Journal articles: 'Children who failed first grade'

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Bowen, François, Frank Vitaro, Margaret Kerr, and Daniel Pelletier. "Childhood internalizing problems: Prediction from kindergarten, effect of maternal overprotectiveness, and sex differences." Development and Psychopathology 7, no. 3 (1995): 481–98. http://dx.doi.org/10.1017/s0954579400006647.

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AbstractResearch on the development of childhood internalizing problems has largely failed to consider that there may be different developmental paths for boys and girls. Additionally, studies have begun with elementary school children who are well beyond their first social experiences. This study follows 144 boys and 125 girls from kindergarten (for most children the time of first social experiences) to fifth grade. We identify the best predictors of fifth grade internalizing problems from kindergarten measure of anxiety-withdrawal, shyness, adaptability, and popularity. We also test whether maternal overprotectiveness moderates the link between kindergarten predictors and fifth-grade internalizing problems. Throughout, we consider boys and girls separately. Peer-rated unpopularity was the best predictor of later problems for both boys and girls, followed by peer-rated shyness for boys and teacher-rated anxiety-withdrawal for girls. Maternal overprotectiveness was more important for boys than girls. For boys overprotectiveness reduced the predictive link between some kindergarten variables and some fifth-grade outcomes; for girls overprotectiveness did not significantly moderate the predictive link. We discuss the advantages of different perspectives (peers, teachers, and mothers) for predicting internalizing problems. We also discuss the roles of early temperament, early social experience, and maternal overprotectiveness versus close temporal experience in developing internalizing problems.

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Harris, Richard E., Erin Morris, Phyllis Warkentin, Adrianna Vlachos, Myron Chang, and Mitchell S. Cairo. "Safety and Efficacy of CBV Followed by Autologous PBSC Transplant in Children with Lymphoma after Failed Induction or First Relapse - a Children’s Oncology Group Study." Blood 104, no. 11 (2004): 899. http://dx.doi.org/10.1182/blood.v104.11.899.899.

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Abstract Purpose: To determine the safety and efficacy of high dose cyclophosphamide, BCNU and etoposide (CBV) chemotherapy followed by autologous non-purged PBSCT in children with Hodgkin’s (HD) and non-Hodgkin’s lymphoma (NHL) who have either failed primary induction therapy or have experienced a first relapse. Methods: At study entry, patients received 2–4 courses of reinduction therapy as determined by the local institution. When a CR or PR was achieved, G-CSF mobilized PBSCs were harvested and patients underwent autologous PBSCT after a preparative therapy of cyclophosphamide 6000 mg/m2, BCNU 450–300 mg/m2, and etoposide 2400 mg/m2. Patients were to receive a set dose of 5x106 CD34 cells/kg. Patients were followed for disease status and toxicities. 69 patients (38 HD, 31 NHL) were entered onto study between April 1998 and June 2002. Survival statistics were calculated as Kaplan Meier estimates. Results: 41/69 (27/38 HD, 14/31 NHL) achieved a CR/PR at the conclusion of reinduction; 14 failed due to PD; 7 had SD; 7 were inevaluable. 38 patients (27 HD, 11 NHL) proceeded to autologous PBSCT. Overall 28/38 (20 HD, 8 NHL) of the transplanted patients survive and 21/28 (15 HD, 6 NHL) are progression free. The survival rates at 12 months and 24 months were 88%(±6) (HD 92%(±6), NHL 78%(±14)) and 73%(±10) (HD 76%(±11), NHL 65%(±22)), respectively. The rates of PFS at 12 months and 24 months were 65%(±8)(HD 72%(±9); NHL 46%(±17)) and 53%(±11) (HD 56%(±12); NHL 46%(±19)), respectively. 10 patients died after PBSCT. The causes of death were PD (N=5), infection (N=4), and toxicity (N=1). The first 17 patients received BCNU 450 mg/m2 and 8 of these experienced grade 3 or 4 pulmonary or renal toxicity. The dose was thus dropped to 300 mg/m2 and an additional 21 patients underwent PBSCT and 3 of these patients developed grade 3 or 4 pulmonary or renal toxicity. The incidence of grade 3 or 4 pulmonary of renal toxicity at 300mg/m2 was significantly lower than that at 450 mg/m2 (p=0.04, Fisher’s exact test). Conclusions: For children with primary resistant or first relapsed lymphoma who achieve a CR or PR after reinduction, CBV preparative therapy followed by PBSCT for children with primarily resistant or relapsed lymphoma results in an acceptable survival but a lower PFS due to a high relapse rate following transplant. A BCNU dose of 300 mg/m2, but not a dose of 450 mg/m2 is well tolerated by these heavily treated patients.

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Rossberg, Siri, Uwe Pleyer, and Susanne Lau. "Omalizumab in three children with severe vernal keratoconjunctivitis." Allergo Journal International 29, no. 6 (2020): 181–86. http://dx.doi.org/10.1007/s40629-020-00128-4.

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Summary Background Vernal keratoconjunctivitis (VKC) is a rare, recurrent form of ocular allergy that can be refractory to topical and systemic treatment. It typically presents as acute and chronic keratoconjunctival inflammation that may lead to visual impairment due to corneal ulcers and scaring. Patients often suffer from atopic IgE-driven comorbidities, especially atopic eczema. Children are frequently affected and often do not tolerate topical treatment well, especially if photophobia and pain impair therapy adherence. We present three children with severe VKC who were not controlled by first- and second-line topical and systemic therapy and finally responded to treatment with the monoclonal anti-IgE antibody omalizumab as third-line treatment. Methods and results We retrospectively analyzed three patients with VKC having failed response to first- and second-line treatment. All three boys had very early allergic rhinoconjunctivitis from age 1–3 with polysensitization: birch, grass pollen, house dust mite, and/or pets. All received subcutaneous or sublingual immunotherapy (SCIT/SLIT) for birch and/or grass pollen without major success. Two patients had comorbidities: allergic asthma and severe atopic dermatitis (AD). For at least 6 months after the first administration, monoclonal anti-IgE antibody omalizumab (150 or 300 mg) was administered subcutaneously every 2–6 weeks in all patients achieving improvement of the clinical grading scale from VKC grade 3–4 to grade 1–2. One patient had a relapse mainly of his AD and achieved complete control of AD and VKC by introduction of dupilumab. Conclusion Although the clinical benefit of omalizumab in asthma and chronic spontaneous urticaria (CSU) has been established in several clinical trials, there are very little data about its effect on severe VKC. In addition to few previously reported cases we can report the rapid effectiveness of omalizumab in VKC clinically and in terms of quality of life. Randomized trials are needed to include omalizumab in third-line treatment of VKC for prevention of visual impairment and further sequelae such as corneal damage.

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Im, Ho Joon, Kyung Nam Koh, Yoshiyuki Takahashi, et al. "Haploidentical Hematopoietic Stem Cell Transplantation in Pediatric Patients with Acquired Severe Aplastic Anemia: Collaborative Study of Three Eastern Asian Countries." Blood 124, no. 21 (2014): 2556. http://dx.doi.org/10.1182/blood.v124.21.2556.2556.

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Abstract Haploidentical hematopoietic stem cell transplantation (HHCT) is indicated for patients with severe aplastic anemia (SAA) who need emergent HCT or for those with refractory SAA who lack a matched related or unrelated donor.°°We evaluated the outcomes of children and adolescents with acquired SAA who received HHCT at three transplant centers in Eastern Asia. This collaborative study reports the feasibility and efficacy of HHCT in children and adolescents with acquired SAA. Between May 2006 and February 2014, 33 patients received HHCT at Asan Medical Center Children’s Hospital in Seoul (n=18), Shanghai Children’s Medical Center (n=8), and Nagoya University Hospital (n=7). Eighteen patients received in vitro T cell-depleted transplantation (TCD-HHCT) and 15 received a graft without in vitro manipulation (non-TCD-HHCT). Of the 33 patients, 27 had failed immnosuppressive therapy prior to HHCT. The donors were the mother in 15 patients, the father in 14, and a sibling in four. The conditioning regimen consisted of fludarabine (FLU), cyclophosphamide (CY), and rabbit ATG (r-ATG) with or without total body irradiation (TBI) in 18 patients who received TCD-HHCT. In the 15 patients who received non-TCD-HHCT, FLU/CY/ATG was used as a conditioning regimen for eight patients and FLU/melphalan/r-ATG/TBI for seven patients. Among the 33 patients, 31 achieved neutrophil engraftment at a median of 12 days (range, 9–34 days) after HHCT. Two patients (one with TCD-HHCT and one with non-TCD-HHCT) failed to achieve primary engraftment. An additional four patients who received TCD-HHCT experienced graft rejection (GR) soon after engraftment, although no patients who received non-TCD-HHCT experienced GR. All of the five patients who experienced early graft failure (GF) after TCD-HHCT received a second HHCT and achieved sustained engraftment. The patient who experienced GF after non-TCD-HHCT died of infection after the second HHCT from the same donor at D+54 from the first HHCT. Acute graft versus host disease (aGVHD) was assessed in 27 patients, excluding the six patients with early GF. Thirteen of the 27 patients developed grade II to IV aGVHD (8 grade II, 4 grade III and 1 grade IV) leading to a cumulative incidence of 48.1%. And five patients developed extensive chronic GVHD. Of the total of 33 patients, three patients (one with TCD-HHCT and two with non-TCD-HHCT) died of TRM. One patient died of severe autoimmune hemolytic anemia after a booster infusion of CD34+ cells for poor graft function at +457 days, one died of infection after salvage transplantation for GF at +54 days from his first HHCT, and one died of pulmonary complications at +236 days. At a median follow-up of 28 months (range, 4-99 months), the overall survival at 2 years was 90.1% (95% CI, 80.7-100%) and all 30 surviving patients were transfusion-independent. Our study suggests that HHCT with or without in vitro T cell depletion is a realistic therapeutic option for pediatric patients with SAA who lack a matched related or unrelated donor. Disclosures No relevant conflicts of interest to declare.

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Vassal, Gilles, Dominique Couanet, Elizabeth Stockdale, et al. "Phase II Trial of Irinotecan in Children With Relapsed or Refractory Rhabdomyosarcoma: A Joint Study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group." Journal of Clinical Oncology 25, no. 4 (2007): 356–61. http://dx.doi.org/10.1200/jco.2006.06.1960.

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PurposeThis phase II study was designed to evaluate the efficacy of irinotecan administered intravenously once every 3 weeks in pediatric patients with recurrent or refractory rhabdomyosarcoma.Patients and MethodsA total of 35 patients younger than age 20 years, with refractory or relapsed rhabdomyosarcoma for which standard treatments have failed, received irinotecan at 600 mg/m2administered as a 60-minute infusion every 3 weeks. Concomitant treatments included atropine for cholinergic symptoms, loperamide for diarrhea at the first liquid stool, and preventive antiemetic treatment. Tumor response was assessed every two cycles until progression according to WHO criteria.ResultsThe best overall response rate to irinotecan was 11.4% (95% CI, 3.2 to 26.7%; 2.9% complete responses, 8.5% partial responses) from all patients recruited. The median times to progression and survival were 1.4 and 5.8 months, respectively. A total of 112 cycles were administered, with a median number of two cycles per patient (range, 1 to 16). The most common grade 3/4 toxicities were neutropenia (46%), abdominal pain or cramping (17%), cholinergic syndrome (14%), nausea/vomiting (11%), anemia (11%), thrombocytopenia (9%), and diarrhea (6%).ConclusionIn heavily pretreated children with a high tumor burden who have been treated with multiagent chemotherapy, irinotecan administered intravenously as a single agent, at 600 mg/m2every 3 weeks, showed an interesting objective response rate and a good tolerance profile in rhabdomyosarcoma.

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Presch, C., O. Eberhardt, T. Wirth, and F. F. Fernandez. "Comparison of arthroscopic and open reduction of conservatively irreducible dislocated hips of children." Journal of Children's Orthopaedics 13, no. 4 (2019): 377–84. http://dx.doi.org/10.1302/1863-2548.13.190057.

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Purpose Children with sonographic grade IV hip dysplasia according to Graf and with failed conservative treatment usually need surgical reduction afterwards. Surgical reduction of the hip can lead to severe complications, the occurrence of residual acetabular dysplasia, osteonecrosis, redislocation and other postoperative complications. This paper investigates whether arthroscopic reduction is a promising alternative to open reduction. Methods We retrospectively examined 66 patients (78 hips) who were not older than two years at the first time of surgery. Arthroscopic reduction was performed on 17 children (19 hips) and open reduction on 49 children (59 hips). Patient records were used to determine redislocation, postoperative complication and residual dysplasia. Radiographs were used to determine Tönnis classification for osteonecrosis and pathological acetabular (AC) angle for residual dysplasia. We considered data up to a two-year follow-up. Statistical evaluation was performed with binary logistic regression. Results After arthroscopic reduction, 6% showed osteonecrosis, compared with 20% with open reduction (p = 0.334). Redislocation was not observed after arthroscopic reduction but for 29% after open reduction (p = 0.005). An improvement of femoral head coverage was achieved with residual dysplasia of 23.5% after arthroscopic reduction, compared with 62% after open reduction (p = 0.002). Conclusion The arthroscopic procedure represents a meaningful alternative to the open procedure due to a lower complication rate, a safe setting, a lower rate of residual dysplasia, no observed redislocation and occurrence of osteonecrosis only once in the arthroscopic group of developmental dysplasia of the hip. The arthroscopic procedure should be tested in further studies and in other clinics in order to broaden the empirical base. Level of Evidence: Level III (retrospective cohort study)

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Li, Chi Kong, Vincent Lee, Frankie WT Cheng, et al. "Unrelated Umbilical Cord Blood Transplant for Children with Leukemia: Single or Double Unit Transplant." Blood 112, no. 11 (2008): 4422. http://dx.doi.org/10.1182/blood.v112.11.4422.4422.

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Abstract Unrelated umbilical cord blood transplant (UCBT) was performed in 24 children (16 M, 8 F) with leukemia in a single institution from June 1998 to May 2008. The leukemia types were Acute Lymphoblastic Leukemia (ALL, n=13), Acute Myeloid Leukemia (AML, n=9) and Juvenile Myelomonocytic Leukemia (JMML, n=2). The disease status was CR2 in 13, CR3/4 in 3, refractory or relapse in 8. Fifteen patients received single unit (SU) and 9 patients received double unit (DU) UCBT. The mean age and body weight were 5.7 ± 3.7 year and 19.5 ± 7.9 kg for SU, 7.7 ± 4.0 year and 24.6 ± 9.9 kg for DU, respectively. The sources of cord blood units were from local public CB bank (n=20) and 4 overseas public CB banks (n=4). The cord blood units were not more than 2 HLA antigen mismatches from the patients, and the DU cord blood were also not more than 2 antigen mismatches between each other. The minimal requirement was nucleated cell (NC) dose &gt; 2.5×107/kg for SU, and &gt; 3.7 ×107/kg for DU. The conditioning was TBI based for ALL and busulphan-based for myeloid leukemia. ATG was routinely included except in 5 patients. The engraftment rate was 70.8% for the whole group, and 66.7% and 77.8% for SU and DU, respectively. All the 4 overseas UCBT failed to engraft and the engraftment rate for local CB bank units was 85%. The 2 JMML had failed engraftment, one received SU and 1 DU. There was no significant difference in the transplanted cell dose for SU and DU (combined dose), NC 6.2±3.8×107/kg vs 8.2±3.5×107/kg, CD34 cell 5.0±7.2 ×105/kg vs 3.8±1.3×105/kg, respectively. However patients who had successful engraftment received higher cell dose, NC 7.9±3.9×107/kg vs 4.5±1.8×107/kg (p=0.042), CD34 cell 5.4±6.3 ×105/kg vs 2.2±1.6×105/kg (p=0.073), respectively. All the 9 DU UCBT showed signs of engraftment with donor DNA detected, but two did not achieve neutrophil engraftment and subsequently failed engraftment. On the first chimerism study on Day 7–10, 3 had mixed chimerism (MC, 50–60% vs 40–50%) and 2 became single donor complete chimerism (CC) in the second week study, one had persistent MC up to 1 month but required second transplant for failed neutrophil engraftment. Six patients had CC with single CB unit since the week 1 and were maintained in 5, and another one had failed neutrophil engraftment. Finally 7 DU UCBT had sustained CC with single donor unit, however the finally successfully engrafted unit had lower CD34 cell dose as compared to the non-engrafted unit (1.5±0.5×105/kg vs 2.4±1.1 ×105/kg, p=0.004), and the NC dose of the 2 units in DU was similar (3.6±1.7.×107/kg vs 4.4±1.8×107/kg (p=0.042). There was no difference in the degree of HLA mismatch between the engrafted and non-engrafted units of DU. The neutrophil engraftment was more rapid with SU as compared with DU, 14.5 vs 19.7 days, p=0.021, the platelet engratment and number of red cell and platelet transfusion was not different. All those with engraftment developed acute GVHD, and the incidence of grade III–IV was similar between SU and DU (33.3% vs 28.6%), and none died from AGVHD. Nine patients died of non-engraftment or transplant related mortality, 3 from leukemia relapse and 12 were alive (7 patients &gt; 3 years). The 2-year survival after UCBT was 47%. In conclusion, DU cord blood could achieve a higher NC dose, but the engraftment of DU was always single unit and 33% had transient MC in the very early week of UCBT. The DU approach may enhance the engraftment of the finally engrafted unit even that had a lower CD34 cell dose.

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Strumberg, D., M. E. Scheulen, R. A. Hilger, et al. "Safety, efficacy and pharmacokinetics of nimotuzumab, a humanized monoclonal anti-epidermal growth factor receptor (EGFR) antibody, as monotherapy in patients with locally advanced or metastatic pancreatic cancer (PC)." Journal of Clinical Oncology 24, no. 18_suppl (2006): 12504. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.12504.

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12504 Background: Nimotuzumab (OSAG101, Theraloc) is a humanized monoclonal antibody (mAb) that binds to the EGFR. In preclinical studies the antibody has shown potent antitumor activity. Based on phase I data, the recommended dose has been established at 200 mg weekly. A previous phase II study in children with high grade brain tumors showed activity of nimotuzumab as a monotherapeutic agent, even in prognostically very unfavorable pontine glioma. No drug related side effects were reported. The present ongoing phase II study was aimed at evaluating the safety and efficacy of nimotuzumab monotherapy in patients (pts) with locally advanced or metastatic PC. Methods: Pts who failed standard chemotherapy with gemcitabine or another first line regimen for advanced disease and had at least one measurable lesion were eligible for the study. Nimotuzumab was given iv as induction therapy at 200 mg once weekly for 6 weeks. Follow up by CT was performed after 8 weeks. Pts continued receiving treatment 3-weekly until disease progression or unacceptable toxicity occurred. Endpoints included tumor response (RECIST), time to disease progression, and safety. Blood samples were collected prior to first dose, at end of infusion, and 3h, 6h, 48h, as well as every time before subsequent nimotuzumab doses were administered. Nimotuzumab concentrations in serum were measured by cellular ELISA. Results: Enrollment is complete, with treatment ongoing. In total, 55 pts were treated (28 women/ 27 men; ECOG status of 1 [n= 41] or 0 [n=14], median age 63.6 yrs [range 46–83 yrs]). Pts evaluable for response: n= 36; CR:0; PR:0; SD:6 pts (median TTP 19.2 weeks; 14.1–26.1). The only reported treatment-related adverse event was rash grade 1 in 1 pt. After 200 mg single dose, the mean value of Cmax was calculated to 141 ± 33 μg/ml. The t1/2 was calculated to 45 h, volume of distribution to 1.46 ± 0.3 l, respectively. The total clearance was determined to 23 ± 6 ml/h. The trough values after 168 h were 6.2 ± 6.3 μg/ml. Conclusions: These data confirm that nimotuzumab is safe and well tolerated. To improve efficacy, a combination trial with gemcitabine is planned. [Table: see text]

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Rao, Vasudha, Katherine Clesham, Jack Luke Bartram, et al. "Excellent Response to Blinatumomab in Children and Young Adults with Refractory B Lineage Acute Lymphoblastic Leukaemia for Persistent MRD or after Debulking Chemotherapy for Higher Disease Burden." Blood 132, Supplement 1 (2018): 5201. http://dx.doi.org/10.1182/blood-2018-99-117051.

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Abstract Introduction: A recent phase I/II study of blinatumomab in children with relapsed/refractory B cell acute lymphoblastic leukaemia (B-ALL), found 39-51% achieved complete, often MRD negative, remission after two cycles of therapy. Higher responses were observed in patients with less than 50% bone marrow blasts, compared to greater than 50% (55.6% vs 32.7% (95% CI 30.8-78.5 and 20.3-47.1 respectively)1. Furthermore, an adult study showed complete minimal residual disease (MRD) response rates of 78% when blinatumomab was used to treat MRD-positive ALL in haematological remission 2. Hence response rates (and toxicity) to blinatumomab are highly correlated with pre-treatment disease burden. We present preliminary data showing an excellent response to blinatumomab in children and young adults with resistant B-ALL who had persistent MRD, or after debulking chemotherapy to achieve a partial remission. Methods: Eleven patients were identified through a national survey. The mean age of patients was 10 years (range 0.7-22 years, 3 infants and 1 Down syndrome ALL). All patients had B-lineage ALL which was CD19 positive. None had active CNS disease at the point of receiving blinatumomab. Prior to administration of blinatumomab, all patients either had persistent MRD following several courses of intensive chemotherapy or received debulking chemotherapy for heavier marrow infiltrates. Pre-blinatumomab chemotherapy to which the patients had failed to obtain an adequate MRD response included UKALL 2011 Regimens A or C, UKALL R3, Interfant 06 or NOPHO high risk blocks. Patients received 5-15 µg/m2 of blinatumomab for 1-2 cycles prior to definitive therapy. Results: Pre-blinatumomab, all patients except one were in morphological remission with MRD measurable by PCR (0.003-1%), the remaining patient had 9% marrow disease by morphology. After 1-2 cycles of blinatumomab all patients had negative MRD when measured by flow cytometry and/or by PCR, giving a 100% response rate. This was followed by Haemopoietic stem cell transplant (HSCT) in nine patients and the remaining two are awaiting transplant. Further data on patient characteristics, CNS status, relapse and survival outcome are being collected and will be presented at the meeting. Minimal toxicity was observed; of the seven patients in whom toxicity data were available, three had grade 1 CRS, which resolved spontaneously without interruption of therapy or treatment with corticosteroids or Tocilizumab. One patient reported grade 1 neurotoxicity. This preliminary UK experience demonstrates that excellent MRD response is observed with minimal toxicity in children and young adults who receive blinatumomab for persistent MRD or after debulking chemotherapy. This provided a bridge to transplant in patients who would otherwise not have benefited from the procedure because of persistent MRD. We are planning to extend these observations by undertaking a study of this strategy in first high-risk B-ALL relapse. Stackelberg Av, Locatelli F, Zugmaier G, et al. Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. Journal of Clinical Oncology. 2016;34(36):4381-4389. Gokbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. Disclosures Ghorashian: Celgene: Other: travel support; Novartis: Honoraria. Marks:Novartis: Consultancy; Pfizer: Consultancy; Amgen: Consultancy. Vora:Amgen: Other: Advisory board; Novartis: Other: Advisory board; Jazz: Other: Advisory board; Medac: Other: Advisory board; Pfizer: Other: Advisory board.

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Teachey, David T., TIffaney Vincent, Kim Smith-Whitley, et al. "Targeting mTOR Signaling Leads To Complete and Durable Responses In Children With Multi-Lineage Autoimmune Cytopenias, Including ALPS, SLE, Evans and CVID." Blood 122, no. 21 (2013): 330. http://dx.doi.org/10.1182/blood.v122.21.330.330.

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Abstract Unlike children with single lineage autoimmune cytopenias, children with autoimmune destruction of multiple cell lineages often have chronic therapy-refractory disease. Many patients develop significant morbidity from long-term corticosteroids, and novel therapeutic approaches are needed. We previously demonstrated that treatment with sirolimus (rapamycin) led to complete responses (CRs) in a small cohort of children (5 of 5) with autoimmune lymphoproliferative syndrome (ALPS) in a retrospective case series. We opened a prospective IRB-approved clinical trial treating children with treatment-refractory ALPS with sirolimus. Based on an early efficacy signal, we broadened the inclusion criteria to any children with autoimmune cytopenias who failed or were intolerant to standard immunosuppressive therapy. We have now treated 27 children on the trial. Twelve of the children have ALPS (aged 18 mo. to 18 yrs). Of these, 10 had a durable CR, which was rigorously defined as resolution of autoimmune cytopenias (normal CBC), lymphoproliferation, and other autoimmune manifestations. One child had a near-CR (NCR) with resolution of autoimmunity but mild breakthrough adenopathy with viral illness. One child had a partial response (PR) with improvement in autoimmune disease. This child had only been on therapy for 2 months. Double negative T cells, the biologic hallmark of ALPS, are no longer detectable in 8 of 12 children, suggesting sirolimus targets the pathogenic cell population. In addition to the 12 children on the trial, we have advised clinicians treating an additional 28 children with ALPS at our own institution and at other centers in the USA and from 13 different countries. By report, the majority of these patients (24 of 28) have had complete and durable responses with sirolimus. These additional anecdotal cases support our finding of a >80% CR rate on our prospective trial. Many of these children have successfully tolerated sirolimus for over 5 years. Correlative studies in murine models in our laboratory demonstrate mTOR signaling is dysregulated in ALPS, suggesting sirolimus is targeted therapy. Two children with common variable immunodeficiency (CVID) and two with systemic lupus erythematosus (SLE) with refractory multi-lineage autoimmune cytopenias were treated on the trial, and 3 of 4 had a CR. One had NCR with resolution of autoimmune destruction of 2 cell lineages but persistent immune thrombocytopenia (ITP; mean platelet count pre-treatment <20,000/mm3; post-treatment > 50,000/mm3). Six children with Evans syndrome (ES) have been treated on the trial with 3 CR, 1 PR, and 2 non-responders (NRs). We have treated 5 children with refractory single lineage autoimmune cytopenias (4 ITP, 1 autoimmune hemolytic anemia) with 1 CR, 1 PR, and 3 NR. Overall CR rates for the trial are 83% (10 of 12) for ALPS, 60% for non-ALPS multi-lineage autoimmune cytopenias (6 of 10), 20% for single lineage disease (1 of 5), and 63% for the entire cohort (17 of 27). The CR + PR rate for children with multi-lineage autoimmune cytopenias is 91% (20 of 22). Of responding patients, all were steroid-refractory or intolerant and most had failed multiple agents (avg: 3; range 2-6). Side effects were mild and included grade (gr) 1-2 mucositis (10 children; resolved after 1 month in most without therapy modification), gr1 diarrhea (1 child), gr2 acne (2), gr1-2 headache (3), and gr2 hyperlipidemia requiring therapy (2 with fish oil and 1 with statin; all responded). One child had such a rapid reduction in splenomegaly that she developed a splenic infarct potentially attributable to the sirolimus. Studies of immune function were performed on a subset of patients. Remarkably, ALPS patients treated with sirolimus had improvement in immune function and developed normal B and T cell numbers and function. In contrast, patients with non-ALPS immune cytopenias developed mild B and T cell immune suppression, as expected. No child developed any documented serious or opportunistic infection. In summary, sirolimus led to complete and durable responses in a majority of children with multi-lineage autoimmune cytopenias. The responses in ALPS were profound, and these results suggest sirolimus should be considered as first-line for these children based on its efficacy and lack of significant toxicity or immunosuppression. More studies are needed for children with ES, CVID, and SLE; however, initial results of this trial are encouraging. Disclosures: Off Label Use: Sirolimus for autoimmune cytopenias. Smith-Whitley:GlycoMimetics, Inc: Research Funding. Lambert:GSK: Research Funding; Nestle: Consultancy; Amgen: Research Funding.

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Tamarkina, Elena, Mohammed El-Sherbiny, Roman Jednak, and John-Paul Capolicchio. "The “incidental anesthetic” — an opportunity for the endoscopic correction of vesicoureteral reflux in children." Canadian Urological Association Journal 3, no. 3 (2013): 225. http://dx.doi.org/10.5489/cuaj.1078.

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Introduction: The endoscopic management of vesicoureteral reflux(VUR) with subureteric injection (STING) has become more popular.The low morbidity associated with the STING procedure hasled to some authors advocating its use as a first-line therapy. Manyparents are uncomfortable with this procedure being performedin children because of the potential morbidity associated with generalanesthesia. We present an alternative without added anestheticmorbidity: offering the parents a STING when their childis undergoing an anesthetic for another surgical indication.Methods: We reviewed the records of 10 children who underwentincidental dextranomer/hyaluronic acid copolymer (DHA) injectionover a 2-year period.Results: We considered the treatment outcome after a single STINGprocedure to be successful in 8 (80%) patients and a failure in 2(20%). Distribution of VUR grade, according to the highest gradeper patient, was high in 5 (50%) patients, moderate in 3 (30%)and low in 2 (20%). We observed no complications.Conclusion: The idea of performing STING in children under incidentalanesthetic introduces yet another possibility in the paradigmof VUR care. Though the long-term efficacy of DHA remains to bedetermined, this option reduces the potential morbidity of DHA asfirst-line therapy while favourably altering the cost benefit.Introduction : L'injection sub-urétérale endoscopique est uneméthode de plus en plus utilisée pour la prise en charge d'un refluxvésico-urétéral (RVU). La faible morbidité associée à cette techniquea amené certains auteurs à recommander son emploi entraitement de première ligne. Bien des parents ne sont pas à l'aiseavec cette suggestion en raison du risque de morbidité lié àl'anesthésie générale. Nous présentons ici une solution de rechangequi n'augmente pas la morbidité liée à l'anesthésie, soit le recoursà l'injection sub-urétérale endoscopique pendant que l'enfantest déjà sous anesthésie pour une autre intervention chirurgicale.Méthodes : Les dossiers de 10 enfants ayant subi une injectionde copolymère de dextranomère / acide hyaluronique (DxAH) aucours d'une période de 2 ans ont été passés en revue.Résultats : Après une seule injection sub-urétérale, l'issue du traitement a été jugée excellente chez 8 patients (80 %) et un écheca été constaté chez 2 patients (20 %). La distribution des stadesde RVU en fonction du stade le plus élevé noté chez chaque patientétait la suivante : grade élevé, 50 %, modéré, 30 % et faible, 20 %.Aucune complication n'a été observée.Conclusion : L'idée de recourir à une injection sub-urétérale pendantune autre intervention nécessitant une anesthésie ajoute uneoption dans l'algorithme de traitement du RVU. Même si l'efficacitéà long terme du DxAH reste à établir, cette option a l'avantagede réduire le risque de morbidité lié au DxAH comme traitementde première ligne tout en modifiant pour le mieux l'équationcoûts-avantages.

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Blomberg, Ben A., Hendrik W. Van Deventer, Stuart Gold, et al. "A Single-Center Retrospective Analysis of a Pediatric Salvage Chemotherapy Regimen for Adults with Relapsed/Refractory Acute Lymphoblastic Leukemia." Blood 126, no. 23 (2015): 4919. http://dx.doi.org/10.1182/blood.v126.23.4919.4919.

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Abstract Background: Relapsed or refractory acute lymphoblastic leukemia (ALL) remains challenging to treat with an extremely poor prognosis. Salvage chemotherapy regimens can achieve complete remission (CR) rates of 30-50%, but CRs are not durable without hematopoietic stem cell transplant (HSCT). Outcomes in untreated adolescents and young adults have improved with the use of pediatric chemotherapy regimens, but data on the use of pediatric chemotherapy regimens in relapsed/refractory adult ALL is lacking. We chose to retrospectively examine the outcomes of adult patients with relapsed ALL at our institution treated with the CCG-1941 pediatric salvage protocol (Gaynon PS, et al. J Clin Oncol 2006). Methods: We conducted a single-center retrospective cohort study of patients aged 18 and older with relapsed/refractory ALL who were treated with the CCG-1941 protocol. Patients received induction with vincristine, dexamethasone, ifosfamide, etoposide, PEG-asparaginase, and methotrexate, as well as intrathecal methotrexate, cytarabine, and hydrocortisone prophylaxis, followed by intensification and continuation phases. This regimen was offered to relapsed/refractory patients who, in the judgement of treating physician, were likely to tolerate multiagent chemotherapy. All adult patients who received this regimen between 2006 and 2015 were included in the analysis. Outcomes of interest were: the CR rate, duration of remission (DOR), toxicity, 30-day mortality, and the rate of patients undergoing HSCT. Results: Between January 2006 and April 2015, 15 patients aged 20-54 (median 31) with first relapse (n=12) or refractory (n=3) ALL were treated with the CCG-1941 regimen. Baseline patient characteristics are described in the Table 1. Seven patients (47%) had alterations to the induction protocol. The majority of these modifications were reduction or omission of PEG-asparaginase or vincristine. All patients experienced infectious complications, most commonly neutropenic fever (n= 12, 80%, 95% CI 52-96). There was one death due to infection, which occurred during an intensification phase. Two patients had grade 3 pancreatitis and two patients had hemorrhage (one grade 2, and one grade 5). 30-day mortality was 7% (95% CI 0-32) due to one fatal intracranial hemorrhage. Median length of hospitalization for induction was 28 days (range 10-61). Twelve patients (80%, 95% CI 52-96) achieved CR, and six of these patients received 1-2 cycles of intensification or continuation. Among the remaining 6 CR patients, one proceeded immediately to HSCT, two received other consolidation, two had early relapse, and one was lost to follow up. Six patients proceeded directly to HSCT, and one more underwent HSCT after receiving subsequent therapies for relapsed disease. The DOR was 81% at 6 months, 54% at 12 months, 36% at 18+ months and 18% at 24 months. One patient has been followed for 63 months and has not recurred. Median follow-up for survivors was 16 months (range 3.6-63). Conclusions: The CCG-1941 regimen appears to be tolerable and efficacious in adult patients with relapsed/refractory ALL. This regimen has been previously reported only in children. Despite the regimen's toxicities, a substantial proportion of patients underwent subsequent stem cell transplantation. Such salvage therapies remain important options for patients with T-ALL and for those B-ALL patients who are not candidates for, or who have failed phenotype-specific immunotherapies. Further prospective, multicenter study is warranted for use of pediatric salvage regimens in the adult patient population. Disclosures Foster: Celgene: Research Funding.

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Grainger, John D., David J. M. Routledge, Alexandra Kruse, et al. "Thrombopoietin Receptor Agonists in Paediatric ITP Patients: Long Term Follow up Data in 34 Patients." Blood 124, no. 21 (2014): 4206. http://dx.doi.org/10.1182/blood.v124.21.4206.4206.

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Abstract Introduction: Immune ThrombocytoPaenia (ITP) in children consists of an isolated thrombocytopaenia (platelet count less than 100 x 109/L) in the absence of any other identifiable cause (Rodeghiero 2009) and is a diagnosis of exclusion. The majority of children diagnosed with ITP remit in the first few months with approximately 30% going on to develop chronic ITP (Thrombocytopaenia persisting > 12 months) (Imbach 2006). The majority of children with chronic ITP are managed supportively and do not require treatment. However, clinically significant bleeding may occur spontaneously or when challenged (e.g. infection, surgery, trauma). For patients who require frequent breakthrough treatment or in whom lifestyle restrictions are unacceptable, the treatment options are limited and the side effects often unacceptable to both families and physicians Initial study reports suggest that thrombopoietin receptor agonists (TPO-RA) are effective and safe in paediatric patients, however longer term follow up data is unavailable Here we present follow-up data on the efficacy and safety on the use of TPO-RA in 34 paediatric patients with Chronic ITP across 5 tertiary referral centres with up to 5 years follow up. Methods: A retrospective case note review was performed for paediatric patients with Chronic ITP who were treated with off-licence TPO-RA in 5 tertiary referral centres. Patients were initially treated on clinical study (PETIT n=25, PETIT2 n=2, or off study n=7). Results: 34 patients (Female n=14, Male n=20) were identified who were treated with TPO-RA between 2009 and 2014. Median age when starting TPO-RA was 10 years of age (Range 2 to 17 years). 70% of patients were White, 12% Asian, 9% Arabic, 6% Hispanic and 3% Mixed ethnicity. Prior to starting TPO-RA all 34 patients had received at least one prior ITP therapy, with 41% receiving ≥3 previous ITP therapies (n=14). 71% had received steroids (n=24), 68% IVIG (n=23), 50% Rituximab (n=17), 27% Anti-D (n=9), 3% steroid sparing agents (n=1) and 3% had undergone splenectomy (n=1). 21% were on concurrent platelet rising therapy when starting TPO-RA (n=7). 97% started on TPO-RA for bleeding and/or thrombocytopaenia (n=33) and 3% started on TPO-RA for surgery (n=1). During this period patients received treatment with Eltrombopag (n=28), Romiplostim (n=5) or both (n=1). Median duration of treatment with Eltrombopag was 30 months (range 6 to 55 months) and Romiplostim was 13 months (range 1 to 32 months). 32 patients were treated for ≥6 months, 28 for ≥1 year, 20 for ≥2 years and 4 for ≥4 years. Median maintenance dose for Eltrombopag was 0.94mg/kg and Romiplostim 7.92micrograms/kg). 53% of patients are still currently taking a TPO-RA (n=18). 1 patient who failed to respond to Eltrombopag, responded to Romiplostim. 50% of patients had a trial off treatment (n=17), with 4 patients remaining off treatment (Eltrombopag n=3, Romiplostim n=1). 4 patients stopped treatment due to the fear of potential side effects, 3 patients stopped treatment due to compliance issues, 4 patients stopped due to a lack of response to treatment and treatment was withdrawn in 1 patient due to subclinical (<grade 1) lens Opacities. 8 patients underwent bone marrow biopsy before and during/after treatment with TPO-RA. Of these 5 showed an increased reticulin grade after starting TPO-RA (Maximally Grade 1 to 2). Conclusion: Our experience demonstrates that both Eltrombopag and Romiplostim are an effective treatment option in paediatric patients with chronic ITP. Both Eltrombopag and Romiplostim were well tolerated with exposures over 5 and 2 years respectively. 4 patients remain off treatment after a treatment ‘holiday’. Therefore withdrawal of treatment should be considered in all patients who are stable on treatment. No new safety concerns were identified but we would advocate continued surveillance. Disclosures Grainger: Amgen: Honoraria; Baxter: Honoraria, Research Funding; GlaxoSmithKline: Honoraria. Off Label Use: Eltrombopag is a thrombopoietin receptor agonist approved for the treatment of thrombocytopenia in adults with chronic ITP. Use in children and adolescents will be discussed.. Bussel:Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel: Honoraria; Novartis: Honoraria; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; IgG of America: Research Funding; GlaxoSmithKline: Equity Ownership, Honoraria, Research Funding; Genzyme: Research Funding; Eisai, Inc.: Research Funding; Cangene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Amgen: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding.

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Chandy, Mammen, Biju George, Auro Viswabandya, Vikram Mathews, Ashish Bajel, and Alok Srivastava. "Fludarabine Based Conditioning for Allogeneic Transplantation in Severe Aplastic Anemia." Blood 106, no. 11 (2005): 2029. http://dx.doi.org/10.1182/blood.v106.11.2029.2029.

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Abstract Patients with severe aplastic anemia (SAA) who are multiply transfused or septic have a poor outcome after allogeneic stem cell transplantation. Forty three patients (31 males and 12 females) with SAA underwent allogeneic BMT using a fludarabine based conditioning regimen between 1998 and 2005. The median age was 20 years (range: 4–38) with 11 children and 32 adults. All donors were 6 antigen matched HLA identical sibling or family donors. Co morbidities seen included bacterial sepsis in 15 patients, fungal pneumonia in 4 and a recent intracranial bleed in 5 patients. Seven patients had failed Antithymocyte or antilymphocyte globulin (ATG/ALG) and two patients had failed their first transplant. The median time from diagnosis to transplant was 12 months (range: 2 – 96) and the median transfusions prior to BMT was 28 (range: 2 – 380). Conditioning therapy consisted of: Fludarabine (Flu) 180 mg/m2 over 6d + Busulfan (Bu) 8 mg/kg over 2d + ATG 40 mg/kg/day over 4 d in 17 patients, Flu 180 mg/m2 over 6d + Cyclophosphamide (Cy) 120 mg/kg over 2d ± ATG 40 mg/kg/day over 4d in 17 patients, Flu/TBI/OKT3 in 4, and Cy 120 + Flu 150mg/m2 in 5 patients. Graft versus host disease (GVHD) prophylaxis consisted of Cyclosporine and mini methotrexate. Graft source was peripheral blood stem cells in 39 patients and G-CSF stimulated bone marrow in 4. The median cell dose was 5.2 x 108 MNC/kg (range: 2.1 – 13.6) for PBSC and 5.2 x 108 TNC/kg (range: 3.7 – 6.8) for bone marrow. Five patients expired within the first 10 days due to sepsis. Thirty seven patients engrafted with a mean time to ANC > 500 of 11.6 days (range: 8 – 18) and median platelet engraftment time of 13 days (range: 8 – 32). One patient had primary graft failure and expired on day 64 due to fungal pneumonia despite a second transplant. Acute GVHD was seen in 14 patients (38%) with Grade III–IV GVHD in 4 (10.5%). Chronic GVHD was seen in 10 patients with 6 having limited and 4 with extensive GVHD. Two patients had secondary graft rejection on day + 24 and +60 respectively and expired due to fungal pneumonia. At a median follow up of 17 months (range: 5 – 78); 29 patients (67.7%) are alive and well. Among patients treated with Flu/Bu/ATG, 12/17 (70.5%) are alive and well while the DFS is 82% (14/17) in patients treated with Flu/Cy ± ATG. Comparison with patients conditioned with Cy/ATG during 1990–2004 is given in the table. This comparison suggests that a fludarabine based conditioning regimen may be better, with less rejection, than Cy/ATG for allogeneic BMT in sick patients with SAA who are infected and multiply transfused at the time of BMT. Comparative data Fludarabine Cy/ATG Number 43 26 Rejection 3 (7%) 7 (27%) DFS 29(67.7%) 11 (46%)

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Chevallier, Patrice, Pierre Bordigoni, Thierry Lamy, Philippe Moreau, Jean-Luc Harousseau, and Noel Milpied. "Safety and Efficacy of Caspofungin as Preventive and Empirical Antifungal Treatment of Neutropenic Allografted Patients." Blood 104, no. 11 (2004): 5024. http://dx.doi.org/10.1182/blood.v104.11.5024.5024.

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Abstract Antifungal therapy is appropriate in neutropenic patients who have unexplained persistent fever, despite receipt of few days of antibacterial therapy. Conventional or liposomal amphotericin B are the preferred agents in this situation for allografted patients but toxicity or interaction with other drugs could limit their prescription. Caspofungin, the first inhibitor of fungal cell wall glucan synthesis, is the only echinocandin approved by the FDA for treatment of candidiasis. In case of suspected or documented aspergillosis infection, caspofungin is generally reserved to patients who failed to respond to amphotericin B or voriconazole. Recently, Walsh et al (ICAAC 2003) demonstrated in a randomised trial that caspofungin was comparable to liposomal amphotericine B in overall success as empirical antifungal therapy of persistently febrile neutropenic patients and was better tolerated. Here, we report our experience of caspofungin as preventive and empirical anti-fungal treatment, between November 2002 and May 2003, in 19 allografted patients with neutropenia (< 500/mm3 neutrophils) ± persistent fever despite at least 4 days of appropriate antibacterial therapy (n=12). There were 15 adult and 4 children, 11 male and 8 female. Median age was 33 years (range: 3–57). There were 6 ALL, 5 AML, 1 Myelodysplasia, 1 CML, 1 Hodgkin disease, 1 NHL, 1 myeloma, 1 aplastic anemia, 1 carcinoma and 1 Ewing sarcoma. A myeloablative conditioning regimen was used in 14 patients consisting of total body irradiation (TBI) plus high-dose chemotherapy in 9 patients and busulfan plus cyclophosphamide in 5 patients. A non myeloablative conditioning regimen was used in 5 patients. For graft-versus-host disease prophylaxis, the regimen was cyclosporin plus methotrexate in 13 patients or ATG in 6 patients. Nine patients received a bone marrow graft, 9 received granulocyte-colony-stimulating factor (G-CSF) mobilized peripheral blood stem-cells and 1 received an unrelated cord blood transplant. Twelve/19 patients have received prophylaxis with fluconazole from day 0 of the graft. Patients received caspofungin at an initial dose of 70 mg then 50 mg per day. Caspofungin was initiated within a median of 10 days after allograft (range: 0–174) including 7 patients receiving preventive caspofungin treatment at the date of aplasia. The mean duration of caspofungin therapy was 16 days (range: 3–72). Caspofungin was well tolerated and not stopped because of toxicity: WHO grade 1 and 2 hepatotoxicity occurred in 5 patients including 3 with previous hepatic abnormalities, WHO grade 1 and 2 nephrotoxicity occurred in 6 patients. No infusion reaction was observed. Only one patient developed a probable invasive bronchopulmonary aspergillosis on day 30 while receiving caspofungin. Seventeen/19 (89%) patients remain alive at least 7 days after the end of caspofungin administration without documented or suspected fungal, bacterial, or viral infection. Resolution of fever occurred in 11/12 febrile neutropenic patients in a median of 2 days (range:2–13) after starting caspofungin. We conclude that caspofungin is safe and effective as preventive and empirical antifungal treatment of neutropenic allografted patients.

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Prasad, Vinod K., Kenneth G. Lucas, Gary I. Kleiner, et al. "Use of Mesenchymal Stem Cells To Treat Pediatric Patients with Severe (Grade III–IV) Acute Graft Versus Host Disease Refractory to Steroid and Other Agents on a Compassionate Use Basis." Blood 110, no. 11 (2007): 2971. http://dx.doi.org/10.1182/blood.v110.11.2971.2971.

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Abstract Background: Severe acute Graft versus Host Disease (aGvHD) refractory to steroids and other immunosuppressive agents carries a high mortality and very poor prognosis. Preliminary studies have shown that mesenchymal stem cells (MSC; Prochymal™ Osiris Therapeutics Inc.) can have immunosuppressive and tissue regenerative properties. We hypothesized that MSC might have efficacy in the treatment of GvHD. Methods: Between July 2005 and June 2007, 12 children (10 boys, 9 Caucasian) at 5 centers with aGvHD who failed steroid and additional immunosuppressive agents (median exposure 3 others) were treated with MSC provided by Osiris for compassionate use after FDA and local IRB approval. MSCs were administered per manufacturer’s instructions, without HLA or other matching, to eligible patients in a median of 30 days (range 16–181) from diagnosis of aGvHD. The cell dose for “induction therapy” was 8×106 cells/kg/dose in first 2 patients and 2×106 cells/kg/dose in all subsequent patients. Cells were given by IV infusion over 1 hour 2×/week for 4 weeks and initial response was assessed at the end of this induction therapy. “Maintenance therapy” 1×/week was continued in patients showing response. Results: The median patient age was 6 yrs (range 0.4–15) and all but one had received unrelated donor transplant (8 UCB, 3 adult MUD). GvHD Grade III and IV was present in 7 and 5 patients respectively. All patients had advanced (stage 3 or 4) gut disease, and 6 also had liver and/or skin involvement. Acute GvHD was diagnosed a median of 81 days (range 22–98) post-transplant and MSC were started at a median of 119 days (range 38–279) post-transplant. Three patients had renal failure requiring dialysis which had developed prior to MSC therapy. Patients received a median of 8 doses (range 3–21) of MSC. A total of 124 doses of MSCs were administered. No infusional or other identifiable toxicity was seen in any patient. One osteopetrosis patient developed ectopic lesions in the scalp and foot, however biopsy showed that no MSC DNA was present. With a median follow-up of 102 days (range 36–756) all 12 patients responded to therapy, with 6 patients having a complete response (CR), and the remainder having a partial response (PR) as defined by an improvement of at least one stage in one system without any worsening in another. Two of the PR patients are still being treated. Two patients responded, stopped therapy and later relapsed, requiring further MSC therapy to which they partially responded. Of 12, 6 patients died a median of 68 days (range 36–185) from the start of therapy. Three each died of multi-system organ failure and infection. Three of these were on dialysis pre-therapy. Conclusion: With short term follow-up in young children, MSC appears to be safe and likely have beneficial activity in severe treatment refractory aGvHD. Additional studies are underway to evaluate the efficacy of this agent in this clinical setting.

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Ostronoff, Fabiana, Mauricio Ostronoff, ANA Patricia Souto Maior, et al. "GCSF-Primed Allo-BMT Following Reduced Intensity Conditioning Regimen In Children with AML- Good Outcome In Patients In 1 st Complete Remission with Rapid Neutrophil Engraftment and Low Incidence of Chronic Gvhd." Blood 116, no. 21 (2010): 4566. http://dx.doi.org/10.1182/blood.v116.21.4566.4566.

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Abstract Abstract 4566 There are few data on reduced intensity conditioning regimen in children with AML and no data for GCSF-primed BMT in this patient population. The related donors for these patients are commonly children as well and the peripheral blood stem cells collection is not often indicated. Primed-GCSF bone marrow harvest yields a higher number of CD34+ cells and a lower number of lymphocytes when compared to PBSCT resulting in faster neutrophil recovery and lower rate of chronic GVHD. From 2003 to 2009, we performed 12 GCSF-primed BMT in children with AML in our center median age 8 y (2-12); 10‰, 2 S; 8 pts in first CR (1 pt with AML 2ary to ALL-T treatment; 1 AML M7; 1 induction failure) and 04 pts with ≥ 2nd CR. FAB classification: 7 patients had AML M2; 2, AML M4; 1, AML-M5; 2, AML M7). These patients were not eligible for myeloablative SCT due to aspergilosis (4 patients), hepato-splenic abscess due to candidia (1 patient), recent sepsis due to Candida 2 pts, giant hamartoma causing restrictive pulmonary disease, severe asthma (1 patient), elevated transaminitis (greater than 5 times of the upper normal limit) due to recent multiple chemotherapies (2 patients), recent treatments with myeolosuppresive chemotherapies greater than 4 cycles complicated by recent infection (2 patients). The protocol was approved by our institutional review board and informed consent was obtained from each patient and donor and or their guardians. Conditioning consisted of fludarabine and TBI in 2 patients; busulfan 4mg/kg/day (day -5 and day -4) and fludarabine 30 mg/m2/day (from day-7 to day -2) in 9 patients. Three of these patients also received Ara-C 1g/m2 (day-5 to day -2). One patient undergoing unrelated donor BMT was conditioned with busulfan 4mg/kg/day (day -5 and day -4) and fludarabine 30 mg/m2/day (from day-7 to day -2) and ATG 10mg/kg/day (day -4 to day -1). GVHD prophylaxis consisted of CSA 5mg/kg/day orally from day -1 to day +90 and MMF 45mg/kg/day orally until day +30. The donors received G-CSF 5 μ g/kg/d subcutaneously for five days (day –4 to day 0) prior to harvest the bone marrow. The median age of the related donors was 9 years (range, 4 to 18 years). The stem cells harvest from the unrelated donor was not primed with GCSF. The median CD34+, CD3+ and CD8+ cell counts collected were respectively 3.5×106 cells/kg (2.5 - 5.0), 32 ×106 cells/kg (29 - 59) and 13×106 cells/kg (12- 25). All patients received GCSF 10 micrograms/kg/day SC from day +1 until neutrophil engraftment. Only 8/12 pts had neutrophil counts ≤ 500/mm3 for a short interval: median 3 days (2-8). There were no infectious complications and all CMV antigenemias were negative. The transfusion requirement was low for all patients. One patient rejected the graft on day+30 and 3 patients had mix chimerism on day +30 and relapsed few weeks later. All the other patients had complete chimerism on day +30 and continue to have stable complete chimerism thereafter. Grade >=II acute GVHD occurred in 2 patients (16.5%). Only one patient who underwent unrelated donor transplantation had steroid-resistant GVHD which responded to alemtuzumab. There were no deaths related to the transplant. Five patients died due to relapsed leukemia 2,3,3,4 and 19 months after the transplant the savage therapy was very difficult: 2 of these pts had chemotherapy refractory leukemia, 2 pts were refractory to conventional BMT and one pt had aspergilosis after the second conventional BMT. This pt had a previous history of aspergilosis. Seven of the 12 patients (58%) are alive and in complete remission of their leukemia 1,2,3,3,4,6 and 7 years after BMT. None of the patients developed extensive chronic GVHD. Among the patients who survived, there were5/7 (71%) is first CR including one case of secondary AML, the case of AML-M7 and one pt who had failed induction chemotherapy. RIC in children who are not eligible for myeloablative SCT can be well tolerated and successful specially in patients who are in first complete remission. In addition, primed-GCSF BMT can be a good strategy to achieve rapid neutrophil engraftment with low rate of chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

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Pallas, Aaron M., Doris R. Entwisle, Karl L. Alexander, and Doris Cadigan. "Children who do Exceptionally Well in First Grade." Sociology of Education 60, no. 4 (1987): 257. http://dx.doi.org/10.2307/2112561.

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Dufour, Carlo, Marta Pillon, Elisa Carraro, et al. "Similar Outcome of Upfront Unrelated and Matched Sibling Donor Hematopoietic Stem Cell Transplantation in Idiopathic Aplastic Anaemia of Childhood and Adolescence: A Cohort Controlled Study on Behalf of the UK Paediatric BMT WP, of the PD WP and of the SAA WP of the EBMT." Blood 124, no. 21 (2014): 256. http://dx.doi.org/10.1182/blood.v124.21.256.256.

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Abstract The classical treatment algorythm of idiopathic severe aplastic anemia (SAA) forsees, if a sibling donor is not available in the family, a first line option represented by immunosuppressive therapy (IST) with ATG and Cyclosporine A (CsA). IST provides a very good survival rate but a fairly high rate of failures (no response, relapse, need for transplant). This is particularly important in childhood and adolescence where faulty hematopoiesis represents a relevant limitation of quality of life. The option of haematopoietic stem cell transplantation (HSCT) from matched unrelated donor (MUD) as front line treatment with no prior failed IST, has never been investigated so far. This study provides for the first time the outcome analysis of 29 consecutive SAA patients who received an upfront unrelated donor HSCT without prior IST, in 9 UK Centres and compares each of these patient with 3 matched controls from the data base of the SAAWP of the EBMT who, in a similar time-span, underwent Matched Sibling Donor (MSD) HSCT. Twenty four patients received HLA-A,-B,-C,-DQ-,-DRB1 matched MUD HSCTs whilst 5 received single antigen/allele Mismatched Unrelated Donor (MMUD) grafts. The conditioning regimen was FCC (Fludarabine, Cyclophosphamide and Alemtuzumab) with the addition of low dose (3cGy) TBI for the MMUD HSCTs. GVHD prophylaxis was with CsA +-Mycophenolate. The primary endpoints were overall survival (OS) and event free survival (EFS). Events were death, disease recurrence, second HSCT, clinical PNH and post-transplant malignancies. Complete remission (CR) was defined as Hb > 10 g/dl, neutrophil count > 1x 109/l and platelet count > 100x109/l. The 87 (3 for each MUD/MMUD HSCT) patients from the EBMT data base who underwent MSD HSCT as first line treatment were matched to the upfront MUD/MMUD cohort by age, gender, time from diagnosis to HSCT and source of stem cells. Their median follow-up was 1.6 years (range 0.01-9.39). In the upfront MUD/MMUD cohort there were 12 males (41%) and 17 females (59%). Median age at HSCT was 8.46 years (range 1.73-19.11), 72% was aged below and 28% above 12 years; median interval from diagnosis to HSCT was 0.39 years (range 0.19-1.35) with 72 % receiving bone marrow and 28% peripheral blood stem cells. The median follow-up was 1.7 years (range 0.19-8.49). The median time to neutrophil recovery (>0.5 x 109/l) was 18 days (range 9-29) and the median time to platelet recovery (>50 x 109/l) was 19 days (range 10-40). The 100 day cumulative incidence (CI) of grade II-IV acute GVHD was 10 ± 6% ; there was only one case of grade III-IV acute GVHD (frequency of 3.5%). The 1 year CI of chronic GVHD was 19 ± 8%. There were 5/29 cases (frequency of 17,2 %), 4 in the MUD and 1 the MMUD subset. Chronic GVHD was limited in all cases and restricted to skin. There were only 2 events in this cohort; one primary graft failure following a HLA-A MMUD HSCT who has now successfully received a second HSCT and one death due to idiopathic pneumonia syndrome. No post-treatment malignancies occurred at last follow-up. The other 27 patients are in CR at last follow-up. The median interval diagnosis-neutrophil recovery was similar in MUD/MMUD (0.39 years; range 0.19-1.35) vs MSD transplants (0,31 years; range 0,1- 0,45) (p=0.93). The 2 year OS was 96%±4% in the upfront MUD/MMUD cohort vs 91%±3% of the MSD cohort (p=0.30). The 2 year EFS was 92%±5% in the upfront cohort vs 87%±4% in MSD (p=0.37) (Fig 1). The 2 year CI of rejection was 4%±4% in the MUD/MMUD vs .1%±1% in the MSD group (p=0.48). This is the first controlled study indicating that in idiopathic SAA of childhood and adolecence upfront MUD/MMUD HSCT using FCC as conditioning regimen, has similar outcome to MSD HSCT. MUD HSCT may be considered a feasible and successful treatment option when children lack a MSD and a MUD is readily available. Figure 1 Figure 1. Comparison of EFS between upfront MUD/MMUD and front-line MSD HSCT. Events were: death, disease recurrence, second HSCT, clinical PNH and post-transplant- malignancies. Table 1 EFS N events 2-yrs Pr (%) (SE) p-value MUD/MMUD 29 2 92 (5) 0.37 MSD 87 11 87 (4) Disclosures Dufour: Pfizer: Consultancy.

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Locatelli, Franco, Kathleen A. Neville, Angelo Rosolen, et al. "Phase 1/2 Study Of Brentuximab Vedotin In Pediatric Patients With Relapsed Or Refractory (R/R) Hodgkin Lymphoma (HL) Or Systemic Anaplastic Large-Cell Lymphoma (sALCL): Preliminary Phase 2 Data For Brentuximab Vedotin 1.8 Mg/Kg In The HL Study Arm." Blood 122, no. 21 (2013): 4378. http://dx.doi.org/10.1182/blood.v122.21.4378.4378.

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Abstract Background Brentuximab vedotin is a CD30-targeted antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Pivotal phase 2 studies reported the efficacy and manageable toxicities of the drug, leading to its approval by the US FDA for use in adult patients with R/R HL and R/R sALCL in 2011. Data for brentuximab vedotin in children with these lymphomas are currently limited but promising. This ongoing phase 1/2 prospective, open-label, multicenter study is the first clinical trial of brentuximab vedotin conducted exclusively in pediatric patients with R/R HL or R/R sALCL (NCT01492088). The phase 1 portion established the recommended phase 2 dose (RP2D) of brentuximab vedotin in pediatric patients with R/R HL or R/R sALCL as 1.8 mg/kg every 3 weeks (Q3wk), and complete response (CR) and partial response (PR) were reported in 88% of patients at the RP2D. Here, we report preliminary phase 2 response, safety and PK findings for the HL patients receiving the RP2D. Methods The phase 2 portion aimed to enroll 15 response-evaluable HL patients at the RP2D, including those R/R HL patients treated at the RP2D in phase 1 (phase 2 data for the sALCL patients are not reported here). The phase 2 primary objective was overall response rate (ORR; CR + PR) at the RP2D; secondary objectives were time to progression, time to response, duration of response, event-free survival, progression-free survival, overall survival, to characterize PK, to further evaluate safety, and to determine immunogenicity of brentuximab vedotin. Patients with R/R HL aged 5 to<18 years, with measurable disease, who were in their second or later relapse, had failed chemotherapy, and were ineligible for, refused, or previously received stem cell transplant, received brentuximab vedotin 1.8 mg/kg by IV infusion Q3wk for up to 16 cycles until progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses will be assessed both by the investigators and independent review facility per IWG revised response criteria for malignant lymphoma; investigator responses are reported here. Blood samples for PK analysis were collected on day 1 (all cycles) immediately before and 5 minutes after the infusion and on prespecified days during cycles 1, 2, and 8. Results 16 patients with R/R HL received at least 1 dose of brentuximab vedotin at the RP2D; median age was 15 years (range, 8–18); 56% were male; Ann Arbor stage at initial diagnosis was 44% stage II, 6% stage III, 44% stage IV, and 6% unknown; median time from initial diagnosis was 16.7 months (range, 0–38) and 50% had B symptoms at baseline. At data cut-off (June 20, 2013), patients had received a median of 3 cycles of treatment (range, 1–16); 10 (63%) patients had discontinued treatment due to: progressive disease (n=7), AEs (n=2), and allogeneic transplant (n=1). Response data were available for 14 patients at data cut-off. The ORR was 64% (95% confidence interval [CI]: 35, 87); 3 (21%; 95% CI: 5, 51) patients achieved CR and 6 (43%; 95% CI: 18, 71) achieved PR. Reponses were typically observed at C2. 12 of 16 (75%) patients had ≥1 AE, and 7 (44%) had grade ≥3 AEs. The most common (>1 patient) AEs were nausea (38%), pyrexia (31%), neutropenia, paresthesia (each 19%), abdominal pain, upper abdominal pain, constipation, decreased appetite, diarrhea, hepatotoxicity, hypokalemia, leukopenia, myalgia, pharyngitis, and vomiting (each 13%). 7 serious AEs (SAEs) occurred in 5 patients; 4 SAEs in 3 patients were considered related to brentuximab vedotin: grade 3 hepatotoxicity and grade 3 febrile neutropenia (n=1); grade 3 anaphylaxis (n=1); and grade 3 pneumonia (n=1). One patient died on C2D4 of unrelated cardiac arrest due to progressive mediastinum enlargement (disease progression). 2 (13%) patients discontinued, 1 due to grade 3 hepatotoxicity on C1D13 and 1 due to grade 3 peripheral neuropathy on C8D4. Preliminary PK data show that brentuximab vedotin remained detectable in the blood just prior to the next infusion over the treatment period; thus, patients remain exposed to brentuximab vedotin from cycle to cycle. Conclusions Brentuximab vedotin 1.8 mg/kg Q3wk (RP2D) was generally well tolerated in pediatric patients with R/R HL and demonstrated preliminary evidence of activity, with an ORR to date of 64%, including 21% CR. The phase 2 portion is ongoing in pediatric patients with R/R HL and R/R sALCL. Disclosures: Off Label Use: Brentuximab vedotin for the treatment of pediatric patients with relapsed or refractory Hodgkin lymphoma. Franklin:Millennium: The Takeda Oncology Company: Research Funding. Fasanmade:Millennium: The Takeda Oncology Company: Employment, Equity Ownership, Research Funding. Wang:Millennium: The Takeda Oncology Company: Employment. Sachs:Millennium: The Takeda Oncology Company: Employment. Mauz-Koerholz:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees.

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Keefe, Peter J., Margaret C. Morrissey, Catherine E. McGuinn, and James B. Bussel. "Randomized Double-Blind Study of Increasing Doses of Eltrombopag in Patients with Chronic ITP." Blood 126, no. 23 (2015): 1057. http://dx.doi.org/10.1182/blood.v126.23.1057.1057.

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Abstract Background: Eltrombopag (Epag) is an oral thrombopoietin receptor agonist used to increase platelet counts in patients with chronic immune thrombocytopenia (cITP). The maximum licensed Epag dose in cITP patients is 75 mg daily, yet some patients do not respond at this dose. Healthy individuals on escalated doses of eltrombopag (100-200 mg) demonstrated a dose dependent platelet response as did patients with thrombocytopenia secondary to chemotherapy. Doses of 100 mg and 150 mg have been approved for use in patients with hepatitis-C induced thrombocytopenia and aplastic anemia respectively. This is the final report of a double-blind, randomized controlled study to determine if Epag, administered at doses up to 150 mg daily, increases platelet counts in cITP patients who failed to respond to 75 mg. Methods: cITP patients³ 1 year old with platelet counts <50,000uL despite >3 weeks of 75mg of Epag daily), stratified by splenectomy status, were enrolled. Patients could continue stable doses of concomitant ITP medications. In the randomized blinded phase (Part 1), patients first received 75 mg daily of active Epag and 25 mg of study drug (Epag or placebo, 2:1). Every two weeks, study drug doses were increased in 25 mg increments to a maximum daily dose of 150 mg. After 8 weeks subjects were unblinded. If on active drug, they entered the open label phase (Part 2); if on placebo, they received open label Epag as per the study protocol escalating to a maximum dose of 150 mg. Two patients entered part 2 before 8 weeks because their counts were >100,000/uL in the blinded phase. Data analysis was descriptive. Mann Whitney U test estimated p-values (α<.05) or platelet count differences between groups. Imputation of platelet counts allowed omitting falsely high or low platelet counts resulting from rescue therapy (e.g. IVIG), or counts in3 patients discontinuing early with good responses after 2, 2, and 4 weeks who thereby did not have counts at weeks 4, 6, and 8. Interim analysis was pre-specified and data is included on 33 of the planned total of 36 patients. Results: As of July 31, 35 patients consented; 26 completed ³8 weeks on study medication. Two patients are in part 1 and 7 dis-enrolled before completing 8 weeks of study drug: 5 failed screening and never received medication; one had bleeding and low counts on placebo; and one had pre-existing reticulin fibrosis 2-3+, discovered after study drug was dispensed but not administered. The most common adverse event (AE) was minor bleeding. Two adults and 2 children developed transaminitis, which was life-threatening in 1 adult on 100mg. The 4 liver AEs occurred between 2 and 20 weeks of Epag dosing with 3/4 subjects on 150 mg daily; 2/4 discontinued Epag. No strokes or thromboembolic events were seen nor did any cataracts develop. Three patients underwent bone marrows: no grade 2-3 fibrosis was seen. Platelet counts for patients on active drug vs placebo separated by week 2 (Figure 1A) and the difference steadily increased until week 8 (p<0.07) reflecting the thrombopoietic effects of increased dose Epag. Increased eltrombopag doses had greater effect in children (avg age 13) than adults (avg age 51) [Figure 1B]. This may reflect more rapid drug metabolism or relative insensitivity to the effects of Epag in children or both; this was first noted in PETIT and PETIT2. Twenty-six patients entered the long-term open-label study. Three discontinued prior to 24 weeks because of transaminase elevation (1) and no response (2); 7 are not yet at 24 weeks; and 6 were also on other treatments, ie IVIG at increased intervals while on Epag, obscuring their responses. Ten patients were on open label medication for >24 weeks past the 8 weeks in part 1 up to 110 weeks. 72% of the long-term counts in these 10 patients were > 50,000/uL while 40% were > 100,000/uL. Six patients took 150 mg daily for >24 weeks while 4 reduced their doses, though not to <75mg daily. Conclusions: The results demonstrate that Eltrombopag at doses of 100-150mg daily can elevate platelet levels in most children and adults with cITP whose platelet counts were <50,000 on 75mg of Epag daily for >3 weeks. Children responded better to increased doses of Epag than did adults and high dose Epag can be used long term without development of cataracts, strokes or other thromboembolic events although an increased frequency of liver events, 12%, occurred. Although the 150 mg dose can be safely continued for many months, monitoring transaminases is essential. Disclosures Off Label Use: Increased doses of eltrombopag. McGuinn:Baxter: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bussel:Momenta: Membership on an entity's Board of Directors or advisory committees; Genzyme: Research Funding; BiologicTx: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Cangene: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity's Board of Directors or advisory committees; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Immunomedics: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Zhai, Zhimin. "Factors Influencing Efficacy of CD19-CAR-T Cells in Children and Adults with Relapsed/Refractory B-Cell Lymphoblastic Leukemia." Blood 132, Supplement 1 (2018): 2656. http://dx.doi.org/10.1182/blood-2018-99-110539.

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Abstract Factors Influencing Efficacy of CD19-CAR-T cells in Children and Adults with Relapsed/Refractory B-cell Lymphoblastic Leukemia An Furun1, Liu Zhenyun2, Wu Fan1, Song Xiaotong2, Li Yingwei1, Cheng Fengwei2, Tao Qianshan1, He Weijie2, Wang Huiping1, Wang Wei2, Xu Huadong2, Zhang Jiakui1, Shen Yuanyuan1, Ruan Yanjie1, Qin Hui1, Wang Xiansheng1, Zhai Zhimin1* Author Affiliations: 1 Hematology Department of the Second Hospital and Hematologic Diseases Research Center of Anhui Medical University 2 Sinobioway Cell Therapy Co., Ltd. Fund: National Natural Science Foundation of China (No. 81670179); Sinobioway Cell Therapy Co., Ltd. *Corresponding Author: zzzm889@163.com Purpose: Using CD19-CD137-ζ CAR-T cell (named Sino19 cell) to treat patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL), assess the efficacy and safety, and the relationship of patients' characteristic to the response rate and long-term outcome. Method: Single-center, phase 1/2 clinical trial (NCT02735291). A total of 1-5×107/kg CD19-CD137-ζ CAR T cells manufactured by lentiviral transfection were infused to treating r/r B-ALL. Before infusion, individualized chemotherapy was given based on the tumor burden and bone marrow hyperplasity, then monitoring temperature, blood pressure etc., so as to determine and handle adverse reactions. CR, EFS, OS and their possible influencing factors were analyzed by SPSS10.01 software. Results: 1) Patients: A total of 40 patients with r/r B-ALL were enrolled, 22 males and 18 females, aged from 2 to 72. Among them, 32 patients were followed at least 2 months post infusion of CAR T-cell; 4 have not reached the minimum time requirement for efficacy assessment; 4 did not have cells infused. In the 32 patients evaluated for efficacy assessment, 2 had primary refractory B-ALL, 30 with relapsed and refractory B-ALL; 7(21.9%) previously received alloHSCT and 2 of them using blinatumomab failed; 23(71.9%) had cytogenetic aberrations relating poor prognosis; 11(34.4%) had extramedullary disease (EMD). 2) Efficacy: Up to the day cutoff, 32 patients who received a Sino19 cell infusion and had at least 2 months of follow up, the total CR rate with or without hematologic recovery was 78.1% (95% CI, 63 to 93), the rates of OS in all who had the infusion of Sino19 cells were 74% (95% CI, 57 to 91) at 6 months and 40% (95% CI, 20 to 60) at 12 months, the median of OS was not reached. Among the 25 patients with CR, 4 patients underwent allogeneic hemtologic stem-cell transplantation (alloHSCT) and alive with no relapse at the cutoff time. The rest of 21 patients had 9.6 months (2.2 to 27.4) of median following-up duration, 5 of them had relapse-free survival for more than 15 months and the longest lasted for 22 months. Except 4 who underwent alloHSCT, the rates of EFS for the other 28 patients were 66% (95% CI, 48 to 84) at 6 months and 32% (95% CI, 14 to 50) at 12 months. 3) Adverse reactions: 91% (29/32) of the patients had fever after CAR T infused. According to the NCI-CTCAE v4.03, 21.9% (7/32) had grade≥3 CRS, 6 reversed with glucocorticoid alone or plus tocilizumab and supportive care, 1 died of disease progression at the same time of CRS. Only 2 patients had transient absent-mindedness or deliration. 4) Factors influencing efficacy: ⅰ) EMD, Patients with EMD showed lower CR (54.5% vs. 90.5%, p=0.032), higher relapse (100% vs. 40%, p=0.019) and shorter OS (P=0.025) and EFS (P<0.001), compare with those without EMD; ⅱ) CAR T-cells in-vivo proliferation, CR rate in patients with no proliferation significantly lower than those with expanding (50% vs. 100%; p=0.021). OS and EFS were also significantly different. ⅲ) Regulatory T cells (Tregs), patients with higher Tregs (more than ULN) had more relapse than that with lower or normal Tregs (91% vs. 11%; p=0.001), the OS and EFS also was obviously poor. ⅳ) Cytogenetic, 4 patients with T315I mutation got CR, but 3 relapsed and all died within 6 months, other 1 undergone alloHSCT. ⅴ) CAR T-cells in vivo detected more than 6 months post-infusion, but its persistence do not show relationship to relapse and OS. C onclusion: The Sino19 cell lead to high CR rates in r/r B-ALL, with good safety profile. Some patients can achieve continuous complete remission. EMD, no in-vivo proliferation, higher Tregs and Ph+ with T315I mutation may hinder the efficacy. This is the first clinical report on the relationship between Tregs and CAR T efficacy. Disclosures No relevant conflicts of interest to declare.

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Shenoy, Shalini, Kenny W. Douglas, Zdenek Korístek, et al. "Plerixafor Is Highly Effective for the Mobilization of Autologous PBSC for Transplant in Children Failing to Mobilize by Conventional Means: International Experience with 40 Children From 19 Centers." Blood 118, no. 21 (2011): 1931. http://dx.doi.org/10.1182/blood.v118.21.1931.1931.

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Abstract Abstract 1931 Mobilization of peripheral blood stem cells (PBSC) for autologous transplant in children can be challenging especially in those with prior intensive chemotherapy and radiotherapy, and with increasing use of sequential high-dose therapy that requires high PBSC collection doses. Plerixafor is currently not licensed for use in children, but is approved for PBSC mobilization in adults. We present a series of 40 children from 19 centers worldwide who had PBSC mobilised with plerixafor off-licence, mostly on the North American or European Compassionate Use Programs. Thirteen of these cases were included in a series presented in abstract form at ASH 2010, and a further 6 were presented at EBMT 2011, and these cases are now presented with updated clinical data; the remaining 21 cases have not been presented elsewhere at the time of submission. Median age was 10 years (range 3 months–17 years); median weight was 31 kg (range 6–78 kg). Diagnoses were neuroblastoma (n=13), Ewing's sarcoma (n=10), medulloblastoma (n=5), lymphoma (n=5), PNET (n=4), multicentric Castleman's disease (n=1), Osteosarcoma (n=1) and Desmoblastic Small Round Cell Tumor (n=1). Most patients had received extensive multi-agent chemotherapy prior to plerixafor mobilization, and 13 had also received radiotherapy. For 7 patients, plerixafor had been introduced on a “rescue” basis in the course of the patient's first PBSC mobilization attempt, because of poor peripheral CD34+ counts predicting a high likelihood of mobilization failure without plerixafor use. The remaining 33 patients had undergone 45 prior failed conventional PBSC mobilization attempts: no apheresis in 31 cases; 8 were suboptimal (CD34+ dose < 2×10^6/kg); 5 procedures had yielded insufficient cells for planned sequential high-dose therapy. Plerixafor was used in 44 mobilization episodes (4 patients had undergone two mobilizations using plerixafor). In 29 cases, the drug was given after G-CSF 10 mcg/kg/day for 4 days, without prior mobilizing chemotherapy. In the remaining 15 cases, plerixafor was introduced to chemomobilization protocols at the time of initial neutrophil recovery, with exact protocols varying between centers. Three plerixafor mobilisation episodes were entirely unsuccessful (no apheresis); 10 episodes were suboptimal (CD34+ dose of <2×10^6/kg); 31 episodes (70%) were successful (>2×10^6/kg). For the 41 episodes where apheresis was undertaken, a median of 3.5×10^6/kg CD34+ cells (range 0.26–11.8) was collected in a median of 2 aphereses (range 1–5) after a median of 2 plerixafor doses (range 1–5). A total of 16 possible plerixafor toxicities were reported, all graded mild or moderate: these were injection site reactions (3), nausea (3), bone pain (3), vomiting (2), diarrhoea (2), insomnia (2) & headache(1). Seven patients were lost to follow-up after plerixafor due to transfer to other centers; of the remainder, 22 patients (67%) remain alive and 16 (48%) remain progression-free at a median of 9 months' follow-up post-plerixafor (range 3–63 months). Autologous PBSC transplant was performed in 27 patients & allograft in 1 patient. All transplanted patients achieved neutrophil engraftment (median of 11 days to neutrophils>1.0×10^9/litre; range 10–23 days). There was one case of secondary AML at >3 years post-autograft. Plerixafor is safe and highly effective in this difficult-to-mobilize patient group. Disclosures: Douglas: Genzyme Europe: Honoraria. Duarte:Genzyme Europe: Honoraria.

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Brethon, Benoit, Laetitia Morel, Arnaud Petit, et al. "Nelarabine Alone or in Combination in High Risk Childhood / Adolescent and Young Adults (AYA) T- Cell Acute Lymphoblastic Leukemia." Blood 124, no. 21 (2014): 3723. http://dx.doi.org/10.1182/blood.v124.21.3723.3723.

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Abstract Introduction: T-cell acute lymphoblastic leukemia (T-ALL) represent 15-20% of childhood/adolescent young adults (AYA) ALL. An intensive chemotherapy is generally needed to obtain the same results than in B-lineage ALL. Day 8 Poor Prednisone Response (PPR) and early resistant disease (refractoriness after induction course or MRD level >10-3 at time point 1 (TP1) and/or TP2) remain particularly challenging as relapses are very difficult to treat especially if they occur early. Nelarabine is a water-soluble prodrug of araG (9-B-arabinofuranosylguanine) which is cytotoxic to T lymphoblasts due to the accumulation of araG nucleotides, especially araGTP, which result in inhibition of ribonucleotide reductase and inhibition of DNA synthesis. Nelarabine was shown to be effective and safe in phase II-III adult and pediatric ALL trials. We describe here a 7 consecutive years experience of nelarabine in “real life” in 3 pediatric / AYA centers. Methods: All children and AYA who received nelarabine in first line therapy or after relapse between 2006 and 2013 were reviewed retrospectively. Classical initial prognostic factors were collected: age, leucocytosis, CNS status, day 8 prednisone response, complete remission (CR) or not, minimum residual disease (MRD) level at TP1 and TP2. Eighty two % of the patients (pts) followed the French FRALLE 2000-T recommendations. Nelarabine, alone or in combination, was used in two groups of pts: group 1: pts in whom nelarabine is given in first line therapy because of high MRD level >10-3 at TP1 and/or TP2 (whatever the level at time of nelarabine infusion) and pts refractory to induction course, and group 2: pts in relapse. Group 1 and 2 are compared for MRD level after nelarabine, number of patients able to go to allogeneic HSCT and overall survival. Finally the safety profile was assessed. Results: 33 T-ALL patients received nelarabine alone (n= 22) or in combination (n= 11, most often with cyclophosphamide and etoposide) from 2006 to 2013. At initial diagnosis, median age was 11.6 y old [3-24], sex ratio 4.5 (M/F 27/6) and median leukocytosis 184.7.109/L [0.1-914]. These patients shared poor risk factors: CNS3 (n=8, 24.1%), D8 PPR (n=23, 69.7%), day 21 M3 bone marrow (n=13, 36.4%), no CR after one induction course (n=6, 18.2%) and MRD level > 10-3 at CR1 (n=15, 42.4%). Regarding group 1 (high MRD level at TP1 and/or TP2 n= 11, refractoriness to induction course n= 5), the status just before nelarabine was: 6 in CR1 with finally MRD <10-3, 5 in CR1 but MRD >10-3 and 5 refractory. Nelarabine was given alone in 12 patients and in combination in 4 patients. MRD level after nelarabine was <10-3 in 12/16 patients. Overall, 11 pts received an allogeneic HSCT and 13/16 (81%) are alive in CR1 at the time of the analysis with a median FU from first nelarabine infusion of 13.7 months [0.8-58.3]. Overall survival is 79.8%+/-10.5 at 5 years. Regarding group 2 (relapsed patients, n= 17), nelarabine was infused at the time of first relapse in 4 patients and in refractory first relapse or more than first relapse in 13 patients. Among these heavily pretreated patients, only 6 obtained a MRD level <10-3 leading to allogeneic HSCT but none of 6 survived. Only one patient survived in CR3 after a success of nelarabine alone and received other chemotherapy without allogeneic HSCT. Regarding toxicities, the only WHO grade III-IV observed side effects are cytopenias (n= 25, 75.8%). Others reported side effects are limited (grade I-II): fever of undetermined origin or infections (n= 7, 21.2%), neurological (n= 6 pts, 18.2%; some of them with more than one side effect: sensory neuropathy in 4, motor neuropathy in 2, headaches in 2, motor-facial neuropathy in 1, ataxia in 1) or muscular (n= 4, 12.1%; 2 myalgia, 1 myositis, 1 amyotrophia), liver toxicities (n= 4, 12.1%; 3 transaminase increases, 1 hyperbilirubinemia). Conclusions: In a non selected population of childhood / AYA high-risk T-ALL, nelarabine was very useful for poor risk patients in first line therapy. The majority of patients received nelarabine as a monotherapy. By contrast nelarabine mostly failed to improve the survival in heavily pretreated relapsed patients. Overall, this study conforts the use of nelarabine in first line T-ALL and high-risk features with acceptable tolerance. The evaluation of nelarabine in selected high-risk patients in a first line setting should be evaluated prospectively to confirm these results. Disclosures Baruchel: JAZZ: Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees.

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Muthaffar, Osama, Klajdi Puka, Luc Rubinger, et al. "Reoperation after failed resective epilepsy surgery in children." Journal of Neurosurgery: Pediatrics 20, no. 2 (2017): 134–40. http://dx.doi.org/10.3171/2017.3.peds16722.

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OBJECTIVEAlthough epilepsy surgery is an effective treatment option, at least 20%–40% of patients can continue to experience uncontrolled seizures resulting from incomplete resection of the lesion, epileptogenic zone, or secondary epileptogenesis. Reoperation could eliminate or improve seizures. Authors of this study evaluated outcomes following reoperation in a pediatric population.METHODSA retrospective single-center analysis of all patients who had undergone resective epilepsy surgery in the period from 2001 to 2013 was performed. After excluding children who had repeat hemispherotomy, there were 24 children who had undergone a second surgery and 2 children who had undergone a third surgery. All patients underwent MRI and video electroencephalography (VEEG) and 21 underwent magnetoencephalography (MEG) prior to reoperation.RESULTSThe mean age at the first and second surgery was 7.66 (SD 4.11) and 10.67 (SD 4.02) years, respectively. The time between operations ranged from 0.03 to 9 years. At reoperation, 8 patients underwent extended cortical resection; 8, lobectomy; 5, lesionectomy; and 3, functional hemispherotomy. One year after reoperation, 58% of the children were completely seizure free (International League Against Epilepsy [ILAE] Class 1) and 75% had a reduction in seizures (ILAE Classes 1–4). Patients with MEG clustered dipoles were more likely to be seizure free than to have persistent seizures (71% vs 40%, p = 0.08).CONCLUSIONSReoperation in children with recurrent seizures after the first epilepsy surgery could result in favorable seizure outcomes. Those with residual lesion after the first surgery should undergo complete resection of the lesion to improve seizure outcome. In addition to MRI and VEEG, MEG should be considered as part of the reevaluation prior to reoperation.

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Kabanova, A. "Literary Reading Lesson in First Grade." Primary Education 8, no. 6 (2021): 35–38. http://dx.doi.org/10.12737/1998-0728-2020-35-38.

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The author of the article proposes for consideration one of the possible options for a lesson in literary reading in the first grade, in which N.N. Nosov “Steps”. The process of reading and working with the text organized by the teacher allows solving subject and metasubject learning problems. The used methodology contributes to the development of educational activities in first-graders. The article provides examples of tasks differentiated by the level of complexity, which take into account the capabilities of children who read well and not well enough. Acquaintance with the work of the writer N.N. Nosova continues at the lesson with reading another of his works - the story “On the Hill”. Conversations conducted by the teacher and collective discussion of the content of the read texts help him to determine not only the degree of their conscious perception by first graders, but also to include children in an active educational dialogue, to form their interest in independent reading.

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Del Bufalo, Francesca, Concetta Quintarelli, Biagio De Angelis, et al. "Academic, Phase I/II Trial on T Cells Expressing a Second Generation, CD19-Specific Chimeric Antigen Receptor (CAR) and Inducible Caspase 9 Safety Switch for the Treatment of B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) and B-Cell Non-Hodgkin Lymphoma (B-NHL) in Children." Blood 134, Supplement_1 (2019): 1341. http://dx.doi.org/10.1182/blood-2019-129821.

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Survival rates of children with relapsed/refractory (r/r) BCP-ALL remain unsatisfactory and little progress has been made in the past 2 decades. Similarly, relapse of childhood B-NHL is usually associated with an aggressive disease and poor outcomes. Targeted immunotherapy with T-cells genetically modified to express a CD19-directed CAR showed an unprecedented antitumor efficacy, leading to the recent FDA and EMA approval of two CD19-CAR products for treatment of BCP-ALL and B-NHL. Relevant toxicities have, however, been reported, mainly related to the development of severe Cytokine Release Syndrome (CRS) and/or of neurotoxicity. At Ospedale Pediatrico Bambino Gesù (OPBG) in Rome, we developed a clinical-grade, 2nd generation, CD19-specific CAR construct, including 4.1bb as costimulatory domain and the inducible caspase-9 safety switch (iC9-CD19-CAR), vehiculated by a retroviral vector, to conduct an academic, phase I/II clinical trial in patients (age 1-25 yrs) affected by BCP-ALL or B-NHL. We now report on the results of the phase I and of the first 8 patients treated in the phase II portion of the study, in terms of feasibility, toxicity, maximum tolerated/recommended dose (MTD/RD) and data on response rate and biological correlates. The phase I, dose-escalation portion of the study included 3 dose levels (DL), namely: DL1, 0.5×106; DL2, 1.5×106; DL3, 3.0×106 CAR+ T cells per kg of recipient body weight. In the phase II portion, patients were treated at the RD identified in the phase I, namely 3.0×106 CAR+cells/kg. All patients received a lymphodepleting regimen consisting of fludarabine and cyclophosphamide for 3 days and iC9-CD19-CAR T cells were subsequently administered as single infusion. Patients were monitored for toxicity, expansion and persistence of iC9-CD19-CAR T cells. Seventeen children were enrolled into the trial and received iC9-CD19-CAR T cells between January 2018 and June 2019. Data were analyzed as of July 20, 2019. The characteristics of the patients are detailed in table 1. The designed dose concentration was successfully produced for all the enrolled patients and we did not observe any production failure. The median transduction rate in the drug product was 54% (range 21-73), while the median vector copy number was 3.8 (range 2.8-6.2). During the phase I portion of the study, no dose limiting toxicities (DLTs) have been recorded, defining the MTD as 3.0×106 CAR+ T cells per kg of recipient body weight. The treatment was overall tolerated and all the toxicities were reversible, the most severe being grade 3-4 neutropenia, thrombocytopenia and/or anemia, occurring in 16/17 (94.1%) patients; in 13/16 patients (81.2%) the hematological toxicity developed before the infusion and persisted after the administration of CAR T cells. Cytokine release syndrome (CRS) occurred in 10/17 patients (58.8%) and was overall moderate, reaching grade 3 (Lee criteria) in one patient only. Notably, none of the patients developed neurotoxicity and no activation of the safety switch was required. All patients were assessed for response at 4 weeks from iC9-CD19-CAR T cell infusion and 13/15 (86.7%) patients with ALL achieved complete remission (CR) with negativity of minimal residual disease (MRD), including 2/3 patients receiving the DL1, 9 patients who had failed a previous allogeneic haematopoietic stem-cell transplantation (HSCT) and 6 patients that had previously received blinatumomab, as CD19-directed immunotherapy. The iC9-CD19-CAR T cells expanded in vivo and were detectable by both flow-cytometry and molecular biology in the blood (Fig.1), bone marrow and cerebrospinal fluid of the responders. One CD19-negative relapse 3 months after infusion was recorded, while 3 additional patients relapsed with CD19+ leukemia blasts. Four patients received HSCT while in CR with MRD negativity because of regrowth of normal CD19+ B cells. The 18-month probability of overall survival for the BCP-ALL cohort is 72.2% (Fig.2). One of the 2 B-NHL patients showed a partial response. Our data indicate that iC9-CD19-CAR T cell in an academic setting is feasible, safe and extremely effective in treating highly resistant/relapsed BCP-ALL. In our trial, no major or life-threatening toxicities were observed and, despite the moderate CRS recorded, high rates of CR were achieved, suggesting that the combination of a retroviral platform and 4.1bb as costimulation is able to mediate a potent antitumor effect Disclosures Merli: Amgen: Honoraria; Novartis: Honoraria; Sobi: Consultancy; Bellicum: Consultancy. Algeri:Bluebird bio: Consultancy, Honoraria; Atara Biotherapeutics: Consultancy, Honoraria; Miltenyi: Honoraria. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Puhalla, Eve M. "Enhancing the Vocabulary Knowledge of First-Grade Children With Supplemental Booster Instruction." Remedial and Special Education 32, no. 6 (2010): 471–81. http://dx.doi.org/10.1177/0741932510362495.

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This study examined the effects of instructional intensity on the acquisition of storybook vocabulary in first graders who were at risk of early reading failure. It also measured whether the intervention was effective for closing the vocabulary knowledge gap between students who were at risk and their average-achieving peers. A total of 66 students participated in the study, 44 identified as at risk and 22 as average-achieving peers. Students identified as at risk were randomly assigned to either a booster group, where they received explicit instruction of selected storybook vocabulary, or a no booster group, where they received vocabulary instruction in the context of read alouds through an experimental Read Aloud curriculum. A repeated measures design was employed to compare the effects of the intervention. Results indicate that students in the booster group significantly outperformed the students in the no booster and average-achieving peers groups on storybook vocabulary measures.

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Amrullah, Afif. "Tanmiyah Mahârah al-Kalâm bi Tathbîqi at-Tharîqah al-Ittishâliyyah: al-Bahts at-Tanfîdziy fî al-Fiah ad-Dirâsiyyah." Alibbaa': Jurnal Pendidikan Bahasa Arab 2, no. 2 (2021): 105–23. http://dx.doi.org/10.19105/alb.v2i2.4701.

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This research was intended to improve student's speaking ability by applying communicative method, and at the same time, to find out the effectiveness of using this teaching method in promoting speaking skills. The problem with this research was formulated interrogatively as follows: Is the implementation of communicative methods capable of improving the speaking skills of eighth grade students at National Islamic Junior School, Bandar Lampung? This research can be categorized as Classroom Action Research, and as subject research. They are all eight grade students at National Islamic Junior School Bandar Lampung. To obtain data, this research used several methods: observation, interview, documentation, and testing. This research is qualitative research, and the data was analyzed in three steps: data reduction, data display, and then interpretation. This research results in the following conclusions: In first session, the students who passed the test 54.40% and who failed 45.59%, in second session, students who passed the test 86.64%, and who failed 13.35%, and in the third session the students who passed test 78.83%, and who failed 21.16%, than can be concluded that implementing a communicative method in teaching Arabic as a second language is capable of improving speaking skills.

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Gombert, Jean Emile. "What do Children Do when they Fail to Count Phonemes?" International Journal of Behavioral Development 19, no. 4 (1996): 757–72. http://dx.doi.org/10.1177/016502549601900405.

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An analysis of children's responses in phoneme counting tasks provides a way of accessing their conception of the smallest phonological unit. Thus, in order to understand the development of phonological awareness, the types of errors children make in these tasks were analysed. A group of 5to 6-year-olds (preliterate), a group of 6to 7-year-olds (grade 1), a group of 7to 8-year-olds (grade 2), and a group of 6to 7-year-olds who, after 4 months of learning to read, were unable to decode new words were presented a task that involved counting phonemes in words and nonwords. In addition to description of the emergence of the ability to focus on phonemic segments, our interest was in analysing the incorrect responses, including the possible types of segmentation as a function of the pronunciation of the items. Nonliterate subjects (preliterate children or nonreaders from grade 1) counted syllables; the beginning readers (grade 1) often failed to analyse the onset or the rime of the syllables into phonemes. Therefore, they appeared to be using an analysis that was intermediate between onset-rime segments and phonemes. The older children (grade 2) tended to count letters as opposed to phonemes, producing more than one tap for a digraph.

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Donelan-McCall, Nancy, and Judy Dunn. "School Work, Teachers, and Peers: The World of First Grade." International Journal of Behavioral Development 21, no. 1 (1997): 155–78. http://dx.doi.org/10.1080/016502597385036.

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Children’s perceptions of their experiences with their school work, and teacher and peer relationships were studied in 44 second-born children, participating with their mothers and siblings in a longitudinal investigation, who were interviewed in October and May of their first-grade year. Overall, the majority of children were very positive about their experiences in all three areas of school adjustment. Modest associations between children’s perceptions of their school work, teacher, and peer experiences suggest that although most children perceived their experiences as positive (or negative) across all three areas, some children reported difficulties in one or two individual areas. In addition, although many children’s reported school experiences remained stable over the year, some children’s perceptions changed. The majority of children whose perceived school experiences were marked by discontinuity over the year were positive at the beginning of the year but relatively negative at the end. Finally, the findings from this investigation draw attention to some of the antecedent variables related to children’s subsequent school experiences, in particular, their emotion understanding and earlier relationships with their older siblings.

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Gubarev, E. I. "The prevention and treatment of myopia in schoolchildren from grade 1 to grade 10 by restoring the ocular accommodation function." Russian Ophthalmological Journal 12, no. 2 (2019): 59–63. http://dx.doi.org/10.21516/2072-0076-2019-12-2-59-63.

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Purpose: to evaluate long term effectiveness of a method of restoring the accommodation function of the eye and preventing the onset and progression of myopia and to propose ways to overcome medical requirements that are difficult to meet.Material and methods. The method consisted in prolonged installations of 1 % tropicamide eye drops and permanent optical correction that corresponded to manifest refraction. 48 schoolchildren aged 7–18 with initial myopia or signs of high risk myopia onset were followed up. The subjects were divided into 2 groups of 24 people each. Group 1 consisted of children who followed medical prescriptions and group 2 consisted of those who did not. The two groups were further subdivided into two subgroups. Subgroup 1A included 12 children with the initial positive cycloplegic refraction up to +1.0 D; subgroup 1B included 12 children with the initial negative cycloplegic refraction from -0.5 D. Subgroup 2A (12 children) had negative cycloplegic refraction who regularly failed to receive treatment (optical correction, eyedrop instillations, medical checkups), and subgroup 2B (12 children) had negative cycloplegic refraction who received practically no treatment for myopia. Regular checkups took place 2–3 times a year for 10 years and included measuring visual acuity, manifest and cycloplegic refraction by skiascopy or subjectively, as well as measuring relative accommodation reserve (RAR) according to the author’s own technique. The treatment envisaged permanent optical correction in accordance with manifest refraction until the age of 18 years, combined with courses of tropicamide 1 % instillations for 1 to 3 months two to three times a year. Results. In group 1A, myopia was prevented in all subjects. In group 1B, the progression stopped after several years of treatment. In subgroup 2A and especially subgroup 2B, myopia progressed, over the 10-year follow-up period reaching the figures of 2.5 and 3.5 D, respectively. Conclusion. The long-term efficiency of the proposed method applied to schoolchildren from grade 1 to grade 10 was confirmed. Ways to overcome the difficulties of following medical requirements were proposed.

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Bondanza, Attilio, Loredana Ruggeri, Dimitris Ziagkos, et al. "An Accelerated CD8+, but Not CD4+, T-Cell Reconstitution Associates with a More Favorable Outcome Following HLA-Haploidentical HSCT: Results from a Retrospective Study of the Cell Therapy and Immunobiology Working Party of the EBMT." Blood 126, no. 23 (2015): 1929. http://dx.doi.org/10.1182/blood.v126.23.1929.1929.

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Abstract Introduction and Aim: HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is increasingly offered to patients with high-risk acute myeloid (AML) or lymphoid leukemia (ALL). Unfortunately, graft manipulation employed to overcome the HLA barrier significantly delays immune reconstitution, posing the patients at risk of infections. Accordingly, non-relapse mortality after haplo-HSCT clearly extends beyond day 100 post-transplant. Over the years, different approaches have been investigated to speed-up immune reconstitution. In the absence of validated immune biomarkers, it is however difficult to evaluate the clinical impact of accelerated immune reconstitution. The aim of this EBMT retrospective study is to explore immune-cell counts early after haplo-HSCT as predictive of its overall outcome. Methods and Patients: Among AML and ALL patients in the EBMT database who underwent haplo-HSCT in the period 2001-2012, criteria for study entry were survival beyond day 100 and availability of differential immune-cell counts (CD3+, CD4+, CD8+ T cells, CD19+ B cells, CD16+/CD56+ NK cells) within this period. Accordingly, statistical analysis was landmarked at day 100. Of 259 patients meeting these criteria (age 2-70, median 33), 67 (26%) were children. The underlying disease was AML in 162 cases (63%), while ALL in the remaining (including 5 cases of bi-phenotypic leukemia). Fifty-two percent of patients were transplanted in CR1. The stem-cell source was G-CSF mobilized peripheral blood in all but one patient (>99%) and 171 received TBI (66%). The graft was manipulated in 199 patients (78%), including CD34-selection (50%), ex vivo T-cell depletion (15%) or both (13%). Female-to-male transplants were 68 (26%), while 204 (79%) recipients were CMV seropositive. Sustained hematopoietic engraftment was reached in 246 patients (95%) Results: The estimated overall survival at 2yrs was43%. The estimated cumulative incidence of death due to relapse was 33%, while that of death due to other causes was 35% (51% of those were infections) The occurrence of grade III-IV GVHD and of chronic GVHD was 9% and 18% (7% extensive), respectively. As expected, overall survival was better in children (62% vs 36%, P=0.002 by Log-rank), who clearly had a lower incidence of death due to causes other than relapse compared with adults (10% vs 37%, P=0.0001). Negative prognostic factors for overall survival were any disease state other than CR1 at time of transplantation (P=0.002) and CMV seropositivity (P=0.009). Type of leukemia, TBI or graft manipulation had no effect on the outcome. By day 100 post-transplant, patients reached the following median immune-cell counts: 100 CD3+ T cells (range 0-2576), 30 CD4+ T cells (0-1714), 48 CD8+ T cells (0-1880), 276 CD16+/CD56+ NK cells (18-3581), 21 CD19+ B cells (0-790). Importantly, CD3+ counts above the first quartile (1Q) of the entire data set (29 cells per microL) were significantly associated with a better overall survival (P=0.0005 by Log rank) and a lower incidence of death due to causes other than relapse (P=0.002 by Gray test). The same held true for CD8+ counts (1Q: 15 cells per microL; P=0.003 on overall survival; P=0.0004 on death due to other causes). CD4+ counts also showed similar correlations, but at higher values (above the median). None of the other immune-cell counts analyzed correlated with clinical outcome. Strikingly, when challenged in multivariate analysis taking into account age category, CMV seropositivity, graft manipulation and CR1 status at transplant, CD3+ and CD8+ counts above the 1Q adjusted to fit optimal cut-off points were still significantly associated with a better overall survival (P=0.006 and P=0.015, respectively), but only CD8+ values associated with a lesser risk of death due to causes other than relapse (P=0.026). Conversely, similarly adjusted median CD4+ counts failed to show any association. Conclusions: Contrary to what is generally accepted, these results indicate that an accelerated CD8+, but not CD4+, T cell reconstitution associates with a more favorable clinical outcome after haplo-HSCT, likely due to its protective role against opportunistic viral infections. Moreover, they suggest that yet to be validated CD8+ cut-off points, rather than the commonly used arbitrary value of 200 CD4+ T cells per microL, should be considered as surrogate biomarkers in clinical trials. Disclosures Bonini: MolMed S.p.A: Consultancy.

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Ahmad Latoo, Manzoor, and Aleena Shafi Jallu. "Subglottic Stenosis in Children: Preliminary Experience from a Tertiary Care Hospital." International Journal of Otolaryngology 2020 (December 15, 2020): 1–7. http://dx.doi.org/10.1155/2020/6383568.

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Introduction. This retrospective study describes our experience in the evaluation and management of infants with subglottic stenosis. Materials and Methods. The study included 10 patients aged between 1 wk and 18 months with 6 cases having congenital subglottic stenosis and 4 cases having acquired subglottic stenosis. Results. 6 patients had grade I, 3 patients had grade II, and 1 patient had grade III subglottic stenosis. Tracheostomy was required in 4 patients at the time of presentation. 7 patients were treated successfully with Bougie dilation followed by topical application of mitomycin, whereas 1 patient who failed to serial dilation needed open reconstructive procedure. Laser excision of the anterior subglottic web was performed in one patient. Another patient with underlying cerebral palsy could not be operated upon and was managed with tracheostomy. Conclusion. Subglottic stenosis may be effectively man-aged with endoscopic surgical techniques, although the number of such sittings required varies with the type and severity of stenosis. Open surgical procedures need to be individualised as per the needs of the patient only after all the other endoscopic possibilities have been exhausted.

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Setiawati, Isye, and Mai Zuniati. "Improving The Students’ Writing Ability In Descriptive Text Through Think-Talk-Write Strategy." Attractive : Innovative Education Journal 1, no. 1 (2019): 72. http://dx.doi.org/10.51278/aj.v1i1.2.

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This research is a Classroom Action Research (CAR). The subject of this research is tenth grade of MA Ma‘arif Roudlotut Tholibin Metro academic year 2018/2019 especially at class X Sains. It is consists of twenty three students. The data collecting techniques are test, observation, and questionnaire. The analysis of the data by using qualitative and quantitative data. The result showed that the students’ score in preliminary study, there was no one who passed the passing grade. Then, in the first cycle it is found that there were 12(52%) students who passed and the rest is 11(47%) students could not pass the passing grade. In cycle 2 there were an increase from cycle 1, that was 20(86%) students reached the passing grade and only 3(13%) who failed to accomplish the passing grade. The researcher concluded that TTW Strategy can improve students‘ writing ability in descriptive text. This showed of students‘ activities by observation, students‘ response by questionnaire, and students‘ score by test. The researcher found some dates that students interested, any progress when learned writing descriptive text by using Think-Talk-Write as strategy and the students felt better and improved for their writing ability in descriptive text. From observation students‘ active in the class. In cycle 2, 20(86%) students reached the passing grade and only 3(13%) who failed to accomplish the passing grade It indicated that think-talk-write strategy has considerable influence toward students’ writing ability in descriptive text and success Key words: Think-Talk-Write Strategy, Writing, Descriptive text

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Makeeva, Vladislava Igorevna. "Greek demons who murdered children." Genesis: исторические исследования, no. 7 (July 2021): 54–68. http://dx.doi.org/10.25136/2409-868x.2021.7.36131.

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This article describes the Ancient Greek mythological characters who were attributed with murdering children: Lamia (&Lambda;&#940;&mu;&iota;&alpha;), Mormo (&mu;&omicron;&rho;&mu;&#974;) and Gello (&gamma;&epsilon;&lambda;&lambda;&#974;).The ssuperstitions associated with these demons remain in Greece to this day, although their images have undergone certain transformation.&nbsp;The object of this research is the mythological representations of the Ancient Greeks, while the subject is demons who murdered children.&nbsp;The goal of this article is to determine the role of children's horror stories in life of the Ancient Greek society.&nbsp;The author reviews the facts testifying to the existence of characters as Lamia, Mormo, Gello and Empusa in the Greek and Roman texts, as well gives characteristics to their images based on the comparative analysis.&nbsp;The conducted analysis reveals the common traits of the demons who murdered children: frightening appearance,&nbsp;combination of human and animal traits, ability to transform, identification with Hecate, as well as the story of the failed motherhood underlying the history of emergence of the demon.&nbsp;The key functions of these mythological characters consisted in explanation of the sudden infant and maternal mortality typical to the ancient times, as well as teaching children and adults a lesson.&nbsp;The first could be frightened with such stories, and the latter had to learn from the tale that demonstrates the harm of reckless following the temptations or refusal of fulfilling the prescribed social roles, socially acceptable&nbsp;behavior.

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Guilbault, Denise Marie. "The Effect of Harmonic Accompaniment on the Tonal Achievement and Tonal Improvisations of Children in Kindergarten and First Grade." Journal of Research in Music Education 52, no. 1 (2004): 64–76. http://dx.doi.org/10.2307/3345525.

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The purpose of this research was to examine the effect of harmonic accompaniment on the tonal achievement and tonal improvisations of young children. The specific problems of this study were the following: (1) Does the addition of a root melody accompaniment to song instruction affect the tonal achievement of children in kindergarten and first grade? (2) Does the addition of a root melody accompaniment to song instruction affect the tonal strength of the improvisations of children in kindergarten and first grade? Results indicated that song instruction with a root melody accompaniment had no significant effect on the tonal achievement of children in kindergarten and first grade. However, children who received song instruction with root melody accompaniment improvised melodies with implied harmonic functions while maintaining the tonic pitch and tonality of the song better than those children who did not have such instruction.

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Reinfjell, Trude, Silja Berg Kårstad, Turid Suzanne Berg-Nielsen, Joan L. Luby, and Lars Wichstrøm. "Predictors of change in depressive symptoms from preschool to first grade." Development and Psychopathology 28, no. 4pt2 (2015): 1517–30. http://dx.doi.org/10.1017/s0954579415001170.

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AbstractChildren's depressive symptoms in the transition from preschool to school are rarely investigated. We therefore tested whether children's temperament (effortful control and negative affect), social skills, child psychopathology, environmental stressors (life events), parental accuracy of predicting their child's emotion understanding (parental accuracy), parental emotional availability, and parental depression predict changes in depressive symptoms from preschool to first grade. Parents of a community sample of 995 4-year-olds were interviewed using the Preschool Age Psychiatric Assessment. The children and parents were reassessed when the children started first grade (n = 795). The results showed that DSM-5 defined depressive symptoms increased. Child temperamental negative affect and parental depression predicted increased, whereas social skills predicted decreased, depressive symptoms. However, such social skills were only protective among children with low and medium effortful control. Further, high parental accuracy proved protective among children with low effortful control and high negative affect. Thus, interventions that treat parental depression may be important for young children. Children with low effortful control and high negative affect may especially benefit from having parents who accurately perceive their emotional understanding. Efforts to enhance social skills may prove particularly important for children with low or medium effortful control.

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Ansari, Arya, and Michael A. Gottfried. "Early Childhood Educational Settings and School Absenteeism for Children With Disabilities." AERA Open 4, no. 2 (2018): 233285841878557. http://dx.doi.org/10.1177/2332858418785576.

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Data from the Early Childhood Longitudinal Study Kindergarten Class of 2010–2011 were used to examine the implications of preschool and full-day kindergarten enrollment for the subsequent school absences of 2,056 children with disabilities. Results suggest that children with disabilities who went to preschool were absent less frequently in kindergarten, but these benefits did not persist through the end of first grade. Conversely, children with disabilities who attended full-day kindergarten programs were absent more frequently during the kindergarten year as compared with children in part-day programs, but these children experienced a sharper drop in absenteeism throughout the following school year resulting in no differences in school absences in first grade. No multiplicative benefits emerged for attending both preschool and full-day kindergarten. And even though these aforementioned benefits of preschool diminished rapidly, there were lingering academic benefits through the end of first grade because of improvements in earlier school attendance.

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Li, Amanda M., George E. Hucks, Amanda M. Dinofia, et al. "Checkpoint Inhibitors Augment CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Relapsed B-Cell Acute Lymphoblastic Leukemia." Blood 132, Supplement 1 (2018): 556. http://dx.doi.org/10.1182/blood-2018-99-112572.

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Abstract Abstract CAR T cell therapy in relapsed B-ALL can result in complete response (CR) rates of 80-90%, but relapse-free survival declines to 60% within the first 12-months due to both CD19-positive and negative relapses. CD19-positive relapses that occur during this time are largely due to early CAR T cell loss. We hypothesize that inhibiting the PD-1:PD-L1 (programmed cell death 1) checkpoint axis may decrease T cell exhaustion, thereby improving CAR T cell function and persistence. We report our single institution experience of the use of PD-1 inhibitors in patients with relapsed or refractory B lymphoblastic malignancies treated with CD19-directed CAR T cell therapy. Methods: Patients treated with CD19-directed CAR T cell therapy (murine CTL019 or humanized CTL119) at the Children's Hospital of Philadelphia who demonstrated repeated early CAR T cell loss or partial/no response to CAR T cell therapy received a PD-1 inhibitor starting no sooner than 14 days after CAR T cell infusion and after resolution of cytokine release syndrome (CRS) symptoms, with the possibility of repeated doses up to every 3 weeks. Results: Fourteen patients, ages 4-17 years, with heavily pretreated, relapsed B-ALL (n=13) or B lymphoblastic lymphoma (n=1), were treated with CD19-directed CAR T cell therapy (CTL019, n=4; or CTL119, n=10) in combination with pembrolizumab (n=13) or nivolumab (n=1). Three of 6 patients treated with CD19 CAR T cells in combination with a PD-1 inhibitor for early B cell recovery re-established B cell aplasia (a reflection of CAR T cell function) for 5-15 months, 2 of whom have persistent B cell aplasia with ongoing pembrolizumab therapy. Four patients started pembrolizumab for bulky extramedullary disease unresponsive to or relapsed after CAR T cells, with 2 partial and 2 complete responses seen. In one patient, significant CAR T cell proliferation was measured within days of starting pembrolizumab and in temporal correlation to radiographic disease response. In 4 patients who failed to achieve disease remission with initial CAR T cell infusion, no CRs were achieved with the addition of pembrolizumab, although partial responses were seen, and one patient progressed with CD19-dim/negative disease. CRS symptoms and fever typical of CAR T cell proliferative responses were observed in 3/14 patients within 2 days of starting pembrolizumab. Other early and delayed adverse effects associated with PD-1 inhibition were tolerable or reversible upon discontinuation, and including 1 case each of acute pancreatitis, hypothyroidism, arthralgias, urticaria, as well as 4 patients with grade 3-4 cytopenias. No grade 5 toxicities or graft-versus-host disease flares occurred. Two patients discontinued pembrolizumab for delayed adverse effects after multiple doses; both patients relapsed/progressed with CD19+ disease a few weeks after discontinuation. Discussion: T cell exhaustion or activation induced CAR T death (AICD) has been suspected to contribute to poor persistence of CAR T cells. We hypothesized that the PD-1 checkpoint pathway may be involved in CAR T cell exhaustion in some cases, which may be overcome by checkpoint inhibition. Here, promising responses were specifically seen in those with early B-cell recovery and bulky extramedullary disease. In contrast, PD-1 inhibition had partial, but no durable, effect in the four B-ALL patients with poor initial marrow response to CAR T cell therapy alone, suggesting a different mechanism such as AICD may be responsible for poor initial responses. No unexpected or fatal toxicities were seen. This cohort shows initial evidence that checkpoint inhibitors can be used effectively and safely with CAR T cell therapy in children with relapsed B-ALL, and that this strategy may augment CAR T cell effect and persistence. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Callahan:Novartis Pharmaceuticals Corporation: Consultancy. Porter:Genentech: Other: Spouse employment; Novartis: Other: Advisory board, Patents & Royalties, Research Funding; Kite Pharma: Other: Advisory board. Lacey:Novartis Pharmaceuticals Corporation: Patents & Royalties; Tmunity: Research Funding; Parker Foundation: Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. June:Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Immune Design: Membership on an entity's Board of Directors or advisory committees; Immune Design: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceutical Corporation: Patents & Royalties, Research Funding; Celldex: Consultancy, Membership on an entity's Board of Directors or advisory committees. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Adaptimmune: Consultancy; University of Pennsylvania: Patents & Royalties. Maude:Novartis Pharmaceuticals Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Sandoval, Jonathan, and Phyllis Fitzgerald. "A high school follow-up of children who were nonpromoted or attended a junior first grade." Psychology in the Schools 22, no. 2 (1985): 164–70. http://dx.doi.org/10.1002/1520-6807(198504)22:2<164::aid-pits2310220210>3.0.co;2-v.

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Amoroso, Loredana, Dominique Valteau-Couanet, Victoria Castel, et al. "Topotecan-vincristine-doxorubicin in metastatic neuroblastoma with insufficient response to rapid COJEC: Results of a SIOPEN Group study." Journal of Clinical Oncology 31, no. 15_suppl (2013): 10016. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.10016.

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10016 Background: This study evaluated the activity and toxicity of a topotecan-vincristine-doxorubicin (TVD) combination administered to patients with stage 4 neuroblastoma failing to achieve adequate metastatic remission after induction therapy (rapid COJEC) according to the HR-NBL-1 SIOPEN protocol. Methods: Patients above 1 year of age with stage 4 neuroblastoma, who failed to achieve adequate metastatic remission with rapid COJEC were eligible. Topotecan was administered at 1.5 mg/m²/day for 5 days, followed by a 48-hour infusion of vincristine, 2 mg/m² and doxorubicin, 45 mg/m². Tumour response was assessed after 2 TVD courses, according to the INSS criteria. Patients achieving CR or VGPR (metastatic CR) or PR (≤ 3 skeletal MIBG spots and cytomorphological CR on 2 bone marrow aspirates) underwent myeloablative therapy (MAT) followed by PBSC rescue. Patients who failed to achieve PR after 2-4 TVD courses, or developed PD were withdrawn from the study and were treated at physicians’ discretion. Results were recorded in the SIOPEN-R-NET database. Results: Sixty-eight patients who did not achieve CR or VPGR after rapid COJEC were enrolled in the study. Responses of 68 assessable patients after 2 TVD courses included 4 CR, 13 VPGR, 26 PR, 7 MR, 14 NR, 2 PD, 2 missing data (major response rate 65 %). Twenty-five patients who achieved CR or VGPR or PR (metastatic CR) received MAT according to protocol. Thirty-three/68 patients are presently alive, no toxic deaths occurred. Toxicity was mostly hematopoietic. Fifty-three patients experienced grade 4 neutropenia, 47 grade 4 thrombocytopenia and 12 grade 4 anemia after the first course. Forty-nine patients developed grade 4 neutropenia, 41 grade 4 thrombocytopenia and 12 grade 4 anemia after the second course. Twenty-six patients required hospitalisation for systemic antibiotic therapy after the first course, and 19 patients after the second. Grade 3-4 stomatitis requiring a liquid diet or TPN was observed in 17 patients after the first cycle and 9 after the second. Conclusions: This TVD combination was active and tolerable in patients with metastatic neuroblastoma after treatment with rapid COJEC. Clinical trial information: 2006-001489-17.

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Jeon, Kyung-Won, Shin-Dong Lee, and Kyung-Hwa Lee. "A Qualitative Research on Early Entrance to the First Grade: Social, Emotional, and Academic Maladjustment." Gifted Education International 17, no. 3 (2003): 280–86. http://dx.doi.org/10.1177/026142940301700310.

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In the past in the Korean educational system, every student should follow the 6-3-3 educational system; therefore, enrichment types of programs can be provided for the children under these circumstances. However, from 1996, 5-year-old children can be admitted to the first grade on the basis of the birth date. The 5-year-old youngsters have been admitted to the first grade and they were observed by their teacher for two months to decide whether they will remain in the first grade or go back to the kindergarten. In screening youngsters, there was no solid and careful procedure for the early admission, consequently there were quite a few drop outs who were not well adjusted in the first grade. If the children have not been carefully screened, there might be a maladjustment problem. For these reasons, many educators, parents, and teachers fear that early entrance to the first grade system is too stressful for preschoolers and deleterious to their healthy social, emotional, and academic adjustment. In fact, some of the early entrants went back to their kindergarten due to the maladjustment. However, there is no in-depth research on the drop-outs and their parents who suffered from psychological stress. Some research had been conducted to study these maladjustments (Jeon, 1998; Lee et al, 1998). However, these studies were basically done by using questionnaires and did not dig out the nature of the maladjustment problems. Therefore, the purpose of the research discussed in this article is to describe and investigate the social, emotional, and academic maladjustment for those early entrants to the first grade educational system in Korea who drop-out early. Exploratory and in-depth interviews were conducted to ascertain the maladjustment experiences for three 5-year-old children drop-outs.

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Kung, Melody. "First-Grade Reading Instruction and Reading Growth: Asian Language Minorities and Native-English-Speaking Peers." AERA Open 5, no. 3 (2019): 233285841986990. http://dx.doi.org/10.1177/2332858419869902.

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The present study explores whether the relation between aspects of first-grade reading instruction and reading growth through eighth grade differed for Asian language minority (LM) children and native-English-speaking (NE) children. The sample consisted of 6,715 NEs and 242 Asian LMs, followed from first to eighth grade. Findings were as follows: (a) The relation between first-grade sounds/letters instruction and reading growth slightly differed for Asian LMs and NEs. For example, Asian LMs who received more sounds/letters instructional emphasis decelerated less through middle grades, and by eighth grade, performed on par with NEs. (b) The relation between first-grade meaning instructional emphasis and reading growth did not differ for the two groups. (c) NEs experienced more deceleration through middle grades. Implications and future directions are discussed.

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TREIMAN, REBECCA, BRETT KESSLER, and DERRICK BOURASSA. "Children's own names influence their spelling." Applied Psycholinguistics 22, no. 4 (2001): 555–70. http://dx.doi.org/10.1017/s0142716401004040.

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We analyzed spellings that were produced by children in kindergarten (N = 115), first grade (N = 104), and second grade (N = 77) in order to determine whether children's own names influence their spellings of other words. Kindergartners overused letters from their own first names (or commonly used nicknames) when spelling. Kindergartners with longer names, who had more own-name letters available for intrusions, tended to produce longer spellings than did children with shorter names. Moreover, the spellings of kindergartners with long names tended to contain a lower proportion of phonetically reasonable letters than did the spellings of children with short names. These effects appeared to be confined to children who read below the first grade level. The results support the view that children's own names play a special role in the acquisition of literacy. They further show that children choose letters in a way that reflects their experience with the letters.

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Begić, Leila, Mirela Duranovića, and Karagić Samrab. "DIFFERENCES IN LANGUAGE SKILLS FIRST GRADE STUDENTS IN RELATION TO THE LENGTH OF ATTENDING KINDERGARTEN." Journal Human Research in Rehabilitation 6, no. 2 (2016): 8–14. http://dx.doi.org/10.21554/hrr.091602.

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Aim of this research was to examine differences in linguistic abilities of first year students in elementary schools depending on time spent in kindergarten. In research, sample of surveyed students consisted of 190 first year students in elementary schools, both genders and ages between 72 and 89 months. The research was conducted in elementary schools on the territory of municipality Maglaj in Bosnia and Herzegovina. Results of this research have shown that during the evaluation of differences in linguistic abilities of first year students in elementary schools depending on time spent in kindergarten, there is statistically significant difference in grammatical variable that describes morphological completion. Children that attended kindergarten more than three school years, showed statistically better results with recognition abilities, understanding and usage of common morphological forms of Bosnian language, compared to children who attended kindergarten only for legally obliging preschool time (minimal 150 hours during one school year). We have to point out that respondents who attended kindergarten more than three school years showed better results in almost every variable that describes linguistic abilities but obtained difference did not appear as statistically significant. Professionals who deal with education and rehabilitation of children in development period should educate and stimulate parents to enroll their children in kindergarten in order to stimulate their speaking - linguistic development and other areas that children are developing in.

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S.M.E, Finnell. "Urinary Tract Infection in Children: An Update." Open Urology & Nephrology Journal 8, no. 1 (2015): 92–95. http://dx.doi.org/10.2174/1874303x01508010092.

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The 2011 American Academy of Pediatrics (AAP) Urinary Tract Infection (UTI):Clinical Practice Guideline for the Diagnosis and Management of the Initial UTI in Febrile Infants and Children 2-24 Months guideline addressed “areas for research” identifying multiple areas where evidence at the time of the publication was lacking. This review discussed the evidence development in those identified areas. In this paper, I will review the latest literature on UTI in children and focus on those areas of research suggested in these guidelines. I will also summarize the related literature since September 2011. Literature related to first UTI in children have contributed important new knowledge since the publication of the 2011 AAP guideline; 1) additional research has failed to clarify the relationship between childhood UTI and adult renal function. 2) High grade vesicoureteral reflux (VUR) has been established as a clear risk factor for scarring, but the condition is rare. Abnormal ultrasound, and fever in combination with non-E coli infection are other important predictors of scarring. 3) Antimicrobial prophylaxis appear to decrease UTI recurrences, but a large amount of antibiotics has to be administrated to prevent one UTI and the prevention works best in children with low grade, not high grade, VUR, 4) cranberry juice may prevent UTI, and 5) new, less aggressive guidelines, seem not to have negative consequences for pediatric patients measured as missed true pathology. Future guidelines would benefit from incorporating this new information.

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Vrooman, Lynda M., Yael Flamand, Victoria Koch, et al. "Pegaspargase Re-Challenge after Grade 2 Hypersensitivity Reaction in Childhood Acute Lymphoblastic Leukemia: Results from DFCI 16-001." Blood 136, Supplement 1 (2020): 30–31. http://dx.doi.org/10.1182/blood-2020-138840.

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Introduction: Hypersensitivity reactions with asparaginase occur frequently in pediatric patients (pts) with acute lymphoblastic leukemia (ALL). The standard approach for pts with reaction to E.coli-derived asparaginase is to switch to Erwinia asparaginase, given concern that clinical reactions reflect presence of neutralizing antibodies; however, Erwinia requires more frequent dosing and is often unavailable. Therapeutic drug monitoring allows for discrimination between pts with pegaspargase hypersensitivity who have sub-therapeutic asparaginase activity and those still able to derive therapeutic benefit from pegaspargase. We prospectively piloted re-challenging pts with pegaspargase after initial Grade 2 hypersensitivity to this agent, with premedication at re-challenge and assessment of serum asparaginase activity (SAA). Methods: Pts aged 1 to &lt; 22 years with newly diagnosed ALL were eligible for DFCI 16-001. Pts received 1 dose of intravenous pegaspargase during Induction, and every 2 weeks for 15 total doses in Post-Induction phases, without routine premedication. Pts were monitored during/after pegaspargase for allergy, with CTCAE version 4.0 event grading. Those with ≥Grade 3 allergy discontinued pegaspargase and were switched to Erwinia. Those with Grade 2 allergic reaction were eligible for pegaspargase re-challenge with pre-medication (acetaminophen, diphenhydramine, and hydrocortisone, or per institutional standard) and slower infusion rate. If &lt; 50% of the intended dose had been administered when reaction occurred, re-challenge was within 1-7 days of initial reaction. If ≥ 50% of the intended dose had been given, re-challenge was at next planned pegaspargase dose. SAA was measured 1-hour, 7-days, and 14-days after the re-challenge infusion (if dose completed). If 1-hour or 7-day level ≥ 0.1 IU/mL, and 14-day level ≥ 0.025 IU/mL, SAA was considered adequate, and the pt continued to receive pegaspargase with premedication. Pts with an inadequate SAA level, or with new ≥ Grade 2 allergic reaction with the re-challenge dose were considered to have failed re-challenge and were changed to Erwinia (or enrolled on a clinical trial of recombinant crisantaspase, an alternative Erwinia preparation). Results: Between 3/2017- 7/2020, 317 eligible pts enrolled. Overall, 81 of 299 (27%) total evaluable pts experienced a first allergic reaction to pegaspargase, 68 pts with Grade 2 reaction, 13 with Grade ≥3. During Induction, 17 of 299 (6%) evaluable pts had allergic reaction to pegaspargase; all Grade 2. Of the 17 Grade 2 reactions, 13 pts (76%) underwent re-challenge in Induction, 9 (69%) re-challenges successful and 4 failed. Post-Induction, 64 of 241 evaluable pts (27%) had a first allergic reaction; 51 Grade 2 and 13 Grade ≥3. Thirty-six of 51 (71%) pts with Grade 2 allergy during Post-Induction underwent re-challenge, as did 1 additional pt with allergy during Induction who was re-challenged with first Post-Induction pegaspargase dose (per protocol guideline, due to receiving ≥50% of Induction dose). Among these re-challenges, 16 were successful, 21 failed. Overall, 25 of 50 (50%) pts who were re-challenged after Grade 2 reaction had a successful challenge and were able to continue pegaspargase. Among the 25 pts with failed re-challenge, 6 pts (24%) had inadequate SAA alone as cause of failure, 17 pts (68%) had an allergic reaction with the re-challenge dose, and 2 (8%) additional patients had both allergic reaction and documented inadequate SAA. Three pts who were successfully re-challenged had a subsequent allergic reaction to pegaspargase. Among the 22 pts who experienced another allergic reaction with pegaspargase (at re-challenge or subsequent dose), 19 pts (86%) experienced Grade 2, and 3 pts experienced Grade 3 reaction. Conclusion: Fifty percent of pts with a Grade 2 reaction to pegaspargase were able to tolerate and achieve adequate SAA when re-challenged with premedication. For those who did react with or after re-challenge, reactions were not more severe. The re-challenge approach limits premedication exposure only to a minority of pts with a history of prior reaction and substantially decreases the number of pts needing to switch to Erwinia asparaginase, which can be challenging to deliver due to administration schedule and drug shortage. Disclosures Place: Novartis: Consultancy, Other: Institutional Research Funding; AbbVie: Consultancy. Silverman:Takeda: Other: advisory board; Servier: Other: advisory board; Syndax: Other: advisory board.

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Mata, Lourdes, Maria José Mackaaij, and Margarida Calado. "Emotional Responses to Reading in the First Grade - The “L.E.R. Cãofiante” Project." Psico-USF 25, no. 2 (2020): 321–30. http://dx.doi.org/10.1590/1413-82712020250210.

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Abstract The “L.E.R. Cãofiante”* project was implemented with first-grade pupils who took part in reading sessions animated by a librarian in partnership with her dogs. The goal was to evaluate the effect of this intervention on children’s emotions regarding reading (enjoyment, anxiety, boredom). The participants were 80 children (47 in the Intervention Group (IG); 33 in the Comparison Group (CG)). Parents and teachers answered a questionnaire about children’s involvement, and the children answered one about reading emotions. For data processing, repeated measures ANOVA was used along with content analysis of the answers to the questionnaires. The results showed different emotional profiles of children in the IG and the CG, mostly regarding enjoyment, which increased in the IG. Data from parents and teachers corroborated this conclusion, emphasising positive experiences which allowed an understanding of the role of dogs in children’s enjoyment and interest in reading.

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Otaiba, Stephanie. "Children who do not respond to early literacy instruction: A longitudinal study across kindergarten and first grade." Reading Research Quarterly 36, no. 4 (2001): 344–49. http://dx.doi.org/10.1598/rrq.36.4.1.

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Journal articles on the topic 'Children who failed first grade'

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