bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exchange of International Staging System for Durie&Salmon Staging System in Therapeutic Strategy for Multiple Myeloma.
Authors: Kurahashi Shingo , Narimatsu Hiroto , Sugimoto Takumi , Sugiura Isamu 
Published: April 2020

Abstract
Introduction: Since multiple myeloma (MM) is not a curative disease and clinical outcome is variable, chemotherapy is started only when patients developed organ impairment or progression of disease. As for clinical staging, Durie&Salmon (DS) system is in use. The International Staging System (ISS) for MM has been recently reported to provide simple and useful prognostic grouping (Greipp et al. 2005). However, its usefulness in therapeutic strategy has not been clearly demonstrated.
Patients and methods: We reviewed medical records of patients with MM, newly diagnosed in Toyohashi Municipal Hospital between May 1997 and April 2004. They were all stratified based on both ISS and DS system.
Results: The median age of 55 patients was 67 years (range; 46–86). M protein isotypes included IgG (n=33), IgA (n=13), BJP (n=6) and IgD (n=1). Fifty-two patients were treated with chemotherapy and 12 of those patients underwent autologous peripheral blood stem cell transplantation. The median follow-up of the patients was 26.8 months (range; 1.4–77.5). Their staging and overall survival (OS) are summarized on the following table. ISS predicted OS more clearly than DS system in our study.
Overall survival based on ISS and DS system ISS DS stage no. of patients OS at 3 yrs no. of patients OS at 3 yrs I 14 1.00 3 0.67 II 22 0.55 20 0.79 III 19 0.25 32 0.40 p-value 0.0102 0.3287
Thirteen of the 14 patients with ISS stage I are alive at median months of 31.5 (10.4–73.8), and only one patient died of secondary malignancy at 44.9 months from diagnosis. The patients with ISS stage I included 86% of DS stage II and III patients, who are usually required treatment.
Conclusions and discussions: ISS could predict clinical outcome more clearly than DS system. The patients’ prognosis was good in ISS stage I although many patients with DS stage II and III was included in this group. We suggests that early treatment to the patients with ISS stage I might not be necessarily required. Further studies are needed to adopt ISS instead of DS system in therapeutic strategy.
Figure Figure
Epidemiology and Features of Multiple Myeloma in a Cohort of 110 Patients from a Central Area of Israel.
Authors: Duek Adrian , Haran Michal , Shvidel Lev , Shtalrid Mordechai , Sigler Erica , Berrebi Alain 
Published: April 2020

Abstract
In the last few years there has been a world wide increase in the incidence of multiple myeloma (MM). Epidemiologic studies have suggested that certain occupational and chemical exposures are likely to increase the risk for MM.
We performed a retrospective clinical and epidemiological study of MM on 110 cases diagnosed during 2000–2005 in our area, which is a rural and agricultural zone of approximately 400000 people. The incidence of MM in our population was 5.5 new cases /100000 people / year. 43% were females (n= 48) and 57 % males (n = 63). 22% of the patients were younger than 60. 58 patients were of European descent (52%), the vast majority of them from the former USSR (including people from near-Chernobyl); 40 from Asia (36%) and 16 patients (14%) from Africa. We separated the population into three categories: non exposed (physician, teacher, housekeeper, secretary, shop assistant, employee, scientific), suspected (painting, cleaning, microbiology, engineer, aviation, building-worker), and exposed: (petroleum, agriculture, plastic manufacture, textile, ammoniac, asphalt, Chernobyl). 65 % did not have any evidence of toxic exposure, in 23% we could document a significant exposure and in 12% there was a possible such exposure. 57% of the patients were in ISS stage I (b2m&lt; 3.5 and albumin &gt; 3.5), 33%- ISS stage II (b2m &lt; 3.5 and albumin&lt; 3.5) and 10% -ISS stage III (b2m &gt; 3.5). Only 13% displayed lytic lesions at the time of survey. Fifty five patients requiring treatment received conventional therapy including APSCT and thalidomide for residual disease. In a cohort of 10 patients thal/dex was given as second line after achievement of a plateau with MP. This oral treatment allows a convenient ambulatory management and does not hamper stem cell harvesting made several months after discontinuation of MP. New clinical trials allowed us to include six patients for treatment with bortezomib.
In conclusion: the high incidence of MM in our area is in accordance with the world wide trend, possibly with a relationship with occupational and environmental risk factors. The heterogeneity of the population of Israel including arabs and new immigrants as well as additional data from others centers of Israel will help us to create a larger data base and to gain a better knowledge of MM in Israel.
Phase I/II Study of Bortezomib in Combination with Liposomal Doxorubicin and Melphalan in Relapsed or Refractory Multiple Myeloma.
Authors: Chari Ajai , Kaplan Lawrence , Linker Charles , Damon Lloyd E. , Navarro Willis H. , Martin Thomas 
Published: April 2020

Abstract
Phase I/II studies using either liposomal doxorubicin (D) or oral melphalan (M) in combination with the proteasome inhibitor bortezomib (V) have found favorable efficacy and tolerance in patients with relapsed and refractory MM. Since these drugs have different mechanisms of action and toxicity profiles, we initiated a phase I/II study to examine the safety and efficacy of combining all three agents (DMV) in relapsed or refractory myeloma.
Study Aims: Starting at 25–50% of the doses used in the two drug combination studies, the objective of this dose escalation study was to evaluate the safety/tolerability of DMV until the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) could be identified. Efficacy was also evaluated.
Methods: Patients with relapsed/refractory MM and progressive disease requiring treatment were enrolled in the study. Dose level 1 consisted of D 10 mg/m2 and M 5 mg/m2 given IV on day 1 with V given by IV push on days 1, 4, 8, and 11. Cycles were repeated every 28 days up to a maximum of 6 cycles. Dose levels of D, M, V (mg/m2) in the subsequent three cohorts were (10, 10, 0.7), (20, 10, 0.7), and (20, 10, 1.0) respectively. Once the MTD has been identified, an additional 17 patients will be enrolled at this dose level in the phase II portion of the study.
Results: 5 patients (2 males, median age 65, range 33–79) have been enrolled in the study thus far. The myeloma subtypes include 2 IgG, 1 IgA, and 2 with light chains only. In this heavily pretreated population (range 2–7 prior therapies), 4 patients received prior autologous stem cell transplantation, 2 had a prior nonmyeloablative allogenic transplant, 4 prior VAD, 1 prior bortezomib, 2 prior oral melphalan, 3 prior thalidomide, 2 prior CC-5013, and 2 prior spinal radiation.
The first dose cohort has been completed without any DLT. One patient had 3 days of Grade 3 neutropenia. All other toxicities were Grade 1–2 including asthenia, vomiting, thrombocytopenia, and headache. Of note, a patient with baseline Grade 2 peripheral neuropathy and on hemodialysis remained stable. A patient with Grade 2 chronic graft versus host disease also remained stable.
Four patients have been enrolled at dose level one. One patient, who had progressive disease after an autologous and a nonmyeloablative allogenic transplant as well as CC5013, had a near CR (IFE+) after the second cycle of DMV. Two patients have had stable disease. One had disease progression after one cycle and subsequently died. The patient on dose level two is too early to evaluate.
Conclusion: Thus far, DMV appears to be well tolerated and no DLT has been observed even in elderly patients with significant comorbidities. The finding of a near CR and SD at only dose level 1 is encouraging particularly since the patients were significantly pretreated. Dose escalation continues to determine the MTD.
Hematopoietic Development of Multipotent Germline Stem Cells Derived from Neonatal Mouse Testis In Vitro and In Vivo.
Authors: Yoshimoto Momoko , Heike Toshio , Chang Hsi , Baba Shiro , Fujino Hisanori , Shinohara Mito K. , Shinohara Takashi , Nakahata Tatsutoshi 
Published: April 2020

Abstract
Recently multipotent stem cells have been established from neonatal mouse testis (Shinohara et al, Cell 2004). This multipotent germline stem cell (mGS) is very similar to embryonic stem cells. It differentiates into various types of somatic cells in vitro and produces teratomas after inoculation into mice. Here we show the characteristics of hematopoietic development from mGS cells.
mGS cells were maintained on mitomycin C treated mouse embryonic fibroblasts. In undifferentiated state, surface markers were almost the same among mGS, ES and EG cell; E-cadherin+, β1 integrin+, CD31+ and c-kit+. For induction, undifferentiated mGS cells were cultured on OP9 stromal cell line. Four days after induction, we detected and sorted FLK1+ cells as much as ES cells. Flk1+ cells were further cultured on OP9 with various cytokines. Erythroid, myeloid, lymphoid, megakaryocyte and mast cells as well as endothelial cells and beating cells were obtained in the same manner as the induction of ES cell and EG cells. mGS cells had colony forming abilities including mix and magakaryocyte colonies. The number of mixed colony was dependent on the combination of cytokines. In erythroid differentiation, mGS showed the two waves of embryonic and definitive erythroid production, which was proved by RT-PCR and immunochemistry. When hematopoietic cells derived from GFP+ mGS cells that were cultured on OP9 for 6 days were transplanted into BM of NODγ mice directly, GFP+ cells were detected in the BM and Spleen by FACS analysis and PCR 4 months after transplantation. FACS analysis showed that GFP+ cells were detected in the side population when BM cells of transplanted mice were stained with Hoechst33324. Immunostaining of the slice of BM showed some GFP+ cells were attached to the endosteal region that is thought to be the niche for hematopoietic stem cells.
Thus, mGS cells have as much capabilities of blood cell production as ES cells and were showed having hematopoietic reconstitution ability. Considering mGS cells can be obtained from postnatal mice, they have strong advantages in research for clinical application.
Immune Dysfunctions of Cultured T Lymphocytes Are Due to a Preferential Expansion of CD4+CD25+ Suppressor Cells.
Authors: Mesel-Lemoine Mariana , Cherai Mustapha , Le Gouvello Sabine , Guillot Maude , Leclercq Virginie , Klatzmann David , Thomas-Vaslin Véronique , Lemoine Francois M. 
Published: April 2020

Abstract
We investigated the causes of the altered functionality of T-cells cultured under conditions designed for cell and gene therapy and the strategies to prevent their defects. We first showed that human T-cells cultured for 6-days with anti-CD3 ± anti-CD28 antibodies and interleukin-2 presented a 50% decrease of their proliferative responses to allogeneic or recall antigens. Similarly, day-6 cultured murine T-cells completely lost their capacity to reject allogeneic skin grafts and to provoke graft versus host disease (GVHD) when infused into irradiated semi-allogeneic mice. Interestingly, injection of higher amount of cultured T-cells restored GVHD induction. Moreover, depletion of CD25+ cells prior to T-cell cultures can prevent these deficiencies both in mice and human. Therefore, we demonstrated that culture conditions used for T-cell therapy preferentially activated and expanded regulatory T-cells (Treg) and thus, we showed that dividing cells sorted from T-cell cultures strongly suppressed the proliferation of autologous T-cells in response to allogeneic stimulation. An increased detection of Foxp3 at mRNA and protein levels in the cultures confirmed the Treg expansion. Overall, we demonstrate that T-cell cultures promote Treg expansion over effector T-cells, leading to deleterious immune functions, and that this imbalance can be prevented by an initial depletion of CD25+ cells.
Stable Mixed Hematopoietic Chimerism in Dogs Conditioned with Donor Antigen, Anti-CD154 Antibody and 100cGy TBI.
Authors: Jochum Christoph , Beste Mechthild , Zellmer Eustacia , Harkey Michael A. , Graves Scott S. , Storb Rainer F. 
Published: April 2020

Abstract
Stable mixed chimerism can be established in dogs given a sublethal dose of 200cGy total body irradiation (TBI) before and immunosupression with mycophenolate mofetil (MMF) and Cyclosporine (CSP). When the TBI dose is reduced to 100 cGy, only transient engraftment is observed. Here we asked whether stable engraftment after 100 cGy TBI could be accomplished by first reducing the intensity of host immune responsiveness with the help of an anti-CD154 antibody which blocks the CD40-CD154 pathway.
Accordingly, recipients were given a single i.v. injection of 5 mg/kg anti-CD154 antibody (day -5) followed one day later by combined i.v./sc. injections of 107 peripheral white blood cells/kg from their intended DLA-identical littermate marrow donors. TBI, 100cGy (delivered at 7 cGy/min), was given on day 0 followed by infusion of a median of 4.22x108 marrow cells/kg. Postgrafting immunosuppression consisted of MMF (10mg/kg, BID, days 0 to 28) and CSP (15 mg/kg BID, days -1 to 35). Six dogs have been transplanted. Two dogs are too early after transplant for evaluation, while four dogs have been followed for &gt;9, 12, &gt;18 and &gt;26 weeks. All four dogs had initial engraftment. Three of four dogs have continued to show stable mixed donor/host hematopoietic chimerism among lymphocytes and granulocytes from the peripheral blood. One dog rejected the graft 12 weeks after transplantation. All six transplanted dogs are alive and well. Besides mild allergic reactions to the antibody in five of the six dogs (redness of the eyes, skin rashes and dry mucous membranes), no additional side effects attributed to the pretransplant treatment were observed.
Data were consistent with previous findings in dogs, in which the costimulatory signal between B7 and CD28 was blocked, and support the hypothesis, that stable marrow allografts would be established by combining non-myeloablative pretransplant host immunosuppression and posttransplant immunosupression of both host and donor cells using MMF and CSP.
Fluorescence In Situ Hybridization Detected MRD and Chimerism in Patients with Hematologic Malignancies after allo-HSCT.
Authors: Qiu Huiying , Xue Yongquan , Jin Jinlan , Wu De Pei 
Published: April 2020

Abstract
Objective Monitoring of minimal residual disease (MRD) and cellular chimerism in patients with hematopoietic malignancies after allogeneic hematopoietic stem cell transplantation(allo-HSCT).
Methods From May 2001 to June 2005, seventy four patients were received allo-HSCT. Including 50 Males and 24 females. 41 patients received sibling HLA-matched BMT, 7 patients received un-related BMT, 9 patients received Nonmyeloablative stem cell transplantation (NST), 14 patients received related haploidentical transplantation and 3 patients received allo-PBSCT. Among them, 45 patients were diagnosed with CML, 13 patients with AML, 14 patients with ALL, one patient with Multiple myeloma and one patient with malignant lymphoma. Chimerism and MRD were monitored using X and Y specific centromeric probes or gene probes for BCR/ABL, MLL and AML1/ETO by fluorescence in situ hybridization (FISH),1000 cells were analysised.
Results Among 18 patients, received sex-matched transplant, we did not found the former chromosome rearrangements in 14 patients after transplantation, MRD were detected in 17% and 10% of cells in two patients, MRD were decreased from 10% to 1% of cells after the reduction of the dose of immunotherapy in one patient four month later, the patient was still in remission one year after transplantation. Another patient died of sever GVHD after the reduction of immunotherapy. 2 patients were found to have the former chromosomal rearrangement 1 and 4 month after transplantation respectively who did not achieve remission after chemotherapy and died 3 and 5 months respectively after transplantation. Over 99% donor chimerisms were found in 44 patients on day 25, donor cells were at a low level (96.2%~98.7) in 7 patients on day 25, and increased over 99% on day 180, they were in remission without relapse. The donor chimerisms decreased gradually in 6 patients, host cells were found over 20 cells, 3 patients showed cytogenetic or hematologic bone marrow relapse, two patients died of sever GVHD after the reduction of cyclosporine A, Over 99% donor chimerisms was achieved in one patient. Conclusion FISH could play a pivotal role in the detection of MRD and chimerism. It is helpful to the evaluation of graft and relapse, to the guide of implement of early immunotherapy.
Kinetics of Hematopoietic Progenitor Cell Mobilization with Cyclophosphamide or Cyclophosphamide Plus AMD3100 Using a Mouse Model.
Authors: Gai Bill Q. , Holt Matthew S. , Nervi Bruno , Rettig Michael P. , Ritchey Julie K. , Bridger Gary , DiPersio John F. 
Published: April 2020

Abstract
Hematopoietic progenitor cells (HPC) mobilized from bone marrow into peripheral blood (PB) are used to reconstitute hematopoiesis following myeloablative therapy. To date, a variety of agents including cytokines, chemotherapy and the combination have been used to mobilize HPC for autologous-HST. Cyclophosphamide (CY) and granulocyte colony-stimulating factor (G-CSF) are two of the most commonly used agents for HPC mobilization. Recently, AMD3100 (AMD), a bicyclam molecule that specifically and reversibly blocks SDF-1 binding to CXCR4, has been shown to have a unique HPC mobilizing capability characterized by a rapid mobilization within 1 to 2 hours after subcutaneous (sc) administration, compared with several days for G-CSF or CY. In contrast to AMD-induced mobilization, G-CSF and CY-induced HPC mobilization require functional neutrophils and an intact G-CSF receptor. We hypothesize that AMD will increase CY mobilization, and early intervention with AMD after CY treatment will increase the migration of HPC into PB in advance of neutrophil recovery. Wild type C57/BL6 mice were divided into 7 groups (n=3). One group was an untreated control and each of the other six groups received CY (200mg/kg) intraperitoneally on day 0, followed by single dose AMD (5 mg/kg sc) on days 3, 4, 5, 6, 8, and 12 after CY, respectively. WBC recovery and HPC mobilization into PB was evaluated with white blood cell (WBC) counts and standard colony-forming unit (CFU) assay, before and 2 hours after AMD administration. Our results showed that AMD can mobilize WBC within 30 minutes after treatment, reaching its peak effect in 2–3 hours with a 3–5 fold WBC increase, and a &gt; 20 fold increase of PB neutrophils compared to baseline. We also demonstrated that AMD, CY, and CY + AMD increased the CFU/ml by 7.1 + 0.4, 22.6 + 8.4, and 42.9 + 16 fold over the baseline, respectively, reaching the peak mobilization for CY on day 6. The CFU/ml returned to baseline 12 days after treatment with CY or CY + AMD. Although the kinetics of mobilization of HPC after CY + AMD were similar to those seen with CY alone (Figure 1), significant mobilization of murine HPC after CY + A occurred 1–2 days (days 4–5) in advance of that seen with CY alone (days 6–8), 1–2 days in advance of neutrophil recovery (days 6–8) and coincident with period of maximal cytoxan-induced neutropenia. The addition of AMD to CY results in synergistic mobilization of HPC which occurs throughout the entire period of CY-induced mobilization. These data suggest that the addition of A to CY for PBSC mobilization will not significantly alter the kinetics of cytoxan-induced mobilization but may permit earlier collections in patients even before significant WBC recovery occurs.
Figure Figure
Clinical Scale Preparation of B Lymphoblastoid Cell Line-Tumor Cell Hybridoma Cells for Vaccination in Patients with Relapsed Ewing’s Sarcoma and Neuroblastoma.
Authors: Lucas Kenneth G. , Mierski Joseph , Kullen Jennifer , Sun Qi 
Published: April 2020

Abstract
Despite improvements in survival for pediatric patients with cancer, for those with recurrent, high risk Ewing’s sarcoma (ES) or neuroblastoma (NB) treatment options are limited. Tumor-specific antigens in these malignancies are poorly characterized, and expression of human leukocyte antigen (HLA) and co-stimulatory molecules may be down-regulated, imparing a cellular immune response. Several groups have studied the use of tumor cell-dendritic cell (DC) hybridoma vaccines in murine tumor models as well as in phase I clinical trials in human cancer. One problem in implementing these vaccine strategies on a clinical scale is the requirement for repeat blood collections or leukapheresis to expand a limited number of DC. B lymphoblastoid cell lines (BLCL) are effective APC expressing HLA as well as key co-stimulatory molecules, and can be rapidly expanded from relatively few peripheral blood mononuclear cells. We have studied the ability of BLCL to be fused to a series of NB and ES cell lines using polyethylene glycol, and the ability to propagate these hybrid cells long term in culture. Using monoclonal antibodies specific for tumor markers (anti-GD2 and CD56 for NB), BLCL (CD19), and by labeling ES tumor cells with fluorescent dye prior to fusion, 3–11% of the resulting cell products represented true fusion cells. This was confirmed in studies in which BLCL transduced to express green fluorescent protein (GFP) were fused with adherent tumor cells, resulting in a population of large green adherent cells with abnormal morphology. Dual fluorescent staining and flow cytometry of green fluorescent dye labeled tumor cells and unlabelled BLCL consistently revealed a mixed population of unfused BLCL, unfused tumor cells, and cells with irregular morphology expressing both CD19 and green fluorescent dye. Despite these findings, these hybrid cells could not be expanded in long term culture, and adherent hybrid cells did not survive in cell culture over 2 weeks. In addition, these hybrid cells could not be selected when tumor cells and BLCL were transduced with different antibiotic resistance genes and then subjected to selection media. Despite the inability to selectively expand tumor cell-BLCL hybridomas for long-term culture, the choice of BLCL as an APC for vaccine permits the preparation of relatively large numbers of fusion cells for serial vaccination or for in vitro stimulation of antigen specific CTL.