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Background/Objectives: Relapsed B-cell acute lymphoblastic leukemia (B-ALL) remains an unresolved matter of concern regarding adverse outcomes. This case study aimed to evaluate the effectiveness of blinatumomab, with or without door lymphocyte infusion (DLI), in treating measurable residual disease (MRD)-positive B-ALL. Methods: All patients who received blinatumomab salvage therapy were included in this study. Eleven patients were included in the study. All patients were evaluated for MRD-negativity. Results: Before starting blinatumomab therapy, seven patients tested positive for MRD, three tested negative, and one had refractory disease. Hematopoietic cell transplantation (HCT) was reserved for five patients with persistent MRD. Six patients became MRD-negative and subsequent HCT was not performed. Only two patients relapsed; one patient died of relapse, and the other one received carfilzomib-based therapy and was MRD-negative thereafter. Nine patients were MRD-negative at a median follow-up of 28 months (15–52 months). Two of three MRD-positive post-transplant patients remained in complete molecular remission after preemptive DLI at the last follow-up date. In the first salvage, blinatumomab may achieve complete remission and bridging to HCT in pediatric patients with end-of-induction MRD-positive B-cell precursor ALL. Conclusions: The decision on how to treat post-transplant relapse continues to affect survival outcomes. Blinatumomab combined with DLI may extend the armamentarium of release options for high-risk pediatric patients. This approach is encouraging for high-risk ALL patients who are MRD-positive post-transplantation. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is an essential part of therapy in the treatment of acute lymphoblastic leukemia (ALL) in children, and inferior intellectual outcomes have been reported in children who are leukemia survivors. Although several studies have demonstrated that the interaction between gut microbiota changes and the brain plays a vital role in the pathogenesis of chemotherapy-induced brain injury, preexisting studies on the effect of MTX on gut microbiota changes focused on gastrointestinal toxicity only. Based on our previous studies, which revealed that MTX treatment resulted in inferior neurocognitive function in developing young rats, we built a young rat model mimicking MTX treatment in a child ALL protocol, trying to investigate the interactions between the gut and brain in response to MTX treatment. We found an association between gut microbiota changes and neurogenesis/repair processes in response to MTX treatment, which suggest that MTX treatment results in gut dysbiosis, which is considered to be related to MTX neurotoxicity through an alteration in gut–brain axis communication. [ABSTRACT FROM AUTHOR]

Summary: This study investigates the potential utility of IKZF1 deletion as an additional high‐risk marker for paediatric acute lymphoblastic leukaemia (ALL). The prognostic impact of IKZF1 status, in conjunction with minimal/measurable residual disease (MRD), was evaluated within the MRD‐guided TPOG‐ALL‐2013 protocol using 412 newly diagnosed B‐ALL patients aged 1–18. IKZF1 status was determined using multiplex ligation‐dependent probe amplification. IKZF1 deletions, when co‐occurring with CDKN2A, CDKN2B, PAX5 or PAR1 region deletions in the absence of ERG deletions, were termed IKZF1plus. Both IKZF1 deletion (14.6%) and IKZF1plus (7.8%) independently predicted poorer outcomes in B‐ALL. IKZF1plus was observed in 4.1% of Philadelphia‐negative ALL, with a significantly lower 5‐year event‐free survival (53.9%) compared to IKZF1 deletion alone (83.8%) and wild‐type IKZF1 (91.3%) (p < 0.0001). Among patients with Day 15 MRD ≥0.01%, provisional high‐risk patients with IKZF1plus exhibited the worst outcomes in event‐free survival (42.0%), relapse‐free survival (48.0%) and overall survival (72.7%) compared to other groups (p < 0.0001). Integration of IKZF1plus and positive Day 15 MRD identified a subgroup of Philadelphia‐negative B‐ALL with a 50% risk of relapse. This study highlights the importance of assessing IKZF1plus alongside Day 15 MRD positivity to identify patients at increased risk of adverse outcomes, potentially minimizing overtreatment. [ABSTRACT FROM AUTHOR]

Introduction: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. Methods: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. Results and discussion: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5–578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p <.01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p <.01). Twenty‐seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p <.01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug‐related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. Conclusions: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed. [ABSTRACT FROM AUTHOR]

With the improvement in children's acute lymphoblastic leukemia (ALL) care, the survival rate in children ALL has improved much. Methotrexate (MTX) plays an essential role in the success of children's ALL treatment. Since hepatotoxicity is commonly reported in individuals treated with intravenous or oral MTX, our study further examined the hepatic effect following intrathecal MTX treatment, which is an essential treatment for leukemia patients. Specifically, we examined the pathogenesis of MTX hepatotoxicity in young rats and explored the impact of melatonin treatment in protection against MTX hepatotoxicity. Successfully, we found that melatonin was able to protect against MTX hepatotoxicity. [ABSTRACT FROM AUTHOR]

Background: Primary malignant mediastinal germ cell tumors (GCTs) are rare pediatric tumors that have a poorer prognosis compared to GCTs occurring elsewhere in the body. The current study aimed to assess the prognostic factors and treatment outcomes of children with primary malignant mediastinal GCT in Taiwan. Methods: The authors retrospectively reviewed children 0–18 years old who were newly diagnosed with primary malignant mediastinal GCT between January 1, 2005 and December 31, 2019 and were registered in the Taiwan Pediatric Oncology Group patient registry. The impact of presenting characteristics, including sex, age, tumor stage, histology subtype, surgical treatment, and chemotherapy regimens of the patients were analyzed. Results: This study enrolled 52 children with malignant mediastinal GCT who had a median age of 16.0 (range, 6.0–17.9) years at diagnosis. The most common histological subtypes were mixed GCTs (n = 20) and yolk sac tumors (n = 15). Advanced disease stage and choriocarcinoma histology subtype were associated inferior outcomes. Children who received surgical treatment exhibited better outcomes compared to those who did not (5‐year overall survival, 78% vs. 7%, p <.001). After comparing patients who received first‐line cisplatin‐ and carboplatin‐based chemotherapy, no difference in treatment outcomes was observed. Multivariate analysis showed that surgical management was the only independent predictor for superior OS. Conclusions: Surgical treatment is recommended for mediastinal GCT. Cisplatin‐based chemotherapy was not superior to carboplatin‐based chemotherapy as first‐line treatment and may be avoided due to toxicity concerns. Surgical treatment is recommended for pediatric malignant mediastinal germ cell tumors. Cisplatin‐based chemotherapy was not superior to carboplatin‐based chemotherapy as first‐line treatment. [ABSTRACT FROM AUTHOR]

Introduction: The large interpatient variability in the pharmacokinetic (PK) parameters of recombinant Factor VIII (rFVIII) observed in haemophilia A hinders efficient and cost‐beneficial prophylactic regimen initiation. Identification of factors influencing the PK of rFVIII may shed more light on personalised treatment. Aim: This study aimed to develop a population PK model in the Taiwanese haemophilia A and evaluate the current national health insurance (NHI) reimbursement guidelines of Taiwan for haemophilia treatment. Methods: A population PK analysis was established based on 69 Taiwanese with moderate or severe haemophilia A. A nonlinear mixed‐effects modelling (NONMEM®) was used to estimate PK parameters and their variabilities. A Monte Carlo simulation was performed to evaluate different prophylactic regimens. Results: A two‐compartment model with first‐order elimination best described the rFVIII data. Weight‐based allometric scaling was related to clearance and central volume of distribution. Blood type and baseline von Willebrand factor (VWF) were significant covariates for clearance. For single dose simulations, a time achieving target level (> 1 IU/dL) was associated with increasing rFVIII dose and VWF level. The multiple dose simulations showed that > 96.4% of patients with high VWF level (> 200%) had predicted trough level > 1 IU/dL for all dosing regimens (15‐40 IU/kg, two to three times weekly). However, for twice weekly dosing, lower percentage (47.62‐62.20%) of patients with blood group O and low VWF level (< 50%) achieved a predicted trough level > 1 IU/dL. Conclusion: The population PK of rFVIII was successfully developed. Dose adjustment based on blood type and VWF level should be considered. [ABSTRACT FROM AUTHOR]

Glucocorticoids play a pivotal role in therapeutic protocols in acute lymphoblastic leukemia (ALL) treatment. Systemic steroids are known to be less likely to elevate the intraocular pressure when compared to topical administration, and reports addressing hypertensive ocular response in the Asian pediatric ALL population are currently limited. We report a case of a nine-year-old girl with acute lymphoblastic leukemia (ALL) who was found to have highly elevated intraocular pressure (IOP) during maintenance treatment when taking oral dexamethasone (6 mg/m2/day). Her IOP increased on day 5 after taking dexamethasone, reached a peak on day 7 or 8, and returned back to baseline on day 13 before anti-glaucoma medications were used. Thus, we prescribed IOP-lowering agents for 10 consecutive days starting on the day oral dexamethasone was administered, and observed that not only did the peak levels lower remarkably, but the IOP levels returned to baseline more rapidly as well. [ABSTRACT FROM AUTHOR]

Background: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL).Methods: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT).Results: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2.Conclusions: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status. [ABSTRACT FROM AUTHOR]

Background/purpose: Real-time quantitative polymerase chain reaction (RQ-PCR) for fusion transcripts and flow cytometry for leukemia-specific markers are widely used for minimal residual disease (MRD) detection in acute lymphoblastic leukemia, but the relation between the results of either method is unclear.Methods: Mononucleated cells from 108 bone marrow samples collected from 55 B-precursor acute lymphoblastic leukemia patients (30 with t(12;21)/ETV6-RUNX1, 16 with t(9;22)/BCR-ABL1 and nine with t(1;19)/TCF3-PBX1) were examined in tandem by RQ-PCR and six-color flow cytometry.Results: MRD results were concordant in 91 of the 108 paired samples (84.2%; K=0.690); 49 samples were MRD-negative while 42 were MRD-positive by both methods, with < 1 log difference in positive MRD estimates in 39 samples (92.9%). Of the 17 discordant samples, 16 were MRD-positive by RQ-PCR but MRD-negative by flow cytometry; the opposite was true in one sample. Kappa value/concordance was 0.690/85.0% (n = 60) for ETV6-RUNX1, 0.842/93.3% (n = 15) for TCF3-PBX1, and 0.535/78.8% (n = 33) for BCR-ABL1. Specific immunophenotypic abnormalities were more prevalent in each genetic subgroup, such as CD38 underexpression, CD58 overexpression, and CD34 overexpression in ETV6-RUNX1, TCF3-PBX1, and BCR-ABL1, respectively.Conclusion: In most follow-up samples, MRD estimates by two methods are in agreement, especially in patients with TCF3-PBX1. [ABSTRACT FROM AUTHOR]

The cement industry is the most energy intensive of Taiwan's manufacturing industries. This paper presents a case study of the greenhouse gas (GHG) inventory in Taiwan's cement industry, which includes an analysis of GHG emission intensity (EI) and the testing of raw meal calcination. The GHG inventory analysis results show that direct GHG emissions (Scope 1) are the largest emission source of the study subject, the H plant. As regards the EI analysis results of Taiwan's cement plants, only one cement plant (H plant) meets the EI limit announced by the Environmental Protection Administration (EPA) of Taiwan. According to the calcination test, the major calcination reaction occurs in the 700–900°C temperature range and accounts for nearly 87% of total CO2emissions. Finally, a modified and feasible process is proposed as a base case for simulating options for GHG reductions in the cement industry. The modified process can reduce coal consumption and pipeline corrosion, and increase the efficiency of waste heat recovery and the calcination rate; these procedures require low investment and operating cost. [ABSTRACT FROM PUBLISHER]

Hemophilic arthropathy causes the damage of synovium, cartilage, and subchondral bone. The present study evaluated the safety and the effect of extracorporeal shockwave therapy (ESWT), a safe treatment widely used in musculoskeletal conditions in patients with hemophilic arthropathy. Between 1 August 2019 and 31 July 2020, seven hemophilia A patients were enrolled and treated with medium-energy ESWT on the knee joint in the first two months after prophylactic coagulation factor administration. At the beginning of the study and at 1-, 2-, 3-, and 6-month follow-ups, the Hemophilia Joint Health Score (HJHS), visual analog scale score (VAS), and Hemophilia Early Arthropathy Detection with Ultrasound score (HEAD-US) were evaluated for therapeutic effectiveness and safety, while serum bone morphogenetic protein 2 (BMP-2) and von Willebrand factor (vWF) levels were analyzed for assessing chondroprotection and bone healing. Magnetic resonance imaging (MRI) of the knee was performed at the beginning of the study and the 6-month follow-ups. As a result, a non-significant decrease in VAS scores (p = 0.151) but not HJHS after treatment was noticed. At the 3-month follow-up, there was a non-significant increase in BMP2 levels (p = 0.171) but not vWF. Ultrasonography showed no disease activity score elevation in five patients and no further disease damage in all patients. Repeated MRI examinations in three patients showed no structural progression during the 6-month follow-up. As to adverse events, redness, local heat, and mild swelling were noted in five patients without breakthrough bleeding. We concluded that medium-energy ESWT might be safe for hemophilic arthropathy once prophylactic coagulation factors are administered. [ABSTRACT FROM AUTHOR]

Intussusception is a common cause of abdominal pain in children. Although most cases are idiopathic, about 10% of cases have a pathologic lead point. Burkitt''s lymphoma is not a common etiology. Burkitt''s lymphoma might present primarily as intussusception in children but has rarely been associated with appendicitis. We report a case in which a 10-year-old obese boy who initially presented with acute appendicitis due to ileocolic intussusception with appendiceal invagination. He underwent one-trocar laparoscopy and antibiotic treatment. The symptoms recurred 10 days after discharge. Colonoscopy disclosed ileocecal Burkitt''s lymphoma as the pathological lead point. This case emphasizes the importance of the age of the patient and the anatomic location of the intussusception related to possible etiology, and hence the most appropriate surgical procedure. [Copyright &y& Elsevier]

Over the past few decades, Taiwan has seen striking improvements in the life expectancy of its 400 registered β-thalassemia major (β-TM) patients due mainly to adequate transfusion regimens and effective iron chelation therapy. Since 1995, Taiwanese citizens have enjoyed universal health care through National Health Insurance (NIH), receiving comprehensive treatment at minimal cost. In 1984, a national program for thalassemia prevention, control, and hematopoietic stem cell transplantation (HSCT) was initiated. Recent data show 1- and 2-year event-free survival rates of 85 and 78%, respectively. Chelation agents like deferoxamine (DFO), deferiprone (L1) and deferasirox (DFRA) are available in Taiwan, and therapy is tailored to individuals based on drug availability and tissue distribution of iron load. Intensive chelation regimens combining L1 and DFO are recommended in patients with cardiac complications, while DFRA has been found to be effective in reducing serum ferritin, with acceptable side effects. Here, we report advances in thalassemia treatment in Taiwan and suggest treatment guidelines. [ABSTRACT FROM AUTHOR]

Transforming growth factor-β2 (TGF-β2) has been implicated in the pathogenesis of proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), due to its ability to stimulate the overproduction of pro-angiogenic factors, such as vascular endothelial growth factor (VEGF), and remodeling of the extracellular matrix (ECM). Although intravitreal triamcinolone acetonide (TA) is clinically useful in the treatment of PVR and PDR, its molecular mechanism has yet to be fully elucidated. The present study investigated whether TA treatment altered TGF-β2-driven biological effects on the behavior of cultured human retinal pigment epithelial (RPE) cells, in order to determine which signaling pathway may be essential for the pharmacological action of TA. The R-50 human RPE cell line was treated with TA in the presence of TGF-β2, followed by analyses of cell viability and contraction using cell viability and collagen gel contraction assays. VEGF mRNA expression and protein production were measured using reverse transcription-quantitative PCR and ELISA, respectively. The phosphorylation status of signaling mediators and the protein expression of type I collagen (COL1A1), α-smooth muscle actin (α-SMA), and ECM-remodeling enzymes, including MMP-2 and MMP-9, were analyzed using western blotting. The gelatinolytic activity of MMPs was detected using gelatin zymography. TA treatment exhibited no prominent cytotoxicity but markedly antagonized TGF-β2-induced cytostatic effects on RPE cell viability and TGF-β2-enhanced contractility in collagen gels. In the context of TGF-β2-related signaling, TA significantly attenuated TGF-β2-elicited Smad2, extracellular-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase (MAPK) phosphorylation. Moreover, TA markedly mitigated TGF-β2-induced VEGF upregulation through ablation of p38 signaling activity. TA also partially attenuated TGF-β2-elicted expression of COL1A1, α-SMA, MMP-2, and MMP-9, but only suppressed TGF-β2-induced MMP-9 gelatinolytic activity. Mechanistically, the MEK/ERK signaling pathway may have a critical role in the TGF-β2-induced upregulation of COL1A1, α-SMA and MMP-9. In conclusion, TA may be considered a useful therapeutic agent for treating TGF-β2-associated intraocular angiogenesis and tissue remodeling, the underlying mechanism of which may involve the ERK and p38 MAPK signaling pathways. [ABSTRACT FROM AUTHOR]

Deferiprone (L1) has been recommended as an effective oral chelation therapy for patients with ß-thalassemia major (TM). From 1999 to 2004, 114 patients with TM from five treatment centers were enrolled in this program: iron (Fe) was chelated with L1 in 57 patients, deferoxamine (DFO) in 26, and combined L1/DFO therapy in 31. We found that serum ferritin (SF) was significantly lower in nine patients receiving L1 for more than 5 years ( p = 0.04), 22 patients receiving L1 for 1–2 years ( p [ABSTRACT FROM AUTHOR]

Objective: Although Epstein-Barr virus (EBV) is known to cause immune thrombocytopenic purpura (ITP), the epidemiology of this pathogen in children with ITP is not known. In the present study, the clinicoepidemiology and laboratory characteristics of EBV-associated ITP in childhood were analysed retrospectively.Methods: The study cohort consisted of 108 children in whom ITP was diagnosed between 1990 and 1998. Patients were divided into EBV or non-EBV groups according to their serological status at diagnosis.Results: Thirty-five (32.4%) of 108 children had ITP associated with acute EBV infection. The clinical manifestations and laboratory data were similar in children with and without acute EBV. Responses to various modalities of therapy were analysed. The average time to achieve complete remission (platelet count > or =150 x 10(9)/L) in EBV and non-EBV groups was 26 and 16 days, respectively.Conclusions: The incidence of childhood ITP associated with acute EBV infection is relatively high in Taiwan. Patients with EBV-associated ITP tended to resolve more slowly than those without EBV infection. [ABSTRACT FROM AUTHOR]