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1
Belisario, A., M. Maccaroni, A. Coramusi, L. Corazza, B. M. Pryor, and P. Figuli. "First Report of Alternaria Species Groups Involved in Disease Complexes of Hazelnut and Walnut Fruit." Plant Disease 88, no. 4 (2004): 426. http://dx.doi.org/10.1094/pdis.2004.88.4.426a.
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During the last 5 years, two new diseases, brown apical necrosis (BAN) and gray necrosis (GN), were observed on English walnut (Juglans regia) and hazelnut (Corylus avellana), respectively (2,3). Both diseases caused severe fruit drop resulting in yield loss often exceeding 30%. Previous work demonstrated that BAN and GN are disease complexes caused by several fungi (Alternaria spp., Fusarium spp., and a Phomopsis sp.) (2,3). In both diseases, preliminary identification of Alternaria spp. revealed they were a complex of small-spored catenulate taxa related to A. alternata. To further characterize these taxa, additional pathogenicity tests and morphological examinations were conducted with isolates obtained from each host. Single-spored isolates were prescreened for pathogenicity by inoculating detached, surface-disinfested hazelnut leaves or walnut leaflets (1). Only isolates that produced foliar lesions after 5 days were used in subsequent fruit inoculations. From this screening, 35 isolates were selected (19 from walnut and 16 from hazelnut). For each isolate, attached fruit of respective hosts were inoculated at bloom by placing 10 μl of a conidial suspension (1 × 106 conidia per ml of H2O + 0.26% agar) onto the stigmas (150 fruit per isolate). Controls (150 fruit) were treated with agar solution only. After 15 days, fruit were examined for development of disease symptoms, and examination continued until fruit maturation (late July). Approximately 20 to 50% of the inoculated fruit displayed discoloration or necrosis of internal tissue, particularly the pericarp and the embryo, although symptoms were more limited than those typically seen in fully expressed BAN and GN. No differences in symptoms were evident among the isolates tested. The controls showed no symptom development initially, although 5% began to develop discoloration at fruit maturity. Fungal isolates used as inoculum were reisolated from all symptomatic fruit by surface disinfesting tissue from the margins of necrotic lesions. For each isolate, the conidial characteristics were described from cultures grown under defined conditions (4). Three distinct groups of isolates were identified. Alternata sp. group isolates produced conidial chains (8 to 20 spores) with numerous secondary and occasionally tertiary chains branching from apical and median cells. Conidia were typically ovate and often possessed a one-celled apical extension. Tenuissima sp. group isolates developed conidial chains (10 to 22 spores) with occasional branching forming secondary chains from apical and median cells. Conidia were ovate to obclavate, often with long apical extensions (10 to 35 μm). Arborescens sp. group isolates developed conidial chains (5 to 12 spores) with numerous secondary, tertiary, and quaternary short chains branching from apical cells. Conidia were typically ovate with minimal apical extensions. Of the walnut isolates, 12, 4, and 3 were from the arborescens, alternata, and tenuissima sp. groups, respectively. Of the hazelnut isolates, 7, 6, and 3 were from the arborescens, alternata, and tenuissima sp. groups, respectively. The finding that Alternaria from several distinct sp. groups can cause similar disease on a single host is consistent with previous work on pistachio, almond, and pear (4). References: (1) A. Belisario et al. Plant Dis. 83:696, 1999. (2) A. Belisario et al. Plant Dis. 86:599, 2002. (3) A. Belisario et al. Inf. Agrario 59:71, 2003. (4) B. M. Pryor et al. Phytopathology 92:406, 2002.
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Gazitt, Yair, Cesar O. Freytes, Cagla Akay, William Bensinger, Karin Badel, and Gary Calandra. "Improved Mobilization of CD34+ Peripheral Blood Stem Cells (PBSC) and Dendritic Cells (DCs) by AMD-3100 (AMD) in Hard to Mobilize Non-Hodgkin’s Lymphoma (NHL) Patients (pts) Mobilized with Standard Dose of G-CSF." Blood 104, no. 11 (2004): 2856. http://dx.doi.org/10.1182/blood.v104.11.2856.2856.
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Abstract PBSC mobilization for auto transplantation of NHL pts with multiple regimens of prior chemotherapy is hard to achieve and 25%–30% of patients experience mobilization failure. AMD is a small bicyclam compound which specifically binds to CXCR4 receptor and blocks signaling through SDF-1. Previous studies in normal donors suggested clear dose dependent CD34+ cell mobilization as a single agent as well as additively with G-CSF with little toxicity (ASH meeting, 2002; 2003). Similarly, previous studies with NHL and Myeloma patients resulted with a dose-dependent augmentation of CD34+ cell mobilization in pts receiving G-CSF with little toxicity. The exact mechanism of AMD-induced mobilization of CD34+ cells was not studied in patients and AMD was not used before for PBSC mobilization in hard to mobilize NHL patients. Furthermore, its effect on mobilization of DCs and lymphoma cells was not studied before. On November 2003, we initiated a phase II study of 10, hard to mobilize NHL patients, receiving 16ug/kg of G-CSF for 4 days and G-CSF followed by 240ug/kg of AMD on day 5, 9 hours before apheresis collection. G-CSF and AMD were continued for additional day or 2, as needed, in order to collect the target dose of ≥ 2x106 PBSC/kg. Ten liters of blood were exchanged in ~4hours of apheresis. Median age was 54 years (44 to 63 years). Of the 10 patients enrolled, 6 pts had diffuse large cell lymphoma and 3 had follicular histology with 8/10 received 2 regimens of chemotherapy, 2 of which received also radiation prior to mobilization. At mobilization, 5/9 pts were primary refractory, 3 pts were in 1st relapse, 1 pt in 2nd relapse and 1 pt in 2nd CR. We determined percent CD34+ cells and percent DC1 and DC2 cells as well as percent lymphoma cell mobilization (by Real time DNA-PCR) at baseline (before administration of G-CSF) and before and after AMD, in the blood and in the apheresis product. To date 7 pts were transplanted. Five pts collected in 1 day and 5 pts collected in 2 days. No adverse events were observed during mobilization. All patients collected ≥ 2x106 PBSC/kg and 7 pts have been transplanted with a dose of 2-7x106 PBSC/kg. All transplanted pts engrafted with a mean of 10 days (9 to 12 days) for ≥ 500ANC and with a mean of 13 days (12–14 days for 6/7 pts) to reach 20K of plts. One pt had a delayed plt engraftment and was engrafted on day 27. Addition of AMD to G-CSF, prior to the first or 2nd PBSC collection resulted in a mean increase of percent CD34+ cells from 0.11% to 0.17% ( p=0.017), with a similar mean increase in CD34+ cells/ul (35/ul to 81/ul; p=0.0001) followed by normalization of CD34+ cells/ul within 24 hours. Similarly, addition of AMD to G-CSF resulted in an increase in the mean of DC1 cells from 79/ul to 156/ul (p=0.009) and from a mean of 62/ul to164/ul (p=0.006) for DC2 cells. One pt had 0.08% lymphoma cells at baseline by DNA-PCR for the major breakage point of the Bcl-2 translocation sequence, with no detectable lymphoma cells in the blood or apheresis collection post AMD. All other pts were negative for lymphoma pre and post AMD by this test. Adverse events and sever adverse events related to study were minimal. We conclude that AMD is a safe drug with clinical benefit in increasing PBSC and DC mobilization with no detectable mobilization of lymphoma cells.
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Cai, Yuli, Chao Liu, Ye Guo, et al. "Analysis of 48 Cases Pediatric Chronic Myeloid Leukemia from China: Results from a Single Institute in China." Blood 134, Supplement_1 (2019): 5911. http://dx.doi.org/10.1182/blood-2019-125565.
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Objective: Chronic myeloid leukemia (CML) is a rare disease among children. It comprises 3% of childhood leukemias. CML in children is different from CML in adult. Here we analyzed the clinical features and prognosis of pediatric CML in a single institute from China. Methods: A retrospective study was performed by reviewing clinical records of pediatric CML from 2002 to 2019. Results: A total of 48 pediatric CML cases were included in the study, with 35 males and 13 females (M: F=2.7:1). Four cases were diagnosed during 2002~2007, 12 cases during 2008~2013 and 32 cases during 2014~2019. Two (4.2%) patients were in accelerate phase (AP) and other 46 patients were in chronic phase (CP) at diagnosis. Median age of onset was 9y (range 1~17y). The most common symptoms were fever (21.6%), fatigue (14.9%) and cough (10.8%). Median size of spleen under left costal margin was 5cm (range 0~21cm). Median WBC count was 15.7/ul, hemoglobin 9.5g/dL, platelet count 58/ul, neutrophils percentage 56% (range 21~74%), basophils percentage 3% (range 1~16%) and median eosinophil percentage was 2% (range 0~19%). Thirty-five patients had done karyotype examination, and 28 cases (80%) with classical Philadelphia chromosome (Ph+). Other 13 patients without Ph chromosome but with BCR/ABL1 fusion gene. In our study, there were 4 patients treated by hydroxyurea and α-interferon, other 44 patients have been used imatinib (IM) 240-340mg/m2 per day. Median time from onset to diagnosis was 0.7 months (range 1 day~12 months). Median follow-up time was 52 months (range 1~200 months), while the 5-year overall survival (OS) and event-free survival (EFS) are 100% and 89.1%, respectively. Different gender, age at diagnosis, WBC count, platelet count, karyotype show no difference in OS and EFS. Four patients suffered from blast crisis (BC) (2 patients progressed after using hydroxyurea for 1 and 33 months, 2 patients progressed after using IM for 36 and 6 months, respectively). One patient's BCR/ABL1 transcript level was increased in 36 months after first administration of IM and recovered at 48 months by adding IM dosage from 200mg to 300mg per day. According to the European LeukemiaNet (ELN) criteria, 95.5% patients achieved complete hematologic response (CHR), 90.5% patients achieved complete cytogenetic response (CCyR) and 66.7% patients achieved major molecular response (MMR) at 3, 12, 18 months after IM administration, respectively. There was obvious correlation between WBC count at diagnosis and early molecular response (EMR). Median WBC count was 4.8/ul in patients with EMR and 38.1/ul in patients without EMR. Other clinical features, such as gender, age at diagnosis, hemoglobin count, platelet count and size of spleen, make no difference in EMR. Conclusion: This is a retrospective study on pediatric CML. The median age at diagnosis is 9 years old. Most of all patients are CML-CP. 5y OS and EFS are 100% and 89.1%. The CHR, CCyR, MMR at 3,12,18 months after IM therapy are 95.5%, 90.5% and 66.7% separately. Until now there is no sufficient data on efficiency and safety specific to pediatric CML patients. Further clinical investigations through international collaboration are need to help more and more patients to achieve treatment-free remission. Disclosures No relevant conflicts of interest to declare.
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Curtis, Susanna A., Neeraja Danda, Zipora Etzion, Hillel W. Cohen, and Henny H. Billett. "Steady State Predictors of Mortality in Adults with Sickle Cell Disease." Blood 124, no. 21 (2014): 1388. http://dx.doi.org/10.1182/blood.v124.21.1388.1388.
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Abstract Background: With improved treatment modalities, longevity for sickle cell disease (SCD) is increasing. Yet there is still a subgroup of adult patients whose survival rate has not improved. These patients, if well defined by evidence based decisions, might be those for whom more aggressive disease modifying therapy would be appropriate. Methods: We identified all patients with SS/Sβ0 seen at our medical center in 2002 whom we were still following in 2012 as well as those who had died between 2002 and 2012. Patients with SC and Sβ+ thalassemia were excluded. ED, clinic, and inpatient admissions over the entire years 2002 and 2012 were obtained. All 2002 and 2012 steady state parameters for a given laboratory test for a given patient were averaged. “Steady State” was defined as those values not within one day of an ED visit or within one week of a hospital admission. Data were assessed for normality; parametric and non-parametric bivariate tests were performed as appropriate. Data from 2002 and 2012 was compared with paired-T tests. Mortality data were analyzed using Kaplan-Meier curves and Cox proportional hazard models. Results: We identified 289 SS/Sβ0 patients in 2012 (ages 18-87, 54% female) who had been present in our system in 2002 (survival cohort). We also identified 70 patients present in 2002 (ages 19-88 at death, 47% female) who had died between 2002 and 2012, inclusive (mortality cohort). Average age at death was 42.1±14.0 years, median survival was 58.3 years (95% CI: 54.5 – 63.0). Survivors had, in 2002, higher HbF, Hb, higher MCHC, lower white blood cell (WBC) counts and creatinine (Cr) levels, and fewer admissions than those who did not survive past 2012 (Table 1). Absolute Reticulocyte count (Retic), MCV, LDH, liver function tests, ED and clinic use were not significantly different between survivor and mortality groups. Cox proportional hazards model showed increased hazard ratios with lower HbF, higher WBC, Cr and increased admissions. When the survivors from 2002 were compared to themselves in 2012, they were shown to decrease HbF, Hb, MCHC, WBC, alkphos, and total bilirubin over time and to increase admissions, ED visits, Retic, MCV, Cr, and weight. Clinic visits, direct bilirubin and LDH were not significantly different. Conclusions: As therapeutic alternatives increase, it may be important to tailor therapy, and the need for better prognostic markers becomes ever more important. We observed here that several known mortality predictors evolve over time. As the “survivor” population ages, they may begin to resemble those with a poorer prognosis with decreased Hb and HbF levels but increased admissions and ED visits. However in our sample, WBC, a recognized factor in mortality and morbidity, decreased further over time in those who survived. Similarly, absolute reticulocyte count increased further over time in the survivors, suggesting an ability of the marrow to respond to the increased anemia. Further studies should be done to distinguish which biomarkers, at what level and in what age groups, are truly predictive of severity in sickle cell disease. Abstract 1388. Table 1: Comparison of 2002 SCD cohort who survived until 2012 with those who did not (left panel) and of a subset of this survivor population with themselves in 2012 2002 All Patient Data Matched Data 2002&2012 Survivor 2002 Mortality 2002 Cox Hazard Survivor 2002 Survivor 2012 N 289 70 359 134 134 Hb (g/dL) 8.5±1.4 7.8±1.4* .82(.65-1.02) 1g/dL 8.4±1.4 8.1±1.5* MCHC (g/dL) 35.2±1.2 34.5±1.8* .85(.69-1.04)1g/dL 35.1±1.2 34.2±1.3# Retic (x10^9/L) 181.3(131.9/237.8) 183.4(128.5/218.2) 1.00(1.00-1.01) 1k/uL 185.9(144.0/236.8) 247.4(168.1/341.2)# WBC (x10^9/L) 11.6±3.6 12.4±4.5 1.11(1.02-1.21)* 1 k/Ul 11.6±3.5 10.8±4.1* Cr (mg/dL) 0.5(0.6/0.7) 0.8(0.6/1.5)# 1.25(1.00-1.55)* 1mg/dL 0.6(0.5/0.7) 0.7(0.6/0.9)# Alb (g/dL) 4.3±.3 4.1±.4# .72(.33-1.57) 1g/dL 4.3±.3 4.2±.5 AlkPhos (U/L) 103.0(86.8/159.8) 121.0(99.6/166.8) 1.3(.91-1.99) 100 U/KL 111.0(86.8/165.0) 91.3(70.0/125.1)# Weight (KG) 58.3±21.3 64.1±15.7* 1.00(.98-1.02) 1 KG 58.4±21.1 66.0±13.9# HbF (%) 15.7(8.4/20.1) 5.5(1.9/12.4)# .94(.90-.98)# 1% 15.9(7.4/20.5) 6.4(4.1/11.8)# ED (per year) 2.6±3.9 1.9±3.3 .96(.88-1.04) 1/year 2.6±3.9 5.2±10.7# Clinic (per year) 6.8±8.3 8.3±11.5 1.01(.99-1.04) 1/year 6.8±8.3 7.3±10.5 Admits (per year) 0.3±0.8 2±2.5# 1.28(1.18-1.38)# 1/year 0.3±0.8 2.1±3.2# *=p<.05, #=p<.01 Disclosures No relevant conflicts of interest to declare.
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Beach, Douglas F., Barry Barnoski, Vimal Patel, Roland Schwarting, Roger Strair, and Neil A. Lachant. "On Being Duped: Duplication of Chromosome 1 [Dup(1)(q21q32)] as the Sole Cytogenetic Abnormality In a Patient Previously Treated for AML." Blood 116, no. 21 (2010): 4863. http://dx.doi.org/10.1182/blood.v116.21.4863.4863.
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Abstract Abstract 4863 Introduction: Cytogenetic studies are an important prognostic tool in the management of hematologic malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While a nonrandom structural gain of 1q may be seen in MDS and AML, it is most commonly due to an unbalanced translocation usually in association with other chromosomal abnormalities. Duplication of the long arm of chromosome 1 [dup(1)(q21q32)] as the sole abnormality in nonlymphoid hematologic malignancies has only rarely been reported. As a result, very little is known about the clinical significance of this chromosomal abnormality. However, it has been suggested that this single aberration is predictive of an increased risk of clonal evolution and poor overall prognosis. Case Presentation: A then 55 year old male presented in June, 2002 with a CBC showing: WBC 36,300/ul (74% blasts with Auer rods), Hgb 7.0 gm/dl, MCV 98fl, platelets 61,000/ul. Bone marrow biopsy was 90% cellular with sheets of blasts. The blasts were positive for CD34, CD117, HLA-DR, CD13, MPO, CD56, and Tdt. A diagnosis of AML M2 was made. Cytogenetics showed 45,X,-Y, t(8;21)(q22;q22). He underwent successful standard induction with “7+3” followed by consolidation with “5+2” and 4 cycles of high dose cytarabine. Subsequent bone marrows after induction and during consolidation showed no evidence of AML. The karyotype was 46,XY with no evidence of t(8;21) by FISH. He has had complete recovery of his blood counts, except for intermittent neutropenia. In May, 2004, G-banding of his bone marrow revealed the presence of a dup(1)(q21q32) as an isolated cytogenetic aberration for the first time. This finding was again seen on follow up studies in 2006, 2007, and 2009. His most recent evaluation in May 2010 showed WBC 5,500/ul (neutrophils 2,200/ul), Hgb 14.0 gm/dl, MCV 92fl, platelets 299,000/ul. Bone marrow biopsy was 40% cellular with trilineage hematopoiesis. The aspirate showed erythroid hyperplasia with megaloblastoid features. No dysplastic RBC or ring sideroblasts were seen. Cytogenetics showed 46,XY,dup(1)(q21q32)[15]/46,XY[5]. FISH for AML1/ETO t(8;21) and for abnormalities of chromosomes 5, 7, 8, and 20 were negative. Discussion: Dup(1q) has been reported as an isolated cytogenetic abnormality in a variety of MDS subtypes. It may be either a primary or secondary chromosomal aberration. It has been suggested that isolated dup(1q) in MDS is a harbinger of disease progression. Recent reports of MDS with either inverted dup(1)(q32 q21) or dup(1)(q21q32) of both chromosome 1 homologs showed no disease progression but had very short follow-up. Conclusion: To our knowledge, this case is the first report of an acquired duplication dup(1)(q21q32) as the sole abnormality in a patient previously treated for AML. This duplication developed approximately 2 years after induction and consolidation chemotherapy. The involved clone is not the original leukemic clone since there is no evidence for t(8;21) or -Y. Six years later, there has been no evidence of progression to MDS or sAML. It is not known why our patient has shown such long survivorship after discovery of dup(1)(q21q32), nor is it known if this chromosomal finding is a treatment related phenomenon. This case suggests that dup(1q) may not be exclusively associated with a poor prognosis. FISH analysis with a 1q21 probe is planned to confirm our G-banding observation. Disclosures: Lachant: sanofi-aventis: Speakers Bureau; glaxosmithkline: Speakers Bureau.
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Hayakawa, Masaki, Masanori Matsumoto, Yumi Yoshii, Hideo Yagi, Hiroshi Kimura, and Yoshihiro Fujimura. "HSCT-Associated Hepatic VOD Is Initiated With Preceding Appearance Of Unusually Large Von Willebrand Factor Multimers In Patient Plasmas." Blood 122, no. 21 (2013): 3625. http://dx.doi.org/10.1182/blood.v122.21.3625.3625.
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Abstract Backgrounds and Aims Hepatic veno-occlusive disease (VOD) associated with hematopoietic stem cell transplantation (HSCT) is characterized by a clinical triad of jaundice (total bilirubin, >2 mg/mL), hepatomegaly with right upper quadrant pain, and ascites and/or unexplained body weight gain (>5% of baseline) within 30 days after operation. Although the pathogenesis of hepatic VOD has not been fully elucidated, the common pathological features are thrombi formed in hepatic central vein. We previously reported that a significant decrease of plasma ADAMTS13 activity was noted in patients undergoing HSCT, who subsequently developed VOD (Park et al, BMT 2002). Then, we showed that plasma antigen levels of von Willebrand factor (VWF) has been kept higher in HSCT-patients with VOD than in those without, and in fact prophylactic infusions of fresh frozen plasma (FFP) with a dose of 10 ml/kg body weight 3 times per week were effective to reduce the frequency of VOD occurrence in high risk patients (Matsumoto et al, BMT 2007). However, more recent studies by ours indicate that FFP infusion alone is not enough to totally eliminate the occurrence (unpublished). Recently, it has been shown that the treatment with recombinant soluble thrombomodulin (rTM) is sometimes highly efficient to reverse VOD progression. But its pharmacokinetics and regimen for the treatment has not been established. As a first step to elucidate a possible combination regimen of FFP and rTM to VOD patients, here we have analyzed the transitional changes of unusually large VWF multimers (UL-VWFMs). The UL-VWFMs are released from damaged endothelial cells and induce platelet hyperagglutination under high shear stress generated in microvasculatures, and are often observed in patient plasmas undergoing HSCT. Patients and Methods During 2011-2012, 45 patients were received allogenic HSCT in the second internal medicine department of our university hospital. None of these patients ,however, were received planned prophylactic FFP infusions, and as a result six patients undergoing allogenic cord blood transplantation (CBT) developed VOD. Clinical features of these 6 patients are shown in Table 1. Under approval of Ethics Committee of Nara Medical University, we consecutively collected patient's citrated plasmas (ca 2.5 ml) and stored at -80°C until use. Using these deep-frozen plasma samples, we here extensively analyzed plasma levels of ADAMTS13 activity (ADAMTS13:AC), VWF antigen (VWF:Ag), and VWF collagen binding activity (VWF: CBA), together with VWF multimer analysis. More importantly, we also measured the corrected platelet count increment (CCI) to evaluate the efficiency of Platelet trsnsfusions. Then, we comprehensively evaluated these data with routine clinical and laboratory findings. Results and Discussion 1) Plasma levels of ADAMTS13:AC were moderately but consistently decreased during two months after HSCT, whereas those of VWF:Ag were kept high, usually more than 200% and often 500% of the normal. 2) The UL-VWFMs appeared soon after HSCT, and continued at least until absolute neutrophil count (ANC) increased to >500 (usually 20-30 days after HSCT). 3) Until platelet engraftment (usually 40-60 days after HSCT), platelet transfusions (every 2-3 days interval) are usually performed to prevent the bleeding complications. During that period, the CCI values were consistently low, but those values were significantly increased during the administration of rTM. 4) Excess platelet transfusions before platelet engraftment induced the consumption of larger VWFMs in patient's plasmas, and often almost simultaneously hepatic VOD developed. Thus, platelet transfusions during the appearance of UL-VWFMs in patient's plasmas may induce platelet clumping in microvasculatures, and lead to the development of thrombotic complications including hepatic VOD. 5) The measurement of plasma levels of VWF:CB activity appeared to well predict the presence of UL-VWFMs. A representative case is shown in Figure. Thus, a combination regimen of FFP and rTM might be advisable when the patients show the early clinical signs of hepatic VOD and the laboratory data such as VWF:CBA suggest the presence of UL-VWFMs in patient's plasmas. Disclosures: Matsumoto: Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees. Fujimura:Alexion Pharma: Membership on an entity’s Board of Directors or advisory committees; Baxter International Inc: Membership on an entity’s Board of Directors or advisory committees.
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Shea, Thomas C., Jonathan Serody, Don Gabriel, et al. "High Relapse Rate Following Alemtuzamab Use in Allogeneic Transplants for Myeloid Hematologic Malignancies." Blood 104, no. 11 (2004): 1826. http://dx.doi.org/10.1182/blood.v104.11.1826.1826.
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Abstract Chakravarti, (Blood, 2002, p1071) and others have described the use of alemtuzamab, a monoclonal antibody that binds to CD52 on T cells, B cells, monocytes and dendritic cells in vivo for control of graft vs host disease in reduced intensity or fully-ablative matched related and unrelated transplant regimens for hematologic malignancies. Control of GVHD has been good, but high relapse rates and infectious complications have been seen. We report our experience with 42 pts who underwent matched related (27) or unrelated (15) bone marrow (8), blood stem cell (33), or both (1) transplants for hematologic malignancies. There were 16 women and 26 men, median age 48, and median f/u is 9 months. All AML pts had high-risk disease defined as beyond CR1 (11), CR1 with high risk cytogenetics (5), AML with tri-lineage dysplasia (6), or failed prior autologous transplant (1) Three had >10% marrow blasts at time of transplant. All other pts had advanced and multiply recurrent disease. All pts received alemtuzamab either at 20 mg/m2/d x 5 (17), or 30 mg/m2/d x 3 (25) between days -8 through -4. The conditioning regimens also included 12.8 mg/kg IV busulfan, (27), 6.4 mg/kg IV busulfan (8), melphalan 140 mg/m2 (6), or Cy/TBI (1). All non-TBI patients received 30 mg/m2/d x 5 of fludaribine. Median recovery of ANC to >500/ul and platelets > 20,000/ul w/o transfusion were 13 and 14 days, respectively. TRM included 1 pt each with intracranial hemorrhage at day 8, multi-organ failure/sepsis at day 28, and IPS/ARDS at day 119. Two of the 3 deaths were in MRD transplants; no serious episodes of VOD were observed. Grade 2–4 GVHD was seen in 4/14 evaluable MUD pts and 1 (sex mismatched) of 26 evaluable MRD pts. CMV reactivation has been seen in nearly all CMV sero+ pts, and bk reactivation was seen in 25 pts with hemorrhagic cystitis in 10. One case of PTLD, 3 graft failures, and one severe case of disseminated adenovirus infection resulting in nephritis, cystitis and transient cardiomyopathy were also seen. Relapse/# evaluable for different diseases are as follows: AML 12/22, Gleevec-resistant CML 3/3, MDS 0/4, MM 3/3, NHL 0/3, ALL 0/3, CLL 0/2. Relapse rates in evaluable MRD pts, 15/26 (58%), were statistically higher compared to MUD pts, 3/14 (21%) (p = 0.05). RR in marrow, 2/8, vs BSC, 16/32, were comparable. Alemtuzamab use has been effective at controlling GVHD and infectious complications can be reduced with early and pre-emptive use of ganciclovir. Nevertheless, high relapse rates remain a significant problem and preclude routine use of this approach in MRD patients with advanced myeloid diseases. Current use of this agent has been individualized for donor (MRD vs MUD) and disease (myeloid vs other) status.〉
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Beltran, Brady E., Erick Cotacallapa, and Jorge J. Castillo. "Survival and Clinicopathological Characteristics of EBV-Positive Diffuse Large B-Cell Lymphoma." Blood 120, no. 21 (2012): 1588. http://dx.doi.org/10.1182/blood.v120.21.1588.1588.
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Abstract Abstract 1588 Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients are <50 years and a specific cut-off for the percentage of EBV expression has not been defined. The goal of this retrospective study is to evaluate clinical and pathological characteristics of EBV+ DLBCL from Peruvian patients. Methods: Between January 2002 and January 2012, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases re positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immuno-histochemistry. Clinical data were reviewed retrospectively and patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4 using a tissue microarray (TMA) technique. The overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: A total of 43 EBV+ DLBCL patients are included in this study. The median age was 73 years (range 25–95 years). Four patients (9% ) were <50 years. The male:female ratio was 2.2:1. B symptoms occurred in 59%, ECOG >21 in 60%, advanced stage (III/IV) in 58%, elevated LDH levels in 44%, and lymphocyte count <1000/uL in 35%. The International Prognostic Index (IPI) score was 0–2 in 39% and 3–5 in 61% of the patients. Extranodal disease occurred in 20 patients (46%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), breast (n=1) and peritoneum (n=1). Three patients had central nervous system involvement (7%), one at presentation and two at relapse. Based on the Hans classification, 76% had non-germinal center profile. Ki67 expression was >80% in 53% of the patients. Eleven evaluated patients had a c-myc-negative status. Chemotherapy was received in 75% of the cases due to poor performance status. The overall response rate with conventional chemotherapy was 46%, with complete response in 39%, partial response in 7%, and no response in 54%. The median survival was 7.5 months. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with median OS of 41, 11 and 1.5 months respectively (p=0.07). A lymphocyte count <1000/uL was a prognostic factor for OS (p=0.001). Conclusions: Based on our study, which is the largest cohort in Latin-America, EBV+ DLBCL is an aggressive entity with frequent extranodal disease and poor response to conventional chemotherapy. The overall survival remains poor. Lymphopenia, as defined as lymphocyte count <1000/uL, appears as a prognostic factor for OS. Disclosures: No relevant conflicts of interest to declare.
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Grace, Rachael F., Carolyn M. Bennett, A. Kim Ritchey, et al. "Response to Steroids Predicts Response to Rituximab In Pediatric Chronic Immune Thrombocytopenia." Blood 116, no. 21 (2010): 3681. http://dx.doi.org/10.1182/blood.v116.21.3681.3681.
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Abstract Abstract 3681 Background: Pediatric Immune Thrombocytopenia (ITP) has an incidence of 4–6/100,000 with 1/3 of cases becoming chronic. Treatment choice is arbitrary, because few studies are powered to identify predictors of therapy response. Increasingly, rituximab is becoming a treatment of choice in those refractory to other therapies (Neunert CE, et al. Pediatr Blood Cancer 2008; 51(4):513). Previous studies in ITP have not examined predictors of response to rituximab or whether response to prior treatments predicts response. Objective: To evaluate univariate and multivariable predictors of platelet count response to rituximab. Methods: After local IRB approval, 550 patients with chronic ITP enrolled in the longitudinal, North American Chronic ITP Registry (NACIR) between January 2004 and June 2010. Eligibility included: ages 6 months-18 years at ITP diagnosis, clinical diagnosis of ITP, and ITP duration >6 months. Primary ITP was defined as isolated thrombocytopenia without associated conditions. Secondary ITP included those patients with immune thrombocytopenia associated with other immune-mediated medical conditions, including Evans Syndrome. Treatment response was defined as a post-treatment platelet count ≥50,000/uL within 16 weeks of rituximab and within 14 days of steroids. Steroids were prescribed as 1–4 mg/kg prednisone or adult equivalent over 4–14 days with or without taper. The NACIR captured treatment responses both retrospectively prior to enrollment and then prospectively, and both periods were included in this analysis. The multivariable logistic regression modeling process utilized SAS 9.1 using binary variables which were either significant in the univariate analysis or clinically important. A backwards elimination procedure was used to select the final model. Results: Seventy-six (13.8%) patients were treated with rituximab. Demographics of the patients treated with rituximab include: 42% male; 81% Caucasian, 17% Black, and 2% Asian. The mean age at diagnosis of ITP was 8.4 ± SD 5.1 years. The median platelet count at diagnosis of acute ITP was 10,000/uL (IQR 5,000-20,000/uL). 19 (25%) patients had secondary ITP or Evans syndrome. Treatment with rituximab had an overall response rate of 63.2% (48/76). Univariate predictors of response to rituximab are shown in Table I. The strongest univariate predictor of response to rituximab was response to steroids. Gender, ethnicity, and race were not predictive of response to rituximab. Furthermore, other variables which did not predict rituximab response include: history of a bleeding score ≥3 (Buchanan and Adix, J Pediatr 2002; 141: 683), symptoms ≥1 month prior to ITP diagnosis, older age (age >5 years), platelets ≥20,000/uL at acute ITP diagnosis, and a positive ANA. In multivariable analysis, response to steroids remained a strong predictor of response to rituximab with an OR 6.2 (95% CI 1.8–21.3, p=0.004). Secondary ITP also remained a strong a predictor of a positive response to rituximab with an OR 5.9 (95% CI 1.2–33.3, p=0.03). Conclusion: In the NACIR, response to steroids and secondary ITP were strong predictors of response to rituximab, a finding not previously reported in children or adults. Although this finding requires further validation, this result may provide evidence that rituximab should be most considered in patients previously responsive to steroids. Disclosures: Off Label Use: Rituximab for chronic ITP. Lambert:Cangene: Membership on an entity's Board of Directors or advisory committees. Klaassen:Novartis: Research Funding; Cangene: Research Funding. Neufeld:Novartis, Inc: Research Funding.
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Beltran, Brady E., Julio C. Chavez, Eduardo M. Sotomayor, and Jorge J. Castillo. "Lymphopenia Is an Adverse Prognostic Factor in EBV-Positive Diffuse Large B-Cell Lymphoma." Blood 124, no. 21 (2014): 5408. http://dx.doi.org/10.1182/blood.v124.21.5408.5408.
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Abstract Background: EBV-positive diffuse large B-cell lymphoma (EBV+ DLBCL) of the elderly is a provisional entity included in the 2008 WHO Classification of Lymphomas. Diagnostic criteria include age >50 years, DLBCL morphology and EBV expression in lymphomatous cells. However, these criteria are evolving as several patients younger than 50 years of age without immunodeficiency have been diagnosed. Also, a specific cut-off for the percentage of EBV expression has not been defined. Lymphopenia, monocytosis, neutrophil-to-lymphocyte ratio (NLR) and the lymphocyte-to-monocyte ratio (LMR) have been reported prognostic in patients with DLBCL and other lymphomas. The goal of this retrospective study is to evaluate these novel prognostic factors in a cohort of EBV+ DLBCL patients. Methods: Between January 2002 and January 2014, all patients meeting criteria for EBV+ DLBCL were included in the analysis. Patients with evidence of immunosuppression were excluded. All cases were positive for the presence of EBV-encoded RNA (EBER) by in situ hybridization, and CD20 and/or PAX-5 expression by immunohistochemistry. Clinical and pathological data were reviewed retrospectively. Lymphopenia was defined as an absolute lymphocyte count <1000/uL, and monocytosis as an absolute monocyte count >600/uL. NLR was defined as the division of the absolute neutrophil count over the absolute lymphocyte count. LMR was defined as the division of the absolute lymphocyte count over the absolute monocyte count. Patient's biopsies were analyzed for the expression of BCL6, CD10, CD30 and MUM-1/IRF4. Overall survival (OS) curves were calculated using the Kaplan-Meier method, and compared using the log-rank test. Results: A total of 45 EBV+ DLBCL patients are included in this study. The median age was 68.9 years (range 25-95 years). Four patients (9%) were younger than 50 years. The male:female ratio was 2.2:1. B symptoms occurred in 60%, ECOG >1 in 55%, advanced stage (III/IV) in 58%, and elevated LDH levels in 44%. The International Prognostic Index (IPI) score was 0-2 in 39% and 3-5 in 61% of the patients. Lymphopenia was seen in 35%, and monocytosis in 69% of patients. Extranodal disease occurred in 23 patients (51%): stomach (n=3), tonsil (n=3), pleura (n=2), palate (n=2), cecum (n=2), bone marrow (n=2), ileum (n=1), bone (n=1), skin (n=1), lung (n=1), meninges (n=1), soft tisue (n=1) and peritoneum (n=1). Based on the Hans classification, 76% had non-germinal center origin. Ki67 expression was >80% in 53% of the patients. Chemotherapy was not received in 25% of the cases due to poor performance status. The Oyama score was: 0 factors (13%), 1 factor (47%), and 2 factors (40%) with 2-year OS of 86%, 49% and 27%, respectively (p=0.016). Lymphopenia was an adverse prognostic factor for OS (HR 3.23, 95% CI 1.24-8.43; p=0.017) in the univariate analysis. The 2-year OS for EBV+ DLBCL patients with lymphopenia was 24%, and 55% for patients without lymphopenia. Monocytosis, NLR and LMR were not significantly associated with OS in our cohort of EBV+ DLBCL patients. Conclusions: Lymphopenia, defined as an absolute lymphocyte count <1000/uL, appears as a prognostic factor for OS in EBV+ DLBCL. Disclosures No relevant conflicts of interest to declare.
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Roe, Christa, Jennifer Rock-Klotz, Elyce Turba, et al. "Sézary Syndrome: Clinicopathological and Immunophenotypical Characteristics and Outcomes." Blood 126, no. 23 (2015): 1546. http://dx.doi.org/10.1182/blood.v126.23.1546.1546.
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Abstract Background Sézary syndrome (SS) is a rare malignant T-cell lymphoproliferative disorder derived from mature CD4+ T-helper/inducer cells. Patients (pts) with SS usually manifest with generalized erythroderma, peripheral blood and lymph node involvement and severe pruritus. Current therapy usually consists of extracorporeal photopheresis, interferon alpha, alemtuzumab, histone deactylase inhibitors (HDACi) and monochemotherapy. SS is considered incurable with conventional skin directed or conventional systemic therapy. Reports in literature suggest overall survival (OS) between 2-5 years. Methods Between 2002 and 2015, 50 pts with SS were evaluated and treated at Moffitt Cancer Center (MCC). Patient demographics, disease/treatment characteristics, responses, and outcomes were collected from our CTCL database. We characterized four groups based on immunophenotype, aberrant loss of CD26 and CD7, or both. Responses to treatment were assessed using standard criteria: complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Descriptive statistics were used to report baseline characteristics. Chi square and t-test were used for comparison of categorical and continuous variables respectively. Kaplan-Meier graphs were used for estimation of OS from time of diagnosis. Results We identified 50 patients with SS with median follow-up of 52 months. Median age was 70 years. Male to female ratio was 1.6:1. Most pts were Caucasians (88%),). A majority of patients (76%) had advanced stage disease (IVA+IVB). Measurable adenopathy was identified in 35 pts (70%). Median number of Sezary cell count in peripheral blood was 1,747/ul. Extracorporeal Photopheresis (ECP) was used in 43 pts (86%). Overall response rate (ORR) after 6 months of therapy was the following: CR 3(6%), PR 9 (18%), SD 7 (14%), PD 24 (48%). The only agents with activity achieving were interferon (ORR 6%, CR 2%), alemtuzumab (ORR 8%, CR6%), MTX (ORR 6%, CR 2%), and bexarotene (ORR10%, CR 2%), Responses to HDAC inhibitors were: romidepsin (ORR 6%, all PR) and vorinostat (ORR 4%, CR 2%). Median OS was 96 months (95% CI 70-121). Based on aberrant immunophenotype patterns, pts were stratified into 4 groups: 1) CD4+CD7+CD26- 26% (13), 2) CD4 + CD 7- CD26+ in 12% (6), 3) CD4+ CD7- CD26- in 34% (17) and 4) CD4+ CD7+ CD26+ in 24% (12). The median OS for CD4+ CD 7- CD26- was 84 months versus not reached (NR) for other groups. This difference was statistically significant when groups 3 and 2 (p <0.05), and groups 3 and 4 (p< 0.02) were compared. However, there was only a trend observed when groups 3 and 2 were compared (p=0.3). The median OS was 86 month if absolute Sezary cell count was >1700/ul compared to 96 mo if < 1700/ul (P< 0.4). Conclusions Pts with SS in this study showed an improved survival compared to historical studies. Advent of ECP, novel targeted agents such as HDACi inhibitors and monoclonal antibodies, earlier diagnosis, and better supportive care have most probably contributed to this phenomenon; except ECP, CR rates were very rare. A majority of the pts require multimodality induction therapy followed by maintenance therapy. Pts with Sezary cell immunophenotype characterized by aberrant loss of both CD26 and CD7 antigens had worse outcome. There was also a tendency for worse OS in pts with higher circulating absolute Sezary cell count. Disclosures Komrokji: Celgene: Consultancy, Research Funding; Incyte: Consultancy; Novartis: Research Funding, Speakers Bureau; Pharmacylics: Speakers Bureau. Sokol:Seatle Genetics: Research Funding; Celgene: Consultancy; Spectrum: Consultancy.
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Mejstrikova, Ester, Edita Kabickova, David Sumerauer, et al. "Acquisition of Isochromosome 7 Is a Late Change in the Pathogenesis of Hepatosplenic Lymphoma, Documented On a Case of Adolescent Girl 5 Years After Renal Transplant with Preceding TCR Gamma-Delta Positive LGL Leukemia." Blood 114, no. 22 (2009): 5031. http://dx.doi.org/10.1182/blood.v114.22.5031.5031.
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Abstract Abstract 5031 Background Post-transplant lymphoproliferative disorders (PTLD) occur in 1-20% of recipients receiving solid organ transplantation. We describe a patient who suffered from hepatosplenic T-cell lymphoma occurring after previous PTLD in a renal transplant recipient. Patient/Methods An 11-yr-old girl underwent kidney transplantation for end-stage Fanconi's nephronophthisis in 2002. In October 2006 significant neutropenia (<200/uL) was firstly detected, without any abnormality in bone marrow (BM) aspirate and without hepato- or splenomegaly. Episodes of neutropenia resolved spontaneously or after enhanced immunosuppression and G-CSF. In January 2007 new episodes of neutropenia and newly significant “monocytosis” were detected in peripheral blood (PB) and BM. Percentage of “monocytes” corresponded with immunophenotypically atypical TCR gamma/delta positive T cells (CD7weakposCD5negCD3bright) in PB and BM. Clonal TCR gamma and delta rearrangements were identified which enabled qPCR minimal residual disease (MRD) assessment. No lymphadenopathy was present, slight hepatosplenomegaly was identified by sonography. Conventional and molecular cytogenetic analyses didn't reveal any chromosomal aberration in PB and BM including changes on chromosome 7. No increased levels of EBV and CMV load by PCR were found. Partial increase of granulocytes and slight decrease of atypical TCR gamma/delta T cells were detected after administration of corticosteroid bolus and mercaptopurin. Three months later she presented with fever, rapidly progressive hepatosplenomegaly and pancytopenia, clinically corresponding with hepatosplenic lymphoma. At this time, newly acquired isochromosome 7q was detected by FISH. Results Initial therapy with campath and fludarabine was ineffective. She didn't respond to the 2nd line treatment (prednisone, vincristine, daunorubicine,asparaginase) and died 2 weeks later from lymphoma progression. Autopsy identified severe hemophagocytosis in the liver. Retrospectively, we identified identical clonal TCR rearrangements in the PB samples from March 2006 (∼0.03% of lymphoma PB MRD level), when neither changes in PB count nor clinical symptoms were found. Conclusion We detected a “pre-lymphoma” phase with clonal expansion of atypical TCR gamma/delta T cells more than 1 year before lymphoma manifestation. The presence of isochromosome 7q was a late change during this lymphoma genesis. Grant support IGA NS/9997-4; IGA NR/9531-3, IGA NS 10480-3, Research Projects MZCR 000064203, MSM0021620813 Disclosures No relevant conflicts of interest to declare.
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Bidot, Carlos J., Yeon-Soong Ahn, Jacob Esquenosi, et al. "Plasma Cholinesterase Activity in ITP Patients with/without Thrombosis." Blood 114, no. 22 (2009): 3997. http://dx.doi.org/10.1182/blood.v114.22.3997.3997.
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Abstract Abstract 3997 Poster Board III-933 Introduction In the process of immune mediated destruction, platelets may become activated and release procoagulant microparticles in ITP (Immune Thrombocytopenic Purpura). Although bleeding is common manifestation, some patients with ITP may suffer thrombotic complications, often presenting with TIA like syndromes. Brain MRI revealed findings consistent with ischemic small vessel disease in this subgroup (J Lab Clin Med 119: 334, 1992, Thromb Res 107:337, 2002). Recently acetylcoholinesterase (AChE) of RBC and/or non-specific plasma cholinesterase (ChE) was reported to be associated with the inflammation of blood vessels and may be a marker of some inflammatory states. In the present study we investigated plasma ChE activity in patients with ITP with or without thrombotic complication. Methods (i) Patients. We measured ChE activity in 49 patients with ITP. They were sub-grouped as having thrombosis (TBS), F/M (11/7), and non-thrombosis (Non-TBS), F/M (23/8). The TBS group included 9 with TIA like syndrome, 6 with CAD and 3 with venous thrombosis. (ii) Assay of ChE was essentially by Ellman's method. In our system, milli-absorbance units/min (mA/min) x 0.065 = umols substrate cleaved/min. Values reported here are in units of mA/min per mL plasma. Normal controls (NC, n=14) had a cutoff of 3000 mA/min per mL plasma (=mean +2SD). (iii) Sample handling. Platelet-poor plasma (PPP) was prepared by centrifuging 10 min at 1800 xg, then frozen in aliquots. For assay, it was diluted 1:20 with saline, then 5 uL and 10 uL were used in 96-well microtiter plate. Results (i) We observed higher level of ChE in the TBS group compared to Non-TBS in ITP. The TBS group (+/- SD) had mean value 2859 ±866, while the Non-TBS group had 2267 ±777 (units as above). This difference was significant, p<0.02. (ii) In TBS groups, we compared TIA subgroup with other TBS subgroup and observed that the n=9 patients with TIA had higher activity compared to the other TBS: 3250 vs 2466 mA/min per mL plasma. However, this difference did not reach significance in this small patient population. Further, 5/9 TIA patients (66%) had ChE activities >3000 (normal cutoff values) compared to only 2/9 (22%) of those with other TBS >3000. Conclusion (i) The ChE activity of ITP patients with TBS is significantly increased compared to Non-TBS in ITP patients. It has been suggested that Blood ChE/AChE may reflect some inflammatory, prothrombotic states. (ii) ITP patients with TIA exhibited higher ChE activity among TBS subgroups in ITP, suggesting that ChE activity may serve as a useful biomarker in TIA like syndrome associated with ITP. However, further study in a larger number of patients is needed to confirm these preliminary findings. Disclosures: No relevant conflicts of interest to declare.
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Panepinto, Julie A., Jeanette Carreras, Mark Walters, et al. "Matched Related Donor Transplants for Sickle Cell Disease: Report from the Center for International Blood and Transplant Research." Blood 106, no. 11 (2005): 2030. http://dx.doi.org/10.1182/blood.v106.11.2030.2030.
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Abstract Allogeneic hematopoietic cell transplantation (HCT) is the only known therapy to cure sickle cell disease though few patients receive this therapy. We report outcomes after HLA-matched sibling HCT in 68 patients with sickle cell disease, transplanted in 1989 to 2002. Of these, 33 (49%) were transplanted between 1999 and 2002. Median age at transplantation was 10 (range 2–30) years. Hemoglobin SS was the predominant genotype. Indications for HCT were predominately stroke (n=24) and recurrent vaso-occlusive crises (n=24); others included acute chest syndrome, increasing transfusion requirement, progressive iron overload and recurrent priapism. Forty-four patients (66%) received ≥ 10 red blood cell transfusions prior to HCT. Twenty patients (26%) had poor performance scores prior to transplantation. Busulfan and cyclophosphamide was the most frequently used conditioning regimen (n=63, 92%). Fifty-five patients (81%) received bone marrow allografts, 9 patients (13%) received mobilized peripheral blood, 3 patients (4%) received umbilical cord blood, and 1 patient received umbilical cord blood and bone marrow from the same donor. All patients achieved neutrophil recovery and the probability of platelet recovery ≥20,000/ul at day 100 was 93% (95% confidence interval [CI], 86–98)%. The probabilities of grades 2–4 acute graft-versus-host disease (GVHD) at day 100 and chronic GVHD at 5 years were 10% (95% CI, 4–19%) and 22% (95% CI, 12–33%), respectively. Sixty-five of 68 patients are alive after HCT with a median follow up of 5 years. The 5-year probabilities of overall and disease-free survival were 97% (95% CI, 88–100%) and 84% (95% CI, 75–95%), respectively. We defined treatment failure (inverse of disease-free survival) as death from any cause or disease recurrence defined as having a hemoglobin S >50%. Recurrent disease was the predominant cause of treatment failure (n=10). Of these 10 patients, 8 had return of clinical symptoms and the remaining 2 were symptom-free. Among patients with recurrent disease, 5 had received >10 red blood cell transfusions pre-transplant and 1 was reported to have red blood cell alloantibodies. Four patients with recurrent disease were transplanted for stroke and 6 for vaso-occlusive crisis. Nine of 10 patients received busulfan and cyclophosphamide for their conditioning and the remaining patient, total body irradiation 200cGy (single fraction), fludarabine and anti-thymocyte globulin. Three patients died; all deaths occurred more than 100 days after HCT. Causes of death were hemorrhage (n=1), multi-organ failure (n=1) and unknown (n=1). Of the 10 patients with stroke that had magnetic resonance imaging (MRI) of the brain pre- and post-transplant, 8 showed stable disease post transplant, one showed improvement and one had a worsening MRI. Overall survival after HCT for sickle cell disease is excellent, however recurrent disease and chronic GVHD remain a concern. Future studies should focus on strategies aimed at reducing disease recurrence.
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Buda, Edwarda M., David C. Van Echo, Brendan Weiss, Daniel L. Cruser, Gauri V. Alvarez, and Thomas J. Reid. "Response to High Dose (HD) Imatinib Therapy in Relapsed c-kit+ Acute Myeloid Leukemia (AML)." Blood 104, no. 11 (2004): 4532. http://dx.doi.org/10.1182/blood.v104.11.4532.4532.
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Abstract BACKGROUND. c-kit is a receptor tyrosine kinase for the ligand stem cell factor and a member of the PDGF receptor family. c-kit positivity, as defined by the presence of CD117 by flow cytometry (FC) in > 20% blasts, is detected in up to 90% of patients with AML, and is a potential target for imatinib, a selective tyrosine kinase inhibitor of c-kit as well as of BCR-ABL, PDGFR, and ARG. Previous reports of treatment with single-agent imatinib at 400 mg/day showed no response in AML (Cortes et al, Cancer 2003), while up to 24% of patients treated with 600 mg/day responded (Kindler et al, Blood 2003, Abstract 3242). Little information is available on the response in AML to imatinib as a single agent at 800 mg/day. CASE AND DISCUSSION. A 42-year old Caucasian male with relapsed c-kit expressing AML with del(9q), concurrent secondary high-grade (HG) glioma and few remaining therapeutic options presented to our service. He was initially diagnosed with primary oligodendrioglioma in January 2001 and underwent subtotal tumor resection, followed by whole brain radiation therapy, followed by 6 cycles of procarbazine, CCNU, and vincristine (PCV) chemotherapy, and entered complete remission (CR). In December 2002, he was diagnosed with AML M2 with del(9q) and was treated with cytosine arabinoside (Ara-C) and daunorubicin (7+3), followed by 3 cycles of consolidation with HD Ara-C, and entered CR. In March 2004, he had recurrent abnormal magnetic resonance imaging of the brain and HG malignant glioma was diagnosed by stereotactic biopsy. He was started on temozolamide but was unable to tolerate treatment due to pancytopenia, and a bone marrow (BM) at another institution disclosed relapsed AML with 75% blasts. Upon presentation to our institution, a BM examination showed > 90% blasts, 53% of which expressed CD117 positivity by FC. Imatinib therapy was initiated at a dose of 400 mg/day and escalated to 800 mg/day (HD) after lack of response. (Table 1.) The peripheral blood (PB) white blood cell count (WBC) peaked on Day 9 of treatment with imatinib and declined thereafter. On Day 21, blasts were undetectable in the PB and there was a proportional increase of PB neutrophils (PMN). By Day 25, the BM blasts decreased to 50% and only 12% blasts showed positivity for CD117. The patient experienced severe muscle/bone pains at the start of imatinib therapy, which resolved within five days. Response to HD imatinib was also accompanied by dramatic decline in serum LDH. The patient’s platelet (PLT) count improved to a peak of 70k on Day 14, declined thereafter, and the patient required PLT transfusion support by Day 31. The patient also received dexamethasone 4 mg q6h for his HG glioma, which remained stable during this time of observation. CONCLUSION. Our case demonstrates that HD imatinib 800 mg/day has significant preferential activity against the CD117+ AML blasts, is active in a shorter time span than previously reported at lower doses, and should be studied further in combination with other agents in AML. The patient’s HG glioma may have been partially stabilized by imatinib as PDGFR overexpression has been reported in secondary glioblastomas. Table 1. Imatinib Dose, mg/day Day WBC x 10-3/uL PMN, % PB Blast, % BM Blast,% BM Blasts CD117 +, % PLT x 10-3/uL - −7 1.8 4 15 > 90 53 34 400 1 17.5 3 21 - - 28 600 7 59.6 5 40 - - 50 800 8 71.0 9 21 - - 41 800 9 100.0 9 30 - - 31 800 14 11.0 22 25 - - 70 800 21 6.3 61 0 - - 31 800 25 4.0 49 0–3 50 12 13
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Rattmann, Ina, David Zhu, Carlo M. Croce, et al. "The Expression of the GTPase-Deficient, Hematopoietic-Specific RhoH GTPase Is Implicated in Development of Chronic Lymphocytic Leukemia (CLL)." Blood 110, no. 11 (2007): 339. http://dx.doi.org/10.1182/blood.v110.11.339.339.
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Abstract RhoH is a hematopoietic-specific small GTPase which is constitutively active due to lack of intrinsic GTPase activity, suggesting that expression levels of RhoH regulate cellular function. Our lab has previously shown that RhoH in T-cells directly interacts with ZAP-70, a critical protein tyrosine kinase in TCR cell signaling and function (Gu et al., Nature Immunol., 2006). As in human B-CLL ZAP-70 expression has been correlated with an unmutated IgVH gene status and poor prognosis, we have investigated RhoH expression and function in B-CLL. PBMC samples from 29 B-CLL patients, all containing >90% CD19+/CD5+ human B-CLL cells, were compared to CD19+ B-cells from normal donors. Significantly higher RhoH mRNA levels were detected in CLL samples by quantitative PCR (p<0.001) with a 2–4 fold increase in the majority of samples. In addition, RhoH levels in these CLL samples were directly correlated with ZAP-70 expression (p<0.01). To further delineate the role of RhoH in the development and progression of B-CLL, we utilized a genetic mouse model of B-CLL, the Eμ-TCL1 transgenic mouse (Bichi et al. PNAS, 2002), and interbred these with Rhoh−/− mice. Starting at 2 months of age peripheral blood of these mice was analyzed every month for different blood cell lineages and in particular for the number of IGM+/CD5+/B220low cells as a readout for the progression of the CLL-like disease. In TCL1 transgenic mice with normal RhoH expression (Rhohwt; TCL1Tg) and with one Rhoh allele knocked out (Rhoh+/−; TCL1Tg) an accumulation of IgM+/CD5+ B-cells was observed which started as early as an age of 3 and 4 months, respectively, and increased dramatically thereafter. In contrast, Rhoh−/−; TCL1Tg showed no significant increase of IgM+/CD5+ B-cells until month 5 with a modest increase thereafter and values were significantly reduced in comparison to Rhohwt; TCL1Tg from month 3–5. As expected, no increase of IgM+/CD5+ B-cells was observed in the nontransgenic controls Rhoh−/+; TCL1NTg, Rhoh−/−; TCL1NTg (data not shown), and Rhohwt; TCL1NTg (Table 1). Table 1: IGM+/CD5+ cells in the peripheral blood. Age [months] Rhoh wt ; TCL1Tg Rhoh +/−;TCL1Tg Rhoh −/−;TCL1Tg Rhoh wt ;TCL1 NTg Mean ± SEM (x1000/ul); () animals analyzed; * p<0.05 in comparison to Rhohwt; TCL1NTG (data collection still in progress) 2 0.12 ± 0.02 (10) 0.28 ± 0.07 (8) 0.15 ± 0.04 (9) 0.08 ± 0.02 (9) 3 0.33 ± 0.09 (11) 0.22 ± 0.06 (8) 0.07 ± 0.03 (8)* 0.07 ± 0.01 (10) 4 0.83 ± 0.38 (11) 0.57 ± 0.20 (18) 0.11 ± 0.05 (16)* 0.08 ± 0.01 (6) 5 3.32 ± 2.27 (6) 1.35 ± 0.46 (17) 0.26 ± 0.06 (15)* 0.11 ± 0.03 (5) 6 4.38 ± 2.41 (7) 5.01 ± 3.01 (9) 0.66 ± 0.23 (8) 0.07 ± 0.02 (5) When mice from each genotype were sacrificed at 6 months of age the number of IgM+/CD5+ B-cells detected in Rhoh−/− TCL1Tg vs Rhohwt TCL1Tg mice was 6-fold reduced in the peritoneal cavity, 3-fold reduced in the bone marrow and a 2-fold reduced in the spleen. In summary our data strongly suggest that RhoH plays a role in the progression of the B-CLL-like disease in the transgenic Eμ-TCL1 mouse model. This will allow detailed molecular studies of the role of RhoH in pathways altered in TCL1-induced expansion of B-cell precursor populations in this model.
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Seibel, Nita L., Barbara L. Asselin, James B. Nachman, et al. "Treatment of High Risk T-Cell Acute Lymphoblastic Leukemia (T-ALL): Comparison of Recent Experience of the Children’s Cancer Group (CCG) and Pediatric Oncology Group (POG)." Blood 104, no. 11 (2004): 681. http://dx.doi.org/10.1182/blood.v104.11.681.681.
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Abstract Recent CCG and POG treatment stategies for patients with T-ALL are significantly different. POG treats T-ALL patients on a separate protocol from that used for B precursor ALL (B-ALL) while CCG treats T-ALL patients on the same protocols utilized for B-ALL patients with protocol assignment determined by the NCI risk classification. We recently reviewed the outcome of patients with T-ALL and high-risk features (age ≥ 10 years and/or initial WBC > 50,000/ul) treated on either the CCG-1961 or POG-9404 clinical trials. POG utilized an intensive anthracycline based multidrug regimen based on the DFCI treatment program and randomized patients at registration to receive or not receive additional high dose methotrexate(HDMTX) with leucovorin rescue. All patients received cranial irradiation (CRT). CCG therapy for high risk T-ALL was based on CCG modified BFM(S-BFM) and Augmented BFM(A-BFM). Patients with <25% blasts on day 7 bone marrow(RER) who achieved remission were randomized in a 2X2 design to standard or augmented intensity and standard duration(1 interim maintenance(IM) and 1 delayed intensification(DI) phase or prolonged duration (2 IM and DI phases). Only RER patients with CNS-3 status received CRT. Patients with a slow response(SER) to induction therapy received A-BFM therapy +/− idarubicin/cyclophosphamide courses during DI phases. All SER patients received CRT. In the POG trial, HDMTX produced a significant improvement in event free survival (EFS). In the CCG trial, for RER patients, augmented intensity regimens produced a better EFS than standard intensity regimens. There was no difference in outcome for patients receiving standard or prolonged duration therapy. Thus we compared the high dose MTX arm from POG 9404 to a composite EFS result for CCG l961 based on induction failure/toxic death rate, augmented intensity therapy(1 or 2 DI phases) for RER patients and A-BFM therapy for SER patients. POG 9404, (opened 6/1996; closed 9/2001) and enrolled 363 T-ALL patients, with 77% having high risk features of which 155 were randomized to HDMTX arms. 5 yr EFS for patients on these arms was 75% and overall survival (S) of 84%. CCG 1961(opened 11/1996;closed 5/2002) entered 2077 patients of which 410 had T-cell disease with 263 RERs. The projected composite 5 year EFS and S estimated for high risk T-ALL patients treated on CCG l961 was 76.9% and 82.5% respectively. Isolated CNS relapse accounted for approximately 2/3 of the relapses in RER patients patients.CNS 3 patients treated on 9404 demonstrated 75% 5 yr EFS as compared to 82% for patients on 1961. Outcome for higher risk T-ALL patients treated by POG and CCG were quite similar. However, the BFM based strategy utilizes significantly less anthracycline and appears to produce a lower rate of bone marrow relapse. We postulate that incorporating low dose cranial RT(1200 cGy) will significantly reduce the incidence of CNS relapse and improve the overall EFS rate. Therefore, COG will utilize an augmented intensity BFM backbone for the first T-ALL protocol.
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Singh, Prabhsimranjot, Sudhamshi Toom, Makardhwaj S. Shrivastava, and William B. Solomon. "A Rare Combination of Genetic Mutations in an Elderly Female: A Diagnostic Dilemma!" Blood 128, no. 22 (2016): 5487. http://dx.doi.org/10.1182/blood.v128.22.5487.5487.
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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.
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Sidharthan, Neeraj, Rema Ganapathy, P. Gangadharan, et al. "Strict Treatment Regimen and Febrile Neutropenia Guidelines Allow Favorable Outcomes for Pediatric ALL in Southern India." Blood 126, no. 23 (2015): 4510. http://dx.doi.org/10.1182/blood.v126.23.4510.4510.
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Abstract Background: Children with Acute Lymphoblastic Leukemia (ALL) in resource-poor countries face major challenges including treatment abandonment and poor overall survival (OS) and event-free survival (EFS). To address these issues, in 2002 a non-profit pediatric hematology-oncology center was established in a tertiary medical institution in Kerala, India to provide high-quality treatment and supportive care at low cost. A standardized approach to pediatric leukemia care began in 2010. We present evidence that outcomes on par with that seen in resource-rich nations can be achieved with a rigorous treatment and supportive care approach. Methods: Following IRB approval, we reviewed clinical information and outcomes of all patients above 1 year and less than 14 years of age treated for newly diagnosed B- or T-ALL between January 1, 2010 and January 31, 2015. Seventy-six children were consecutively treated and all are included in this analysis. B-ALL patient treatment was stratified according to BFM relapse risk criteria with standard risk (SR) defined by age 1-6 yrs, peripheral WBC < 20 X 106/ul, good prednisolone response, absence of t(9:22) and t(4:11), and a day 33 marrow in remission by morphology. At any age, poor prednisolone response, t(9:22) or t(4:11), or day 33 marrow not in remission defined high risk (HR), and patients not meeting SR or HR criteria were intermediate risk (IR). Minimal residual disease assessment (MRD) was not utilized in risk stratification or treatment decisions. All patients were treated as per BFM 2002 with modifications. All patients received 4-drug (Vincristine/ Daunorubicin/ L Asparaginase/ Prednisolone) induction and Phase 2 induction of cyclophosphamide, cytosine arabinoside, and daily 6-mercaptopurine (6-MP), followed by consolidation with oral 6-MP and IV methotrexate (MTX), 2 gm/m2 x 4 for SR and IR B-ALL and 5 gm/m2 x 4 for HR B-ALL, T-ALL, and CNS disease. Phase 1 reinduction utilized adriamycin and dexamethasone. The Phase 2 reinduction regimen closely mirrored Phase 2 induction. HR B-ALL and T-ALL patients received 12 Gy prophylactic cranial irradiation, and those with CNS disease 18 Gy. Maintenance therapy consisted of daily oral 6-MP, weekly oral MTX, and monthly IV Vincristine and oral Dexamethasone for 104 weeks. Prophylactic intrathecal MTX was given 11 times through reinduction and every 3 months in maintenance. Febrile neutropenia protocols were enforced to ensure less than 30 minutes elapsed from presentation with fever > 38o C to initiation of broad spectrum antibiotics. To minimize sepsis risk, prophylactic GCSF was given between cycles to target ANC > 0.5 x 106/uL. OS and EFS were assessed by Kaplan-Meier method. Patients were censored at last follow-up. Abandonment was treated as an event in calculating EFS. Kuppuswami Socioeconomic Scale (KES) was applied using phone interviews of guardians. Results: Median follow-up time was 30.3 months (range, 1.9-61 months). One patient (1.3%) died during induction, 1 was censored at loss to follow-up upon transfer of treatment to another center, none abandoned treatment, and 6 (7.9%) relapsed, with 1 (1.3%) relapse within 90 days of diagnosis. At median follow-up, the OS was 93.4% and EFS 90.8% (95% CI, 81.1%-99.1%). SR accounted for 28 (36.8%), IR for 36 (47.4%), and HR for 11 (14.5%) patients. OS by risk stratification is shown in Figure 1. KES analysis on the 65 contactable families revealed a median family income between Indian Rs. 14,000-37,000 (US $218-577)/month, and 14 (21.5%) having income less than Rs. 9,300 (US $145)/month. Thirty (46.1%) stratified as lower-middle class or lower. The primary wage earner had less than a high school education in 21 (32.3%), and was at a clerical or lower work level in 46 (70.8%) of families. Conclusion: Our data demonstrate that, for pediatric ALL, results similar to resource-rich countries can be provided in resource-poor areas through a tertiary care center maintaining adherence to globally accepted guidelines for treatment and management of treatment-associated complications. We plan to report minimum 5-year follow-up for all patients in future. Future prospective studies will examine the role of MRD-based stratification and allogeneic transplant options for high-risk patients, as well as seek to extend the low rates of toxic death and abandonment to neighboring centers by implementation of best practices throughout the region. Figure 1. OS by Risk Stratification Figure 1. OS by Risk Stratification Disclosures No relevant conflicts of interest to declare.
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Gaziev, Javid, Antonella Isgro, Katia Paciaroni, et al. "Outcomes of Unrelated Bone Marrow Transplantation in Patients with Thalassemia." Blood 132, Supplement 1 (2018): 5777. http://dx.doi.org/10.1182/blood-2018-99-109764.
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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.
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Deol, Abhinav, and Charles A. Schiffer. "BCR/ABL: The Clonal Bully." Blood 118, no. 21 (2011): 4417. http://dx.doi.org/10.1182/blood.v118.21.4417.4417.
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Abstract 4417 Chronic myeloid leukemia (CML) is characterized by the presence of t(9;22) leading to the BCR/ABL fusion gene while other myeloproliferative disorders such as polycytemia vera (PV) and primary myelofibrosis (PMF) may have a point mutation at V617 F codon of janus kinase 2 gene. Myelodysplastic syndrome (MDS) is thought to arise from an abnormality in the hematopoietic stem cell leading to impaired production of blood cells. In these diseases an abnormal clone proliferates and then suppresses normal hematopoiesis. We present 3 very unusual patients in whom CML was diagnosed a few years after the diagnosis of another clonal hematological disorder and in whom there was re-emergence of the original disorder after successful treatment of the CML. The first patient is an 88 yr old female who was diagnosed with PV in 1998 and treated with multiple phlebotomies, hydroxyurea and anagrelide. A bone marrow biopsy in 2002 showed the presence of the t(9;22) in 6 of 6 metaphases. She was treated with imatinib but failed to achieve a complete cytogenetic response and was switched to dasatinib which had to be stopped secondary to congestive heart failure. Nilotinib was then started but she developed QTc prolongation and failed to achieve a cytogenetic response. She was then managed with hydrea for many years and interestingly, manifested prominent cyclic leukocytosis. In 2010, analysis of blood showed a JAK2 mutation. She recently was begun on protocol treatment with ponatinib. Although moderate splenomegaly and leukocytosis persisted after 5 months of therapy, 0/26 metaphases demonstrated t (9;22) while gain/trisomy of 1q, an abnormality commonly seen in other myeloproliferative disorders and in particular, PV, was detected in 11/26 metaphases, The second patient is a 64 year old man who was initially diagnosed with PV during workup for elevated hematocrit in 2002. A JAK2 mutation was detected subsequently. Phlebotomy was discontinued in 2007 and he was maintained on hydroxyurea. In 2010, he was noted to have a WBC of 100,000/ul and underwent a bone marrow biopsy which showed the t(9;22). He was found to be in accelerated phase of CML and was initiated on dasatinib. At last follow up visit, the patient is in a cytogenetic remission for CML but was noted to have elevated hemoglobin; a repeat JAK2 is pending. The third patient is an 82 year old man who was diagnosed in 2005 with MDS with normal cytogenetics, when he was evaluated for macrocytic anemia. He was initially observed and subsequently treated with erythropoietin for decreasing hemoglobin. A bone marrow biopsy was repeated when his hemoglobin continued to decrease in 2009 and showed t(9;22) in 1/20 cells. He was started on imatinib and achieved a complete molecular response. About 3 months later he fractured his humerus and was found to have extramedullary acute myeloid leukemia which was positive by fluorescence in situ hybridization for BCR/ABL. His bone marrow at this time was negative for BCR/AB by RT-PCR but showed dysplatic changes. He was treated with radiotherapy to his arm and was switched to nilotinib. CML continues to be in a molecular remission, with low but stable blood counts. These 3 patients had an antecedent diagnosis of a clonal hematological disorder prior to developing CML. In 2 of the patients the CML became the dominant “bully” clone suppressing the manifestations of the PV clone. With targeted therapy directed at BCR/ABL, the CML clone was suppressed and the underlying disease again became apparent. In one patient, the presumed PV clone had evolved further with typical cytogenetic changes. It is unclear whether the CML developed from the original MPD/MDS clone or whether it represents an entirely independent disorder. In either event, the ability to successfully suppress the CML with specific therapy provides insights into the competitive interactions amongst abnormal clones and indeed, with normal hematopoiesis. Disclosures: No relevant conflicts of interest to declare.
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Eapen, Mary, Michael Haagenson, Brent Logan, et al. "Use of Peripheral Blood Grafts Is Associated with Increased Acute and Chronic Graft-Versus-Host Disease without Improved Survival after Unrelated Donor Transplantation." Blood 106, no. 11 (2005): 443. http://dx.doi.org/10.1182/blood.v106.11.443.443.
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Abstract Data from the CIBMTR indicate that approximately 70% of unrelated donor hematopoietic stem cell transplants (HCT) in the U.S. utilize peripheral blood (PB) rather than bone marrow (BM) as a graft source. Comparative studies verifying its benefit, however, are lacking. We, therefore, performed a retrospective analysis comparing the results of 275 unrelated PB and 620 unrelated BM transplants in adults 18–60 years of age with acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) or chronic myeloid leukemia (CML), transplanted in 2000–2002. 73% of PB grafts were matched at HLA A, B, C (low resolution) and DRB1, 21% were mismatched at a single locus and 6% were mismatched at ≥ 2 loci. 69% of BM grafts were matched, 26% were mismatched at a single locus and 5% were mismatched at ≥ 2 loci. Median follow-up was 24 (range, 6–48) and 34 (range, 6–54) months for PB and BM recipients, respectively. Groups were similar except PB recipients were less likely to have CML, were more likely to have MDS and were transplanted more recently. Incidences of neutrophil recovery (95% vs. 90% at day 100, p=0.01) and platelets ≥20,000/ul (81% vs. 66%, at 1-year, p <0.0001) were significantly higher after PB than BM transplants. Incidences of grades 2–4 but not grades 3–4 acute graft-versus-host disease (GVHD) were significantly higher after PB than BM transplants (56% vs.45%, at day 100, p=0.003). Chronic GVHD was also significantly higher after PB transplants (54% vs. 39%, at 3 years, p<0.0001). Despite higher rates of grade 2–4 acute and chronic GVHD after PB transplantation, incidence of relapse was similar in the two groups for both early and advanced leukemia. In multivariate analysis, risks of treatment-related mortality (TRM), treatment failure (relapse or death) and overall mortality during the first 9 months after transplantation were similar. However, among patients surviving the first 9 months, subsequent risks of TRM (relative risk [RR] 1.90, 95% confidence interval [CI], 1.14–3.17, p=0.01) and treatment failure (RR 1.60, 95% CI 1.06–2.44, p=0.03) were significantly higher in the PB cohort. Three-year adjusted (from multivariate models) probabilities of leukemia-free survival were 29% and 31%, p=0.5, after PB and BM transplantation, respectively; corresponding probabilities of overall survival were 31% and 32%, p=0.8. While these data do not indicate a survival advantage with either stem cell source by disease or risk group, PB is associated with earlier engraftment. This advantage is offset by higher rates of grades 2–4 acute and chronic GVHD, leading to a higher risk of late adverse events. Randomized clinical trials are necessary to better define the relative risks and benefits of PB in the setting of unrelated donor HCT.
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Yu, S. M., and Y. H. Lee. "First Report of Pseudomonas cichorii Associated with Leaf Spot on Soybean in South Korea." Plant Disease 96, no. 1 (2012): 142. http://dx.doi.org/10.1094/pdis-08-11-0653.
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Unusual symptoms were observed on 5% of the soybean (Glycine max (L.) Merill) plants in commercial fields in South Korea in September 2008 and 2009. The lesions were at first water soaked, then enlarged and turned dark brown or black, often with concentric white rings and sometimes surrounded by a bright yellow halo. Most lesions were roughly circular to irregular. Six bacteria were isolated on tryptic soy agar (TSA) media from plants of soybean cv. Daewon. The isolate JBC1 formed colonies that were whitish to greenish, circular with convex elevation, and unable to grow anaerobically or at 37°C. Cells of the isolate were rod shaped with polar multitrichous flagella. The isolate was positive for the following characteristics: production of fluorescent and diffusible pigment on King's medium B, production of oxidase, ability to rot potato, and utilization of l-arabinose, d-aspartate, citrate, galactose, glucose, meso-inositol, mannitol, and meso-tartrate. However, the isolate was negative in the following tests: formation of yellow colonies on peptone sucrose agar and yeast extract dextrose calcium carbonate agar media, levan formation, production of nondiffusible pigment, urease and arginine dihydrolase, hydrolysis of starch, nitrate reduction, and utilization of d-arabinose, benzoate, geraniol, l-rhamnose, d-sorbitol, sucrose, and trehalose (1). The isolates elicited a clear hypersensitive reaction in tobacco leaves. The carbon source oxidation pattern analyzed by Biolog (Hayward, CA) GN database indicated that the isolate belonged to Pseudomonas cichorii (Swingle 1925) Stapp 1928. DNA was isolated with a commercial genomic DNA extraction kit (Solgent, Daejeon, South Korea) and the 16S rDNA was amplified using universal 27F and 1492R primers. The 1,367-bp amplicon was sequenced (GenBank Accession No. JF951725) and had 100% sequence identity with P. cichorii Accession No. EF101976.1. Phylogenetic analysis based on 1,367 bp of the 16S rDNA sequence also revealed that isolate JBC1 was closely related to P. cichorii. Healthy soybean plants of cv. Jangyeop were spray inoculated with 20 ml of a 108 suspension prepared from a 2-day-old culture grown on TSA. Healthy plants sprayed with just water served as noninoculated checks. Typical disease symptoms that were observed in the field developed on leaves of soybean plants 3 days after spray inoculation, while the check plants remained symptomless. The bacteria reisolated from inoculated plants were confirmed to be identical to the original strain by 16S rDNA analysis and the Biolog test. Inoculation on tomato, watermelon, melon, and oriental melon plants resulted in dark brown or black lesions forming on leaf margins and tips, which is different from those on soybean plants (2,3). With paprika and eggplant, necrotic spots with concentric white rings developed on the leaves of each plant. We propose leaf spot as the name for this disease on soybean. To our knowledge, this is the first report of leaf spot on soybean caused by P. cichorii, which is becoming a more important pathogen in subtropical regions and greenhouses (4). References: (1) B. Cottyn et al. Syst. Appl. Microbiol. 32:211, 2009. (2) A. Obradovic et al. Plant Dis. 86:443, 2002. (3) E. Pauwelyn et al. J. Phytopathol. 159:298, 2011. (4) S. M. Walkil et al. Nigeria J. Appl. Biosci. 38:2540, 2011.
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Duncavage, Eric J., Jennifer O'Brien, Kiran R. Vij, et al. "Detection of Clonal Hematopoiesis in Cytopenic Patients Using Targeted Sequencing." Blood 126, no. 23 (2015): 1654. http://dx.doi.org/10.1182/blood.v126.23.1654.1654.
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Abstract Introduction: The clinical diagnosis of myelodysplastic syndrome (MDS) relies on the presence of persistent cytopenias, not otherwise explained, and evidence of morphologic dysplasia in the bone marrow. Low grade MDS (bone marrow blasts <5%) is defined by the presence of morphologic dysplasia in at least 10% of cells in one or more cell lineage. Low grade MDS is particularly challenging to diagnose, as morphologic dysplasia may be subtle and is subject to high inter-observer variability. The ability to diagnose low grade MDS can be improved by incorporating cytogenetic evaluation of the bone marrow, especially in the setting of equivocal morphologic dysplasia. However, many MDS cases (up to 60%) lack cytogenetic abnormalities, limiting the overall utility of cytogenetics. Multiple recent studies have demonstrated that the majority of MDS patients (over 80% in some studies) harbor recurrent somatic mutations in a core group of genes. We sought to determine if targeted DNA sequencing of genes recurrently mutated in MDS and AML could be useful in the evaluation of cytopenic patients with a normal karyotype being evaluated for the possible diagnosis of MDS. Methods: We screened patients who presented for evaluation of MDS between 2002 and 2014 that had consented for sequencing studies and had banked samples. Patients were selected based on 1) World Health Organization defined cytopenia (WBC <1,800/µL, hemoglobin <10g/dL, platelets <100k/µL) in at least one lineage, 2) bone marrow blasts <5%, 3) WBC <14k/uL, 4) normal cytogenetics, and 5) absence of prior therapy for MDS. Bone marrow specimens were independently re-reviewed by two board certified hematopathologists. DNA was extracted from cryopreserved bone marrow and skin (to serve as a source of normal DNA) and enriched for a panel of 285 commonly mutated myeloid genes. Captured DNA libraries were sequenced on a HiSeq 2500 instrument with 2x101bp reads. The resulting data was analyzed for single nucleotide variants (SNVs) and insertions/deletions (indels) using VarScan2 in paired normal mode. Results: Thirty-eight patients met the selection criteria, and 30 of these had bone marrow aspirates available for morphologic review and were included in the study. A mean unique coverage depth of 913x was achieved for targeted genes and all reported variants had >50x coverage, variant allele fractions (VAFs) >3%, and minor allele frequencies (MAFs) < 1% in any population. Of the 30 sequenced cases, 25 had a somatic mutation in at least one gene (mean 3.3 mutations/case, range 1-10 mutations/case). The most commonly mutated gene was TET2 (7 cases), followed by ASXL1 (5 cases), EZH2 (4 cases), SRSF2 (4 cases), and U2AF1 (4 cases). Of the 285 sequenced genes, 44 were mutated in at least one case, and 14 were mutated in 2 or more cases. The mean VAF (variant reads/total reads) of detected mutations was 27% (range 3-98%). Morphologic review demonstrated definitive dysplasia (≥10% of cells in least one lineage) made by two pathologists in 18 of 30 cases (supporting the clinical diagnosis of MDS), no dysplasia in 6 of 30 cases, and equivocal dysplasia (where hematopathologists did not agree that dysplasia was ≥10%) in 6 of 30 cases. Thirteen of 18 cases (72%) with definitive dysplasia had a mutation, 5/6 cases (83%) without dysplasia had mutations, and 6/6 (100%) cases with equivocal dysplasia harbored somatic mutations. The mean VAF of mutations was 17.5% in cases without dysplasia, 29% in cases with equivocal dysplasia, and 28% in cases with definitive dysplasia. All of these groups included mutations in canonical MDS genes such as TET2, DNMT3A, SRSF2, RUNX1, and EZH2. Conclusions: In this cohort of 30 cytopenic patients with normal cytogenetics, 80% harbored a somatic mutation in at least one myeloid-associated gene. Somatic mutations were detected in 5 of 6 cases without definitive dysplasia (<10% dysplasia) and 6 of 6 cases with equivocal dysplasia. Notably, canonical MDS mutations were found even in the absence of dysplasia. These findings suggest that clonal hematopoiesis may be present in the majority of cytopenic patients independent of dysplasia, a finding that requires independent validation. Identification of somatic gene mutations in patients with morphologically equivocal MDS or cytopenic patients without definitive dysplasia provides a means for tracking clonal disease that could be used to monitor patients for subsequent development of definitive MDS. Disclosures Duncavage: DI&P Consulting: Consultancy; Cofactor Genomics: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.
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Nguyen, Loan, Charity A. Karpac, Johanna A. Kremer Hovinga, et al. "Sporadic Bloody Diarrhea-Associated Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) in Adults in Oklahoma: Comparison to Adults with Severe Adamts13 Deficiency and to Children with Typical HUS." Blood 110, no. 11 (2007): 1317. http://dx.doi.org/10.1182/blood.v110.11.1317.1317.
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Abstract The frequency, presenting features and clinical outcomes of sporadic TTP-HUS following a prodrome of bloody diarrhea in adults are not described. The Oklahoma TTP-HUS Registry enrolled 237 consecutive patients over age 18 years with their first episode of clinically diagnosed TTP from 11-13-1995 (the date of our initial ADAMTS13 measurement) to 12-31-2006 for whom plasma exchange treatment (PEX) was requested. ADAMTS13 activity was measured on 218 (92%) patients immediately before their first PEX. 16 (7%) of these 218 patients presented with a prodrome of acute bloody diarrhea. 42 (19%) patients had ADAMTS13 activity <10%. 2 patients who presented with acute bloody diarrhea had ADAMTS13 activity <10%; they are analyzed with the bloody diarrhea patients; ADAMTS13 activity in the remaining 14 patients was 40–100%. Children with typical HUS are not usually treated with PEX and therefore are not all included in the Registry. Data on children were retrieved from the Children’s Hospital of Oklahoma for 2002–2006 to identify all children with typical HUS; 28 children were identified. E. coli O157:H7 infection was identified in 5 adults (of 12 tested) and 19 children (of 25 tested). No source for E. coli O157:H7 infection was identified. There were no case clusters except for one family with 2 affected children. In 2 of the adults with bloody diarrhea, a colectomy was performed before the correct diagnosis was made. Patient characteristics Adults, bloody diarrhea prodrome (n=16) Adults, ADAMTS13 deficiency (n=40) Children, diarrhea prodrome (n=28) * p≤0.05 for adult bloody diarrhea prodrome compared to adult ADAMTS13 deficient patients; ** p≤0.05 for adult bloody diarrhea prodrome compared to children bloody diarrhea prodrome patients; †seizure, stroke, coma, focal abnormalities anytime during the course; ‡most abnormal values on the day of diagnosis ± 7 days; median §defined by ↑ Cr ≥ 0.5 mg/dL x 2 days or Cr ≥4.0 and dialysis. Age (years, median) 58 40* 3.8** Female (%) 80% 81% 64% Race (% white) 94% 53%* 75% Severe neurologic abnormalities† 63% 45% 7%** Platelet count (/μL)‡ 24,000 10,000* 34,000 Hematocrit (%)‡ 22 21 18** LDH (/UL) ‡ 1410 1431 1161 Creatinine (mg/dL)‡ 2.7 1.0* 3.7 Acute renal failure§ 50% 8%* 57% Response to PEX (%) 81% 85% NA Dialysis (%) 31% 3%* 57% Death (30 days) 31% 15% 0%** Relapse (%) 0% (0/10) 38% (13/34)* NA Conclusions: TTP-HUS following bloody diarrhea is an endemic, sporadic disorder among adults that is less common and less familiar than in children. Distinct from children, adults with bloody diarrhea have a higher frequency of severe neurologic abnormalities and death; distinct from adults with severe ADAMTS13 deficiency, adults with bloody diarrhea are primarily white, have a higher frequency of acute renal failure, and have not relapsed. Although the role of PEX in the recovery of adult patients presenting with bloody diarrhea is unclear, PEX may be appropriate initial treatment since the mortality is high, many patients appear to respond, and patients with severe ADAMTS13 deficiency may also present with bloody diarrhea apparently caused by intestinal ischemia.
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Makhani, Sarah S., Ronit Reich-Slotky, Pashna N. Munshi, et al. "Sustained Hematopoietic Recovery after Salvage Autologous Stem Cell Transplants after Long Term Storage of Cryopreserved Hematopoietic Progenitor Stem Cells (HPSC)." Blood 134, Supplement_1 (2019): 4475. http://dx.doi.org/10.1182/blood-2019-122111.
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Background: Salvage autologous hematopoietic stem cell transplantation (HSCT) is an effective treatment for patients with relapsed multiple myeloma (MM). Adequate HPSC after multiple cycles of dose-intense melphalan (mel) can be harvested, cryopreserved, and stored to allow for such future transplants. Many investigators reported sustained CD34+ cell viability using in vitro assays such as colony forming units (CFU-GM) potency of HPSCs after long term storage. Data on engraftment outcomes using these products demonstrating in vivo viability are limited. This study describes a large single center experience evaluating the engraftment potential of HPSC used in salvage transplantation after long-term storage in patients with MM, in comparison to initial treatment. Study Design and Methods: We conducted a retrospective chart review of patients with MM undergoing salvage HSCT, whose initial cell collection occurred between January 2002 and May 2016. This review identified 59 patients, all conditioned for initial transplants with dose-intense Mel 200 mg/m2, and who received autologous HPSC stored > 1 year after initial HSCT. HPSC were cryopreserved and stored in vapor phase liquid nitrogen at a temperature of ≤-150°C. Conditioning regimens for salvage transplants were mel (n=11), mel/bortezomib (bor) (n=32), mel/bor/thalidomide (n=6), BEAM (n=1), and Super BEAM (n=9). Patients who received a planned tandem transplant only (less than a year apart) were excluded. For patients receiving tandem HSCT followed by salvage HSCT, the first of the tandem HSCTs was considered for this analysis (n=5). Differences in CD34+ cell doses and days to engraftment between first and salvage transplant were tested using a paired 2-tailed t-test. Univariate and multivariable linear regressions were used to determine association between storage time and days to engraftment. Results: From 2002 to 2017, transplant data from 59 MM patients were analyzed (Table 1). Forty-nine (83%) patients had a Salmon Durie stage IIIA or IIIB at first diagnosis. The median age at first diagnosis was 57.5 (range, 36-73) years. A median collection dose of 16.0 × 106 CD34+ cells per kilogram (range, 7.9-62.5) was reached during HPSC collection with a median of 3 collections (range, 1-7) per patient. All 59 patients collected upon first mobilization attempt. The median age of patients at time of first and salvage transplants was 59 and 62 years, respectively. As predicted, the patient's age at salvage transplant was significantly greater than the age at first transplant (p<0.001). The median storage time between day of initial collection and salvage transplant was 4.0 years (range 1-14.6), with 37% (n=22) and 8% (n=5) stored for over 5 and 8 years, respectively. The median time between first and salvage transplants was 4.0 years (range 1-14.5). Patients achieved sustained neutrophil engraftment (ANC>500 /uL) at a median of 11 days after both the first and salvage transplant (ranges, 9-18 and 8-15 respectively, p=0.041) (Figure 1). The median time to sustained platelet engraftment (>20 x 109/L) was 13 days (range, 9-36) after first HSCT and 14 days (range 8-45) after salvage HSCT (p=0.842) (Figure 1). The CD34 dose for the salvage transplant was significantly higher than the first transplant, with patients undergoing the first HSCT receiving a median CD34+ cell dose of 5.3 × 106/kg (range 3.0-14.1), compared to a median of 6.1 × 106/kg (range 3.4-13.8) for the salvage HSCT (p=0.04). There was no association between the CD34 dose infused and days to ANC (p=0.755) or platelet (p=0.669) engraftment. After adjusting for age at transplant and CD34 dose, there was no association between duration of cryopreservation and days to ANC (p=0.658) and platelet (p=0.725) engraftment (Figure 2). There were no graft failures reported in either the first or salvage HSCT. Conclusion: Long-term cryopreservation did not affect engraftment outcomes in patients with MM receiving salvage autologous HSCT, despite the addition of salvage chemotherapy. There was no association between engraftment kinetics and storage duration in patients receiving a salvage transplant when controlling for CD34 dose and recipient age. Although it is possible that these cell products may have lost HPSC viability but still contained more than adequate viable HSC for HSCT, there was no evidence of delayed engraftment, particularly of platelets, suggestive of low numbers of viable HSCT. Disclosures Biran: Celgene: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Merck: Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Goldberg:Bristol-Myers Squibb: Consultancy; Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership. Siegel:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Rowley:Allergan: Equity Ownership; Fate Therapeutics: Consultancy.
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Sergueeva, Adelina, Galina Miasnikova, Ekaterina Lisina, et al. "Thrombotic Complications Are Associated with Phlebotomy Therapy in Patients with Chuvash Polycythemia." Blood 126, no. 23 (2015): 936. http://dx.doi.org/10.1182/blood.v126.23.936.936.
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Abstract Background: In Chuvash polycythemia (CP) (Problemi Gematologii I Perelivaniya Krovi 1974, 10:30), impaired degradation of hypoxia inducible factor (HIF)-1α and HIF-2α from a homozygous germline VHLR200W mutation leads to augmented hypoxic responses during normoxia (Nat Genet 2002, 32:614). In addition to elevated hematocrit, CP is marked by leg varices, benign vertebral hemangiomas, decreased systemic blood pressure, increased systolic pulmonary artery pressure, and by the defining phenotypes of thrombosis and early mortality (Blood 2004, 103:3924; Haematologica 2012, 97:193). There is no effective therapy. While phlebotomy has been recommended for idiopathic polycythemia by the British Committee for Standards in Haematology (Br J Haematol 2005, 130:174) and is administered to some CP patients, its benefits are unknown. Phlebotomy-induced iron deficiency inhibits PHD2 enzyme, the principal negative regulator of HIFs, which further augments hypoxic responses. This affects the transcription of many genes (BCMD 2014, 52:35). Hypoxia-regulated IRAK1 is augmented in inflammation and may promote thrombosis (Circ Res. 2013, 112:103). Methods: 165 patients with CP were enrolled in a registry between 2001 and 2009 after providing written informed consent. Survival analysis was used to examine the predictors of new thrombosis and death during the follow-up period. mRNA from peripheral blood mononuclear cells (PBMCs) was profiled by Affymetrix Human Exon 1.0 ST Array in 42 of the subjects. Results: The median age at enrollment was 35 years and 90 participants were females, 25 had a history of one thrombosis, 5 of two thromboses and 3 of three thromboses. In the year prior to study entry, 72 had received phlebotomy therapy (Table 1). In July 2015 the median follow-up was 9.0 years (range 1-14.5). During this follow-up period, 30 (18.2%) participants had one new thrombosis, 6 (3.6%) had two new thromboses and 17 (10.3%) died. The median age of death was 55 years (range 16-76) and deaths were related to thrombotic cerebrovascular accident (n = 4), myocardial infarction (n = 4), mesenteric or portal vein thrombosis (n = 3), other major thromboembolic events (n = 2) and trauma or unknown cause (n = 2). Baseline characteristics of older age, prior thrombosis, pentoxifylline treatment, smoking and splenomegaly were independently associated with greater thrombosis risk during follow-up (P < 0.003). After adjustment for these variables, the estimated probability of new thrombosis at 10 years was 26% in those receiving phlebotomies compared to 12% in those not phlebotomized (log rank P = 0.014) (Figure 1). There was also a trend for increased risk of death with phlebotomy: estimated probability 8.7% versus 3.7% (P = 0.15). Examination of gene transcripts affecting thrombosis by logistic regression identified 12 protective and 16 risk genes at 5% false discovery rate. Upregulation of two mRNAs was of singular significance: 1) IL1RAP, a proximal signaling adaptor of IRAK1 (Immunity 1997, 7: 837) and 2) THBS1, encoding thrombospondin1 (Blood 2015, 125: 399). Both genes have known roles in thrombosis promotion and we previously reported that THBS1 is upregulated in CP (BCMD 2014, 52:35). Further analysis revealed a further upregulation of THBS1 in patients with baseline history of phlebotomy (β=0.41, P=0.046). Conclusion: These findings underscore a high rate of thrombosis and death in patients with CP and reveal a potential role of increased IRAK1/IL1RAP signaling in these complications. They raise the possibility that phlebotomy therapy has a detrimental rather than beneficial effect, possibly contributed to by increased THBS1 expression. Table 1. Baseline characteristics by phlebotomy in the year prior to enrollment. Results in median (interquartile range) or n (%); four without phlebotomy data. No phlebotomy N=89 Received phlebotomy N=72 Age (years) 32 (18-48) 37 (26-49) 0.08 Female gender, n (%) 52 (58%) 34 (47%) 0.16 Smoking, n (%) 18 (20%) 24 (33%) 0.060 History of thrombosis, n (%) 20 (23%) 12 (17%) 0.4 Splenomegaly, n (%) 2 (2.3%) 2 (2.8%) 0.8 ASA treatment, n (%) 27 (30%) 36 (50%) 0.011 Pentoxifylline, n (%) 7 (7.9%) 17 (23.6%) 0.005 BMI (kg/m2) 20.4 (18.3-22.9) 21.6 (19.9-24.6) 0.010 Systolic BP (mm Hg) 109 (100-123) 118 (105-124) 0.6 Diastolic BP (mm Hg) 76 (68-84) 78 (71-83) 0.8 Hemoglobin (g/dL) 18.1 (16.4-21.0) 17.9 (16.0-19.8) 0.5 WBC (per uL) 5.7 (4.6-7.0) 5.5 (4.6-6.7) 0.9 Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
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Albuquerque, Monica Soares de, Armiliana Soares Nascimento, Cácio Lopes Mendes, et al. "Endodontic retreatment due to secondary periapical injury: case report." ARCHIVES OF HEALTH INVESTIGATION 9, no. 6 (2020): 503–6. http://dx.doi.org/10.21270/archi.v9i6.4959.
Full textAbstract:
Pulp diseases commonly happens because of the actions of bacteriological factors and show their characteristic signs and symptoms over the time. With pulp necrosis, a degenerative process starts and when there is no early treatment, it is possible to occur periapical lesions as a result of aggression to the pulp. In cases of periapical secondary lesions, clinical signs and symptoms persist and are related to secondary infection due to persistent bacterial contamination, also to operative factors, inadequate obturation or poor coronary restoration. This study aimed to report a case of endodontic retreatment and clinical and radiographic follow-up for 8 years, of chronic periapical abscess case, in which after retreatment, clinical signs and symptoms are no longer observed and bone neoformation is noticed.
 Descriptors: Periapical Diseases; Endodontics; Periapical Abscess.
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Shafqat, Faseeha. "STRUGGLING FIELD OF SPEECH-LANGUAGE PATHOLOGY IN PAKISTAN." Rehabilitation Journal 4, no. 2 (2020): 165–66. http://dx.doi.org/10.52567/trj.v4i02.2.
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The need of speech and language pathology (SLP) as a specialized field in Pakistan emerged with the education of deaf. Development in education of deaf began in Pakistan by Mr. Siddique Akbar Makhdum in 1949. Later in 1951 College for the Teachers of the Deaf in Lahore was established with the collaboration of USAID and faculty from US to teach speech-language pathology. The basic courses introduced were speech, language and audiology. In the tenure of 6th president of Pakistan General Zia-ul-Haq, many organizations were formed to serve special needs children. In his time special education centers were developed in Islamabad, Lahore and Karachi. One of its kind was Speech and Hearing Centre, Karachi, which was established in 1983 and aimed to advocate Auditory Verbal Therapy (AVT).1 In 1991, Post graduate diploma in speech-language therapy (PGD-SLT) was launched with collaboration of NIRM (formerly called National Institute of Handicapped NIHd), UNDP and National Institute of Psychology (NIP), Quaid-e-Azam University, Islamabad. Ministry of Women Development, Social Welfare and Special education took this initiative. Diane Schaffer from USA and Linda from England were two expert speech therapists who came to Pakistan to teach and train PGD-SLT students in NIRM. Speech and Hearing Association of Pakistan (SHAP) was formed in January 2000.2 On 13th June 2002 SHAP got registered under Sindh Government with registrar of societies Act 21 of 1860. Currently Ms. Amina Siddiqui is President and Dr. Nadeem Mukhtar is Vice President of SHAP. In 2006-2007 Special Education Department of Karachi University launched masters in speech Therapy program. In 2007 Zia-u-Din Hospital started clinical services and collaborated with SHAP to develop the College of Speech Language & Hearing Sciences (CSLHS) where nation’s first 4-year Bachelor’s program in Speech Language Therapy was launched in 2007.2 In 2010 Riphah University Islamabad started MS program in speech-language pathology under supervision of Dr. Ayesha Kamal Butt. In 2013 Isra University Islamabad campus started M.Phil SLP degree program and PhD in Rehabilitation Sciences which opened way to doctoral degree for SLPs as well. In 2019 Riphah International University also launched PhD in Rehabilitation Sciences program. King Edward Medical University also launched BS program in 2008. Currently there are 16 institutes offering BS, 5 institutes offering MS/MPhil and 6 institutes offering diploma in SLP. On 9th October 2019 Pakistan Speech and language pathologist association (PSLPA) was formed by pioneers of field in Pakistan. It is federally registered under the society’s registration act 21 of 1860. Launch day of PSLPA i.e. 9th October was also declared as National Speech Pathology Day. President and Vice President of PSLPA are Dr. Nazia Mumtaz and Ms. Saima Tariq respectively. Although the field of speech-language pathology in Pakistan headed up in 1990 but research in the field began with the commencement of degree programs. The lag between practice and research resulted in the lack of culturally appropriate standardized practices which has yet not been eradicated fully. Despite efforts of existing associations to eliminate malpractice and quackery from the field, it is still going on a huge scale. In fact many practicing SLPs are yet not registered with any association because on legal grounds there is not yet any such compulsion for them on national level. In many states, like other medical professions, it is mandatory for SLPs to be licensed through a state authority in order to practice their speciality.3 The licensing process includes such steps that helps to maintain and establish stringent standards for licensure candidacy and practice. In Pakistan there is a dire need of state’s recognized licensing system that could assure provision of genuine SLPs to public through a standardized vetting process that internationally involves qualifying degree education, supervised clinical experience and examination. Graduate programs are producing culturally consistent researches, even though application of these researches is slow and rare to an extent that out dated traditional practices still dominates. Consequently patients and their families suffer with no or slow pace of progress. There are also centers where patients treated by SLP students are not supervised and guided by senior therapists hence their trial and error learning only benefits them in making stronger clinical record books but at the cost of patient’s wastage of time and student’s malpractice. One reason behind lack of desired clinical supervision is recruitment of less number of SLP clinical supervisors in teaching hospitals as compared to number of students and case load. In many institutes SLP departments are provided with too low budget to equip their clinics with latest assessment and treatment tools due to which students could not get know how of latest practices happening in the field at international level. A huge proportion of clients that take speech therapy sessions are children and adolescents. Regarding pediatric speech therapy, many families raise issues that they are not allowed to observe or stay in sessions. Furthermore, non-provision of appropriate parent training which is contrary to roles and responsibilities of SLPs,4 is also a critical issue that puts parents or guardians in psychological stress when they try to work with their affected family member. Like other countries, in Pakistan the solution of all aforesaid problems can only be found with integration of evidence based practices (EBP). Only with evidence based practices Pakistani SLPs can make informed, evidence based decisions in their practices along with provision of high quality services reflecting the needs, choices, interests and values of target population.
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Gupta, Kartik, Shivaraj Nagalli, Mike Pate, Nitin Gharpure, Sumanth Prabhu, and Navkaranbir S. Bajaj. "Abstract 106: Circulating Immune Cells as Predictive Markers of Cardiovascular Mortality in Ambulatory US Adults: Insights From NHANES." Circulation: Cardiovascular Quality and Outcomes 13, Suppl_1 (2020). http://dx.doi.org/10.1161/hcq.13.suppl_1.106.
Full textAbstract:
Introduction: While inflammation is associated with worse cardiovascular (CV) prognosis, the relative prognostic importance of circulating immune cell populations for predicting CV mortality is unknown. Methods: We used data from 3 cycles of NHANES (1999-2000, 2001-2002, 2003-2004) to estimate the prognostic importance of total leukocyte count (TLC), and differential leukocyte counts in participants ≥20 years of age and TLC in normal clinical range (4,000-11,000 cells/μL). The cause of death was derived from the National Death Index. We estimated the relative importance of different immune cell markers, and compared the prognostic importance of the dominant immune cell marker with components of the Framingham Risk Score (FRS). We used partial χ2 and standardized domination statistic to estimate the relative importance of immune markers in predicting CV mortality. Results: Among 10, 825 participants (49% women, 51% self-reported Non-Hispanic White) eligible for this analysis, the median age was 49 years (Interquartile Range [IQR] 35 to 66). Over a median follow-up of 13.2 years (IQR 11.4 to 14.8), there were 620 deaths due to CV causes. The hazard of CV mortality increased by 11% with every 1000 cells/uL increase in TLC after adjusting for co-morbidities (Hazard Ratio [HR] 1.11 95% CI 1.02, 1.21, p=0.011). Among the immune cell markers assessed, the monocyte-lymphocyte ratio had the highest domination to predict CV mortality ( Figure Panel A ). The hazard of CV mortality increased by 14% with every 1 unit increase in the monocyte-lymphocyte ratio in the fully adjusted model (HR 1.14 95% CI 1.07, 1.22, p<0.001). Among participants aged ≥30 years without prevalent CV disease, FRS was calculated in 8,190 participants (75.7% of total). As compared to the individual components of FRS, the monocyte-lymphocyte ratio had higher relative importance in predicting CV mortality than gender, smoking status, HDL, total cholesterol and treatment for hypertension ( Figure Panel B ). Conclusion: In this study of a large representative adult US population with TLC within the clinically normal range, we found that readily available circulating immune markers are independently associated with CV mortality. The monocyte-lymphocyte ratio was the best predictor of CV mortality and outperformed 5 risk factors included in the FRS.
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Thi Hong Nhung, Pham, Do Hanh Nguyen, Bui Thi Yen, Do Thi Le Hang, Vu Thi Thom, and Dinh Doan Long. "Genotyping ITS and matK regions of Hedera nepalensis K. Koch in Vietnam." VNU Journal of Science: Medical and Pharmaceutical Sciences 36, no. 3 (2020). http://dx.doi.org/10.25073/2588-1132/vnumps.4241.
Full textAbstract:
This study develops procedures for cloning ITS and matK genes on six specimens in order to exploit and conserve the genetic resources of H. nepalensis and evaluate its genetic diversity based on molecular markers. The study methods include DNA extraction from dried leaf samples, amplification of ITS and matK regions using PCR, sequencing and comparing with the sequences on Genbank. The study results include a successfully-established process of cloning ITS and matK genes; successful amplification and sequencing of the ITS and matK regions. The results also show that four samples (N1-N4) were 100% homologous to H. nepalensis and H1and H2 samples were 100% homologous to H. helix. The results provide data and tools for further studies of exploitation and development of the H. nepalensis K. Koch genetic resources in Vietnam.
 Keywords
 ITS, matK, Hedera nepalensis K. Koch, PCR
 References
 [1] V.V. Chi. Dictionary of Vietnamese Medicinal Plants, Publ. House Medicine, Ho Chi Minh City, 2012 (in Vietnamese).[2] D.H. Bich, D.Q. Cuong, B.X. Chuong, N. Thuong, D. T. Dam. The medicinal plants and animals in Vietnam, Hanoi Sci. Technol. Publ. House Hanoi, 2006 (in Vietnamese).[3] A. Sadat, M. Alam, A. Rauf, W. Ullah, Biological screening of ethyl acetate extract of Hedera nepalensis stem, Afr J Pharm Pharmacol, 6 (2012) 2934-2937. https://doi.org/10.5897/AJPP12.828.[4] T. Li, H. Pan, Y. Feng, H. Li, Y. Zhao, Bioactivity-guided isolation of anticancer constituents from Hedera nepalensis K. Koch, S Afr J Bot, 100 (2015) 87-93. https://doi.org/10.1016/j.sajb.2015.05.011.[5] L. Jafri, S. Saleem, N. Ullah, B. Mirza, In vitro assessment of antioxidant potential and determination of polyphenolic compounds of Hedera nepalensis K. Koch, Arab J Chem, 10 (2017) 3699-3706. https://doi.org/10.1016/j.arabjc.2014.05.002. [6] S. Saleem, L. Jafri, I. ul Haq, L.C. Chang, D. Calderwood, B.D. Green, B. Mirza, Plants Fagonia cretica L. and Hedera nepalensis K. Koch contain natural compounds with potent dipeptidyl peptidase-4 (DPP-4) inhibitory activity, J Ethnopharmacol, 156 (2014) 26-32. https://doi.org/10.1016/j.jep.2014.08.017.[7] W.J. Hashmi, H. Ismail, F. Mehmood, B. Mirza, Neuroprotective, antidiabetic and antioxidant effect of Hedera nepalensis and lupeol against STZ+ AlCl 3 induced rats model, DARU, 26 (2018) 179-190. https://doi.org/10.1007/s40199-018-0223-3.[8] H. Ismail, A. Rasheed, I.-u. Haq, L. Jafri, N. Ullah, E. Dilshad, M. Sajid, B. Mirza, Five indigenous plants of Pakistan with Antinociceptive, anti-inflammatory, antidepressant, and anticoagulant properties in Sprague Dawley rats, Evid Based Complement Alternat Med, 2017 (2017). https://doi.org/10.1155/2017/7849501[9] N.D. Thanh. DNA marker techniques in study and selection of plant. Journal of Biology. 36 (2014) 265-294 (in Vietnamese). https://doi.org/10.15625/0866-7160/v36n3.5974.[10] P.Z. Goldstein, R. DeSalle, Review and interpretation of trends in DNA barcoding, Front Ecol Evol, 7 (2019) 302. https://doi.org/10.3389/fevo.2019.00302.[11] S. Abugalieva, L. Volkova, Y. Genievskaya, A. Ivaschenko, Y. Kotukhov, G. Sakauova, Y. Turuspekov, Taxonomic assessment of Allium species from Kazakhstan based on ITS and matK markers, BMC plant biol, 17 (2017) 258. https://doi.org/10.1186/s12870-017-1194-0.[12] R.M. Bhagwat, B.B. Dholakia, N.Y. Kadoo, M. Balasundaran, V.S. Gupta, Two new potential barcodes to discriminate Dalbergia species, PloS one, 10 (2015) e0142965. https://doi.org/10.1371/journal.pone.0142965[13] D. Grivet, R. Petit, Phylogeography of the common ivy (Hedera sp.) in Europe: genetic differentiation through space and time, Mol Ecol, 11 (2002) 1351-1362. https://doi.org/10.1046/j.1365294x.2002.01522.x.[14] R. Li, J. Wen, Phylogeny and biogeography of Dendropanax (Araliaceae), an amphi-Pacific disjunct genus between tropical/subtropical Asia and the Neotropics, Syst Bot, 38 (2013) 536-551. https://doi.org/10.1600/036364413X666606.[15] Y. Sun, D. Skinner, G. Liang, S. Hulbert, Phylogenetic analysis of Sorghum and related taxa using internal transcribed spacers of nuclear ribosomal DNA, Theor Appl Genet, 89 (1994) 26-32. https://doi.org/10.1007/BF00226978[16] P. Cuénoud, V. Savolainen, L.W. Chatrou, M. Powell, R.J. Grayer, M.W. Chase, Molecular phylogenetics of Caryophyllales based on nuclear 18S rDNA and plastid rbcL, atpB, and matK DNA sequences, Am J Bot, 89 (2002) 132-144. https://doi.org/10.3732/ajb.89.1.132.[17] D. Bošeľová, J. Žiarovská, L. Hlavačková, K. Ražná, M. Bežo, Comparative analysis of different methods of Hedera helix DNA extraction and molecular evidence of the functionality in PCR Acta fytotechn zootechn, 19 (2016) 144-149. https://doi.org/10.15414/afz.2016.19.04.144-149.[18] D.D. Long, Comparative analysis of different DNA extraction methods and preliminary analysis of genetic diversity of Hedera nepalensis K. Koch. in Vietnam based on GBSSI marker, VNU Journal of Science: Medical and Pharmaceutical Sciences, 35 (2019) 88-95 (in Vietnamese). https://doi.org/10.25073/2588-1132/vnumps.4165 [19] J.H. Cota-Sánchez, K. Remarchuk, K. Ubayasena, Ready-to-use DNA extracted with a CTAB method adapted for herbarium specimens and mucilaginous plant tissue, Plant Mol Biol Rep, 24 (2006)161. https://doi.org/10.1007/BF02914055.[20] S. Xu, D. Li, J. Li, X. Xiang, W. Jin, W. Huang, X. Jin, L. Huang, Evaluation of the DNA barcodes in Dendrobium (Orchidaceae) from mainland Asia, PloS one, 10 (2015) e0115168. https://doi.org/10.1371/journal.pone.0115168.[21] P. Vargas, H.A. McAllister, C. Morton, S.L. Jury, M.J. Wilkinson, Polyploid speciation in Hedera (Araliaceae): Phylogenetic and biogeographic insights based on chromosome counts and ITS sequences, Pl Syst Evol, 219 (1999) 165-179. https://doi.org/10.1007/BF00985577[22] X. Lei, Y.W. Wang, S.Y. Guan, L.J. Xie, L. Xin, C.Y. Sun, Prospects and problems for identification of poisonous plants in China using DNA barcodes, Biomed Environ Sci, 27 (2014) 794-806. https://doi.org/10.3967/bes2014.115.[23] H. Sun, W. McLewin, M.F. Fay, Molecular phylogeny of Helleborus (Ranunculaceae), with an emphasis on the East Asian‐Mediterranean disjunction, Taxon, 50 (2001) 1001-1018. https://doi.org/10.2307/1224717.
 
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Childhood Studies, Journal of. "Call for Papers - Innovative Professional Learning in Early Childhood Education and Care: Inspiring Hope and Action." Journal of Childhood Studies 41, no. 3 (2016). http://dx.doi.org/10.18357/jcs.v41i3.16399.
Full textAbstract:
<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>
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Childhood Studies, Journal of. "Call for Papers - Innovative Professional Learning in Early Childhood Education and Care: Inspiring Hope and Action." Journal of Childhood Studies 42, no. 1 (2017). http://dx.doi.org/10.18357/jcs.v42i1.16889.
Full textAbstract:
<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>
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Childhood Studies, Journal of. "Appel de soumissions - L’apprentissage professionnel innovant en éducation à la petite enfance : inspirer l’espoir et l’action." Journal of Childhood Studies 41, no. 3 (2016). http://dx.doi.org/10.18357/jcs.v41i3.16400.
Full textAbstract:
<p><strong>Rédacteurs invités: Joanne Lehrer (Université du Québec en Outaouais), Christine Massing (Université de Regina), Scott Hughes (Université Mount Royal), Alaina Roach O’Keefe (Université de l’Île-du-Prince-Édouard)</strong></p><p><strong></strong>Non seulement l’apprentissage professionnel est-il considéré comme essentiel à l’amélioration de la qualité éducative et comme soutien à l’apprentissage et au développement des enfants (par exemple, Lazarri <em>et al.</em>, 2013, Vandenbroeck <em>et al</em>., 2016), mais certains éléments de la formation initiale et continue ont été identifiés comme critiques pour transformer les identités professionnelles et la pratique des éducatrices (en SGÉ) et des enseignantes (au préscolaire). Par exemple, la réflexion critique et soutenue (Thomas et Packer, 2013), les expériences d’apprentissage ciblant des équipes entières (Vangrieken <em>et al</em>, 2016), les pratiques collaboratives qui visent le pouvoir d’agir des praticiennes (Helterbran et Fennimore, 2004) et la direction (Dolmer <em>et al., </em>2008) sont toutes considérées comme des moyens efficaces afin de soutenir l’apprentissage professionnel.</p><p>Bien qu’il semble y avoir consensus dans les écrits sur <em>ce qui doit être fait</em>, et même sur <em>la façon dont cela devrait être fait</em>, de nombreuses contraintes empêchent la mise en œuvre et le maintien d’un système d’apprentissage professionnel durable et transformationnel en éducation à la petite enfance. Vandenbroeck et ses collaborateurs (2016) vont au-delà de l’accent mis sur les individus et les équipes en identifiant deux autres niveaux nécessaires pour des systèmes compétents d’apprentissage professionnel : des partenariats entre les programmes locaux de l’éducation à la petite enfance et les institutions sociales, culturelles et éducatives (collèges et universités); et la gouvernance en matière de vision, de finances et de suivi. Dans le contexte canadien, la <em>Fédération canadienne des services de garde à l’enfance</em> a également souligné l’importance d’une stratégie cohérente visant à renforcer la main-d’œuvre en services de garde éducatifs (CCCF, 2016). Toutefois, l’éducation à la petite enfance au Canada relève des gouvernements provinciaux et territoriaux. Par conséquent, les conditions, les règlements, les exigences de certification, les programmes et les systèmes d’éducation varient considérablement d’une province ou d’un territoire à l’autre. Les exigences en matière d’éducation pour la qualification, par exemple, peuvent comprendre une formation non formelle (dans les Territoires du Nord-Ouest et au Nunavut), une formation de courte durée, un certificat d’un an ou un diplôme de deux ans. Cela complique les efforts pour définir qui est le professionnel de la petite enfance et quelles sont les possibilités constitutives de l’apprentissage professionnel (Prochner <em>et al</em>., 2016). Bien que ces disparités puissent entraver l’élaboration d’une stratégie cohérente, Campbell et ses collaborateurs (2016) ont récemment affirmé que l’on pourrait approfondir les apprentissages, en partageant et en appréciant la riche diversité des approches en matière d’apprentissage professionnel, à la fois au sein des provinces et des territoires et intra provinces et territoires. De plus, des exemples provenant d’autres pays permettraient d’élargir la discussion et d’élargir notre compréhension des possibilités (Vandenboreock <em>et al</em>., 2016).</p><p>Ce numéro spécial est donc consacré aux partages d’histoires d’espoir et d’actions concertées, reliant la théorie à la pratique. Nous attendons des propositions canadiennes et internationales liées aux pratiques d’apprentissage professionnel qui s’étendent au-delà des programmes individuels, mettant en vedette des partenariats et des efforts de mobilisation communautaire à l’intérieur et à travers différents contextes éducatifs liés à la petite enfance (Centres de la Petite Enfance, maternelle, halte-garderie, etc.) et en lien avec diverses thématiques : philosophiques, pratiques, critiques, transformatrices, personnelles et d’espoir. Chaque soumission répondra à une ou à plusieurs des questions clés, y compris, mais sans s’y limiter à :</p><ul><li>Comment conceptualiser l’apprentissage professionnel en éducation à la petite enfance?</li><li>Comment établir et maintenir des partenariats efficaces pour favoriser l’apprentissage professionnel?</li><li>Quelles stratégies de mobilisation communautaire transformatrice pourraient être partagées?</li><li>Comment les stratégies novatrices peuvent-elles être appliquées à une plus grande échelle?</li><li>Comment les pratiques d’évaluation et d’apprentissage professionnelles peuvent-elles être perturbées?</li><li>Quelle histoire de l’apprentissage professionnel avez-vous besoin de (ou voulez-vous) raconter?</li><li>Comment votre communauté a-t-elle été transformée par une activité, une pratique ou un évènement ou particuliers?</li><li>Comment la vie et l’avenir des enfants peuvent-ils être façonnés positivement par l’engagement dans les partenariats et la mobilisation?</li><li>Où pourrions-nous être dans 5, 10 ou 15 ans?</li></ul><p>Nous accepterons des soumissions dans des formats multiples, y compris des articles de recherche, des articles théoriques, des pièces multimédias, des œuvres d’art, des recensions de livres, etc. Ils peuvent être présentés en anglais, en français ou dans toute langue autochtone canadienne reconnue.</p><p>La date limite pour les soumissions est fixée au 1<sup>er</sup> aout 2017.</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>