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Ampaiwan Chuansumrit,1 Werasak Sasanakul,1 Nongnuch Sirachainan,1 Suttikarn Santiwatana,1 Praguywan Kadegasem,1 Pakawan Wongwerawattanakoon,2 Noppawan Tungbubpha,1 Juthamard Chantaraamporn1 1Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2Department of Nursing, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandCorrespondence: Ampaiwan Chuansumrit, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand, Tel +66 2 2011749, Fax +66 2 2011748, Email ampaiwan.jua@mahidol.ac.thObjective: The study aimed to report a 3-decade successive establishment of care for women/girls from families with haemophilia.Methods: A retrospective analysis was conducted on 462 women/girls from 243 families from 1987 to 2021.Results: Combining phenotypic analysis of coagulation factor and genotypic analysis of either linkage analysis or mutation detection confirmed the status of all obligate haemophilia carriers (A118, B19). For potential carrier, 159 proven carriers (A130, B29) and 146 noncarrier status (A126, B20) were diagnosed except 20 potential carriers (A16, B4). Only 54 prenatal diagnoses were requested resulting in normal males (n = 21), males with haemophilia A (n = 12) and females with either normal or carrier status (n = 21). Additionally, 40 women/girls with haemophilia carrier received a diagnosis of severe haemophilia A with Turner’s syndrome (n = 2) and mild haemophilia (A31, B7). The skewed X-chromosome inactivation of the nonmutant factor VIII/IX carrying X-chromosome of 8% (2/25) was found in mild haemophilia. Factor concentrate and desmopressin are prescribed for these affected women/girls. The response of women/girls with either haemophilia carrier or haemophilia was amazement with their religious beliefs and cultural acceptance.Conclusion: Appropriate care for women/girls from families with haemophilia concerning diagnosis

Werasak Sasanakul, Ampaiwan Chuansumrit, Nongnuch Sirachainan, Praguywan Kadegasem Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandCorrespondence: Ampaiwan Chuansumrit, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand, Tel +66 2 2011749, Fax +66 2 2011748, Email ampaiwan.jua@mahidol.ac.thBackground: Adequate replacement for patients with hemophilia is costly, especially in countries with limited resources.Objective: Factor VIII gene mutations among Thai patients with hemophilia A were analyzed for the most common mutation. The cost-effectiveness of finding one female without family history of hemophilia possessing the most common factor VIII mutation was compared with the cost of treating one patient with hemophilia.Methods: In all, 109 unrelated patients with hemophilia A, defined as sporadic cases (n=58) and hereditary cases (n=51), were enrolled for genotypic analysis.Results: Intron 22 inversion was prominently found in 34 sporadic (58.6%) and 27 hereditary (51.9%) cases. The screening for intron 22 inversion among females without family history of hemophilia at antenatal care has been optionally suggested. A female with a positive result will undergo further prenatal diagnosis of hemophilia in her male offspring. On the contrary, a female with a negative test result remains at risk to have a hemophiliac son caused by other factor VIII gene mutations not included in the screening but the risk is not as high as intron 22 inversion. Although the screening of factor VIII mutation among females without family history of hemophilia is against the current practice, it has been initiated due to the inadequate treatment provided to patients with hemophilia in countries with limited resources. The study calculated approximately one female with intron 22 inversion would exist among 17,064 females without family history of hemophilia. The cost of scree

Pediatric thromboembolism is a rare and heterogenous disease. As a result, there is a paucity of knowledge with regard to natural history, management, and outcomes of most types of pediatric venous and arterial thromboembolism. International research collaboration is needed to fill these knowledge gaps. Not only randomized controlled trials, but also representative observational studies are required to answer all research questions. Therefore, the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis initiated the International Pediatric Thrombosis Network (IPTN). The aims of the IPTN include (1) development of the Throm-PED registry to facilitate international prospective observational studies, and (2) establishment of a network of pediatric thrombosis centers experienced in effectively conducting clinical trials and observational studies. The IPTN needs dedicated clinicians all over the world and several funding sources to obtain high-quality research data to reach its ultimate goal of improving care in children with thrombosis. The aim of this communication is to call for active participation in the IPTN to all physicians taking care of children with thrombosis worldwide.

Jariya Waisayarat,1 Sirithep Plumworasawat,1 Soamarat Vilaiyuk,2 Nongnuch Sirachainan21Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; 2Department of Pediatrics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAbstract: Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by venous and/or arterial thromboses, pregnancy morbidity (predominantly repeated fetal losses), and the presence of phospholipid antibodies. The estimated annual incidence of APS is 5 new cases per 100,000 people. The most common thrombotic events in patients with APS in order of frequency are stroke, transient ischemic attack, deep vein thrombosis, and pulmonary embolism. Patients with APS may develop an intracardiac thrombus, which is a life-threatening complication with a high risk of increased morbidity and mortality; however, it is treatable by surgical removal, extensive anticoagulant administration, and prevention of other complications. Catastrophic APS, which is a rare and severe condition diagnosed based on rapidly progressive thromboembolic events involving three or more organs, systems, or tissues, occurs in less than 1% of all patients with APS. We herein report an autopsy case of catastrophic APS in a 12-year-old Thai boy with multiple thromboembolic events including intracardiac thrombus formation with a positive lupus anticoagulant test result. To the best of our knowledge, this is the youngest reported patient with APS to date.Keywords: antiphospholipid syndrome, intracardiac thrombus, catastrophic antiphospholipid syndrome, antiphospholipid antibodies &nbsp

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

Background Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. Methods We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. Findings Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0.004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0.001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2.02 (95% CI 1.04-3.85; p=0.038) and 3.98 (1.71-9.26; p=0.001). Integrated analyses of molecular subgroupings with clinical prognostic factor

BACKGROUND: LMD in children with recurrent medulloblastoma and other PNETs carries a poor prognosis and novel therapies are urgently needed to improve disease control. Somatostatin receptor-2 (SSR-2)is overexpressed in medulloblastoma and other central PNETs and can serve as a target for radionuclide tagged somatostatin analogues like 177Lu-DOTA-TATE that has shown considerable efficacy in adults with SSR-2 positive neuro-endocrine tumors. As a preliminary step prior to testing this agent in children with LMD, we performed an efficacy study of i.t. 177Lu-DOTA-TATE in athymic rats bearing LMD from MBL. METHODS: The subarachnoid space was accessed through the animal's cervical spine and a catheter was threaded along the dorsal aspect of spinal cord to the lumbar region and injected with 1 x 107 D341 human MBL cells and treatment initiated 3 days later. Groups of 10 animals received a single i.t. dose of 2, 3, or 5 mCi of 177Lu- DOTA-TATE or saline control. Animals were followed 300 days for survival. RESULTS: Treatment with 2 mCi resulted in an increase in median survival of 58.3% compared with saline control (p < 0.001). Treatment with 5.0 mCi of 177Lu-DOTA-TATE increased median survival by 75.0% compared with the saline control group while a single dose of 3.0 mCi 177Lu-DOTA-TATE increased median survival compared with saline controls by 519.4%. Long-term survivors were seen in 0 of 10 animals treated with saline, 4 of 11 treated with 3 mCi, and 3 of 12 treated with 5.0 mCi. CONCLUSION: Intrathecal 177Lu- DOTA TATE is efficacious in controlling LMD from medulloblastoma in athymic rats. A phase I trial of this agent is being planned in children with LMD from recurrent MBL and other CNS PNETs. INTRODUCTION: Medulloblastoma/PNET is the most common malignant brain tumor in children. For children older than 3 years, the treatment of high risk group includes surgery, craniospinal (CSI) radiation therapy (30-36 Gy) plus local boost radiotherapy (54-56 Gy) and adjuvant c

Ampaiwan Chuansumrit1, Pantep Angchaisuksiri2, Nongnuch Sirachainan11Departments of Pediatrics and 2Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University,  Bangkok, ThailandAbstract: Hemophilia patients with inhibitors faced the constraint of inadequate treatment for several years before the era of recombinant factor VIIa (rFVII). Initially, rFVIIa was used in the compassionate-use programs. After a worldwide license was issued, more than 1.5 million doses were administered. Bleeding of joints and muscles was controlled effectively by means of an early home treatment program, with either a standard dose of 90 μg/kg every 2 to 3 hours for a few doses or a single dose of 270 μg/kg. For more serious bleeding episodes or minor surgery, an initial dose of 90 μg/kg was given every 2 hours for 24 to 48 hours followed by increased intervals of 3 to 6 hours according to the severity of bleeding and efficacy of bleeding control. In cases of major surgery such as orthopedic procedures, the same regimen can be applied except for a higher initial dose of 120 to 180 μg/kg. However, increasing the dose should be considered if there are unexpected bleeding complications since the half-life and clearance of rFVIIa differ between individuals. In addition, prophylaxis is administered to a small number of patients. Finally, the reported thromboembolic events found in hemophilia patients with inhibitors receiving rFVIIa are extremely low, much less than 1%.Keywords: bleeding disorder, hemophilia, inhibitor, NovoSeven, recombinant factor VIIa