Evaluation of next-generation sequencing for measurable residual disease monitoring in three major fusion transcript subtypes of B-precursor acute lymphoblastic leukaemia.

The use of next-generation sequencing (NGS) for monitoring measurable residual disease (MRD) in acute lymphoblastic leukaemia (ALL) has been gaining traction. This study aimed to investigate the utility of NGS in MRD monitoring for the three major fusion transcript (FT) subtypes of B-precursor ALL (B-ALL). The MRD results for 104 bone marrow samples from 56 patients were analysed through NGS and real time quantitative reverse transcription PCR (RT-qPCR) for the three major FTs: BCR::ABL1, TCF3::PBX1, and ETV6::RUNX1. To validate the NGS approach, NGS-MRD was initially compared with allele-specific oligonucleotide-qPCR-MRD, and the coefficient of determination was good (R2=0.8158). A subsequent comparison of NGS-MRD with FT-MRD yielded a good coefficient of determination (R2=0.7690), but the coefficient varied by subtype. Specifically, the R2 was excellent for TCF3::PBX1 ALL (R2=0.9157), good for ETV6::RUNX1 ALL (R2=0.8606), and subpar for BCR::ABL1 ALL (R2=0.5763). The overall concordance between the two methods was 83.7%, and an excellent concordance rate of 95.8% was achieved for TCF3::PBX1 ALL. Major discordance, which was defined as a >1 log difference between discordant NGS-MRD and FT-MRD, occurred in 6.7% of the samples, with all but one sample being BCR::ABL1 ALL. Among the four non-transplanted patients with BCR::ABL1-MRD (+)/NGS-MRD (-), three did not relapse after long-term follow-up. Our finding indicates that NGS-MRD has a better prognostic impact than RT-qPCR-MRD in ETV6::RUNX1 and BCR::ABL1 ALL, whereas in TCF3::PBX1 ALL, both methods exhibit comparable efficacy.

The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats.

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.

Refining risk stratification in paediatric B-acute lymphoblastic leukaemia: Combining IKZF1plus and Day 15 MRD positivity.

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.

Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

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.

Melatonin protects against methotrexate hepatotoxicity in young rats: Impact of PI3K/Akt/mTOR signaling.

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.

Surgical treatment confers prognostic significance in pediatric malignant mediastinal germ cell tumors.

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.

Steroid-Induced Ocular Hypertension in a Pediatric Patient with Acute Lymphoblastic Leukemia: A Case Report.

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.

The Application of Focused Medium-Energy Extracorporeal Shockwave Therapy in Hemophilic A Arthropathy.

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.

Influence of blood group and von Willebrand factor on population pharmacokinetics and dose individualization of recombinant factor VIII in Taiwanese patients with haemophilia A.

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.

Characteristics and outcomes of second cancers in patients with childhood cancer: A report from the Taiwan Pediatric Oncology Group.

BACKGROUND: Patients with childhood cancer are at increased risk for the development of second cancers. METHODS: A national multicenter survey of second cancers conducted by the Taiwan Pediatric Oncology Group retrieved retrospective data from the database at the Children Cancer Foundation in Taiwan beginning in 1995. The characteristics of second cancers and associations of patient demographic and clinical characteristics with time to death due to a second cancer were analyzed. RESULTS: We examined the records of 8782 patients with a primary cancer diagnosed between January 1, 1995 and December 31, 2013, and a total of 99 patients with a second cancer were identified. The most common type of second cancer was acute myeloid leukemia (n = 35), followed by acute lymphoblastic leukemia (n = 15), central nervous system (CNS) tumors (n = 15), and sarcomas (n = 10). Secondary hematological malignancies occurred earlier than other secondary cancers. The frequencies of second CNS tumors and second bone cancers and sarcomas were notably increased when prior radiation doses increased from zero, low dose to high dose. The overall 5-year survival of patients with a second cancer was poor (33.7%). Multivariate survival analysis revealed that the year of primary diagnosis ≤2002, secondary hematological malignancies, and age at second cancer diagnosis ≤9.3 years or >26.8 years increased the risk of death following second cancer. CONCLUSION: Children who develop a second cancer have an unfavorable outcome. Early detection and improved treatment for second cancers are needed.

Triamcinolone acetonide modulates TGF­ß2­induced angiogenic and tissue­remodeling effects in cultured human retinal pigment epithelial cells.

Transforming growth factor­ß2 (TGF­ß2) has been implicated in the pathogenesis of proliferative vitreoretinopathy (PVR) and proliferative diabetic retinopathy (PDR), due to its ability to stimulate the overproduction of pro­angiogenic 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 TGF­ß2­driven 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 R­50 human RPE cell line was treated with TA in the presence of TGF­ß2, 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 transcription­quantitative PCR and ELISA, respectively. The phosphorylation status of signaling mediators and the protein expression of type I collagen (COL1A1), α­smooth muscle actin (α­SMA), and ECM­remodeling enzymes, including MMP­2 and MMP­9, were analyzed using western blotting. The gelatinolytic activity of MMPs was detected using gelatin zymography. TA treatment exhibited no prominent cytotoxicity but markedly antagonized TGF­ß2­induced cytostatic effects on RPE cell viability and TGF­ß2­enhanced contractility in collagen gels. In the context of TGF­ß2­related signaling, TA significantly attenuated TGF­ß2­elicited Smad2, extracellular­regulated kinase (ERK)1/2 and p38 mitogen­activated protein kinase (MAPK) phosphorylation. Moreover, TA markedly mitigated TGF­ß2­induced VEGF upregulation through ablation of p38 signaling activity. TA also partially attenuated TGF­ß2­elicted expression of COL1A1, α­SMA, MMP­2, and MMP­9, but only suppressed TGF­ß2­induced MMP­9 gelatinolytic activity. Mechanistically, the MEK/ERK signaling pathway may have a critical role in the TGF­ß2­induced upregulation of COL1A1, α­SMA and MMP­9. In conclusion, TA may be considered a useful therapeutic agent for treating TGF­ß2­associated intraocular angiogenesis and tissue remodeling, the underlying mechanism of which may involve the ERK and p38 MAPK signaling pathways.

Methotrexate Neurotoxicity Is Related to Epigenetic Modification of the Myelination Process.

With the improvement of the survival rate of acute lymphoblastic leukemia (ALL) in children, some children ALL survivors reveal inferior intellectual and cognition outcome. Methotrexate (MTX), while serving as an essential component in ALL treatment, has been reported to be related to various neurologic sequelae. Using combined intrathecal (IT) and intraperitoneal (IP) MTX model, we had demonstrated impaired spatial memory function in developing rats, which can be rescued by melatonin treatment. To elucidate the impact of MTX treatment on the epigenetic modifications of the myelination process, we examined the change of neurotrophin and myelination-related transcriptomes in the present study and found combined IT and IP MTX treatment resulted in altered epigenetic modification on the myelination process, mainly in the hippocampus. Further, melatonin can restore the MTX effect through alterations of the epigenetic pathways.

Comparison of Two Quantitative PCR-Based Assays for Detection of Minimal Residual Disease in B-Precursor Acute Lymphoblastic Leukemia Harboring Three Major Fusion Transcripts.

Two quantitative PCR (qPCR)-based methods, for clonal immunoglobulin or T-cell receptor gene (Ig/TCR) rearrangements and for fusion transcripts, are widely used for the measurement of minimal residual disease (MRD) in patients with B-precursor acute lymphoblastic leukemia (ALL). MRD of bone marrow samples from 165 patients carrying the three major fusion transcripts, including 74 BCR-ABL1, 54 ETV6-RUNX1, and 37 TCF3-PBX1, was analyzed by using the two qPCR-based methods. The correlation coefficient of both methods was good for TCF3-PBX1 (R2 = 0.8088) and BCR-ABL1 (R2 = 0.8094) ALL and moderate for ETV6-RUNX1 (R2 = 0.5972). The concordance was perfect for TCF3-PBX1 ALL (97.2%), substantially concordant for ETV6-RUNX1 ALL (87.1%), and only moderate for BCR-ABL1 ALL (70.6%). The discordant MRD, positive for only one method with a difference greater than one log, was found in 4 of 93 samples (4.3%) with ETV6-RUNX1, 31 of 245 samples (12.7%) with BCR-ABL1, and none of TCF3-PBX1 ALL. None of the eight non-transplanted patients with BCR-ABL1-MRD (+)/Ig/TCR-MRD (-) with a median follow-up time of 73.5 months had hematologic relapses. Our study showed an excellent MRD concordance between the two qPCR-based methods in TCF3-PBX1 ALL, whereas qPCR for Ig/TCR is more reliable in BCR-ABL1 ALL.

Treatment outcomes of pediatric acute myeloid leukemia: a retrospective analysis from 1996 to 2019 in Taiwan.

Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0-18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996-December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008-2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996-2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1-RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008-2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008-2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008-2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents' use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan.

RAS pathway mutation is an added-value biomarker in pediatric Philadelphia-negative B-cell acute lymphoblastic leukemia with IKZF1 deletions.

BACKGROUND: IKZF1deletion is an unfavorable factor in Philadelphia negative (Ph -) B-cell acute lymphoblastic leukemia. However, the effects of IKZF1 deletions co-existing genetic alterations in Ph (-) ALL have not been extensively studied. METHODS: Bone marrow samples from 368 children with Ph (-) ALL were analyzed by using multiplex ligation-dependent probe amplification kit for detection of gene deletions and Sanger sequencing for mutational analysis of RAS pathway genes. The outcome was analyzed on 215 patients treated with Taiwan Pediatric Oncology Group-ALL-2002 protocol. RESULTS: IKZF1 deletions were present in 12.8% and IKZF1plus in 6.3% of patients. Mutations of RAS pathway genes were detected in 25.0% of IKZF1-deleted patients. The 10-year event-free survival (EFS) of IKZF1-undeleted patients was significantly better compared with IKZF1-deleted patients (80.0% vs. 47.8%, p = 0.001). Compared with outcome of patients harboring IKZF1 deletion alone, no difference in EFS was observed in patients with IKZF1plus , whereas three patients carried both IKZF1 and ERG deletions had a superior 10-year EFS (100%). The 10-year EFS of patients with any gene mutation of RAS pathway was worse than that of patients with wild-type genes (79.1% vs. 61.6%, p = 0.033). In multivariate analysis, RAS pathway mutations and IKZF1 deletion were independent predictors of inferior EFS. Co-existence of IKZF1 deletion with RAS pathway mutations had a worst 10-year EFS (11.1 ± 10.5%) and 10-year OS (53.3 ± 17.6%). CONCLUSIONS: Our results showed that RAS pathway mutation is an added-value biomarker in pediatric IKZF1-deleted Ph (-) ALL patients.

Development of a Novel Interactive Multimedia E-Learning Model to Enhance Clinical Competency Training and Quality of Care among Medical Students.

Clinical competencies consisting of skills, knowledge, and communication techniques should be acquired by all medical graduates to optimize healthcare quality. However, transitioning from observation to hands-on learning in clinical competencies poses a challenge to medical students. The aim of this study is to evaluate the impact of a novel interactive multimedia eBook curriculum in clinical competency training. Ninety-six medical students were recruited. Students in the control group (n = 46) were taught clinical competencies via conventional teaching, while students in the experimental group (n = 50) were taught with conventional teaching plus interactive multimedia eBooks. The outcomes of clinical competencies were evaluated using Objective Structured Clinical Examination (OSCE) scores, and feedback on their interactive eBook experiences was obtained. In the experimental group, the average National OSCE scores were not only higher than the control group (214.8 vs. 206.5, p < 0.001), but also showed a quicker improvement when comparing between three consecutive mock OSCEs (p < 0.001). In response to open-ended questions, participants emphasized the importance of eBooks in improving their abilities and self-confidence when dealing with 'difficult' patients. Implementing interactive multimedia eBooks could prompt a more rapid improvement in clinical skill performance to provide safer healthcare, indicating the potential of our innovative module in enhancing clinical competencies.

Melatonin rescued methotrexate-induced spatial deficit and hyperhomocysteinemia and increased asymmetric dimethylarginine in plasma and dorsal hippocampus in developing rats.

AIMS: With the improvement of the survival rates in children acute lymphoblastic leukemia (ALL), some children ALL survivors show impaired cognitive function. Methotrexate (MTX), an essential component in ALL treatment, has been reported to be related to neurologic sequelae and to increased oxidative stress through its interactions with enzymes in the folate pathway. Asymmetric dimethylarginine (ADMA) is the main endogenous inhibitor of nitric oxide synthase, and increased ADMA may result from increased oxidants. Melatonin is an antioxidant; however, its role in MTX neuropathy is not well studied. We developed a rat model mimicking child ALL treatment to explore peripheral and central homocysteine and ADMA regulation after MTX and found potential treatment choice. MAIN METHODS: Preweaning male Sprague-Dawley rats were used in this study. Experiment 1 evaluated spatial performance in rats with intrathecal (IT) MTX, intraperitoneal (IP) MTX, or combined IT and IP MTX, protocols mimicking ALL treatment in children. Experiment 2 focused on rats with combined IT and IP MTX, evaluating spatial performance and plasma and dorsal hippocampal homocysteine and ADMA levels, their regulation, and the protective effect of melatonin. KEY FINDINGS: Combined IT and IP MTX treatment caused in spatial deficits in developing rats, and melatonin restored the spatial performance. Alterations in peripheral and central homocysteine and ADMA concentrations and their regulation were found and could be alleviated by melatonin treatment. SIGNIFICANCES: Combined IP and IT MTX treatment caused spatial deficits in developing rats. Melatonin could restore spatial performance through alleviating the effects on the imbalance of oxidative stress.

Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study.

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.