Outcome of Reinduction Chemotherapy with a Modified Dose of Idarubicin for Children with Marrow-Relapsed Acute Lymphoblastic Leukemia: Results of the Childhood Acute Lymphoblastic Leukemia (CALL)-0603 Study.

This multicenter, prospective trial was conducted to develop an effective and safe reinduction regimen for marrow-relapsed pediatric acute lymphoblastic leukemia (ALL) by modifying the dose of idarubicin. Between 2006 and 2009, the trial accrued 44 patients, 1 to 21 years old with first marrow-relapsed ALL. The reinduction regimen comprised prednisolone, vincristine, L-asparaginase, and idarubicin (10 mg/m²/week). The idarubicin dose was adjusted according to the degree of myelosuppression. The second complete remission (CR2) rate was 72.7%, obtained by 54.2% of patients with early relapse < 24 months after initial diagnosis and 95.0% of those with late relapse (P = 0.002). Five patients entered remission with extended treatment, resulting in a final CR2 rate of 84.1%. The CR2 rate was not significantly different according to the idarubicin dose. The induction death rate was 2.3% (1/44). The 5-year event-free and overall survival rates were 22.2% ± 6.4% and 27.3% ± 6.7% for all patients, 4.2% ± 4.1% and 8.3% ± 5.6% for early relapsers, and 43.8% ± 11.4% and 50.0% ± 11.2% for late relapsers, respectively. Early relapse and slow response to reinduction chemotherapy were predictors of poor outcomes. In conclusion, a modified dose of idarubicin was effectively incorporated into the reinduction regimen for late marrow-relapsed ALL with a low toxic death rate. However, the CR2 rate for early relapsers was suboptimal, and the second remission was not durable in most patients.

Improved Outcome of a Reduced Toxicity-Fludarabine, Cyclophosphamide, plus Antithymocyte Globulin Conditioning Regimen for Unrelated Donor Transplantation in Severe Aplastic Anemia: Comparison of 2 Multicenter Prospective Studies.

Hematopoietic stem cell transplantation (HSCT) is a curative therapy for severe aplastic anemia (SAA); however, the optimal conditioning regimen for HSCT with an unrelated donor has not yet been defined. A previous study using a fludarabine (FLU), cyclophosphamide (Cy), and antithymocyte globulin (ATG) conditioning regimen (study A: 50 mg/kg Cy once daily i.v. on days -9, -8, -7, and -6; 30 mg/m(2) FLU once daily i.v. on days -5, -4, -3, and -2; and 2.5 mg/kg of ATG once daily i.v. on days -3, -2, and -1) demonstrated successful engraftment (100%) but had a high treatment-related mortality rate (32.1%). Therefore, given that Cy is more toxic than FLU, we performed a new phase II prospective study with a reduced-toxicity regimen (study B: 60 mg/kg Cy once daily i.v. on days -8 and -7; 40 mg/m(2) FLU once daily i.v. on days -6, -5, -4, -3, and -2; and 2.5 mg/kg ATG once daily i.v. on 3 days). Fifty-seven patients were enrolled in studies A (n = 28) and B (n = 29), and donor type hematologic recovery was achieved in all patients in both studies. The overall survival (OS) and event-free survival (EFS) rates of patients in study B was markedly improved compared with those in study A (OS: 96.7% versus 67.9%, respectively, P = .004; EFS: 93.3% versus 64.3%, respectively, P = .008). These data show that a reduced-toxicity conditioning regimen with FLU, Cy, and ATG may be an optimal regimen for SAA patients receiving unrelated donor HSCT.

Higher Gemcitabine Dose Was Associated With Better Outcome of Osteosarcoma Patients Receiving Gemcitabine-Docetaxel Chemotherapy.

BACKGROUND: Efficacy of gemcitabine and docetaxel (GEM + DOC) chemotherapy in patients with recurrent or refractory osteosarcoma was evaluated. METHODS: Data of 53 patients from 9 institutions, who received GEM (675 or 900 mg/m(2) on days 1 and 8) and DOC (100 mg/m(2) on day 8), were retrospectively reviewed. RESULTS: GEM + DOC was administered as adjuvant (n = 25) or palliative chemotherapy (n = 28). Patients received a median 3 courses (range, 1-10 courses). Objective response rate (CR + PR, where CR is complete response and PR is partial response) and disease control rate (CR+ PR + SD, where SD is stable disease) were 14.3% and 28.6%, respectively. Disease control rate was higher in patients receiving 900 mg/m(2) GEM than in patients receiving 675 mg/m(2) (50.0% vs. 12.5%, P = 0.03). Higher GEM dose was associated with better survival, both in adjuvant (1-year overall survival, 90.9 ± 8.7% vs. 38.5 ± 13.5%, P = 0.002) and palliative settings (50.0 ± 14.4% vs. 31.3 ± 11.6%, P = 0.04). CONCLUSIONS: Further studies are necessary to investigate the efficacy of more aggressive and higher doses of GEM + DOC chemotherapy in osteosarcoma.

Favorable outcome of hematopoietic stem cell transplantation using a targeted once-daily intravenous busulfan-fludarabine-etoposide regimen in pediatric and infant acute lymphoblastic leukemia patients.

Conditioning regimens for pediatric acute lymphoblastic leukemia (ALL) usually include total body irradiation (TBI), but TBI may result in serious sequelae. Busulfan and cyclophosphamide have been used as an alternative to TBI. Etoposide also has been widely used to enhance antileukemic effect. However, toxicities have been reported in some studies using busulfan, cyclophosphamide, and etoposide regimen. A reduced toxicity myeloablative regimen using busulfan and fludarabine showed promising results. Also, therapeutic drug monitoring (TDM) and administration of targeted doses of busulfan have been recommended to improve the outcome of hematopoietic stem cell transplantation (HSCT). In this study, we evaluated the outcome of HSCT using a targeted once-daily i.v. busulfan-fludarabine-etoposide (BuFluVP) regimen in pediatric and infant ALL. Busulfan (age ≥ 1 year, 120 mg/m(2); age < 1 year, 80 mg/m(2)) was administered once daily as the first dose on day -8, and a targeted dose of busulfan was used according to the TDM results on days -7 to -5. Forty-four patients were evaluated. Donor-type neutrophil engraftment was achieved in all patients. Veno-occlusive disease occurred in 7 patients (15.9%), but all patients were successfully treated. Cumulative incidence of treatment-related mortality and relapse were 9.1% and 9.9%, respectively. One-year overall survival and event-free survival rates of all patients were 86.2% and 83.8%, respectively. Twelve patients (27.3%) were infants at diagnosis, and their 1-year overall survival rate was 83.3%. Our study demonstrated that HSCT using a targeted once-daily i.v. BuFluVP regimen showed favorable outcomes and could be an option for HSCT in pediatric and infant ALL.

Cytomegalovirus infection in seropositive unrelated cord blood recipients: a study of 349 Korean patients.

To gain insight into the natural history of cytomegalovirus (CMV) infection following unrelated cord blood transplantation (UCBT) in seropositive patients, we analyzed the data of 349 seropositive patients who received UCBT in Korea between 2000 and 2011. CMV reactivation occurred in 49 % (171/349) of the CMV-seropositive transplant recipients at a median of 31 days post UCBT. One hundred sixty-four out of 171 patients (96 %) received preemptive therapy. The median duration of CMV reactivation was 29 days. In multivariate analysis, weight >22 kg, use of total body irradiation, use of pre-transplant antithymocyte globulin, graft-versus-host disease (GVHD) prophylaxis with mycophenolate mofetil, and presence of grade II-IV acute GVHD were independent predictors of CMV reactivation. CMV reactivation did not impact transplantation-related mortality (TRM), leukemia relapse, or survival. CMV disease was diagnosed in 62 patients (17.8 %) at a median 55 days after UCBT. Longer duration of CMV reactivation was the only risk factor for progression to CMV disease (p = 0.01). CMV disease resulted in higher TRM (56.0 vs. 31.4 %, p < 0.01) and lower survival (36.1 vs. 55.1 %, p = 0.02).

Unrelated donor cord blood transplantation for non-malignant disorders in children and adolescents.

This study analyzes the data reported to the Korean Cord Blood Registry between 1994 and 2008, involving children and adolescents with non-malignant diseases. Sixty-five patients were evaluated in this study: SAA (n = 24), iBMFS, (n = 16), and primary immune deficiency/inherited metabolic disorder (n = 25). The CI of neutrophil recovery was 73.3% on day 42. By day 100, the CI of acute grade II-IV graft-versus-host disease was 32.3%. At a median follow-up of 71 months, five-yr OS was 50.7%. The survival rate (37.5%) and CI of neutrophil engraftment (37.5%) were lowest in patients with iBMFS. Deaths were mainly due to infection, pulmonary complications, and hemorrhage. In a multivariate analysis, the presence of >3.91 × 10(5) /kg of infused CD34 + cells was the only factor consistently identified as significantly associated with neutrophil engraftment (p = 0.04) and OS (p = 0.03). UCBT using optimal cell doses appears to be a feasible therapy for non-malignant diseases in children and adolescents for whom there is no appropriate HLA-matched related donor. Strategies to reduce transplant-related toxicities would improve the outcomes of UCBT in non-malignant diseases.

Open-label bendamustine monotherapy for pediatric patients with relapsed or refractory acute leukemia: efficacy and tolerability.

This open-label, single-arm, phase I/II, dose-escalation study was designed to determine the recommended phase II dose (RP2D), pharmacokinetics, tolerability, and efficacy of bendamustine in pediatric patients (age ranging from 1 to 20 y) with histologically proven relapsed/refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Patients (27 with ALL, 16 with AML) received intravenous bendamustine on days 1 and 2 of each treatment cycle. Phase I involved planned dose escalation of bendamustine to establish the RP2D for phase II. Objectives included overall response rate, duration of response, and tolerability. Eleven patients were treated in phase I, and the RP2D was 120 mg/m. In phase II, 32 patients received bendamustine 120 mg/m. Two patients with ALL (bendamustine 90 mg/m) experienced complete response (CR). Among patients who received bendamustine 120 mg/m, 2 experienced partial response (PR); 7 had stable disease. The overall response rate (CR+CR without platelet recovery [CRp]) was 4.7% and biological activity rate (CR+CRp+PR) was 9.3%. No AML patients responded. The most common adverse events were anemia, neutropenia, thrombocytopenia, pyrexia, nausea, vomiting, and diarrhea. Bendamustine monotherapy has acceptable tolerability in heavily pretreated children with relapsed/refractory ALL or AML and appears to have some activity in ALL, warranting further studies in combination trials.

Ewing sarcoma/peripheral primitive neuroectodermal tumor in the adrenal gland of an adolescent: a case report and review of the literature.

Ewing sarcoma/peripheral primitive neuroectodermal tumors (ES/pPNETs) typically occur in the long or flat bones, the chest wall, extraskeletal soft tissue, or less frequently, in solid organs. They can arise from anywhere in the body; however, ES/pPNETs arising from the adrenal gland are very rare, especially in children and adolescents. Herein, the authors report a case of an ES/pPNET in the adrenal gland of a 17-year-old girl, who was successfully treated with a multimodal treatment, with a brief review of the pertinent literature.

Clinical characteristics and treatment outcome of Langerhans cell histiocytosis: 22 years' experience of 154 patients at a single center.

Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology. Large studies by single institutions have been infrequent because of the rarity of the disease and the diversity of clinical manifestations. In this study, the clinical characteristics, prognostic factors, and treatment outcomes were analyzed. Medical records were analyzed retrospectively for the 154 patients diagnosed and treated with LCH at Seoul National University Children's Hospital from January 1986 to December 2007. A total of 154 patients were evaluated. One hundred and six patients (68.8%) had single system disease, 48 patients (31.2%) had multisystem disease. Twenty-nine patients (18.8%) had risk organ involvement. Twenty-nine patients (18.8%) relapsed and the overall survival (OS) of the total study population was 97.1% with a median follow-up period of 7.0 years. Patients less than 4 years old, with involvement more than 2 organs and with risk organ involvement showed lower progression free survival (PFS) (P = .001, <.001, and <.001, respectively). Estimated 10-year PFS of patients with and without risk organ involvement were 52.6% and 83.8%, respectively. Patients with single system LCH had excellent prognosis showing 89.6% of PFS and 100% of OS. Patients with multisystem LCH also had a high survival rate, although the incidences of relapse remain to be solved. A new strategy to decrease the incidence of relapse is needed.

Pre-engraftment syndrome after unrelated cord blood transplantation: a predictor of engraftment and acute graft-versus-host disease.

Pre-engraftment syndrome (PES) is poorly characterized, and its clinical significance and the prognostic impact after unrelated cord blood transplantation (CBT) are unclear. To address these issues, we retrospectively analyzed the incidence, risk factors, and clinical outcomes of PES in unrelated CBT recipients. Data of 381 patients who received unrelated CBT from 18 medical centers in Korea were reviewed. PES was defined as unexplained fever >38.3°C not associated with infection, and/or unexplained skin rash with or without evidence of fluid retention before neutrophil recovery. PES developed in 102 patients (26.8%) at a median of 7 days after CBT. Of these patients, 74 patients (72.5%) received intravenous corticosteroid at a median dose of 1 mg/kg/day, and of these, 95% showed clinical improvement. Risk factors for developing PES included low risk disease, myeloablative conditioning, graft-versus-host disease (GVHD) prophylaxis without methotrexate or corticosteroid, and >5.43 x 10(7)/kg infused nucleated cells. Absence of PES was one of the risk factors for graft failure in multivariate analysis. The cumulative incidence of grade II to grade IV acute GVHD by 100 days after CBT was higher in patients with PES than in those without PES (56.0% versus 34.4%, P < .01). PES was not associated with chronic GVHD, treatment-related mortality, relapse, or overall survival. PES seems to be common after CBT and may be associated with enhanced engraftment without significant morbidity.

Founder effects in two predominant intronic mutations of UNC13D, c.118-308C>T and c.754-1G>C underlie the unusual predominance of type 3 familial hemophagocytic lymphohistiocytosis (FHL3) in Korea.

Familial hemophagocytic lymphohistiocytosis (familial HLH or FHL) is a potentially fatal autosomal recessive disorder. Our previous study demonstrated that UNC13D mutations (FHL3) account for ~90 % of FHL in Korea with recurrent splicing mutation c.754-1G>C (IVS9-1G>C). Notably, half of the FHL3 patients had a monoallelic mutation of UNC13D. Deep intronic mutations in UNC13D were recently reported in patients of European descent. In this study, we performed targeted mutation analyses for deep intronic mutations and investigated on the founder effect in FHL3 in Korean patients. The study patients were 72 children with HLH including those with FHL3 previously reported to have a monoallelic UNC13D mutation. All patients were recruited from the Korean Registry of Hemophagocytic Lymphohistiocytosis. In addition to conventional sequencing of FHL2-4, targeted tests for c.118-308C>T and large intronic rearrangement mutations of UNC13D were performed. Haplotype analysis was performed for founder effects using polymorphic markers in the FHL3 locus. FHL mutations were detected in 20 patients (28 %). Seventeen patients had UNC13D mutations (FHL3, 85 %) and three had PRF1 mutations (FHL2, 15 %). UNC13D:c.118-308C>T was detected in ten patients, accounting for 38 % of all mutant alleles of UNC13D, followed by c.754-1G>C (26 %). Haplotype analyses revealed significantly shared haplotypes in both c.118-308C>T and c.754-1G>C, indicating the presence of founder effects. The deep intronic mutation UNC13D:c.118-308C>T accounts for the majority of previously missing mutations and is the most frequent mutation in FHL3 in Korea. Founder effects of two recurrent intronic mutations of UNC13D explain the unusual predominance of FHL3 in Korea.

Quantitative comparison of CDKN2B methylation in pediatric and adult myelodysplastic syndromes.

BACKGROUND/AIMS: Transcriptional repression of tumor suppressor genes is determined by the quantity of promoter hypermethylation. We analyzed the methylation quantity of CDKN2B in pediatric myelodysplastic syndromes (MDS). METHODS: Quantitative measurement of CDKN2B methylation was performed in 25 pediatric MDS patients and 12 controls using pyrosequencing, and the result was compared with those from 74 adult MDS cases and 31 adult controls. The association between CDKN2B methylation quantity and factors related to prognosis including bone marrow blast percentage and karyotype was analyzed. RESULTS: Pediatric MDS patients showed a higher methylation level (MtL) of CDKN2B than pediatric controls (2.94 vs. 1.62; p = 0.031) but a lower level than adult MDS patients (8.76; p < 0.001). MtL was higher in pediatric MDS cases with >5% blasts than in pediatric controls (3.78 vs. 1.62; p = 0.052). Pediatric MDS cases with abnormal karyotype showed a higher MtL than pediatric controls (5.95 vs. 1.62; p = 0.045). CONCLUSIONS: We confirmed that methylation of CDKN2B is associated with the pathogenesis and prognosis in pediatric MDS. The difference in MtLs between pediatric and adult MDS might be related to the physiological hypermethylation of tumor suppressor genes in aging.

Irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide for refractory or relapsed medulloblastoma/PNET in pediatric patients.

PURPOSE: The treatment outcome of pediatric refractory or relapsed brain tumor is very dismal, and effective salvage chemotherapy is not established. The combination of irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide was administered to pediatric patients with refractory or relapsed brain tumors as a salvage treatment at our institution. METHODS: The combination regimen was administered since June 2006 and consisted of irinotecan (300 mg/m(2), d0), vincristine (2 mg/m(2), d0), cisplatin (60 mg/m(2), d0), cyclophosphamide (1,000 mg/m(2), d1), and etoposide (100 mg/m(2)/day, d0-2). Patients could concurrently receive radiotherapy, surgery, and/or high-dose chemotherapy and stem cell rescue. The medical records of all patients were retrospectively analyzed. RESULTS: Thirteen patients with refractory or relapsed brain tumor were included (medulloblastoma, n = 12; central nervous system primitive neuroectodermal tumor, n = 1). Median time from diagnosis to this combination chemotherapy was 30 months (range, 3-111 months), and median cycle administered was four cycles (range 1-22 cycles). Objective tumor response at the end of chemotherapy was 38.5 % including three patients with complete response and two with partial response. One patient showed complete response and achieved long-term survival with this combination chemotherapy, and two patients achieved long-term survival with multimodality treatments. There was no grade III or IV toxicity related to this combination chemotherapy except for thrombocytopenia and neutropenia. CONCLUSIONS: The combination of irinotecan, vincristine, cisplatin, cyclophosphamide, and etoposide may produce objective responses in pediatric patients with refractory or relapsed medulloblastoma or primitive neuroectodermal tumor.

Respiratory viral infections after hematopoietic stem cell transplantation in children.

This study was performed to characterize respiratory viral infections in pediatric patients undergoing hematopoietic stem cell transplantation (HSCT). Study samples included 402 respiratory specimens obtained from 358 clinical episodes that occurred in the 116 children of the 175 consecutive HSCT cohort at Seoul National University Children's Hospital, Korea from 2007 to 2010. Multiplex reverse-transcription polymerase chain reactions were performed for rhinovirus, respiratory syncytial virus (RSV), parainfluenza viruses (PIVs), adenovirus, human coronavirus (hCoV), influenza viruses and human metapneumovirus. Viruses were identified in 89 clinical episodes that occurred in 58 patients. Among the 89 clinical episodes, frequently detected viruses were rhinovirus in 25 (28.1%), RSV in 23 (25.8%), PIV-3 in 16 (18.0%), adenovirus in 12 (13.5%), and hCoV in 10 (11.2%). Lower respiratory tract infections were diagnosed in 34 (38.2%). Neutropenia was present in 24 (27.0%) episodes and lymphopenia was in 31 (34.8%) episodes. Sixty-three percent of the clinical episodes were hospital-acquired. Three patients died of respiratory failure caused by respiratory viral infections. Respiratory viral infections in pediatric patients who have undergone HSCT are common and are frequently acquired during hospitalization. Continuous monitoring is required to determine the role of respiratory viruses in immunocompromised children and the importance of preventive strategies.

Growth after hematopoietic stem cell transplantation in children with acute myeloid leukemia.

Previous studies have shown that hematopoietic stem cell transplantation (HSCT) may result in growth impairment. The purpose of this study was to evaluate the growth during 5 yr after HSCT and to determine factors that influence final adult height (FAH). We retrospectively reviewed the medical records of acute myeloid leukemia (AML) patients who received HSCT. Among a total of 37 eligible patients, we selected 24 patients who began puberty at 5 yr after HSCT (Group 1) and 19 patients who reached FAH without relapse (Group 2). In Group 1, with younger age at HSCT, sex, steroid treatment, hypogonadism and hypothyroidism were not significantly associated with growth impairment 5 yr after HSCT. History of radiotherapy (RT) significantly impaired the 5 yr growth after HSCT. Chronic graft-versus-host disease (cGVHD) only temporarily impaired growth after HSCT. In Group 2, with younger age at HSCT, steroid treatment and hypogonadism did not significantly reduce FAH. History of RT significantly reduced FAH. Growth impairment after HSCT may occur in AML patients, but in patients without a history of RT, growth impairment seemed to be temporary and was mitigated by catch-up growth.

Clinical characteristics of pediatric thalassemia in Korea: a single institute experience.

Few literatures have elaborated on the clinical characteristics of children with thalassemia from low-prevalence areas. A retrospective analysis was conducted on children genetically confirmed with thalassemia at Seoul National University Children's Hospital in Korea. Nine children (1α thalassemia trait, 6ß thalassemia minor, 2ß thalassemia intermedia) were diagnosed with thalassemia at median age of 4.3 yr old with median hemoglobin of 9.7 g/dL. Seven (78%) children were incidentally found to be anemic and only 2 with ß thalassemia intermedia had presenting symptoms. Five children (56%) were initially misdiagnosed with iron deficiency anemia. Despite the comorbidities due to α thalassemia mental retardation syndrome, the child with α thalassemia trait had mild hematologic profile. Children with ß thalassemia intermedia had the worst phenotypes due to dominantly inherited mutations. None of the children was transfusion dependent and most of them had no complications associated with thalassemia. Only 1 child (11%) with codon 60 (T→A) mutation of the HBB gene needed red blood cell transfusions. He also had splenomegaly, cholelithiasis, and calvarial vault thickening. Pediatricians in Korea must acknowledge thalassemia as a possible diagnosis in children with microcytic hypochromic hemolytic anemia. High level of suspicion will allow timely diagnosis and managements.

Cross-cultural adaptation of the korean version of the minneapolis-manchester quality of life instrument-adolescent form.

We verified the reliability and validity of the Korean version of the Minneapolis-Manchester Quality of Life Instrument-Adolescent Form (KMMQL-AF) among Korean childhood cancer survivors. A total of 107 childhood cancer patients undergoing cancer treatment and 98 childhood cancer survivors who completed cancer treatment were recruited. To assess the internal structure of the KMMQL-AF, we performed multi-trait scaling analyses and exploratory factor analysis. Additionally, we compared each domains of the KMMQL-AF with those of the Karnofsky Performance Status Scale and the Revised Children's Manifest Anxiety Scale (RCMAS). Internal consistency of the KMMQL-AF was sufficient (Cronbach's alpha: 0.78-0.92). In multi-trait scaling analyses, the KMMQL-AF showed sufficient construct validity. The "physical functioning" domain showed moderate correlation with Karnofsky scores and the "psychological functioning" domain showed moderate-to-high correlation with the RCMAS. The KMMQL-AF discriminated between subgroups of different adolescent cancer survivors depending on treatment completion. The KMMQL-AF is a sufficiently reliable and valid instrument for measuring quality of life among Korean childhood cancer survivors.

Highly variable pharmacokinetics of once-daily intravenous busulfan when combined with fludarabine in pediatric patients: phase I clinical study for determination of optimal once-daily busulfan dose using pharmacokinetic modeling.

Busulfan has a narrow therapeutic range, and in children, pharmacokinetic variability has been found to be high even after the use of intravenous (i.v.) busulfan. Recently, a reduced toxicity myeloablative regimen showed promising results, but the data of busulfan pharmacokinetics in hematopoietic stem cell transplantation (HSCT) using a targeted busulfan/fludarabine regimen in children has not yet been reported. We performed therapeutic drug monitoring (TDM) after once-daily i.v. busulfan combined with fludarabine and analyzed the outcomes. Busulfan (i.v.) was administered once daily for 4 consecutive days. The daily target area under the curve (AUC) was 18,125-20,000 µg*h/L/day (4415-4872 µmol*min/L/day), which was reduced to 18,000-19,000 µg*h/L/day (4384-4628 µmol*min/L/day) after a high incidence of toxicity was observed. A total of 24 patients were enrolled. After infusion of busulfan on the first day, patients showed AUC that ranged from 12,079 to 31,660 µg*h/L (2942 to 7712 µmol*min/L) (median 16,824 µg*h/L, percent coefficient of variation (%CV) = 26.5%), with clearance of 1.74-6.94 mL/min/kg (median 4.03 mL/min/kg). We performed daily TDM in 20 patients, and during the daily TDM, the actual AUC ranged from 73% to 146% of the target AUC, showing high intraindividual variability. The %CV of busulfan clearance of each individual ranged from 7.7% to 38.7%. The total dose of busulfan administered for 4 days ranged from 287.3 mg/m(2) to 689.3 mg/m(2). Graft failure occurred in 3 patients with total AUC less than 74,000 µg*h/L (18,026 µmol*min/L), and 2 patients with relatively high total AUC experienced veno-occlusive disease. Busulfan pharmacokinetics showed high inter- and intraindividual variability in HSCT using a targeted busulfan/fludarabine regimen, which indicates the need for intensive monitoring and dose adjustment to improve the outcome of HSCT. Currently, we are performing a newly designed phase II study to decrease regimen-related toxicities and reduce graft failure by setting an optimal target AUC based on this study.

Early engraftment of G-CSF-primed allogeneic bone marrow transplantation in pediatric patients regardless of donor-recipient weight differences.

Harvesting sufficient progenitor cells from bone marrow (BM) for pediatric patients is a challenging process, especially from smaller donors. Growth factor administration to donors prior to harvest results in an enrichment of the graft and leads to early engraftment. A total of 41 patients received a human leukocyte antigen-identical sibling transplantation using granulocyte colony-stimulating factor (G-CSF)-primed BM. All donors received G-CSF 10 µg/kg/day for 2 days prior to harvest. The median weight difference between donor and recipient was 3.9 kg (range, -29.8 to 32 kg), and the median number of CD34(+) cells harvested was 4.16 × 10(6)/kg (range, 1.17-31.9 × 10(6)/kg). The median time to neutrophil engraftment was 12 days (range, 10-27 days), and the time for platelet engraftment was 20 days (range, 12-64 days). The cumulative incidence of acute grade 2 to 3 graft-versus-host disease (GVHD) and chronic GVHD was 4.9% and 5.1%, respectively. An analysis according to the weight difference between donor and recipient showed there was no significant difference in harvested CD34(+) cell dose and in time required for engraftment between smaller and heavier donor recipients. G-CSF-primed BM allows successful engraftment and provides a valuable alternative to unstimulated BM and peripheral blood stem cells with good engraftment and tolerable GVHD even in patients with smaller donors.

Pediatric infratentorial ependymoma: prognostic significance of anaplastic histology.

Pediatric infratentorial ependymomas are difficult to cure. Despite the availability of advanced therapeutic modalities for brain tumors, total surgical resection remains the most important prognostic factor. Recently, histological grade emerged as an independent prognostic factor for intracranial ependymoma. We retrospectively reviewed the treatment outcome of 33 pediatric patients with infratentorial ependymoma. Progression-free survival (PFS) and overall survival (OS) rates were calculated and relevant prognostic factors were analyzed. Fourteen patients (42%) were under the age of 3 at diagnosis. Gross total resection was achieved in 16 patients (49%). Anaplastic histology was found in 13 patients (39%). Adjuvant therapies were delayed until progression in 12 patients (36%). Actuarial PFS rates were 64% in the first year and 29% in the fifth year. Actuarial OS rates were 91% in the first year and 71% in the fifth year. On univariate analysis, brainstem invasion (P = 0.047), anaplastic histology (P = 0.004), higher mitotic count (P = 0.001), and higher Ki-67 index (P = 0.004) were significantly related to a shorter PFS. Gross total resection (P = 0.029) and a greater age at diagnosis (P = 0.033) were significantly related to a longer PFS. On multivariate analysis, anaplastic histology alone was significantly related to a shorter PFS (P = 0.023). Gross total resection (P = 0.039) was significantly related to a longer overall survival (OS) on multivariate analysis. Anaplastic histology and gross total resection were the most important clinical factors affecting PFS and OS, respectively. Anaplastic histology, mitotic count, and Ki-67 index can be used as universal and easily available prognostic parameters in infratentorial ependymomas.