Academic literature on the topic 'D 3.5 UL 2009 T936'

ABSTRACT Background Nutrients are added to the diet through fortification/enrichment and dietary supplements (DSs). Meeting the US Dietary Reference Intakes (DRIs) varies by nutrient and population subsegments. Objective The aim of this study was to assess the relative role of naturally occurring, enriched/fortified, and DS sources of 15 micronutrients with reference to the DRIs. Methods We used the NHANES 2009–2012 (≥2 y old, n = 16,975) data, the ILSI North America Fortification database, and the National Cancer Institute usual intake method. Results Prevalence of nutrient intake from naturally occurring sources below the Estimated Average Requirement (EAR) varied from 5% for vitamin B-12 to 100% for vitamin D, with ≥40% of the population below the EAR for 8 of the 14 nutrients (ages ≥2 y). With enrichment/fortification, the percentage below the EAR decreased to the following for vitamins A (35%), C (34%), and B-6 (7%), folate (8%), thiamin (5%), riboflavin (3%), niacin (1%), and iron (2%). Nutrients from DSs further improved intakes related to the EAR for 12 nutrients (ages ≥2 y). For 9–18-y-olds, the percentages of nutrient intakes below the EAR were 14–50% higher than for 2–8-y-olds. The Tolerable Upper Intake Level (UL) was exceeded among children aged 2–8 y for folate (41.7%), niacin (10.1%), and zinc (39.9%), whereas among ages ≥2 y and 9–18 y no prevalence of intakes over the UL exceeded 10%. Conclusions Fortification/enrichment constitutes a meaningful contribution to reducing the percentage of individuals with less than the EAR for their demographic. These data underscore the need to encourage better dietary patterns to improve the intake of nutrients at risk of low intake.

Abstract Introduction. Bone marrow transplantation from an HLA-matched related or unrelated donor remains the only curative treatment for patients with thalassemia. Although one third of patients with thalassemia can find a matched unrelated donor (MUD) few patients were treated by MUD transplantation. Early experience with the use of MUD transplant in class 3 patients with thalassemia resulted in high rates of graft rejection and transplant-related mortality with thalassemia-free (TFS) survival of 53% (La Nasa G et al. Blood 2002). Significant improvements in MUD transplantation in recent years have prompted us to consider it also for high risk patients with thalassemia. Methods . All patient-donor pairs were typed at high resolution for HLA-A, -B, -C, -DRB1, -DQA1, -DQB1, and DPB1. Fourteen consecutive patients with a median age of 5 years (range, 2-17.2) received unrelated bone marrow transplantation for thalassemia. Four patients were in class 1, 2 were in class 2 and 8 were in class 3 of risk. All patients were treated with the conditioning regimen consisting of weight-based IV Bu, thiotepa (10 mg/kg/d), CY (200 mg/kg) and thymoglobulin (10 mg/kg) preceded by preconditioning with hydroxyurea (30 mg/kg/d), azathioprine (3 mg/kg/d) from D −45, and fludarabine (30 mg/m2/d) from D −16 through D −12. Patients received CSA, methylprednisolone and a short course of MTX as GVHD prophylaxis. Results. Between May 2009 and December 2017 un unrelated donor search was performed for 47 patients at our Institute. Forty one patients were Caucasian and 6 patients black African origin. Among Caucasians 16/41 (39%) found a 10/10 and 5/41 (12%) a 9/10 HLA allele-matched unrelated donor, while 1 of 6 black African patients (16.6%) found a 10/10 HLA-matched donor. Among 22 patients with a suitable donor (10/10 or 9/10 HLA allele-matched) 14 received transplantation, 2 patients withdrew consent, 1 patient's donor refused donation, and the remaining 5 patients are awaiting transplant. Twelve patients received 10/10 and 2 patients 9/10 HLA allele-matched grafts. Eight patients had permissive DPB1 mismatches while 2 patients had non-permissive mismatches in the HvG direction and 4 patients in the GvH direction. Median TNC/kg and CD34+/kg infused were 7.2x108 (range, 3.95-12.5) and 7.75x106 (range, 3.47-16.4), respectively. Sustained engraftment occurred in all patients. The median time to neutrophil and platelet recovery was 20 days (range, 15-27) and 19 days (range, 15-28), respectively. All but one patient showed 100% donor chimerism. The patient with stable mixed chimerism (48% donor DNA) has remained transfusion independent for over 3 years with hemoglobin levels >13.5-14 g/dL. Grade 2 and 3-4 acute GVHD occurred in 3 (21%) and 2 (14%) patients, respectively. Two patients developed mild (skin) or severe (skin, gut and liver) chronic GVHD. There was no association between non permissive DPB1 mismatches in the GvH direction and GVHD. All but one patient are alive and are off immunosuppressive therapy. One patient died due to chronic GVHD-related complications. The median follow-up among surviving patients was 2.8 years (range, 0.8-8.6). The 5-year OS and TFS probabilities were 90% (95% CI 47 to 99%) (Figure 1). Patients showed suboptimal CD4+ recovery within the first year: absolute (mean±SEM) cells/ul of CD4+ at 6 months was 223±48. At 12 and 24 months recovery of CD4+, CD8+, CD19+ and CD56+ were 597±122, 1077±228, 331±75, 229±64 and 812±284, 1067±405, 218±82, 112±22, respectively. One patient developed mild to moderate hepatic sinusoidal obstruction syndrome which resolved with supportive care. CMV reactivation occurred in 9 patients and none developed CMV disease. One patient developed adenovirus gastroenteritis. EBV reactivation occurred in 4 patients; one developed posttransplant lymphoproliferative disorder that was successfully treated with Rituximab. Bacterial infections were common: 5 (38%) patients developed gram negative or gram positive sepsis and 4 (29%) patients pneumonia. Probable invasive fungal infections occurred in 2 (14%) patients. Conclusions. This study showed that unrelated donor BMT can successfully cure a proportion of patients with thalassemia. Remarkably, despite 57% of patients were in class 3 of risk the 5-year OS and TFS rates were 90%. We conclude that class 3 patients with thalassemia who have a suitably matched unrelated donor should not be denied the option of transplantation. Disclosures No relevant conflicts of interest to declare.

7028 Background: Inhibition of cholesterol synthesis and uptake sensitizes AML blasts to chemotherapy (Blood 104: 1816, 2004). A prior Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also reported an encouraging response rate (Blood 109: 2999, 2007). SWOG S0919 therefore evaluated the complete remission (CR) rate in a larger number of pts with relapsed AML treated with the pravastatin dose arrived at in the Phase 1 trial. Methods: Pts were treated at SWOG institutions from Aug 2009 through Nov 2012. Pravastatin was supplied by Bristol-Meyers Squibb. The protocol was approved by each institution’s review board. Eligibility: age ≥ 18 yrs, relapsed AML, cardiac ejection fraction ≥ 45%, CR/ CR with incomplete count recovery (CRi) following most recent chemotherapy lasting ≥ 3 months, no prior hematopoietic cell transplant. Treatment: oral pravastatin 1280 mg Days 1-8, idarubicin 12 mg/m2/d IV Days 4-6, and cytarabine 1.5 g/m2/d continuous IV infusion Days 4-7. Pts achieving a CR could receive 2 cycles of consolidation. CR and CRi were defined by IWG criteria. Fifty eligible pts were to be accrued. If ≥ 21 pts achieved CR or CRi, the regimen would be considered sufficiently effective (critical level = 4.8% if true CR rate = 30% and power of 90% if true CR rate = 50%). Results: The study closed to accrual on Nov 1, 2012 after meeting the defined criterion for a positive study. Thirty-six pts with a median age of 59 yr (range 23-78) were enrolled. Seventeen pts (47%) were male and the median WBC was 2800/ uL (range 700-110,600). The median time from initial dx to registration was 18 mo (range 5-136). Relapse status: 1st: 17 pts (47%), 2nd: 15 (42%), 3rd: 2 (5.5%), and 4th: 2 (5.5%). Eighteen pts have died, 3 during treatment. The response rate was 75% (95% CI 58-88%; 20 CR, 7 CRi); and the median overall survival was 10 mo. The p-value comparing 75% to 30% (null response rate) is 3.356 x 10-8. Duration of last CR (≤ 6 months) and prior high dose cytarabine exposure did not affect response to protocol treatment. Conclusions: The CR/ CRi in this relapsed population is encouraging. We plan to evaluate the efficacy of this regimen in higher-risk patients. Clinical trial information: NCT00840177.

TPS6635 Background: FLT3-ITD AML are associated with poor prognosis. We identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 2008; Borthakur G., Haematologica, 2010). FLT3-ITD is associated with overexpression of chemokine receptor CXCR4 and we found increased in vivo activity of S combined with CXCR4 inhibitor Plerixafor (P) and G-CSF (G) (Zeng Z et.al. Blood 2009). Here we report first data testing this concept in patients with R/R FLT3-ITD AML. Methods: G (10 ug/kg) and P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400-600mg), S on d 1 - 28(one cycle). G/P was held when blasts > 5x104/uL. CD34, 38, 123, CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were measured by flow cytometry. Results: 10 patients have been treated so far : 2 achieved CRp, 4 PR and 4 failed (NR), for an overall response rate of 6/10; 3/6 responders and 4/4 NR were previously treated with FLT3 inhibitors. 4/10 pts. developed hyperleukocytosis (and missed 1 to 5 doses of G/P), 6 skin rash and 3 hypertension. Analysis of cells mobilized in 22 cycles revealed a 29-fold increase in WBC, 41-fold in absolute blasts, 77-fold in granulocytes. Increase in circulating stem/progenitor cells was as follows: CD34+: 231-fold, CD34+/38- : 90-, CD34+/38-/123+(LSC) : 148-, CXCR4+: 139-, VLA-4+ : 68- and CD44+: 82-fold. Increase in LSC was correlated with baseline blasts and VLA4, not with CXCR4. FISH confirmed mobilization of leukemic cells. Increased levels of pERK and pAKT were observed in mobilized cells. Conclusion: The combination of G-CSF+Plerixafor appears superior in increasing circulating leukemic blasts and stem/progenitor cells in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast increase 2.1-fold; Uy et al. Blood, in press). Treatment resulted in 2/10 CRp and 4/10 PRs. Mobilized stem/progenitor cells displayed increased MAPK/AKT signaling and increased CXCR4 expression. This is the first clinical report of G-CSF/Plerixafor for the “mobilization” of AML cells, aimed at removing them from their protective bone marrow microenvironment. The initial results are providing proof-of–principle of this concept.

Introduction: JAK2 is located on chromosome 9p24 and includes 25 exons encoding a protein of about 1132 amino acids. JAK2 is one of the four Janus family non-receptor protein tyrosine kinases. JAK2V617F is by far the most prevalent mutation in BCR-ABL1-negative Myeloproliferative neoplasms (occurs in ∼95% of patients with polycythemia vera, in ∼55% with essential thrombocythemia and in ∼65% with primary myelofibrosis) 1, 2. More than 80% of hemochromatosis patients are homozygous for a C282Y mutation in HFE gene, and a smaller proportion are compound heterozygous for both the C282Y mutation and an H63D mutation3. Here we present the first case of an elderly female with concomitant diagnosis of Polycythemia Vera (PV) and hemochromatosis. To our knowledge, there is no literature about the co-existence or associations of these diseases. Case Reports: 75 year old female, former smoker with PMH of hemochromatosis and COPD with recent exacerbation, presented to the oncology clinic after hospital discharge for continuing care of her hemochromatosis requiring phlebotomy. She reports to have had multiple phlebotomies in the past fifteen years. Patient denied any history of liver disease, diabetes, arthralgia, skin pigmentation or sleep problems. Vital signs and examination were within normal limits. Her initial work up reported significantly elevated hemoglobin of 17.4gm/dl, hematocrit of 56.1%, RBC count of 6.98M/UL with MCV 80.4 fl, MCH 24.9 pg and platelet count of 673 K/UL. Peripheral smear showed normal red cell morphology and few giant platelets. Subsequently, further lab testing revealed ferritin of 25.7ng/ml. Her elevated hematocrit was further evaluated and erythropoietin was surprisingly <1mIU/ml. Genetic testing for HFE gene mutation screen was positive for homozygous C282Y mutation. Due to high suspicion for Polycythemia Vera, JAK2 mutation was also tested, which to our surprise, came back positive for JAK2 V617F point mutation. Patient is diagnosed with Polycythemia Vera and Hereditary Hemochromatosis and is recommended to start Aspirin, continue phlebotomy to maintain Hematocrit below 45% and take hydroxyurea for thrombocytosis. Discussion: It is interesting to note the co-existence of two un-related diseases. Franchini M et al analyzed 52 patients with PV for 12 HH gene mutations and found no significant association between the two conditions4. Hannuksela J et al studied C282Y and H63D mutations in 232 patients with hematological malignancies and reported no significant association5. Beaton and Adams in their review article about the myths and realities of hemochromatosis reports an elevated hemoglobin, in hemochromatosis's patient as a myth, based on their review of 634 C282Y homozygous patients at London health Science center, with mean hemoglobin of 145±13 g/L6. Our case re-iterates the importance of clinical suspicion of polycythemia Vera in a hemochromatosis patient with elevated hematocrit and undetectable erythropoietin. The coincidence is, phlebotomy is the treatment for both conditions as long as patient is fairly asymptomatic. References: 1. Ayalew Tefferi; Molecular drug targets in myeloproliferative neoplasms: mutant ABL1, JAK2, MPL, KIT, PDGFRA, PDGFRB and FGFR1; J Cell Mol Med. 2009 Feb; 13(2): 215-237. 2. Cross NC (2011); Genetic and epigenetic complexity in myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2011:208-214. 3. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet1996; 13:399-408. 4. Analysis of hemochromatosis gene mutations in 52 consecutive patients with polycythemia vera. Franchini M1, de Matteis G, Federici F, Solero P, Veneri D. Hematology. 2004 Oct-Dec;9(5-6):413-4. 5. Prevalence of HFE genotypes, C282Y and H63D, in patients with hematologic disorders. Hannuksela J, Savolainen ER, Koistinen P, Parkkila S. Haematologica. 2002 Feb;87(2):131-5. 6. The myths and realities of hemochromatosis Melanie D Beaton, Paul C Adams Can J Gastroenterol. 2007 February; 21(2): 101-104. PMCID: PMC2657669 Disclosures No relevant conflicts of interest to declare.

Abstract Abstract 142 FLT3-ITD AML are associated with poor prognosis. Our group identified Sorafenib (S) as potent inhibitor of FLT3-ITD (Zhang W, JNCI, 2008; Borthakur G., Haematologica, 2010). FLT3-ITD is also associated with overexpression of the chemokine receptor CXCR4. Utilizing preclinical in vitro and in vivo models we determined increased activity of S when combined with CXCR4 inhibitor Plerixafor (P) and G-CSF (G) (Zeng Z et.al. Blood 2009). Here we report clinical and translational data testing this concept in patients with R/R FLT3-ITD AML. Clinical trial: G (10 ug/kg) and P(240 ug/kg) were given s.c. QOD on days 1 – 13, S (400–600mg) on d 1 – 28(one cycle). G/P was held when blasts exceeded 5×104/uL. Cell populations expressing CD34, 38, 123, CXCR4 (1D9, 12G5), VLA4, CD44 and phospho-proteins were assessed at baseline and at multiple time points during treatment by flow cytometry of up to 10 parameters and by flow cytometric mass spec using CyTOF. Results: 13 patients have been treated so far; responses are as follows: 1 CR, 3 CRp, 6 PR and 4 failed (NR), for an overall response rate of 10/13 (77%); One patients achieved 2 CRp. Six/13 patients, including 3/6 responders and 3/4 NR were previously treated with and considered refractory to FLT3 inhibitors. Four patients had additional D835 mutations: 2 failed and 2 achieved PRs, none of the CR/p patients carried this mutation. Side effects included hyperleukocytosis in 3/10 pts.(who missed 1 to 5 doses of G/P), skin rash (5 pts.), hand foot syndrome (3 pts.) hypertension (7 patients), diarrhea (10 pts.), nausea (8 pts.), headache (6 pts.), muscle weakness (3 pts.) and anorexia (5 pts.). Analysis of cells mobilized in 22 treatment cycles revealed massive mobilization: a 29-fold increase in WBC, 41-fold in absolute blasts and 77-fold in granulocytes. Increases in the numbers of circulating stem/progenitor cells: CD34+: 231-fold, CD34+/38-: 90-, CD34+/38-/123+(LSC): 148-, CXCR4+: 139-, VLA-4+: 68- and CD44+: 82-fold. Increase in circulating LSC was positively correlated with baseline blasts and VLA4 levels, but not with baseline CXCR4. Serial FISH analyses confirmed the preferential mobilization of leukemic vs. non-leukemic cells and 10-color flow cytometry demonstrated altered levels of pERK and pAKT but not of pSTAT3 in mobilized cells. Surprisingly, CXCR4 levels in mobilized cells were increased. CyTOF analysis of up to 29 parameters documented mobilization of primitive LSC. Conclusions: The combination of G-CSF+Plerixafor appears superior in increasing the number of circulating leukemic blasts and stem/progenitor cells in FLT3-ITD AML, as compared to Plerixafor alone in R/R AML(blast increase 2.1-fold; Uy et al. Blood, 2012). Treatment resulted in 4/13 CR and CRp and 6/13 PRs, for an overall response rate of 77%. Mobilized stem/progenitor cells displayed altered MAPK/AKT signaling and increased CXCR4 expression. This is the first clinical study of G-CSF/Plerixafor for the “mobilization” of AML cells, aimed at removing them from their protective bone marrow microenvironment and the initial results are providing proof-of–concept and encouraging clinical responses. Disclosures: Off Label Use: Clofarabine in AML. Burger:Pharmacyclics: Consultancy, Research Funding. Kantarjian:Genzyme: Research Funding.

Abstract Abstract 2555 High hyperdiploidy is present in 30% of children with acute lymphocytic leukemia (ALL), and is associated with a favorable prognosis. We evaluated pts with newly diagnosed ALL treated on SWOG trials S9400 (1995–2000) and S0333 (2005–2010) to determine the prevalence and prognostic impact of hyperdiploidy in adults with ALL. Additionally, we examined the prognostic impact of hypodiploidy, a feature typically associated with a poor prognosis in children. Methods: One-hundred and eighty-five pts treated on S9400 and S0333 with successful cytogenetic (CG) analysis were included. The treatment regimens were: S9400 [Induction: Daunorubicin (D), vincristine (V), prednisone (P), PEG-asparaginase (PEG); Consolidation: Cytoxan (Cy), cytarabine (AraC), 6-mercaptopurine (6MP), intrathecal methotrexate (IT Mtx). Consolidation was followed by allogeneic stem cell transplant or maintenance chemotherapy] and S0333: Double Induction Chemotherapy [Induction 1: D, V, P, PEG; Induction 2: high dose AraC, mitoxantrone, decadron. Consolidation: Cy, AraC, 6MP, Mtx; consolidation was followed by maintenance therapy]. Karyotypes were centrally reviewed and clonal abnormalities described according to ISCN (2009). Hyperdiploidy was defined as: low hyperdiploidy [47–49 chromosomes (cs)], high hyperdiploidy (51–65 cs), near triploidy (66–79 cs), and near tetraploidy (84–100 cs). Hypodiploidy was defined as: near haploidy (25–29 cs), low hypodiploidy (31–39 cs), and high hypodiploidy (42–45 cs). When more than one cell line was present, ploidy was assigned by the most complex clonal karyotype. Hypodiploidy and hyperdiploidy were analyzed as prognostic factors for complete response (CR) rate and residual disease (RD) by logistic regression and chi-square tests; and for overall survival (OS) and relapse-free survival (RFS) by proportional hazards. Multivariable analyses were stratified by study and using the baseline variables: age, WBC, lineage, and CG risk. Results: The median age was 32 yrs (range 17–64), and median WBC at diagnosis 17.2 K/uL (range 0.6–396.6). CG risk was ascribed by (Pullarket V et al. Blood 2008; 111: 2563). Forty-five pts (24%) had normal CG, and 73 (39%) had poor risk CG. Fourteen pts (8%) had hypodiploidy (2: low hypodiploidy; 12: high hypodiploidy). Fifty-three pts (29%) had hyperdiploidy [40: low hyperdiploidy, 10: high hyperdiploidy (5%), 3: near tetraploidy or tetraploidy (2%)]. The CR rate for all pts was 72%; with a median RFS of 15 mos (95% CI: 12–29 mos) and median OS of 28 mos (95% CI: 21–36 mos). There was no significant association with ploidy status and age, WBC, or lineage. However, there was an increased prevalence of the t(9;22) in the high hypodiploidy group compared to the normal/pseudo diploidy group (p=0.049). Neither hypodiploidy nor hyperdiploidy were predictive of CR or RD; although pts with hypodiploidy had a higher rate of RD (p=0.062). The 2 pts with low hypodiploidy had very poor outcomes (1 had RD and died after 11 mos; the other relapsed after 3 mos from CR and died 4 mos after study registration). There were no statistically significant differences in OS, CR rate, or RFS between the ploidy groups even after adjusting for baseline characteristics in multivariate analysis. Surprisingly, when excluding pts with poor risk CG there was still a trend towards a worse RFS (29 vs. 32 months, p=0.20) and OS (40 vs. 68 mos, p=0.29) in pts with hyperdiploidy compared to normal/pseudodiploidy. In addition, the 3 pts in the high hyperdiploidy group without poor risk CG had poor OS (median 23 mos). Conclusions: The prevalence of high hyperdiploidy is much lower in adults with ALL, compared to children. The prevalence of hypodiploidy and near tetraploidy/tetraploidy is comparable to that seen in children with ALL. Hypodiploidy and high hyperdiploidy were not prognostic factors for outcome in this group of patients. Given the low prevalence of these abnormalities, it is possible that larger numbers of pts may be needed to detect such a difference. The poor outcomes of pts with low hypodiploidy are consistent with findings by Moorman et al. (Blood 2006; 109: 3189). However, in contrast to Moorman's results, there was no evidence of an association of hyperdiploidy with age/WBC, and there was a trend towards a worse prognosis in this subset of patients. This suggests that the biology and prognosis of high hyperdiploidy may be affected more by WBC and age in the adult population. Disclosures: No relevant conflicts of interest to declare.

Abstract Backgrounds and Aims The classic hallmarks of Upshaw Schulman syndrome (USS) are severe newborn jaundice with a negative Coombs test that requires an exchange transfusion and repeated childhood episodes of thrombocytopenia and microangiopathic hemolytic anemia that are reversed by infusions of fresh frozen plasma. But now, it is well established that USS is a hereditary deficiency in the activity of von Willebrand factor (VWF)-cleaving protease, termed ADAMTS13. The inheritance mode is autosomal recessive, and their parents are usually asymptomatic carriers having one disease-causing mutation (DCM) of the gene. In the absence of ADAMTS13, unusually large VWF multimers (UL-VWFMs) released from vascular endothelial cells are inappropriately cleaved, leading to platelet hyperagglutination under high shear stress. Thus, USS is alternatively called congenital thrombotic thrombocytopenic purpura (TTP). But, unlike acquired TTP, clinical signs of USS patients are usually mild during childhood and often an isolated thrombocytopenia is found. Further, now it is known that TTP-bouts are aggravated or initiated by the following factors: 1) severe infections such as influenza, 2) pregnancy, 3) 1-deamino-8-D-arginine vasopressin (DDAVP) administration, 4) interferon therapy, 5) heavily drinking alcohol, and 6) aging. So far, in worldwide approximately 150 patients with USS have been found, of which we identified 51 patients in Japan. Among them, 48 patients were received ADAMTS13 gene analysis, and a pair of DCMs, either homozygotes or compound heterozygotes, was identified in all patients except for one. Interestingly, these DCMs are quite different from those found in patients of Western countries and United States, but several DCMs in Japanese patients are also found in Korean and Chinese patients. Thus, it appears that Caucasians and Asians have two different DCM routs for ADAMTS13. Further, since USS is an extremely rare disease, no one can predict the life-long clinical outcome in these patients. Thus, in this study using our cohort of 51 Japanese USS patients, we have extensively analyzed a long-term phenotype, with special references to pregnancy and renal failure that requires hemodialysis. Methods and Patients ADAMTS13 activity and its neutralizing antibodies (inhibitors) were determined by chromogenic ADAMTS13-act-ELISA [Kato et al. Transfusion, 2006], and the IgG type binding antibodies were assayed as described [Ferrari et al, JTH 2009]. Fifty-one patients with USS (19 males and 32 females, born in 1931-2013) were enrolled in this study. None of the patients had the neutralizing antibodies, but 6 patients (6/51, 12%) developed the IgG type non-neutralizing antibodies. Results and Discussion Pregnancy: We identified 26 episodes of pregnancy in 15 patients with USS (Table 1). Briefly, 22 pregnancies were identified before a diagnosis of USS, and as consequence 3 episodes are related to abortion, 10 episodes to stillbirth, and 9 episodes to live birth, in which 6 babies were premature. In contrast, 4 pregnancies were after a diagnosis of USS, and they all had the planned FFP infusions from the early phase of pregnancy, resulting in all successful deliveries, but with 2 premature babies. Renal failure: We identified that 6 male patients finally fell into the end-stage severe renal diseases that required hemodialysis, of which 4 patients were deceased (Table 2). Median time from a diagnosis of USS to dialysis initiation was 15 years (range 1-25). Curiously, all these patients except for one had received FFP infusions biweekly after a diagnosis of USS. Causes of death in these 4 patients were the followings: heart failure (n=1), renal failure (n=1), and sudden death (n=2). The reason why all the patients, who fell into severe renal dysfunction, are male left unaddressed. Disclosures: Fujimura: Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees. Matsumoto:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees.

<p><strong>Guest editors: Joanne Lehrer (Université du Québec en Outaouais), Christine Massing (University of Regina), Scott Hughes (Mount Royal University), and Alaina Roach O’Keefe (University of Prince Edward Island)</strong></p><p>Not only is professional learning conceptualised as critical for increasing educational quality and enhancing children’s learning and developmental outcomes (e.g. Lazarri et al., 2013; Munton et al., 2002; Penn, 2009; Vandenbroeck et al., 2016), but specific elements of professional learning (in both initial and continuing education, or preservice and in-service learning) have been identified as essential to transforming early childhood educators’ and preschool teachers’ professional identities and practice. For example, critical and supported reflection (Thomas &amp; Packer, 2013), learning experiences that target entire teams (Vangrieken, Dochy, &amp; Raes, 2016), collaborative and empowering practice (Helterbran &amp; Fennimore, 2004), and competent leadership (Colmer et al., 2008) have all been found to be effective means of supporting professional learning.</p><p>While there appears to be consensus in the literature around <em>what</em> needs to be done, and even around <em>how</em> it should be done, numerous constraints prevent the implementation and maintenance of sustainable and transformational professional learning in ECEC. Vandenbroeck and colleagues (2016) go beyond the focus on individuals and childcare teams, identifying two further levels necessary for competent systems of professional learning: partnerships between local early childhood programs and social, cultural, and educational institutions (such as colleges and universities); and governance regarding vision, finance, and monitoring. In the Canadian context, the Canadian Child Care Federation has also stressed the importance of a system-wide strategy to strengthen the child care workforce (CCCF, 2016). However, early childhood services in Canada are under the purview of the provincial and territorial governments and, therefore, the conditions, regulations, certification requirements, curriculum documents, and educational systems vary widely from jurisdiction to jurisdiction. The educational requirements for certification, for example, may include no formal training (in NWT and Nunavut), one entry-level short course, one-year certificates, or two-year diplomas. This complicates efforts to define who the early childhood professional is and what opportunities are constitutive of professional learning (Prochner, Cleghorn, Kirova, &amp; Massing, 2016). While these disparities within the field may impede the development of a cohesive strategy, Campbell et al. (2016) recently asserted that much can be learned from sharing and appreciating the rich diversity of approaches to professional learning both within and across provinces and territories. In addition, examples from other countries serve to broaden the discussion and expand our understanding of what is possible (Vandenboreock et al., 2016).</p><p>This special issue, then, is dedicated to sharing stories of hope and coordinated action, linking theory with practice. We seek Canadian and international submissions related to professional learning practices that extend beyond individual programs, showcasing partnerships and community mobilization efforts within and across various settings for young children (child care, Kindergarten, drop-in centres, etc.) in relation to philosophical, practical, critical, transformative, personal, and/or hopeful themes. Each submission will respond to one or more of the key questions, including, but not limited to:</p><ul><li>How can professional learning be conceptualised?</li><li>How do we build and maintain effective partnerships to foster professional learning?</li><li>What strategies for transformative community mobilization might be shared?</li><li>How can innovative strategies be applied on a wider scale?</li><li>How might taken-for-granted professional learning and evaluation practice be disrupted?</li><li>What story about professional learning do you need (or want) to tell?</li><li>How has your community been transformed through a particular activity, event, or practice?</li><li>How might the lives and futures of children be positively shaped by engagement in partnerships and mobilization?</li><li>Where might we be in 5, 10, or 15 years through such endeavours?</li></ul><p>We welcome submissions in multiple formats, including research articles, theoretical papers, multimedia pieces, art work, book reviews, and so forth. These may be submitted in English, French, or in any Canadian Indigenous language. </p><p>Submissions are due August 1, 2017 and should be submitted as per <a href="http://journals.uvic.ca/index.php/jcs/about/submissions#onlineSubmissions">Journal of Childhood Studies submission guidelines. </a></p><p><strong><br /></strong></p><p> </p><p>References</p><p>Campbell, C., Osmond-Johnson, P., Faubert, B., Zeichner, K., Hobbs-Johnson, A. with S. Brown, P. DaCosta, A. Hales, L. Kuehn, J. Sohn, &amp; K. Steffensen (2016). <em>The state of educators’ professional learning in Canada</em>. Oxford, OH: Learning Forward.</p><p>Canadian Child Care Foundation [CCCF], (2016). <em>An Early Learning and Child Care Framework for Canada’s Children</em>. Retrieved from: http://www.cccf-fcsge.ca/wp-content/uploads/CCCF_Framework-ENG.pdf</p><p>Colmer, K., Waniganayake, M. &amp; Field, L. (2014). Leading professional learning in early childhood centres: who are the educational leaders<em>?, Australasian Journal of Early Childhood</em>, 39(4), 103-113.</p><p>Helterbran, V.R. &amp; Fennimore, B.S. (2004). Early childhood professional development: Building from a base of teacher investigation. <em>Early Childhood Education Journal, 31</em>(4), 267-271.</p><p>Lazarri, A., Picchio, M., &amp; Musatti, T. (2013). Sustaining ECEC quality through continuing professional development: systemic approaches to practitioners’ professionalization in the Italian context. <em>Early Years: An International Research Journal, 33</em>(2), 133-145.</p><p>Munton, T., Mooney, A., Moss, P., Petrie, P., Calrk, A., Woolner, J. et al., (2002). <em>Research on ratios, group size, and staff qualifications and training in early years and childcare settings</em>. London: University of London.</p><p>Penn, H. (2009). <em>Early childhood education and care: Key lessons from research for policy makers</em>. Brussels: Nesse.</p><p>Prochner, L., Cleghorn, A., Kirova, A., &amp; Massing, C. (2016). <em>Teacher education in diverse settings: Making space for intersecting worldviews</em>. Rotterdam, The Netherlands: Sense Publishers.</p><p>Thomas, S., &amp; Packer, D. S. (2013). A Reflective Teaching Road Map for Pre-service and Novice Early Childhood Educators. <em>International Journal of Early Childhood Special Education</em>, <em>5</em>(1), 1-14.</p><p>Vandenbroeck, M., Peeters, J., Urban, M. &amp; Lazzari, A. (2016). Introduction. In M. Vandenbroeck, M. Urban &amp; J. Peeters (Eds.) <em>Pathways to Professionalism in Early Childhood Education and Care</em>, (pp. 1-14). London: Routledge.</p><p>Vangrieken, K., Dochy, F., &amp; Raes, E. (2016). Team learning in teacher teams: team entitativity as a bridge between teams-in-theory and teams-in-practice. <em>European Journal Of Psychology Of Education - EJPE (Springer Science &amp; Business Media B.V.)</em>, <em>31</em>(3), 275-298. doi:10.1007/s10212-015-0279-0</p>

<table id="announcementDescription" width="100%"><tbody><tr><td><p><strong>Guest editors: Joanne Lehrer (Université du Québec en Outaouais), Christine Massing (University of Regina), Scott Hughes (Mount Royal University), and Alaina Roach O’Keefe (University of Prince Edward Island)</strong></p><p>Not only is professional learning conceptualised as critical for increasing educational quality and enhancing children’s learning and developmental outcomes (e.g. Lazarri et al., 2013; Munton et al., 2002; Penn, 2009; Vandenbroeck et al., 2016), but specific elements of professional learning (in both initial and continuing education, or preservice and in-service learning) have been identified as essential to transforming early childhood educators’ and preschool teachers’ professional identities and practice. For example, critical and supported reflection (Thomas &amp; Packer, 2013), learning experiences that target entire teams (Vangrieken, Dochy, &amp; Raes, 2016), collaborative and empowering practice (Helterbran &amp; Fennimore, 2004), and competent leadership (Colmer et al., 2008) have all been found to be effective means of supporting professional learning.</p><p>While there appears to be consensus in the literature around <em>what</em> needs to be done, and even around <em>how</em> it should be done, numerous constraints prevent the implementation and maintenance of sustainable and transformational professional learning in ECEC. Vandenbroeck and colleagues (2016) go beyond the focus on individuals and childcare teams, identifying two further levels necessary for competent systems of professional learning: partnerships between local early childhood programs and social, cultural, and educational institutions (such as colleges and universities); and governance regarding vision, finance, and monitoring. In the Canadian context, the Canadian Child Care Federation has also stressed the importance of a system-wide strategy to strengthen the child care workforce (CCCF, 2016). However, early childhood services in Canada are under the purview of the provincial and territorial governments and, therefore, the conditions, regulations, certification requirements, curriculum documents, and educational systems vary widely from jurisdiction to jurisdiction. The educational requirements for certification, for example, may include no formal training (in NWT and Nunavut), one entry-level short course, one-year certificates, or two-year diplomas. This complicates efforts to define who the early childhood professional is and what opportunities are constitutive of professional learning (Prochner, Cleghorn, Kirova, &amp; Massing, 2016). While these disparities within the field may impede the development of a cohesive strategy, Campbell et al. (2016) recently asserted that much can be learned from sharing and appreciating the rich diversity of approaches to professional learning both within and across provinces and territories. In addition, examples from other countries serve to broaden the discussion and expand our understanding of what is possible (Vandenboreock et al., 2016).</p><p>This special issue, then, is dedicated to sharing stories of hope and coordinated action, linking theory with practice. We seek Canadian and international submissions related to professional learning practices that extend beyond individual programs, showcasing partnerships and community mobilization efforts within and across various settings for young children (child care, Kindergarten, drop-in centres, etc.) in relation to philosophical, practical, critical, transformative, personal, and/or hopeful themes. Each submission will respond to one or more of the key questions, including, but not limited to:</p><ul><li>How can professional learning be conceptualised?</li><li>How do we build and maintain effective partnerships to foster professional learning?</li><li>What strategies for transformative community mobilization might be shared?</li><li>How can innovative strategies be applied on a wider scale?</li><li>How might taken-for-granted professional learning and evaluation practice be disrupted?</li><li>What story about professional learning do you need (or want) to tell?</li><li>How has your community been transformed through a particular activity, event, or practice?</li><li>How might the lives and futures of children be positively shaped by engagement in partnerships and mobilization?</li><li>Where might we be in 5, 10, or 15 years through such endeavours?</li></ul><p>We welcome submissions in multiple formats, including research articles, theoretical papers, multimedia pieces, art work, book reviews, and so forth. These may be submitted in English, French, or in any Canadian Indigenous language. </p><p><span>Submissions are due August 1, 2017</span> and should be submitted as per <a href="http://journals.uvic.ca/index.php/jcs/about/submissions#onlineSubmissions">Journal of Childhood Studies submission guidelines. </a></p><p><strong><br /></strong></p><p> </p><p>References</p><p>Campbell, C., Osmond-Johnson, P., Faubert, B., Zeichner, K., Hobbs-Johnson, A. with S. Brown, P. DaCosta, A. Hales, L. Kuehn, J. Sohn, &amp; K. Steffensen (2016). <em>The state of educators’ professional learning in Canada</em>. Oxford, OH: Learning Forward.</p><p>Canadian Child Care Foundation [CCCF], (2016). <em>An Early Learning and Child Care Framework for Canada’s Children</em>. Retrieved from: http://www.cccf-fcsge.ca/wp-content/uploads/CCCF_Framework-ENG.pdf</p><p>Colmer, K., Waniganayake, M. &amp; Field, L. (2014). Leading professional learning in early childhood centres: who are the educational leaders<em>?, Australasian Journal of Early Childhood</em>, 39(4), 103-113.</p><p>Helterbran, V.R. &amp; Fennimore, B.S. (2004). Early childhood professional development: Building from a base of teacher investigation. <em>Early Childhood Education Journal, 31</em>(4), 267-271.</p><p>Lazarri, A., Picchio, M., &amp; Musatti, T. (2013). Sustaining ECEC quality through continuing professional development: systemic approaches to practitioners’ professionalization in the Italian context. <em>Early Years: An International Research Journal, 33</em>(2), 133-145.</p><p>Munton, T., Mooney, A., Moss, P., Petrie, P., Calrk, A., Woolner, J. et al., (2002). <em>Research on ratios, group size, and staff qualifications and training in early years and childcare settings</em>. London: University of London.</p><p>Penn, H. (2009). <em>Early childhood education and care: Key lessons from research for policy makers</em>. Brussels: Nesse.</p><p>Prochner, L., Cleghorn, A., Kirova, A., &amp; Massing, C. (2016). <em>Teacher education in diverse settings: Making space for intersecting worldviews</em>. Rotterdam, The Netherlands: Sense Publishers.</p><p>Thomas, S., &amp; Packer, D. S. (2013). A Reflective Teaching Road Map for Pre-service and Novice Early Childhood Educators. <em>International Journal of Early Childhood Special Education</em>, <em>5</em>(1), 1-14.</p><p>Vandenbroeck, M., Peeters, J., Urban, M. &amp; Lazzari, A. (2016). Introduction. In M. Vandenbroeck, M. Urban &amp; J. Peeters (Eds.) <em>Pathways to Professionalism in Early Childhood Education and Care</em>, (pp. 1-14). London: Routledge.</p><p>Vangrieken, K., Dochy, F., &amp; Raes, E. (2016). Team learning in teacher teams: team entitativity as a bridge between teams-in-theory and teams-in-practice. <em>European Journal Of Psychology Of Education - EJPE (Springer Science &amp; Business Media B.V.)</em>, <em>31</em>(3), 275-298. doi:10.1007/s10212-015-0279-0</p></td></tr></tbody></table>