bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutator Genes UDG and AID Appear To Be Normal in Class-Switch Deficient and Clonally Homogeneous Waldenstrom’s Macroglobulinemias Having Either Germline or Hypermutated Clonotypic IgH VDJ.
Authors: Kriangkum Jitra , Taylor Brian J. , Strachan Erin R. , Treon Steven P. , Mant Michael J. , Reiman Tony , Belch Andrew R. , Pilarski Linda M. 
Published: April 2020

Abstract
Clonotypic B cells of Waldenstrom’s macroglobulinemia (WM) are characterized as CD20+IgM+IgD+ cells that are usually somatically mutated in IgH VDJ but for some patients, the clonotypic IgH VDJ is germline (unmutated).For both mutated and unmutated clones, WM lack ongoing somatic hypermutation (SHM) and class switch recombination (CSR). This may be due to abnormalities in switching and/or mutator genes. To understand the nature of unswitched tumor B cells, uracil DNA glycosylase (UDG) and activation-induced cytidine deaminase (AID), the two essential elements for CSR, were analysed in WM. Analysis of 12 WM clones characterized by somatic hypermutation showed that the mutation profile of VH genes had normal transition/transversion ratios at C or G, and thus did not suggest UDG abnormalities. Expression of AID was determined by single stage RT-PCR. Out of 14 patients studied (2 unmutated and 12 mutated VH clones), two of them (WM1-01 and WM1-08,with mutation rates of 0% and 6.2% respectively) gave positive bands. In WM1-01, despite having a germline IgH VDJ, AID is consistently expressed in two bone marrow samples collected three years apart and from which the identical unmutated clonotypic VDJ sequence was isolated. Full-length (FL) AID transcripts of WM have a conserved sequence, thus ruling out the possibility of functional defects due to point mutation. In addition, detection of AID in an unmutated VH clone suggested that lack of SHM does not result from an inability to produce AID. In addition to FL transcripts, three other splice variants were identified in both patients. Single cell analysis indicated that only a small compartment (10% or less), not all, of clonotypic B cells expressed AID, and multiple isoforms may be detectable in individual cells. Whether these splice variants that contain truncated C-terminal ends play a role in the regulation of CSR in WM remains to be investigated. Splice variants, nevertheless, may not characterize tumor B cells since up to 10% of AID-expressing normal activated B cells (n=3) also carried them. In vitro activation of clonotypic WM B cells by CD40L and IL4, using conditions that induced CSR in normal B cells, did not yield detectable class switching in WM B cells. In cultures of B cells from WM, the number of non-clonal B cells increased but the clonotypic B cells did not appear to expand, as indicated by the reduction of clonotypic IgM transcript at 5-days of culture. Thus, as well as failing to undergo somatic mutation or class switching, WM tumor B cells appear unresponsive to CD40L+IL4. They may be fundamentally unresponsive to signals for class switching and their clonal expansion may depend upon alternate signaling pathways.
Primary Central Nervous System Lymphoma of T Cell Origin: A Descriptive Analysis of 45 Cases from the International PCNSL Collaborative Group.
Authors: Shenkier Tamara , Blay Jean-Yves , O’Neill Brian P. , Poortmans Philip , Janke Kristoph , Abrey Lauren E. , Neuwelt Edward , Tsang Richard , Batchelor Tracy , Harris Nancy , Ferreri Andres J. , Ponzoni Maurilio , O’Brien Peter , Rubenstein James , Connors Joseph M. 
Published: April 2020

Abstract
To describe the demographic and tumor related characteristics and outcomes for patients with primary T-cell central nervous system lymphoma (TPCNSL). A retrospective series of patients with TPCNSL was compiled from twelve cancer centers and seven countries. This study involved 35 male and 10 female patients with a median age of 60 years (range 3–84). Twenty (44%) had Eastern Cooperative Oncology Group performance status (PS) of 0 or 1. Twenty six (58%) had involvement of a cerebral hemisphere and sixteen (36%) had lesions of deeper sites in the brain. Two patients had primary spinal cord lesions and one had meningeal disease only. Serum lactate dehydrogenase (LDH) was elevated in 7 of the 22 cases (32%) and cerebrospinal fluid (CSF) protein was elevated above normal in 19 of the 24 cases (79%) with available data. The median disease specific survival (DSS) for all patients was 25 months (95% confidence interval (CI) 11–38 months). The two and five-year DSS were 51 % (CI 35–66 %) and 17 % (CI 6–34 %) respectively. Univariate and multivariate analyses were conducted for the following factors: age (≤ 60 vs. &gt; 60 years), PS (0 or 1 vs. 2, 3 or 4), involvement of deep structures of the central nervous system (no vs. yes), and methotrexate (MTX) use in the primary treatment (yes vs. no). Only PS and MTX use were significantly associated with better outcome with hazard ratios (HR) of 0.2 (CI 0.1–0.4) and 0.4 (CI 0.2–0.8) respectively. This is the largest series ever assembled of TPCNSL. The presentation and outcome appear similar to that of PCNSL of B cell origin. PS 0 or 1 and administration of MTX are associated with better survival. TPCNSL does not appear to require a different therapeutic management approach than B-cell PCNSL.
A Selective Inhibitor of c-Met Blocks an Autocrine HGF Growth Loop in ANBL-6 Cells and Prevents Migration and Adhesion of Myeloma Cells.
Authors: Borset Magne , Hov Hakon , Holt Randi U. , Ro Torstein B. , Fagerli Unn-Merete , Hjorth-Hansen Henrik , Baykov Vadim , Christensen James G. , Waage Anders , Sundan Anders 
Published: April 2020

Abstract
We examined the role of the hepatocyte growth factor (HGF) receptor c-Met in multiple myeloma by applying a novel selective small-molecule tyrosine kinase inhibitor, PHA-665752, directed against the receptor.
Four biological sequels of HGF related to multiple myeloma were studied: (1) proliferation of myeloma cells; (2) secretion of interleukin-11 from osteogenic cells; (3) migration of myeloma cells; and (4) adhesion of myeloma cells to fibronectin. We also examined effects of the c-Met inhibitor on intracellular signaling pathways in myeloma cells.
PHA-665752 effectively blocked the biological responses to HGF in all assays, with 50 % inhibition at 5-15 nM concentration and complete inhibition at around 100 nM. PHA-665752 inhibited phosphorylation of several tyrosine residues in c-Met (Y1003, Y1230/1234/1235, and Y1349), blocked HGF-mediated activation of Akt and p44/42 Mitogen-activated protein kinase (MAPK), and prevented the adaptor molecule Gab1 from complexing with c-Met. In the HGF-producing myeloma cell line ANBL-6, PHA-665752 revealed an autocrine HGF/c-Met-mediated growth loop. The inhibitor also blocked proliferation of purified primary myeloma cells, suggesting that autocrine HGF/c-Met-driven growth loops are important for progression of multiple myeloma. Conclusions: Collectively, these findings support the role of c-Met and HGF in the proliferation, migration, and adhesion of myeloma cells and identify c-Met kinase as a therapeutic target for treatment of patients with multiple myeloma.
Pretreatment Cytogenetic Abnormalities in Polycythemia Vera (PV) Determines the Effectivnes of Imatinib : Studies from a Multi-Institutional Trial.
Authors: Najfeld Vesna , Silver Richard T. , Hoffman Ronald , Salvado August , Weinberg Rona , Fruchtman Steven 
Published: April 2020

Abstract
In patients (pts) with hypereosinophilic syndrome imatinib selectively inhibits a receptor for the platelet-derived growth factors, PDGFRA and PDGFRB, and the receptor for stem cell factor (c-kit), the expression of which is increased in PV. Preliminary data suggests imatinib reduces phlebotomy requirements and may suppress endogenous erythroid colonies in PV. One goal of the multi-institutional trial of imatinib in PV (400 mg po/day at initiation) was to determine the possibility of eliminating abnormal cytogenetic clones. Of 27 PV pts enrolled, 20 had cytogenetic studies. Fifteen pts showed a normal initial karyotype and 5 pts (25%) were cytogenetically abnormal at imatinib initiation. These included: trisomy 9 (2 pts), isochromosome for 9p and 9q (1pt), monosomy 21 (1 pt) and del(5)(q15q32) (1pt). Fifteen sequential cytogenetic studies of 180 metaphase cells from 3 pts showing chromosome 9 abnormalities did not show a reduction in the percentage of abnormal cells. In contrast, monosomy 21, present in 5 of 25 metaphases was gradually eliminated with imatinib within 7 months. In the subsequent 8 months two follow up studies demonstrated only normal cells in 40 metaphase and 600 interphase cells. Deletion (5)(q15q32), detected in 55% metaphase and 77% interphase cells (using EGR1 probe), prior to imatinib, was reduced to 23% in interphase cells within 5 months. However, conventional cytogenetics showed 15 of 16 metaphase cells (94%) with del(5q), consistent with a proliferative advantage of the del(5q) clone. In addition, there was marked diminution in splenomegaly. Due to imatinib intolerance and persistent thrombocytosis of over 1 X 106, the drug was discontinued. To further elucidate the mechanism of imatinib in PV, progenitor cells were grown before and during imatinib treatment. Before imatinib, from the marrow sample showing 77% del(5q) cells, both epo- dependent and independent colonies, as well as CFU colonies were examined and all 800 evaluated interphase cells were normal. With a diminution of the del(5q) clone to 23%, 600 cellsi from epo independent colonies did not show del (5q). The inability to detect del (5q) in progenitor marrow cells is consistent with the notion that PV, like CML, has a multistep pathogenesis in which chromosome abnormalities are a later event in clonal progression. These observations further suggest that imatinib did not eradicate rearrangements of chromosome 9. However, 2 of 5 pts with abnormalities, -21 and del(5q), had either complete eradication or diminution of the abnormal cytogenetic clone. These findings suggest that different cytogenetic abnormalities, representing different molecular events, determine the diverse responses to imatinib observed in PV. Thus, cytogenetic abnormalities may be useful in predicting the biologic effect of imatinib in patients with PV.
Phase 2 Multicenter Trial of Gallium Nitrate in Patients with Advanced Non-Hodgkin’s Lymphoma (NHL).
Authors: Pro Barbara , Bociek R. G. , Chitambar Christopher R. , Gregory Stephanie A. , Leonard John P. , Smith Sandra , Novick Steven 
Published: April 2020

Abstract
While approved for treatment of cancer-related hypercalcemia, gallium nitrate (Ganite®; GN) has displayed broad antitumor activity as a single agent in Phase 2 trials, particularly in patients (pts) with bladder disease, Hodgkin’s disease, and NHL who received GN by bolus or continuous IV infusion (CIVI). To establish the safety profile and clincial activity in a large cohort of patients with a wide variety of histologies, we conducted a Phase 2 study in pts with both T- and B-cell lymphoma who had relapsed from standard anti-lymphoma therapy.
Eligibility criteria included: relapsed NHL; ECOG PS ≤ 2; measurable disease; adequate renal and hepatic function. GN was administered by CIVI daily via ambulatory infusion pump x 7 days every 3 wks at 1 of 2 daily dose levels, 200 or 300 mg/m2/d. Evaluation for efficacy required treatment with ≥ 2 cycles; all treated pts were considered evaluable for safety. A total of 88 pts were accrued to the trial, 44 pts at each dose level. Pt characteristics included: median age, 61 yrs (range 19–83); median prior regimens, 5 (range 1–13); median prior drugs, 9 (range, 1–15); median prior rituximab regimens, 2 (range, 1–6); no. of pts with prior stem cell transplant, 25 (28%); no. of pts with prior radiation therapy, 29 (33%).
At the 300 mg/m2 dose level, 30 pts are evaluable for response. The ORR in this dose level was 30% (7% CR or uCR), including 3/12 pts with diffuse LCL (DLCL) (2 post-BMT), 3/11 with follicular lymphomas (1 post-BMT), 2/3 pts with mantle cell NHL (1 CR), 0/2 pts with SLL, and 1/2 pts with peripheral T-cell NHL (1 uCR). The results in the 200 mg/m2 dose level are preliminary and currently under evaluation.
Most frequent (&gt; 10%) grade 3/4 adverse reactions (through July 2004) included: anemia (32%); hypocalcemia (19%) (occasionally requiring parenteral replacement with Ca++ and Mg++); dyspnea (15%); and hypotension (11%). Optic neuritis or visual disturbance occurred in 4 pts: 3 pts at the 300 mg/m2 dose level (after 2, 3 and 6 cycles, respectively) and 1 pt at the 200 mg/m2 dose level (after 7 cycles). All patients discontinued therapy as a consequence of this adverse event; two pts were treated with high-dose corticosteroids. All patients improved after discontinuation.
These results demonstrate that gallium nitrate is an active and well tolerated agent in a heavily pretreated population of patients with NHL and suggest that it may be particularly useful in patients who cannot tolerate myelosuppressive regimens.
Preliminary Phase II Study Results of BBR2778 in Combination with Cyclophosphamide, Vincristine, and Prednisone in Patients with Relapsed Aggressive Non-Hodgkin’s Lymphoma.
Authors: Herbrecht Raoul , Borchmann Peter , Wilhelm Martin , Morschhauser Franck , Hess Georg , Kutz Klaus , Comis Silvia , Laffranchi Bernard L. , Engert Andreas 
Published: April 2020

Abstract
Background: Pixantrone (BBR 2778) is a novel aza-anthracenedione with superior activity compared to doxorubicin and mitoxantrone in various tumor models including hematological malignancies. Pixantrone single agent therapy led to major responses in patients (pts) with aggressive lymphoma including diffuse large B-cell lymphoma (DLCL). The safety of a CHOP-like regimen with pixantrone replacing doxorubicin (CPOP) was assessed in a dose-ranging study indicating a recommended dose of 150 mg/m² for pixantrone.
Method: In this phase II study the primary objective was to assess the efficacy of the CPOP regimen (cyclophosphamide 750 mg/m² d1, pixantrone 150mg/m² d1, vincristine 1.4mg/m² d1, limited to 2mg, and prednisone 100mg d1 to 5) in pts with relapsed DLCL, transformed follicular lymphoma (tFL) and mantle cell lymphoma (MCL) for a total of 6 cycles given every 3 weeks. Hematopoietic growth factors were not permitted for the first cycle and used thereafter according to the ASCO guidelines. Inclusion/exclusion criteria included at least one but not more than two previous chemotherapy lines containing an anthracycline/anthracenedione with a cumulative dose of less than 450mg/m² doxorubicin equivalent, a left ventricular ejection fraction (LVEF) &gt;50%, no meningeal involvement, and HIV negative serology.
Results: 21 pts have currently been included. Data is available for the first 15 pts. Main baseline characteristics are: median age 65 y [35 – 76]; DLCL 10 cases, tFL 2 cases, MCL 3 cases; stage I/II 4 cases, stage III/IV 11 cases; median number of previous therapy lines 2 [1–5], median prior cumulative dose of anthracyclines 320 mg/m² [104 – 452 mg/m²]. 48 cycles of CPOP have been administered to date, with a median number of 4 per pt. Most common grade 3 or 4 adverse events were neutropenia [39 episodes in 10 (67%) pts], leucopenia [37 episodes in 10 (67%) pts], thrombocytopenia [3 episodes in 3 (20%) pts] and febrile neutropenia [8 episodes in 4 (27%) pts]. There was no treatment related death and no grade 3 or 4 organ toxicity. Treatment was delayed in 6 pts and the doses of pixantrone and cyclophosphamide were reduced in 5 pts for a grade 4 hematological toxicity or infection. Only one patient had a decrease of ≥10% of LVEF from 72% at screening to 56% after 6 cycles without clinical symptoms. Out of 12 pts currently evaluable for response, 6 (50%) responded to CPOP therapy: 5 CR and 1 PR (responses maintained for ≥8 weeks).
Conclusion : These early results of the CPOP regimen with 150 mg/m² of pixantrone indicates a high response rate in pts with relapsed aggressive B cell lymphoma with an acceptable and manageable safety profile.
Superagonistic Anti-CD28 Antibody TGN1412 as a Potential Immunotherapeutic for the Treatment of B Cell Chronic Lymphocytic Leukemia.
Authors: Lin Chia-Huey , Kerkau Thomas , Guntermann Christine , Trischler Martin , Beyersdorf Niklas , Scheuring Yvonne , Tony Hans-Peter , Kneitz Christian , Wilhelm Martin , Mueller Peter , Huenig Thomas , Hanke Thomas 
Published: April 2020

Abstract
B cell chronic lymphocytic leukemia (B-CLL) is characterised by an accumulation of malignant B cells, and impaired humoral and cellular immune responses. Evasion strategies of leukemic cells appear to involve down-regulation of co-stimulatory molecules as well as increased resistance to apoptosis. Here we provide data supporting a novel concept to treat B-CLL with a humanized, superagonistic monoclonal antibody specific for CD28 (TGN1412). Superagonistic anti-CD28 antibodies have been shown to activate human T cells in vitro without requirement for engagement of the T cell antigen receptor (Luhder et al., J. Exp. Med. 2003. 197(8):955–66). Indicative of their activation, TGN1412-triggered T cells from healthy donors upregulate, among other activation markers, CD40L, that has been reported to promote anti-leukemic effects when ectopically expressed on B-CLL cells (Wierda et al., Blood. 2000. 96 (9): 2917–2924). In this report, the responses of PBMCs from B-CLL patients to soluble TGN1412 were examined. We show that in a dose-dependent fashion, polyclonal T cell activation was induced by TGN1412 including proliferation, cytokine production and induction of activation markers such as CD25, CD71, CD134 (Ox40), CTLA-4 (CD152) and CD154 (CD40L). Significantly, modulation of malignant B-CLL cells was also observed. MHC class II molecules (HLA-DR), CD95 and the co-stimulatory molecules CD80 and CD86, but not the proliferation marker Ki-67, were strongly up-regulated upon TGN1412 stimulation. These data suggested that improved antigen-presenting functions of B-CLL cells were induced by TGN1412. Accordingly, preliminary data indicate that B-CLL cells isolated from TGN1412 stimulated cultures induced enhanced proliferation of both allogeneic and autologous T cells, and importantly, TGN1412 activated T cells exhibited enhanced CTL-activity against B-CLL cells. In conclusion, our data suggest that TGN1412 induces polyclonal T cell expansion and activation as well as increased APC function of B-CLL cells. They imply that TGN1412 may have future therapeutic benefit for B-CLL patients.
Characterization of T Cell Epitopes of the Receptor for Hyaluronic Acid Mediated Motility (RHAMM/CD168) in Acute Myeloid Leukemia.
Authors: Schmitt Michael , Li Li , Ringhoffer Mark , Barth Thomas , Wiesneth Markus , Dohner Hartmut , Greiner Jochen 
Published: April 2020

Abstract
To improve the clinical outcome of patients with acute myeloid leukemia (AML), immune therapies targeting leukemia associated antigens (LAAs) might be an approach complementary to chemotherapy and transplantation of hematopoetic stem cells. The receptor for hyaluronic acid mediated motility (RHAMM/CD168) has been defined as a LAA with specific expression. To define T cell epitopes of RHAMM/CD168 towards specific T cell immunotherapies, ten peptides were synthesized considering different computer algorithms and subjected to ELISPOT assays for interferon gamma and granzyme B, and to Cr-51 release assays. CD8+ T cells taken from the peripheral blood (PB) of 13 AML patients and presensitized with the RHAMM/CD168-derived peptides R3 (ILSLELMKL) or R5 (SLEENIVIL) did specifically recognize T2 cells pulsed with R3/R5. In contrast, CD8+ T cells isolated from the PB of 21 healthy volunteers were not able to lyse R3 or R5 pulsed T2 cells, even after presensitization. COS7 cells co-transfected with HLA-A*0201 and RHAMM/CD168 were lysed by R3 or R5 presensitized CD8+ T cells. Single HLA-A*0201 or RHAMM/CD168 transfected COS7 were not recognized. Cross-reactivity of the T cells was excluded by the use of unrelated peptides. K562 cells positive for RHAMM/CD168, but lacking HLA-class I molecules were not recognized indicating T cells and not NK cells as effector cells. The HLA class-I restricted lysis of COS-7 HLA-A*0201 and RHAMM/CD168 double- transfectants was confirmed by HLA class-I blocking antibody experiments. In an AML patient having received AML blast-derived dendritic cells, a higher frequency of RHAMM/CD168-peptide specific T cells was observed after four vaccinations when compared to his T cell status before vaccination. RHAMM/CD168 is also expressed in patients with other hematological malignancies which suggests a broad clinical applicability of its newly characterized T cell epitope peptides as a potential cancer vaccine.
Single Oral Administration of KRN383, a Novel Flt3 Inhibitor, Induces Eradication of the Xenograft Tumor Harboring Flt3 Mutation in Mice.
Authors: Nishiyama Uichi , Ozai Masako , Yoshioka Rieko , Yoshino Tetsuya , Ogasawara Yuko , Kitahori Miyuki , Yoshioka Eiji , Kubo Kazuo , Komeno Yukiko , Kurokawa Mineo , Ogawa Seishi , Chiba Shigeru , Osawa Tatsushi , Kuwaki Tomoaki , Hirai Hisamaru , Miwa Atsushi 
Published: April 2020

Abstract
Constitutively activating mutations of the Flt3 receptor tyrosine kinase including internal tandem duplication (ITD) mutations are the most common genetic abnormality and are associated with a poor prognosis in acute myeloid leukemia (AML) patients. Therefore, Flt3 is a potential therapeutic target in AML. We show here the results of pre-clinical studies on KRN383, a novel orally active quinoline-urea derivative.
KRN383 inhibited autophosphorylation of ITD mutant (IC50=1.3nM) and wild type (IC50=0.4nM) Flt3 in the leukemia cell line MV4-11 and THP-1, respectively. KRN383 induced cell cycle arrest, apoptosis and suppression of proliferation (IC50=0.8nM) of MV4-11 in vitro. Single (80mg/kg) or consecutive (20mg/kg/d X 28d) oral administration of KRN383 induced eradication (longer than 6mo) of tumor xenograft (MV4-11) subcutaneously implanted in all nude mice. All these effects were superior to those of SU11248, a precedent Flt3 inhibitor. In addition, single (80mg/kg) administration of KRN383 prolonged the survival of SCID mice to which MOLM-13 (ITD mutant positive leukemia cell line) was intravenously transplanted. The advantage of KRN383 over SU11248 was more obvious in in vitro studies in which the inhibition of Flt3 autophosphorylation and cellular proliferation induced by transient exposure with those drugs was determined. These results indicate that KRN383 has therapeutic potential in ITD mutant positive AML. Furthermore, eradication induced by single administration of KRN383 suggests that KRN383 provides feasibility to set wide variety of clinical regimens including multi-cycle and combination therapies. In vitro activity of Ki23819, hydrochloride salt of KRN383, is also to be reported in this ASH meeting (Komeno et al.).