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Background Parosteal osteosarcoma (POS) is a unique low grade osteosarcoma. Two separate oncogenes, MDM2 and CDK4, are specifically amplified in POS. Its clinical behavior is usually indolent. In some occasions, it may progress to high grade and become fatal. Malignant transformation with high grade differentiation is the most reliable indicator to predict its aggressiveness and metastatic potential. This study is to discover the relationship between gene amplification and grading. Methods Retrospective analysis of MDM2/CDK4 expression/amplification using immunostaining, multiplex quantitative polymerase chain reaction (MQPCR) and fluorescence in situ hybridization (FISH) were studied on 14 patients with recurrent POS. Results Forty tumor specimens in formalin-fixed paraffin-embedded blocks from 14 patients of POS were included in this study. Twenty-seven tumors are low-grade, 13 are high-grade. All POS showed increased expression of both MDM2 and CDK4 proteins, but not those from conventional osteosarcoma. Except some tumors were non-informative (poor DNA quality), the rest of POS had a marked increase of MDM2 and CDK4 genes copies by MQPCR, and confirmed by MDM2 FISH. Moreover, the folds of amplification increase as tumors progress. And, the amplification folds in high-grade POS are consistently higher than those of conventional ones. Conclusion FISH and MQPCR are both useful assays for estimating oncogene amplification status in bone tumors. Amplification levels of MDM2 and CDK4 are related to tumor grading and progression. Molecular determination of gene amplification status can be a reliable alternative for predicting clinical behavior of POS at small biopsies.

BACKGROUND Despite aggressive treatment including surgery, radiotherapy, and adjuvant chemotherapy, the outcome of pediatric high-risk embryonal brain tumors remains poor; especially in young children, in whom early radiotherapy inevitably brings significant long-term morbidities. Single or tandem autologous stem cell transplant has been reported to improve outcomes; but optimal use is not well defined. METHODS Pediatric patients with high-risk embryonal brain tumors who underwent tandem transplant as consolidation from August 2011 to December 2017 were included. We performed a retrospective chart review and analyzed the outcomes to identify possible prognostic factors. RESULTS Eleven pediatric patients with high-risk embryonal brain tumors were enrolled. They received double or triple autologous transplant at complete response in 5 patients and at partial response in 6 for a total of 24 transplants. There were five atypical teratoid rhabdoid tumors, four medulloblastoma, one primitive neuroectodermal tumors, and one pineoblastoma. Median age at diagnosis was 1.8 years (range, 0.6-11.2 years) and at transplant was 2.2 years (range, 1.2-11.9 years). Thiotepa-based regimens were used in 13 cycles of conditioning. All patients achieved successful engraftment. No transplant-related mortality was identified. With a median follow-up of 21.2 months (range, 6.9-51.8 months), seven patients had disease progression. Disease entity and the use of one or more cycles of thiotepa-based regimen during tandem transplant had statistically significant impact on both progression-free survival and overall survival. CONCLUSION With successful engraftment and manageable toxicity, tandem transplant in pediatric patients with high-risk embryonal brain tumor is feasible and safe. Patients receiving tandem transplant with one or more cycles of thiotepa-based regimen might have better outcome than those without. In combination with salvage radiotherapy, a favorable 2-year overall survival could be achieved in the majority of patients.

Objective To provide strategies for monitoring and treating severe lung involvement in Gaucher disease. Study design We reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms. Results His respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of β-glucocerebrosidase were reported in three months. Conclusion This is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.

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.

Ammonia (including NH3 and NH4+) is a major pollutant of freshwater environments. However, the toxic effects of ammonia on the early stages of fish are not fully understood, and little is known about the effects on the sensory system. In this study, we hypothesized that ammonia exposure can cause adverse effects on embryonic development and impair the lateral line system of fish. Zebrafish embryos were exposed to high-ammonia water (10, 15, 20, 25, and 30 mM NH4Cl; pH 7.0) for 96 h (0–96 h post-fertilization). The body length, heart rate, and otic vesicle size had significantly decreased with ≥15 mM NH4Cl, while the number and function of lateral-line hair cells had decreased with ≥10 mM NH4Cl. The mechanoelectrical transduction (MET) channel-mediated Ca2+ influx was measured with a scanning ion-selective microelectrode technique to reveal the function of hair cells. We found that NH4+ (≥5 mM NH4Cl) entered hair cells and suppressed the Ca2+ influx of hair cells. Neomycin and La3+ (MET channel blockers) suppressed NH4+ influx, suggesting that NH4+ enters hair cells via MET channels in hair bundles. In conclusion, this study showed that ammonia exposure (≥10 mM NH4Cl) can cause adverse effects in zebrafish embryos, and lateral-line hair cells are sensitive to ammonia exposure.

Acidification of freshwater ecosystems is recognized as a global environmental problem. However, the influence of acidic water on the early stages of freshwater fish is still unclear. This study focused on the sublethal effects of acidic water on the lateral line system of zebrafish embryos. Zebrafish embryos were exposed to water at different pH values (pH 4, 5, 7, 9, and 10) for 96 (0–96 h post-fertilization (hpf)) and 48 h (48∼96 hpf). The survival rate, body length, and heart rate significantly decreased in pH 4-exposed embryos during the 96-h incubation. The number of lateral-line neuromasts and the size of otic vesicles/otoliths also decreased in pH 4-exposed embryos subjected to 96- and 48-h incubations. The number of neuromasts decreased in pH 5-exposed embryos during the 96-h incubation. Alkaline water (pH 9 and 10) did not influence embryonic development but suppressed the hatching process. The mechanotransducer channel-mediated Ca2+ influx was measured to reveal the function of lateral line hair cells. The Ca2+ influx of hair cells decreased in pH 5-exposed embryos subjected to the 48-h incubation, and both the number and Ca2+ influx of hair cells had decreased in pH 5-exposed embryos after 96 h of incubation. In addition, the number and function of hair cells were suppressed in H+-ATPase- or GCM2-knockdown embryos, which partially lost the ability to secrete acid into the ambient water. In conclusion, this study suggests that lateral line hair cells are sensitive to an acidic environment, and freshwater acidification could be a threat to the early stages of fishes.

Juvenile myelomonocytic leukemia (JMML) is a rare hematologic malignancy in children. Its presentations include anemia, thrombocytopenia, monocytosis, skin rash, marked hepatomegaly, and/or splenomegaly. Fever and respiratory involvement are common. Here, we report a case of a premature neonate with initial symptoms of respiratory distress. She gradually developed clinical manifestations of JMML that mimicked neonatal sepsis. Three weeks after birth, JMML was diagnosed. This is the first reported case of JMML presenting in a premature infant in Taiwan.

Objective: This article reviews the current standard of care for osteosarcoma and the experience of Taipei Veterans General Hospital. Data Sources and Study Selection: We searched PubMed using the keyword “osteosarcoma” and article type “Clinical Trial.” Prospective, randomized, Phase II/III clinical trials which resulted in practice change were enrolled. In addition, retrospective studies from Taipei Veterans General Hospital were also included. Results: For localized conventional osteosarcoma, combined perioperative chemotherapy with surgical resection dramatically improved long-term outcomes. Combination chemotherapy with methotrexate, Adriamycin, and cisplatin (MAP) is currently widely accepted to be the optimal regimen. The efficacy of chemotherapy has increased the likelihood of a limb-salvage approach, which has become the mainstay of surgery. In Taipei Veterans General Hospital, MAP plus ifosfamide was used and could achieve a 5-year overall survival (OS) rate of 77% and progression-free survival (PFS) rate of 70% for all patients. For nonmetastatic osteosarcoma, the 5-year OS and PFS rates reached 90% and 83%, respectively. For recurrent/metastatic disease, there is currently no satisfactory systemic therapy. Removal of all tumors should be attempted if clinically feasible, because one-third of patients may survive for 5 years or more if the tumors are completely resected. Conclusion: Perioperative chemotherapy is associated with excellent OS, PFS, and limb salvage rates and is the current standard of care for osteosarcoma.

Environmental contamination by anticancer pharmaceuticals has been widely reported. These drugs are not readily biodegradable, and their parent compounds and/or metabolites have been detected in surface waters and groundwater throughout the world. Adverse effects of anticancer drugs occur frequently in cancer patients, and a large body of clinical knowledge has accumulated. However, the effects of these drugs on aquatic organisms have not been thoroughly studied. This study aimed to investigate the effects of acute exposure to a common anticancer drug, vincristine (VCR), on zebrafish embryonic development and skin function. After 96 h of VCR exposure (0, 1, 10, 15, and 25 mg/L), significant teratogenic effects were observed, including growth retardation, pericardial edema, spine, tail, and yolk sac malformations (VCR ≥ 15 mg/L), a decreased heart rate, and ocular malformations (VCR ≥ 10 mg/L). The value of the half lethal concentration for zebrafish embryos was 20.6 mg/L. At ≥10 mg/L VCR, systemic ion contents and acid secretion in the skin over the yolk-sac decreased, and these findings were associated with decreases in skin ionocytes (H+-ATPase-rich cells and Na+-K+-ATPase-rich cells). Also, the microridge-structure of skin keratinocytes was significantly damaged. The number of lateral line hair cells was reduced when VCR was ≥10 mg/L, and functional impairment was detected when VCR was as low as 1 mg/L. Results of this in vivo study in zebrafish embryos indicate that acute exposure to VCR can lead to developmental defects, impairment of skin functions, and even fish death.

This study aimed to assess the sublethal effects of a platinum-based compound, cisplatin, using a zebrafish model. Zebrafish embryos were incubated in different concentrations of cisplatin at 0–96 h post-fertilization. Using a non-invasive, scanning ion-selective electrode technique (SIET), we measured the functions of hair cells (Ca2+ influx) and ionocytes ([H+] gradients). The survival rate, hatching rate, phenotype, body length, whole-body ion (Na+, Cl−, and Ca2+) and Pt contents were also determined. The effects of cisplatin on zebrafish embryos were demonstrated as first impairing hair cell function (at 1 μM of cisplatin), the hair cell number, and body ion content of Cl− (at 10 μM of cisplatin), then decreasing ionocyte acid secretion and overall body ion contents of Na+ and Ca2+ (at 50 μM of cisplatin). The body length and ionocyte density decreased at 100 μM of cisplatin, and survival decreased at 500 μM of cisplatin. As the cisplatin concentration increased, the accumulation of Pt in fish embryos also increased. These results revealed that hair cells are significantly more susceptible to cisplatin toxicity than ionocytes. By determining the lowest observed effective concentration of cisplatin that caused in vivo functional alterations of zebrafish hair cells and skin ionocytes, this model demonstrated 500-fold greater sensitivity than by detecting changes in survival, for early assessment of the effects of platinum-based chemotherapeutic drugs on fish.

BACKGROUND Currently, little information is available on childhood cancer incidence rates in Eastern Asia. The objective of this study was to report the first population-based cancer surveillance of children and adolescents in Taiwan. METHODS Data from the Taiwan Cancer Registry were examined for cancer frequencies and incidence rates among individuals ages birth to 19 years from 1995 to 2009. Types of cancers were grouped according to the International Classification of Childhood Cancer. Rates were compared by sex and age. For further comparisons with other countries, rates were age standardized to the 2000 world standard population in 5-year age groups. Trends in incidence rates also were evaluated. RESULTS In total, 12,315 individuals were diagnosed with childhood cancers, for an age-standardized incidence rate (ASR) of 132.1 per million person-years from 1995 to 2009. The male-to-female incidence rate ratio was 1.19. Overall, leukemias were the most common cancer (ASR, 39.1 per million person-years), followed by central nervous system neoplasms (15.8 per million person-years), and lymphomas (15.3 per million person-years). During the 15-year study period, the incidence rates increased by 1% annually. Compared with other countries, the rate of hepatic tumors was 2 times greater in Taiwan. The rate of germ cell neoplasms in Taiwan was similar to that in the United States and was 1.3 to 1.9 times greater compared with Canada, Brazil, Israel, and Japan. CONCLUSIONS Based on the current data, the observed increase in overall incidence rates was attributable only marginally to improvements in case ascertainment and diagnostic procedures. The high rates of malignant hepatic tumors and germ cell neoplasms in Taiwan suggest variations in the background risk factors. Cancer 2014;120:3545–3553. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. The authors examine cancer incidence patterns in children and adolescents based on a national, population-based cancer registry of 12,315 individuals in Taiwan from 1995 to 2009. The high rates of malignant hepatic tumors and germ cell neoplasms in Taiwan suggest variations in background risk factors.

Zebrafish lateral-line hair cells are an in vivo model for studying hair cell development, function, and ototoxicity. However, the molecular identification and properties of the mechanotransducer (MET) channel in hair cells are still controversial. In this study, a noninvasive electrophysiological method, the scanning ion-electrode technique (SIET), was applied for the first time to investigate properties of MET channels in intact zebrafish embryos. With the use of a Ca2+-selective microelectrode to deflect hair bundles and simultaneously record the Ca2+flux, the inward Ca2+flux was detected at stereocilia of hair cells in 2- to ∼4-day postfertilization embryos. Ca2+influx was blocked by MET channel blockers (BAPTA, La3+, Gd3+, and curare). In addition, 10 μM aminoglycoside antibiotics (neomycin and gentamicin) were found to effectively block Ca2+influx within 10 min. Elevating the external Ca2+level (0.2–2 mM) neutralized the effects of neomycin and gentamicin. However, elevating the Mg2+level up to 5 mM neutralized blockade by gentamicin but not by neomycin. This study demonstrated MET channel-mediated Ca2+entry at hair cells and showed that the SIET to be a sensitive approach for functionally assaying MET channels in zebrafish.

To identify the prognostic factors and long-term outcome of the Ewing sarcoma family of tumors (ESFT), data on 50 patients with ESFT treated at Taipei Veterans General Hospital between February 1991 and March 2014 were retrospectively considered. The influence of patient demographics, tumor features, and clinical and therapeutic parameters on overall survival (OS) and progression-free survival (PFS) rates were assessed. The results revealed that 21 of the 50 patients (42%) were metastatic at diagnosis. The median follow-up time was 1.8 years. The 5-year OS and PFS for patients who were nonmetastatic were 61.6% and 55.5%, respectively, and 18.8% and 15.4% for patients who were metastatic, respectively. The key adverse prognostic factor was metastasis at diagnosis. Radiotherapy for local control was associated with improved PFS. The high rate of primary metastasis and poorer outcomes of nonmetastatic ESFT compared with results from Western studies, along with previously reported low rates of ESFT in Taiwanese people, suggest that genetic factors play a role in the pathogenesis of ESFT and chemotherapy pharmacokinetics and pharmacodynamics. Radiotherapy in local treatment should be considered more aggressively in Taiwanese patients with ESFT.

Chronic graft-versus-host disease (cGVHD) is one of the most frequent and serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Nephrotic syndrome (NS) is an uncommon and underrecognized manifestation of cGVHD. We report a patient who developed NS 18 months after allogeneic bone marrow transplantation. The onset of NS was accompanied by active manifestations of cGVHD, and immunosuppressants had not been tapered recently. Renal biopsy revealed membranous nephropathy. The patient failed to improve with three combined immunosuppressants (prednisolone, cyclosporine, and mycophenolate mofetil), but achieved partial remission after intravenous immunoglobulin (IVIG) infusion. Twenty-four months after the diagnosis of NS, the patient was still in hematological remission, with normal serum creatinine level, urinary protein loss of 0.7–1.9 g/day and mild oral mucositis. Our report suggests that NS can be a cGVHD-related immune disorder in HSCT patients. Monitoring of renal parameters, especially proteinuria, is important in cGVHD patients. Our case indicated that post-transplant NS, occurring without history of tapering or following immunosuppressant withdrawal, presents a more severe activity of cGVHD and a relatively severe clinical course. IVIG may modify and control the refractory GVHD-related NS, and can be one of the choices of treatment.

Population-based studies on soft tissue sarcomas (STS) incidence beyond extremities and trunk wall are lacking in Asia. In this study, we aimed to report the incidences of STS arise in any part of the body. The data of primary STS registered in the population-based Taiwan Cancer Registry during 2007 and 2013 was acquired via the Health and Welfare Data Science Center, Taiwan. Histologic subtype-, age-, and gender-specific STS incidence rates of all sites were analyzed. A total of 11393 subjects were identified, with an age-standardized incidence rate of 5.62 (95% CI, 5.51-5.73) per 100,000 person-years. Approximately 30% of STS occurred in soft tissues (ICD-O-3 topography codes of C47, C49), and 70% occurred in all other primary sites (ICD-O-3 topography codes of C00-C80 except C47, C49, C40 and C41). The three most common primary sites other than soft tissues were stomach (15.9%), skin (14.3%) and small intestine (10.5%). Gastrointestinal stromal tumor (GIST) was the most common subtype, accounting for 29.2% of STS, followed by liposarcoma (11.5%) and leiomyosarcoma (9.7%). For overall STS, no significant incidence trend was identified during 2007-2013. However, a significant declining trend in incidence rate of undifferentiated pleomorphic sarcoma was found (annual percentage change, APC, -7.8%). By contrast, a significant upward trend was identified in other specified sarcomas (APC, 7.3%). For the first time, this analysis demonstrated that STS incidence varied by histologic subtype, gender, age, and primary site in Asians. In the future, more population-based studies should be performed in Asians for comparison with the results from Western countries to better clarification if racial variation exists in any subtype-specific incidence rates of STS. Citation Format: Giun-Yi Hung, Jiun-Lin Horng, Chueh-Chuan Yen. Incidences of malignant primary soft-tissue sarcomas regardless of primary site: A nationwide population-based study in Taiwan [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1204.

To determine whether T cell engraftment and recovery of B cell immunity could be improved, we prospectively treated 15 children with severe combined immunodeficiency disease (SCID) with megadoses of haplocompatible CD34+ cells and a fixed number of CD3+ cells without previous myeloablative chemotherapy. Evidence of T cell engraftment was seen in 73% of patients (95% confidence interval [CI] = 48%-90%). Engraftment was more likely in patients with X-linked SCID and in those with evidence of maternal engraftment at the time of diagnosis. In patients with T cell engraftment, the median time to development of a CD4 count > 200 cells/mm3 and a phytohemagglutinin response > 50% of control was 1.2 and 4.9 months, respectively. Clearance of preexisting infections occurred after a median of 2.8 months. B cell function developed in 33% of engrafted patients (95% CI = 14%-61%). The 1-year event-free survival (EFS) rate was 60% (95% CI = 36%-80%), and the overall survival (OS) rate was 87% (95% CI = 61%-98%), with a median follow-up of 39 months. The use of megadoses of CD34+ cells with a fixed number of CD3+ cells in nonmyeloablative hematopoietic stem cell transplantation (HSCT) in patients with SCID is associated with excellent engraftment, T cell recovery, and OS; however, B cell function does not recover in most patients.

Background In Taiwan, children with malignancies are treated under the protocols of the Taiwan Pediatric Oncology Group (TPOG). The purpose of this study was to determine the change in left ventricular (LV) function in pediatric patients undergoing chemotherapy. Methods A total of 19 pediatric patients (mean age, 12.5 ± 4.6 years; 11 males, 8 females) were enrolled. We divided the patients into 2 groups: (1) osteogenic sarcoma (OGS) group ( n = 12; Group I); and (2) non-osteogenic sarcoma (non-OGS) group ( n = 7; Group II). The accumulated dosages of anthracycline in Group I and II patients were 144.3 ± 56.4 mg/M 2 and 131.7 ± 105.5 mg/M 2 ( p = 0.735), respectively. The children received echocardiography to investigate the parameters of LV systolic function, LV diastolic function, and myocardial performance index (MPI) after the entire chemotherapy course. Results Higher E/A ratio (1.71 ± 0.37), shorter isovolumic relaxation time (IRT, 42 ± 19.14 ms), and shorter deceleration time (DT, 140.3 ± 40.6 ms) were demonstrated in these patients. There was no statistically significant difference in the E/A ratio and DT between the 2 groups. Group I children were older (14.4 ± 3.7 vs. 9.3 ± 4.5 years; p = 0.015) and had lower MPI (0.20 ± 0.02 vs. 0.28 ± 0.07; p = 0.031) than Group II children. Conclusion The children treated with chemotherapy using the TPOG protocol had a shorter IRT, higher E/A ratio and shorter DT. No significant evidence of anthracycline-related cardiotoxicity was found in any of the children in this study undergoing chemotherapy with the TPOG protocol.

Acute pancreatitis is a rare complication during chemotherapy for pediatric patients with solid tumors. We report a 9-year-old boy with osteosarcoma who experienced 2 episodes of pancreatitis 1 day and 48 days after infusion of ifosfamide (IFOS), respectively. From a MEDLINE search, this is the 3 rd reported case and 2 nd reported pediatric case of IFOS-induced pancreatitis, and only this case experienced late-onset pancreatitis.

Most epidemiological studies of soft tissue sarcoma (STS) were performed in the Western countries, and only limited data highlighting that in the Asian population. The aim of this study is to conduct a comprehensive analysis for the incidence rates of STS in Taiwan. This was a population-based study analyzing the incidence rates and trends of the primary STS over extremities and trunk wall during 2003 to 2011 by using the nationwide Taiwan Cancer Registry. More specific analyses were conducted for subtypes. Incidence rates of overall STS by cities and counties were also investigated. A total of 3843 cases were diagnosed with STS during the study period, giving an age-standardized rate (ASR) of 1.63 per 100,000 person-years. Liposarcoma was the most frequent subtype, followed by undifferentiated pleomorphic sarcoma and leiomyosarcoma. STS was more frequently diagnosed in males and angiosarcoma was the most prominent sex-specific type. ASR increased with age in most of the STS subtypes and varied by histologic subtype. The incidence of peripheral primitive neuroectodermal tumor was highest in children, whereas rhabdomyosarcoma revealed a bimodal age distribution. Annual percent change (APC) of STS was 2.2%, and significant change in trend was only in males (APC, 3.5%, P

Background Evidence from our recent study suggested that the overall trend for cancer incidence in children and adolescents has been increasing in Taiwan. Methods To analyze geographic variations in this trend, cancer frequencies and incidence rates of disease groups were quantified according to geographic areas among 12,633 patients aged

We describe a little girl with tetralogy of Fallot (TOF) who was found to have a huge peripheral primitive neuroectodermal tumor (pPNET) when she developed progressive difficulty in standing and crawling at the age of 11 months. The tumor was located in the left paraspinal region (T4-T12), with intraspinal extension causing severe compression. Nine days after surgical decompression with laminectomy, chemotherapy was initiated with alternative courses of vincristine, doxorubicin, cyclophosphamide, etoposide, and ifosfamide every 3 weeks. The muscle power in her legs recovered substantially after 2 courses of chemotherapy. Although peripheral blood for cytogenetic study revealed no chromosome abnormality, recent cytogenetic analysis has revealed a high frequency of reciprocal translocation t(11;22)(q24;q12) detected in pPNET and a strong association between TOF and chromosome 22q11 microdeletion (del 22q11). Both genetic defects involve chromosome 22q in the close region. This case report illustrates the necessity of investigating for cytogenetic change in chromosome 22 and close follow-up due to the possibility of subsequent development of malignancies in patients with TOF.

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

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

The anion exchanger (AE) plays critical roles in physiological processes including CO2 transport and volume regulation in erythrocytes and acid-base regulation in renal tubules. Although expression of the AE in inner-ear hair cells was reported, its specific localization and function are still unclear. Using in situ hybridization, we found that the AE1b transcript is expressed in lateral-line hair cells of zebrafish larvae. An immunohistochemical analysis with a zebrafish-specific antibody localized AE1b to stereocilia of hair cells, and the expression was eliminated by morpholino knockdown of AE1b. A non-invasive, scanning ion-selective electrode technique was applied to analyze mechanotransducer (MET) channel-mediated Ca2+ influx at stereocilia of hair cells of intact fish. Ca2+ influx was effectively suppressed by AE1b morpholino knockdown and inhibitor (DIDS) treatment. Elevating external Ca2+ (0.2 to 2 mM) neutralized the inhibition of DIDS. Taken together, this study provides solid evidence to show that AE1b in stereocilia is required for the proper functioning of MET channels.

Atopic dermatitis (AD) is one of the common allergic diseases in children. The presence of allergic diseases was found to have association with the risk of developing attention-deficit hyperactivity disorder (ADHD) or autistic spectrum disorder (ASD) in children, but it is still inconclusive. This study was to investigate the longitudinal relationship between AD developed during toddlerhood and subsequent development of ADHD or ASD in later childhood. Toddlers born between 1998 and 2008 and diagnosed with AD at the age younger than 3 years and older than 1 month were retrieved from Taiwan's National Health Insurance Research Database. Age- and gender-matched toddlers with no lifetime AD were enrolled as the control group. All enrolled toddlers were followed until 2011 to identify the development of ADHD or ASD. Multivariate Cox regression analysis was performed to analyze the hazard ratios (HRs). The risks associated with allergic comorbidities were analyzed. A total of 18,473 toddlers were enrolled into the AD group. The presence of AD significantly increased the risk of developing ADHD (HR = 2.92, 95% confidence interval [CI] = 2.48-3.45) or ASD (HR = 8.90, 95% CI = 4.98-15.92) when aged 3 years or older. Children from the AD group with 3 comorbidities together, namely, allergic rhinitis, allergic conjunctivitis, and asthma, had the greatest risk of developing ADHD and ASD (ADHD: HR = 4.67, 95% CI = 3.81-5.43; ASD: HR = 16.65, 95% CI = 8.63-30.60). In conclusion, toddlers who suffer from AD at the age younger than 3 years are at a higher risk of developing ADHD and ASD during later childhood. Pediatricians taking care of toddlers with AD should have knowledge of this increased risk of developing ADHD and ASD later in life, especially when children have certain comorbidities such as allergic rhinitis, allergic conjunctivitis, and asthma.

The aim of this study was to compare survival before and after 2004 and define the prognostic factors for high-grade osteosarcomas beyond those of typical young patients with localized extremity disease. Few studies have reported the long-term treatment outcomes of high-grade osteosarcoma in Taiwan. A total of 202 patients with primary high-grade osteosarcoma who received primary chemotherapy at Taipei Veterans General Hospital between January 1995 and December 2011 were retrospectively evaluated and compared by period (1995–2003 vs 2004–2011). Patients of all ages and tumor sites and those following or not following controlled protocols were included in analysis of demographic, tumor-related, and treatment-related variables and survival. Overall survival and progression-free survival at 5 years were, respectively, 67.7% and 48% for all patients (n = 202), 77.3% and 57.1% for patients without metastasis (n = 157), and 33.9% and 14.8% for patients with metastasis (n = 45). The survival rates of patients treated after 2004 were significantly higher (by 13%–16%) compared with those of patients treated before 2004, with an accompanying 30% increase in histological good response rate (P = .002). Factors significantly contributing to inferior survival in univariate and multivariate analyses were diagnosis before 2004, metastasis at diagnosis, and being a noncandidate for a controlled treatment protocol. By comparison with the regimens used at our institution before 2004, the current results support the effectiveness of the post-2004 regimens, which consisted of substantially reduced cycles of high-dose methotrexate and a higher dosage of ifosfamide per cycle, cisplatin, and doxorubicin, for treating high-grade osteosarcoma in Asian patients.

Objective: For diagnosing osteosarcoma correctly, a combination of clinical, radiological and histological examinations is required. Erroneous treatment may cause local contamination and systemic seeding in patients. The purpose of this study was to compare outcomes of planned and unplanned treatment for osteosarcoma. Methods: A retrospective review of patients with high-grade osteosarcoma who received appropriate surgical treatment and chemotherapy (n ¼ 134) and those who were misdiagnosed and received unplanned surgery (n ¼ 16) between July 1995 and February 2005. Results: Patients who received unplanned treatment were older (mean age: 29.7 vs. 19.7 years; P ¼ 0.003) and had a smaller mean tumor volume (119 vs. 280 ml; P ¼ 0.015). The 5-year survival rate was not statistically different between the groups. Patients who had unplanned treatment had a higher local recurrence rate (43.8 vs. 17.9%; P ¼ 0.024) and a shorter mean time for recurrence (11.9 vs. 20.8 months; P ¼ 0.036). Furthermore, in patients who underwent unplanned treatment, lung metastases occurred earlier (6.1 vs. 16.2 months P ¼ 0.021) and the final limb salvage rate was less (68.7 vs. 87.3%; P , 0.001). Conclusions: Unplanned treatment for high-grade osteosarcoma can result in failure of local control and earlier systemic metastases.

The long-term outcome of 1390 children with acute lymphoblastic leukemia (ALL), treated in two successive clinical trials (Taiwan Pediatric Oncology Group (TPOG)-ALL-97 and TPOG-ALL-2002) between 1997 and 2007, is reported. The event-free survival improved significantly (P=0.0004) over this period, 69.3+/-1.9% in 1997-2001 to 77.4+/-1.7% in 2002-2007. A randomized trial in TPOG-97 testing L-asparaginase versus epidoxorubicin in combination with vincristine and prednisolone for remission induction in standard-risk (SR; low-risk) patients yielded similar outcomes. Another randomized trial, in TPOG-2002, showed that for SR patients, two reinduction courses did not improve long-term outcome over one course. Decreasing use of prophylactic cranial irradiation in the period 1997-2008 was not associated with increased rates of CNS relapse, prompting complete omission of prophylactic cranial irradiation from TPOG protocols, beginning in 2009. Decreased use of etoposide and cranial irradiation likely contributed to the low incidence of second cancers. High-risk B-lineage ALL, T-cell, CD10 negativity, t(9;22), infant, and higher leukocyte count were consistently adverse factors, whereas hyperdiploidy >50 was a consistently favorable factor. Higher leukocyte count and t(9;22) retained prognostic significance in both TPOG-97 and TPOG-2002 by multivariate analysis. Although long-term outcome in TPOG clinical trials is comparable with results being reported worldwide, the persistent strength of certain prognostic variables and the lower frequencies of favorable outcome predictors, such as ETV6-RUNX1 and hyperdiploidy >50, in Taiwanese children warrant renewed effort to cure a higher proportion of patients while preserving their quality of life.

Five osteosarcoma (OS) cell lines, 37 OS tumors and 9 corresponding non-neoplastic samples were genotyped by Affymetrix 10 K 2.0 SNP array. Regions of high level amplification and homozygous deletion were identified and validated by quantitative PCR and FISH. Certain recurrent cytogenetic alterations were more frequent in recurrent/metastatic than in primary OS. These included deletion of 6q14.1, 6q16.2-q22.31, and 8p23.2-p12, amplification of 8q21.12, 8q22.3-q24.3 and 17p12, and loss of heterozygosity (LOH) at 2q24.3-q31.2, 5q11.2, 6p21.31-p21.1, 6q14.1-q16.2, 8p22-p12, 9q22.1, 10q21.1-q22.1, 10q23.31-q24.1, 12q15-q21.1 and 21q21.2-q21.3. Most of the LOH calls were associated with deletion, but a subset of them was associated with normal or increased copy number (CN). A consensus 3q13.31 deletion localized to a region within the limbic system-associated membrane protein (LSAMP) gene was also identified. The FISH evaluations demonstrated highly-localized homozygous or heterozygous LSAMP deletions in 6 of 11 primary OS. qRT-PCR evaluations of the two major alternative LSAMP transcripts demonstrated reduced expression of 1b isoform transcript in each of three OS with LSAMP exon 1b deletion. Further, the 1a isoform transcripts in these same OS had either reduced expression or a premature termination codon in LSAMP exon 2. This SNP genotyping study identified chromosomal aberrations associated with disease progression in OS and disclosed LSAMP as a novel tumor suppressor gene in OS. The study also demonstrated that CN and LOH analyses were able to detect distinct subsets of genetic abnormalities in OS.

Background and Objectives Enumeration of hematopoietic progenitor cells (HPC) using an automated hematology analyzer provides rapid, inexpensive, and less technically dependent prediction of peripheral blood stem cell (PBSC) mobilization. This study aimed to incorporate HPC enumeration along with other predictors for optimizing a successful harvest. Materials and Methods Between 2007 and 2012, 189 consecutive patients who proceeded to PBSC harvesting with a preharvest HPC ≥ 20 x 106 /L were recruited. A failed PBSC mobilization was defined as < 2 x 106 CD34+ cells/kg. Variables predicting a successful harvest identified by multivariate logistic regression and correlation analysis were subjected to classification and regression tree (CART) analysis. Results A total of 154 (81.5%) patients successfully achieved mobilization of CD34+ cells (median 8.18 x 106 CD34+ cells/kg). Five independent host predictors including age ≥ 60, a diagnosis of solid tumor, prior chemotherapy cycles ≥ 5, prior radiotherapy, and mobilization with G-CSF alone or high-dose cyclophosphamide, as well as laboratory markers including HPC and mononuclear cell (MNC) counts, were used for CART analysis. The number of host predictors with a cutoff at two, HPC cutoff at 28 x 106/L and MNC cutoff at 3.5 x 109 /L were best discriminative for successful prediction. In the decision tree algorithm, patients predicted as good mobilizers (0 to 2 risk factors) had a higher success rate (150/169, 88.8%) than that (4/20, 20.0%) of those predicted as poor mobilizers (3-5 risk factors). Moreover, patients predicted as good mobilizers and further with a HPC enumeration ≥ 28 x 106/L had a high probability of achieving successful mobilization (138/148, 93.2%). Conclusion Our CART algorithm incorporating host predictors, HPC enumeration and MNC count may improve prediction and thus increase the success of PBSC mobilization. Further prospective validation is necessary. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Discontinuation of E. coli- asparaginase in patients with acute lymphoblastic leukemia (ALL) upon severe allergic reactions is unavoidable. We aimed to examine the outcomes following E.coli- asparaginase discontinuation upon severe allergic reactions in ALL. Patients and methods : In Taiwan Pediatric Oncology Group (TPOG)-2002-ALL protocol (enrolled 2002-2012), intramuscular E. coli- asparaginase (Kyowa Hakko, Japan) was given at 5000 IU/m2 per dose thrice weekly for 3 weeks during the remission induction therapy of high-risk (HR) and very-high-risk (VHR) groups. During the first 20 weeks of continuation therapy, HR patients received weekly intramuscular E. coli- asparaginase 10,000 IU/m2 per dose every week. They also received two reinduction treatments during which E.coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 3 weeks. Patients in VHR groups received one reinduction treatment during which E. coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 2 weeks. Patients in standard-risk (SR) group, received no E. coli- asparaginase in induction, but were randomized to receive one or two reinduction phases, during which E. coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 2 weeks. The scheduled cumulative doses of E.coli- asparaginase in each risk group were 30,000 IU/m2 or 60,000 IU/m2 in SR, 265,000 IU/m2 in HR and 75,000 IU/m2 in VHR group. We evaluated outcome of children enrolled in TPOG-2002-ALL protocol who had E. coli- asparaginase discontinued due to severe allergic reactions (marked swelling and redness at the injection site or anaphylaxis) between 2002 and 2012, and compared outcomes between those who with Erwinase continued and those who without after the discontinuation of E. coli- asparaginase. The distributions of the Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) were compared using log-rank test. Chi-square test was used to compare each parameter between groups. Results: In 700 patients from 10 hospitals retrospectively studied, 52 patients had E. coli- asparaginase treatment discontinued due to the development of severe pancreatitis in 17 patients, severe thrombosis in 2, and severe allergic reactions in 33. In Taiwan, Erwinase has been available since 2012, and could be purchased from foreign countries before. PEG-asparaginase is not available in Taiwan. In the 33 patients had E. coli- asparaginase discontinued due to severe allergic reactions, 17 continued Erwinase and 16 did not. The parameters between these two groups were similar. They were of more HR group reflecting that HR patients received more E. coli- asparaginase than other patients. The 5-year OS did not differ significantly among the 648 patients without discontinuation (81±1.6%, mean±S.E.), the 17 with allergic reactions and continued with Erwinase (88±7.8%) and the 16 with allergic reactions not treated with Erwinase (87±8.6%). The P value for the difference between the latter two groups was 0.96. In the 16 patients who did not receive Erwinase, all the 10 patients, who had received >= 50% scheduled dose of E.coli- asparaginase before discontinuation, survived without events. Conclusions: We suggest that patients who had received 50% or more of the scheduled doses of E. coli- asparaginase before the development of severe allergic reactions do not need to continue treatment with Erwinase. This may be helpful in those who cannot afford Erwinase or in the vast majority of the world where Erwinase is not available. It also raises a question on that how much asparaginase is enough for the treatment of childhood ALL. Disclosures No relevant conflicts of interest to declare.

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

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