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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.

To examine the trajectory of decisional conflict and anxiety experienced by adolescents after the cancer diagnosis, and explore their perceptions on participation in shared decision-making (SDM).This longitudinal study used incorporated data from questionnaires and interviews.Participants recruited from an academic hospital in southern Taiwan ranged in age from 13 to 20 years with a cancer diagnosis within 1 month and received cancer treatment. Each participant completed questionnaires on decisional conflict and anxiety at diagnosis, 1, 3, and 6 months later. Individual interviews were to gain an in-depth understanding of SDM.Total scores on decisional conflict changed significantly over time (F = 2.98, p = 0.039); the scores at 1 month were higher than 3 months (t = 2.18, p = 0.04) and 6 months (t = 2.97, p = 0.008). Participants perceived significantly different levels of values clarify (F = 9.49, p 0.01) and support (F = 8.46, p 0.01) over time. Only 27.3% of participants were anxiety-free. No significant differences were found in anxiety over time. The perception of SDM was a situational involvement.Decisional conflict changed over time. Participants experienced greater decisional conflict at 4-8 weeks after diagnosis and their anxiety did not decrease over time. The different levels of participation in SDM during their treatment trajectory were found.Participants experienced the highest decisional conflict during diagnosis, and highlighted how their roles in healthcare discussions varied from direct participation to indirect involvement. Further research is needed to develop an SDM model which accommodates different levels of needs and implements timely support.

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.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.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.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.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL), the most common childhood cancer, originates from lymphoid precursor cells in bone marrow committed to the B-cell lineage. Environmental factors and genetic abnormalities disturb the normal maturation of these precursor cells, promoting the formation of leukemia cells and suppressing normal hematopoiesis. The underlying mechanisms of progression are unclear, but BCP-ALL incidence seems to be increasing in parallel with the adoption of modern lifestyles. This study hypothesized that air pollution and haze are risk factors for BCP-ALL progression. The current study revealed that indeno(1,2,3-cd)pyrene (IP), a major component of polycyclic aromatic hydrocarbons (PAHs) in air, promotes oncogenic activities (proliferation, transformation, and disease relapse) in vitro and in vivo. Mechanistically, IP treatment activated the aryl hydrocarbon receptor (AHR)–indoleamine-2,3-dioxygenase (IDOs) axis, thereby enhancing tryptophan metabolism and kynurenine (KYN) level and consequent promoting the KYN–AHR feedback loop. IP treatment decreased the time to disease relapse and increased the BCP-ALL cell count in an orthotopic xenograft mouse model. Additionally, in 50 clinical BCP-ALL samples, AHR and IDO were co-expressed in a disease-specific manner at mRNA and protein levels, while their mRNA levels showed a significant correlation with disease-free survival duration. These results indicated that PAH/IP exposure promotes BCP-ALL disease progression. Graphical abstract

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.

Aims To investigate practice patterns in exit-site care and identify the risk factors for exit-site infection. Design A quantitative cross-sectional design. Methods Data were collected in 12 peritoneal dialysis (PD) centres in 2018. Daily exit-site care practice patterns and exit-site status of patients receiving PD were assessed through interviews and questionnaires. Results/findings Most of the 1,204 patients adhered with the protocols about main aspects of exit-site care, such as cleansing agents selection, frequency of cleansing, catheter fixation, and following the catheter protective measures. However, their adherence levels on hand hygiene, mask wearing, observing exit site, examining secretion, and communicating with PD staff were rather low. Eighty-four patients' exit sites were evaluated as problematic exit site (PES). And 186 patients had catheter-related infection (CRI) history. After multivariable logistic regression analysis, diabetes (OR = 1.631), traction bleeding history (OR = 2.697), antibiotic agents use (OR = 2.460), compliance on mask wearing (OR = 0.794), and observing exit site (OR = 0.806) were influencing factors of CRI history. Traction bleeding history (OR = 2.436), CRI history (OR = 10.280), and effective communication (OR = 0.808) with PD staff were influencing factors for PES. Conclusions The adherence levels on different aspects of exit-site care were varied in patients having PD. Their self-care behaviours did correlate with the exit-site status. Impact The adherence level of patients' exit-site care practice needs attention of medical staff. Further studies about the optimal procedure in exit-site care were warranted.

Background Existence of breast cancer stem cells (BCSCs) is implicated in disease relapse, metastasis, and resistance of treatment. β1,3-Galactosyltransferase 5 (B3GALT5) has been shown to be a pro-survival marker for BCSCs. However, little is known about the prognostic significance of B3GALT5 in breast cancer. Methods Paired tissues (tumor part and adjacent non-tumor part) from a cohort of 202 women with breast cancer were used to determine the expression levels of B3GALT5 mRNA by qRT-PCR. Kaplan–Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of relapse-free survival (RFS) and overall survival (OS). Both breast cancer cells and cancer stem cells (BCSCs) were used to see the in vitro effects of knockdown or overexpression of B3GALT5 on cell migration, invasion, and epithelial-to-mesenchymal transition (EMT). A patient-derived xenograft (PDX) model was used to see the in vivo effects of knockdown of B3GALT5 in BCSCs on tumor growth and metastasis. Results Higher expression of B3GALT5 in 202 breast cancer tissues, especially in adjacent non-tumor tissue, correlated with poor clinical outcomes including shorter OS and RFS in all patients, especially those with early stage breast cancer. In vitro studies showed B3GALT5 could enhance cell migration, invasion, mammosphere formation, and EMT. Of note, B3GALT5 upregulated the expression of β-catenin and EMT activator zinc finger E-box binding homeobox 1 (ZEB1) pathway in BCSCs. In vivo studies showed B3GALT5 expression in BCSCs is critical for not only tumor growth but also lymph node and lung metastasis in PDX mice. Conclusion Our results demonstrated the value of B3GALT5 as a prognostic marker of breast cancer, especially among the early stage patients, and its crucial roles in regulating EMT, cell migration, and stemness thereby promoting breast cancer progression.

BACKGROUND AND OBJECTIVES: In response to the COVID-19 pandemic outbreak and to ensure the safety of epidemic prevention in the hospital, the hospital has established mitigation strategies in advance including risk assessment and effect analysis to control hospital visitors and accompanying persons. The study aims to assess the effectiveness of mitigation strategies implemented to effectively prevent the invasion and spread of the virus. METHOD: Conduct a status analysis in accordance with the Healthcare Failure Mode and Effect Analysis (HFMEA) 4-step model, construct a response workflow, confirm the failure mode and potential causes, perform hazard matrix analysis and decision tree analysis, and formulate risk control management measures. RESULTS: For the 4 main processes and 9 subprocesses of the accompanying carers and contract caregivers entering the hospital, 26 potential failure modes and 42 potential causes of failure were analyzed. Following implementing improvement measures including strategies targeting the accompanying person, mitigation workflow failure rates decreased from 42 to 13 items, the pass rate for the maximum body temperature cutoff increased from 53.1% to 90.8%, and the compliance rate of hand washing increased from 89.5% to 100%. CONCLUSION: The HFMEA model can effectively implement preventive risk assessment and workflow management of high-risk medical procedures. The model can adjudicate the health of hospital visitors during the epidemic/pandemic, provide epidemic/pandemic education training and preventive measure health education guidance for hospital visits, and improve their epidemic prevention cognition. When combined, these strategies can prevent nosocomial infection to achieve the best anti-epidemic effect.

The present study discusses the expression and effect of the SOX17 gene in endometrioid adenocarcinoma. MTT assay is performed to determine the growth inhibition ratio of the DNA methyltransferase inhibitor 5-AZA for endometrial carcinoma cells, and the real-time fluorescence quantification PCR (qRT-PCR) was used to detect the mRNA expression of SOX17, β-catenin, and CyclinD1 in endometrial carcinoma tissues before and after using 5-AZA to treat the endometrial carcinoma cell line. There were 30 cases on endometrioid adenocarcinoma tissues and 10 cases on normal endometrial tissues. The results revealed that the expression of SOX17 in endometrioid adenocarcinoma tissues was downregulated (P 0.05; R = −0.463, P

Purpose: Congenital hemolytic anemia caused by red blood cell (RBC) membrane defects is a heterogeneous group of disorders. The present study aimed to search the causative gene mutations in patients with RBC membrane disorders in Taiwan. Materials and Methods: Next-generation sequencing approach using whole-exome sequencing (WES) was performed. Sanger sequencing was performed for confirmation of variants detected in WES in patients and their family members. Results: Five causative variants, including two ANK1, two SPTA and one SPTB variants, were detected in four patients. All these variants, except one SPTA1 variant c.83G > A (p.R28H), are novel variants. Their pedigree analysis showed one de novo SPTA1 mutation c.83G > A (p.R28H) combined with αLELY, one de novo ANK1 mutation c.1034C > A (p.A345E), one autosomal dominant combined SPTA1 c.4604A > C (p.Q1535P) and SPTB c.6203 T > C (p.L2068P) mutations and one autosomal dominant ANK1 c.4462C > T (p.R1488X) mutation. Conclusions: Our data demonstrated that WES is an efficient tool for determining genetic etiologies of RBC membrane disorders and can facilitate accurate diagnosis and genetic counseling. Additional studies should be conducted on larger cohorts to investigate the distribution of gene mutations in patients with RBC membrane disorders in Taiwan.

Immune tumor microenvironment (TME) in neuroblastoma (NBL) contributes to tumor behavior and treatment response. T cells and natural killer (NK) cells have been shown to play important roles in the neuroblastoma TME. However, few reports address the clinical relevance of natural killer T cells (NKTs) and interleukin-15 (IL-15), one of the crucial cytokines controlling the activation and expansion of NK/NKT cells, in NBL. In this study, we examined NKT immunoscores and IL-15 expression in both MYCN-amplified and MYCN-non-amplified NBL to correlate with clinical outcomes such as event-free survival (EFS) and overall survival (OS). From Gene Expression Omnibus (GEO) datasets GSE45480 (n = 643) and GSE49711 (n = 493), we found that NKT immunoscore and IL-15 expression were both significantly lower in MYCN-amplified NBL, and similar results were observed using our clinical NBL samples (n = 53). Moreover, NBL patients (GEO dataset GSE49711 and our clinical samples) with both lower NKT immunoscore and IL-15 expression exhibited decreased EFS and OS regardless of MYCN gene amplification status. Multivariate analysis further showed that the combination of low NKT immunoscore and low IL-15 expression level was an independent prognostic factor for poor EFS and OS in our NBL patients. These findings provide the rationale for the development of strategy to incorporate IL-15 and NKT cell therapy into the treatment regimen for neuroblastoma.

Removing As(Ⅲ)from water steadily and efficiently is still a challenging global issue. In this study, novel FeMnNi-LDHs were prepared by a co-precipitation method using Fe, Mn, and Ni as lamellar cations, and the structure were characterized by XRD, TEM, FT-IR, and XPS techniques, and the adsorption performance and mechanism of As(Ⅲ)was explored. The results showed that FeMnNi-LDHs have typical characteristic peaks of layered double hydroxides, with sharp peaks and high crystallinity. The TEM images also show obvious layered structures. The adsorption kinetics of As(Ⅲ)on FeMnNi-LDHs agree with the quasi second-order kinetic model, and the isotherm adsorption curve agrees with the Freundlich isotherm equation. The maximum adsorption capacity at 45℃ was 240.86 mg·g

Objective Haemophilia A and B are disorders caused by the lack of clotting factors VIII and IX, respectively. Repeated bleeding into the same joint leads to haemophilic arthropathy (HA). Interleukin (IL)-1β is responsible for the pro-inflammatory response and IL-37 is induced by IL-1β stimuli to have an anti-inflammatory response and prevent uncontrolled inflammation and tissue damage. Our objective was to investigate plasma levels of IL-1β and IL-37 in patients with severe haemophilia with different severities of HA. Methods Peripheral blood samples were collected from 14 patients with severe haemophilia A and 6 with severe haemophilia B, and 18 healthy individuals. Plasma levels of IL-1β and IL-37 were detected by immunoassay, and severity of HA was evaluated using the Pettersson scoring system. Plasma levels of IL-1β and IL-37 were analysed in patients with severe haemophilia grouped by Pettersson score and in healthy individuals. Results Plasma levels of IL-1β and IL-37 were significantly higher in patients with severe haemophilia compared with healthy individuals and significantly lower in those with moderate to severe HA than in those with no or mild HA. Conclusions Plasma levels of IL-1β and IL-37 may be useful to track HA progression in patients with severe haemophilia.

Background Workplace bullying is commonly experienced by nurses worldwide. Purpose This study was conducted to examine the determinants of different types of workplace bullying and their relationship to depression in female nurses. Methods A cross-sectional correlational study was employed, and 484 female nurses from a large medical center in southern Taiwan completed the questionnaire. Data were analyzed using logistic regression analysis. Results Being unmarried and working in medical/surgical units were found to be the major determinants of work-related bullying, whereas being unmarried was found to be the single determinant of person-related and physical-intimidation bullying. Moreover, work-related and person-related bullying were both found to be significant determinants of depression. Conclusions/implications for practice Nursing administrators should establish workplace-bullying prevention and management strategies by setting reasonable and equal workloads for nurses, assigning tasks equitably, and building depression-related support and consultation groups.

BACKGROUND The genetic background of patients with hemoglobin (Hb) H disease in Taiwan has been investigated; however, the clinical features and treatment outcomes were not reported. OBJECTIVE To analyze the clinical features and genotypes of patients with HbH who reside in Taiwan. METHODS We conducted a retrospective analysis of the clinical and molecular characteristics of 38 patients with HbH disease who were undergoing treatment at Kaohsiung Medical University Hospital, Taiwan. RESULTS Initial Hb levels were lower and the numbers of patients requiring iron-chelation therapy were higher in the nondeletional HbH group than in the deletional HbH group (P

Autoimmune cytopenia (AIHA, AITP or AIN) were uncommon paraneoplastic manifestations of HL and have been recognized in patients after HSCT with dismal outcome. We presented a case of 16-yr-old male with Hodgkin's lymphoma who developed severe AIC involving all three cell lineages after autologus bone marrow transplantation. No disease relapse was noted. Treatments with steroid, IVIG and immunosuppresants were in vain and the disease course was complicated with sepsis and deep vein thrombosis. Rituximab was administered along with broad-spectrum antibiotics and low-molecular weight heparin. The condition became stable and pancytopenia recovered after four doses of rituximab treatment. Severe multi-lineage AIC post HSCT is usually refractory to first-line treatment and difficult to manage. Second-line treatment, such as rituximab, and dedicated care for pancytopenia-induced or treatment-related complications may provide a better outcome.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. While ALL therapies are highly effective, western studies have shown excesses late life effects of therapies in survivors. In this survey, we recruited subjects being diagnosed as ALL before the age of 18‐year‐old and had been in complete continuous remission for at least 3 years. Subjects were arranged to receive three cognitive tests (Wechsler intelligence test, Conners' continuous performance test, and Wisconsin card sorting test). Standardized questionnaires were used to inquiry about attention problem in real life context. Treatment outcome were compared between the standard risk and high/very high risk groups. Final survivors were 42 subjects (26 males, 16 females) with median current age of 17.8 years. Subjects were diagnosed to be with ALL at a median age of 4.8 years. The median survival time (from discontinuation of ALL treatment to the study date) was 8.4 years. Results indicated that 17 subjects (40.5%) had chronic physical conditions in need of clinical management and six subjects (14.3%) had mental condition. For the performance‐based cognitive outcome, the average full scale intelligence quotient was 91.7 ± 13.8. Ten percent of the subjects had problem in test of attention, 20% had problem in test of impulsivity and 42.8% of the subject had problems in executive function. When judged from real life contexts, 19 subjects (42%) were with obvious attention problems. Group comparison between standard risk vs high/very high risk patients revealed no difference in neurocognitive outcomes. We hope that this information may benefit the implementation of follow‐up program for Taiwanese pediatric leukemia survivors.

PURPOSE To examine the effects of walking exercise on exercise tolerance, fatigue, sleep quality, and quality of life (QOL) for children and adolescents with cancer. METHODS A 6-week walking exercise regimen was implemented in pediatric hematological and oncological wards and in clinics of a medical center in Taiwan. A 6-min walk test (6MWT), fatigue, sleep quality, and QOL were measured at baseline and for six subsequent weeks. RESULTS Adherence to the walking exercise regimen was achieved by 72-89% of the participants in this study. Significant improvements in exercise tolerance were observed after two weeks and they continued through week 6 (F = 17.07, p

Backgrounds and Purposes Minimal residual disease (MRD) monitoring has been proved to be the most important prognostic predictor in childhood acute lymphoblastic leukemia (ALL). The nationwide TPOG-ALL-2013 protocol (TPOG-2013), adapted from the St. Jude Total Therapy XV Study and Total Therapy XVI Study, was launched since January 2013. This is the first MRD-directed protocol for treatment of childhood ALL in Taiwan. Here, we report the improved treatment outcomes and the impacts of adherence to MRD time points. Patients and Methods Totally, 402 patients aged between 1-18 years and diagnosed before December 31, 2018, who had MRD monitoring at the major central laboratory (Chang Gung Memorial Hospital-Linkou), were enrolled with the last follow-up on June 30, 2019. According to TPOG-2013, two MRD measurements were scheduled on days 15-19 of induction (MRD1 time point, TP1) and days 35-42, end of induction (MRD2 time point, TP2) to make the definitive risk stratification to guide subsequent therapy. The methodologies of MRD measurement included multicolor flow cytometry for leukemia-associated immunophenotypes (LAIP) (82.3% of TPOG-2013 cohort), qPCR assay for clonally rearranged antigen-receptor genes (Ig/TCR) if no LAIP (12.5%). Since January 2018, reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) was applied to patients carrying fusion transcripts (5.2%) of TCF3-PBX1, ETV6-RUNX1, BCR-ABL1, KMT2A-AFF1 (AF4) and KMT2A-MLLT3. The clinical features and outcomes of patients treated with TPOG-2013 were compared with those of 1,300 patients treated with the previous TPOG-ALL-2002 protocol (TPOG-2002), which did not integrate the MRD monitoring. Results The median follow-up time of the 402 patients of TPOG-2013 cohort was 32.5 months (range, 1.0-79.2 months). There were no significant differences in gender, age, WBC counts, and lineage at diagnosis between the patients treated with TPOG-2002 and TPOG-2013. However, based on the MRD data, the percentages of patients assigned to each risk group of TPOG-2013 was statistically differed from those of TPOG-2002 (P< 0.0001). The 5-year event-free survival (EFS) (% ± SE) was significantly improved from 78.1 ± 1.2 of TPOG-2002 to 85.4 ± 2.5 of TPOG-2013 (P< 0.0001). Further, the cumulative incidences (% ± SE) of isolated CNS relapse and any CNS relapse significantly decreased from 4.0 ± 0.5 to 0.3 ± 0.3 (P= 0.001) and from 5.8 ± 0.7 to 1.2 ± 0.9 (P= 0.001), respectively. The issue of non-adherence to MRD monitoring emerged since the implementation of MRD-directed TPOG-2013. For further analysis, 321 (80%) patients with exact adherence (EA) to both TPs were assigned as MRD EA group; 80 (20%) patients who were non-adherence (NA) to either one of TPs as MRD NA group; and one patient died between the two TPs was excluded for the comparative outcome analysis. The rate of non-adherence decreased significantly from 26.5% in 2013 to 2.4% in 2018. The major causes of non-adherence for both TPs were delaying MRD monitoring due to neutropenic fever and documented infections. In MRD EA group, 12.5% of patients were upgraded to higher-risk treatment groups based on their MRD results. The MRD NA group had older age (≥ 10 years), lower standard-risk and lower incidence of ETV6-RUNX1 compared with MRD EA group. There were significant differences in outcomes between MRD EA and MRD NA groups: the 5-year EFS were 89.4 ± 2.4 and 71.9 ± 7.4, respectively (P= 0.0005), overall survival (OS) were 90.9 ± 2.1 and 75.6 ± 5.8, respectively (P= 0.0003), and the cumulative incidence of isolated CNS relapse were 0 and 1.4 ± 1.3, respectively (P= 0.048) (Figure 1). In multivariate analysis, older age (≥ 10 years), higher WBC count (≥ 50 × 109/L) at diagnosis and MRD non-adherence were independent predictors for inferior EFS. In addition to these three factors, a higher-risk classification also predicted an inferior OS (Figure 2). Conclusions Contemporary MRD-directed therapy has improved the treatment outcomes of childhood ALL in Taiwan. The adherence to MRD time points remains a significantly prognostic predictor in the era of MRD-guided treatment. Disclosures No relevant conflicts of interest to declare.

Aims and objectives To determine the effectiveness of an oral health care program for preventing ventilator-associated pneumonia (VAP). Background Research has shown a significant correlation between oral bacteria and VAP, indicating that an oral health care program plays a very important role in VAP prevention. Design and methods A quasi-experimental study was used and conducted in the intensive care unit in a medical centre. A total of 199 mechanically ventilated patients were enrolled and divided into two groups: the experimental group (n = 99) and control group (n = 100). The experimental group was cared for using an evidence-based oral health care program, and the control group was cared for using routine nursing care procedures. Each group received the assigned treatment for four consecutive days. Results The incidence of VAP in the experimental group (4%, 4/95) was significantly lower than that in the control group (21%, 18/82). The oral assessment guide (OAG) mean score (9.16 ± 2·07) of the experimental group was significantly different (P

Background/Aims Transfusion dependent subjects are at a great risk of viral hepatitis infection. We aimed to evaluate the prevalence and factors associated with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among transfusion-dependent patients in Taiwan. Methods A total of 140 patients (67 thalassemic patients, 70 hemophilic patients, two patients with hereditary spherocytosis and one patient with von Willebrand disease) were prospectively enrolled to evaluate the prevalence and factors associated with viral hepatitis and spontaneous HCV clearance. All patients were tested for HBV and HCV serology and virology. Two consecutive serum samples, at least 1 year apart, were collected to clarify HCV seroclearance. Results The seropositivity rate of hepatitis B surface antigen (HBsAg), HCV antibody (anti-HCV), and both HBsAg/anti-HCV were 6.4%, 45.7% and 5%, respectively. Logistic regression analysis of factors associated with anti-HCV seropositivity included age (odds ratio/95% confidence interval [OR/CI]: 1.12/1.07–1.18, P

B-cell precursor acute lymphoblastic leukemia (BCP ALL) is the most common childhood leukemia, with a cure rate of 80%. Nevertheless, disease relapse is the most important prognostic factor for the disease outcome. We aimed to elucidate the role of Wnt secretion-regulating protein, Wntless (Wls)/GPR177, on disease outcome in pediatric patients with BCP ALL, and assess its pathogenetic role in the regulation of the disease. Wls expression was characterized and correlated with Wnt pathway signaling in the bone marrow leukemia cells isolated from 44 pediatric patients with BCP ALL. The overexpression of Wls was detected in leukemia cells and was significantly correlated with the disease relapse and poor survival in the patients. The high expression of Wls also correlated with the Wnt expression and consequent downstream signaling activation, which was shown to provide essential proliferation, transformation and anti-apoptotic activity during leukemogenesis. These results indicated that Wls played an essential role in disease relapse and poor survival in patients with BCP ALL. Therefore, Wls may provide a potential future therapeutic target, particularly for patients who do not respond to existing therapies and suffer relapse.

Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous absence of the survival of the motor neuron (SMN) 1 gene (SMN1), and it is the leading genetic cause of infant mortality. The severity of SMA is directly correlated with SMN protein levels in affected patients; however, the cellular regulatory mechanisms for SMN protein expression are not completely understood. In this study, we investigated the regulatory effects between SMN expression and miR-9a, a downstream noncoding small RNA. Using an inducible SMN short hairpin RNA interference (shRNAi) system in NSC 34 and human skin fibroblast cells, cellular miR-9 levels and SMN protein repression were time-dependently upregulated. Conversely, cellular miR-9 levels decreased when HeLa cells were transfected with SMN protein fused with green fluorescent protein. In SMA-like mice spinal cords and human primary skin fibroblasts isolated from patients with different degrees of SMA, human SMN exhibited a disease severity-dependent decrease, whereas cellular miR-9 levels increased. These results clearly suggested that cellular SMN proteins regulated miR-9 expression and that miR-9 expression was related to SMA severity. Thus, miR-9 may be a marker for SMA prognosis.

Advanced therapies have improved outcomes and also resulted in a growing risk of long-term adverse health events. This study intends to estimate incidences of adverse health events and examine differences in adverse health events among childhood cancer survivors, and to understand the concerns of mothers after their child has completed cancer treatment. An explanatory sequential mixed-method was used. A total of 201 paediatric cancer survivors' mothers with mean age 43.6 years were recruited. Of the survivors, 12.4% experienced five or more adverse health events. The incidence of adverse health events of altered body image, fatigue and neurocognitive problems were 31.54%, 14.77% and 12.53% respectively. Among survivors, significant differences in adverse health events of pain, endocrine problems and altered body image issues were identified. Survivors receiving radiotherapy, bone marrow transplants or completing treatment after 6-10 years experienced significantly more adverse health events. Maintaining health was the greatest concern for mothers, and the qualitative reports of their concerns could be categorised: living in uncertainty, and keeping forward-looking. Childhood brain tumour survivors were identified as experiencing more adverse health events than other survivors. The need for healthcare teams to consider mothers' health concerns was highlighted.

Hemophilic arthropathy is the most common chronic complication in patients with hemophilia. The pathogenesis of hemophilic arthropathy involves the inflammatory processes associated with rheumatoid arthritis (RA). Determining the severity and/or progression of joint damage is crucial when evaluating the effect of treatment modalities. Identifying reliable biomarkers in the peripheral blood of patients with hemophilic arthropathy may be beneficial in clinical practice. Circulating soluble vascular cell adhesion molecule-1 (sVCAM-1), E-selectin, and P-selectin levels are elevated in patients with RA. Our study investigated whether these soluble adhesion molecules can be used as biological indicators in the course of joint damage in patients with hemophilia A. Patients with hemophilia A (mild, moderate, and severe) were enrolled. The plasma levels of sVCAM-1, E-selectin, and P-selectin in patients with hemophilia A and control were measured using specific enzyme-linked immunosorbent assay kits. Joint damages were evaluated using Pettersson scores. No statistically significant differences were observed in E-selectin and P-selectin levels between patients and controls. The sVCAM-1 level was significantly higher in patients with hemophilia A than in controls. The differences remained significant in patients with severe hemophilia A but not in patients with mild or moderate hemophilia A. The degree of hemophilic arthropathy was evaluated using Pettersson scores, and a score higher than 5 indicated marked arthropathy. Patients with more than 1 joint with marked arthropathy showed significantly higher sVCAM-1 levels. sVCAM-1 levels in patients with hemophilia A are associated with the severity of hemophilic arthropathy.

Aims To evaluate the acceptability and efficacy of a psycho-educational intervention designed to improve effective coping and reduce symptom severity in children with cancer. Background Cancer treatments increase survival rates and also cause physical and psychological effects on children with cancer. A psycho-educational intervention is used to assist children and adolescents with these effects and its efficacy has been described in several studies. Design A randomized controlled trial. Methods Participants being treated were recruited and randomly assigned to two groups from September 2011–February 2013 in Taiwan. The intervention group received a psycho-educational intervention in addition to standard care, while the control group received only standard care. Each participant was assessed using a paediatric cancer coping scale and perceived symptom severity was evaluated at three time points (baseline, 1 month and 3 months). A repeated-measures analysis of variance was used to estimate the effects of intervention. Qualitative findings were analysed using content analysis. Results No significant difference in coping scores was found between groups, but the experimental group reported significantly lower scores in gastrointestinal problems and pain. Most symptoms decreased significantly over time in both groups, except for gastrointestinal problems. The scores in pain, bone marrow suppression and body image showed significant interaction effects between groups on changes over time. Qualitative results reported that participants evaluated the intervention positively, especially about receipt of psychological support and learnt coping skills. Conclusions The psycho-educational intervention administered was acceptable for children with cancer and was found to reduce gastrointestinal problems and pain.

We report here that the Jun dimerization protein 2 (JDP2) plays a critical role as a cofactor for the transcription factors nuclear factor-erythroid 2-related factor 2 (Nrf2) and MafK in the regulation of the antioxidants and production of reactive oxygen species (ROS). JDP2 associates with Nrf2 and MafK (Nrf2-MafK) to increase the transcription of antioxidant response element-dependent genes. Oxidative-stress-inducing reagent led to an increase in the intracellular accumulation of ROS and cell proliferation in Jdp2 knock-out mouse embryonic fibroblasts. In Jdp2-Cre mice mated with reporter mice, the expression of JDP2 was restricted to granule cells in the brain cerebellum. The induced pluripotent stem cells (iPSC)-like cells were generated from DAOY medulloblastoma cell by introduction of JDP2, and the defined factor OCT4. iPSC-like cells expressed stem cell-like characteristics including alkaline phosphatase activity and some stem cell markers. However, such iPSC-like cells also proliferated rapidly, became neoplastic, and potentiated cell malignancy at a later stage in SCID mice. This study suggests that medulloblastoma cells can be reprogrammed successfully by JDP2 and OCT4 to become iPSC-like cells. These cells will be helpful for studying the generation of cancer stem cells and ROS homeostasis.

The development of intelligent control system based on environmental parameters tobacco redrying. The use of the FNN neural network to determine the temperature and humidity of the air conditioning units running time, on this basis, the paper presents an improved network of four framework structure. The model has a simple calculation; each layer of the network the derivation are obvious physical meaning, stability control safety and energy conservation in the actual operation.

The authors shall discuss Heinz inequalities involving Riemann-Liouville fractional integrals for certain unitarily invariant norms. By using the convexity of function and fractional Hermit-Hadamard integral inequality, some refinements of Heinz inequalities are derived.

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).

Background Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or “low-risk” in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. Procedure From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol. SR patients were randomized to receive single or double reinduction courses. The patients enrolled before 2009 received CrRT, while those enrolled later did not. The Kaplan–Meier method was used to estimate survival rates and the difference between two groups was compared by the two-sided log-rank test. Results In 1,366 eligible patients, the 5-year overall survival (OS) was 81.6 ± 1.1% (standard error) and 5-year event-free survival (EFS) was 74.3 ± 1.2%. In SR patients, the 5-year OS for one and two reinduction courses was 91.6 ± 2.1% and 93.7 ± 1.8%, respectively, and the 5-year EFS was 85.2 ± 2.7% and 89.8 ± 2.3%, respectively. There were no significant differences in survival between these two groups. Patients with MLL or BCR-ABL1 had the worst outcomes: 5-year EFS was 23.4 and 31.8% and 5-year OS was 28.6 and 44.7%, respectively. There was no significant difference in CNS relapse or survival between the era with or without CrRT. Conclusions For SR patients, one-course reinduction was adequate. Triple intrathecal therapy alone successfully prevented CNS relapse.

Objectives The current study aimed at the rapid identification of the copy number of α-globin genes for the diagnosis of α-thalassemia. Design and methods To identify the copy number of α-globin genes in α-thalassemia, we developed a novel method using a multiplex polymerase chain reaction (PCR) in combination with the CE analysis. Results The proposed method provides a rapid detection of the common α-globin gene deletions. Sixty-six patients with α-thalassemia and 46 normal controls were included in the present study. The obtained results showed good correlation with those obtained by gap PCR. Moreover, a low amount of maternal cell contamination in the fetus specimen for the prenatal diagnosis of hemoglobin Barts hydrops fetalis as well as the rare multiplicated α-globin genes can be identified using this method. Conclusion This method provides a convenient and efficient tool for the rapid identification of the copy number of α-globin genes in α-thalassemia and the individuals with α-globin gene multiplication.

Hemophilia A is a hereditary genetic disorder caused by acongenital deficiency of coagulation factor VIII (FVIII) and re-placement therapy with FVIII products is the mainstay care. Thehealth-related quality of life of patients has been much improvedwith a favorable orthopedic outcome after prophylactic regimensintroduced [1]. However, managing patients with hemophilia Awho have inhibitory antibodies against infused FVIII, which neu-tralize the infused FVIII and result in treatment failure, is still anobstacle in their treatment course [2]. The presence of FVIIIinhibitors occurs in 20–30% of patients with hemophilia A [2–4] and are generally categorized into low responders (LR) andhigh responders (HR) according to their inhibitor titers and/oranamnestic response to FVIII. Although several treatment strate-gies, such as bypass therapy, plasma exchange and extra-corporealimmunoabsorption, which aim to overcome the impact of FVIIIinhibitors, may control the bleeding event in short term, buteradicating the FVIII antibodies is the main goal of managementfor these patients.Immune tolerance induction (ITI) therapy is the only provenmodality for achieving antigen-specific tolerance to FVIII andeliminating FVIII antibodies in patients with hemophilia A [5].Since ITI was first described by Brackmann and Gormsen in1977, various regimens using different FVIII dosages and inter-vals with or without concurrent immune modulation therapy havebeen used [6–10]. Although there are several large study cohorts,including North America Immune Tolerance Registry (NAITR),International Immune Tolerance Registry (IITR) and the GermanImmune Tolerance Registry (GITR), conducted for determinationof optimal practices, the dosing regimens and FVIII purity of ITItreatment were still under debate [11–13]. The experiments pub-lished in literature from many study groups recruited patientsmainly from Europe and North America [14–19]. Therefore, theapplication and experience of ITI in Eastern Asian is still limited.In this report, we conducted ITI therapy with various dosingregimens for our patients with FVIII inhibitor attempted to iden-tify whether low-dose ITI can be an alternative strategy besideshigh-dose ITI or bypassing therapies.

Two single nucleotide polymorphisms (SNPs) of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, A1298C and C677T, were widely considered to be related with various neoplasia disorders. We established a simple and effective capillary electrophoresis (CE) method for detection of two SNPs in MTHFR gene simultaneously. DNA samples were amplified by multiplex PCR with universal fluorescence-labeled primer and analyzed by single-strand conformation polymorphism (SSCP)-CE method. The CE method was performed using 1.5% hydroxyethyl cellulose in 1× TBE buffer containing 1M urea. The PCR products after SSCP procedure were electrokinetically injected at -10 kV, 30s. Separation voltage was -6 kV and the temperature was set at 20°C. The optimal SSCP-CE method was applied to detect two polymorphisms in MTHFR gene of acute lymphoblastic leukemia (ALL) and attention-deficit/hyperactivity disorder (ADHD) patients. Genotyping results were evaluated in terms of relationships between outcomes for ADHD patients after ALL chemotherapy and ALL disease. The SSCP-CE method and multiplex PCR with universal fluorescence primer were used as the fast technique for screening two SNPs in MTHFR gene, A1298C and C677T. The genotyping data were coincident with DNA sequencing. This SSCP-CE method was found feasible for detecting mutation of MTHFR gene in populations.

As Moore’s law, critical dimension (CD) become smaller and smaller, and CD control become the task of process developing and wafer fabrication. Gate shrinkage by wet process is one choice of non-lithography techniques to achieve smaller CD requirement. The common wet chemicals used in poly silicon etch, such as NH4OH, KOH, TMAH, HF/HNO3mixture, SC1, are usually limited in metal non-adapted process or intrinsically high etch rate of low-thermal-budget (small crystal grain size) /high- phosphorus-dosage poly silicon. Moreover, the unique etching behaviors of former mentioned chemicals are lattice dependency and higher etching rate along poly silicon grain boundary. This paper successfully demonstrated reversed trend of higher thermal budget and non-doped poly silicon with higher wet etching rate, and smooth etching surface by adding ionic surfactant. The unique properties can be used in metal adapted flash gate shrinkage and get adjustable shrinkage amount between control gate and floating gate poly silicon with different thermal budget and dopant dosages. Figure 1 shows three kinds of poly silicon, Non-doped poly silicon with high thermal budget (ND-HT), high phosphorous dosage doped with high thermal budget (HD-HT) and high phosphorous dosage doped with low thermal budget (HD-LT), etch rate are collected by three levels ionic surfactant concentrations in TMAH chemical, TMAH with low ionic surfactant concentration (L-TMAH), TMAH with medium ionic surfactant concentration (M-TMAH) and TMAH with high ionic surfactant concentration (H-TMAH). With increased ionic surfactant amount, high-phosphorous-doped poly silicon etching rate is obviously decreased. In H-TMAH split, HD-HT and HD-LT etching rate become similar. From selectivity curve, the selectivity of ND-HT/HD-HT (dosage difference) and ND-HT/HD-LT (dosage and thermal budget difference) increase with ionic surfactant amount increased, but selectivity of HD-HT/HD-LT (thermal budget difference) decrease. It means thermal budget effect is suppressed by higher ionic surfactant amount, and etch rate of high phosphorous doped poly silicon becomes lower than non-doped poly silicon. In 2xnm NAND Flash process and beyond, smaller gate pitch and higher aspect ratio are the process tasks to dry and wet etching. Taper gate etching profile is inevitable, and easily result in gate to gate leak or short issue. Floating gate poly silicon (FG) is usually with lower phosphorous doped and with higher thermal budget, and control gate poly silicon (CG) is usually with higher phosphorous doped and with lower thermal budget. Based on the unique property of higher ionic surfactant concentration in TMAH, gate shaping application is proposed. Poly gate profile can be modified, such as floating gate poly silicon footing issue, and get smaller gate critical dimension, shows as Figure 2. Figure 3-a and 3-b indicate that two TMAH splits, with high and low concentration of ionic surfactants, are adopted to gate structure in 2xnm NAND Flash process and TEM images show, after H-TMAH treatment, more FG bottom CD shrink and sidewall profile smoother than L-TMAH. Table 1 shows FG/CG etching selectivity of L-TMAH is around 0.8 and H-TMAH is around 3.22. By adjusting ionic surfactant ratio in TMAH, poly silicon, with different phosphorous doped dosage and thermal budget, shrinkage amount can be precisely adjusted.