nuclear factor one (NFI) transcription factors are essential for normal astrocytic differentiation. Here, we investigate whether family members NFIA and NFIB act as effectors of cellular differentiation in glioblastoma. We analysed expression of NFIA and NFIB in mRNA expression data of high-grade astrocytoma and with immunofluorescence co-staining. Furthermore, we induced NFI expression in patient-derived subcutaneous glioblastoma xenografts via in vivo electroporation. The expression of NFIA and NFIB is reduced in glioblastoma as compared to lower grade astrocytomas. At a cellular level, their expression is associated with differentiated and mature astrocyte-like tumour cells. In vivo analyses consistently demonstrate that expression of either NFIA or NFIB is sufficient to promote tumour cell differentiation in glioblastoma xenografts. Our findings indicate that both NFIA and NFIB may have an endogenous pro-differentiative function in astrocytomas, similar to their role in normal astrocyte differentiation. Overall, our study establishes a basis for further investigation of targeting NFI-mediated differentiation as a potential differentiation therapy.
Published: 2019

30. 911 Immune profiling reveals enrichment of distinct immune signatures in high-risk oral potentially malignant disorders

Author: Joe Poh Sheng Yeong, Hans Prakash Sathasivam, Kue Peng Lim, Shin Hin Lau, Zuraiza Mohamad Zaini, Christian H. Ottensmeier, Sok Ching Cheong, Chai Gan, Bernard Kok Bang Lee, Hany Ariffin, Thomas George Kallarakkal, Natalia Savelyeva, Rosnah Binti Zain, and Gareth J. Thomas
Subjects: Pharmacology, Immune profiling, Cancer Research, Immune system, Oncology, Immunology, Molecular Medicine, Immunology and Allergy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Biology, RC254-282
Abstract: BackgroundPatients with oral potentially malignant disorders (OPMD) having moderate or severe oral epithelial dysplasia (OED) have a greater risk of developing oral squamous cell carcinoma (OSCC) compared to mild OED with an odds ratio of 2.4.1 The involvement of specific immune cell types associated with malignant transformation have been reported, giving rise to clinical trials in immunoprevention. However, the immune landscape of OPMD remains understudied. In this study, we aimed to elucidate the immune landscape of high-risk OPMD by transcriptomic profiling for the identification of potential immunoprevention strategy.MethodsHistological evaluation was performed on hematoxylin and eosin (H&E)-stained tissues to investigate the differences of lymphocyte infiltration in benign lesions (n=16), high-risk OPMD consisted of moderate and severe OED (n=46) and early-stage OSCC (n=6). Formalin-fixed paraffin-embedded tissue sections of selected cases from each sample type were subjected to RNA sequencing. Weighted-gene-correlation network analysis (WGCNA) was used to identify key gene modules expressed in specific disease type.2 The immune landscape of high-risk OPMD was elucidated by the enrichment of immune signatures using single-sample gene set enrichment analysis.3–5 The response of high-risk OPMD to anti-PD1 treatment was predicted by the detection of T-cell-inflamed condition.6 Validation was performed by multiplex immunofluorescent (mIF) staining.ResultsOur H&E evaluation showed that lymphocyte infiltration into the epithelial was seen in 80% of high-risk OPMD and early-stage OSCC, compared to 9% of benign lesion. Gene modules identified from WGCNA analysis revealed that genes involved in immune-related pathways were overexpressed in high-risk OPMD and in early-stage OSCC when compared to benign lesion, but unchanged between high-risk OPMD and early-stage OSCC. We further demonstrated that immune signatures representing lymphocyte infiltration, MHC-I antigen presentation and cytotoxic immune responses were enriched in high-risk OPMD, indicating the presence of immune surveillance. High-risk OPMD can be grouped into the T-cell-inflamed and non-immune reactive subtypes. The T-cell-inflamed subtype is enriched with T cells, interferon signaling and PD-1/PD-L1 immune checkpoint proteins, suggesting that these lesions may be amenable to anti-PD1 treatment. Meanwhile, the non-immune reactive subtype demonstrated low enrichment in signatures for immune cell infiltration, indicating a need of intervention to induce lymphocyte infiltration. Using mIF staining, we observed an increase of CD45+ immune cell population expressing PD-L1 in high-risk OPMD.ConclusionsImmune surveillance is a prominent feature of high-risk OPMD. However, different subsets of high-risk OPMD exist, suggesting a need of different immunoprevention approaches to prevent disease progression which warrants further investigation.AcknowledgementsThis study was supported and funded by the Global Challenge Research Fund by the Medical Research Council, UK (MR/P024351/1) and Cancer Research Malaysia. We thank the Ong Heng Tiang & Ong Sek Pek Foundation for scholarship sponsorship.ReferencesIocca O, Sollecito TP, Alawi F, et al. Potentially malignant disorders of the oral cavity and oral dysplasia: a systematic review and meta-analysis of malignant transformation rate by subtype. Head Neck 2020;42:539–55.Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 2008;9:559.Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102:15545–50.Chen YP, Wang YQ, Lv JW, et al. Identification and validation of novel microenvironment-based immune molecular subgroups of head and neck squamous cell carcinoma: implications for immunotherapy. Ann Oncol 2019;30:68–75.Thorsson V, Gibbs DL, Brown SD, et al. The immune landscape of cancer. Immunity 2018;48:812–30.Ayers M, Lunceford J, Nebozhyn M, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest 2017;127:2930–40.Ethics ApprovalThe use of clinical specimens in this study has been approved by the Medical Ethics Committee, Faculty of Dentistry, University of Malaya [DF OS1624/0073(L)], and The National Medical Research Register, Malaysia [NMRR-16-1764-32566 (IIR)].
Published: 2021

31. ALL-079 Association of T-Cell Receptor Repertoire Diversity With L-Asparaginase Hypersensitivity in Childhood Acute Lymphoblastic Leukemia

Author: Shawn HR Lee, Zhenhua Li, Evelyn HZ Lim, Winnie HN Chin, Chiew Kean Hui, Chen Zhi Wei, Bernice LZ Oh, Ah Moy Tan, Hany Ariffin, Jun J Yang, and Allen EJ Yeoh
Subjects: Cancer Research, Oncology, Hematology
Published: 2022

32. Poster: ALL-079 Association of T-Cell Receptor Repertoire Diversity With L-Asparaginase Hypersensitivity in Childhood Acute Lymphoblastic Leukemia

Author: Shawn HR Lee, Zhenhua Li, Evelyn HZ Lim, Winnie HN Chin, Chiew Kean Hui, Chen Zhi Wei, Bernice LZ Oh, Ah Moy Tan, Hany Ariffin, Jun J Yang, and Allen EJ Yeoh
Subjects: Cancer Research, Oncology, Hematology
Published: 2022

33. Gut microbiota dysbiosis in survivors of childhood acute lymphoblastic leukemia and the association with immune dysregulation and metabolic derangement

Author: P'ng Loke, Hany Ariffin, Yvonne A. L. Lim, Yin Ling Woo, Ling Ling Chua, and Reena Rajasuriar
Subjects: Metabolic derangement, biology, business.industry, Immunology, medicine, Gut flora, Immune dysregulation, biology.organism_classification, medicine.disease, business, medicine.disease_cause, Dysbiosis, Childhood Acute Lymphoblastic Leukemia
Published: 2021

34. p53, stem cell biology and childhood blastomas

Author: Hany Ariffin, Hind Hafsi, Pierre Hainaut, and Lixian Oh
Subjects: Hepatoblastoma, 0301 basic medicine, Cancer Research, business.industry, Retinoblastoma, Cancer, medicine.disease, Wilms Tumor, Embryonic stem cell, Neuroblastoma, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, Cancer research, Animals, Humans, Cytotoxic T cell, Medicine, Tumor Suppressor Protein p53, Child, business, Stem cell biology
Abstract: Childhood blastomas, unlike adult cancers, originate from developing organs in which molecular and cellular features exhibit differentiation arrest and embryonic characteristics. Conventional cancer therapies, which rely on the generalized cytotoxic effect on rapidly dividing cells, may damage delicate organs in young children, leading to multiple late effects. Deep understanding of the biology of embryonal cancers is crucial in reshaping the cancer treatment paradigm for children.p53 plays a major physiological role in embryonic development, by controlling cell proliferation, differentiation and responses to cellular stress. Tumor suppressor function of p53 is commonly lost in adult cancers through genetic alterations. However, both somatic and germline p53 mutations are rare in childhood blastomas, suggesting that in these cancers, p53 may be inactivated through other mechanisms than mutation. In this review, we summarize current knowledge about p53 pathway inactivation in childhood blastomas (specifically neuroblastoma, retinoblastoma and Wilms' tumor) through various upstream mechanisms. Laboratory evidence and clinical trials of targeted therapies specific to exploiting p53 upstream regulators are discussed.Despite the low rate of inherent TP53 mutations, p53 pathway inactivation is a common denominator in childhood blastomas. Exploiting p53 and its regulators is likely to translate into more effective targeted therapies with minimal late effects for children. (see Video Abstract, Supplemental Digital Content 1, http://links.lww.com/COON/A23).
Published: 2019

35. Doing less, accomplishing more for childhood acute lymphoblastic leukaemia (ALL)

Author: Allen Eng Juh Yeoh, Bernice L. Z. Oh, and Hany Ariffin
Subjects: Pediatrics, medicine.medical_specialty, business.industry, Risk Factors, MEDLINE, Medicine, Lymphoblastic leukaemia, Humans, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, business, Child
Published: 2021

36. Challenges in the Management of Childhood Intracranial Germ Cell Tumors in Middle-Income Countries

Author: Nor Faizal Ahmad Bahuri, Revathi Rajagopal, Jen Chun Foo, Sheng Hoay Leong, Raja Rizal Azman, Vida Jawin, Eric Bouffet, Daniel C. Moreira, Jasmin Loh, Dharmendra Ganesan, Kein-Seong Mun, Hany Ariffin, Nicholas G. Gottardo, and Tsiao Yi Yap
Subjects: Male, Pediatrics, medicine.medical_specialty, Time Factors, Adolescent, medicine.medical_treatment, Quality of life, Antineoplastic Combined Chemotherapy Protocols, Humans, Medicine, Child, Developing Countries, Survival rate, Retrospective Studies, Chemotherapy, Germinoma, Brain Neoplasms, business.industry, Incidence (epidemiology), Malaysia, Disease Management, Hematology, Neoplasms, Germ Cell and Embryonal, Prognosis, medicine.disease, Combined Modality Therapy, Survival Rate, Oncology, Child, Preschool, Pediatrics, Perinatology and Child Health, Quality of Life, Vomiting, Female, Germ cell tumors, Neoplasm Recurrence, Local, medicine.symptom, business, Developed country, Follow-Up Studies
Abstract: Background A higher incidence of pediatric intracranial germ cell tumors (iGCTs) in Asian countries compared with Western countries has been reported. In Malaysia, the literature regarding pediatric iGCTs have been nonexistent. The aim of this study was to review the management, survival, and long-term outcomes of pediatric iGCTs at a single tertiary center in Malaysia. Patients and methods We retrospectively reviewed data from patients aged below 18 years with iGCTs treated at the University Malaya Medical Center (UMMC) from 1998 to 2017. Results Thirty-four patients were identified, with a median follow-up of 3.54 years. Sixteen (47%) patients had pure germinoma tumors (PGs), and the remaining patients had nongerminomatous germ cell tumors (NGGCTs). The median age was 12 years, with a male:female ratio of 4.7:1. Abnormal vision, headache with vomiting, and diabetes insipidus were the commonest presenting symptoms. Twenty-eight patients received initial surgical interventions, 24 were treated with chemotherapy, and 28 received radiotherapy. Eight patients experienced relapses. The 5- and 10-year event-free survival rates were similar at 61.1%±12.6% and 42.9%±12.1% for PG and NGGCT, respectively. The 5- and 10-year overall survival rates were the same at 75.5%±10.8% and 53.3%±12.3% for PG and NGGCT, respectively. Four patients died of treatment-related toxicity. Most of the survivors experienced good quality of life with satisfactory neurological status. Conclusions The survival rate of childhood iGCTs in UMMC was inferior to that reported in developed countries. Late diagnosis, poor adherence to treatment, and treatment-related complications were the contributing factors. Although these results highlight a single institution experience, they most likely reflect similar treatment patterns, outcomes, and challenges in other centers in Malaysia.
Published: 2021

37. Three-Year Follow-up of 2-Dose Versus 3-Dose HPV Vaccine

Author: Eli Engel, Richard Tytus, Katrina M. Nolan, Simon Dobson, Shelly Senders, Daron G. Ferris, Zafer Kurugöl, Oliver Bautista, Sandhya Sankaranarayanan, Javier Díez-Domingo, Alain Luxembourg, Li-Min Huang, Punnee Pitisuttithum, Surita Roux, Alfred J. Saah, Richard E. Rupp, Andrea Schilling, Lone Kjeld Petersen, Young Tae Kim, Jacob Bornstein, Yae Jean Kim, Hany Ariffin, and Ege Üniversitesi
Subjects: Adult, Male, medicine.medical_specialty, Adolescent, Dose-Response Relationship, Immunologic, Human Papilloma Virus Vaccine, Alphapapillomavirus, Antibodies, Viral, Young Adult, 03 medical and health sciences, 0302 clinical medicine, 030225 pediatrics, Internal medicine, medicine, Humans, Papillomavirus Vaccines, Human papillomavirus, Child, medicine.diagnostic_test, biology, business.industry, Immunogenicity, Vaccination, Titer, Regimen, [No Keyword], Immunoassay, Pediatrics, Perinatology and Child Health, biology.protein, Female, Antibody, business, Biomarkers, Follow-Up Studies
Abstract: BACKGROUND AND OBJECTIVES: Human papillomavirus (HPV) antibody responses to the 9-valent human papillomavirus (9vHPV) vaccine among girls and boys (aged 9-14 years) receiving 2-dose regimens (months 0, 6 or 0, 12) were noninferior to a 3-dose regimen (months 0, 2, 6) in young women (aged 16-26 years) 4 weeks after last vaccination in an international, randomized, open-label trial (NCT01984697). We assessed response durability through month 36. METHODS: Girls received 2 (months 0 and 6 [0, 6]: n = 301; months 0 and 12 [0, 12]: n = 151) or 3 doses (months 0,2, and 6 [0, 2, 6]: n = 301); boys received 2 doses ([0, 6]: n = 301; [0, 12]: n = 150); and young women received 3 doses ([0, 2, 6]: n = 314) of 9vHPV vaccine. Anti-HPV geometric mean titers (GMTs) were assessed by competitive Luminex immunoassay (cLIA) and immunoglobulin G-Luminex immunoassay (IgG-LIA) through month 36. RESULTS: Anti-HPV GMTs were highest 1 month after the last 9vHPV vaccine regimen dose, decreased sharply during the subsequent 12 months, and then decreased more slowly. GMTs 2 to 2.5 years after the last regimen dose in girls and boys given 2 doses were generally similar to or greater than GMTs in young women given 3 doses. Across HPV types, most boys and girls who received 2 doses (cLIA: 81%-100%; IgG-LIA: 91%-100%) and young women who received 3 doses (cLIA: 78%-98%; IgG-LIA: 91%-100%) remained seropositive 2 to 2.5 years after the last regimen dose. CONCLUSIONS: Antibody responses persisted through 2 to 2.5 years after the last dose of a 2-dose 9vHPV vaccine regimen in girls and boys. in girls and boys, antibody responses generated by 2 doses administered 6 to 12 months apart may be sufficient to induce high-level protective efficacy through at least 2 years after the second dose., Merck Sharp Dohme CorpMerck & Company, Funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc, Kenilworth, NJ.
Published: 2021

38. Inherited Pediatric Cancer in Low- and Intermediate-Resource Countries

Author: Hany Ariffin, Pierre Hainaut, Patrícia Ashton Prolla, and Maria Isabel Achatz
Subjects: education.field_of_study, medicine.diagnostic_test, business.industry, Population, Cancer, Developing country, medicine.disease, Pediatric cancer, Germline mutation, medicine, Family history, education, business, Socioeconomic status, Demography, Genetic testing
Abstract: Childhood cancer statistics are scarce and incomplete in most emerging and low-income countries (ELIC), in which up to 75% of the cases may arise. In many low-resource contexts, lack of awareness, scarce diagnostic resources, and poor access to care are serious barriers to the recognition of inherited pediatric cancer. Family history is rarely investigated in a systematic way, and genetic testing is usually limited or absent in most ELIC. Therefore, the burden of inherited childhood cancer in low-resource countries is poorly known and is most likely underestimated. Available data reveal important differences in the clinical patterns of inherited childhood cancer between high- and low-income regions. These differences are largely explained by biases in detection, diagnosis, reporting, and management due to constrained socioeconomic resources. Only a small number of national cancer institutions in ELIC have formulated coordinated programs toward inherited childhood cancer. In this chapter, we describe leading initiatives in two intermediate-resource countries representative of large populations in transitions: Malaysia and Brazil. We also discuss the identification in defined population groups of germline mutations due to founder effects, which can lead to large clusters of inherited childhood cancers. Finally, we provide a brief overview of the patterns of retinoblastoma and nephroblastoma in the low-income settings of sub-Saharan Africa, and we discuss the plausible contribution of germline mutations to cancer burden in these areas.
Published: 2021

39. Association of Genetic Ancestry With the Molecular Subtypes and Prognosis of Childhood Acute Lymphoblastic Leukemia

Author: Shawn H. R. Lee, Federico Antillon-Klussmann, Deqing Pei, Wenjian Yang, Kathryn G. Roberts, Zhenhua Li, Meenakshi Devidas, Wentao Yang, Cesar Najera, Hai Peng Lin, Ah Moy Tan, Hany Ariffin, Cheng Cheng, William E. Evans, Stephen P. Hunger, Sima Jeha, Charles G. Mullighan, Mignon L. Loh, Allen E. J. Yeoh, Ching-Hon Pui, and Jun J. Yang
Subjects: Male, Cancer Research, Adolescent, Racial Groups, Correction, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, United States, Asian People, Oncology, Ethnicity, Humans, Child, Original Investigation
Abstract: IMPORTANCE: Racial and ethnic disparities persist in the incidence and treatment outcomes of childhood acute lymphoblastic leukemia (ALL). However, there is a paucity of data describing the genetic basis of these disparities, especially in association with modern ALL molecular taxonomy and in the context of contemporary treatment regimens. OBJECTIVE: To evaluate the association of genetic ancestry with childhood ALL molecular subtypes and outcomes of modern ALL therapy. DESIGN, SETTING, AND PARTICIPANTS: This multinational, multicenter genetic association study was conducted from March 1, 2000, to November 20, 2020, among 2428 children and adolescents with ALL enrolled in frontline trials from the United States, South East Asia (Singapore and Malaysia), and Latin America (Guatemala), representing diverse populations of European, African, Native American, East Asian, and South Asian descent. Statistical analysis was conducted from February 3, 2020, to April 19, 2021. MAIN OUTCOMES AND MEASURES: Molecular subtypes of ALL and genetic ancestry were comprehensively characterized by performing RNA sequencing. Associations of genetic ancestries with ALL molecular subtypes and treatment outcomes were then evaluated. RESULTS: Among the participants in the study, 1340 of 2318 (57.8%) were male, and the mean (SD) age was 7.8 (5.3) years. Of 21 ALL subtypes identified, 8 were associated with ancestry. East Asian ancestry was positively associated with the frequency of somatic DUX4 (odds ratio [OR], 1.30 [95% CI, 1.16-1.45]; P
Published: 2022

40. Retinal vessel analysis as a novel screening tool to identify childhood acute lymphoblastic leukemia survivors at risk of cardiovascular disease

Author: Sudhashini Chandrasekaran, Tom MacGillivray, Rosli Es, Ling Ling Chua, Mohamad Shafiq Azanan, Hany Ariffin, Lixian Oh, Tong Foh Chin, Tengku Ain Kamalden, Revathi Rajagopal, Norlina Ramli, Reena Rajasuriar, Tsiao Yi Yap, and Emanuele Trucco
Subjects: Adult, Male, Oncology, Central retinal artery, medicine.medical_specialty, Adolescent, Childhood leukemia, Disease, Endothelial activation, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, medicine.artery, Internal medicine, Humans, Mass Screening, Medicine, Screening tool, Survivors, Endothelial dysfunction, Childhood Acute Lymphoblastic Leukemia, Framingham Risk Score, business.industry, Retinal Vessels, Retinal, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Prognosis, medicine.disease, Retinal vessel, chemistry, Cardiovascular Diseases, Case-Control Studies, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Arterial stiffness, Cardiology, Female, business, Follow-Up Studies, 030215 immunology
Abstract: BACKGROUND Microvascular endothelial dysfunction is central to the pathogenesis of cardiovascular disease (CVD). The eye offers direct access for endothelial health assessment via the retinal microvasculature. The aim of the study was to investigate whether image-based retinal vessel analysis is a feasible method of assessing endothelial health in survivors of childhood acute lymphoblastic leukemia (cALL). MATERIALS AND METHODS Cardiovascular risk factors (CRFs) were estimated using the 30-year Framingham Risk Score in 73 childhood leukemia survivors (median age: 25; median years from diagnosis: 19) and 78 healthy controls (median age: 23). Radial arterial stiffness was measured using pulse wave analyzer, while endothelial activation markers were measured by soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). Retinal fundus images were analyzed for central retinal artery/vein equivalents (CRAE/CRVE) and arteriolar-venular ratio (AVR). RESULTS cALL survivors had higher CRF (P
Published: 2020

41. Pediatric Solid Tumor Care and Multidisciplinary Tumor Boards in Low- and Middle-Income Countries in Southeast Asia

Author: Amos Hong Pheng Loh, Hany Ariffin, Mohd Yusran Othman, Catherine G. Lam, Chatchawin Assanasen, Shui Yen Soh, Shireen Anne Nah, Sally Blair, and Anette Sundfor Jacobsen
Subjects: Cancer Research, medicine.medical_specialty, education, MEDLINE, Medical Oncology, Southeast asia, 03 medical and health sciences, 0302 clinical medicine, Multidisciplinary approach, 030225 pediatrics, Neoplasms, Medicine, Humans, Child, Developing Countries, Asia, Southeastern, Specialist care, Oncologists, business.industry, Pediatric Solid Tumor, ORIGINAL REPORTS, Oncology, Low and middle income countries, Pediatric Oncology, 030220 oncology & carcinogenesis, Family medicine, business
Abstract: PURPOSEPediatric solid tumors require coordinated multidisciplinary specialist care. However, expertise and resources to conduct multidisciplinary tumor boards (MDTBs) are lacking in low- and middle-income countries (LMICs). We aimed to profile the landscape of pediatric solid tumor care and practices and perceptions on MDTBs among pediatric solid tumor units (PSTUs) in Southeast Asian LMICs.METHODSUsing online surveys, availability of specialty manpower and MDTBs among PSTUs was first determined. From the subset of PSTUs with MDTBs, one pediatric surgeon and one pediatric oncologist from each center were queried using 5-point Likert scale questions adapted from published questionnaires.RESULTSIn 37 (80.4%) of 46 identified PSTUs, availability of pediatric-trained specialists was as follows: oncologists, 94.6%; surgeons, 91.9%; radiologists, 54.1%; pathologists, 40.5%; radiation oncologists, 29.7%; nuclear medicine physicians, 13.5%; and nurses, 81.1%. Availability of pediatric-trained surgeons, radiologists, and pathologists was significantly associated with the existence of MDTBs ( P = .037, .005, and .022, respectively). Among 43 (89.6%) of 48 respondents from 24 PSTUs with MDTBs, 90.5% of oncologists reported > 50% oncology-dedicated workload versus 22.7% of surgeons. Views on benefits and barriers did not significantly differ between oncologists and surgeons. The majority agreed that MDTBs helped to improve accuracy of treatment recommendations and team competence. Complex cases, insufficient radiology and pathology preparation, and need for supplementary investigations were the top barriers.CONCLUSIONThis first known profile of pediatric solid tumor care in Southeast Asia found that availability of pediatric-trained subspecialists was a significant prerequisite for pediatric MDTBs in this region. Most PSTUs lacked pediatric-trained pathologists and radiologists. Correspondingly, gaps in radiographic and pathologic diagnoses were the most common limitations for MDTBs. Greater emphasis on holistic multidisciplinary subspecialty development is needed to advance pediatric solid tumor care in Southeast Asia.
Published: 2020

42. Flash survey on severe acute respiratory syndrome coronavirus-2 infections in paediatric patients on anticancer treatment

Author: Triantafyllia Brozou, Jelena Lazic, Gabor G. Kovacs, Maria E.V. Alonso, Chi Kong Li, Gábor Ottóffy, Ondrej Hrusak, Pernilla Grillner, Adriana Balduzzi, Tomas Kalina, Sarah Elitzur, Joshua Wolf, Massimo Provenzi, Hany Ariffin, Ajay Vora, Jan Stary, Barbara Buldini, Nerea Domínguez-Pinilla, Karin Mellgren, Allen Eng Juh Yeoh, Valentino Conter, Rob Pieters, Jutte van der Werff ten Bosch, Luciano Dalla-Pozza, Jean-Pierre Bourquin, Martin Schrappe, Martin Stanulla, Owen P. Smith, Kjeld Schmiegelow, Roula Farah, Susana Rives, Andishe Attarbaschi, Carmelo Rizzari, Maria S. Felice, Atsushi Manabe, Gabriele Escherich, A Kolenova, María del Pozo Carlavilla, Melchior Lauten, Jan Styczyński, Arndt Borkhardt, Clinical sciences, Growth and Development, Pediatrics, Hrusak, O, Kalina, T, Wolf, J, Balduzzi, A, Provenzi, M, Rizzari, C, Rives, S, del Pozo Carlavilla, M, Alonso, M, Dominguez-Pinilla, N, Bourquin, J, Schmiegelow, K, Attarbaschi, A, Grillner, P, Mellgren, K, van der Werff ten Bosch, J, Pieters, R, Brozou, T, Borkhardt, A, Escherich, G, Lauten, M, Stanulla, M, Smith, O, Yeoh, A, Elitzur, S, Vora, A, Li, C, Ariffin, H, Kolenova, A, Dallapozza, L, Farah, R, Lazic, J, Manabe, A, Styczynski, J, Kovacs, G, Ottoffy, G, Felice, M, Buldini, B, Conter, V, Stary, J, and Schrappe, M
Subjects: 0301 basic medicine, Male, Cancer Research, Pediatrics, medicine.medical_specialty, Adolescent, Pneumonia, Viral, Anticancer chemotherapy, Antineoplastic Agents, Disease, Asymptomatic, 03 medical and health sciences, Betacoronavirus, 0302 clinical medicine, Children, Diabetes mellitus, Neoplasms, Surveys and Questionnaires, medicine, Humans, Viral, Pediatrics, Perinatology, and Child Health, Young adult, Child, Pandemics, immunosuppression, SARS-CoV-2, business.industry, Incidence (epidemiology), COVID-19, Pneumonia, medicine.disease, Obesity, COVID-19 Drug Treatment, 030104 developmental biology, Oncology, El Niño, 030220 oncology & carcinogenesis, Female, Immunosuppression, Coronavirus Infections, medicine.symptom, business
Abstract: INTRODUCTION: Since the beginning of COVID-19 pandemic, it is known that the severe course of the disease occurs mostly among the elderly, whereas it is rare among children and young adults. Comorbidities, in particular, diabetes and hypertension, clearly associated with age, besides obesity and smoke, are strongly associated with the need for intensive treatment and a dismal outcome. A weaker immunity of the elderly has been proposed as a possible explanation of this uneven age distribution. Thus, there is concern that children treated for cancer may allso be at risk for an unfavourable course of infection. Along the same line, anecdotal information from Wuhan, China, mentioned a severe course of COVID-19 in a child treated for leukaemia. AIM AND METHODS: We made a flash survey on COVID-19 incidence and severity among children on anticancer treatment. Respondents were asked by email to fill in a short Web-based survey. RESULTS: We received reports from 25 countries, where approximately 10,000 patients at risk are followed up. At the time of the survey, more than 200 of these children were tested, nine of whom were positive for COVID-19. Eight of the nine cases had asymptomatic to mild disease, and one was just diagnosed with COVID-19. We also discuss preventive measures that are in place or should be taken and treatment options in immunocompromised children with COVID-19. CONCLUSION: Thus, even children receiving anticancer chemotherapy may have a mild or asymptomatic course of COVID-19. While we should not underestimate the risk of developing a more severe course of COVID-19 than that observed here, the intensity of preventive measures should not cause delays or obstructions in oncological treatment.
Published: 2020

43. Observational study on the current status of thalassaemia in Malaysia: a report from the Malaysian Thalassaemia Registry

Author: Ida Shahnaz Othman, Hany Ariffin, Kogilavani Gunasagaran, Che Hadibiah Che Mohd Razali, Seoh Leng Yeoh, Hamidah Alias, Aisyah Muhammad Rivai, Zulaiha Muda, Hishamshah Ibrahim, Asohan Thevarajah, Nazzlin Dizana Din, Rahman Jamal, Mohamed Najib Mohamed Unni, Gek Bee Ong, Kok Hoi Teh, Zarina Abdul Latiff, and Norsarwany Mohamad
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, thalassaemia, Ethnic group, lcsh:Medicine, Disease, registry, Young Adult, hemic and lymphatic diseases, Health care, parasitic diseases, haemoglobinopathy, Humans, Medicine, Blood Transfusion, In patient, Registries, Child, database, Malay, Cause of death, healthcare burden, business.industry, lcsh:R, Malaysia, Age Factors, Infant, General Medicine, Middle Aged, Chelation Therapy, language.human_language, Blood Disorder, Child, Preschool, Ferritins, language, Thalassemia, Female, Observational study, Public Health, business
Abstract: ObjectiveThalassaemia is the most common inherited blood disorder in Malaysia. This study aims to report the current status of thalassaemia in Malaysia and provide a comprehensive understanding of the disease through data obtained from the Malaysian Thalassaemia Registry.DesignData were extracted from the Malaysian Thalassaemia Registry, a web-based system accessible to enrolled users through www.mytalasemia.net.my.SettingThe Malaysian Thalassaemia Registry data was recorded from reports obtained from 110 participating government and university hospitals in Malaysia.ParticipantsThe patients were those attending the 110 participating hospitals for thalassaemia treatment.InterventionData were collected from the Malaysian Thalassaemia Registry from 2007 until the fourth quarter of 2018.Primary outcome measure7984 out of 8681 patients with thalassaemia registered in the Malaysian Thalassaemia Registry were reported alive.ResultsMajority of the patients were reported in the state of Sabah (22.72%); the largest age group affected was 5.0–24.9 years old (64.45%); the largest ethnic group involved was Malay (63.95%); and the major diagnosis was haemoglobin E/β-thalassaemia (34.37%). From the 7984 patients, 56.73% were on regular blood transfusions and 61.72% were on chelation therapy. A small fraction (14.23%) has undergone splenectomy, while the percentage of patients with severe iron overload (serum ferritin ≥5000 µg/L) reduced over time. However, cardiac complications are still the main cause of death in patients with thalassaemia.ConclusionData gathered into the registry can be used to understand the progression of the disorder, to monitor iron overload management and to improve the outcomes of treatment, to enhance preventive strategies, reduce healthcare burden and improve the quality of life. Sustainability of the Malaysian Thalassaemia Registry is important for surveillance of thalassaemia management in the country and help the national health authorities to develop more effective policies.
Published: 2020

44. PROFILE OF PEDIATRIC SOLID TUMOR CARE AND MULTIDISCIPLINARY TUMOR BOARDS IN SOUTHEAST ASIA

Author: Shireen Anne Nah, Amos Hong Pheng Loh, Hany Ariffin, Mohd Yusran Othman, Chatchawin Assanasen, Sally Blair, Shui Yen Soh, Anette Sundfor Jacobsen, and Catherine G. Lam
Subjects: medicine.medical_specialty, business.industry, education, Specialty, Pediatric Oncologist, Workload, Pediatric Surgeon, Southeast asian, Subspecialty, Competence (law), Multidisciplinary approach, Family medicine, medicine, business
Abstract: Background Pediatric solid tumors require coordinated multidisciplinary specialist care. However, expertise and resources to conduct multidisciplinary tumor board (MDTB) meetings are lacking in low- and middle-income countries (LMICs). We aimed to profile practices and perceptions on MDTBs among pediatric solid tumor units (PSTUs) in Southeast Asian LMIC countries. Methods Using online survey forms, availability of specialty manpower and MDTBs among PSTUs was first determined. From the subset of PSTUs with MDTBs, 1 pediatric surgeon and 1 pediatric oncologist from each center were queried using 5-point Likert scale questions adapted from published questionnaires. Results In 37/46 (80.4%) identified PSTUs, pediatric-trained oncologists, surgeons, radiologists, pathologists, radiation oncologists, nuclear medicine physicians and nurses were available in 94.6%, 91.9%, 54.1%, 40.5%, 29.7%, 13.5% and 81.1% of PSTUs, respectively. Availability of pediatric-trained surgeons, radiologists and pathologists were significantly associated with existence of MDTBs (p=0.037, 0.005, 0.022 respectively). Among 43/48 (89.6%) respondents from 24 PSTUs with MDTBs, 90.5% of oncologists reported >50% oncology-dedicated workload versus 22.7% of surgeons. Views on benefits and barriers did not significantly differ between both groups. Majority agreed MDTBs helped improve accuracy of treatment recommendations and team competence. Complex cases, insufficient radiology and pathology preparation, and need for supplementary investigations, were the top barriers. Conclusions Availability of pediatric-trained subspecialists was a significant prerequisite for pediatric MDTBs. Most PSTUs lacked pediatric-trained pathologists and radiologists. Correspondingly, gaps in radiographic and pathological diagnoses were the commonest limitations. Greater emphasis on holistic multidisciplinary subspecialty development is needed to advance pediatric solid tumor care in Southeast Asia.
Published: 2020

45. T-cell-replete haploidentical bone marrow transplantation for X-linked severe combined immunodeficiency

Author: Vida Jawin, Hany Ariffin, Kee Seang Chew, and Surendran Thavagnanam
Subjects: Bone marrow transplantation, business.industry, T cell replete, Immunology, medicine, General Medicine, X-linked severe combined immunodeficiency, medicine.disease, business, Letter to the Editor
Published: 2020

46. Expression of p53 N-terminal isoforms in B-cell precursor acute lymphoblastic leukemia and its correlation with clinicopathological profiles

Author: Hany Ariffin, Lixian Oh, Sandrine Blanchet, Pierre Hainaut, Faculty of Medicine, University of Malaya [Kuala Lumpur, Malaisie], University of Malaya [Kuala Lumpur, Malaisie], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), This work was supported by the University Malaya Research Grant (UMRG) (RP049B-17HTM) in University Malaya, Malaysia and by INCa Grant PLBIO16–271 ‘p53 Metabolism’ at IAB Grenoble, France., Bodescot, Myriam, University of Malaya = Universiti Malaya [Kuala Lumpur, Malaisie] (UM), and Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)
Subjects: 0301 basic medicine, Gene isoform, Protein isoform, Male, Cancer Research, Oncogene Proteins, Fusion, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:RC254-282, p53 tumour suppressor protein, 03 medical and health sciences, Childhood ALL, 0302 clinical medicine, Western blot, [SDV.CAN] Life Sciences [q-bio]/Cancer, Recurrence, Cell Line, Tumor, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, Genetics, medicine, Biomarkers, Tumor, Humans, Protein Interaction Domains and Motifs, RNA, Messenger, Gene, Protein isoforms, B cell, Messenger RNA, Mutation, medicine.diagnostic_test, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Molecular biology, Gene Expression Regulation, Neoplastic, 030104 developmental biology, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Female, Bone marrow, Protein Multimerization, Tumor Suppressor Protein p53, Research Article
Abstract: BackgroundTP53mutations occur in only about 3% of primary and 10–20% of relapse B-cell precursor acute lymphoblastic leukaemia (BCP-ALL). However, alternative mechanisms may contribute to functionally impairing the p53 pathway in the absence of a mutation. Candidate mechanisms include overexpression of p53 mRNA variants encoding either dominant-negative p53 protein isoforms such as Delta40p53 and Delta133p53, or modulatory isoforms such as p53beta, which counteract the effects of Delta133p53 on replicative senescence in T-lymphocytes.MethodsWe used semi-quantitative reverse-transcriptase PCR (RT-PCR) and Western blot to investigate the expression of full length p53 (TAp53), Delta40p53, Delta133p53 or p53beta in diagnostic marrow from a clinical cohort of 50 BCP-ALL patients withoutTP53mutation (29 males and 21 females, age range 2–14 years) and in the bone marrow cells of 4 healthy donors (used as controls).ResultsIrrespective of isoforms, levels of p53 mRNA were low in controls but were increased by 2 to 20-fold in primary or relapse BCP-ALL. TAp53 was increased in primary BCP-ALL, Delta40p53 was elevated in relapse BCP-ALL, whereas Delta133p53 and p53beta were increased in both. Next, mRNA levels were used as a basis to infer the ratio between protein isoform levels. This inference suggested that, in primary BCP-ALL, p53 was predominantly in active oligomeric conformations dominated by TAp53. In contrast, p53 mostly existed in inactive quaternary conformations containing ≥2 Delta40 or Delta133p53 in relapse BCP-ALL. Western blot analysis of blasts from BCP-ALL showed a complex pattern of N-terminally truncated p53 isoforms, whereas TAp53beta was detected as a major isoform. The hypothesis that p53 is in an active form in primary B-ALL was consistent with elevated level of p53 target genesCDKN1AandMDM2in primary cases, whereas in relapse BCP-ALL, onlyCDKN1Awas increased as compared to controls.ConclusionExpression of p53 isoforms is deregulated in BCP-ALL in the absence ofTP53mutation, with increased expression of alternative isoforms in relapse BCP-ALL. Variations in isoform expression may contribute to functional deregulation of the p53 pathway in BCP-ALL, specifically contributing to its down-regulation in relapse forms.
Published: 2020

47. RAS activation via CRLF2 signaling is a widespread mechanism in Down syndrome acute lymphoblastic leukemia regardless of RAS mutations

Author: Jürgen Groet, Hany Ariffin, Shirley Kow-Yin Kham, Wee Joo Chng, Zhenhua Li, David Koschut, Allen Eng Juh Yeoh, Emanuela Giarin, Debleena Ray, David M. Weinstock, Giuseppe Basso, Dean Nižetić, and Ivan Alić
Subjects: PTPN11, Mutation, Down syndrome, Chemistry, Mechanism (biology), Lymphoblastic Leukemia, RAS Mutation, medicine, Cancer research, medicine.disease_cause, Ligand (biochemistry), medicine.disease, PI3K/AKT/mTOR pathway
Abstract: BackgroundDown syndrome acute lymphoblastic leukemia (DS-ALL) is characterized by the high frequency of CRLF2-rearrangements, JAK2-mutations, or RAS-pathway mutations. Intriguingly, JAK2 and RAS mutations are mutually exclusive in leukemic sub-clones, causing dichotomy in therapeutic target choices.ResultsHere we show that in primary leukemic cells from DS-ALL, in the absence of RAS-mutations, wild-type (wt)RAS is active, and/or can be induced by the physiological ligand TSLP of the transmembrane-receptor CRLF2. We show active/inducible RAS in 14/20 (70%) of primary DS-ALL samples analyzed, 8 of which had no RAS-mutations, but 75% of those had either mutated or hyperphosphorylated JAK2. No wtRAS cases with mutated/hyperphosphorylated JAK2 were observed that lacked activated RAS protein. We prove in a cell model that elevated CRLF2 in combination with constitutionally active JAK2 is sufficient to activate wtRAS. We show that TSLP boosts the direct binding of active PTPN11 to wtRAS. Pre-inhibition of RAS or PTPN11, but not of PI3K or JAK signaling, prevented TSLP-induced RAS-GTP boost.Using multivariate-clustering based on RAS-activity/inducibility we show significant separation between standard-risk and high-risk DS-ALL groups. Cox proportional-hazards model showed protein-activity (but not mutation status) as independently predictive of outcome.ConclusionsOur data indicate that RAS protein activity levels (and not JAK2/RAS mutation profiles), are predictive of outcome. Importantly, our data suggest that inhibition of RAS and direct RAS-pathway components should be combined with PI3K/mTOR and/or JAK2 inhibitors for high-risk cases. Therapeutically this is relevant for >75% of DS-ALL and our additional data suggest that it warrants further investigation in high-risk non-DS-ALL.
Published: 2020

48. Abstract PO-156: The impact of genetic ancestry on the biology and prognosis of childhood acute lymphoblastic leukemia

Author: Shawn Lee, Federico Antillon, Deqing Pei, Wenjian Yang, Kathryn G Roberts, Zhenhua Li, Meenakshi Devidas, Wentao Yang, Cesar Najera, Hai Peng Lin, Ah Moy Tan, Hany Ariffin, Cheng Cheng, William E. Evans, Stephen P. Hunger, Sima Jeha, Charles G. Mullighan, Mignon L. Loh, Allen EJ Yeoh, Ching-Hon Pui, and Jun J. Yang
Subjects: Oncology, Epidemiology
Abstract: BACKGROUND: Although cure rates of childhood acute lymphoblastic leukemia (ALL) have improved significantly with risk-adapted therapy, stark racial disparities persist in both the incidence and treatment outcomes of ALL. There is a paucity of data describing the genetic basis of these disparities, especially in relation to modern ALL molecular taxonomy and in the context of contemporary treatment regimens. AIMS: To determine the associations of genetic ancestry with ALL biology, and the relevance of genetic ancestry to survival outcomes of modern ALL therapy. Methods: This was a multi-national genomic study of 2,428 children with ALL on front-line trials from United States, Singapore, Malaysia, and Guatemala, representing diverse populations of European, African, Native American, East Asian, and South Asian descent. We performed RNA-sequencing to characterize ALL molecular subtype and genetic ancestry, and then evaluated associations of genetic ancestries with ALL biology and treatment outcomes. Results: Of 21 ALL subtypes, 11 showed significant associations with ancestry. The frequency of somatic DUX4 gene rearrangement was positively correlated with both East Asian and South Asian ancestries; and genomic alterations in ZNF384 and PAX5 increased with East Asian ancestry. By contrast, occurrence of CRLF2 rearrangements was linked to Native American ancestry. ETV6-RUNX1 fusion became less frequent as Native American ancestry increased, with the opposite observed for ETV6-RUNX1-like ALL. There was a marked preponderance of T-ALL in children of African descent. African ancestry was also positively correlated with the prevalence of TCF3-PBX1 and MEF2D fusions. Survival outcomes differed significantly by genetic ancestry, where African and Native American ancestries were both associated with poorer event-free survival (African: HR, 2.3; 95% CI, 1.4 – 3.8; P=0.001; Native American: HR, 2.5; 95% CI, 1·0 – 5.9; P=0.044) and overall survival (African: HR, 2·4; 95% CI, 1.2 – 4.7; P=0.012 for African; Native American: HR, 3.3; 95% CI, 1.1 – 10.0; P=0.033). Importantly, even after adjusting for biological subtypes and clinical features, Native American and African ancestries remained independently associated with poor prognosis. Conclusions: ALL biology and prognosis are highly associated with genetic ancestry, pointing to a genetic basis for racial disparities in ALL. Biology-driven treatment individualization is needed to eliminate racial gaps in outcomes. Citation Format: Shawn Lee, Federico Antillon, Deqing Pei, Wenjian Yang, Kathryn G Roberts, Zhenhua Li, Meenakshi Devidas, Wentao Yang, Cesar Najera, Hai Peng Lin, Ah Moy Tan, Hany Ariffin, Cheng Cheng, William E. Evans, Stephen P. Hunger, Sima Jeha, Charles G. Mullighan, Mignon L. Loh, Allen EJ Yeoh, Ching-Hon Pui, Jun J. Yang. The impact of genetic ancestry on the biology and prognosis of childhood acute lymphoblastic leukemia [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-156.
Published: 2022

49. Focal Segmental Membranoproliferative Glomerulonephritis: A Histological Variant of Denys-Drash Syndrome

Author: Y C Yap, Hany Ariffin, F. Abd Ghani, M Appadurai, Lixian Oh, M Fazarina, and A B Karmila
Subjects: 0301 basic medicine, Male, Denys–Drash syndrome, Pathology, medicine.medical_specialty, Genes, Wilms Tumor, Nephrotic Syndrome, Glomerulonephritis, Membranoproliferative, 030105 genetics & heredity, Wilms Tumor, Pathology and Forensic Medicine, Nephropathy, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Membranoproliferative glomerulonephritis, medicine, Humans, Pseudohermaphroditism, WT1 Proteins, 030219 obstetrics & reproductive medicine, business.industry, Wilms' tumor, General Medicine, medicine.disease, Denys-Drash Syndrome, Optimal management, Child, Preschool, Pediatrics, Perinatology and Child Health, Mutation, Kidney Diseases, Abnormality, business
Abstract: Introduction: Denys-Drash Syndrome (DDS) consists of a triad of pseudohermaphroditism, Wilms'tumor and nephropathy. This condition may manifest as a complete triad or in an incomplete form; with either one or a combination of the above features. The characteristic glomerular abnormality in DDS is diffuse mesangial sclerosis (DMS).Case report: We report two cases of DDS with focal membranoproliferative glomerulonephritis (MPGN). Both of our cases were males with ambiguous genitalia. They had a similar heterozygous germline mutation in exon 9 of WT1, c.1180C>T, p.R394W; a known mutation hotspot for DDS. Case 1 had nephropathy at the age of 4 years and Case 2 at 2.5 years with different rates of progression to end-stage renal failure. Conclusion: Our findings, in combination with other reports, illustrate the clinicopathological heterogeneity of DDS. There are no universal recommendations for optimal management of patients with DDS due to the inability to accurately predict affected individuals' progress.
Published: 2019

50. Effective Response Metric: a novel tool to predict relapse in childhood acute lymphoblastic leukaemia using time-series gene expression profiling

Author: Hany Ariffin, Limsoon Wong, Yi Lu, Allen Eng Juh Yeoh, Hai Peng Lin, Difeng Dong, Nan Jiang, Thuan Chong Quah, Ah Moy Tan, Jan Trka, and Zhenhua Li
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Risk Assessment, Disease-Free Survival, 03 medical and health sciences, 0302 clinical medicine, Predictive Value of Tests, Recurrence, Internal medicine, medicine, Humans, Cumulative incidence, Child, Gene Expression Regulation, Leukemic, business.industry, Gene Expression Profiling, Hazard ratio, Infant, Cancer, Hematology, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Minimal residual disease, Confidence interval, Survival Rate, Gene expression profiling, 030104 developmental biology, medicine.anatomical_structure, Child, Preschool, 030220 oncology & carcinogenesis, Female, Bone marrow, Metric (unit), business
Abstract: Accurate risk assignment in childhood acute lymphoblastic leukaemia is essential to avoid under- or over-treatment. We hypothesized that time-series gene expression profiles (GEPs) of bone marrow samples during remission-induction therapy can measure the response and be used for relapse prediction. We computed the time-series changes from diagnosis to Day 8 of remission-induction, termed Effective Response Metric (ERM-D8) and tested its ability to predict relapse against contemporary risk assignment methods, including National Cancer Institutes (NCI) criteria, genetics and minimal residual disease (MRD). ERM-D8 was trained on a set of 131 patients and validated on an independent set of 79 patients. In the independent blinded test set, unfavourable ERM-D8 patients had >3-fold increased risk of relapse compared to favourable ERM-D8 (5-year cumulative incidence of relapse 38·1% vs. 10·6%; P = 2·5 × 10-3 ). ERM-D8 remained predictive of relapse [P = 0·05; Hazard ratio 4·09, 95% confidence interval (CI) 1·03-16·23] after adjusting for NCI criteria, genetics, Day 8 peripheral response and Day 33 MRD. ERM-D8 improved risk stratification in favourable genetics subgroups (P = 0·01) and Day 33 MRD positive patients (P = 1·7 × 10-3 ). We conclude that our novel metric - ERM-D8 - based on time-series GEP after 8 days of remission-induction therapy can independently predict relapse even after adjusting for NCI risk, genetics, Day 8 peripheral blood response and MRD.
Published: 2018

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