bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combination Chemotherapy Using Cyclophosphamide and High Dose Dexamethasone with or without Radiotherapy for the Treatment of Multiple Myeloma.
Authors: Kim Chul Soo , Lee Moon Hee , Kim Inho , Moon Yeonsook , Nahm Chung Hyun , Kim Hun Chung , Kim Woo Cheol , Loh John J.K. 
Published: April 2020

Abstract
Forty two people (men 22, women 20) diagnosed as Durie-Salmon stage IIIA or B multiple myeloma were treated with a combination chemotherapy consisting of cyclophosphamide at 400mg and dexamethasone at 40mg (CHD) regardless of body surface for 4 or 5 consecutive days every 3 or 4 weeks from August 1996 through July 2005. The treatment was repeated as long as the patient could tolerate or until disease progressed. The chemotherapy was given to 36 chemo-naïve patients as primary therapy and to 6 patients exposed to VAD (vincristine, doxorubicin, dexamethasone) as salvage therapy. Palliative loco-regional radiotherapy was also given to 20 of 44 patients. A total of 433 cycles (mean 10.3, range 2~28 per individual) of chemotherapy were given and the response evaluation was made in accordance to the criteria of Dr. Blade. SD (stable disease) was defined as reduction or increase of myeloma protein within 25%. Six of 36 chemo-naïve patients who did not respond to CHD received salvage therapy consisting of VAD or MP (melphalan plus prednisone). Eleven patients (26%) attained CR (complete remission) at a median of 7 cycles (range 4~10), 15 (36%) achieved PR (partial remission) at a median of 3 cycles (range 2~16), 12 (28%) stayed at SD, and 4 patients (10%) showed PD (progressive disease). The measurement of survival duration was started at the beginning of the CHD chemotherapy. The measurement was censored in 6 patients at the time of stem cell transplant, 5 autologous (one was disease free at 108 months after transplant), and 1 allogeneic. On a mean follow-up period of 15.1 months (range 3~59), 15 people remained alive at 3, 3, 3, 4, 6, 6, 8, 10, 14, 15, 16, 16, 16, 26, and 37 months. The mean response duration and OS (overall survival) of the patients who entered CR were 7 (range 2~18) and 31.3 (range 6+~59) months respectively. The correspondent durations of the patients in PR were 7.9 (range 2+~28) and 15 (range 3+~37+). The corresponding durations of the patients in SD were 8.3 (range 2~26) and 13.5 (3+~48). The mean OS duration of the patients in PD was 5.3 (range 3~8). The difference in OS durations between patients in PR and those in SD was not statistically meaningful. Five of 6 patients exposed to VAD responded to CHD, whereas one of 5 patients exposed to CHD did to VAD. Two of 4 patient exposed to CHD responded to MP. Adverse effect was minimal with non-fatal events including 5 febrile episodes of unknown origin, 3 cases of pneumonia, 2 cases of urinary tract infection, 1 case of peritonitis, 1 case of herpes zoster, and 1 case of intractable nausea during the 433 chemotherapy courses. There were 2 cases of fatal septicemia and 1 case of fatal pneumonia during the period. CHD combination chemotherapy seems an active and less toxic regimen in the treatment of multiple myeloma.
Low Dose Clofarabine Causes Significant Hematologic Toxicity in a Phase II Study of Relapsed or Refractory Multiple Myeloma.
Authors: Uy Geoffrey L. , Ruddell Alisa M. , Devine Steven M. , Tomasson Michael H. , DiPersio John F. , Vij Ravi 
Published: April 2020

Abstract
Clofarabine (Clolar™) is a purine nucleoside analog recently approved for the treatment of refractory pediatric ALL. The compound is structurally related to fludarabine and cladribine and has demonstrated activity in refractory adult and pediatric acute leukemias. In phase I studies of adults with clofarabine administered on days 1–5 of a 28 day cycle, the dose limiting toxicity (DLT) among patients with solid tumors and lymphoproliferative disorders was myelosuppression with a maximum tolerated dose (MTD) of 2 mg/m2 and 4 mg/m2 respectively. In contrast, for patients with acute leukemia the DLT was hepatotoxicity with the MTD of 40 mg/m2. Based on in vitro toxicity against myeloma cell lines and its activity in lymphoid malignancies, we initiated a phase II open-label study of low dose clofarabine in patients with relapsed or refractory multiple myeloma. This trial was designed using an optimal two-stage design (alpha =0.05 and power=0.9) with response rate as the primary endpoint. Nine patients will be enrolled in stage I. If one or more responses are observed, an additional 8 patients will be enrolled in stage II. Clofarabine 4mg/m2/day was given on days 1–5 of a 28 day cycle for up to 12 cycles or until disease progression. Eight patients have been enrolled to date. Baseline characteristics are as follows: median age 49 years (range 43–67), IgG (6 patients), IgA (1), light chain only (1). All had Stage IIIA disease and had previously undergone autologous transplants with a median of 3.5 (range 2–6) prior chemotherapy regimens. Hematologic toxicities were common in the first 6 patients treated. One patient developed Grade 3 thrombocytopenia (≤ 75,000/mm3), but all six had a &gt;50% decrease in their platelet counts with recovery by day 28 of therapy. All six patients also developed neutropenia, Grade 3 (ANC ≤ 1000/mm3) in 4 patients and Grade 4 (ANC ≤ 500/mm3) in 2 patients. Interestingly, the timing of cytopenias was discordant between platelet and neutrophil counts. While platelet counts nadir on day 15, neutrophil counts nadir at day 25–28 of chemotherapy as platelet recovery is occurring. Dose delays of 1 to 2 weeks and dose reduction to 2 mg/m2/day have been required of all patients. Low dose clofarabine 4 mg/m2 x 5 days results in significant marrow suppression with a dose limiting toxicity of neutropenia. Alternative dosing schedules should be studied in future trials with clofarabine. Response data and toxicities for stage I will be complete and updated at the time of presentation.
In Vitro Generation of Highly-Purified Functional Invariant NKT Cells: A Strategy for Immunotherapy in Multiple Myeloma.
Authors: Song Weihua , van der Vliet Hans J.J. , Wang Ruojie , Prabhala Rao , Podar Klaus , Tai Yu-Tzu , Catley Laurence , Shammas Masood , Anderson Kenneth C. , Balk Steven P. , Exley Mark A. , Munshi Nikhil C. 
Published: April 2020

Abstract
Invariant NKT (iNKT) cells are characterized by the expression of invariant T-cell receptor encoded by Vα24-JαQ and NK receptors. iNKT cells recognize glycolipid antigens with CD1d restriction, and play an important immunoregulatory role in innate immunity. Through the production of IFN-γ, iNKT cells can contribute to immune surveillance in malignancy. However, in progressive multiple myeloma (MM), as well as in other advanced cancers, iNKT cells have a marked deficiency of ligand-dependent IFN-γ production. Thus, the development of effective iNKT cells is a novel strategy for the immunotherapy of MM. In this study, we report the establishment of highly purified primary iNKT cell lines from healthy donors and MM patients. iNKT cells derived from peripheral blood or bone marrow mononuclear cells were enriched with anti-TCRVα 24 mAb or anti-6B11 mAb and further expanded by several rounds of stimulation with α-GalCer-loaded dendritic cells. Phenotype analysis confirmed 95% purity in expanded iNKT cell lines. No significant phenotypic difference was observed in iNKT cells between healthy donors and MM patients. Most of iNKT cell lines are CD4+ cell lines (CD4+ cells &gt; 90%, with less than 2% were CD8+ cells). Majority of iNKT cells expressed CD161 and CD28, whereas CD56 expression was at very low level. Following anti-CD3 or α-GalCer-loaded dendritic cells stimulation, iNKT cells showed strong proliferative activity as measured by 3H-TdR incorporation assay. These cells expressed high level of CD25 and produced high levels of IFN-γ as well as IL-2 as measured by ELISA assay. These results provide the preclinical feasibility of producing large volume of highly-enriched functional iNKT cells from myeloma patients and rationale to clinically evaluate the efficacy of adoptive transfer of iNKT cells in MM. Based on these results a clinical study is under development.
Thalidomide and Dexamethasone in Newly Diagnosed Multiple Myeloma.
Authors: McHugh Johnny , Keane Colm , Otridge Brian W. , Thornton Patrick , O’Gorman Peter 
Published: April 2020

Abstract
PURPOSE: Thalidomide and dexamethasone has been shown to have excellent antimyeloma activity in both relapsed and newly diagnosed patients. This combination offers a potential oral, less toxic alternative to standard regimens. This retrospective study evaluates the activity of the combination of thalidomide and dexamethasone in patients with newly diagnosed multiple myeloma.
METHODS: Thirty-two patients with newly diagnosed multiple myeloma were treated with thalidomide and dexamethasone. The median age of the patients was 69yrs (range 46 to 83). The median serum paraprotein level was 38g/l (range 2 to 76g/l). The median bone marrow plasma cell percentage was 50% (range 10% to 99%) The first sixteen patients were commenced on thalidomide at 200mg od with the dose increased by 200mg every two weeks if tolerated to a maximum of 800mg od. The most recent sixteen patients were commenced on thalidomide at 100mg od with the dose increased to a maximum of 200mg if tolerated. All patients received dexamethasone 10mg qds 4-days-on/4-days-off for the first four weeks and for a four day pulse every four weeks subsequently.
RESULTS: Twenty-two of the thirty-two patients (69%) showed a greater than 50% reduction in serum paraprotein and/or urinary Bence Jones protein (BJP) from baseline. From the lower thalidomide dose group thirteen out of sixteen patients(81%) showed a greater than 50% reduction in serum paraprotein and/or urinary BJP from baseline compared with nine out of sixteen (56%) in the higher thalidomide dose group. Thirteen patients (40%) showed a reduction in serum paraprotein and/or urinary BJP of greater than 90%, eight from the lower thalidomide dose group and five from the higher thalidomide dose group. Six of the patients failed to complete one month of treatment due to toxicities. They were all from the higher thalidomide dose group. Toxicities included drowsiness (eleven patients), constipation (six patients), rash (four patients) and peripheral neuropathy (four patients). None of the patients have suffered a venous thromboembolic event. Fewer toxicities were noted in the lower dose thalidomide group.
CONCLUSION: The combination of thalidomide and dexamethasone is safe and effective in the treatment of newly diagnosed multiple myeloma. There is less toxicity and no loss of efficacy with lower doses of thalidomide.
Distinct Gene Expression Pattern of CD34+ Stem and Progenitor Cells Mobilized by Pegfilgrastim after Cytotoxic Therapy in Multiple Myeloma in Comparison to G-CSF.
Authors: Bruns Ingmar , Steidl Ulrich , Kobbe Guido , Fenk Roland , Kliszewski Slawomir , Pechtel Sabrina , Haas Rainer , Kronenwett Ralf 
Published: April 2020

Abstract
Background: Current regimens for peripheral blood stem cell (PBSC) mobilization in patients with multiple myeloma are based on daily subcutaneous injections of G-CSF starting shortly after cytotoxic therapy. Recently a polyethylenglycole (PEG)-conjugated G-CSF (pegfilgrastim) has been introduced which has a substantially longer half-life than the original formula. Here, we compared the molecular phenotypes of CD34+ stem and progenitor cells mobilized by G-CSF with those mobilized by pegfilgrastim.
Study design and Methods: We examined immunomagnetically enriched CD34+ cells from leukapheresis products of 8 patients who received G-CSF and of 8 patients who were given pegfilgrastim using Affymetrix HG Focus GeneChips covering 8793 genes. The statistical scripting language ‘R’ was used for data analysis. Significantly differentially expressed genes were identified with the Significance Analysis of Microarrays (SAM) algorithm.
Results: Comparing CD34+ cells mobilized by G-CSF with pegfilgrastim-mobilized CD34+ cells 108 genes were differentially expressed (fold change 1.25 – 14.0, q- value 2.45–14.44%). 38 genes had a higher and 70 genes had a lower expression in CD34+ cells mobilized by G-CSF.
We found upregulation of genes characteristic for erythropoietic differentiation including haemoglobin chains and Erythroid Kruppel-like factor in G-CSF-mobilized CD34+ cells. Utilizing clonogenic assays we were able to functionally corroborate this finding as G-CSF-mobilized cells gave rise to a significantly higher number of burst-forming units erythroid (BFU-E) as compared to colony forming units granulocyte-macrophage (CFU-GM) (p=0.016). Cell cycle regulating genes were differentially expressed as well. Genes encoding for proteins that cause cell cycle arrest including human HTm4 were upregulated in G-CSF-mobilized cells, as opposed to an upregulation of cell cycle-promoting genes including Cyclin D2 and Hepatocyte Leukemia Factor (HLF) in pegfilgrastim-mobilized cells.
Moreover in pegfilgrastim-mobilized CD34+ cells we saw an upregulation of multiple genes involved in cellular immunogenicity like MHC class I and II antigens and genes encoding for proteins playing a role in antigen presentation.
Conclusion: Unconjugated G-CSF seems to be associated with an increased mobilisation of erythroid progenitors or an induction of erythropoiesis. Pegfilgrastim might result in mobilization of more immunogenic CD34+ cells. Unconjugated G-CSF and pegfilgrastim both seem to have an effect on cell cycle. Unconjugated G-CSF might rather induce cell cycle arrest and pegfilgrastim seems to lead to an increase of the cell cycle activity. This may be due to potentially different effects of continuously high serum levels of G-CSF maintained by pegfilgrastim and the pulsatile daily G-CSF injections on CD34+ cells.
Peripheral Blood Stem Cell Mobilization by G-CSF Alone and Engraftment Kinetics Following Autologous Transplantation in Children and Adolescents with Solid Tumor.
Authors: Watanabe Hiroyoshi , Watanabe Tsutomu , Suzuya Hiroko , Wakata Yoshifumi , Onishi Toshihiro , Nakagawa Ryuji , Okamoto Yasuhiro , Abe Takanori , Kawano Yoshifumi , Kagami Shoji , Takaue Yoichi 
Published: April 2020

Abstract
The purpose of this study was to examine the yield of PBSC, mobilized with G-CSF alone, and engraftment kinetics after autologous transplantation in pediatric cancer patients. In 55 patients (median age; 7 years, range 0–21) with various pediatric and adolescent solid tumors, PBSC were mobilized with G-CSF alone, and the yields of PBSC and engraftment following autologous PBSCT were evaluated retrospectively. Patients were categorized according to prior treatment; patients who had received less than 4 or 4 cycles of chemotherapy with/without local irradiation (Group 1: N= 21), patients who received more than 4 cycles of chemotherapy or 3 or more cycles of chemotherapy with extended irradiation (Group 2: N= 23), and patients who received high-dose chemotherapy with stem cell support (Group 3: N= 11). Ten microgram per kg of G-CSF was injected subcutaneously for mobilization when patients showed no influence of previous chemotherapy, and administration was continued for five days. The peaks of CD34+ cells and CFU-GM were observed on day 5 of G-CSF administration essentially in all patients. Aphereses were performed on days 5 and 6 of G-CSF treatment. Mobilization failure was observed in four patients in all groups. Compared with the results in patients mobilized by chemotherapy plus G-CSF (N=18), the progenitor cell yields were lower in those mobilized with G-CSF alone. However, there were no significant differences in WBC engraftment speed compared to the chemotherapy plus G-CSF mobilization group, although platelet recovery was delayed in patients with G-CSF alone, especially in patients in Group 3. The median time taken for ANC and platelet counts to reach 500 and 20K was 12 days (range 8–28) and 15 days (8–55), respectively, in all patients who were mobilized by G-CSF alone except for patients with progressive disease. In summary, mobilization with G-CSF alone can mobilize a sufficient number of CD34+ cells for successful autografting and sustained hematological reconstitution in pediatric patients with cancer, even in heavily pre-treated patients. Mobilization with G-CSF alone might offer some advantages, such as ease of determining a collection schedule without a daily determination of CD34+ cells in the blood, and the avoidance of neutropenic fever and additional transfusion.
Myeloid Progenitors Protect Against Radiation-Induced Intestinal Injury.
Authors: Brown Janice (Wes) , Shashidhar Sumana , Habtezion Aida , Burns-Guydish Stacy M. , Wang Sophia Y. , Domen Jos , Fong Tim , Contag Christopher H. , Omary M. Bishr 
Published: April 2020

Abstract
Gastrointestinal mucositis is a serious complication of intensive chemotherapy and radiotherapy (XRT) resulting in severe pain, impaired nutrition and an increased susceptibility to infection. We have previously reported that a single infusion of common myeloid and granulocyte-monocyte progenitors (CMP/GMP, c-kit+Sca-1+ CD34+ CD16/32+Lin-Thy1-) protects mice against lethal challenge with bacterial or fungal pathogens following chemotherapy or myeloablative radiation. Additionally, this protection is not HLA-restricted and correlates with the tissue myeloid content. We now present our findings on the effects of CMP/GMP infusion against radiation-induced injury in the gastrointestinal mucosa and liver. Following 950 cGy irradiation, Balb/c mice (H2d) received infusions of one of the following: [1] hematopoietic stem cells (HSC, c-kit+Thy1loLin-Sca-1+); [2] freshly isolated 10,000 CMP/20,000 GMP + HSC; or [3] 500,000 mixed myeloid progenitors (MP) expanded in vitro from HSC. In all cases, the HSC were MHC-matched (H2d), and CMP/GMP were MHC mis-matched (H2b). A cohort of mice served as XRT controls. Mice were sacrificed at d+6 or d+9 post-transplantation. Gross examination of the gastrointestinal tissues showed that mice in the XRT and HSC groups had severe hemorrhagic diarrhea in contrast to the mild to moderate diarrhea observed in the groups receiving either freshly isolated CMP/GMP or the expanded MP. At both time points, histologic examination of gastrointestinal tissue from the XRT controls revealed sub-mucosal bleeding in gastric and intestinal tissue; necrosis and ulceration in the stomach; crowding of villus-proximal epithelial cells in the small intestine; ulcerative areas and small foci of inflammation in the colon; and necrosis, portal tract damage, and dilated sinusoids/central veins in the liver. In comparison, the histologic changes were significantly less dramatic in the stomachs, colons, and livers of the mice that received either freshly isolated CMP/GMP or in vitro expanded MP. In a parallel experiment, irradiated mice were transplanted with bioluminescent CMP/GMP from transgenic FVB.luc+ mice (H2q) constitutively expressing firefly luciferase. Imaging of the live mice as well as harvested organs at d+6 and d+9 post-transplantation indicated the presence of CMP/GMP in the stomach and intestine, correlating with sites of attenuated XRT damage in our histologic analysis. These findings support the observation that repletion of the myeloid progenitor pool enhances the recovery of radiation-injured mucosa, and raises the possibility that similar applications may be considered in the human clinical setting.
Therapeutic Blockade of ICOS:ICOSL Interaction Alleviates Acute Graft Versus Host Disease.
Authors: Richter Guenther , Mollweide Andreas , Uhlmann Esther , Burdach Stefan 
Published: April 2020

Abstract
Inducible costimulator (ICOS) interaction with its ligand (ICOSL) is involved in several T cell effector functions. The abundant expression of ICOSL in a variety of target tissues of acute graft versus host disease (GVHD) provided the rationale to investigate its role in acute GVHD development. C57BL/6 mice were lethally irradiated and reconstituted with allogeneic spleen cells in the absence or presence of ICOSL-blocking reagents. Mice reconstituted with allogeneic spleen cells experienced 12–16% weight loss around day 4 after transplantation and died untreated of acute GVHD within 7–10 days after transplantation. Mice treated from day 3 after transplantation with an anti-ICOSL mAb gained weight again and survived for additional 18 days, although the treatment was already stopped at day 11 after transplantation. Such mice revealed less T cells in spleen at day 4 after transplantation with reduced effector activity. In contrast, the anti-ICOSL treatment starting from day 0 did not prevent GVHD. The difference between therapeutic (day 3) and prophylactic (day 0) anti-ICOSL treatment was independent of CD25+CD4+ regulatory T cells since their depletion did not abrogate the therapeutic effect of ICOSL blockade. Similarly, depletion of NK cells did not improve prophylactic anti-ICOSL treatment. However, our results clearly show that delayed, i.e. therapeutic blockade of ICOS:ICOSL interaction can interfere with acute GVHD development and alleviates disease significantly in a polyclonal T cell setting.
Use of Dendritic Cells Versus Peripheral Blood Lymphocytes To Segregate Alloreactive and Regulatory T Cells during Allogeneic Transplantation.
Authors: Katz Tami , Avivi Irit , Stroopinski Dina , Oliven Anna , Zuckerman Tsila , Karitzky Sandra , Moeneclaey Guy , Vasir Baldev , Rosenblatt Jacalyn , Lenahan Corrie , Rowe Jacob M. , Avigan David 
Published: April 2020

Abstract
A fundamental research objective in allogeneic transplantation is the selective depletion of alloreactive T cell populations that are responsible for GVHD while preserving mediators of anti-tumor immunity and immune reconstitution. Alloreactive T cells may be identified by their expression of activation markers, such as CD25, following stimulation by recipient antigen presenting cells. However, CD25 expression is also present on regulatory T cells, which suppress alloreactivity through the expression of inhibitory ligands such as CTLA-4 and GITR. In an effort to develop an optimal strategy to segregate these populations, we have examined the effect of conditions of allogeneic stimulation on the balance of alloreactive and regulatory T cell populations. Stimulation of lymphocytes with irradiated peripheral blood mononuclear cells results in a gradual increase in the percentage of CD4/CD25+ cells over 7 days of culture. Mean percentage of CD4/CD25 at day 3 and 6 was 3% and 11%, respectively. On day 3 of stimulation, these cells demonstrate a characteristic activated phenotype with low intensity of CD25 expression and absence of GITR and CTLA-4 expression. Following isolation by magnetic bead separation, CD25+ cells demonstrated high levels of proliferation in response to restimulation with allogeneic PBMC. In contrast, minimal proliferation was observed following stimulation of the CD25- fraction. On day 6 of culture increased intensity of CD25 expression was observed in a fraction of the stimulated population. A majority of this population now expressed GITR and CTLA-4, consistent with a regulatory phenotype. Lymphocytes stimulated with mature DC demonstrated a markedly different pattern. A marked rise in CD4+/CD25+ cells with high levels of CD25 expression was noted early in the culture period; Mean CD4+/CD25+ cells on day 3 of culture were 9%. These cells were uniformly positive for CTLA-4 and GITR. A further increase in the percentage of cells demonstrating a regulatory phenotype was noted on day 6 of culture. We have demonstrated that the balance of activated and regulatory cells is determined by the nature of the antigen presenting cell and the duration of T cell stimulation. Based on these findings, we plan to conduct a clinical trial in which patients will undergo allogeneic transplantation following the selective removal of alloreactive T cell populations.