Journal articles: 'Two-level transplant evolution'

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Rubio, Marie T., Vahid Asnafi, Eric Delabesse, Gandhi Damaj, Nathalie Dhedin, Bruno R. Varet, Agnes Buzyn, and Elizabeth A. Macintyre. "Prediction of Relapse Risk by Day 100 BCR-ABL Quantification after Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukaemia." Blood 106, no. 11 (November 16, 2005): 2020. http://dx.doi.org/10.1182/blood.v106.11.2020.2020.

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Abstract CML relapse after allogeneic SCT is a relatively frequent situation and is clearly correlated to disease status, time from diagnosis to transplant and T cell depletion. Defining other risk factors could help modulate post transplant immunosuppression. We evaluated the value of early minimal residual disease (MRD) quantification to predict relapse of CML patients receiving standard allogeneic SCT. MRD was analysed by RQ-PCR at Day 100 in 38 patients with a follow up after transplant > 1 year and was expressed as BCR-ABL/ABL, qualified by objective evaluation of RNA amplifiability relative to local normal values for MRD samples (the Quality Index or QI). This QI allows objective evaluation of the degree of correction for positive results and modification of the limits of detection for negative results. Thirty six of 38 patients received conventional conditioning regimen with either BU/CY or TBI/CY and classical prevention of GVHD based on cyclosporin and methotrexate. The median time from diagnosis to transplant was 21 months and median follow up of the cohort was 76.8 months. Patients were allocated to two groups according to their Day 100 RQ PCR level. We compared the characteristics and evolution of the 14 patients with a high MRD level (Day 100 RQ PCR >10−4) to that of the 24 patients with a low MRD level (Day 100 RQ PCR <10−4). There were no significant differences in terms of disease status at transplant, median age at transplant, time from diagnosis to transplant, type of conditioning regimen, source of stem cells, sex mismatch, grade of acute GVHD or incidence of chronic GVHD between the two groups. We show that Day 100 BCR-ABL transcript levels >10−4 by RQ-PCR represents an independent risk factor of relapse after conventional non T cell depleted SCT. These data should favour risk-adapted post transplant immunosuppression based on a single time point early evaluation of MRD.

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Muzikova, Katerina, Eva Fronkova, Lucie Sramkova, Leona Reznickova, Renata Formankova, Petr Sedlacek, Jan Stary, and Jan Trka. "Detectable Minimal Residual Disease before Haematopoietic Stem Cell Transplantation Predicts Extremely Poor Prognosis in Children with Acute Lymphoblastic Leukaemia." Blood 106, no. 11 (November 16, 2005): 2037. http://dx.doi.org/10.1182/blood.v106.11.2037.2037.

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Abstract The level of minimal residual disease (MRD) prior to allogeneic haematopoietic stem cell transplantation (HSCT) was shown to be an independent prognostic factor for the outcome of paediatric patients with high-risk acute lymphoblastic leukemia (ALL). Retrospective studies which used (semi-)quantitation of clone-specific immunoglobulin/T-cell receptor (Ig/TCR) rearrangements documented feasibility and practicality of such an approach. Recently, this approach was disputed by Imashuku et al (BMT 2003) due to great occurrence of the clonal evolution and generally high MRD levels prior HSCT in their cohort. In our prospective study, MRD before and after HSCT was monitored in a cohort of 36 children with ALL consecutively transplanted in our centre between VIII/2000 and VII/2004. We used a quantitative real-time PCR approach introduced and standardised by European Study Group on MRD in ALL. In 25 of 36 patients MRD level prior HSCT was assessed (9 patients lacked adequately sensitive Ig/TCR target; two lacked analysable DNA prior HSCT). Seventeen patients were MRD-negative prior HSCT (including two with MRD level below the quantitative range 10(−4)) and 8 were MRD-positive up to 9x10(−2). In the MRD-positive subgroup, 7 events (6 relapses) occurred post-transplant in striking contrast to only one relapse in MRD-negative subgroup (EFS log-rank p<0.0001). MRD proved to be the only significant prognostic factor in a multivariate analysis (p<0.0001). Adoptive immunotherapy including donor lymphocyte infusions in patients with adverse dynamics of MRD after HSCT had only limited and/or temporary effect. Clonal evolution did not present a problem precluding MRD monitoring in any of patients suffering a post-transplant relapse. We show that MRD quantitation using clonal Ig/TCR rearrangements represents a feasible approach for the risk assessment in paediatric ALL patients undergoing allogeneic HSCT. However, our ability to respond to detectable MRD levels after HSCT and to avert an impending relapse is very limited. The change of the approach to MRD-positive patients prior HSCT is necessary because of very questionable benefit of HSCT in these children. Supported by grants MSM0021620813, FNM 9735 and GAUK 62/2004.

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Galvão, Maria Margarida, Zulma Fernandes Peixinho, Nelson Figueiredo Mendes, Luiz Estevão Ianhez, and Emil Sabbaga. "Endolymphatic irradiation in preparation for renal transplantation: a 26-year's follow-up." Sao Paulo Medical Journal 116, no. 3 (May 1998): 1710–14. http://dx.doi.org/10.1590/s1516-31801998000300004.

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OBJECTIVE: The aim of the present study was to analyze the long-term evolution of patients submitted to endolymphatic irradiation as a pre-transplant preparation. SETTING: Referral center of university hospital. DESIGN: Case-control study. MAIN OUTCOMES MEASURES: The study was designed to evaluate the incidence of rejection, kidney loss, leukopenia, infection, and graft survival in the group treated (group 1) prior to surgery, compared to a control group (group 2) composed of patients under identical clinical conditions (sex, age, type of donor, immunosuppressive therapy and time of transplant) that did not undergo treatment preparation. PATIENTS: Patients were selected from amongst transplantation candidates on a long-term waiting list, some with a high level of antibodies against panel. The control group was chosen from amongst recently transplanted patients. Patients in the treated group received lipoiodine containing 131I with specific activity ranging between 4 and 6 mCu/ml. RESULTS: A significant difference between the two groups was found with regard to the incidence of rejection crises (21.0% in group 1 and 73.6% in group 2; P= 0.003), and the maintenance dose of azathioprine (smaller in group 1; P< 0.01). As to kidney graft loss due to rejection, a tendency to significance could be identified (10.5% in group 1 and 42.1% in group 2; P= 0.063); however, the difference was not significant between the two groups in terms of reversibility of rejection episodes during the first 60 post-transplant days. CONCLUSIONS: The authors concluded that this method, besides being relatively innocuous (there was no compromising of either the thyroid gland or of gonad function and there was no increase in tumor incidence), has an extended immunosuppressive effect, and can be indicated for cadaveric renal allograft recipients, especially those showing high panel reactivity.

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Jan, Max, Matt J. Leventhal, Elizabeth A. Morgan, Jordan Chase Wengrod, Anewsha Nag, Samantha D. Drinan, Bruce M. Wollison, et al. "Recurrent Genetic HLA Loss in Acute Myeloid Leukemia Relapsed after Matched Unrelated Allogeneic Hematopoietic Cell Transplant." Blood 132, Supplement 1 (November 29, 2018): 817. http://dx.doi.org/10.1182/blood-2018-99-113911.

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Abstract Introduction: Leukemic escape from the graft versus leukemia (GVL) effect of allogeneic hematopoietic cell transplantation (HCT) is poorly understood. During prolonged periods of post-transplant remission, immunologic selection pressure can favor relapse mediated by acquired resistance to GVL-mediated clearance, such as loss of mismatched HLA in haploidentical transplants. We hypothesized that genetic mechanisms of immune evasion can cause late relapses after matched unrelated donor transplants for myeloid malignancies. Methods: We evaluated 580 adult patients with myeloid malignancies who underwent allogeneic HCT at our institution between 2001 and 2014 and experienced subsequent disease relapse. In 19% of these patients (n=112) relapse occurred at least one year after transplantation. The 25 patients included in the study had specimens banked at each of three timepoints: 1) prior to transplantation, with AML or MDS involvement, 2) approximately 100 days after transplantation, during the period of remission 3) at the time of disease relapse. The indications for transplantation were AML (n = 20) and MDS (n = 5). Transplants were from matched unrelated (n=14), matched related (n=9), and mismatched unrelated (n=2) donors. 12 patients received myeloablative conditioning and 13 received reduced-intensity conditioning regimens. Targeted sequencing of 187 genes, selected based on pathogenic involvement in myeloid malignancies or suspected involvement in immune evasion, was performed on all three timepoints from each patient. Genome-wide microarray-based copy number assessment was performed onthe pre-transplant specimen and post-transplant relapse specimens. Results: We identified three recipients with relapse-specific HLA loss via 1-8 Mb deletions or chromosome 6p arm-level copy neutral uniparental disomy (UPD). One of the HLA alterations was a deletion spanning HLA-B and HLA-C in a donor/recipient pair mismatched at HLA-C. However, in two other cases, relapse-specific HLA losses were identified in donor/recipient pairs that were fully matched at A, B, C, and DRB1. These findings suggest that HLA loss may allow leukemic cells to escape allogeneic immune recognition of minor HLA discrepancies and/or the presentation of minor histocompatibility antigens in the context of matched MHC presentation. These three HLA losses were identified among 14 recipients of matched unrelated donor HCT. HLA losses were not identified among recipients of matched related (n = 9) or mismatched unrelated (n = 2) allogeneic HCT. To evaluate potential interactions between canonical myeloid driver mutations and immunologic alterations, we defined the genetic characteristics of paired pre-transplant MDS/AML samples and post-transplant relapsed samples. In 22 out of 25 cases, at least one driver mutation that was present in the pre-transplant sample was also detected in the relapse sample. Clonal genetic evolution was common at the time of relapse and predominantly involved the acquisition of new subclonal mutations affecting mitogenic signaling (n = 9) and myeloid transcription factors (n = 11). TP53 alterations, including point mutations and 17p deletions were identified in 6 out of 25 patients, including two that remained stable before and after transplantation, and four that were newly detected at the time of relapse. Conclusions: We identified recurrent HLA loss via 6p UPD and segmental deletions in 3 out of 14 patients with late relapse after matched unrelated HCT. Although HLA loss has been observed at relapse after haploidentical HCT, the role of HLA loss as a mechanism of relapse after non-haploidentical HCT has remained unclear. HLA loss in cases with late relapse indicates a prolonged period of immunologic equilibrium, where effective GVL serves as a selective pressure for clonal genetic mechanisms of alloimmune evasion. In the context of MURD HCT, HLA loss provides genetic evidence that allogeneic immune recognition may be mediated by minor histocompatibility antigens and suggests opportunities for novel immunologic approaches for relapse prevention. Disclosures Ho: Jazz Pharmaceuticals: Consultancy. Nikiforow:Kite Pharma: Consultancy. Antin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Soiffer:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

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Claudiani, Simone, Francesca Lunghi, Fabio Giglio, Giorgia Levati, Maria Teresa Lupo Stanghellini, Sarah Marktel, Matteo Carrabba, et al. "Treosulfan Based Myeloablative Regimen Provides High Rate Of Allogeneic Engraftment and Low Toxicity In Patients With Advanced Myelofibrosis,." Blood 122, no. 21 (November 15, 2013): 5504. http://dx.doi.org/10.1182/blood.v122.21.5504.5504.

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Abstract Abstract 5504 Backgroud Allogeneic transplantation (HSCT) is the only potentially curative therapy for myelofibrosis, even in the era of new drugs that only impact on selected manifestations of disease. The time to evolution of myelofibrosis in advanced phases is variable (months to several years). The choice to proceed to allogeneic transplantation is based on several clinical variables; conditioning regimen and time to transplantation may influence the outcome of HSCT. Here we present our experience in a group of patients with myelofibrosis transplanted in Our Center with a myeloablative regimen based on full dose of treosulfan. Methods We retrospectively evaluated 20 patients (15 male) with primary myelofibrosis (14) and post-ET (essential thrombocythemia) myelofibrosis (6) who underwent HSCT at our institute from July 2005 to February 2013. In this cohort we included 4 patients in blast phase, 3 of which received a brief course of chemotherapy prior to transplant; 4 patients who underwent a second allogeneic transplantation for disease relapse (2) or graft failure (1); 1 patient referred at our Institute in graft failure 3 months after first HSCT. Only 1 patient had splenectomy before HSCT. Results The median age at diagnosis was 59 years (range 41-76). JAK2 V617F mutation was positive in 7 and unknown in 3 patients. In post-ET MF patients, the median time to transformation in MF was 134 months (60-144). The median time from diagnosis to transplant was 14 months (4-101 months). The median age at transplant was 62 years. DIPSS score at transplant was low in 1, int-1 in 3, int-2 in 13 and high in 3 patients. We adopted myeloablative regimen based on treosulfan 42 gr/ms and fludarabine 150 mg/ms, plus TBI 4 Gy in 7 patients. GvHD prophylaxis was based on ATG, Rituximab and CSA/MTX (8 pts) or rapamycin (11 pts). The graft was PBSCs (19) and BM (1) from related HLA-identical donor (7 pts), matched unrelated donor (5 pts) and haploidentical donor (8 pts). The incidence of graft failure and poor graft function was 5% and 20% respectively. The median time to neutrophils engraftment was 20 days. The incidence of acute and chronic graft versus host disease was 50% and 40% respectively. Cumulative incidence of TRM (transplant related mortality) was 45 %; day 100 OS (overall survival) was 70% while 2 year OS was 40%. In multivariate analysis there was no statistically significant correlation between individual factors (including WBC, hemoglobin, platelets, ferritin, beta2-microglobulin, IgA, IgG, IgM, LDH, psuedocholinesterase levels, age, Sorror comorbidity score, donor match, bone marrow kariotype) and survival. However, we found that a linear composition of level of peripheral blasts (0%, ≥1%, ≥5%), bone marrow CD34+ cells (<5%, ≥5%, ≥20%), spleen size and number of red blood cells units transfused pre-HSCT is able to predict the outcome (p-value 0.03), even if each factor alone is not strongly correlated with survival. There was no statistical significant correlation between the outcome and DIPSS score, Bacicalupo score and Lille score. Conclusions A myeloablative regimen based on full dose treosulfan provide a 95% rate of primary allogeneic engraftment and 40% overall survival in myelofibrosis at advanced stage, with low extra-hematological toxicity in frail patients. Allogeneic transplantation after myeloablative low-toxicity regimens may be offered in myelofibrosis in early chronic phase of disease and for younger patients, two conditions usually linked with durable engraftment, low toxicities and low rate of relapse. Disclosures: No relevant conflicts of interest to declare.

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Khoriaty, Rami, Matthew Vasievich, Morgan Jones, Lesley Everett, Bin Zhang, Ivan Maillard, and David Ginsburg. "Disparate SEC23B Deficient Phenotypes in Humans and Mice." Blood 120, no. 21 (November 16, 2012): 974. http://dx.doi.org/10.1182/blood.v120.21.974.974.

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Abstract Abstract 974 SEC23 is a core component of the COPII coated vesicle that mediates the transport of cargo proteins from the endoplasmic reticulum to the Golgi apparatus. Mutations in human SEC23B, one of two mammalian SEC23 paralogs, results in the autosomal recessive disease, congenital dyserythropoietic anemia type II (CDAII). In contrast, SEC23B deficient mice were recently reported to die perinatally with massive pancreatic degeneration, with no evidence of anemia at birth (Tao, et al., 2012. Proc.Natl.Acad.Sci.U.S.A. 109:E2001–9.) To examine the impact of SEC23B deficiency on hematopoietic function in mice surviving beyond the immediate perinatal period, lethally irradiated C57BL/6J mice were transplanted with fetal liver cells (FLC) collected from E17.5 embryos that were either wild-type (WT) or homozygous for the previously reported Sec23b gene trap allele (Sec23bgt/gt). Recipients of Sec23bgt/gt FLC were indistinguishable from their WT transplant controls and exhibited none of the phenotypic characteristics of CDAII (anemia, increased bi/multi-nucleated RBC precursors, narrower band size and increased shift of the membrane protein band 3 on SDS gel electrophoresis, or RBC double membrane appearance by electron microscopy). To test for a more subtle defect in hematopoietic reconstitution, Sec23bgt/gt FLCs were co-transplanted with WT GFP+ FLC in a 1:1 ratio, with no competitive difference observed over the course of 18 weeks of follow-up. Transplant of marrow from these chimeric animals into secondary recipients demonstrated continued equivalence of Sec23bgt/gt and WT hematopoietic stem cells. To rule out an incidental mutation in a nearby gene (“passenger gene”) as the cause of the pancreatic phenotype in SEC23B-deficient mice, two Sec23b bacterial artificial chromosome transgenes were crossed into the Sec23bgt line, with both demonstrating complete rescue of the Sec23bgt/gt pancreatic phenotype, with normal survival to adulthood. Sec23bgt/gt murine embryonal fibroblasts express a SEC23B/βGEO fusion protein consistent with the gene trap insertion into Sec23b intron 19, and this fusion protein co-immunoprecipitates with SEC24A (Tao, et al., 2012. Proc.Natl.Acad.Sci.U.S.A. 109:E2001–9). To rule out a contribution of the SEC23B/βGEO fusion protein to the disparate human and mouse SEC23B-deficient phenotypes, a second, conditional SEC23B allele was analyzed, in which exons 5 and 6 are flanked by loxP sites (Sec23bfl). Deletion of exons 5 and 6 results in frame shift and stop codon in exon 7. Mice with an erythroid-specific deficiency of SEC23B were generated by crossing the Sec23bfl allele to an EpoR-Cre transgene. Sec23bfl/-/EpoR-CreTg+ mice exhibit no anemia compared to their WT litter mates. Transplant recipients of FLCs from E16.5 embryos homozygous for a germline deletion of Sec23b exons 5 and 6 (Sec23b−/−) were also indistinguishable from mice receiving WT FLCs. Pancreas-specific knock-out generated by crossing the Sec23bfl allele to a p48-Cre or Pdx1-Cre transgene confirmed the pancreatic phenotype observed. This suggests that the perinatal lethality in Sec23b deficient mice may be the result of the loss of pancreatic Sec23b expression. To explore the mechanism for the disparate human and mouse SEC23B-deficient phenotypes, the expression patterns for SEC23A and SEC23B were examined in mice and humans by RT PCR and western blotting. The ratio of SEC23B/SEC23A expression is higher in mouse pancreas (12.7) compared to bone marrow (2.6), whereas in humans, the ratio is higher in the bone marrow (7.8) relative to pancreas (5.5) (normalized to liver). Taken together with the high degree of sequence similarity between SEC23A and SEC23B (∼ 85% identity at the amino acid level), we hypothesize that these 2 SEC23 paralogs overlap extensively at the level of protein function, with the disparate deficiency phenotypes due primarily to differences in tissue and developmentally-specific gene expression programs that have shifted extensively during recent mammalian evolution. These findings have important implications for the comparative function of other closely related paralogous genes. Further studies of the overlapping functions of SEC23A and SEC23B and their relevant protein cargos should provide new insight into the pathogenesis of CDAII and potential therapeutic approaches. Disclosures: Ginsburg: Shire Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Portola Pharmaceuticals: Consultancy; Catalyst Biosciences: Consultancy; Baxter Pharmaceuticals: benefit from payments to Children's Hosptial, Boston, and the University of Michigan Patents & Royalties; Merck Pharmaceuticals: Consultancy.

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Sinclair, Paul B., Lars Buechler, Joanna Cheng, Jake Clayton, Claire Schwab, Lisa Jones, Helen Blair, et al. "Clonal Progression Including Evolution Of An iAMP21 Chromosome In Xenograft Models Of BCP-ALL." Blood 122, no. 21 (November 15, 2013): 2485. http://dx.doi.org/10.1182/blood.v122.21.2485.2485.

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Abstract Insight into the role of recurrent genomic changes arising in leukemia has depended largely on the functional analysis of cell lines and transgenic animals. However not all acquired abnormalities are represented in available cell lines and a few are too complex to be faithfully engineered in animal models. One such abnormality is intrachromosomal amplification of chromosome 21 (iAMP21), a heterogeneous cytogenetic rearrangement, with a distinct clinical profile, occurring in 2% of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The most highly amplified segment of iAMP21 varies in size and copy number but has always included a 5.1 Mb common region of amplification (CRA). Regions flanking the most highly amplified segment have profiles that may be step-like, or more complex combinations of lower level amplification, normal copy number and deletion. Abnormalities at other chromosomal locations such as deletions of IKZF1, CDKN2A/B or RB1 and rearrangements activating CRLF2 co-occur with iAMP21 but have never been shown to precede its formation. To investigate clonal evolution and to provide a resource for future functional studies, we established xenografts from three cases of iAMP21 BCP-ALL in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Signs of disease were seen between 6 and 8 months after intrafemoral injection and autopsy revealed marked splenomegaly in all cases. Cells isolated from the bone marrow and spleen, were positive for human B cell markers CD19 and CD10. Disease onset was more rapid (3-6 months) when primografts were transplanted and cells from these secondary mice were used to establish leukemia in a third generation. Whole body imaging of mice transplanted with xenograft cells, transduced with a lentivirus expressing luciferase, revealed the rapid spread of disease from the injection site to the contralateral femur, sternum, pelvis, ribs, spine and skull, with the spleen becoming the major site of engraftment at late stage disease. Comparison of SNP 6.0 array profiles of presentation and xenografts samples revealed several examples of post-transplant genomic progression which, with the exception of a biallelic deletion of the CDKN2A/B locus, had not previously been reported in iAMP21 patients. Additional copies of chromosomes 9 and 12 in patient samples were lost in xenografts resulting in copy number neutral loss of heterozygosity (CNN-LOH) for chromosome 12 but not 9. Analysis of further primary iAMP21 BCP-ALL cases identified two with CNN-LOH for part of the long arm of chromosome 12, suggesting involvement of an imprinted locus in this region. iAMP21 chromosomes were retained in all xenografts, supporting evidence that it is a primary abnormality. However, as these rearrangements have been considered to be stable once formed, we were surprised to observe acquisition of a non–contiguous deletion of chromosome 21 in one secondary mouse and all of its tertiary recipients. The deletion was proximal to the CRA and resulted in extension of pre-existing haploinsufficient regions by 6.6 Mb. Evolution of this iAMP21 chromosome was confirmed by fluorescence in-situ hybridisation (FISH) using probes targeting the deletion, with loss of signal observed in all cells from mice carrying the deletion but in no cells from the presentation sample or unaffected mice. Although we cannot rule out that the deletion arose in response to adaptive pressure specific to the xeno-environment, opportunities to observe similar progression in patients have been limited because FISH analysis has generally targeted only the CRA and few paired presentation/relapse samples have been analysed by genomic array. While it remains likely that overrepresentation of oncogenes within the CRA acts as a primary driver of iAMP21 BCP-ALL, the additional deletion may highlight the position of tumour suppressor genes involved in leukemia progression. As these patients are treated as a single clinical entity, an important implication of these data is that the position and extent of deletions in iAMP21 rearrangements may influence response to therapy. In conclusion, xenografts of iAMP21 BCP-ALL closely resemble human primary disease and will make valuable pre-clinical models for basic and translational research. As models for the study of clonal evolution they support previous evidence that iAMP21 is a primary abnormality and have revealed novel forms of clonal progression. Disclosures: No relevant conflicts of interest to declare.

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Adair, Jennifer E., Christopher R. Burtner, and Hans-Peter Kiem. "Maintenance of Leukocyte Telomere Length after Transplant and Chemoselection in Macaques with Polyclonal Gene Modified Cell Engraftment." Blood 126, no. 23 (December 3, 2015): 3236. http://dx.doi.org/10.1182/blood.v126.23.3236.3236.

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Abstract Hematopoietic stem and progenitor cell (HSPC) gene therapy relies on stable therapeutic levels of gene-modified HSC engraftment. The variant methylguanine methyltransferase gene, P140K, can increase gene modified cells levels in vivo after administration of O6-benzylguanine (O6BG) and non-myeloablative bis-chloroethylnitrosurea (BCNU). However, the biological consequences of chemoselective pressure on HSPC are unknown. It is known that HSPC transplantation causes leukocyte telomere shortening, likely due to proliferative demand on engrafted blood progenitor cells required for hematopoietic reconstitution following myeloablative conditioning. Additionally, telomere shortening is associated with chromosomal instability preceding malignant evolution in blood cells. We and others demonstrate stable telomere length in pigtail and rhesus macaques following myeloablative transplantation of autologous lentivirus gene modified HSPCs. However, the selective pressure placed on P140K-modified HSC after O6BG/BCNU treatment may contribute to telomere attrition. To test this hypothesis, we performed a longitudinal assessment of telomere length on peripheral blood leukocytes using a quantitative PCR method in five pigtail macaques. Macaques received myeloablative total body irradiation (1020cGy) followed by infusion of autologous HSPC gene-modified with either a gammaretrovirus or a lentivirus encoding the P140K transgene. In all animals, O6BG/BCNU effectively increased the contribution of gene-modified cells in the blood. However, in two animals (J02370 and M02426), chemoselection was associated with a loss in total leukocyte telomere length. We sorted modified and non-modified cells in J02370 based on a fluorescent marker, and found that gene-modified leukocytes in animal J02370 displayed significantly shorter telomeres than the non-modified leukocytes. To determine the relative number of gene-modified clones contributing to this phenomenon, we investigated gene-modified clonal contribution over time in each of the five animals. Telomere shortening in animals J02370 and M02426 correlated temporally with emergence of clonal dominance in vivo, whereas animals displaying stable leukocyte telomere length maintained clonal diversity in vivo. In both J02370 and M02426, shorter total leukocyte telomere length was stably maintained with stable levels of the respective dominant clones for up to 1,700 days. Telomere shortening in these animals could be attributed to either increased cell division during clonal outgrowth, or to clonal selection of a progenitor that originally began with shorter telomeres. Importantly, our data suggest that chemoselective pressure on transduced HSPC does not impact telomere length in the setting of polyclonal hematopoiesis. While clonality may exert a negative effect on telomere length, this level of telomere attrition is not associated with malignant transformation or bone marrow failure in this animal model. Disclosures No relevant conflicts of interest to declare.

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Brown, Jennifer R., Stacey M. Fernandes, Siddha Kasar, Kevin Hoang, Martin Moorhead, Victoria Carlton, Malek Faham, David B. Miklos, and Aaron C. Logan. "Next-Generation Sequencing Reveals Clonal Evolution at the Immunoglobulin Loci in Chronic Lymphocytic Leukemia." Blood 124, no. 21 (December 6, 2014): 3302. http://dx.doi.org/10.1182/blood.v124.21.3302.3302.

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Abstract Background: Immunoglobulin (Ig) gene rearrangement is a hallmark of early B-cell development. Chronic lymphocytic leukemia (CLL) is typically considered a malignancy of mature B-cells and is thought to originate from the oncogenic transformation of a single pre- or post-germinal B-cell. Activation-induced deaminase (AID), an enzyme that induces somatic hypermutation (SHM) at the heavy and light chain Ig loci, has been shown to be active in CLL cells in vitro (Patten et al., Blood 2012). Previous studies suggest that multiple CLL-specific Ig clonotypes related by SHM may be present in patients (pts) with dominant CLL clones possessing somatically mutated or unmutated Ig loci (Logan et al., PNAS 2011; Campbell et al., PNAS 2008). To our knowledge, evolution of the dominant CLL-specific Ig clonotype over the course of treatment has not been demonstrated. Here we utilized the LymphoSIGHT™ method, a next-generation sequencing-based method for lymphocyte characterization and quantification, to quantify clonal evolution at the Ig heavy and kappa chain (IGH and IGK) loci in 63 pts with CLL. Methods: Samples were collected at Stanford University and the Dana-Farber Cancer Institute. Peripheral blood mononuclear cells were isolated, and genomic DNA was extracted. Using unbiased universal primer sets, we amplified IGH and IGK variable, diversity, and joining gene segments. Amplified products were sequenced and analyzed using standardized algorithms for clonotype determination (Faham et al., Blood 2012). CLL-specific clonotypes were identified for each patient based on their high frequency (>5%) within the B-cell repertoire of a diagnostic (dx) sample. The highest frequency CLL clonotype identified in a dx sample is termed the “index clonotype”. Dx and post-treatment peripheral blood samples were assessed for evidence of evolved CLL clonotypes using LymphoSIGHT. A clonotype was considered “evolved” based on CDR3 sequence homology to the dx “index clonotype.” Results: CLL clonotypes were identified in dx samples from 63 pts (51 unmutated IGHV; 12 mutated), and we assessed post-treatment samples for the presence of CLL clonotype-associated oligoclonality. Two of 63 pts exhibited clonal evolution in post-treatment samples. One patient with unmutated CLL was MRD negative for over 7 years following allogeneic hematopoietic cell transplant (HCT), and subsequently became MRD positive with the evolved clonotype (differing by 1 nucleotide from the index clonotype) leading to clinical relapse 9 months after MRD positivity, while the original index clone remained undetectable. The patient was treated with ibrutinib upon clinical relapse and continues to have detectable MRD with the same evolved CLL clonotype (Fig 1A). In a second patient with mutated IGHV, we observed several evolved clonotypes in the dx sample. Multiple evolved clonotypes, including 5 that exhibited a significant increase in their frequency relative to the index clonotype, were present in the follow-up sample after treatment with fludarabine and rituximab (Fig 1B). These evolved clonotypes differed from the index clonotype by 1-4 nucleotides, but otherwise shared CDR3 identity, excluding independently arisen B cell clonotypes. Conclusions: We observed evidence of clonal evolution at Ig loci in a small subset (3.2%) of pts with CLL undergoing treatment. The presence of evolution in pts with CLL indicates that either the SHM mechanism, including the AID enzyme, remains active after neoplastic transformation, or the evolved clonotypes arose through a mechanism distinct from SHM. These evolved CLL clonotypes may have a selective advantage, and may be useful as surrogate markers for other oncogenic mutations providing resistance to therapy. Additional cases are under investigation and updated results will be presented. Figure 1. CLL clonal evolution during therapy. MRD levels of two related Ig clonotypes, expressed as leukemia molecules per million leukocytes in peripheral blood, are shown at multiple time points following allogeneic HCT (A). In another patient undergoing conventional treatment, the level of each individual evolved clonotype as a fraction of the total CLL molecules is plotted at dx and post treatment time points. The index clone, evolved clones with increasing levels post-treatment, and evolved clones with decreasing levels post-treatment are shown in red, blue, and white, respectively (B). Figure 1A. Figure 1A. Figure 1B. Figure 1B. Disclosures Moorhead: Sequenta, Inc.: Employment, Equity Ownership. Carlton:Sequenta, Inc.: Employment, Equity Ownership. Faham:Sequenta, Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Gauslaa, Yngvar, and Knut Asbjørn Solhaug. "High-Light-Intensity Damage to the Foliose Lichen Lobaria Pulmonaria within Natural Forest: The Applicability of Chlorophyll Fluorescence Methods." Lichenologist 32, no. 3 (May 2000): 271–89. http://dx.doi.org/10.1006/lich.1999.0265.

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AbstractThe annual course of irradiance was recorded at two vertical and even-aged neighbouring Quercus stems, one rich in L. pulmonaria, one without. Irradiance never exceeded 610 μmol photons m−2 s−1 at the L. pulmonaria site, whereas the L. pulmonaria-deficient site could experience 2 h daily 2000 μmol photons m−2 s−1, and 6 h above 1000 μmol photons m−2 s−1 during a clear day in early spring. Thalli of L. pulmonaria were transplanted to these two stems. During the first 40 days (April–May), transplants at the L. pulmonaria-deficient site developed severe chlorophyll degradation, and a substantial reduction in maximal PS II efficiency (Fv/Fm) even when measured after a 48-h recovery period at low light intensity. Extensive bleaching was formed along light-exposed sides of the tiny ridges on the upper side. Subsequent to this damage, FV/FM gradually rose to nearly normal levels during the following year. This apparent recovery was probably mainly due to irreversible loss of damaged chlorophyll, but also to some level of acclimation. No damage was observed in control transplants on the L. pulmonariarich tree, which were the only transplants gaining sufficient growth for new attachment to the new substratum during the 397-day transplantation period. Nevertheless, a fine-scale, but highly significant seasonal variation in FV/FM of control transplants reflected variations of even low irradiance levels. FV/FM, as measured after a 48-h recovery period at low light intensity, is an efficient meth for recording permanent high light damages at and shortly after damage is formed. However, FV/FM is not a useful estimator of chronic long-term damage.

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Kumar, Shaji, Ian W. Flinn, Stephen J. Noga, Parameswaran Hari, Robert M. Rifkin, Natalie Scott Callander, Manish Bhandari, et al. "Safety and Efficacy of Novel Combination Therapy with Bortezomib, Dexamethasone, Cyclophosphamide, and Lenalidomide in Newly Diagnosed Multiple Myeloma: Initial Results from the Phase I/II Multi-Center EVOLUTION Study." Blood 112, no. 11 (November 16, 2008): 93. http://dx.doi.org/10.1182/blood.v112.11.93.93.

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Abstract Background: Combination regimens incorporating bortezomib (VELCADE®, Vc), lenalidomide (REVLIMID®, Rev), dexamethasone (Dex) and cyclophosphamide (Cy) (Vc–Dex, Rev–Dex, Vc–Dex–Rev [VDR], and Vc–Dex–Cy [VDC]), have all shown substantial activity in previously untreated multiple myeloma (MM). A combination of all four agents (VDCR) may result in even greater activity. This randomized multi-center 3-arm phase I/II EVOLUTION study is investigating the efficacy and safety of VDR, VDC, and VDCR as initial therapy in previously untreated MM patients (pts). We now report safety and efficacy results from the phase l dose-escalation portion of the study, which sought to determine the maximum tolerated dose (MTD) of the VDCR regimen. These results represent the first clinical data with this novel 4-drug combination that includes bortezomib, lenalidomide, an alkylator, and a corticosteroid. Methods: Pts received Vc 1.3 mg/m2 IV (d 1, 4, 8, 11), Dex 40 mg PO (d 1, 8, 15), Rev 15 mg PO (d 1–14), plus Cy 100, 200, 300, 400, or 500 mg/m2 PO (d 1, 8) for up to eight 21-d cycles, followed by Vc 1.3 mg/m2 (d 1, 8, 15, 22) for four 42-d maintenance cycles. Pts received prophylactic antibiotics, acyclovir, transfusion support and concomitant anticoagulants as required. Eligible pts wishing to receive autologous stem cell transplant (ASCT) could undergo stem cell mobilization any time after cycle 2, and discontinue therapy for ASCT any time after cycle 4. The MTD was defined as the highest dose of Cy in combination with VDR resulting in ≤1 dose-limiting toxicity (DLT) in 6 pts. A DLT was defined as: platelet count <25,000/mm3 lasting >7 days or any platelet count <10,000/mm3; grade 4 neutropenia lasting >7 days; any ≥grade 3 non-hematologic toxicity considered to be related to Cy except for inadequately treated nausea, vomiting, and diarrhea, or any toxicity resulting in a >2 week treatment delay. Results: Twenty-six pts were enrolled; 1 pt was not dosed due to a heart problem and was excluded (dose level 4) and 4 pts were not evaluable for DLT. In the 25 treated pts, median age was 61 years (range 49–79); 52% were male; 48% had ISS Stage lI and 4% Stage III disease, and 44% had KPS ≤80%. At data cut-off, 11 pts remain on treatment and 9 have undergone successful ASCT. To date, median treatment duration is 4 cycles (range 2–11). Two pts experienced DLT: 1 grade 4 febrile neutropenia at dose level 4 (Cy 400 mg/m2), and 1 grade 3 herpes zoster virus reactivation despite antiviral prophylaxis at dose level 5 (Cy 500 mg/m2). The recommended phase II dose of Cy in the VDCR regimen was the highest planned dose of 500 mg/m2. The most common treatment-emergent AEs were constipation (64%), fatigue (60%), and nausea (52%). Hematologic toxicities were acceptable, with grade 3 neutropenia in 16% of patients, grade 4 in 4%, and grade 4 thrombocytopenia in 4%. Peripheral neuropathy (56%), included 8% grade 3 but no grade 4; no deep-vein thrombosis/pulmonary embolism events were reported. Overall rate of serious AEs was 40%; the only SAE reported in >1 pt was febrile neutropenia (2 pts). Best responses to date by International Uniform Response Criteria are shown in the table. Preliminary response rates are: 100% ≥PR, 68% ≥VGPR, 32% CR/nCR, 28% CR/stringent CR and 20% sCR. Ten pts have undergone stem cell mobilization with median CD34+ yield of 4.95×106/kg. Conclusions: VDCR was well tolerated and hematologic toxicities were manageable. The current study shows that the VDCR regimen is feasible and highly active in newly diagnosed myeloma and merits further testing in clinical trials. Enrollment to the 3 arms (VDR, VDC and VDCR) of the phase ll portion of the study and testing for minimal residual disease by flow cytometry are ongoing. Best unconfirmed response to date with VDCR Dose level 1 2 3 4 5 Cyclophosphamide dose, mg/m2 100 200 300 400 500 Enrolled 3 4 4 8 7 Treated 3 4 4 7 7 Still on treatment – 1 1 2 7 Best unconfirmed response to date CR (sCR) 2 (2) 1 (1) 1 (1) 2 1 (1) VGPR (nCR) 1 – 3 (1) 4 2 PR – 3 – 1 4

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Radhakrishnan, Neetu, and Mark A. Hoffman. "Hypercalcemia in B-Cell Chronic Lymphocytic Leukemia: Report of a Case and Review of the Literature." Blood 106, no. 11 (November 16, 2005): 5009. http://dx.doi.org/10.1182/blood.v106.11.5009.5009.

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Abstract A 53 year old man with Rai stage IV CLL was being treated with R-HyperCVAD when he presented between cycles with fatigue, lethargy and pancytopenia. Clinical examination revealed diffuse adenopathy and splenomegaly. Serum calcium was 13.6 mg/dl, phosphorus level was 2.7 mg/dl, and alkaline phosphatase was 54 U/L. PTH was 4 Units/L (10–65), PTHrP < 0.2 pmole/L (0–1.9), 1–25 (OH) Vitamin D < 10pgm/ml (22–67). Quantitative immunglobulins: IgA 10 mg/dl, IgG 252 mg/dl, IgM 50 mg/dl. Immunofixation revealed a faint IgG lambda paraprotein. There were no lytic lesions on skeletal survey. Bone marrow biopsy revealed focal large cell transformation (Richter’s syndrome). Cytogenetics revealed 3 metaphases with complex cytogenetic abnormalities, indicating clonal evolution. The hypercalcemia resolved with appropriate therapy, but despite subsequent treatment with CAMPATH, he died 2 weeks after diagnosis. A review of reported patients with CLL and hypercalcemia in the literature was performed from 1980 onwards using MEDLINE and PubMed; only those cases in which clinical aspects, biochemistry, PTH levels, imaging studies and concurrent pathology (if obtained) were documented, are summarized in this analysis (n=13). Rai stage: I n=1, II n=4, III n=3, IV n=5. Immunoreactive PTH levels were low or normal in 100% of patients. In 5 cases in which it was measured, 1–25 (OH) Vitamin D levels were not elevated. PTHrP was normal in 2 cases and elevated in 1. In nine patients, multiple lytic bone lesions were present on skeletal radiology. Two patients had osteopenia without lytic lesions. Two had no lytic lesions. Six of ten patients had evidence of transfomation on lymph node and/or bone marrow biopsy performed at the time of evaluation for hypercalcemia. Prognosis was poor (range 0.5–12 months) with only one patient surviving post allo-transplant. In conclusion, hypercalcemia in CLL is rare. Osteolytic lesions are present in the majority of cases. PTH levels are low, and thus this hormone is not mediating the hypercalcemia. The evidence is also against a role of elevated Vitamin D. Histological transformation is seen in half of the cases. Survival is poor after diagnosis of hypercalcemia. The mechanisms(s) of the osteolysis and hypercalcemia remain to be defined.

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Brousse, Valentine, Lucie Hertz-Pannier, Jean-Louis Bresson, and Mariane De Montalembert. "Regular Blood Transfusion Does Not Prevent Progression of Cerebral Lesions Evidenced by Magnetic Resonance Imaging in Children with Sickle Cell Disease (SCD)." Blood 108, no. 11 (November 16, 2006): 792. http://dx.doi.org/10.1182/blood.v108.11.792.792.

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Abstract Purpose: The effects of chronic transfusion on the cerebral vessel abnormalities in SCD patients are unknown. Chronic transfusion has been reported to be effective in preventing recurrence of overt strokes, and occurrence of a first stroke in children with abnormal transcranial Doppler ultrasonography (TCD). However, cerebrovascular events may occur despite adequate prevention, suggesting that transfusion therapy does not cure nor even stabilize vessels disease. We conducted a single center retrospective study to determine the evolution of cerebral lesions in SCD children on regular transfusion therapy using magnetic resonance imaging. Material and methods: Children with homozygous sickle cell anemia chronically transfused for first or secondary prevention of stroke were included in the study. All patients had been started in a program of monthly transfusions, maintaining constantly hemoglobin S level below 30%, in the month following the stroke or the abnormal TCD. They underwent cerebral magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) every one to two years. An expert neuroradiologist unaware of the date of the imaging and unaware of the identity of the patients reviewed resulting images. Standard MRI criteria were used to identify lacunae, cerebral atrophy, infarcts and leucoencephalopathy, with progressive grading. Standard MRA criteria were used to identify arterial tortuosity, stenosis/occlusion and moya-moya with progressive grading. All MRI and MRA were scored, and these scores were compared longitudinally in each patient using a Paired Rank test. Results: 18 children (9 males, 9 females) were enrolled. Chronic transfusion therapy was prescribed and initiated for 10 patients with initial strokes (mean age at the stroke 6,8 +/− 2,5 yrs) and 8 patients with abnormal TCD (mean age at the TCD 7,2 +/− 2,9 yrs). Mean follow-up was 6,8 +/− 4,1 yrs in the stroke group, 1,7 +/− 1,0 yrs in the abnormal TCD group. A total of 45 MR images were reviewed (median MR/patient: 3 [2–4]). Initial scores were lower in the abnormal TCD group than in the stroke group (mean score respectively 1 [0–7] versus 12 [2–26]). Comparison of longitudinal scores in the group of patients with initial stroke evidenced progression of lesions (p=0,008). The longitudinal scores were not significantly different in the abnormal TCD group, but this may be explained by the shorter follow-up. Conclusion: Blood transfusion maintaining permanently HbS level <30% does not prevent progression of cerebral micro or macro vascular lesions in SCD children having had a 1st stroke. A lengthier follow-up is needed to reach a conclusion in the case of children with abnormal TCD. Our results support the case that early bone marrow transplant therapy should be applied to prevent progression of cerebral vasculopathy in SCD children at risk.

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Blanquer, Miguel, Francisca Iniesta, Miguel Angel Perez-Espejo, Jose Meca, Joaquín Gómez Espuch, Ramón Villaverde, Virginia Izura, et al. "Intraspinal Infusion of Bone Marrow Mononuclear Cells to Treat Amyothrophyc Lateral Sclerosis, Results of a Controlled Phase I-II Study." Blood 112, no. 11 (November 16, 2008): 2896. http://dx.doi.org/10.1182/blood.v112.11.2896.2896.

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Abstract Introduction: Patients with Amyothrophyc Lateral Sclerosis (ALS) typically endure a progressive paralysis due to the continued loss of motoneurons that leads them to death in less than 5 years. No treatment has changed its natural history. Intraspinal injections of bone marrow mononuclear cells (MNC) have been able to ameliorate the course of ALS in murine models, acting as pumps of trophic factors that keep the motoneurons functional. We have designed a phase I/II clinical trial to check the feasibility of this approach in humans. Material and Methods: 10 patients were required for this study. Inclusion criteria required a medullar onset of the disease, a forced vital capacity (FVC) >50% and under 90% desaturation time inferior to 2% of the sleeping time. Sixty mL of bone marrow were harvested under sedation. A ficoll procedure was performed in order to obtain the MNC, which were resuspended in 2 mL of saline. After laminectomy, the MNC were infused through a spinal needle in 2 injections 10 and 6 mm deep in the posterior tract of T3–T4 under electrophysiological surveillance. This level was chosen aiming the preservation of the lower intercostals function as a mean to stop the deterioration of the FVC, and thus prolong this patient’s survival. Patients are followed for 6 months before the infusion, to establish the individual evolution of the disease, and every three months for 1 year after the procedure. Results: 26 of 116 clinical histories submitted for revision to enter the trial initially met the inclusion criteria. Out of 26, 15 patients had to be excluded because they didn’t meet the inclusion criteria either in the first or subsequent visits prior to the procedure. Seven patients, 3 males and 4 females (median age 46 years, range 32 – 61) have been infused so far. All patients had received multiple prior medical treatments. Median time from diagnosis to cellular infusion was 20 months (range 15 – 47). We infused a total of 402 ×106 (240–602.8) MNC, including 3.16 ×106 (0.96–10.25) CD34+ cells. After ≥6 months of follow-up, assessment of the FVC’s evolution and the score points of the international ALS-FRS, Norris and MRC scales, revealed that of two rapidly evolving patients, one achieved stabilization of the progression and one was unaffected by the intervention. Five patients whose disease evolved more slowly also achieved stabilization of the functional scales or maintained basal FVC values (Fig. 1). Serial magnetic resonance image studies did not show any spinal cord damage. There were two severe adverse reactions (AE): 1 syncope secondary to constipation, and 1 admission due to a high tract respiratory infection with transient respiratory insufficiency in the patient in which the transplant was ineffective. Other AEs of WHO grade 1 or 2 and less than 2 months of duration were: constipation (7), intercostal pain (3), CSF hypotension (2) and lower limbs paresthesias (5, 1 of them persistent). After 6 months of follow-up, all patients had asymptomatic abolition of the somato-sensorial potentials of the posterior tract. Conclusions: The procedure was safe and feasible. No major complications or significant morbility was observed. Stabilization of the disease was achieved in 6 of the first 7 patients included in the protocol. The only unresponsive patient had developed bulbar involvement at the time of the infusion, an already known adverse prognostic factor for response to this type of cellular therapy. Figure Figure

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Leskovar, Daniel I., and Yahia A. Othman. "Direct Seeding and Transplanting Influence Root Dynamics, Morpho-Physiology, Yield, and Head Quality of Globe Artichoke." Plants 10, no. 5 (April 29, 2021): 899. http://dx.doi.org/10.3390/plants10050899.

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The objective of this two-year field study was to assess the influence of stand establishment methods (direct seeding or transplanting) on root growth dynamics, shoot morphology, leaf physiology, yield, and quality of globe artichoke (Cynara cardunculus). Three artichoke cultivars were evaluated, ‘Green Globe Improved’ (GGI), ‘Imperial Star’ (IS), and ‘Romolo’ (ROM). Plants established with the transplanting method had higher mean root length intensity (La), root length, and root surface area as compared to plants established by direct seeding. The topsoil (0–20 cm) had on average higher La, root length, and root surface area than deeper soil profiles. Transplanted plants had higher plant shoot width and leaf area index (LAI) chlorophyll content index (SPAD) than direct seeded plants at the vegetative stage in 2015. The improvement of root and shoot growth in transplants (compared to direct seeding) also resulted in higher (p < 0.05) marketable yield (21.1 vs. 19.9 ton ha−1 in 2015 and 18.3 vs. 13.7 ton ha−1 in 2016). Additionally, 46–50% of the total yield occurred during the first 30 days of harvest in the transplanting method compared to 13–38% for direct seeding. No significant differences were found between planting methods or cultivars in leaf-level gas exchange (photosynthesis, stomatal conductance, and transpiration) and cynarin concentration in the marketable heads. Although chlorogenic acid was similar in both establishment methods in 2015, direct seeding had higher concentration in 2016. Comparing cultivars, GGI had higher root length, surface area, root volume, and earlier and higher marketable yield than ROM. However, ROM had higher mean root length intensity (La; total root length per specific area in soil profile) than GGI in both growing seasons. This study showed significant and consistent improvements in root and shoot traits, and yield for transplants as compared to direct seeded plants.

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Perales, Miguel, Ying Taur, Ingrid Leiner, Marissa N. Lubin, Boze Susac, Eric G. Pamer, and Juliet N. Barker. "Quantitative Assessment of T Cell Repertoire Recovery after Double Unit Cord Blood Transplantation Demonstrates Early T Cell Diversity and Correlation Between CMV Reactivation and CD8 Clonal Domimance." Blood 124, no. 21 (December 6, 2014): 1158. http://dx.doi.org/10.1182/blood.v124.21.1158.1158.

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Abstract Introduction: Double-unit cord blood transplantation (DCBT) is a viable therapy for adults with high-risk hematologic malignancies who lack an adult donor. However, lack of transfer of memory T cells in the graft is associated with an increased risk of viral infections. To study immune reconstitution, we recently described a novel method that combines 5' rapid amplification of complementary DNA ends (RACE) PCR and deep sequencing to quantify T cell receptor (TCR) diversity after allogeneic hematopoietic stem cell transplant (van Heijst, Nat Med 2013). In that study, we showed that recipients of DCBT recover TCR diversity comparable to healthy donors by 12 months. We now report results of a prospective analysis of CD4+ and CD8+ T cell repertoire recovery in DCBT recipients and correlation with clinical outcomes. Methods: We prospectively collected samples from 33 DCBT recipients. The median age was 45 years (range 26-71), 18 (55%) were CMV seropositive, and the majority (n = 17, 52%) had non-European ancestry. Diagnoses included 20 (61%) acute leukemias and 13 (39%) lymphomas. Conditioning was myeloablative (n=1, 3%), reduced intensity (n=28, 85%), or non-myeloablative (n=4, 12%), and all patients received GVHD prophylaxis with cyclosporine-A and mycophenolate mofetil and no ATG. Patients received double-unit CB grafts (4-6/6 HLA-A,-B antigen, -DRB1 allele donor-recipient matched); this was supplemented with haploidentical CD34-selected PBSC in 18 patients. The 66 units had a median donor-recipient HLA-allele match of 6/8 (range 3-8). Infused total nucleated cell doses were 2.3 (1.7-3.3) and 1.9 (1.3-2.5) for the larger and smaller units, respectively. Samples were collected from the DCB grafts, recipient day+21 bone marrow, and peripheral blood at days +30, 60, 90, 120, 180 and 365 post-transplant. TCR-β sequences from each sample were amplified and sequenced using the Illumina/MiSeq sequencing platform after isolation of CD4+ and CD8+ T cells. TCR abundances were assessed at the level of clonotype and TCR diversity was calculated using inverse Simpson index. Results: Of the 33 patients, long-term samples were obtained in 25 patients, short-term samples (≤ day 100) in 6 patients who died early after DCBT, and no samples other than the graft for 2 patients. The remainder of the results focuses on 25 patients with complete samples. As previously shown, there is a 1-2-log increased diversity in CD4+ vs. CD8+ T cells (Figure). Furthermore, median CD4+ steady-state diversity is achieved early by day 60. In contrast, there is a higher rate of clonal dominance in CD8+ compared to CD4+ T cells (24/25 vs. 11/25, p=0.0001 by Fisher test). Several patterns of clonal dominance were observed, including two main patterns in CD8+ T cells. In 7/24 patients, clonal dominance is established by day 60 and persists throughout, whereas in 12/24 patients, clonal dominance fluctuates throughout follow-up. In CD4 +T cells, where less dominance is observed, a similar distribution is seen, though prolonged clonal dominance is rare. Interestingly, some of the dominant clones can be detected in the graft and are present in the day 21 marrow sample. Persistent clonal dominance in CD8+ T cells was seen 6/9 patients with CMV reactivation, whereas ongoing fluctuation was seen in 9/12 patients without CMV reactivation. In 2 patients with fluctuating clones who reactivated CMV, 1 had low level and the other a late viremia. In contrast, no link to a specific pattern was observed in patients with HHV6 viremia or acute GVHD. Finally, when we assessed similarity in clonal distribution between time points, there was more similarity in CD8+ than CD4+ T cells. Conclusions: This novel deep TCR repertoire sequencing provides a quantitative picture of T cell recovery after DCBT and supports the following: 1) separate analysis of CD4+ and CD8+ T cell populations is critical given different patterns of recovery in T cell subsets; 2) there is significant turnover in CD4+ clones but with overall limited dominance, whereas there is less turnover in CD8+ clones; 3) although the grafts contain predominantly naïve T cells, the clonal evolution of CD8+ T cells strongly suggests generation of virus-specific T cells that control viral infection; and 4) CMV appears to be an important driver of CD8+ T cell clonal expansion after CBT. Ongoing analyses are correlating immune recovery with cord blood unit dominance as well as the biology of GVHD and relapse. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Shouval, Roni, Joshua Fein, Myriam Labopin, Nicolaus Kröger, Rafael F. Duarte, Peter Bader, Bonini Chiara, et al. "Transplantation Outcome By Disease Risk and Donor Type over Time: An Analysis of 100,000 Allogeneic Stem Cell Transplantation on Behalf of the Acute Leukemia Working Party of the EBMT." Blood 130, Suppl_1 (December 7, 2017): 668. http://dx.doi.org/10.1182/blood.v130.suppl_1.668.668.

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Abstract Background: Donor type is a key modifiable determinant of outcome following allogeneic hematopoietic stem cell transplantation (HSCT). Utilizing a dataset of more than 100,000 allogeneic transplantations registered with the European Society for Blood and Marrow Transplantation (EBMT), we sought to characterize the evolution of outcomes in transplantation with different donor types across levels of disease-associated risk. Methods: This retrospective study included adult patients treated for hematologic malignancies who underwent first allogeneic HSCT between 2000 and 2015 in EBMT centers. Cord-blood transplantations were excluded, as were patients for whom diagnosis, disease status, or donor relationship were unknown. Missing values were accounted for by multiple imputations. A three-level disease-risk scheme (low, intermediate, and high), was defined by introducing combinations of diagnosis and disease status into a Cox multivariate model for overall survival (OS), similar to the method employed in creating the Disease Risk Index (Armand et al., Blood, 2014). Additional covariates included in the model were reflective of patient, disease, transplant, and center related features. Patients were classified according to a combination of disease risk, donor type, and HSCT year (2000-2005, 2006-2010, 2011-2015). A variable capturing the grouping was introduced into a Cox multivariate analysis adjusted for major transplantation parameters, with the reference category being a matched sibling donor in low-risk disease transplanted between 2011 and 2015. OS was estimated using the Kaplan-Meier method. Competing risk analysis was used to calculate cumulative incidence of non-relapse mortality (NRM) and relapse. Results: A total of 106,086 patients were included in the analysis, with a median age of 48 years (IQR 36-58); Twenty five percent of patients were transplanted between 2000 - 2005, 33% between 2006 and 2010 and 42% between 2011 and 2015. The leading indications for HSCT were acute leukemia (58%), myeloproliferative neoplasms (11%) and non-Hodgkin's lymphomas (10%). Recipients had either HLA matched sibling donors (MSD) (46%), unrelated donors (overall 50%; HLA matched 10/10 (MUD) [20%], mismatched HLA 9/10 (MMUD) [6%], mismatched HLA<9/10 [2%], imputed HLA match [21%]) or haploidentical (Haplo) (4%) donors. Graft source was primarily peripheral blood (81%). Myeloablative conditioning was used in 53% of cases. The median follow-up was 3.6 years (95% CI 3.5-3.6). The risk of overall mortality varied depending on the combination of donor type, disease risk and transplantation year (figure A). In low and intermediate risk disease, a matched sibling donor had the most favorable outcome across year-periods. However, in high-risk disease, overlapping hazard ratios (HRs) were observed between MSD and MUD in 2011-2015 (2.8 [2.6-3.0] versus 3.0 [2.8-3.2], respectively). The cumulative incidence for NRM for MSD vs. MUD in high-risk disease transplanted from 2011-2015 was 26.1% (23.8-28.6) vs. 35.3% (32.6-38.3, p < 0.0001), respectively. Similarly, relapse incidence was 50.7% (48.0-53.6) vs. 41.0% (38.3-44.0, p < 0.0001). In high disease risk, the risk for mortality has decreased over the years for MSD and MUD, and even more so for transplantations from Haplo donors (2000-2005 HR 5.11 [4.3-6.1]; 2011-2015 HR 3.9 [3.5-4.3]). In the low-risk setting, transplantations from Haplo donors had a comparable risk to MSD and MUD (2011-2015 Low risk: MSD reference, MUD 1.2 [1.1-1.3], Haplo 1.3 [1.2-1.5]). A representative example is seen in Figure B: the probability of 2-year overall survival between 2011-2015, low risk in MSD was 66.5% (95% CI 65.0-68.0), MUD 63.4% (61.7-65.1), and Haplo 60.4 (56.9-64.1). Conclusion: Survival has improved following allogeneic HSCT over the past two decades. This improvement is especially clear in the case of haploidentical donors, though MSD and MUD are still associated with better outcomes. In high-risk disease, the risk of mortality is equivalent between matched sibling and matched unrelated donors. Notably, the probability for NRM is higher with MUD, but relapse incidence is lower, emphasizing the importance of graft-versus-tumor effect in the high-risk setting and the ongoing need for NRM reduction strategies. Disclosures Kröger: Janssen Global Services, LLC: Speakers Bureau; Amgen Inc.: Speakers Bureau; Novartis AG: Research Funding; RIEMSER Pharma: Research Funding; Neovii Pharmaceuticals AG: Speakers Bureau; Novartis AG: Speakers Bureau; Sanofi: Speakers Bureau. Bader: Novartis, Medac, Amgen, Riemser, Neovii: Consultancy, Honoraria, Research Funding. Kuball: Miltenyi: Research Funding; Gadeta (www.gadeta.nl): Consultancy, Equity Ownership, Patents & Royalties: on gdT cells and receptors and isolation strategies , Research Funding. Snowden: Sanofi: Honoraria. Mohty: Sanofi: Honoraria, Speakers Bureau.

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Fabiani, Silvia, Simona Fortunato, and Fabrizio Bruschi. "Solid Organ Transplant and Parasitic Diseases: A Review of the Clinical Cases in the Last Two Decades." Pathogens 7, no. 3 (July 31, 2018): 65. http://dx.doi.org/10.3390/pathogens7030065.

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The aim of this study was to evaluate the occurrence of parasitic infections in solid organ transplant (SOT) recipients. We conducted a systematic review of literature records on post-transplant parasitic infections, published from 1996 to 2016 and available on PubMed database, focusing only on parasitic infections acquired after SOT. The methods and findings of the present review have been presented based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist. From data published in the literature, the real burden of parasitic infections among SOT recipients cannot really be estimated. Nevertheless, publications on the matter are on the increase, probably due to more than one reason: (i) the increasing number of patients transplanted and then treated with immunosuppressive agents; (ii) the “population shift” resulting from immigration and travels to endemic areas, and (iii) the increased attention directed to diagnosis/notification/publication of cases. Considering parasitic infections as emerging and potentially serious in their evolution, additional strategies for the prevention, careful screening and follow-up, with a high level of awareness, identification, and pre-emptive therapy are needed in transplant recipients.

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Toor, Amir A., Roy T. Sabo, Harold M. Chung, Catherine H. Roberts, Rose H. Manjili, Shiyu Song, David C. Williams, William Clark, Masoud H. Manjili, and John M. McCarty. "Favorable Outcomes in Patients with High Donor-Derived T Cell Count Following In Vivo T Cell Depleted Reduced Intensity Allogeneic Stem Cell Transplantation." Blood 118, no. 21 (November 18, 2011): 3043. http://dx.doi.org/10.1182/blood.v118.21.3043.3043.

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Abstract Abstract 3043 In patients undergoing T cell depleted stem cell transplantation (SCT) a high rate of mixed chimerism is seen. Further, chimerism analysis does not consistently predict risks of GVHD or relapse upon withdrawal of immunosuppression (IS) in these patients. Thus, a reliable predictor for the expected evolution of mixed T cell chimerism is needed to help in clinical decision-making for withdrawal of IS and donor lymphocyte infusion (DLI). An alternative immune parameter is T cell recovery post-transplant. We combined this measure with T cell chimerism and examined the predictive value of a calculated donor-derived T cell count for clinical outcomes following SCT. Patients were enrolled in a randomized clinical trial examining two different doses of rabbit anti-thymocyte globulin (ATG 2.5 or 1.7 mg/kg/day; Thymoglobulin®, Genzyme, Cambridge, MA) given IV on day –9 through –7, followed by total body irradiation (4.5 Gray), administered in 3 doses on day –1 and 0 (NCT00709592). Donor engraftment was measured by PCR of short tandem repeat alleles in each donor and patient at 4, 8, 12, and 24 weeks following SCT on whole blood, granulocytes, and total T cells. Between 2008 and 2011, 25 patients were enrolled in this trial, and 22 patients were eligible for this analysis. Nine of the 22 patients had mixed T cell chimerism (≥5% recipient DNA) at 8 weeks post-transplant, and of these 33% (n=3) became fully donor T cell chimeric after withdrawal of IS over the ensuing weeks. One of the 9 patients had improved donor chimerism after DLI. Of the 13 patients who were full donor chimeric in T cells, one patient reverted from full donor to mixed chimerism. Donor-derived CD3+ T cell count (dd CD3) was calculated from T cell chimerism and absolute blood CD3+ T cell count. Median dd CD3+ cell count at 8 weeks following SCT was 433 ƒýL (range: 3–2464). After calculating the sum of receiver operating characteristic area under the curves (AUC), a dd CD3 of 110ƒýL was found to be the optimal cut-off value with both the highest AUC sum and the highest AUC for each measure (cumulative acute and chronic GVHD: 0.79, remission: 0.74, whole blood chimerism: 0.88), and was subsequently used to distinguish between low (<110; n=8) and high (>110; n=14) values of dd CD3. A significant correlation was found between this single dd CD3 level discriminator and higher rates of cumulative GVHD (Fishers Exact Test: p = 0.024), remission (p = 0.0524) and full donor whole blood chimerism at ≥12 weeks following SCT (p < 0.0001) in patients with high-dd CD3 cell counts. Furthermore, Bayesian analysis showed higher whole blood mixed chimerism rates (Posterior Probability = 0.99), lower GVHD rates (PP = 0.99), and lower remission rates (PP = 0.99) in the low-dd CD3 group. Both overall survival and time to relapse favored the high-dd CD3 group (vs. low-dd CD3 group). However, while the relationship was significant for relapse (p = 0.028), it was only marginally significant for overall survival (p = 0.07). When measured after withdrawal of IS, declining donor or persistent mixed T cell chimerism was observed in patients who had mixed T cell chimerism and low- dd CD3 at eight weeks post SCT (Fig 1A), whereas those with high- dd CD3 had increasing donor T cell chimerism (Fig 1B). Granulocyte chimerism too was modulated by dd CD3 in patients with mixed chimerism and early DLI arrested the decline of donor hematopoiesis in a patient with low-dd CD3. NK cell counts were significantly higher in the high-dd CD3 group than in the low-dd CD3 group at 8 weeks (p = 0.044; PP = 0.99). No significant relationships were found between dd CD3 levels and donor age, donor type, total ATG dose, and infused graft CD34+ or CD3+ cell dose.Figure 1AFigure 1A. In conclusion, we report the effect of an easily calculable measure of donor T cell reconstitution on clinical outcomes following SCT (particularly GVHD), stability of engraftment and disease relapse. Donor-derived CD3+ cell count may help in the decision-making regarding IS withdrawal and DLI timing in allogeneic SCT recipients. We will be confirming the optimal dd CD3 cell count parameter in larger patient cohorts with comparable disease biology for validation in regimens of varying myeloablative intensities. Disclosures: Toor: Genzyme: Research Funding. Off Label Use: ATG in stem cell transplantation.

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Wei, Peng, Wenwen Wang, Yang Yang, and Michael Yu Wang. "Level set band method: A combination of density-based and level set methods for the topology optimization of continuums." Frontiers of Mechanical Engineering 15, no. 3 (June 21, 2020): 390–405. http://dx.doi.org/10.1007/s11465-020-0588-0.

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Abstract The level set method (LSM), which is transplanted from the computer graphics field, has been successfully introduced into the structural topology optimization field for about two decades, but it still has not been widely applied to practical engineering problems as density-based methods do. One of the reasons is that it acts as a boundary evolution algorithm, which is not as flexible as density-based methods at controlling topology changes. In this study, a level set band method is proposed to overcome this drawback in handling topology changes in the level set framework. This scheme is proposed to improve the continuity of objective and constraint functions by incorporating one parameter, namely, level set band, to seamlessly combine LSM and density-based method to utilize their advantages. The proposed method demonstrates a flexible topology change by applying a certain size of the level set band and can converge to a clear boundary representation methodology. The method is easy to implement for improving existing LSMs and does not require the introduction of penalization or filtering factors that are prone to numerical issues. Several 2D and 3D numerical examples of compliance minimization problems are studied to illustrate the effects of the proposed method.

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Saida, Satoshi, Tao Zhen, Erika Mijin Kwon, Guadalupe Lopez, and Paul P. Liu. "Distinct Roles of GATA2 in Development and Evolution of CBFB-MYH11 AML." Blood 132, Supplement 1 (November 29, 2018): 770. http://dx.doi.org/10.1182/blood-2018-99-110636.

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Abstract Introduction. Core binding factor acute myeloid leukemia (CBF-AML) is caused by the dysfunction of a heterodimeric protein complex composed of the transcription factor RUNX1 and its partner CBFb. An inversion of chromosome 16 generates a fusion between CBFB and MYH11. The encoded fusion protein, CBFb-smooth muscle myosin heavy chain (SMMHC), contributes to the pathogenesis of CBF-AML. Our previous reports suggest that CBFB-MYH11 contributes to leukemogenesis by up-regulation of genes such as Gata2, which is an essential hematopoietic transcription factor. On the other hand, we recently identified recurrent monoallelic deletions of GATA2 on chromosome 3 in relapsed CBF-AML patients (Sood et al., Leukemia 30:501-504, 2016). From these findings we propose two hypotheses; 1) up-regulation of GATA2 contributes to leukemogenesis by CBFB-MYH11 in the initiation phase; 2) GATA2 deficiency contributes to the relapse of CBF-AML. Methods. Two datasets (GSE19194 and GSE102388) from microarray and RNA-Seq were used to determine Gata2 expression level in Cbfb-MYH11 preleukemic murine hematopoietic cells. Cbfb-MYH11 conditional knock-in (Cbfb+/56M), Gata2 conditional knockout (Gata2+/f), and Mx1-Cre transgenic mice were crossed to generate Gata2+/fCbfb+/56MMx1-Cre mice. Mice were injected with pIpC to induce the expression of Cbfb-MYH11 and/or knockout of Gata2 through Cre-recombinase activation. For transplantation assays, spleen cells obtained from leukemic mice were injected into irradiated recipient mice through tail vein. For in vitro colony forming assays, colonies were counted after 10 days in culture. Cell apoptosis was determined by Annexin V and 7AAD staining. Results. To test the first hypothesis, we determined the expression level of Gata2 in preleukemic cells in the Cbfb-MYH11 expressing mice. Data from both microarray and RNA-seq experiments revealed that Gata2 was highly expressed in the preleukemic hematopoietic cells of the Cbfb-MYH11 mice, as compared to those of the WT mice, and this finding was confirmed by qRT-PCR. Based on published ChIP-seq data, Gata2 is likely a direct transcriptional target of CBFb-SMMHC. Next, we determined the impact of Gata2 deficiency on leukemogenesis by Cbfb-MYH11. qRT-PCR showed reduced Gata2 expression in bone marrow cells from Gata2+/fCbfb+/56MMx1-Cre mice 12 days after pIpC injection (0.029±0.0092 vs 0.076±0.014; p=0.0089). Colony forming ability was decreased for the pre-leukemic bone marrow cells in Gata2+/fCbfb+/56MMx1-Cre mice when compared to Cbfb+/56MMx1-Cre mice (mean 37.2±6.35 vs. 74.23±8.335; p=0.0002). In addition, the Gata2+/fCbfb+/56MMx1-Cre mice had a smaller abnormal myeloid population in the bone marrow, which is capable of inducing leukemia, when compared with Cbfb+/56MMx1-Cre mice (mean 0.43±0.14% vs. 1.42±0.34%; p=0.0092). Most significantly, Gata2+/fCbfb+/56MMx1-Cre mice developed leukemia with a much longer latency than Cbfb+/56MMx1-Cre mice (median survival 215 days vs 125 days; p=0.0007). To test hypothesis 2, we compared the phenotype of the end stage mice for each genotype. Gata2+/fCbfb+/56MMx1-Cre mice had higher WBC count in peripheral blood than Cbfb+/56MMx1-Cre mice (mean 92,000±20,429 cells/ul vs. 35,644±12,001 cells/ul; p=0.0243), which is a poor prognostic marker in human leukemia. Leukemic cells from Gata2+/fCbfb+/56MMx1-Cre mice also had lower percentage of Annexin V positive cells than Cbfb+/56MMx1-Cre mice in short term culture (31.0±7.1 vs. 68.9±6.5%; p=0.0117). More importantly, upon transplantation, the recipient mice transplanted with Gata2+/fCbfb+/56MMx1-Cre leukemia cells developed leukemia much faster than recipient mice transplanted with equal numbers of Cbfb+/56MMx1-Cre leukemia cells (median survival 35.5 vs. 91.0 days; p<0.0001). Conclusions. Our findings suggest that Gata2 plays important but distinct roles in two different stages of Cbfb-MYH11 leukemia. Reduction of Gata2 activity delays leukemia development in primary Cbfb-MYH11 knockin mice, while contributing to a more aggressive phenotype in leukemic phase as shown in primary leukemic mice and transplanted recipients, which may be correlated with leukemia relapse in human patients. We are analyzing data from whole exome sequencing and RNA-seq to understand the mechanism underlying the observed phenotypes, and the findings will be presented at the annual meeting. Disclosures No relevant conflicts of interest to declare.

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Jaccard, Arnaud, Anne Lazareth, Lionel Karlin, Sylvain Choquet, Laurent Frenzel, Laurent Garderet, Mamoun Dib, et al. "A Prospective Phase II Trial of Lenalidomide and Dexamethasone ( LEN-DEX) in POEMS Syndrome." Blood 124, no. 21 (December 6, 2014): 36. http://dx.doi.org/10.1182/blood.v124.21.36.36.

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Abstract Background. POEMS syndrome is a rare form of B cell dyscrasia combining a proliferation usually of plasma cells, a polyneuropathy, osteocondensing bone lesions and multiple other clinical signs. The pathogenesis is not well understood but VEGF plays a major role. In patients with one or two sclerotic plasmacytoma and no bone marrow involvement, first line therapy should include radiation. For patients with diffuse sclerotic lesions, bone marrow involvement or absence of any bone lesion and for those who have not demonstrated stabilization of their disease 3 to 6 months after completing radiation systemic therapy is indicated, the most effective being high dose chemotherapy with autologous stem cell transplant (ASCT). Radiation of a single lesion is effective in about every other case and is accompanied by a fairly slow improvement of the neurological symptoms, often after initial worsening. ASCT seems to be accompanied by a number of important complications, in particular engraftment syndrome. Outside these 2 treatments there is no consensus therapy. Lenalidomide (LEN), a drug without serious neurological toxicity, has the advantage of being both anti-angiogenic and cytotoxic to malignant plasma cells (Richardson PG, Blood 2002;100(9):3063-7). We have recently reported a series of 20 French patients with POEMS syndrome treated by LEN with a good efficacy. We now report the first 27 patients of a prospective phase II trial using LEN + dexamethasone (LEN-DEX), 2 cycles preceding radiation or high dose treatment trying to obtain a rapid clinical response and to avoid engraftment syndrome or 9 cycles followed by 1 year LENalone in patients who cannot receive radiation or ASCT. Methods. Newly diagnosed or relapsing patients with POEMS syndrome who needed to be treated were eligible. Patients who can be treated by local radiation or intensive treatment with stem cell support receive two 28 day cycles of LEN 25 mg PO Days 1-21 and DEX 40 mg PO Days 1,8,15,22 before radiation or intensive treatment (Group 1), the other patients receive 9 cycles of the same LEN-DEX (Group 2) and then 12 cycles of continuous low dose LEN (10 mg). LEN dose was tapered to 10 mg for patients with a creatinine clearance between 30 and 50 ml/min and DEX to 20 mg for patients above 75 years of age and for those who were frail patients. Main eligibility criteria included a diagnosis of POEMS syndrome according to criteria by Dispenzieri et al (Am J Hematol 2012;87(8):804-14), an age of 18 or more, a creatinine clearance above 30 ml/min, no prior treatment with or contraindication to LEN and no uncontrolled thrombosis. Serum and plasma VEGF, serum electrophoresis, immunofixation and free light chain measurements were centrally monitored. Neurologic evaluations were performed using the Overall Neuropathy Limitations Scale (ONLS), the Neurological Impairment Scale (NIS) and the 10 meter walk test (10MWT). The primary endpoint was evaluation of the effectiveness of LEN-DEX combination using biological responses (decrease of monoclonal protein and serum VEGF level) and secondary endpoints were clinical and particularly neurological responses. Results. Twenty-seven patients have been included in 12 centres, median age was 61 (range 32-75), the median follow-up was 6.6 months (range 2-24). Eighteen patients were in group 1, with radiotherapy in 10 patients and ASCT in 8 patients; 9 patients were in group 2. Nineteen patients were in first line and 8 already treated. Only 2 patients experienced grade 3-4 adverse events due to LEN (cytopenia) and 2 patients had allergic rashes, no thrombotic event occurred. No engraftment syndrome was noted in the 5 patients already treated with ASCT. To date, no patient have died. Evolution of VEGF median values in serum and plasma, M-spike and dFLC levels and evolution of neurological measurements are reported in table 1. Neurological improvement was very rapid in some patients, using ONLS and 10MWT 11/18 evaluable patients had a neurological improvement after 2 cycles with an improvement of 1 or more of the ONLS score and/or change of 0.1 m/s or more in the 10MWT. Only one patient who progressed after nine cycles received another therapy. Conclusion. This is the first prospective trial of LEN-DEX in POEMS syndrome. This combination seems well tolerated in this disease with a good efficacy on VEGF measurements and rapid neurological improvement in the majority of patients. Updated data will be presented at the meeting. Figure 1 Figure 1. Disclosures Jaccard: Celgene: Drug supply to Trial Other. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Moreau:celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Jeran, Z., A. R. Byrne, and F. Batič. "Transplanted Epiphytic Lichens as Biomonitors of Air-Contamination by Natural Radionuclides Around the Žirovski VRH Uranium Mine, Slovenia." Lichenologist 27, no. 5 (September 1995): 375–85. http://dx.doi.org/10.1006/lich.1995.0035.

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AbstractSamples of Hypogymnia physodes were transplanted to the environment of the former uranium mine at Žirovski vrh, Slovenia for two exposure experiments. The levels of the long-lived radionuclides, 238U, 226Ra and 210Pb in lichen material were measured after 4 and 7 months in the first experiment, and 4, 8 and 12 months in the second, and compared with the levels in lichens growing in-situ from the same sampling locations. They were also compared with the nuclide levels found in air particulates by gamma spectrometry obtained at the regular site monitoring stations. The results showed that each of the radionuclides had its own distribution pattern in this environment. The highest 226Ra levels were found in lichens in the near vicinity of the dry-tailings pile, while U concentrations were high in the valley of the confluence of the Todraščica and Brebovščica streams close to the former yellow-cake production plant in Todraž, and then decreased downstream. 210Pb was the most uniformly distributed radionuclide and exhibited the highest level. The results also confirm that active biomonitoring with transplanted lichens can be a useful and cheap supplement to instrumental air pollution monitoring.

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Camara, Aichetou, Anaïs Razurel, Christelle Moreau, Thérésa Kwon, Marion Caseris, Olivier Bourdon, and Sonia Prot-Labarthe. "P44 Vaccine in pediatric chronic kidney disease (CKD) and hemodialysis." Archives of Disease in Childhood 105, no. 9 (August 19, 2020): e29.2-e30. http://dx.doi.org/10.1136/archdischild-2020-nppg.53.

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AimsChronic kidney disease is a major risk factor of vaccine preventable infectious diseases due to the altered immune system and the natural evolution of the disease. There are differences in the prescription of some vaccines for this population. The aim of this study is to elaborate a vaccination protocol for chronic kidney disease and haemodialysis patients for a better immunization coverage, care and prevention against preventable infectious diseases.MethodsThe study was conducted by a multidisciplinary team composed by pharmacists, infectious disease paediatrician and nephrology paediatricians. After a literature research (in Medline with MeSH terms: ‘Kidney Failure, Chronic’, ‘Renal Dialysis’ and ‘Vaccines’)1 2, we compared the French immunization schedule3 for the general population with patient with chronic kidney disease or haemodialysis patients and confront it to the physician practice in our nephrology unit. For each vaccine, we collected the following data: indication, any difference concerning dose, schedule, re-administration, antibody titration and reason for these differences.ResultsThe literature analysis showed disparate practices among countries and even medical centres. The most concerned vaccines were: hepatitis A and B virus vaccine, pneumococcal vaccine, flu and measles vaccines. The difference between vaccine scheduled concerned the indication (meningococcus A, B, C, Y and W135, papillomavirus), dose (hepatitis B), the schedule (hepatitis B, hepatitis A, pneumococcal, measles), re-administration (hepatitis B, varicella), antibody titration (hepatitis B, varicella). Patients with chronic kidney disease are more susceptible to develop hepatitis B infection. As for adult population, the haemodialysis patients are vaccinated with double dose4 of hepatitis B vaccine. The antibodies titration at our hospital is made twice a year and anti-HBs level needed are 30 to 50 UI/mL. Hepatitis A is a recommended vaccine for risk population including haemodialysis patients and chronic kidney disease patients. The vaccination schedule is the same for haemodialysis patients with two doses but the second dose is administered earlier, i.e. six months after the first with an antibody screening. For the pneumococcal vaccine, an additional dose is administered at 3 month of age for premature and at risk children and the conjugated vaccine potentiates the polyosidic vaccine. For measles, the second dose may be omitted if the antibody titration confirms the protection to allow the patient to be registered earlier on the renal transplant list. Flu vaccination is recommended with the same dose and schedule that the other patients, but tetravalent vaccines should always be chosen.ConclusionsChildren with chronic kidney disease or on haemodialysis are more at risk of vaccine preventable infectious diseases and should be vaccinated earlier before beginning dialysis. The specific immunization schedule will be presented and may be used by other hospital and countries for concerned patients.ReferencesBakkaloğlu SA, et al. Vaccination Practices in Pediatric Dialysis Patients Across Europe. A European Pediatric Dialysis Working Group and European Society for Pediatric Nephrology Dialysis Working Group Study. Nephron 2018;138:280–286.Costa NCP, da Canhestro MR, Soares CMBM & Rodrigues JS. Monitoring of post-vaccination anti-HBs titles vaccine in children and adolescents in the pre-dialysis of chronic kidney disease. Braz. J. Nephrol. 2017;39:296–304.DGS_Anne.M, DICOM_Jocelyne.M, DGS_Anne.M & DICOM_Jocelyne.M. Le calendrier vaccinal. Ministère des Solidarités et de la Santé (2019). Available at: https://solidarites-sante.gouv.fr/prevention-en-sante/preserver-sa-sante/vaccination/calendrier-vaccinal (Accessed: 28th June 2019)Misurac JM, et al. Immunogenicity of augmented compared with standard dose hepatitis B vaccine in pediatric patients on dialysis: a midwest pediatric nephrology consortium study. Clin. J. Am. Soc. Nephrol 2017;12:772–778.

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Gowin, Krisstina L., Amylou C. Dueck, John O. Mascarenhas, Ronald Hoffman, Craig B. Reeder, John Camoriano, Katherine Gano, et al. "Interim Analysis of a Phase II Pilot Trial of Ruxolitinib Combined with Danazol for Patients with Primary Myelofibrosis (MF), Post Essential Thrombocythemia-Myelofibrosis (Post ET), and Post Polycythemia Vera Myelofibrosis (PV MF) Suffering from Anemia." Blood 124, no. 21 (December 6, 2014): 3206. http://dx.doi.org/10.1182/blood.v124.21.3206.3206.

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Abstract Introduction: Approximately 75% of myelofibrosis (MF) patients develop anemia during evolution of the disease process predicting decreased survival. Previous studies exploring the effect of danazol in the treatment of anemia in MF demonstrate responses in anemia of 30-55%. Ruxolitinib has demonstrated improvement in MF related splenomegaly, symptom burden, and even survival yet improvements in cytopenias are uncommon. We designed a phase II multicenter pilot study to evaluate the efficacy and tolerability of combination therapy with ruxolitinib and danazol in MF patients with anemia. Methods: This is a pre-planned interim analysis of a Simon optimum two-stage phase II trial designed to include a minimum of 10 and a maximum of 27 patients. Participants received ruxolitinib 10mg (plat >75 x10x9) BID or 5mg (plat <75 x10 x9) BID with danazol 200mg orally TID. Dose escalation was allowed after completion of 28 days for lack of response or for disease progression. Patients without progression were continued for 6 cycles at 56 days each. Treatment modifications were based on adverse events including thrombocytopenia, leukopenia, and elevation in creatinine and transaminases. Treatment responses were evaluated by the IWG-MRT response criteria (Blood 2013). Patient reported outcome questionnaires (MPN-SAF and EORTC QLQ-C30) were administered at baseline, prior to treatment cycles, and at study discontinuation. Results: Patients: Ten of the 12 evaluable patients enrolled (median age 70.5, range 57-78, M:F ratio 4:1) are included in this analysis. Eight patients had primary MF (PMF), 1 had post essential thrombocytosis (ET) MF, and 1 had post polycythemia vera (PV) MF. Jak2 V617F mutation was positive in 30%. At the time of enrollment 40% had received an erythrocyte transfusion in the last month and all were DIPSS Int-2 or higher. Median baseline hemoglobin was 9.0 g/dL (range 8.3 - 12.4). Median baseline platelet level was 172 x10 (9)/L (range 56 - 346). Most (90%) had received prior therapy and many were refractory to multiple lines of therapy prior to enrollment. Three (30%) patients had previously participated in a JAK inhibitor clinical trial. Tolerability: Among 6 patients who have completed treatment, median duration of treatment was 39 days (range 24-287) with treatment discontinuation due to progression of disease in 2 patients, allogeneic stem cell transplant in 1, alternative treatment in 1, unrelated adverse event (hyponatremia) in 1, and unrelated death (leukemic transformation with intracranial hemorrhage) in 1. Hematologic Grade 3 or > adverse events included anemia (60%), neutropenia (20%), and leukopenia (10%). Non-hematologic Grade 3 or > adverse events included electrolyte abnormalities (20%), edema (10%), infection (10%), and intracranial hemorrhage (10%). Efficacy: Treatment response per IWG-MRT response criteria included stable disease (SD) in 8/10 (80%), clinical improvement in 1/10 (10%), and progressive disease (PD) in 1 (10%). The median change in hemoglobin and platelet count from baseline was -0.05 g/dL (range -0.5 - 1.8) and 28.5 x10(9)/L (range -143 – 118) respectively, however 4/10 (40%) and 7/10 (70%) had improvement at some point during treatment in level of anemia and/or thrombocytopenia. The median follow-up time was 2 months (range 0.9-9.4). Among 6 patients with a baseline and at least one post-baseline MPN-SAF TSS, 2/6 (30%) of patients had at least a 10-point (clinically meaningful) improvement, with 1 of the 2 achieving the stricter 50% improvement from baseline. Responses might have been confounded due to impact of prior therapies. Conclusions: On interim analysis, ruxolitinib and danazol combination therapy demonstrates modest additional clinical benefit, however in a group of exceedingly high risk MF patients with significant anemia and prior single agent JAK inhibitor failures. Preliminary data suggests improvement in anemia and/or thrombocytopenia in some treated patients however only one clinical improvement per IWG-MRT criteria was observed. Combination therapy was well tolerated with no major incremental toxicity attributable to the addition of danazol. Maturation of data is needed to fully evaluate efficacy of ruxolitinib and danazol combination therapy prior to continuation of accrual. Disclosures Mascarenhas: Incyte Corporation: Consultancy, Research Funding; Novartis Pharmaceuticals Corporation: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding. Tibes:Seattle Genetics, Inc.: Research Funding. Mesa:Incyte: Research Funding; Novartis: Consultancy; Gilead: Research Funding; Genentech: Research Funding; Promedior: Research Funding; Ns Pharma: Research Funding; Celgene: Research Funding; Lilly: Research Funding; Cti: Research Funding.

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Swain, D. P., and B. E. Riddell. "Variation in Agonistic Behavior between Newly Emerged Juveniles from Hatchery and Wild Populations of Coho Salmon, Oncorhynchus kisutch." Canadian Journal of Fisheries and Aquatic Sciences 47, no. 3 (March 1, 1990): 566–71. http://dx.doi.org/10.1139/f90-065.

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We compared agonistic behavior of newly emerged coho salmon (Oncorhynchus kisutch) between hatchery and wild populations using mirror image stimulation tests. We used hatchery populations from two different regions of Vancouver Island B.C., each matched with a wild population from its region. In both comparisons, hatchery juveniles were more aggressive than wild juveniles. Rates of aggressive display increased with time since emergence for both hatchery and wild fish, as did the differences in behavior between the two types. By the sixth day of observation (13 d postemergence), the overall effect of fish type was highly significant for all aggressive behaviours. Since the individuals compared were reared from eggs under identical conditions, these differences are presumably genetic. Comparisons involved relatively few families from each population. However, because heritability was moderate to low within populations, and variance between population types exceeded variance among families within populations, these results indicate real differences at the population level. These results may have important implications for programs to rebuild wild populations using hatchery transplants and for selective breeding programs to develop domestic stocks of coho.

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Bonadies, Nicolas, Anita Feller, Alicia Rovo, Axel Ruefer, Sabine Blum, Bernhard Gerber, Georg Stuessi, et al. "Trends of Classification, Incidence, Mortality, and Survival of MDS Patients in Switzerland Between 2001 and 2012." Blood 128, no. 22 (December 2, 2016): 5539. http://dx.doi.org/10.1182/blood.v128.22.5539.5539.

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Abstract Background and Aims: Myelodysplastic syndromes (MDS) are mainly diagnosed in the elderly with an increasing burden on healthcare systems. As a consequence, population-based studies are important in order to estimate the evolution of this emerging disease in different countries. Objectives: The objective of this study was to provide trends ofannual case frequency, morphological subtypes, incidence, mortality and survival of patients diagnosed with MDS in Switzerland between 2001 and 2012. Methods: A retrospective, population-based, epidemiological study was carried out on MDS cases reported to the Swiss Cantonal Cancer Registries and aggregated by the National Institute for Epidemiology and Cancer Registration. The Swiss Federal Statistical Office provided mid-year population estimates and cause of death statistics. Due to changes in the WHO classification of MDS, data was stratified for two time periods 2001-2007 and 2008-2012, respectively. 56 million person-years (py) were observed, covering 60%-65% of the Swiss population, during a time period of 12 years. Results: 2138 MDS cases were reported with a median age of 77 years (range of means: 75-78 years). The estimated annual case frequency increased from 263 to 316 (+20%) but the overall age-standardized (adjusted) incidence-rate did not change between the time periods (Table 1). A substantial increase in incidence was only visible for men aged 80-84 (+57.7%), men aged 85+ (+29.3%) and women aged 85+ (+13.4%). With respect to mortality rates, a 10% decline was observed for men aged 85+. Incidence and mortality were very low below the age of 60 years but the rates steeply increased thereafter (Figure 1a). Irrespective of time period, incidence- and mortality-rates were almost twice as high among men compared to women (Figure 1b). Classification in MDS subtypes was poor and improved only modestly from 20% to 39% with a higher awareness for diagnosis of higher-risk diseases. Relative survival at 5 years (RS at 5y) for all patients was 37% in 2008-2012 with better survival for younger patients < 65 years (61%) compared to older patients > 65 years (24-37%). No differences in survival could be observed between the two time periods (Figure 2). Conclusions: In this study we provide the first population-based, epidemiologic data from MDS patients in Switzerland. The analysis showed a 20% increase of annual incidence mainly due to population aging and not explained by increase in age-specific risk. This observation will impact on the future prevalence of the disease and its burden on healthcare systems.The age-specific incidence-ratesin patients > 75 years increased markedlyconsistent with the general increase of cancer-incidence in the elderly population. An increased diagnostic awareness of higher-risk disease seems to shift the population-based data for MDS sub-classification. We observed that younger patients without classified MDS subtypes have a similar survival like lower-risk disease, indicating that lower-risk MDS is underreported. Unsurprisingly, our data showed that younger patients have a better survival than elderly patients. This is most likelyrelated to higher frequency of lower-risk diseases in younger patients and their eligibility for allogeneic HSCT. However,the lack of a survival benefit observed in elderly patients on population-based level, after introduction of hypomethylating agents as standard treatment for transplant ineligible patients, is intriguing. The underlying reasons require further health-service research investigations. Relevance: The currently available data from CCRs in Switzerland is insufficient for detailed health service research on MDS patients, since important data is lacking on treatment, side effects and outcomes. A new cancer registration law with mandatory notification of cancer cases will be implemented in Switzerland by 2018. Moreover, the Swiss MDS Study Group has launched a Swiss MDS Registry that has started recruitment in 2016. Both initiatives will be of great value to improve data collection in order to foster future health service research of MDS patients in Switzerland with international collaborators. Table 1 Incidence and Mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Table 1. Incidence and Mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Figure 1 Incidence and mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Figure 1. Incidence and mortality of MDS in Switzerland in 2001-2007 and 2008-2012 Figure 2 Age-specific relative survival of MDS patients diagnosed in 2001-2007 and 2008-2012 Figure 2. Age-specific relative survival of MDS patients diagnosed in 2001-2007 and 2008-2012 Disclosures Bonadies: Bristol-Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Ruefer:Novartis: Consultancy; Celgene: Consultancy, Research Funding. Gerber:Celgene: Consultancy. Benz:Celgene: Consultancy. Lehmann:Novartis: Consultancy.

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Ribeil, Jean-Antoine, Patrícia Santos Ressende Cardoso, Aurelie Stanislas, Vanessa Maria Fenelon Costa, Benjamin Deloison, Milza Cintra Januario, Caroline Charlier, et al. "French-Brazilian Survey On Pregnancy in Sickle Cell Disease A Study of the International Sickle Cell Disease Observatory." Blood 120, no. 21 (November 16, 2012): 3215. http://dx.doi.org/10.1182/blood.v120.21.3215.3215.

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Abstract Abstract 3215 Introduction: The International Sickle Cell Disease Observatory (ISCDO) is an international group, established in 2011, including representatives from countries where sickle cell disease (SCD) is highly prevalent, in order to collect and share information of SCD patient's to improve patients care and quality of life, to define common guidelines, to develop advanced targeted approaches and transfer innovative practices worldwide. One of the first ISCDO study is a survey of pregnancy in SCD in France and Brazil. Context: Pregnancy in SCD has been associated with complications and adverse outcomes with an increased incidence of vaso-occlusive, infectious, obstetrical and neonatal complications. Recently, in Paris (France) and Belo Horizonte (BH) (Brazil), integrated care sickle-obstetric units were created, associating sickle cell haematologist, obstetrician and infectious disease specialists, experienced in the care of these high risk pregnancies. Our aim is to compare in two different geographic institutions the prognostic and evolution of SCD in pregnant women with the prospective goal to build up a clinical score in order to better determine appropriate treatment. Methods: We conducted a retrospective study on 253 pregnancies (120 Paris, 133 BH) characterized by 147 Hb SS, 91 Hb SC, 14 Hb SBeta, 2 Hb SD hemoglobinopathy. An e-crf was developed, to screen: the pre-pregnancy, the ante-partum rates of SCD-specific and infectious complications. We compared the obstetrical and the newborns health parameters and complications, the rate of Caesarean section, the perinatal and the maternal mortality in both countries. Results and Discussion: In both populations, 60% of women had a maternal age between 21–30 years old (yo). However, in Brazil there was a higher rate of young pregnant women (14–20 yo) (4% Paris; 20% BH) while in France, patients were older (>31 yo) (36% Paris; 18% BH). In the history of SCD women followed in Paris we noticed that: -Most of these patients had a severe form of SCD with 53% who had experienced an acute chest syndrome and 9% with a symptomatic cerebral vasculopathy, several infectious complications with 26% of pyelonephritis, -A high level of obstetrical complications with 35% of miscarriage and 10% of intrauterine foetal death. The patients followed in Paris during their pregnancy, were treated according to the French guidelines published in 2009. According to these guidelines 67% of patients were transfused and 17% patients were not transfused because of a post-transfusion reaction history. Caesarean section was performed in most cases in both populations (79% in Paris with 23% performed in emergency; 66% in BH). In both populations, there was 1 materno-foetal death. Furthermore, in BH, 15 perinatal deaths and 7 patient deaths were observed. In the Paris' group, there was no other perinatal death and 1 maternal death following a post-transfusional reaction after delivery. The key difference between the 2 study groups concerns the foetal/neonatal morbidity and mortality. These results lead us to compare the 2 health care structures to try to find out the medical guidelines to significantly reduce the frequency of these severe clinical events. In Paris, we introduce oxygenotherapy at home during pregnancy (2l/min) in patients who were transfused because of severe SCD symptomatology (33 patients) and who could not anymore be transfused because of a severe post-transfusion reaction history (11 patients). For these subgroups of patients, we found that 40% of them didn't experience any VOC complications, or preeclampsia. The introduction of oxygenotherapy at home during pregnancy might have a positive impact in reducing the occurrence of a number life threatening complications in these high risk pregnant woman especially when they cannot be appropriately transfused. This study is the first initial step of an international effort by the ISCDO to optimise the treatment of SCD pregnant women, to harmonize the guidelines in different countries and develop new methods of diagnosis and treatment. By improving care and the sharing knowledge of these pregnancies, we would like to increase worldwide access to the development of directed family cord blood banks in families with SCD and the access to hematopoietic stem cell transplant and other innovative therapies in developing and emerging countries where SCD is highly prevalent. Disclosures: No relevant conflicts of interest to declare.

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Rousselet, G., M. Bachouchi, P. Busson, F. de Vathaire, H. Wakasugi, G. Schwaab, N. Azli, J. P. Armand, E. Cvitkovic, and T. Tursz. "Clinical implications of the serum level of CD23 in patients with undifferentiated nasopharyngeal carcinoma." Journal of Clinical Oncology 11, no. 11 (November 1993): 2143–49. http://dx.doi.org/10.1200/jco.1993.11.11.2143.

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PURPOSE In contrast with other carcinoma cells, cells from nude mice transplanted undifferentiated carcinoma of nasopharyngeal type (UCNT) release the soluble fragment of the CD23 antigen (sCD23). We sought to study the level of sCD23 in sera of untreated UCNT patients. PATIENTS AND METHODS Pretherapeutic sera from 65 consecutive, locally advanced, initially nonmetastatic UCNT patients were assayed for sCD23. Patients were treated with a neoadjuvant chemotherapy/full-dose radiotherapy sequence. The mean follow-up duration is 50.5 months (range, 28 to 77). The Cox proportional hazards model was used to study the association between sCD23 levels and clinical signs and disease evolution. RESULTS sCD23 levels showed an association with disease-free survival (DFS; P = .08) and overall survival (OVS; P = .08). Patients with sCD23 levels greater than a cutoff value of 0.6 ng/mL (greater cutoffs were found to be equally significant, but less sensitive), have a relative risk (RR) of relapse of 3.3 (95% confidence interval, 1.6 to 6.9; P = .002), and an RR of death of 2.9 (95% confidence interval, 1.2 to 7.3; P = .02), when taking other prognostic factors into account. CD23 does not correlate with either the response to treatment or the development of metastases, but appears to be related to local control (cutoff, 0.6 ng/mL; RR = 5.1 [95% confidence interval, 1.2 to 21.7]; P = .02). CONCLUSION The serum level of sCD23 appears to be an independent prognostic factor for initially nonmetastatic, locally advanced UCNT patients, treated with chemotherapy and radiotherapy. Our data indicate an association between this marker and local relapses. Thus, a simple enzyme-linked immunoadsorbent assay (ELISA) could help to identify a high-risk group among nonmetastatic UCNT patients. CD23 could be a marker for two groups of UCNT tumors, with distinct biologic characteristics and clinical behaviors.

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Poot, Pieter, Roy Bakker, and Hans Lambers. "Adaptations to winter-wet ironstone soils: a comparison between rare ironstone Hakea (Proteaceae) species and their common congeners." Australian Journal of Botany 56, no. 7 (2008): 574. http://dx.doi.org/10.1071/bt08155.

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In south-western Australia, a rare plant community is found on shallow, winter-wet ironstone soils, which occur on coastal plains as isolated islands in a matrix of surrounding deeper sandy soils. To test for local adaptation of species endemic to these communities and potential inhibitory effects of ironstone soils on other species, we compared two rare ironstone Hakea species with four of their common congeners. The common congeners were chosen from nearby winter-wet habitats on deeper sandy soils and from non-wetland woodland habitats (i.e. two species in each habitat group). Seedlings of all species were grown on ironstone soil and subjected to waterlogging in a glasshouse experiment. Significant habitat-related differences emerged only when seedlings were waterlogged. When compared with their controls, shoot and root growth rates of ironstone endemics were less affected by waterlogging than those of their common congeners. This was partly associated with their large accumulation of leaf starch, and their substantial adventitious-root formation. Leaves of ironstone endemics also exhibited consistently higher concentrations of Cu and Zn. In contrast to the effect of waterlogging in the glasshouse experiment, natural waterlogging of seedlings transplanted into ironstone communities led to high mortality, but only in the non-wetland Hakea species. Mortality was strongly associated with the intensity of flooding events, with very small differences in inundation level (10–15 mm) strongly influencing seedling survival. Our results suggest that the chemistry of the waterlogged ironstone soil, and species adaptations to it, are important for understanding distribution patterns of these Hakea species.

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Timper, Patricia, Roger N. Gates, and Joe H. Bouton. "Response of Pratylenchus spp. in tall fescue infected with different strains of the fungal endophyte Neotyphodium coenophialum." Nematology 7, no. 1 (2005): 105–10. http://dx.doi.org/10.1163/1568541054192216.

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Abstract The presence of the fungal endophyte Neotyphodium coenophialum in tall fescue (Festuca arundinacea) confers resistance to some plant-parasitic nematodes but also results in the production of ergot alkaloids. Recently, new strains of N. coenophialum have been isolated from wild tall fescue and artificially inoculated into elite tall fescue cultivars. These strains produce low to nil levels of ergot alkaloids and are referred to as non-ergot strains. Our objective was to determine whether non-ergot strains of the endophyte confer the same level of resistance to Pratylenchus spp. as the endemic strain in tall fescue. In a glasshouse experiment, nematode resistance was compared in two fescue cultivars (Jesup and Georgia 5) infected with either the endemic strain (E+), or two non-ergot strains, AR542 and AR584. An additional non-ergot strain, AR514, was tested only in cv. Jesup. Cultivars Georgia 5 and Jesup without endophytes (E−) were used as controls. The endophtye status of the plants was confirmed and then three plants per cultivar/endophyte combination were transplanted into 10 cm square pots. The pots were inoculated with a mixed culture of Pratylenchus zeae and P. scribneri in the first trial and a pure culture of P. scribneri in the second trial of the experiment. After 8 weeks, the number of nematodes within the roots from each pot was determined. Numbers of Pratylenchus spp. in either cv. Georgia 5 or cv. Jesup containing the non-ergot strain AR542 were not different from numbers in E− plants. AR514 also did not confer resistance to the nematodes in cv. Jesup. By contrast, the non-ergot strain AR584 appears to confer resistance to Pratylenchus spp. in cv. Georgia 5, but not in cv. Jesup; however, the level of resistance in cv. Georgia 5 was less than the resistance conferred by the endemic endophyte. Genetic differences between the two tall fescue cultivars may affect growth of the endophyte or production of a nematode toxin or deterrent by the endophyte. As only a small subset of endophyte strains has been tested, we are screening additional non-ergot strains for resistance to P. scribneri.

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Kawamura, K., S. Murase, and S. Yuasa. "Development of the rodent cerebellum and synaptic re-formation of donor climbing terminals on spines of the host Purkinje dendrites after chemical deafferentation." Journal of Experimental Biology 153, no. 1 (October 1, 1990): 289–303. http://dx.doi.org/10.1242/jeb.153.1.289.

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Reinnervation of host Purkinje cells by donor climbing fibers was observed in the following experiments. Medullary primordial tissue (from E14-E16) containing the inferior olive was grafted into a host rat cerebellum, in which the inferior olivary complex and climbing fibers had been destroyed by intraperitoneal injection of 3-acetylpyridine (3-AP). After 3 weeks, immature as well as mature types of climbing fiber terminals bearing packed round vesicles were found that had established synaptic contacts on dendritic spines of the host Purkinje cells. Quantitative analysis at the ultrastructural level has been carried out. The main results are as follows. (1) The number of preterminals that formed synaptic contacts with spines of the host Purkinje dendrites in the transplanted material increased by 3.4-fold compared to the control (3-AP-treated non-grafted material). (2) The number of mature climbing-type preterminals increased from 0.3-0.9% to 5% after grafting (cf. 22% in normal brain tissue), and the number of immature climbing-type preterminals also increased from 2–10% (control) to 20% after grafting. These changes were statistically significant (P less than 0.01). (3) The number of parallel-type preterminals increased from 13% (control) to 27% after grafting, which was also statistically significant (P less than 0.01). Thus, it appears that the donor climbing fibers grow and develop to find unoccupied spines on the host Purkinje dendrites and establish synaptic contacts, and also that the host parallel fibers may generate axonal sprouts to search their new targets and ultimately to form synaptic contacts with unoccupied spines. In the process of re-modeling the brain, competition for targets is likely to occur between the two kinds of axonal processes, i.e. the donor climbing fibers and the host parallel fibers.

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Palladini, Giovanni, Stefan Schönland, Giampaolo Merlini, Paolo Milani, Arnaud Jaccard, Frank Bridoux, Wilfried Roeloffzen, et al. "First Glimpse on Real-World Efficacy Outcomes for 2000 Patients with Systemic Light Chain Amyloidosis in Europe: A Retrospective Observational Multicenter Study By the European Myeloma Network." Blood 136, Supplement 1 (November 5, 2020): 50–51. http://dx.doi.org/10.1182/blood-2020-140708.

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Introduction: Systemic light chain (AL) amyloidosis is a plasma cell dyscrasia in which a toxic plasma cell clone causes devastating multiorgan complications and death, and substantially affects the quality of life of patients (pts). Current therapeutic options are not regulatory approved and are typically based on modified treatments that are used for multiple myeloma. The aim of EMN23 study is to thoroughly describe patterns of AL amyloidosis management in a large-scale real-world evidence (RWE) setting throughout Europe, to understand different treatment strategies and their evolution, and evaluate resource utilization. Methods: EMN23 is an ongoing, retrospective, observational, multicenter study aiming to enroll 5000 pts in 10 countries (13 Sites) across Europe; Austria, Czech Republic, France, Germany, Greece, Italy, the Netherlands, Portugal, Spain, and UK. Pts must have documented systemic AL amyloidosis, and a first-line treatment start date between 2004 and 2018. Results are presented in 2 chronological cohorts, 2004-2010, and 2011-2018, with 2010 being an important landmark, since bortezomib, cyclophosphamide, dexamethasone (CyBorD) regimen was introduced in clinical practice. Pts who received treatment in the context of an interventional clinical trial were not analyzed for treatment and efficacy results. The current analysis presents baseline disease characteristics, treatment patterns and efficacy outcomes. Informed consent or a non-opposition letter was collected for all alive pts, depending on the regulatory environment of each country, and a waiver of consent was obtained for the deceased. Results: In total, 2031 pts from Austria (1.9%), Czech Republic (0.9%), France (9.2%), Germany (3.6%), Greece (12.6%), Italy (58.7%), the Netherlands (7.2%), Portugal (1.0%), and Spain (4.9%) have been analyzed; 67.9% of pts started treatment after 2010. Median age at diagnosis was 66 years and 54.5% were males, while 48.2% had ECOG performance status ≤1. Heart (71.9%), kidney (67.2%), soft tissue (19.7%) and nervous system (18.5%) were most often involved at diagnosis, and 17.2%, 36.2%, 21.1% and 15.2% of pts were at cardiac stage I, II, IIIA and IIIB, according to Mayo staging system, respectively, while for 10.3% of pts staging was not reported. There was a slight increase of pts with stage III in the more recent era. In the period 2004-2010, 52.8% of the pts had at least 2 lines of therapy, which dropped to 35.2% in the period 2011-2018. A 6.4% of pts received autologous stem cell transplant at first line. The prevailing first-line regimen in 2004-2010 was melphalan with dexamethasone (MDex; 50.6% of the pts), replaced by CyBorD (46.1%) in the post-2010 period. The predominant first-line regimens were different in various countries in 2004-2010, but in general CyBorD was the most extensively used regimen after 2010. Overall, the most frequent second-line regimen was BorD (29.8%), which was also the treatment of choice for 15.7% of the pts who had frontline therapy with MDex in the pre-2010 period; and lenalidomide dexamethasone (RD, 25.5%) which was also favored following frontline treatment with CyBorD for 10.6% of the pts in the post-2010 period. In the 2004-2010 era, 31.7% of the pts achieved a hematologic VGPR or CR at first line, which was slightly improved to 37.2% in the post-2010 period. Notably, 29.9% and 23% of pts did not achieve a hematologic response (no response or disease progression) in the two periods, respectively (p=0.001). Mortality in the first months of treatment remained roughly at the same level, with the 3-month overall survival (OS) rate at 82.3% for both cohorts, whereas the median OS increased from 43.5 months in the pre-2010 period to 50.1 months in the post-2010 period (p=0.525). There was a trend towards an improvement in the median OS of stage IIIA pts from 9.5 to 25.9 months, pre- and post-2010, respectively, however, no change was observed for stage IIIB pts (2.7 to 3.5 months). Conclusions: Therapeutic options for AL amyloidosis have changed considerably over time. After 2010 CyBorD became the prominent first-line treatment; the proportion of pts not achieving a response was reduced by 23% and a trend towards improvement of OS for stage IIIA disease was observed, but the prognosis of stage IIIB pts remained dismal and early mortality remained unchanged. Early diagnosis is still an unmet need, and improved therapies are essential. Figure 1 Disclosures Palladini: Celgene: Other: Travel support; Jannsen Cilag: Honoraria, Other. Schönland:Janssen, Prothena, Takeda: Honoraria, Other: travel support to meetings, Research Funding. Milani:Celgene: Other: Travel support; Pfizer: Other: Speaker honoraria; Janssen: Other: Speaker honoraria. Jaccard:Janssen: Consultancy, Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Janssen., Research Funding; Celgene: Honoraria, Other: A.J. has served in a consulting or advisory role for Janssen and has received honoraria from, received research funding from, and had travel, accommodations, or other expenses paid for or reimbursed by Celgene., Research Funding. Bridoux:Celgene: Honoraria; Baxter: Consultancy; Janssen: Honoraria. Cibeira:Amgen: Honoraria, Other: Educational lectures; Celgene: Honoraria, Other: Educational lectures; Akcea Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational lectures. Agis:Janssen: Honoraria, Research Funding; Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria. Minnema:Amgen: Honoraria; Servier: Honoraria; Janssen Cilag: Honoraria; Celgene Corporation: Honoraria, Research Funding; Gilead: Honoraria. Bergantim:AMGEN, Celgene, Janssen, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Speaker honoraria; Celgene, AMGEN/SPH/APCL: Other: Grants, Research Funding. Hajek:Oncopeptides: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaMar: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. João:Takeda: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy; BMS: Consultancy. Wechalekar:Celgene: Honoraria; Janssen: Honoraria, Other: Advisory; Caelum: Other: Advisory; Takeda: Honoraria, Other: Travel. Sonneveld:Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy; Skyline Dx: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Kastritis:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Genesis Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. OffLabel Disclosure: This is a RWE study on AL amyloidosis, and currently there are no regulatory approved therapeutic options for the disease.

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Wang, Xiaoli, Cing Siang Hu, Joseph Tripodi, Vesna Najfeld, Bruce Petersen, Raajit K. Rampal, Noushin Farnoud, Christopher Famulare, John Mascarenhas, and Ronald Hoffman. "Myeloproliferative Neoplasm (MPN) Blastic Transformation Occurs at the Level of Hematopoietic Stem Cells." Blood 132, Supplement 1 (November 29, 2018): 101. http://dx.doi.org/10.1182/blood-2018-99-117348.

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Abstract Myeloproliferative neoplasm-blast phase (MPN-BP) and de novo acute myeloid leukemia (AML) each have distinct mutational patterns and clinical courses. MPN-BP patients have a particularly dismal prognosis with a median survival of less than 6 months with currently available therapies. So far, the cellular hierarchy that characterizes MPN-BP and the evolution of various leukemia-initiating clones (LIC) in MPN-BP have not been well delineated. We therefore established an in vivo MPN-BP xenograft model to address these questions. Among the 22 patients with MPN-BP studied 11 were cytogenetically normal while the remainder had multiple chromosomal abnormalities including del(5), del(20q), del(14), +1q, del(17p). 86% of the patients had at least 2 myeloid malignancy gene mutations including JAK2, ASXL1,TET2, MPL, SF3B1, RUNX1, U2AF1, PTPN11, IDH1/2, SRSF2 and TP53. These findings indicate that MPN-BP is characterized by multiple mutational events and cytogenetic abnormalities. T cell-depleted mononuclear cells from 8 of 14 patients engrafted in NSG mice {>0.5% hCD45+ cells in bone marrow (BM)}. Among them, samples from 6 patients resulted in a high degree of hCD45+ cell chimerism (34.6±6.4% in BM) and recapitulated numerous aspects of MPN-BP within 4 months, including the presence of at least 20% hCD45dimCD33+ cells or hCD34+ cells, or at least 20% blasts as detected by morphological examination of the marrow and leukemia cell dissemination to the spleen and PB. These mice had a 2.8±0.6- fold increase in splenic weight as compared to mice receiving PBS alone. The leukemic mice were characterized by reduced blood counts, suggesting that MPN-BP cells suppressed normal murine hematopoiesis, or led to cytopenias due to hyper-splenism. Moreover, the greater degrees of blast cell chimerism and the higher frequency of leukemia initiating cells as determined by limiting dilution analyses correlated with a shorter time to leukemia initiation and an inferior clinical outcome of the transplanted NSG mice. Grafts from each of these 6 MPN-BP patients produced a large number of donor-derived myeloid cells and a smaller number of lymphoid cells (mostly CD3+ and few CD19+). Cells belonging to each of these lineages and leukemic cells in primary recipients produced from Pts 4, 5, 6 and 11 had an identical proportion of chromosomally abnormal and mutated cells as primary cells [Pt 4: JAK2V617F, TET2 and PHF6; Pt 5 and 11: Del (20q), +8; Pt 6: +1q, del(17p)], except that a small proportion of T cells from Pts 5 and 11 lacked chromosomal abnormalities. Furthermore, the degree of MPN-BP engraftment and leukemic cell burden increased with the subsequent 3 serial transplantations even when the recipients received progressively smaller numbers of MPN-BP cells from the prior recipient. Primary Pt 6 originally had a JAK2V617F+ PV but lost JAK2V617F at the time the MPN-BP occurred at which time there were two clonal cell populations, one with +1q (12%) and the other del(17p) (80%), the site of the TP53 gene, as well as normal cells (8%). In the primary recipient NSG the donor derived cells were JAK2V617F- but contained +1q (1%) and del(17p) (98.5%) and cytogenetically normal (0.5%). +1q and JAK2V617F were not observed, while cells containing the TP53 deletion alone were detected in donor derived leukemic cells, mature myeloid and T cells in the secondary and subsequent serial recipients. Furthermore, del(17p) was found in phenotypically isolated HSCs, MPPs, MLPs, CMPs, GMPs, MEPs, and mature T cells within the CD33- cell fraction as well as CD45dimCD33+ AML blasts selected from primary MPN-BP cells from Pt6. However, +1q was found exclusively in purified MLPs and MEP. These observations establish that cytogenetic and mutational events that lead to MPN-BP occur at different stages along the developmental HSC hierarchy and that a small population of normal HSCs persist. Furthermore, in JAK2V617F+ MPNs that develop MPN-BP and lose JAK2V617F, additional cytogenetic events occur at different stages along the JAK2V617F- MPN-BP-stem cell hierarchy. Our ability to serially transplant the LIC from these patients has allowed us to create the first MPN-BP PDX model that will not only extend our understanding of MPN-BP stem cell biology but might also prove useful for screening drugs to treat MPN-BP. Disclosures Rampal: Jazz: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Stemline: Research Funding; Constellation: Research Funding; Celgene: Honoraria. Mascarenhas:Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche: Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Promedior: Research Funding; Janssen: Research Funding. Hoffman:Formation Biologics: Research Funding; Summer Road: Research Funding; Merus: Research Funding; Incyte: Research Funding; Janssen: Research Funding.

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Triviai, Ioanna, Thomas Stuebig, Anita Badbaran, Silke Zeschke, Victoria Panagiota, Michael Heuser, Carol Stocking, and Nicolaus Kroger. "EZH2 Mutations Are Drivers of Clonal Hematopoiesis and Leukemic Transformation in a Mouse Model of Primary Myelofibrosis." Blood 124, no. 21 (December 6, 2014): 3211. http://dx.doi.org/10.1182/blood.v124.21.3211.3211.

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Abstract Primary Myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by aberrant myeloid differentiation, associated with disruption of the bone marrow niche with subsequent fibrosis development and a high risk of leukemic transformation. The phenotypical complexity observed in PMF likely reflects the heterogeneous mutation profile of the neoplastic stem cells driving the disease. In our former work, we identified a CD133+ hematopoietic stem / progenitor cell (HSPC) population from patient peripheral blood that can drive major PMF morbidity parameters in a xenotransplantation mouse model. Mutational analysis of the JAK2 locus at the single cell level within the CD133+ population showed highly variable levels of cells with a JAK2+/+, JAK2V617F/+, or JAK2V617F/V617F genotype, indicating that clonality is unlikely driven by JAK2 mutations. In two of these patient samples, and in a third patient sample with CALR-fs* mutations, we identified a high load of missense mutations in EZH2 (45 to 95%), suggesting they may be critical for the clonal expansion of the neoplastic stem cell compartment. EZH2 mutations are found in circa 7% of PMF patients and are correlated with poor prognosis. EZH2 is a critical enzymatic subunit of the Polycomb Repressor Complex 2, which initiates gene repression of select genes through its intrinsic activity for methylating lysine-27 of histone H3 (H3K27). To date, the exact contribution of EZH2 mutations to PMF evolution or AML transition has not been clarified. CD133+ HSPC carrying EZH2 mutations either with JAK2 or CALR mutations were transplanted into immunodeficient NOD-scid-gamma (NSG) mice. Mice engrafted with patient samples carrying either EZH2-Y633C and JAK2-V617F or EZH2-Y733* and CALR-fs* mutations showed a strikingly similar phenotype, including high human cell engraftment (10-20%), skewed myelopoiesis, dysplastic human megakaryocytes, splenomegaly, anemia, and fibrosis in either the BM or spleen. In the case of xenotransplanted mice receiving CD133+ cells with a low JAK2 burden and EZH2-D265H mutations, we observed the highest engraftment in our mouse model (62-95%) and in one case AML transition with >50% CD133+ human blasts in murine bone marrow. Notably, AML arose from a CD133+ EZH2D265H/+ cell that lacked JAK2V617Fmutation. We thus conclude that EZH2 mutations confer to CD133+ neoplastic stem cells a predisposition to clonal aberrant hematopoiesis; whereas acquisition of JAK2V617F or CALR mutations likely leads to the observed myeloproliferation and disruption of megakaryocytic and erythroid regulation . Moreover, our results demonstrate that epigenetic mutations (like EZH2D265) and not JAK2V617F are critical for AML transition. Our data underscore the importance of post-transcriptional modifiers of histones in altering the epigenetic landscape of neoplastic stem cells, whose clonal growth sustains aberrant myelopoiesis and expansion of pre-leukemic clones. Disclosures No relevant conflicts of interest to declare.

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Zipeto, Maria Anna, Angela Court Recart, Nathaniel Delos Santos, Qingfei Jiang, Leslie A. Crews, and Catriona HM Jamieson. "Inflammatory Cytokine-Responsive ADAR1 Impairs Let-7 Biogenesis and Promotes Leukemia Stem Cell Generation." Blood 126, no. 23 (December 3, 2015): 4014. http://dx.doi.org/10.1182/blood.v126.23.4014.4014.

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Abstract Background In advanced human malignancies, RNA sequencing (RNA-seq) has uncovered deregulation of adenosine deaminase acting on RNA (ADAR) editases that promote therapeutic resistance and leukemia stem cell (LSC) generation. Chronic myeloid leukemia (CML), an important paradigm for understanding LSC evolution, is initiated by BCR-ABL1 oncogene expression in hematopoietic stem cells (HSCs) but undergoes blast crisis (BC) transformation following aberrant self-renewal acquisition by myeloid progenitors harboring cytokine-responsive ADAR1 p150 overexpression. Emerging evidence suggests that adenosine to inosine editing at the level of primary (pri) or precursor (pre)-microRNA (miRNA), alters miRNA biogenesis and impairs biogenesis. However, relatively little is known about the role of inflammatory niche-driven ADAR1 miRNA editing in malignant reprogramming of progenitors into self-renewing LSCs. Methods Primary normal and CML progenitors were FACS-purified and RNA-Seq analysis as well as qRT-PCR validation were performed according to published methods (Jiang, 2013). MiRNAs were extracted from purified CD34+ cells derived from CP, BC CML and cord blood by RNeasy microKit (QIAGEN) and let-7 expression was evaluated by qRT-PCR using miScript Primer assay (QIAGEN). CD34+ cord blood (n=3) were transduced with lentiviral human JAK2, let-7a, wt-ADAR1 and mutant ADAR1, which lacks a functional deaminase domain. Because STAT signaling triggers ADAR1 transcriptional activation and both BCR-ABL1 and JAK2 activate STAT5a, nanoproteomics analysis of STAT5a levels was performed. Engrafted immunocompromised RAG2-/-γc-/- mice were treated with a JAK2 inhibitor, SAR302503, alone or in combination with a potent BCR-ABL1 TKI Dasatinib, for two weeks followed by FACS analysis of human progenitor engraftment in hematopoietic tissues and serial transplantation. Results RNA-seq and qRT-PCR analysis in FACS purified BC CML progenitors revealed an over-representation of inflammatory pathway activation and higher levels of JAK2-dependent inflammatory cytokine receptors, when compared to normal and chronic phase (CP) progenitors. Moreover, RNA-seq and qRT-PCR analysis showed decreased levels of mature let-7 family of stem cell regulatory miRNA in BC compared to normal and CP progenitors. Lentiviral human JAK2 transduction of CD34+ progenitors led to an increase of ADAR1 transcript levels and to a reduction in let-7 family members. Interestingly, lentiviral human JAK2 transduction of normal progenitors enhanced ADAR1 activity, as revealed by RNA editing-specific qRT-PCR and RNA-seq analysis. Moreover, qRT-PCR analysis of CD34+ progenitors transduced with wt-ADAR1, but not mutant ADAR1 lacking functional deaminase activity, reduced let-7 miRNA levels. These data suggested that ADAR1 impairs let-7 family biogenesis in a RNA editing dependent manner. Interestingly, RNA-seq analysis confirmed higher frequency of A-to-I editing events in pri- and pre-let-7 family members in CD34+ BC compared to CP progenitors, as well as normal progenitors transduced with human JAK2 and ADAR1-wt, but not mutant ADAR1. Lentiviral ADAR1 overexpression enhanced CP CML progenitor self-renewal and decreased levels of some members of the let-7 family. In contrast, lentiviral transduction of human let-7a significantly reduced self-renewal of progenitors. In vivo treatments with Dasatinib in combination with a JAK2 inhibitor, significantly reduced self-renewal of BCR-ABL1 expressing BC progenitors in the bone marrow thereby prolonging survival of serially transplanted mice. Finally, a reduction in ADAR1 p150 transcripts was also noted following combination treatment only suggesting a role for ADAR1 in CSC propagation. Conclusion This is the first demonstration that intrinsic BCR-ABL oncogenic signaling and extrinsic cytokines signaling through JAK2 converge on activation of ADAR1 that drives LSC generation by impairing let-7 miRNA biogenesis. Targeted reversal of ADAR1-mediated miRNA editing may enhance eradication of inflammatory niche resident cancer stem cells in a broad array of malignancies, including JAK2-driven myeloproliferative neoplasms. Disclosures Jamieson: J&J: Research Funding; GSK: Research Funding.

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Ferreira, Ana Carina, Marco Mendes, Cecília Silva, Patrícia Cotovio, Inês Aires, David Navarro, Fernando Correia Caeiro Pereira, et al. "P1680MINERAL METABOLISM CHANGES AFTER RENAL TRANSPLANTATION." Nephrology Dialysis Transplantation 35, Supplement_3 (June 1, 2020). http://dx.doi.org/10.1093/ndt/gfaa142.p1680.

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Abstract Background and Aims Successful renal transplant restores many physiologic abnormalities, including improvement of chronic kidney disease-mineral and bone disorder (CKD-MBD) syndrome, and modifications of bone-related molecules in disease and health can help to understand pathophysiology of this syndrome. The aim of this study was to analyse the evolution of some of the new CKD-MBD players [alpha-klotho, fibroblast grow factor (FGF) 23, sclerostin] pre and post transplantation and the associations between those and the usual markers of the CKD-MBD disease [parathyroid hormone (PTH), bone alkaline phosphatase (bAP), calcitonin, vitamin D (vitD), phosphorus (Pi), Calcium (Ca) and Magnesium (Mg)] pre and post transplant. We also looked at the differences between values in the two time-points (delta). Method We performed a prospective cohort study of a consecutive sample of de novo single renal transplanted patients in our unit. At inclusion, demographic, clinical and transplant-related data were collected, X-ray of the pelvis and hands (for Adragão score) and echocardiographic findings were recorded. All patients were submitted to a bone biopsy and laboratorial evaluation at baseline (time 0). Patients were followed for 12 months (time 1), after which performed laboratorial evaluation, a second bone biopsy, echocardiogram, X-ray of pelvis and hands, bone densitometry and non-contrast cardiac CT (Agatston score). Continuous variables are presented as medians and categorical variables as frequencies. Associations between variables were performed using Wilcoxon matched-pairs test and Spearman correlation test. STATA software was used and p < 0.05 was considered statistically significant. Results We recruited 85 patients from 1st October 2015 to 1st March 2018. At the end of 12 months, 6 patients refuse to perform the 2nd evaluation, 5 had primary non-function of the kidney graft, 1 had no sample on bone biopsy in time 0 and 4 patients died. We performed a 2nd evaluation in 69 patients and included those in this study. Mean age 50.2±12.4 years, 48 men, 53 caucasian (78.8%), median BMI 24.5 (22.7 – 27.8), median dialysis vintage 55 (42 – 84). We observe a significant reduction on phosphorus (delta: -1.1 mg/dl), magnesium (delta: -0.5 mg/dl), PTH (delta: -297.7 pg/ml), Calcitonin (delta: -0.9 ng/L), sclerostin (delta: -1.1 ng/ml), bone alkaline phosphatase (delta: -11.5 U/L) and FGF23 (delta: -1656.5 RU/ml). Both calcium (delta: 0.7 mg/dl) and alpha-klotho (delta: 265.7 pg/ml) serum levels increase, with no significant changes in vitamin D levels. With restoring renal health (time 1) and comparing with time 0, PTH maintain the negative correlation with sclerostin (p=0.02) and the positive correlation with FGF23 (p=0.0002) as in time 0; modify the correlation with Pi, becoming a negative correlation instead of positive (p=0.001) and gain new correlations with Ca (p=0.001) and vitamin D levels (p=0.03). Also, PTH correlated with the delta FGF23 (rho=-0.4, p=0.003) and sclerostin correlated with delta PTH (p=0.01). FGF23 didn’t associate with delta PTH, neither PTH associated with delta sclerostin. FGF23 didn’t reveal statistical association with Pi or Ca levels after transplant, contrasting with positive associations in pre transplant (p=0.002, p<0.0001). On the contrary, sclerostin developed a new correlation with Pi (p=0.0004) and a negative correlation with Ca (p=0.01). We didn’t find correlations between these molecules and alpha-klotho. Conclusion In conclusion, it seems that sclerostin influences PTH levels and that PTH is the stimulus for the increase or decrease of FGF23 serum levels (as we found a positive association between those two molecules in both time-points and a negative association between PTH and the difference of FGF23 pre and post transplant). Levels of Ca and Pi seemed to be directly influenced by the level of PTH in post transplant, and those minerals seemed to be key factors for sclerostin secretion.

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Journal articles on the topic 'Two-level transplant evolution'

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