An Infant-Type Hemispheric Glioma With SOX5::ALK: A Novel Fusion.

Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK. After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia.

BACKGROUND: This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes. METHODS: Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase-polymerase chain reaction, multiplex ligation-dependent probe amplification, and RNA-sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG-ALL-2013 study enrolled patients who received MRD-directed therapy. RESULTS: The 5-year event-free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD-guided therapy, those with ETV6-RUNX1 fusion and high hyperdiploidy had the highest 5-year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR-ABL1 ALL. Recently identified subtypes like DUX4-rearranged, ZNF384-rearranged, MEF2D-rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high-risk or very-high-risk subtypes, the TPOG-ALL-2013 regimen did not confer significant improvements compared to TPOG-ALL-2002, and the outcomes of BCR-ABL1-like, MEF2D-rearranged, and KMT2A-rearranged ALL subtypes (in addition to those of T-cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients. CONCLUSIONS: The TPOG-ALL-2013 study yielded outcomes superior to those of patients treated in the preceding TPOG-ALL-2002 study. This study provides important data to inform the design of future clinical trials in Taiwan. PLAIN LANGUAGE SUMMARY: MRD-directed therapy improved the outcomes for pediatric ALL, especially standard-risk patients. Genomic analyses and MRD might be used together for risk-directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan.

Biphasic Roles of Hedgehog Signaling in the Production and Self-Renewal of Outer Radial Glia in the Ferret Cerebral Cortex.

The neocortex, the center for higher brain function, emerged in mammals and expanded in the course of evolution. The expansion of outer radial glia (oRGs) and intermediate progenitor cells (IPCs) plays key roles in the expansion and consequential folding of the neocortex. Therefore, understanding the mechanisms of oRG and IPC expansion is important for understanding neocortical development and evolution. By using mice and human cerebral organoids, we previously revealed that hedgehog (HH) signaling expands oRGs and IPCs. Nevertheless, it remained to be determined whether HH signaling expanded oRGs and IPCs in vivo in gyrencephalic species, in which oRGs and IPCs are naturally expanded. Here, we show that HH signaling is necessary and sufficient to expand oRGs and IPCs in ferrets, a gyrencephalic species, through conserved cellular mechanisms. HH signaling increases oRG-producing division modes of ventricular radial glia (vRGs), oRG self-renewal, and IPC proliferation. Notably, HH signaling affects vRG division modes only in an early restricted phase before superficial-layer neuron production peaks. Beyond this restricted phase, HH signaling promotes oRG self-renewal. Thus, HH signaling expands oRGs and IPCs in two distinct but continuous phases during cortical development.

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.

Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation.

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.

Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan.

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

Outcomes Following Discontinuation of E. coli l-Asparaginase Upon Severe Allergic Reactions in Children With Acute Lymphoblastic Leukemia.

BACKGROUND: Discontinuation of E. coli l-asparaginase in patients with acute lymphoblastic leukemia (ALL) is unavoidable upon severe allergic reaction. We sought to examine outcomes following E. coli l-asparaginase discontinuation due to severe allergic reactions. PROCEDURE: We evaluated the outcome of children enrolled in Taiwan Pediatric Oncology Group-2002-ALL protocol between 2002 and 2012, who had E. coli l-asparaginase discontinued due to severe allergic reactions, and compared the outcomes of those who continued with Erwinia l-asparaginase (Erwinase) with those who did not. RESULTS: Among 700 patients enrolled in this study, 33 patients had E. coli l-asparaginase treatment discontinued due to severe allergic reactions. Five-year overall survival did not differ significantly among the 648 patients without discontinuation (81 ± 1.6%, mean ± SE), compared to 17 patients with allergic reactions and treated with Erwinase (88 ± 7.8%) and 16 patients with allergic reactions but not treated with Erwinase (87 ± 8.6%). Among 16 patients who did not receive Erwinase, all 10 who received ≥50% of the scheduled doses of E. coli l-asparaginase before discontinuation survived without events. CONCLUSIONS: Erwinase treatment may not be needed for some ALL patients with severe allergy to E. coli l-asparaginase if ≥50% of prescribed doses were received and/or therapy is augmented with other agents.

Association Between Leg Muscle Thickness and Walking Test With the Hemophilia-Specific Functional Parameters.

OBJECTIVE: The aim of the study is to evaluate the muscle thickness and walking test in people with hemophilia A and their correlation to joint health and functional impairments. DESIGN: This is a cross-sectional study. RESULTS: Twenty-nine severe/moderate people with hemophilia A were enrolled. Muscle thickness of quadriceps and medial gastrocnemius was measured using ultrasound. Joint health and functional capacity were assessed using Hemophilia Joint Health Score, Hemophilia Early Arthropathy Detection with Ultrasound, 6-Minute Walking test, Hemophilia Quality of Life Questionnaire for Adults, and Hemophilia Activities List. Quadriceps muscle thickness significantly correlated with Hemophilia Joint Health Score knee, Hemophilia Early Arthropathy Detection with Ultrasound knee, and Hemophilia Activities List. Calf muscle thickness significantly correlated with the Hemophilia Joint Health Score ankle. After adjusted age and body mass index, calf muscle thickness was inversely associated with the Hemophilia Joint Health Score ankle. Six-Minute Walking test was found to significantly correlate with Hemophilia Joint Health Score total, Hemophilia Early Arthropathy Detection with Ultrasound total, Hemophilia Quality of Life Questionnaire for Adults, and Hemophilia Activities List. CONCLUSIONS: Muscle thickness and the distance of 6-Minute Walking Test were linked to assessment of joint health, quality of life, and activity participation in people with hemophilia A. Ultrasound measurement of muscle thickness and walking test seem to be useful tools for the assessment of joint health and functional status in people with hemophilia A.

B3GNT3 expression suppresses cell migration and invasion and predicts favorable outcomes in neuroblastoma.

Aberrant expression of the simple mucin-type carbohydrate antigens such as T, Tn, sialyl-T and sialyl-Tn is associated with poor prognosis in several cancers. ß1,3-N-acetylglucosaminyltransferase-3 (B3GNT3), a member of the ß3GlcNAcT family, is responsible for forming extended core 1 (T antigen) oligosaccharides. The role of B3GNT3, which is expressed in various tissues including human fetal brain, in regulating neuroblastoma (NB) formation and cell behaviors remains unclear. Here, we showed that increased B3GNT3 expression evaluated using immunohistochemistry in NB tumor tissues correlated well with the histological grade of differentiation as well as a favorable Shimada's subset of pathology. Univariate and multivariate analyses revealed that positive B3GNT3 expression in tumor tissues predicted a favorable prognosis in NB patients independent of other prognostic markers. B3GNT3 overexpression suppresses T antigen formation and malignant phenotypes including migration and invasion of SK-N-SH cells, whereas B3GNT3 knockdown enhances these phenotypes of SK-N-SH cells. Moreover, B3GNT3 expression decreased phosphorylation of focal adhesion kinase (FAK), Src, paxillin, Akt and ERK1/2. We conclude that B3GNT3 predicts a favorable cancer behavior of NB and suppresses malignant phenotypes by modulating mucin-type O-glycosylation and signaling in NB cells.

Analysis of factors correlated with the development of pseudophakic retinal detachment--a long-term study in a single medical center.

BACKGROUND: To analyze the possible factors correlated with the development of retinal detachment (RD) after cataract extraction and intraocular lens (IOL) implantation in a single medical center. METHODS: We performed a retrospective chart review of patients receiving cataract extraction and posterior chamber IOL implantation from January 2000 to June 2010 at one medical center. We analyzed demographic characteristics, medical history, axial length (AL), operation method, intraoperative and postoperative complications, Nd-YAG posterior capsulotomy and records for RD. RESULTS: The 9,184 patients analyzed included 6,464 males and 2,720 females, mean age 71.8 ± 9.1 years. The cumulative 7-year RD rate was 0.84 %. Young age, long axial length and intraoperative complications were significantly associated with the risk of pseudophakic RD. Although not a statistically significant factor for the whole group, Nd-YAG posterior capsulotomy represented a significant risk in those with high myopia stratified by axial length. In moderate myopic group, both intra-operative complication and Nd-YAG posterior capsulotomy showed more tendencies to increase risk of RD, but only intra-operative complication had significant difference. CONCLUSIONS: Young age, myopia and intra-operative complications were significant risk factors for the development of RD after cataract extraction and IOL implantation. Post-operative Nd-YAG posterior capsulotomy led to more risk for pseudophakic RD in myopic eyes, especially high myopia. The risk of pseudophakic RD should be considered before deciding to perform cataract extraction and the following capsulotomy in myopic eyes, particularly those for refractive indication in young patients.

High HbA1c level was the most important factor associated with prevalence of diabetic retinopathy in Taiwanese type II diabetic patients with a fixed duration.

BACKGROUND: To identify the prevalence and related risk factors for diabetic retinopathy (DR) in non-insulin dependent diabetes in Taiwan. METHODS: A retrospective review of type II diabetic patients in the Diabetes Shared Care System database of our Hospital enrolled from 2002 to 2009. A retinopathy severity score was assigned according to fundus examination by indirect ophthalmoscopy or binocular biomicroscopy. RESULTS: Data was collected on 901 subjects, 497 males and 404 females. Of these, 230 (25.53 %) had DR at enrolment. Compared with patients without DR, those with DR were more likely to be female (p = 0.03) or have higher HbA1c (p < 0.001), longer duration of diabetes (p < 0.001), hypertension (p < 0.001), higher systolic blood pressure (p < 0.001), higher diastolic blood pressure (p = 0.05), as well as impaired renal function (p = 0.001). In subgroup analysis stratified by diabetes duration, HbA1c was the most consistent independent risk factor associated to the prevalence of DR. Higher systolic blood pressure and female sex were significantly independent risk factors only in patients with a duration of diabetes < 4 years. On the contrary, old onset age showed a protective effect against DR only in those with a disease duration > 8 years. CONCLUSIONS: High HbA1c level was the most important factor associated with prevalence of DR in Taiwanese type II DM patients with a fixed duration.

A pharmaco-economic evaluation of deferasirox for treating patients with iron overload caused by transfusion-dependent thalassemia in Taiwan.

BACKGROUND/PURPOSE: The newly available iron chelator deferasirox (Exjade, Novartis) is expected to provide better long-term clinical outcomes and improved quality of life for patients with thalassemia than its predecessor, deferoxamine (Desferal, Novartis), because of its oral tablet form. METHODS: We used the Markov model to estimate total additional lifetime costs and quality-adjusted life years (QALYs) gained with deferasirox versus deferoxamine in patients with transfusion-dependent thalassemia. Patients were assumed to be 2 years of age at initiation of chelation therapy. Clinical outcomes in terms of morbidity and mortality from associated complications and life expectancy for the study population were estimated using the databases of the Bureau of National Health Insurance and the Health and Vital Statistics of Taiwan. Treatment costs were based on analyses of health insurance claims for patients with transfusion-dependent thalassemia. Utilities in terms of quality of life were also included in the model. The incremental cost-utility ratio of deferasirox versus deferoxamine was defined by the ratio of the difference in expected lifetime costs to the difference in QALYs. One-way sensitivity analyses were performed to examine the robustness of the results to key assumptions. RESULTS: Patients treated with deferasirox are expected to experience a lower incidence of associated complications and obtain 2.3 QALYs (discounted) at an additional lifetime cost of US$36,291 per patient (US$15,596 per QALY). Sensitivity analyses showed that the unit drug cost of deferasirox had the greatest impact on the incremental cost-utility ratio. In addition, the incremental cost-utility ratio will increase by delaying the starting age (2 years of age in our study) of chelation therapy. CONCLUSION: Compared with infusional deferoxamine, oral deferasirox improved clinical outcomes and quality of life in terms of iron chelation in transfusion-dependent patients with thalassemia at a reasonable cost from a healthcare perspective.

The Health Care Utilization and Medical Costs in Long-Term Follow-Up of Children Diagnosed With Leukemia, Solid Tumor, or Brain Tumor: Population-Based Study Using the National Health Insurance Claims Data.

BACKGROUND: Childhood cancer survivors are at a high risk of medical consequences of their disease and treatment. There is growing information about the long-term health issues of childhood cancer survivors; however, there are very few studies describing the health care utilization and costs for this unique population. Understanding their utilization of health care services and costs will provide the basis for developing strategies to better serve these individuals and potentially reduce the cost. OBJECTIVE: This study aims to determine the utilization of health services and costs for long-term survivors of childhood cancer in Taiwan. METHODS: This is a nationwide, population-based, retrospective case-control study. We analyzed the claims data of the National Health Insurance that covers 99% of the Taiwanese population of 25.68 million. A total of 33,105 children had survived for at least 5 years after the first appearance of a diagnostic code of cancer or a benign brain tumor before the age of 18 years from 2000 to 2010 with follow-up to 2015. An age- and gender-matched control group of 64,754 individuals with no cancer was randomly selected for comparison. Utilization was compared between the cancer and no cancer groups by χ2 test. The annual medical expense was compared by the Mann-Whitney U test and Kruskal-Wallis rank-sum test. RESULTS: At a median follow-up of 7 years, childhood cancer survivors utilized a significantly higher proportion of medical center, regional hospital, inpatient, and emergency services in contrast to no cancer individuals: 57.92% (19,174/33,105) versus 44.51% (28,825/64,754), 90.66% (30,014/33,105) versus 85.70% (55,493/64,754), 27.19% (9000/33,105) versus 20.31% (13,152/64,754), and 65.26% (21,604/33,105) versus 59.36% (38,441/64,754), respectively (all P<.001). The annual total expense (median, interquartile range) of childhood cancer survivors was significantly higher than that of the comparison group (US $285.56, US $161.78-US $535.80 per year vs US $203.90, US $118.98-US $347.55 per year; P<.001). Survivors with female gender, diagnosis before the age of 3 years, and diagnosis of brain cancer or a benign brain tumor had significantly higher annual outpatient expenses (all P<.001). Moreover, the analysis of outpatient medication costs showed that hormonal and neurological medications comprised the 2 largest costs in brain cancer and benign brain tumor survivors. CONCLUSIONS: Survivors of childhood cancer and a benign brain tumor had higher utilization of advanced health resources and higher costs of care. The design of the initial treatment plan minimizing long-term consequences, early intervention strategies, and survivorship programs have the potential to mitigate costs of late effects due to childhood cancer and its treatment.

Feasibility and Toxicity of Interval-Compressed Chemotherapy in Asian Children and Young Adults with Sarcoma.

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.

Clinical features, prognostic factors, and their relationship with antiplatelet antibodies in children with immune thrombocytopenia.

We investigated and evaluated the demographics, clinical and laboratory features, treatment responses, and disease duration of 25 children with immune thrombocytopenia (ITP) eligible for detection of antiplatelet antibodies. We found that patients without antecedent of preceding infection (API) were more likely to have anti-GPIa/IIa than those with API (42.9% vs. 5.5%, P=0.048). Age groups of <2 years and 2 to 10 years were more likely to show response (R) or complete response (CR) to given treatments, whereas none of the patients whose onset age >10 years showed R or CR to given treatments (88.9% and 100% vs 0%, P=0.001). The percentage of newly diagnosed ITP was higher in age groups of <2 years (100%) and in 2 to 10 years (90%) than the age group of >10 years (16.7%, P=0.001). Patients without API (71.4%) were more likely to develop chronic ITP than those with API (5.6%, P=0.002). In conclusion, younger age was a favorable prognostic factor, especially in patients <2 years of age with respect to treatment responses and disease duration. In addition, API was associated with a short disease course as well as absence of anti-GPIa/IIa.

Otologic and audiologic features of ethnic Chinese patients with Turner syndrome in Taiwan.

BACKGROUND/PURPOSE: Otologic and audiologic characteristics of Turner syndrome (TS) have been well documented in Caucasian-but not in Asian-populations. We report these features and possible causative factors for hearing loss in ethnic Chinese TS patients in Taiwan. METHODS: The study was a cross-sectional trial that analyzed patients diagnosed with TS. We enrolled patients for otologic evaluations and age-appropriate pure tone audiometry. To explore the potential associations with hearing loss, we studied patient karyotype, history of recurrent otitis media (OM) and various craniofacial anomalies. RESULTS: The 46 patients (mean age 17.3 years, range 5-34 years) enrolled, 22 (47.8%) had a history of recurrent OM. Otoscopic examination identified eardrum abnormalities in 45.6% of patients with myringosclerosis as the most common condition. A total of 21.7% patients showed auricular anomalies. Audiologic analysis revealed five cases (10.7%) with conductive hearing loss (CHL) and eight cases (17.4%) with sensorineural hearing loss (SNHL). Among patients with a history of recurrent OM, CHL prevailed (p = 0.0192) over SNHL (p = 0.1278). Karyotype and craniofacial anomalies were not associated with CHL or SNHL (p > 0.05). CONCLUSION: We found varying degrees of otologic and audiologic abnormalities among the TS in ethnic Chinese population. About one-half of the patients had recurrent OM, which was more likely to be associated with CHL in early life. Therefore, regular surveillance, early diagnosis, and the initiation of appropriate treatment are crucial in improving the hearing and speech in children with TS as well as in preventing short- and long-term associated complications.

Clinical features and major histocompatibility complex genes as potential susceptibility factors in pediatric immune thrombocytopenia.

BACKGROUND/PURPOSE: Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disorder with diverse response rates to treatments that include corticosteroids, intravenous immunoglobulins (IVIG), and splenectomy. The predisposing causes of this autoimmune disorder, one of which is immunogenetic susceptibility, have not been fully determined. We investigated whether clinical features and human leukocyte antigen (HLA) genotypes influence the occurrence, treatment response, and disease duration of childhood ITP in Taiwan. METHODS: We performed HLA genotyping of 70 Taiwanese children with ITP and of 70 healthy controls and compared the data. Demographic data were also collected and evaluated. RESULTS: The frequencies of heterozygous HLA-A11 and the HLA-Cw1 allele were both significantly decreased in the ITP group (p = 0.0160 and p = 0.0089, respectively), whereas the frequency of heterozygous HLA-DQ5 was significantly increased in the ITP group (p = 0.0057). Patients with HLA-DRB1*11 or -DRB1*15 were more likely to respond poorly to corticosteroids than IVIG (p = 0.0446 and p = 0.0008, respectively). In addition, we observed a positive association between HLA-A11 homozygosity and the development of persistent or chronic ITP [odds ratio (OR) = 6.3165, p = 0.0479]. The presence of HLA-DRB1*08 was, however, negatively correlated with the development of persistent or chronic ITP (OR = 0.1729, p = 0.0657). Children with antecedent of preceding illness (API) and with a younger age of onset were more likely to experience a better treatment response and shorter course of ITP. CONCLUSION: We suggest that API, age of onset, and particular HLA class I and class II alleles, may be involved in and influence the occurrence and disease duration of childhood ITP, as well as responses to different therapeutic approaches.

Adrenal Crisis Mimicking COVID-19 Encephalopathy in a Teenager with Craniopharyngioma.

There is an increasing number of reported cases with neurological manifestations of COVID-19 in children. Symptoms include headache, general malaise, ageusia, seizure and alterations in consciousness. The differential diagnosis includes several potentially lethal conditions including encephalopathy, encephalitis, intracranial hemorrhage, thrombosis and adrenal crisis. We report the case of a 17-year-old boy with a positive antigen test of COVID-19 who presented with fever for one day, altered mental status and seizure, subsequently diagnosed with adrenal insufficiency. He had a history of panhypopituitarism secondary to a suprasellar craniopharyngioma treated with surgical resection; he was treated with regular hormone replacement therapy. After prompt administration of intravenous hydrocortisone, his mental status returned to normal within four hours. He recovered without neurologic complications. Adrenal insufficiency can present with neurological manifestations mimicking COVID-19 encephalopathy. Prompt recognition and treatment of adrenal insufficiency, especially in patients with brain tumors, Addison's disease or those recently treated with corticosteroids, can rapidly improve the clinical condition and prevent long-term consequences.

Atypical Teratoid/Rhabdoid Tumor in Taiwan: A Nationwide, Population-Based Study.

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

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.