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Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200–2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5–10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15–24 days. Median nadirs (IQR) were neutrophil count, 134 (30–396) × 106/L at day 11 (10–12), recovery by day 15 (14–17) and platelet count, 35 (23–83) × 109/L at day 11 (10–13), recovery by day 17 (14–21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.

The half life of recombinant factor VIII-Fc (rFVIII-Fc) for people with hemophilia A (PwHA) varies greatly. Understanding the factors influencing the variation and assessment of rFVIII-Fc half life is important for personalized treatment. Eighty-five severe-type PwHA with rFVIII-Fc treatment receiving an evaluation of half life by the Web-Accessible Population Pharmacokinetic (PK) Service—Hemophilia during 2019–2021 were retrospectively enrolled. The 50-patient PK profiles before 2021 were used for analysis and developing prediction models of half life, and the 35-patient PK profiles in 2021 were used for external validation. The patients in the development cohort were aged 8–64, with a median rFVIII-Fc half life of 20.75 h (range, 8.25–41.5 h). By multivariate linear regression analysis, we found two, four, and five predictors of rFVIII-Fc half life for the blood groups non-O, O patients, and overall patients, respectively, including baseline VWF:Ag, BMI, VWF:activity/VWF:Ag ratio, body weight, O blood group, inhibitor history, HCV infection, and hematocrit. The three prediction equations of rFVIII-Fc half life (T) were respectively developed as T for non-O group patients = −0.81 + 0.63 × (BMI, kg/m2) + 6.07 × (baseline VWF:Ag, IU/mL), T for O group patients = −0.68 + 13.30 × (baseline VWF:Ag, IU/mL) + 0.27 × (BW, kg) − 1.17 × (BMI, kg/m2) + 16.02 × (VWF:activity/VWF:Ag ratio), and T for overall patients = −1.76 + 7.24 × (baseline VWF:Ag, IU/mL) − 3.84 × (Inhibitor history) + 2.99 × (HCV infection) − 2.83 × (O blood group) + 0.30 × (Hct, %), which explained 51.97%, 75.17%, and 66.38% of the half life variability, respectively. For external validation, there was a significant correlation between the predicted and observed half lives in the validation cohort. The median half life deviation was +1.53 h, +1.28 h, and +1.79 h for the equations of non-O group, O group, and overall group patients, respectively. In total, eight predictors influencing rFVIII-Fc half life were identified. Prediction equations of rFVIII-Fc half life were developed for the non-O and O blood groups and overall PwHA with a good degree of external validation. The equations could be applied to patients aged 8–64 without the need for PK blood sampling and clinically valuable for personalized therapy.

Shiue-Wei Lai,1– 3 Chia-Yau Chang,3,4 Shin-Nan Cheng,1,5,6 Shu-Hsia Hu,1 Chung-Yu Lai,7 Yeu-Chin Chen1,2 1Hemophilia Care and Research Center, Tri-Service General Hospital, Taipei, Taiwan; 2Division of Hematology/Oncology, Department of Internal Medicine, Tri-service General Hospital, National Defense Medical Center, Taipei, Taiwan; 3School of Medicine, Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei, Taiwan; 4Division of Pediatric Hematology/Oncology, Hemophilia Center, Taipei Medical University Hospital, Taipei, Taiwan; 5Department of Pediatrics, Tungs’ Taichung MetroHarbor Hospital, Taichung, Taiwan; 6Department of Pediatrics, National Defense Medical Center, Taipei, Taiwan; 7Graduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei City, 114, TaiwanCorrespondence: Yeu-Chin ChenDivision of Hematology/Oncology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Section 2, Chenggong Road, Neihu, Taipei, 114, TaiwanTel +886-2-87927208Fax +888-2-87927209Email yeuchin99@gmail.comBackground: von Willebrand factor ristocetin cofactor activity (VWF:RCo) is the standard functional assay used for von Willebrand disease (VWD) diagnosis. However, it has some drawbacks including being time consuming and labor intensive and having high inter-laboratory variability. The HemosIL VWF activity assay has the advantages of both high speed and automation. The purpose of this study was to prospectively compare these two functional assays for type 1 VWD detection.Methods: Plasma samples from 108 subjects were assessed in this study. HemosIL VWF activity was measured with the HemosIL latex immunoturbidimetric commercial kits by the ACL TOP coagulation analyzer. VWF:RCo was measured by platelet aggregation method. Pearson correlation analyses were performed to estimate the correlation of HemosIL VWF activity with VWF:RCo. Receiver-operator characteristic (ROC) curve analysis was used to evaluate the performance of the two diagnostic tests.Results: The correlation coefficient between VWF:RCo and HemosIL VWF activity was 0.874 overall and was 0.761 and 0.811 in the cohorts of type 1 VWD and non-VWD, respectively. The sensitivity and specificity of HemosIL VWF activity assay for type 1 VWD identification were 94.7% and 80.0%, respectively, and the ROC curve of HemosIL VWF activity was larger than that of VWF:RCo (0.928 vs 0.863, p=0.0138). Finally, the positive and negative predictive values of the HemosIL VWF activity assay for type 1 VWD detection were 72.0% and 96.6%, respectively.Conclusion: Our results demonstrate that the HemosIL VWF activity assay was an effective method for type 1 VWD screening and diagnosis. It carried good sensitivity and specificity and had a higher ROC curve than VWF:RCo besides showing good correlation with VWF:RCo. With its advantages of greater speed and automated performance, these results suggest that the HemosIL VWF activity assay was reliable and precise in the clinical setting.Keywords: von Willebrand factor antigen, von Willebrand disease, VWF ristocetin cofactor activity, VWF:RCo, HemosIL VWF activity

People with hemophilia (PWH), especially severe hemophilia, often experience bleeding episodes, which occur mostly at major joints. Intramural hematoma of the gastrointestinal (GI) tract is a rare, potentially life-threatening clinical bleeding manifestation in PWH. Prompt identification and timely administration of clotting factor concentrates are of utmost importance for effective management and optimal patient outcomes. In this report, we present the case of a 48-year-old male with severe hemophilia A. The patient developed a spontaneous intramural hematoma of the jejunum, leading to signs of acute abdomen, bloody stool, and paralytic ileus. Conservative management with factor VIII (FVIII) infusion was successfully administered. However, within a span of three months, the patient suffered from a recurrent episode of intramural hematoma, which was again effectively treated with conservative therapy. Subsequently, prophylactic FVIII therapy was administered to the patient, resulting in the absence of recurrence for over three years. Inspired by this case, we conducted a comprehensive review of the relevant literature and gathered data from 79 reported cases of intramural hematoma that were documented between the years 1956 and 2022. We classified these cases based on the site affected within the gastrointestinal (GI) tract (spread across five different locations) and proceeded to conduct a simple pooling analysis on the data collected, which subsequently revealed that the overall mortality rate of intramural hematoma in people with hemophilia (PWH) was found to be 12.2%, while children have a higher mortality rate (23.3%) than adults (4.9%). We hope this case report and literature review increase awareness of this rare bleeding manifestation in PWH, the effectiveness of conservative treatment, and the possibility of prophylaxis against recurrence.

Twenty-one gliomas in patients aged 0-21 years were evaluated for drug sensitivity by ex vivo expanded circulating tumor cells (CTC). The results were correlated with clinical outcomes. Venous blood samples were obtained prior to drug treatment. Peripheral blood mononuclear cells were processed in a 3D cell culture system (EVA Select™, Cancer Free Biotech Ltd., Taipei, Taiwan) and cultured for 3 weeks. Expanded CTCs were successfully cultured into organoids from 18 out of 21 patients and were analyzed for ATP abundance. Staining with CD45, a marker for blood cells, and pancytokeratin, a marker for keratinocytes, was performed on the cultured cells. Staining of GFAP, a marker of glioma cells, was performed in a subset of samples. These cells were then tested in cytotoxicity assays in triplicate with a panel of chemotherapeutic and targeted agents at clinically relevant concentrations. The surviving fraction was normalized to a buffer-only control. Based on the percentage of cell viability, the agent was chosen for clinical treatment. Comparing the results among low-grade glioma (LGG; n = 6), diffuse midline glioma (DMG; n = 4), and high-grade glioma (HGG, n = 8; including glioblastoma multiforme [GBM; n = 5]), the mean surviving fraction to temozolomide was similarly high across the three tumor types (LGG vs. DMG vs. HGG = 57.5% vs. 50.6% vs. 49.5%, respectively). 6 of 6 patients in the LGG group showed CTC sensitivity to at least one chemotherapeutic agent tested. The clinical response of patients treated with selected agents was evaluated with the RANO criteria at 6 months after initiation of treatment. Among the 24 agents tested with clinical correlation, the CTC surviving fraction after exposure to the agent was significantly higher in patients who had progressive disease within 6 months (n = 11; 68%) vs. in patients with no progression at 6 months (n = 13; 39%; P = 0.039). Treating CTCs with histone deacetylase inhibitors in vitro resulted in a consistently lower surviving fraction (15.1% ± 12.0%) for DMG and HGG/GBM; however, clinical correlation was not available. The 1 patient with clinical correlation with HGG had a 34.9% surviving fraction to a Tyrosine kinase inhibitor (TKI) in vitro and showed a 42.9% shrinkage at 6 months after treatment with the TKI. The expansion of CTCs in patients with relapsed/refractory pediatric gliomas provides the ability to test drug sensitivity of patient-derived organoids. Our data suggest a correlation between the ex vivo drug sensitivity of CTCs and clinical response. Citation Format: Yen-Lin Liu, Yin-Ju Chen, Shu-Huey Chen, Yu-Mei Liao, Wu Shih-Pei, Yi-Hsuan Chen, Wan-Ling Ho, Liang-Yi Juo, Chia-Yau Chang, Jinn-Li Wang, Min-Yu Su, Pei-Chin Lin, Shih-Chung Wang, James S. Miser, Tai-Tong Wong, Yuan-Hung Wu, Peng Yuan Wang, Thierry Burnouf, Jeng-Fong Chiou, Long-Sheng Lu. Application of in vitro drug screening of circulating tumor cells in pediatric glioma therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6723.

Background: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive embryonal brain tumor most commonly presenting in young children. Methods: We performed a nationwide, population-based study of AT/RT (ICD-O-3 code: 9508/3) in Taiwan using the Taiwan Cancer Registry Database and the National Death Certificate Database. Results: A total of 47 cases (male/female = 29:18; median age at diagnosis, 23.3 months (IQR: 12.5–87.9)) were diagnosed with AT/RT between 1999 and 2014. AT/RT had higher prevalence in males (61.70%), in children < 36 months (55.32%), and at infratentorial or spinal locations (46.81%). Survival analyses demonstrated that patients ≥ 3 years of age (n = 21 (45%)) had a 5y-OS of 41% (p < 0.0001), treatment with radiotherapy only (n = 5 (11%)) led to a 5y-OS of 60%, treatment with chemotherapy with or without radiotherapy (n = 27 (62%)) was associated with a 5y-OS of 45% (p < 0.0001), and patients with a supratentorial tumor (n = 11 (23%)) had a 5y-OS of 51.95%. Predictors of better survival on univariate Cox proportional hazard modeling and confirmed with multivariate analysis included older age (≥1 year), supratentorial sites, and the administration of radiotherapy, chemotherapy, or both. Gender had no effect on survival. Conclusion: Older age, supratentorial site, and treatment with radiotherapy, chemotherapy, or both significantly improves the survival of patients with AT/RT.

Background In 10%-18% of mild-type hemophilia A (HA) patients, mutations cannot be found by routine DNA analysis. Objective We aimed to identify the genetic defects by mRNA analysis of F8 gene in mild HA patients without mutation in exonic DNA. Patients and methods From 2006 to 2016, we identified F8 exon mutations in 39 of 49 mild HA patients using routine genetic testing. We then evaluated the 10 remaining patients from six unrelated families without exonic DNA mutation by performing cDNA sequence analysis. Results Nine of the 10 (90%) patients were confirmed to have F8 gene mutation. Eight patients from four unrelated families were notably found to have presence of an aberrant 675-bp fragment. Sequencing of this fragment showed that there were two separate new alternative splicing exons of 35 bp and 55 bp within intron 18, which formed a 90-bp insertion between exon 18 and exon 19 (E18ins90bpE19) in the mRNA. Based on direct sequencing, this alternative splicing transcript appears to have resulted from deep intronic variant c.5999-277G>A of intron 18. Conclusions Our study suggests that deep intronic variant of c.5999-277G>A may be a hot spot mutation for mild hemophilia patients without mutation in exonic DNA.

Background The prevalence of obesity in patients with hemophilia (PWH) varies among different ethnicities, and its influence on joint bleeding and hemophilic arthropathy has not been studied in Taiwan population. We explored the prevalence and clinical correlates of obesity and the impact of body mass index (BMI) on annual joint bleeding rate (AJBR) and hemophilic arthropathy in PWH in Taiwan. Methods We retrospectively collected clinical information on 140 severe/40 moderate PWH from 2006 to 2014. The patients' median age was 31.5 years, ranged from 6 to 73 years. Their BMI, 6 index joints score by Pettersson scoring, AJBR, and other clinical data were analyzed. Results The prevalence of overweight and obesity by age group was 7.1% in PWH aged ≤10 years, and rapidly increased to 34.5% in PWH aged 11 to 18 years, 46.7% in PWH aged 18 to 29 years, 61.8% in PWH aged 30 to 39 years, 60.6% in PWH aged 40 to 49 years, and 48% in PWH aged ≥50 years, respectively. Two peak rates were 72.7% in PWH aged 35 to 44 years and 66.7% in PWH aged >65 years. Age, HCV infection, knee score, elbow score, and total 6 index joints scores were found to correlate positively with BMI. However, subtype and severity of hemophilia, ankle scores, HBV and HIV infection did not correlate with BMI. Finally, BMI was found to correlate positively with AJBR in both adult and pediatric PWH. Conclusion The prevalence of overweight and obesity in adolescent and adult PWH was higher than those in the general male population in Taiwan, which rapidly increased with age to peak in PWH aged 35 to 44 years and >65 years. High index joint score, with the exception of ankle scores, positively correlated with high BMI. Further, BMI and obesity also had positive correlation with AJBR in PWH. To our knowledge, this is the first study examining these associations in PWH in Taiwan.

Haemophilia care in Taiwan has come a long way over the past 35 years, from the absence of specialised haemophilia treatment centres before 1984 to the establishment of treatment centers in the majority of medical centers, the listing of haemophilia as a catastrophic illness with full treatment reimbursement by the Taiwan National Health Insurance (NHI), and the implementation of full NHI coverage for prophylaxis therapy. This has led to outcome improvements such as reduced bleed-related morbidity and mortality, fewer viral infections, and enhanced overall multi-modality care. Most people with haemophilia (PWH) are now able to live normal, active lives. Early diagnosis has improved through increased awareness, physician education, and prenatal diagnosis; while comprehensive care, including state of the art rehabilitation and orthopaedic management for haemophilic arthropathy, eradication therapy for chronic hepatitis C, and better treatments for human immunodeficiency virus, allows PWH to enjoy a better quality of life and improved survival. Efforts are now being made to raise prophylaxis rates through full NHI reimbursement and the use of extended half-life recombinant factor products. Overall, Taiwan has made great strides in haemophilia care and we would like to share these experiences for the benefit of all healthcare providers involved in haemophilia care.

Background Hemophilia is a rare bleeding disorder characterized by deficiency of FVIII or FIX resulting in ineffective clot formation due to impaired thrombin generation. Fitusiran is a subcutaneously (SC) administered investigational siRNA therapeutic agent which targets antithrombin to enhance thrombin generation potential and rebalance hemostasis in people with hemophilia (PwH), irrespective of inhibitor status. Here, we present results from a Phase 3 study of the efficacy and safety of fitusiran prophylaxis compared with on-demand (OD) treatment with factor concentrates in PwH A or B without inhibitors (ATLAS-A/B; NCT03417245). Methods This Phase 3, multicenter, multinational, randomized, open-label study evaluated the efficacy and safety of fitusiran in males aged ≥12 years with severe hemophilia A or B without inhibitors, previously treated OD. Eligible participants (pts) were randomized 2:1 to receive either once-monthly 80 mg SC fitusiran prophylaxis (fitusiran arm) or OD factor concentrates for treatment of bleeding episodes (OD arm) for a treatment period of 9 months. The primary endpoint was annualized bleeding rate (ABR) in the efficacy period (Day 29 post-first fitusiran dose up to Day 246). Secondary endpoints included annualized spontaneous bleeding rate (AsBR) and annualized joint bleeding rate (AJBR) in the efficacy period and health-related quality of life (HRQoL) in the treatment period, measured by Haem-A-QoL. Safety and tolerability were assessed throughout the study. Results Overall, 120 pts were randomized (fitusiran arm n=80; OD arm n=40); 79 pts (98.8%) in the fitusiran arm and 37 pts (92.5%) in the OD arm completed the study. A total of 93 pts had hemophilia A (fitusiran arm n=62, OD arm n=31) and 27 pts had hemophilia B (fitusiran arm n=18, OD arm n=9). Baseline demographics and characteristics were similar in both arms. Median observed ABR was 0.0 (IQR, 0.0 to 3.4) in the fitusiran arm and 21.8 (IQR, 8.4 to 41.0) in the OD arm; 40 pts (50.6%) in the fitusiran arm experienced no bleeds that required treatment with OD factor concentrates. A significant reduction in estimated ABR was achieved in the fitusiran arm vs the OD arm (89.9% reduction [95% CI, 84.1% to 93.6%], p Seventy-nine pts received at least 1 dose of fitusiran and 40 patients were randomized to the OD arm and included in the safety analysis. Overall, 62 pts (78.5%) in the fitusiran arm and 18 pts (45%) in the OD arm experienced ≥1 treatment emergent adverse event (TEAE). A total of 5 treatment emergent serious adverse events (TESAEs) were reported in 5 pts (6.3%) in the fitusiran arm and 9 TESAEs were reported in 5 pts (12.5%) in the OD arm. TESAEs in the fitusiran arm included cholelithiasis (2 pts, 2.5%), cholecystitis, lower respiratory tract infection, and asthma (1 pt each, 1.3%). In the fitusiran arm, 2 pts (2.5%) experienced TEAEs that resulted in fitusiran discontinuation (cholecystitis and increased alanine aminotransferase). No TEAEs of thrombosis and no fatal TEAEs were reported. Conclusions All key primary and secondary endpoints were met in this Phase 3 study. Specifically, once-monthly 80 mg SC fitusiran prophylaxis demonstrated a significant reduction in ABR, AsBR and AJBR (all ~90%) in people with severe hemophilia A or B without inhibitors compared with OD treatment. This reduction in bleeding was associated with a meaningful improvement in HRQoL. Reported TESAEs were generally consistent with previously identified risks of fitusiran. With the aim of further enhancing the benefit-risk profile of fitusiran, a revised regimen with reduced dose and frequency is currently being evaluated in ongoing clinical studies. Figure 1 Figure 1. Disclosures Srivastava: Roche: Other: Advisory Board, Research Funding; Novo Nordisk: Other: Advisory Board, Research Funding; Sanofi: Other: Advisory Board, Research Funding; Pfizer: Other: Advisory Board, Research Funding; Takeda: Other: Advisory Board, Research Funding; Bayer Healthcare: Other: Grant Review & Awards Committee. Rangarajan: Sanofi: Other: Advisory Board; Pfizer: Other: Advisory Board; Reliance Life Sciences: Consultancy; Takeda: Other: Advisory Board, Conference Support, Speakers Bureau. Kavakli: Pfizer, Bayer, Takeda, Roche, Novo Nordisk: Honoraria; Pfizer, Bayer, Roche, Novo Nordisk, Takeda: Speakers Bureau; Roche, Bayer, Pfizer, Novo Nordisk, Takeda: Membership on an entity's Board of Directors or advisory committees. Klamroth: Bayer, Leo: Research Funding; Bayer, Biotest, Biomarin, BMS, CSL Behring, Daiichi Sankyo, Leo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, SOBI, Takeda: Honoraria; Bayer, Biotest, Biomarin, BMS, CSL Behring, Daiichi Sankyo, Novo Nordisk, Octapharma, Pfizer, Roche, Sanofi, SOBI, Takeda: Speakers Bureau. Kenet: Alnylam: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Opko Biologics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Shire: Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding; Nat'l Hemophilia Ctr and Coagulation Unit and Amalia Biron Res Inst of Thromb & Hemost, Sheba Medical Ctr, Tel Hashomer, Israel: Current Employment; BioMarin Pharmaceutical: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Uniquore: Honoraria, Membership on an entity's Board of Directors or advisory committees; BPL: Research Funding. Khoo: NSW Health Pathology: Current Employment; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau. You: Eulji University Hospital: Current Employment. Malan: PHOENIX Pharma (Pty) Ltd, Qgeberha, South Africa: Current Employment, Research Funding; St Francis Hospital, Qgeberha, South Africa: Membership on an entity's Board of Directors or advisory committees. Frenzel: Pfizer: Research Funding; Roche: Research Funding; SOBI: Research Funding; CSL Behring: Research Funding. Stasyshyn: CSL Behring: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau; Octapharma: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy, Research Funding, Speakers Bureau; Grifols: Consultancy, Speakers Bureau; Shire: Consultancy, Honoraria, Research Funding; Institute of Blood Pathology and Transfusion Medicine of National Academy of Medical Sciences of Ukraine: Current Employment; Sanofi: Honoraria, Research Funding; Roche: Speakers Bureau; LFB: Honoraria, Research Funding. Poloskey: Sanofi: Current Employment, Current equity holder in publicly-traded company. Andersson: Sanofi: Current Employment, Current equity holder in publicly-traded company; WEST advisory committee member: Membership on an entity's Board of Directors or advisory committees. Mei: Sanofi: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Patents & Royalties. Pipe: Sangamo Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Advisory Board; ASC Therapeutics: Consultancy, Other: Scientific Advisory Board; Apcintex: Consultancy; Bayer: Consultancy; Biomarin: Consultancy; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; Freeline: Consultancy; Grifols: Consultancy; HEMA Biologics: Consultancy; Novo Nordisk: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy; GeneVentiv: Consultancy, Membership on an entity's Board of Directors or advisory committees; YewSavin: Research Funding; Siemens: Research Funding.

Introduction: It was well-known that severe-type patients with hemophilia A (PwHA) had great variability in bleeding phenotypes. Factors effecting bleeding patterns of PwHA include at least treatment modality and interindividual various procoagulant and anticoagulant levels. We aimed to investigate what clinical variables could predict bleeding frequency of severe PwHA and to develop models for predicting bleeding phenotypes among severe PwHA with/without FVIII prophylaxis therapy. Methods and materials: Totally 51 severe-type previously-treated PwHA from two Hemophilia Centers in Taiwan were enrolled, who received standard half life (SHL) rFVIII products with complete consecutive bleeding records at least more than 6 months, and their medical charts 2017－2018 were retrospectively viewed. The clinical data were collected for analysis, including age, body mass index (BMI), body weight (BW), ABO blood groups, hemoglobin (Hb), hematocrit (Hct), HCV infecton, HIV infection, treatment modality, baseline VWF levels, and genetic defects. Baseline VWF activity meant the data via VWF:ACL activity or VWF:RCo. Clinical variables for annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR) were evaluated by multivariate linear regression (MVLR) analysis. Results: The cohort of 51 severe-type PwHA included 8 boys and 43 adults, aged 8-64. For treatment modality, there were 19 patients receiving episodic treatment (ET) and 32 receiving prophylaxis therapy (PT) with intermediate-dose standard half life (SHL) rFVIII. The mean study period was 11.9 months, range 10－14.5 months. Among them, there were 31 with HCV infection and 4 with HIV infection. PwHA with non-O blood group were 31 and those with O blood group 20. The mean baseline VWF:Ag was 115.6±55.5%, range 50%－294.7%. The mean baseline VWF:activity was 105.4±52.1%, range 41.3%－307%. ABR of ET group and PT group were 46.1±29.2 and 6.8±7.1, respectively. (p (1) Predictive ABR = 56.5 - 37.8 * (Treatment model) - 11.8 * baseline VWF:Ag (IU/mL). (2) Predictive e AJBR = 41.9 - 28.6 * (Treatment model) - 12.0 * baseline VWF:Ag (IU/mL) + 10.0 * (HCV infection). (1 if Treatment model is PT, 0 if Treatment model is ET. 1 if HCV infection or anti-HCV antibody is positive, 0 if HCV infection or HCV antibody is negative.) Separate prediction models developed from MVLR analysis could explain 52.51% of the ABR variability and 50.56% of the AJBR variability. The correlation between predicted and observed bleeding frequency was significantly strong.(P-rank>0.7, p-value Conclusion: Prophylaxis therapy and baseline VWF:Ag levels were the strongest two inverse predictors for ABR and AJBR. Positive HCV infection was another predictor for AJBR. The prediction models provided with an insight into personal bleeding quantified patterns and may identify PwHA with high bleeding risks based on individual characteristics of treatment modality, baseline VWF:Ag, and HCV infection. Our approach is of help for individualized treatment and refining of dosing strategies. Disclosures No relevant conflicts of interest to declare.

Introduction: Bleeding phenotypes of severe-type patients with hemophilia A (PwHA) vary greatly, which influence factor consumption and medical cost. Factors affecting bleeding patterns of PwHA include various procoagulant and anticoagulant factors, joint condition and physical activity, etc. We aimed to investigate clinical factors influencing by-nature bleeding frequency of severe-type PwHA during episodic treatment. Methods and materials: There were 19 non-inhibitor, severe-type, previously treated PwHA aged >20 years, who had at least one to five major joints arthropathy, retrospectively enrolled from two hemophilia centers for analysis. They had been refusing prophylaxis therapy with FVIII product due to heavy burden of frequent intravenous FVIII injection and had long-term episodic treatment. Clinical informations were collected from November 2017 to November 2018, including age, body mass index (BMI), body weight, ABO blood grouping, HCV and HIV infection status, baseline VWF:Ag and VWF:activity, mutation of F8 gene. Annualized bleeding rate (ABR) and annualized joint bleeding rate (AJBR), weekly doses and annualized factor consumption costs (calculated by new Taiwan dollars, NTD) were obtained from the patients' medical records. Results: The PwHA with ABR 24.(P-value 13.(P-value 145% had significantly older age (34.9 vs 53.2 years, P-value 28 had significantly lower ABR (58.2 vs 12.2 per year, P-value Conclusion: For severe-type adult PwHA with episodic treatment, baseline VWF:Ag or VWF:activity >145% was associated with lower ABR, AJBR, weekly dose, and annualized factor cost. BMI >28 was associated with lower ABR, AJBR, and weekly dose consumption. Baseline VWF:Ag and BMI were revealed as inverse influencing factors for ABR and AJBR, respectively. The results of our study could be useful for clinicians to have an insight into diversity of bleeding phenotypes of by-nature severe-type PwHA. For developing countries where factor concentrate resources are not enough, these clinical influencing factors might be helpful for the management of therapeutic strategies and resource allocation for severe PwHA. Disclosures No relevant conflicts of interest to declare.

Introduction: Stand half-life (SHL) rFVIII had been used in patients with hemophilia A (PwHA) for episodic treatment (ET) and prophylaxis therapy (PT) for years. Extended half-life (EHL) rFVIII had been available since 2014, also available in Taiwan since 2018, and resulted in markedly increased willingness for PT because it reduced injection burden. We aimed to investigate the real-world bleeding outcomes, weekly factor doses, and factor costs of severe-type PwHA with pre-switch SHL rFVIII and post-switch EHL rFVIIIFc prophylaxis in Taiwan, and made a pre-switch and post-switch comparison. Methods and Materials: There were totally 51 non-inhibitor, severe-type PwHA, with complete bleeding records before and after switching from SHL rFVIII to EHL rFVIII-Fc, enrolled from two hemophilia centers during Nov, 2018－July, 2019. Most of them had various degree of one to more major joints arthropathy, except children. The medical charts were retrospective reviewed and data were collected, including body features and factor regimen, etc. Patients' annualized bleeding/joint-bleeding rate (ABR/AJBR), weekly doses (WD), annualized factor costs (AFC) were obtained from the chart records of pre-switch 12 months and post-switch at least more-than 6-month until July, 2019. Data from scheduled operation or hospitalization due to trauma or accidence were excluded. Results: There were 8 boys and 43 adults, the median age of all PwHA when switching was 35.6 years (10.5-62). Before switching, these 51 PTP treated with SHL rFVIII who received ET (ET group), irregular prophylaxis (IP group), and regular prophylaxis (RP group) were 19 (37.3%), 7 (13.7%), and 25 (49%), respectively. Bleeding records of 51 PTP treated with SHL rFVIII were traced back with 11.8±0.9 months. After switching to rFVIII-Fc, 3 PwHA receiving ET were excluded, and bleeding records of 48 received RP were obtained with 14.7±4.6 months. Pre-switch and post-switch prophylaxis rate were 62.7% (32/51) and 94.1% (48/51), respectively. For comparison of pre-switch and post-switch outcomes: Median ABR was reduced from 48, 12, and 4 to 1.15, 1.9, and 1.5 for ET, IP, and RP group, respectively. Median AJBR was reduced from 32, 11, and 4 to 0.95, 0.7, and 1.2 for ET, IP, and RP group, respectively. Median WD was increased from 38.4, 52.9, and 63.6 IU/kg/wk to 84.6, 84.5, and 84.9 IU/kg/wk for ET, IP, and RP group, respectively. Median AFC was increased from 4,141,800, 4,064,000 and 5,129,700 NTD to 7,042,325, 5,835,450, and 5,762,810 NTD for ET, IP, and RP group, respectively. Comparing pre-switch and post-switch outcomes of children and adults who received pre-switch and post-switch prophylaxis, median ABR was reduced from 3 and 5 to 1.35 and 1.85 for children and adults, respectively. Median AJBR was reduced from 3 and 4 to 1.35 and 1.15 for children and adults, respectively. Median WD was increased from 58.8 and 58.3 IU/kg/wk to 87.85 and 83.85 IU/kg/wk for children and adults, respectively. Median AFC was increased from 4,104,225 and 5,879,025 NTD to 4,419,800 and 6,024,916 NTD for children and adults, respectively. For all PwHA, zero ABR accounted for 5.9% (3/51) with pre-switch SHL rFVIII treatment and for 20.8% (10/48) with post-switch rFVIII-Fc prophylaxis. Zero AJBR accounted for 9.8% (5/51) with SHL rFVIII treatment and for 33.3% (16/48) with rFVIII-Fc prophylaxis. For PwHA with pre- and post-switch prophylaxis, zero ABR accounted for 12.5% (1/8) and 8.3% (2/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 25% (6/24) respectively, for children and adults on rFVIII-Fc prophylaxis. Zero AJBR accounted for 12.5% (1/8) and 16.7% (4/24), respectively, for children and adults on SHL rFVIII prophylaxis and 25% (2/8) and 37.5% (9/24) respectively, for children and adults on rFVIII-Fc prophylaxis. Conclusion: In real-world setting, for pre-switch ET group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >95%, and mean WD increased >50%. For pre-switch IP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR reduced >80%, and mean WD increased >35%. For pre-switch RP group, switch to rFVIII-Fc prophylaxis made both mean ABR and AJBR also reduced >45%, and mean WD increased >20%. The proportions in zero ABR and zero AJBR as post-switch rFVIII-Fc prophylaxis were increased. No matter in ET, IP, or RP group, after switching to RP with rFVIII-Fc, improvement for bleeding outcomes was quite evident. Disclosures No relevant conflicts of interest to declare.

Sarcomas of bone, soft tissue, or neural origin may occasionally invade the central nervous system (CNS), causing diagnostic and therapeutic challenges. We aim to investigate the clinical features of sarcomas involving the CNS at initial presentation. During 2015/01–2019/12, nine consecutive patients (4 Males and 5 Females) younger than 30 years of age treated at a University Healthcare System in Northern Taiwan were included. The median age was 8.7 years (range, 2–24 years); diagnoses were Ewing Sarcoma with EWSR1 rearrangements (n=4), CIC-NUTM1 Sarcoma (n=1), Osteosarcoma (n=2), Malignant Peripheral Nerve Sheath Tumor (MPNST; n=1), and extramedullary myeloid sarcoma (n=1). The tumors originated from the skull (n=1), dura (n=1), vertebra (n=4), spinal canal (n=1), or extra-CNS sites (n=2). Four patients had metastases (1 Ewing sarcoma, 2 osteosarcoma, and 1 extramedullary myeloid sarcoma). The main symptom at diagnosis was facial/eye pain (n=2), back pain (n=3), arm weakness (n=1), or gait disturbance (n=3). Upfront neurosurgical decompression (n=7) or urgent radiotherapy (n=1) was performed in most patients. At a median follow-up duration of 20.1 months, the overall survival rate was 70%. All patients with Ewing sarcoma (n=4) and CIC-NUTM1 sarcoma (n=1) achieved Complete Response after surgery, interval-compressed chemotherapy, radiotherapy, and adjuvant chemotherapy. Patients with stage IV osteosarcoma (n=2) had Partial Response; the patients with MPNST and extraskeletal myeloid sarcoma died of Progressive Disease at 18 and 3 months after diagnosis, respectively. We conclude that timely decompression, early diagnosis, and histology-driven multimodality treatment are effective strategies in managing sarcomas involving the CNS.

Introduction: Routine prophylaxis (RP) has been a standard therapeutic strategy for person with hemophilia (PWH) since 2007. However, frequent injection resulting in patients' burden decreased rates of RP. Extended half-life (EHL) product rFVIII-Fc can reduce the injection burden of RP compared with standard half-life (SHL) rFVIII and was started to be used in Taiwan since November, 2018. The reports of real-world pharmacokinetics (PK) and clinical experience of rFVIII-Fc in Asian countries were relatively few. We aimed to share our clinical experience of rFVIII-Fc for previously-treated patients (PTP) with hemophilia A iin Taiwan. Materials & Methods: We reviewed retrospectively the charts of 49 PTP with hemophilia A, including 44 severe type, 3 moderate type, and two mild type disease, who switched from SHL FVIII to rFVIII-Fc from Nov., 2018 to May, 2019 at Taipei Medical University Hospital, a referral center for hemophilia. Among them, 36 severe-type PTP had finished complete recovery rate (RR) and PK study, including 2 with on-demand therapy and 34 with RP having PK coming from blood sampling before and 30 min after infusion, post-infusion 24h, 48h or 72h. The online WAPPS-hemo website was used for calculate individual half life. Other clinical data were also analyzed, including body mass index (BMI), lean body weight (LBW), ABO blood grouping, inhibitor status currently and in the past, times of visiting emergency room (ER) due to bleeding. Many PTP had hemophilic arthropathy with symptoms of morning stiffness, rheumatic joint pain, chronic joint pain, and limited exercise tolerance, we also reviewed their feedbacks of effects on above symptoms after switching. Results: After switching to rFVIII-Fc, the rates of RP of 40 severe-type elevated from 47.5% (SHL rFVIII) to 90% (rFVIII-Fc). Among the 36 PTP with RP, the patient number of those who receive RP 60-65iu/kg every 5 day (Q5D), 45-50 iu/kg every 4 days (Q4D), and 30-35 iu/kg every 3 days (Q3D) were initially 31, 5 and zero, respectively and then became 27, 7, and 2 respectively. Among the 36 patients completing the PK study, their mean age was 33.8 + 12.9 years (14-62), the mean terminal half life was 19.0 + 4.4 hrs (11-25.75 hrs), the mean recovery rate (RR) was 2.4 + 0.5 (1.55-3.33), and the mean trough level was 3.2 + 1.9% ( Conclusion: The rates of RP elevated markedly from 47.5% to 90% after switching from SHL FVIII to rFVIII-Fc. Most (75%) of PTP with RP had received injection Q5D during the study period. O blood type was an associated factor for shorted half life and trough level of rFVIII-Fc. Having inhibitors before was associated factors for shorted half life and smaller RR of rFVIII-Fc. BMI, body weight, and LBW were correlates of RR. The frequency of visiting ER due to bleeding reduced during 6 months after switching. More than 60% of PTP with RP reported improved morning stiffness, rheumatic joint pain, chronic joint pain, and exercise tolerance. Disclosures No relevant conflicts of interest to declare.

In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan.In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL).Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance.With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).

Central nervous system (CNS) involvement is not rare in extraocular retinoblastoma, and it is not surprising to find it in view of its route of spread. However, although spinal recurrence presenting as spinal cord compression (SCC) is a form of CNS involvement, it is extremely rare. This report describes two patients with unilateral retinoblastoma with spinal recurrence presenting as SCC. The first patient developed erythematous swelling of the right foot and weakness of the bilateral lower limbs at 7 months after left enucleation. Examination revealed pitting edema of bilateral feet and muscle power of 2+ to 3+, with intact sensory function. The second patient developed weakness of the bilateral lower limbs, and defecative and urinary difficulty for 2 days at 8 months after left enucleation. Examination revealed pitting edema of bilateral feet and muscle power of 2+, with defective sensory function. Both patients received surgery and local irradiation after SCC. The first patient refused chemotherapy and survived only 4 months due to disease progression. The second patient received systemic and intrathecal chemotherapy, and survived 19.5 months without disease progression. Spinal recurrence with SCC should be suspected when leg weakness or bowel or bladder disturbance occurs in patients with retinoblastoma.

Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia (AML) and is rare in children (< 10% of childhood AML). It tends to bleed with disseminated intravascular coagulation (DIC) and intracranial hemorrhage complication is often fatal. We report a 12-year-old child with APL who suffered a subdural hemorrhage and initially presented with a subtle headache mistaken as the side effect of all-trans-retinoic acid (ATRA). Blood component therapy and a pediatric dosage of ATRA (25 mg/m2/day) combined with idarubicin as induction chemotherapy were administered in the first week, but the bleeding diathesis persisted and DIC profiles showed no improvement. The patient then developed photophobia, neck stiffness, and constant headache. Evidence of increased intracranial pressure (IICP) and persistent bleeding from previous venous puncture sites were also noticed clinically. DIC and life-threatening IICP were beyond control until the ATRA dosage was increased to adult levels (45 mg/m2/day). This case suggests that the ATRA dosage for pediatric APL patients must be modified according to clinical condition. Emergency brain imaging should be considered in APL patients with signs of IICP to distinguish intracranial lesions from ATRA complications.

Acute leukemia can result in leukemic infiltration of many organs, but leukemic infiltration of the bladder is rare. The authors describe an 8-year-old girl with acute lymphoblastic leukemia who, during marrow relapse, had uncontrollable gross hematuria secondary to leukemic infiltration of the bladder. Cystoscopic biopsy confirmed the diagnosis. Literature review revealed 13 cases of acute leukemia with bladder involvement. Although leukemic infiltration of the bladder is rare, it should be considered in patients with acute leukemia and hematuria. Urine cytology might help detect bladder involvement.

Background In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan. Procedure In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL). Results Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy >50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance. Conclusions With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).

Pediatric oncology/hematology patients, especially those with acute lymphoblastic leukemia (ALL), often undergo repeated painful invasive procedures. Deep sedation, mandatory for these procedures in young children, can reduce patient anxiety and get their compliance during procedures. This study assessed clinical experience of employing methohexital or thiamylal with midazolam as sedative for elective invasive procedures in children with ALL. Between November 1997 and March 2004, 20 out of 33 ALL children received deep sedation after evaluation, mainly because of relatively young age (mean age 4.60 +/- 2.03 years). A total of 176 procedures were done, with 139 being intrathecal therapy. There were 98 and 78 procedures for the methohexital and thiamylal groups, respectively. The average dosages to complete the procedures were 2.2 +/- 1.2 mg/kg for methohexital and 3.4 +/- 2.1 mg/kg for thiamylal. One out of the 176 procedures was failed due to bradycardia, hypotension and cyanosis, in the methohexital group. Otherwise, no significant adverse events were found. Increased heart rate (HR) during stable blood pressure (BP) was observed in both groups. In conclusion, under careful monitoring and performed by experienced practitioners, the application of methohexital or thiamylal combined with midazolam to achieve deep sedation for invasive procedures in young children with ALL is safe.

We report the results of unrelated cord blood transplantation (CBT) in a 12-year-old boy with Philadelphia chromosome- positive chronic myelogenous leukemia in the chronic phase and a high body weight (68.5 kg at transplantation). Only 1 of the 2 units used engrafted. This unit was not human leukocyte antigen (HLA) class II identical with the patient and had a much larger number of nucleated cells than the other unit (approximately 2.4:1). To our knowledge, this case report is the first to describe successful CBT from two unrelated donors to a cancer patient, who had the highest body weight among CBT recipients in Taiwan.

The mortality rate of patients with retinoblastoma still varies in developing countries, and data for Asia and Taiwan are relatively scarce. In this retrospective study, we aimed to describe the survival characteristics and prognostic factors of 54 retinoblastoma cases diagnosed at the Taipei Veterans General Hospital between 1982 and 2004.From medical records, we retrospectively analyzed the data of 54 consecutive children diagnosed in our hospital between 1982 and 2004 as having retinoblastoma. Data on sex, laterality, age at diagnosis, presenting signs, family history, duration of symptoms, lag time for treatment, spread of tumor, treatment mode, and survival time were collected.Seventy-five percent of the cases were unilateral and 25% of the cases were bilateral. The mean patient age at the time of diagnosis was 26.3 months. The mean duration of symptoms was 2.96 months. After diagnosis, the mean lag time before treatment was 2.59 months. The most common presenting signs were leukocoria (71.4%), red, painful, or tearing eye (18.4%), strabismus (14.3%), and blurred vision (14.3%). Only 3 of 52 cases (5.8%) were familial. The most common sites of extraocular invasion included the central nervous system (seven cases) and the orbit (seven cases). In 13.7% of the cases, parents had refused the treatment suggested by the doctors. None of the patients developed a secondary neoplasm. The 5-year overall survival rate was 80.9% (unilateral, 88.1%; bilateral, 64.3%). The survival rate of patients with an interval between onset and treatment of5 months was 90.9%, and that for an interval of5 months was 60.9%. The survival rate of those with a lag time of2.5 months was 90.0%, and that of those with one of2.5 months was 31.3%. The survival rate of patients with intraocular and extraocular disease was 96.9% and 39.2%, respectively. Extraocular disease was an independent factor indicating a poor prognosis, determined by multivariate analysis.The mortality rate of patients with retinoblastoma is higher in Taiwan than in developed countries. The proportion of patients' parents refusing or delaying treatment in Taiwan is high. The factors for a poor prognosis were an interval between onset and treatment of5 months, a lag time before treatment of2.5 months, and extraocular disease. The duration of symptoms was not a prognostic factor. The only independent factor indicating a poor prognosis was extraocular disease.

Some studies have proved that intravenous busulfan with cyclophosphamide (used as a component of conditioning regimens for hematopoietic stem cell transplantation) is safer and has fewer complication than oral busulfan in adults, whereas the same proof in pediatric patients is only limited, with no reported data so far from Asian countries. In this study, we aimed to evaluate the efficacy and complications of IV busulfan in pediatric patients.Three pediatric patients with acute myeloid leukemia were treated by intravenous busulfan combined with cyclophosphamide to compare retrospectively with the treatment with oral busulfan plus intravenous cyclophosphamide in another three pediatric cases having transplantation in the same institute.The results showed that the intravenous busulfan-based regimen had better compliance and less adverse effects including mucositis, hepatic toxicity, transplant-related hepatic veno-occlusive disease, and acute graft-versus-host disease than oral busulfan-based treatment.The conditioning regimen of intravenous busulfan combined with cyclophosphamide is an acceptable alternative for pediatric patients with hematological malignancies in Taiwan. The long-term benefit and adverse effects of intravenous busulfan should be further explored.

Ganglioneuroma is a rare, differentiated, benign and slow-growing tumor that commonly arises from sympathetic ganglion cells. Most of them are asymptomatic and found incidentally. We here report a quite rare case of silent huge ganglioneuroma growing in both posterior mediastinum and retroperitoneum occurring in a 3.5-year-old girl. The patient was relatively well before and incidentally found to have a huge chest mass by chest X-ray film at an episode of respiratory tract infection. Computed tomography showed a huge tumor extending from bilateral posterior mediastinum to the level of the adrenal gland in the retroperitoneum. Initially, neuroblastoma was highly suspected and 24-hour urine vanillyl mandelic acid was slightly elevated. Cytology by bone marrow aspiration revealed no tumor nests or clumps. Biopsy and pathology proved it as ganglioneuroma (GN). Due to too extensive involvement of the tumor and compression of the vital vessels, surgical removal became difficult. The family of the patient refused surgery due to there being no significant symptoms. Because of the potential for growth of unresectable GN and because the component of neuroblasts could not be completely excluded, the patient was still in dangerous status. The only thing we can do is to keep the family alert and continue regular follow-up.

We report here a 6-year-old girl with fibrous dysplasia (FD) of the mandibular bone. She had a growing mass with local pain over right chin after a severe trauma, which was thought to be chronic osteomyelitis (OM). After failure of antibiotic treatment, malignant bone tumor was suspected from imaging studies including magnetic resonance imaging (MRI). FD of the mandible with chronic OM was confirmed one year after its onset by repeated biopsy performed at our hospital. Causes of delayed diagnosis may include (1) FD of the mandibular bone and chronic OM have similar characteristics clinically and radiographically, (2) the previous biopsy was not performed at appropriate site, and (3) failure to include fibrous dysplasia in the differential diagnosis. In this report, we also review the features in radiology and MRI of OM and FD, which may help differentiate the diagnosis. When a patient with mandibular FD has acute symptoms, the possibility of superimposed OM or malignant change should be considered.

Primary distal type renal tubular acidosis (RTA-type1) results from defects of distal renal tubules in urinary acidification. In attempt to evaluate the clinical features, growth and outcome of primary distal type RTA in Taiwan, we retrospectively studied 28 patients (16 males and 12 females) of primary distal type RTA in our hospital in the past 13 years. The mean age at diagnosis was 2 years and 6.8 months old. Hematuria was found in 5 out of 25 cases (20%). Nephrocalcinosis was found in 5 out of 21 cases (23.8%). The mean value of Uca/Ucr was 0.313 +/- 0.067 in those older than 2 years and 0.262 +/- 0.152 in those younger than 2 years. Rickets was suspected in only one child by radiologic study. At initial diagnosis, the mean bone age was delayed for 16 months. The older the patient was, the more delayed was the bone age. The mean value of height was -2.81 standard deviation score (SDS); the mean value of body weight was -2.44 SDS; and the mean value of growth velocity in height was -2.62 SDS. After alkali therapy given from 8.5 months to 5 years and 7 months, improvement was found in height up to -1.69SDS, in body weight up to -1.10SDS, and in height velocity up to 1.06SDS.

Background Thrombus formation, a phenomenon primarily related to increased platelet activation, plays a key role in cardiovascular and cerebrovascular diseases. Although the established antiplatelet agents, such as aspirin and clopidogrel, have been shown to be beneficial in treating thromboembolic diseases, they have considerable limitations. Hence, the development of more effective and safe antithrombotic agents is necessary to satisfy a substantial unmet clinical need. In recent years, the favorable properties of imidazole-related drugs have prompted medicinal chemists to synthesize numerous novel therapeutic agents. The chemical structure of the benzimidazole backbone has proven antiplatelet properties. Moreover, synthetic oligosaccharides have exhibited antiplatelet properties. Therefore, we developed a new aldo-benzimidazole-derived oligosaccharide compound, M3BIM, for achieving a stronger antiplatelet effect than the drugs which are being used in clinical aspects. We investigated the effects of M3BIM on platelet activation ex vivo and its antithrombotic activity in vivo. Results M3BIM (10–50 μM) exhibited a more potent activity in inhibiting platelet aggregation stimulated by collagen than it did in inhibiting that stimulated by thrombin in washed human platelets. The M3BIM treatment revealed no cytotoxicity in zebrafish embryos, even at the highest concentration of 100 μM. In addition, M3BIM inhibited the phosphorylation of phospholipase Cγ2, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs; extracellular signal-regulated kinase 2 and c-Jun N-terminal kinase 1), and markedly reduced the ATP-release reaction and intracellular calcium mobilization in collagen-activated platelets. By contrast, M3BIM showed no effects on either collagen-induced p38 MAPK and Akt phosphorylation or phorbol 12, 13-dibutyrate-induced PKC activation and platelet aggregation. Moreover, the M3BIM treatment substantially prolonged the closure time in human whole blood, and increased the occlusion time in mesenteric microvessels and attenuated cerebral infarction in mice. For the study of anticoagulant activities, M3BIM showed no significant effects in the prolongation of activated partial thromboplastin time and prothrombin time in mice. Conclusion The findings of our study suggest that M3BIM is a potential therapeutic agent for preventing or treating thromboembolic disorders.