Interdigitating dendritic cell sarcoma (IDCS) and histiocytic sarcoma (HS) are two distinct rare hematolymphoid neoplasms, and HS derived from a likely pre-existing IDCS has never been reported in ...the English literature. Diagnosis of such entities in excised specimens is difficult, but becomes more difficult with the scant amount of materials obtained with fine needle aspiration (FNA) and core needle biopsy. Here we present an interesting and unique case of an IDCS located within a mesenteric mass, which was initially diagnosed as IDCS from the cytology of FNA and core needle biopsy specimens. After brief chemotherapy, the patient again developed abdominal pain, and a HS was diagnosed based on the excised segmental small intestinal specimen. While the exact relationship between the IDCS and HS cannot be ascertained, it is most likely that the HS is derived from the IDCS, although co-existing HS in addition to IDCS from the cytology specimen cannot be completely ruled out.
Stromal cell–derived factor 1 (SDF-1) is a chemokine that binds to the CXCR4 receptor. Its functions include acting as a chemotactic factor for hematopoietic stem and progenitor cells. We recently ...reported the synthesis of a small cyclized peptide analog (31 amino acids) of the terminal regions of SDF-1 that had biological function comparable to the native molecule (67 amino acids). In the present study, we investigated the effects of SDF-1 analogs (CTCE0021 and CTCE0214) in the chemotactic migration of peripheral blood hematopoietic cells (lineage-negative and CD34
+ cells). Enhanced chemotaxis of normal and G-CSF-mobilized hematopoietic cells was observed with both SDF-1 analogs in a dose-dependent manner. The increases were statistically significant (
p ≤ 0.016 by one-way ANOVA) at analog concentrations of 50 to 100 μg/mL. Colony-forming progenitor cells were not affected by exposure to the analogs up to 100 μg/mL. When different doses of the SDF-1 analog CTCE0214 were administered to mice, significant increases in circulating hematopoietic cells (identified by flow cytometry as lineage
low/−, Sca-1
+, and c-kit
+) were observed after a single injection of 75 μg per animal. The effect was apparent at 4 hours and became significant at 24 hours. These results suggest that SDF-1 analogs can be considered for mobilization of hematopoietic stem cells.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CD33 is a cell surface marker of committed myelomonocytic precursors and circulating monocytes, and is also found on acute myeloid leukemia (AML) cells. CD33 belongs to a family of sialic ...acid–binding cell surface proteins named Siglecs, among which there are 7 other functional CD33-related Siglecs (CD33rSiglecs). We sought to characterize the spectrum of expression of the other CD33rSiglecs on bone marrow precursors and AML cells and asked if they can potentially serve as targets for therapy.
Cell surface CD33rSiglecs were analyzed by flow cytometry. The ability of certain anti-Siglec antibodies to target toxin-mediated cell killing of Siglec-expressing cell lines was characterized and compared.
We demonstrate that Siglecs-3, -5, -6, -7, and -9 are expressed on subsets of normal bone marrow precursors, including promonocytes and myelocytes. Furthermore, most AML (but not ALL) cells express these Siglecs. There is substantial variability in Siglec type and expression level between cases, with each having a unique “CD33rSiglec fingerprint.” Individual anti-Siglec antibodies along with a saporin toxin–conjugated secondary antibody can target myelomonocytic leukemia cells for death, and targeting of multiple Siglecs improves cell killing. Cytotoxicity was further enhanced by sialidase treatment of target cells, which improves antibody binding. We also confirmed that antibody binding induced rapid internalization of Siglecs from the cell surface, which is a requirement for cell killing via saporin.
Multiple CD33rSiglecs are expressed on normal and malignant myelomonoyctic cells. Targeting these Siglecs, possibly in combinations, could improve anti-CD33 antibody therapy or be used as an alternative to anti-CD33.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose
Patients with malignancy sometimes develop painful mucositis and require patient-controlled analgesia (PCA) to treat their pain. Pain disrupts sleep and there is some evidence that analgesic ...medications also disrupt sleep. This study examined whether treatment with the sedative hypnotic eszopiclone could improve self-reports of sleep, fatigue, and pain as well as decrease opioid self-administered via PCA.
Methods
Inpatients who developed mucositis severe enough to require PCA treatment were randomized double-blind to a 2-day trial on eszopiclone or placebo-administered at bedtime. Patients completed questionnaires which assessed sleep, pain, and fatigue. PCA medication was calculated in terms of morphine equivalents. Data were analyzed with unpaired
t
tests and repeated measures analysis of variance.
Results
Twenty-two patients were randomized to placebo and 23 to eszopiclone. Groups were comparable in age and treatment characteristics. Mean pain scores were lower in the eszopiclone group at all time points (morning
p
= 0.01, afternoon
p
= 0.04, evening
p
= 0.04). The eszopiclone group reported increased sleep time (
p
< 0.05), fewer nighttime awakenings (
p
< 0.001), better self-reported sleep quality (
p
= 0.01), and depth (
p
= 0.04). There were no significant differences between eszopiclone and placebo in terms of self-reports of fatigue or opioid usage.
Conclusion
Sedative hypnotic agents improve sleep and analgesia even in the setting of considerable pain and discomfort.
•AML with RARG rearrangement is a novel subtype of AML with some unique clinical, immunophenotypic, and genetic characteristics.•AML with RARG rearrangement is insensitive to ATRA and ATO and carries ...a poor prognosis.
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Acute myeloid leukemia (AML) with retinoic acid receptor γ (RARG) rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to alltrans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four patients with AML with RARG rearrangements were identified. Bleeding or ecchymosis was present in 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of the cases, respectively. Immunophenotyping showed the following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6, NUP98, HNRNPc, HNRNPm, PML, and NPM1. WT1- and NRAS/KRAS-mutations were common comutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (∼29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA sequencing data from 201 patients with AML showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis. This study is registered with the Chinese Clinical Trial Registry (ChiCTR2200055810).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Introduction: Human bone marrow aging is typified by decreased cellularity, stem cell exhaustion and myeloid lineage bias that may set the stage for development of myeloid malignancies. ...Secondary AML (sAML) is a malignancy that has been associated with alterations in RNA processing genes and currently has few effective treatment options available. A central goal of future therapeutic strategies is to prevent disease relapse and therapeutic resistance by selectively targeting unique gene products that are essential to LSC but not normal HSC function. Therefore, we established whole gene, long non-coding RNA (lncRNA), splice isoform, and RNA editing signatures of benign versus malignant bone marrow progenitor cell aging, and evaluated the therapeutic efficacy of splicing-targeted agents in pre-clinical humanized in vitro and in vivo model systems.
Methods: Whole transcriptome sequencing (RNA-Seq) was performed on FACS-purified hematopoietic stem (CD34+CD38-Lin-) and progenitor cells (CD34+CD38+Lin-) from aged (average age = 65.9 ± 6.8 years old) versus young (average age = 25.8 ± 3.0 years old) adult healthy bone marrow samples, and in leukemia stem cells (LSC) from patients with sAML (average age = 71.4 ± 7.9 years old). Comparative gene set enrichment analyses (GSEA), splice isoform, lncRNA, and RNA editing profiles were identified for normal and malignant progenitor cell aging. Then, we evaluated the spliceosome modulatory agent 17S-FD-895 in splicing reporter activity, PCR, and functional in vitro hematopoietic progenitor and in vivo LSC primagraft assays.
Results: Disruption of pre-mRNA splicing activity has recently been implicated as a therapeutic vulnerability in some types of cancer. Comparative whole transcriptome RNA sequencing (RNA-seq) analyses revealed pre-mRNA splicing factor gene expression was significantly disrupted in human AML LSC compared with age-matched normal progenitors. Comparative splice isoform RNA-seq and qRT-PCR validation revealed recurrent intron retention and exon skipping in expressed transcripts, such as PTK2B and several protein phosphatase gene products. Notably, transcription factor profiling of AML LSC demonstrated downregulation of key tumor suppressor genes, such as IRF8 and TP53. We then investigated the LSC inhibitory efficacy of a stable and potent splicing modulatory agent, 17S-FD-895, in humanized stromal co-culture and AML LSC primagraft assays. Pharmacological spliceosome modulation disrupted AML LSC maintenance in vivo by altering splicing of stem cell survival and AML-associated transcripts at doses that spared normal hematopoietic progenitors.
Conclusions: Detection and targeted modulation of aberrant RNA processing provides an innovative strategy for AML LSC eradication with implications for treatment of a variety of human malignancies and other age-related disorders.
Citation Format: Leslie A. Crews, Larisa Balaian, Heather S. Leu, Nathaniel P. Delos Santos, Angela C. Court, Anil Sadarangani, Maria A. Zipeto, James J. La Clair, Reymundo Villa, Sheldon R. Morris, Rainer Storb, Anna Kulidjian, Edward D. Ball, Michael D. Burkart, Catriona H.M. Jamieson. RNA processing signatures of normal versus malignant progenitor cell aging predict leukemia stem cell sensitivity to RNA splicing modulation. abstract. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 915.
In acute myelogenous leukemia (AML), the FLT3 receptor tyrosine kinase (RTK) is highly expressed with 30% of patients expressing a mutated, constitutively active form of this protein. To inhibit this ...receptor, VX-322 was developed and found to be very potent against both the FLT3 and c-KIT RTKs with enzyme K i values of <1 nM and a cellular IC50 between 1 and 5 nM. It was efficacious in a FLT3-ITD dependent myeloproliferative mouse model, doubling survival compared to other FLT3 inhibitors, with 25% of the mice cured. Upon treatment of primary AML patient blast cells, the dual inhibition of FLT3 and c-KIT was superior to inhibitors targeting a single RTK. Thus, this compound may represent an improved pharmacologic and selectivity profile that could be effective in the treatment of AML.
Objective To develop a novel method of generating multiple autologous acute myeloid leukemia (AML) reactive T-cell lines as a step toward adoptive immunotherapy for AML. Materials and Methods AML ...peripheral blood mononuclear cells (MNC), including >90% AML blasts and 1% to 3% T cells, were seeded in limiting dilution culture in which AML blasts were induced to undergo dendritic cell (DC) differentiation. T cells were primed and activated with the addition of a cytokine combination. Results Highly reactive anti-AML T-cell lines (both CD4+ and CD8+ ) were generated, selected, and expanded. The estimated average frequency of AML-reactive T cells or precursors was 6 ± 3/1,000,000 AML peripheral blood mononuclear cells (n = 11). Robust intracellular interferon-γ (IFN-γ) release from T-cell lines was demonstrated by flow cytometry after stimulation by autologous AML cells, but not an autologous B-lymphoblastoid cell line (LCL). These T-cell lines caused specific lysis of autologous AML cells, but not autologous LCL or allogeneic AML cells, and they depleted autologous AML colony-forming cells (CFC), but not normal CFC. Most CD4+ T-cell lines exerted strong proapoptotic effects on AML cells. AML cell apoptosis by CD4+ T-cell lines correlated with IFN-γ secretion. Conclusion This study demonstrates a methodology for generating large numbers of AML-reactive cytotoxic T cell lines (either class I or II restricted) that may be useful clinically in adoptive immunotherapy. This study also provides estimates of AML-reactive T-cell frequency in patients with AML.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
There was no consensus on the optimal use of G-CSF after hematopoietic stem cell transplantation. In this study, the practice of using G-CSF, based on the CD34+ cell number, at the University of ...California, San Diego Blood and Marrow Transplant Unit (UCSD BMT) was evaluated by performing a five-year retrospective analysis of data from patients undergoing autologous and allogeneic transplantation. Various outcomes, such as time to neutrophil and platelet engraftment and length of post-transplant hospital stay are assessed in relation to use of G-CSF and number of CD34+ cells infused. It has been found that the use of G-CSF is associated with faster neutrophil engraftment and shorter length of post-transplant hospital stay without affecting time to platelet engraftment in patients undergoing autologous transplantation. In addition, the number of CD34+ cells do not influence outcomes in autologous and allogeneic transplant patients if they are treated with G-CSF. As a result of this evaluation, the G-CSF protocol at UCSD BMT Unit is revised. The main change is to implement the use of G-CSF in all patients undergoing autologous transplantation regardless of the number of CD34 + cells. No changes in the allogeneic transplantation protocol are made as a result of this analysis.
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IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UKNU, UL, UM, UPUK
Highlights • RGI-2001 when given to patients receiving HCT is safe and well tolerated. • In a subset of patients receiving RGI-2001, an increase of Treg percentage and number was seen. • In patients ...receiving RGI-2001, increases in Treg percentage and number were correlated with lower incidence and severity of GVHD and with concomitant sirolimus use.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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