bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lymphoplasmacytic Cells and Mast Cells Are Targets for Imatinib Mesylate (Gleevec, Glivec) in Waldenstrom’s Macroglobulinemia.
Authors: Tournilhac Olivier , Santos Daniel Ditzel , Xu Lian , Hatjiharissi Evdoxia , Tsu Yu , Catley Laurie , Hunter Zachary , Branagan Andrew , Burger Renate , Shringarpure Reshma , Boyce Joshua , Anderson Kenneth C. , Treon Steven P. 
Published: October 2019

Abstract
Recently, we demonstrated that in Waldenstrom’s macroglobulinemia (WM), clonal lymphoplasmacytic cells (LPC) appear to derive growth and survival signals from excess mast cells (MC) present in the bone marrow (BM). (Tournilhac et al, JCO 2004 22:571S). We therefore have sought agents which could target both LPC and MC. One such candidate is imatinib mesylate which has shown activity in certain mast cell disorders likely on the basis of its ability to target the tyrosine kinases, CD117 (Stem Cell Factor Receptor, c-kit), and Platelet Derived Growth Factor Receptor (PDGFa-R). By flow cytometric analysis, we demonstrated CD117 expression on sorted LPC from 17/22 (76.2%) WM patients, above 20% in 13 cases, whose expressionwe confirmed by RT-PCR analysis. Moreover, we also demonstrated expression of PDGFa-R along with its ligand PDGFa in BM LPC from 16/18 (88.9%) and 7/10 (70%) WM patients.. In addition to CD117, we found by RT-PCR analysis a PDGFa expression in LAD and HMC-1 MC lines and in KU the basophilic cell lines KU as well as in sorted BM MC (FcER1+ CD117+) from 3/10 (30%) WM patients. Importantly, co-culture of sorted LPC from WM patients along with 0.5% paraformaldehyde fixed LAD cells or ex vivo expanded (EVE) BM MC induced proliferation of sorted LPC from WM patients, which was inhibited at pharmacologically achievable levels of imatinib mesylate with an IC50 of 0.5–10 μmoles/L. Moreover, imatinib mesylate inhibited the LAD, HMC-1 and KU cell lines as well as EVE cord blood MC or EVE BM MC at an IC50 of 0.01–1 μmoles/L. Lastly, imatinib mesylate also inhibited proliferation of both MC and LPC when unfixed LAD or ex vivo MC were incubated with WM LPC with an IC50 of 1–10 μmoles/L. These studies therefore demonstrate that both LPC and MC are therapeutic targets for imatinib mesylate, and provide the framework for clinical studies evaluating its use in WM.
First-Line Treatment of Multiple Myeloma with a Combination of Thalidomide, Dexamethasone, and Zoledronate (TDZ) in an Inner-City Population with High HIV Prevalence.
Authors: Klueppelberg Uwe , Smith Eric , Chen Laurie , Aloba Chona M. , Shapira Iuliana , Moezi Mehdi M. , Batuman Olcay 
Published: October 2019

Abstract
Background: The combination of thalidomide and dexamethasone is a rescue regimen for multiple myeloma (MM) in relapse, and for pretransplant in newly diagnosed patients. The bisphosphonate zoledronate mitigates bone resorption and possibly tumor growth and angiogenesis. The long-term utility of this combination in a newly diagnosed inner-city MM population with high prevalence of HIV-infection is addressed in this phase II trial. MM is reported with increased frequency in patients with HIV infection, and optimal treatment of MM in these patients is unknown.
Methods: Of 30 consecutive enrollees, 22 (16F/6M) were evaluable. Mean age was 61 years (range = 43–82); all had skeletal lesions, and 27% (n = 6) were HIV+ (mean age = 47, range 46–50, all female). Patients received thalidomide 100 mg QD, dexamethasone 10–40 mg PO on Days 1–4, 9–12, and 17–20 monthly for six months, then on Days 1–4 monthly; and zoledronate 4 mg IV monthly, until progression or relapse. Baseline β2-microglobulin indicated high risk for all patients (mean = 6.2 μg/ml, SD = 3.8). At enrollment, 4 patients had AIDS, and 3 were on HAART.
Results: Overall response rate (> 50% decrease in M protein) was 72% (n = 13), and 83% (n = 5) in HIV+ patients. In 27% (n = 6), M protein levels were < 0.3 g/dL, including 3 HIV+ patients on HAART. In 23% (n = 5), M protein was reduced by < 50%. Median time to response was 2 months, and mean time on TDZ was 11 months. TDZ treatment decreased serum β2-microglobulin (P <.001). Two patients relapsed, and one patient with HIV and concomitant plasmacytoma did not respond. All three eventually died. Response to treatment was unaffected by HIV status or antiretroviral treatment. Side effects of TDZ were reversible by anticoagulant therapy or dexamethasone reduction.
Conclusions: TDZ had significant activity against newly diagnosed MM, suggesting that zoledronate may facilitate response with lower doses of thalidomide. HIV status did not affect response, indicating that this regimen is compatible with concomitant antiretroviral treatment and is equally effective in HIV+ patients. These findings underscore the potential effectiveness of this combination of anti-myeloma agents as a long-term alternative, particularly in patients for whom transplant therapy is not feasible.
HOXB4 Enforces Equivalent Fates of ES-Cell-Derived and Adult Hematopoietic Cells.
Authors: Pilat Sandra , Sebastian Carotta , Bernhard Schiedlmeier , Ute Modlich , Kenji Kamino , Elke Will , Andreas Mairhofer , Peter Steinlein , Wolfram Ostertag , Hartmut Beug , Christopher Baum , Hannes Klump 
Published: October 2019

Abstract
In the context of somatic gene therapy of the hematopoietic system, transplantation of molecularly defined and, hence, “safe” clones would be highly desirable. However, techniques which allow gene targeting, subsequent <i>in vitro</i> selection and clonal expansion are only available for embryonic stem (ES−) cells. Previously, it has been shown that <i>in vitro</i> differentiated ES-cells engraft when ectopically expressing HOXB4, but it remained unclear whether these cells could fully resemble adult bone marrow function after transplantation<sup>1</sup>. We here demonstrate for the first time the functional equivalence of <i>in vitro</i> differentiated ES-cells and adult bone marrow cells mediated by HOXB4. Differentiated ES-cells expressing HOXB4 from a retroviral vector and grown <i>in vitro</i> for 20 days, recapitulated the growth and differentiation properties of adult bone marrow cells after transplantation into
Rag2<sup>(−/−)</sup>γC<sup>(−/−)</sup> and C57Bl/6J recipient mice. Furthermore, we show that the amount of ectopically expressed HOXB4 influences differentiation in both systems in a similar manner. HOXB4 enforced myeloid and suppressed T-lymphoid development over a wide range of expression levels, whereas only high expression levels of HOXB4 were detrimental for erythroid development (P-values for C57Bl/6J mice, Student’s t-test, 2-sided:
CD3 + : eGFP<sup>low</sup> vs. HOX<sup>low</sup> = 0.003; eGFP<sup>high</sup> vs. HOX<sup>high</sup> = 0.021;
Ter119 +: eGFP<sup>low</sup> vs. HOX<sup>low</sup> = 0.920; eGFP<sup>high</sup> vs. HOX<sup>high</sup> = 0.0122; HOX<sup>low</sup> vs. HOX<sup>high</sup> = 0.005).
Incompatibility of high levels of HOXB4 expression with erythroid differentiation was also directly demonstrated using a recently described <i>in vitro</i> ES-cell differentiation system<sup>2</sup>. Histological analysis of the “HOXB4-transplanted” mice revealed increased granulopoiesis both in sternal bone marrow and in spleen sections. However, all stages of granulocytic differentiation were present and neither were immature cells detected in the periphery nor was leukemic infiltration detected in other organs. Hence, none of the animals became leukemic during the observation period. In summary, ES-cells should be considered a promising alternative to bone marrow stem cells carrying the potential of safe somatic gene therapy, provided that human ES-cells can be similarly manipulated. Nonetheless, advanced cell therapy will certainly require regulated expression of HOXB4 to avoid unwanted effects such as disturbed lineage differentiation. This work was supported by the German Research Foundation (KL1311/2-3 and 2-4), German Cancer Aid (10-1763-OS5) and the Austrian Industrial Research Promotion Fund (808714).
Specific Elimination of Alloreactive T Lymphocytes Using Photodynamic Therapy Prevents GVHD and Enables Rapid Immune Reconstitution.
Authors: Boumedine Radia Sidi , Krosl Gorazd , Vaillancourt Marc , Perreault Claude , Roy Denis-Claude 
Published: October 2019

Abstract
Graft-versus-host disease (GVHD) and impaired immune reconstitution are the primary obstacles limiting the efficacy of allogeneic stem cell transplantation (SCT).
Graft-versus-host disease (GVHD) and impaired immune reconstitution are the primary obstacles limiting the efficacy of allogeneic stem cell transplantation (SCT). The purpose of this study was to determine whether selective depletion of donor alloantigen-specific T lymphocytes using photodynamic therapy (PDT) would prevent GVHD and enable immune reconstitution in the context of MHC-mismatched SCT. This question was addressed in an MHC-incompatible mouse model of GVHD. The donor (C57BL/6; H-2b) derived spleen cells were first activated against C3H/HeJ (H-2k) host spleen cells in a one-way mixed lymphocyte culture and then exposed to photodynamic treatment, using dibromorhodamine methyl ester (TH9402) as a photosensitizer. Activated T cells showed preferential retention of this photosensitizer compared to resting lymphocytes. In addition, in vitro experiments revealed that PDT eradicated a significantly higher proportion of activated than resting T cells. When lethally irradiated H-2k mice (C3H/HeJ and B10BR) were transplanted with C57BL/6 derived T cell-depleted bone marrow cells supplemented with C57BL/6 derived spleen cells activated with C3H/HeJ targets, they rapidly succumbed to acute GVHD (within 10–47 days). In contrast, both mouse strains receiving histoincompatible C57BL/6 T cells previously exposed to PDT after activation against C3H/HeJ survived until the end of the observation period (>100 days)(p<0.0001). Additionally, transplantation of treated T cells induced lethal GVHD in C57BL/6 histoincompatible strains of mice (third party), suggesting PDT specifically eradicated activated T cells while sparing most resting T lymphocytes. Analysis of immune recovery, evaluating T and B cell populations in thymus and spleen, activated T cells components (CD44, CD62L, CD69), proliferative responses (anti-CD3 and conA), and Vβ repertoire indicated that T and B cell reconstitution in MHC-mismatched mice transplanted with treated primed cells was similar to that of mice transplanted with treated or control autologous cells indicating that immune cells were preserved and functional. These results demonstrate that PDT can selectively eliminate alloreactive T cells and prevent the development of GVHD, while sparing T cells reactive against non-host antigens, thus offering protection against infection and disease relapse.
Comparison between Progenitor Cells from Mobilized Peripheral Blood (PB) in Healthy Donors and Non-Hodgkin’s Lymphoma (NHL) Patients.
Authors: Villaron Eva M. , Almeida Julia , Lopez-Holgado Natalia , Sanchez-Guijo Fermin M. , Alberca Mercedes , Blanco Belen , Sanchez-Abarca Luis I. , Lopez Olga , Perez-Simon Jose A. , Miguel Jesus F. San , del Cañizo Consuelo 
Published: October 2019

Abstract
INTRODUCTION: Peripheral blood stem cell (PBSC) mobilization is impaired in patients receiving chemotherapy but, as far as we know there is no data about the impact of chemotherapy on different PB progenitor cell subpopulations.
AIM: to ascertain whether or not immature or committed progenitor cell are affected by chemotherapy prior PBSC mobilization in NHL patients.
MATERIAL AND METHODS: a total of 27 PB samples from NHL patients and 36 PB samples from healthy donors were studied. Immunophenotypic analysis of CD34+ cell subpopulations was performed using the following four colour combinations of monoclonal antibodies (FITC/PE/PC5/APC): CD90/CD133/CD38/CD34 and CD71/CD13/CD45/CD34. In order to study committed progenitor cells “in vitro”, standard colony-forming assays were used and, in order to investigate the behaviour of the uncommitted progenitors Delta Assays of plastic adherent progenitor cells (PΔ) were performed.
RESULTS: The comparison between NHL patients and healthy donors is shown in Table 1. The relationship between data obtained by flow cytometry and cultures was statistically significant (p<0.05, r>0.568) for all the progenitors analysed.
Table 1: Results of Immunophenotypic and Functional Assays
LNH patients Healthy donors p Data expressed as median (range). 1. Percentage among CD34+ cells. 2. Number of CFU/10 5 planted cells. 3. Number of CFU/10 6 planted cells % CD34 0.16(0.04–3.65) 0.57(0.11–1.81) 0.013 Immunophenotypic Data Erithroid 1 0.05(0.01–0.60) 0.14(0.02–0.42) 0.098 Myelo–monocytic 1 0.11(0.02–2.41) 0.37(0.07–1.18) 0.014 Immature 1 0.01(0.00–0.63) 0.05(0.01–0.19) 0.014 CFU-GM 2 70(4–440) 90(0–904) 0.327 Clonogenic and Delta Assays data BFU-E 2 62(6–172) 85(0–240) 0.046 CFU-Mix 2 18(0–124) 42(0–140) 0.018 CFU Δ3 356(0–3509) 953(90–8320) 0.033
CONCLUSIONS: We can conclude that in NHL, mobilized committed and above all immature progenitors are impaired when compared with healthy subjects, both analysed by immunological and functional assays. Only granulomonocytic progenitors analysed by a functional approach seemed to be preserved.
Amifostine Can Reduce Oral Mucositis after High-Dose Melphalan Conditioning in Patients with Multiple Myeloma: A Retrospective Study.
Authors: Italiano Antoine , Chamorey Emmanuel , Foa Cyril , Peyrade Frédéric , Otto Josiane , Thyss Antoine 
Published: October 2019

Abstract
Autologous peripheral blood stem cell (PBSC)- supported high-dose melphalan (HDM) is now considered standard therapy in the treatment of multiple myeloma, at least for patients under 65 years. Oral mucositis is a frequent non-hematological complication which causes severe pain, interferes with patient nutrition and can lead to systemic infection. Amifostine (WR-2721; Ethyol), a phosphoaminothiol, is a prodrug that protects a broad range of normal tissues from the cytotoxic damage induced by anticancer agents. We retrospectively compared two groups of patients with stage II/III previously untreated multiple myeloma who received between April 96 and May 2004 an induction chemotherapy with 3 or 4 cycles of VAD (vincristine, adriamycin, dexamethasone) followed by HDM (200 mg/m²) and autologous PBSC transplantation. These two groups either received (group A, n = 10 ) or did not receive (group B, n= 32) amifostine (740 mg/m²) before HDM. The occurrence of grade 3/4 oral mucositis was significantly decreased in group A in comparison to group B (10% versus 53%, p =0.023) with no difference for the time to mucosal recovery. Supportive care differed between the two groups: only 2 patients (20%) needed opioid treatment in group A versus 22 patients (69%) in group B ( p=0.005) and 1 patient (10%) required parenteral nutrition in group A compared to 16 patients (50%) in group B (p= 0.015). The occurrence of severe infectious complications did not differ between the two groups (0% versus 12,5%, p= 0.56). Amifostine did not affect haematological recovery, the median time to granulocyte recovery to > 500/μl was similar in the two groups (8,4 days versus 9,9 days, p=0.22). Moreover, there is no statistically significant difference between the amifostine and control group for the disease response. The tolerability of amifostine was excellent and no adverse effects were reported. This study suggest that amifostine can reduce mucosal damage associated with high dose melphalan-based therapy, reducing, as a consequence, the necessity of nutrition and analgesic support, without compromising therapeutic benefit. Obviously, these interesting results have to be confirmed by larger randomised trials.
Quantitative Analysis of the Correlation of Human Polyomavirus and Hematuria in Patients after Stem Cell Transplantation.
Authors: Lu Yuhong , Radonic Aleksandar , Thulke Stefanie , Nitsche Andreas , Siegert Wolfgang 
Published: October 2019

Abstract
Objective: quantitative evaluation of viruria (DNA-uria) and hematuria in patients with SCT and analyze both relationship clinically.
Methods and Materials: two PCR assays for detecting viruses in clinical specimens are established: quantifying virus load by real-time PCR and distinguishing BKV and JCV by seminested PCR. Intensity of hematuria, that is the dominant sign of hemorrhagic cystitis, was assessed by urinestick and classified into 6 grades: negative (−), trace or 1–10 (+), 11–25 (++), 26–80 (+++), 81–200 (++++) erythrocytes in 1 milliliter urine, and macrohematuria (+++++). 531 urine specimens were collected from 41 patients with SCT. Data were analyzed through SPSS software package.
Results: Prevalence rate of polyoma viruria and hematuria following SCT were 80% and 73% in this study cohort and 45% and 20 % in urine specimens. No viral genomes were detected in DNA extracted from blood cells and plasma. BK, BK integrating with JC, JC and non-identified virus-variants, respectively, were shed in 15, 11, 3, 4 patients in urine and were detected in 99, 21, 32, 11 urine samples. Data of 25 patients with specimens collected before SCT showed that only 5 cases sheded polyoma virus in urine, comparing with 21 cases with polyoma viruria post-SCT, demonstrates significant difference (P<0.0001). Risk factors of polyoma viruria were not found. The median of maximal virus load was higher in male than female (2.1x109 vs. 9.1x106, P=0.031, Mann Whithney), and in patients with hemorrhagic cystitis than without (2.5 x1010 vs. 4.7x107, P=0.043). There were no documents of hematuria pre-SCT. Recipients with stem cells originating from bone marrow underwent more frequently hematuria than from peripheral blood cells. This is likely due to more patients with standard conditioning therapy in BMT group (90% vs. 57%, P=0.032). The application of anti-thymocyte glolubin impacted likely on incidence of hematuria (88% vs. 47%, P=0.008). This is identical with the results of the study reported by Rabenau HF. The significant statistic relationship between polyoma viruria and hematuria is not available by defining entities as positive and negative. Indeed BK-viruria prevalence in 35% urine specimens containing erythrocytes >= ++ and in 17% urine specimens with negative and only trace red blood cells, while hematuria with amount of erythrocytes >=++ presented in 21% BK-viruria, nevertheless in 9% urine specimens with negative or non-amplifying virus-variants, 7% JC-viruria and 6% BK integrating with JC-viruria (P=0.016). Time conformability was observed in onset of most viruria and hematuria within 2nd-3rd weeks post SCT.
Conclusions: the course of SCT exerts explicitly impact on the reactivation of polyomavirus in urinary tract and BK-virus attribute likely to the onset of severer hematuria. Co-factors and pathogenesis are needed to continue exploring.
Safety and Tolerability of Anti-Bacterial Prophylaxis during the Post-Engraftment Phase after Myeloablative Hematopoietic Stem Cell Transplantation.
Authors: Hayes-Lattin Brandon , Bubalo Joseph , Dunn Adam , Subbiah Nan , Allen Bryon , Balleisen Suzanne , Curtin Peter T. , Jacoby Carol , Leis Jose F. , Mauro Michael J. , Simic Aleksandra , Schubach Susan , Maziarz Richard T. 
Published: October 2019

Abstract
Background: Bacterial infections, including infections with Gram-negative organisms, frequently complicate the post-engraftment phase after myeloablative allogeneic hematopoietic stem cell transplantation. In this pilot study, we investigated the safety and tolerability of administering antibacterial prophylaxis from the time of engraftment (absolute neutrophil count of >1500/mm3 for 2 days) through day +100. Moxifloxacin was chosen for its broad spectrum of bacterial coverage and for its ability to target both bacterial topoisomerase IV and DNA gyrase, limiting the development of antimicrobial resistance.
Methods: Twenty-three patients with engraftment after allogeneic transplantation at OHSU received moxifloxacin 400 mg po daily upon discontinuation of any antibiotics used for the treatment of pre-enrollment bacterial infection. Rates of bacterial infection, bacteremia, and colonization were recorded. Comparisons were made with a cohort of 60 consecutive patients undergoing myeloablative transplantation at OHSU without similar antibacterial prophylaxis from 2001–2002.
Results: The median duration of moxifloxacin prophylaxis was 77 days (range 7–87). Five patients had dose interruptions due to nausea associated with graft-versus-host disease and two patients elected not to restart study medication. Only 3 patients had dose interruptions during empiric antibiotic therapy for possible bacterial infection. Overall, moxifloxacin was well tolerated in this patient population, with 5 episodes of grade 3/4 toxicity felt possibly related to study drug (2 orthostatic hypotension in one patient, 2 nausea, and 1 hypertension). Five patients had episodes of transaminitis which were unlikely to be due to study medication, and which responded to discontinuation of antifungal therapy (4) or to treatment of liver GVHD (1). No cardiac arrhythmias or tendonopathy were observed. Compared to historic controls, a marked decrease in post-engraftment phase bacterial infections was observed. The control cohort, 16 patients experienced 17 episodes of Gram-negative and 22 patients had 25 episodes of symptomatic Gram-positive infections during the post-engraftment phase without prophylaxis. In contrast with moxifloxacin prophylaxis, 2 patients experienced 3 Gram-negative infections (χ2, p=0.079), 1 patient had an anaerobic infection, and 7 patients had 9 symptomatic Gram-positive infections.
Conclusions: Prophylactic moxifloxacin dosed throughout the post-engraftment phase has been well tolerated, safe, and associated with a fewer bacterial infections compared to historic controls. The efficacy of this prophylaxis strategy will best be determined in a planned randomized, placebo-controlled trial.