bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment Situation for Newly Diagnosed Multiple Myeloma (MM) Patients in Germany (GER)- First Results from a Representative Multicentre Treatment Survey.
Authors: Freund Mathias R.F. , Knauf W. , Goldschmidt H. , Einsele H. , Nowrousian M. R. , Berdel W. E. , Poenisch W. , Straka C. , Kellermann L. , Bammer S. , Angermund R. 
Published: April 2020

Abstract
Background: Over the past decade new treatment options and drugs significantly altered the treatment paradigm and treatment guidelines for patients with MM have been established (e.g. ASCO). However, it was not evaluated how these options were integrated into clinical practice. We performed a representative multicentric treatment survey to elucidate the current GER treatment reality.
Method: GER centres (ctr) likely to treat MM (university hospitals (UH), non-university hospitals with (SH) and without (NSH) specialized departments, and office based hematologists (OBH) were asked to provide feedback on current treatment modalities and patient no. Among the feedback received, statistical analyses were performed to calculate sample size to ensure representative data. Ctr detected were asked to participate in a treatment registry for all patients with treatment decision (start, change or end of treatment) in a current quarter of the year (Q3/04). Data were verified by monitoring anonymized patient’s source data.
Results: 889 ctr were contacted. 163 ctr (18%) responded with 981 patients, which represents 11% of the MM prevalence in GER. We selected 59 ctr (9 UH, 16 SH, 11 NSH and 23 OBH), sample size 500. All ctr participated. 278 male and 222 female patients were enrolled, median age 64 yrs. Therapy was watchful waiting (3%), primary therapy (42.2%), 2nd line therapy (29.8%), further therapy (21.2%) and maintenance therapy (3%). MM was diagnosed Durie & Salmon stage I, II and III in 18%, 20% and 62%, 77.2% A and 22.8% B. Diagnose was mainly made in SH (33%), followed by OBH (25%), UH (23%) and NSH (18%). Primary treatment was performed mainly at the site of diagnosis with very few forwarding to higher specialized ctr, though the patients were ≤ 60 yrs. old. The mean value of treatment lines performed prior to actual treatment decision was 1.90, differing by treating ctr with a mean value of 2.09 in UH, 1.94, 2.12 and 1.97 in SH, NSH and OBH. Autologous SCT was only performed in UH and in SH and in a total of 43% of patients below age 65. In other ctr main primary treatment option were Melphalan combinations (39%) followed by VAD/VID (27%) and Bendamustine combinations (8%). Participation in a clinical trial was 24% in UH, 15% in SH, 0% in NSH and 8% in OBH. A multivariate analysis revealed site of treatment, age, stage of disease, participation in a clinical trial and status of insurance relevant for treatment decision.
Conclusion: Treatment of MM in GER is highly decentralized resulting in a variability of primary treatment. This representative survey shows treatment decisions for primary treatment of an individual patient is dependend on site of treatment, age, stage of disease, participation in a clinical trial and status of insurance.
Poor Survival of IgD Multiple Myeloma Following High-Dose Melphalan and Autologous Stem Cell Transplantation.
Authors: Jeong Yong Pil , Kim Shin , Ko Ock Bae , Koo Ja Eun , Lee Danbi , Suh Cheolwon 
Published: April 2020

Abstract
Background: IgD multiple myeloma(MM) accounts for 2% of MM subtypes in western countries and has been reported to have poorer prognosis than other subtypes.
Aims: The purpose of this study was to compare the survival following high-dose melphalan and autologous stem cell transplantation (ASCT) between IgD MM and other subtypes.
Methods: Between November 1996 and January 2005, a total of 77 patients with MM who were treated by ASCT at Asan Medical Center were available for analysis.
Results: A total of 9 patients with IgD MM were identified, accounting for 11% of all MM patients. There were 36 patients(47%) with IgG MM, 17 patients(22%) with IgA and 16 patients(20%) with free light chain. Each MM subtype had similar distribution of SWOG stage at ASCT (Table 1). With median follow up of 17 months, median overall survival(OS) was 39 months. IgD MM had the lowest survival among the MM subtypes (p&lt;0.01). Median OS of IgD MM, IgG MM, IgA MM, and free light chain MM were 12 months, 62 months, 40 months, and 55 months, respectively. Kaplan-Meier survival curve according to MM subtype was as Fig 1.
Summary/conclusion: In this small-sized single center study from Korea, IgD MM had a poorer survival than other subtype after ASCT.
Distribution of SWOG stage vs Ig type Subtype/SWOG stage I II III IV IgD MM 2 5 1 0 IgG MM 14 18 3 1 IgA MM 6 9 2 0 Free light chain MM 1 10 5 0 Fig 1 Cumulative Survival Rate Fig 1. Cumulative Survival Rate
Circulation Plays an Essential Role in Distributing Mammalian Yolk Sac Definitive Hematopoietic Progenitor Cells to the Embryo Proper; Using the Ncx1 Knockout Mouse Model To Prevent Circulation.
Authors: Lux Christopher , McGrath Kathleen , Conway Simon , Palis James , Yoder Mervin C. 
Published: April 2020

Abstract
The yolk sac is the lone site of primitive hematopoiesis. The role of the yolk sac in generating definitive hematopoietic progenitors, however, has remained controversial. One complicating factor preventing an accurate investigation of this subject has been the onset of early circulation which alters the localization of hematopoietic progenitors. An Ncx1 knockout mouse (which fails to initiate a heartbeat) is used here to investigate the temporal and spatial distribution of definitive hematopoietic progenitor cells (HPCs: adult type BFU-E, CFU-GM, CFU-GEMM) in an environment lacking circulation. Embryos were harvested from timed pregnancies from Ncx1 heterozygote crosses beginning at the onset of circulation 8.5 days post conception (E8.5) and ending 36 hours later (E10). Developmental age was determined by somite pair number. All embryos were carefully separated from their yolk sacs and both samples were digested and plated in methylcellulose using a previously published definitive hematopoietic progenitor colony assay. Colonies were counted at seven days and then collected for genotyping. In embryos of all genotypes at E8.5, definitive HPCs were enriched more than 28 fold in the yolk sac compared to the embryo proper (EP), but following redistribution by a functional circulation in E10 wild type and heterozygous embryos, the ratio drops to a 3 fold enrichment in the yolk sac (similar to the 3–5 fold enrichment previously reported at this age; KM & JP, Blood 2003). Ncx1 null embryos lacking circulation produced few HPCs in the EP and never redistribute the HPCs as late as E10 resulting in a 72 fold enrichment in the yolk sac even at E10. Whole mount ζ-hemoglobin mRNA staining was carried out to visualize the distribution of blood cells in the yolk sac and embryo proper in the presence and absence of circulation. The staining pattern in null embryos confirms that cells from the yolk sac blood band remain in the yolk sac and are not found in the EP. Our findings support a model in which the primitive and definitive hematopoietic progenitors are generated in the yolk sac and are only redistributed to the EP upon the onset of circulation. Not only is the yolk sac an important source of definitive HPCs, it is the developing embryo’s primary source through E10.
Up-Front Therapy for Multiple Myeloma: A Survey of Practice Patterns in the USA.
Authors: Natarajan Kavita , Lyman Gary H. , Ballester Oscar F. 
Published: April 2020

Abstract
Introduction: Several treatment programs are available for the initial management of patients with multiple myeloma, with no clear documented advantage(s) of one regimen over the others in terms of time to progression (TTP) or overall survival (OS).
Materials and Methods: A questionnaire was mailed to 540 randomly selected members of ASH during early 2005. Practitioners were asked their choice of therapy for newly diagnosed myeloma patients during 2004, based on 2005 NCCN guidelines, including: 1) melphalan/prednisone (MP), 2) vincristine / adriamycin / decadron (VAD), 3) high-dose decadron (HD), 4) thalidomide / decadron (Thal/Dex), 5) doxyl / vincristine / decadron (DVD); the options of a clinical trial (CT) or “other” were also included. Physicians were asked about factors influencing their choice of therapy for individual patients and their recommendations for autologous stem cell transplantation as part of the initial treatment schema.
Results: Surveys were returned by 123 physicians(19.2%), of which 93 contained evaluable data. Among responders, 52% were in private practice and 47% in academic institutions and 74% respondants reporting having been in practice for more than 10 years. A large majority of physicians (74%) utilized 3 or more different regimens, only 10.7% of responders used a single regimen for all of their patients. Thal/Dex was used by 87% of responders, with 47% of them recommending this regimen in ≥ 50% of their patients. MP, HD and VAD were used by 67.7%, 49% and 44% of responders, but only 10.7%, 4% and 3% respectively, recommended them to ≥ 50% of their patients. DVD was used by 25% of physicians. Of respondants, 64.5% did not accrued patients to clinical trials and only 7.5% of physicians accrued ≥ 50% of their patients to clinical trials. No significant differences in the choice of regimen were apparent based on years of practice. Physicians in academic centers tended to use HD (p =.002) and accrue patients to CT (p=. 001) more often than those in private practice. Factors identified as important in selecting initial therapy for individual patients included: age (92%); performance status (95%); prognostic factors, such as β2-microglobulin and cytogenetics (75%); and candidacy for stem cell transplantation (93%). Respondants consider autologous stem cell transplantation as part of the initial therapy for all eligible patients (47%), only those with responsive disease (42%) and normal renal function (30%); only in selected cases (76%).
Conclusions: Thal/Dex appears to be currently the most commonly recommended up-front therapy for multiple myeloma in the USA, in spite of the lack of published data documenting patient benefit in terms of TTP and OS. A sizable proportion of physicians do not recommend autologous stem cell transplantation as part of the initial therapy of newly diagnosed myeloma patients despite confirmed randomized clinical trials documenting benefit.
Modified Thalidomide, Cyclophosphamide and Dexamethasone (TCD) to Patients with Multiple Myeloma as Primary Therapy Prior to Peripheral Blood Stem Cell Collection.
Authors: Yang Deok-Hwan , Lee Je-Jung , Kim Yeo-Kyeoung , Baek Jin-Ho , Sohn Sang-Kyun , Jin Choi-Young , Shin Ho-Jin , Kim Hyeoung Joon 
Published: April 2020

Abstract
In the treatment of multiple myeloma (MM), autologous peripheral blood stem cell (PBSC)-supported high-dose melphalan is now considered standard therapy, especially for younger patients. Before PBSC, a new immunomodulatory drug, thalidomide, has replaced VAD regimen as the induction therapy of choice prior to hematopoietic stem cell procurement. Thalidomide has alternative mechanisms of action and usually combines with dexamethasone or alkylating agent, but the optimal doses and the intervals of chemotherapy has been evaluated. We reported preliminary data that the patients with previously untreated multiple myeloma were treated by combined different dose-scheduled thalidomide, cyclophosphamide, and dexamethasone as primary therapy and performed autologous stem cell collection. A total of 52 patients with MM were initially treated thalidomide-based chemotherapy from June 2003. Thalidomide was given with the three different method: 400mg/day on D1–5, D15–19 (arm A), 50mg/day daily (arm B) combined with cyclophosphamide 150mg/m2 P.O. on D1–4 and dexamethasone 20mg/m2 P.O. or I.V. on D1–5, D15–19, or thalidomide 200mg/day daily combined with dexamethasone 20mg/m2 on D1–4, 9–12, 17–20 in odd cycles and on D1–4 in even cycles (arm C), repeated every 28 days. Low-dose aspirin or warfarin was taken as prophylaxis for thrombosis. Thirty-nine (arm A: 17, arm B: 12, arm C: 10) of the 52 patients who received at least 4 cycles or more were evaluated for response and toxicity. Median age was 65 (range: 39–80) years and the total number of 158 cycles of toxicities were evaluated. After median 4 months of time to response followed, the overall response rate was 71.8% (76.5% v 75.0% v 60.0%), including 23% (17.5% v 23% v 28%) of complete or near complete response. Two patients (5.1%) died due to infection during treatment. When the toxicity of therapy was evaluated with more Grade III, two patients (5.1%) showed neurotoxicity, six patients (15.4%) showed neutropenia, and two patients (5.1%) had deep-vein thrombosis. Thirteen patients who achieved more than partial response proceeded to PBSC collection and yielded a median number of 3.78 x 106 CD 34+ cells/kg. This low or intermediate dose or periodic thalidomide combination showed positive responses, reducing toxicities, and adequate numbers of blood stem cells in patients eligible for subsequent high-dose chemotherapy.
Thymoglobulin (Polyclonal Rabbit Anti Thymocyte Globulin) Has In Vitro Activity in Multiple Myeloma.
Authors: Kumar Shaji , Timm Michael , Kimlinger Terry , Kline Michael , Haug Jessica L. , Rajkumar S. Vincent , Greipp Philip R. 
Published: April 2020

Abstract
Background: Multiple myeloma is a plasma cell malignancy that remains incurable with current approaches and newer therapies are needed to improve the outcome of patients with MM. While monoclonal antibody base therapies have been successful in some of the hematological malignancies, especially lymphoma, such approaches have not been very useful in the setting of myeloma. Targeting of antigens like CD138 on the myeloma cell surface has been hampered by the ubiquitous nature of this protein in the body. Thymoglobulin (polyclonal rabbit antithymocyte globulin, Genzyme) has been extensively evaluated in the setting of allogeneic blood and marrow transplantation and is currently in clinical use. Given the polyclonal nature of this product, it has antibodies against several B cell antigens and forms the rationale for its evaluation in B cell malignancies like myeloma.
Methods: MM cell lines were cultured in RPMI 1640 containing 10% fetal bovine serum supplemented with L-Glutamine, penicillin, and streptomycin. The KAS-6/1 cell line was also supplemented with 1 ng/ml IL-6. Cytotoxicity following drug treatment was measured using the MTT viability assay. Drug induced apoptosis in the cell lines was measured by flow cytometry after staining with Annexin V-FITC and propidium iodide (PI). Apoptosis in primary patient derived plasma cells following treatment was measured after staining for Apo 2.7.
Results: rATG was cytotoxic in vitro to several MM cell lines (RPMI 8226, U266, OPM1, OPM2) including the IL-6 dependent cell line Kas6/1. The LC50 in most of the cytotoxicity assays was around 1 mg/mL. Additionally, rATG was cytotoxic MM cell lines resistant to conventional agents such as doxorubicin (Dox40), melphalan (LR5) and dexamethasone (MM1R). The drug retained its cytotoxicity when myeloma cells were grown in the presence of various cytokines like IL-6, IGF-1 and VEGF. rATG treatment resulted in a time and dose dependent induction of apoptosis in MM cell lines. rATG was also able to induce apoptosis of freshly isolated myeloma cells from patient marrows. When tested in combination with other anti-myeloma agents an additive effect was seen with doxorubicin, PS341 and melphalan.
Conclusions: Thymoglobulin appear to have in vitro activity against various myeloma cell lines as well as patient derived primary myeloma cells. Ability of the drug to overcome resistance to conventional drugs as well as the effect of combining rATG with these agents points towards non-overlapping mechanisms of action. Ongoing studies are trying to identify the particular B-cell antigens that are targeted by correlating response to expression of various B cell antigens expressed by these cell lines. These studies will provide the rational for future clinical development of this agent in myeloma alone or in combination with other agents.
Dose Reduced Conditioning and CD3/CD19 Depletion for Haploidentical Allogeneic Hematopoietic Cell Transplantation in Adults: Fast Engraftment and Low Toxicity.
Authors: Bethge Wolfgang A. , Faul Christoph , Bornhaeuser Martin , Lang Peter , Handgretinger Rupert , Kanz Lothar 
Published: April 2020

Abstract
Haploidentical hematopoietic cell transplantation (HHCT) has been made feasible with the use of megadoses of CD34+ peripheral blood stem cells. Despite this progress, HHCT is still complicated by high treatment related toxicity, slow engraftment and immune reconstitution. A new regimen using graft CD3/CD19 depletion with anti-CD3- and anti-CD19-coated microbeads on a CliniMACS device and dose reduced conditioning may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, natural killer-, dendritic- and graft-facilitating-cells. As dose reduced conditioning fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2) and OKT-3 (5 mg/day, day -5 to +14) without posttransplant immunosuppression was used. So far 9 consecutive adult patients have been transplanted with this regimen. Median age of the patients was 37 (range, 27–58) years and the diagnoses were AML (n=3), ALL (n=3), NHL (n=2) and multiple myeloma (n=1). All patients were high risk with relapse after preceding hematopoietic cell transplantation. The CD3/CD19 depleted haploidentical grafts contained a median of 8 x 10E6 (range, 5.2–17x10E6) CD34+ cells/kg, 6x10E7 (range, 0.02–8.6 x10E7) CD56+ cells/kg and 2x10E4 (range, 0.006–8.2x10E4) CD3+ T-cells/kg. 8 of 9 patients had a donor-recipient KIR-mismatch. The conditioning regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis and nausea. In 4/9 patients reversible peripheral neuropathy grade 2–3 occurred, combined with multifocal leucencephalopathy in one patient. Subsequently the dose of fludarabine was reduced to 150 mg/m2. Engraftment was rapid with median time to neutrophils &gt;500/μL of 13 (range, 10–17) days, platelets &gt;20000/μL of 11 (range, 8–14) days and full donor chimerism after two weeks in all patients. All evaluable patients had fast immune reconstitution with T-cells &gt;100/μL by day +100. Five cases of grade 2 skin GVHD rapidly responded to steroids. Three patients with controlled fungal pneumonia at time of transplant had resolution of infiltrates with neutrophil reconstitution and antifungal therapy. Treatment related mortality in the first 100 days was low with one death due to idiopathic pneumonia syndrome. Three patients died after day 100, one each due to relapse, systemic adenoviral infection and CMV infection. Overall survival is 5/9 patients with a median follow-up of 406 days (range, 44–661). In conclusion, this regimen seems to be promising in adult high risk patients lacking a suitable donor and a prospective phase I/II study is ongoing.
Generation of a Common Progenitor Population from Human Embryonic Stem Cells That Gives Rise to Both Embryonic Erythropoiesis and Definitive Hematopoiesis.
Authors: Zambidis Elias T. , Osborne Jihan , Civin Curt I. 
Published: April 2020

Abstract
Human embryonic stem cells (hESC) provide a valuable new tool for dissecting the earliest developmental events of human hematopoietic-stem progenitor cell (HSPC) genesis. We have recently reported the efficient step-wise differentiation of hESC to embryonic (primitive) erythroid cells followed by definitive erythro-myeloid hematopoietic cells from human embryoid bodies (hEB). Hematopoiesis proceeds spontaneously from hEB-derived cells and appears to model the earliest events of embryonic and definitive hematopoiesis in a manner resembling human yolk sac development.
We now extend our studies to define conditions which may favor differentiation into definitive hematopoietic cells from hEB. We previously demonstrated that hEB-derived primitive hematopoiesis requires fetal calf serum, but proceeds in the absence of supplemented recombinant growth factors to developing hEB’s. We now show that supplementing hEB differentiation cultures with a broad array of hematopoietic growth factors dramatically enhances the number of primitive erythroblasts, definitive myeloid, BFU-E, CFU-E, and multi-potent mixed colonies in methylcellulose CFC assays while not affecting the kinetics of hematopoietic differentiation. The inclusion of VEGF-165 during hEB differentiation was found to have an exceptionally potent effect in increasing the multilineage generation of both primitive and definitive hEB-derived hematopoietic cells. To further define the hEB-derived population which gives rise to primitive and definitive hematopoiesis we FACS-purified a population of CD45-CD31+CD34+ hEB cells which we and others have shown are capable of both endothelial and hematogenous differentiation. Co-culture of this purified population in serum-containing OP9 stromal layers gave rise primarily to definitive-type erythro-myeloid cells including mature beta-globin-expressing erythroid cells, neutrophils, monocytes/macrophages, CD41+ megakaryocyte precursors, and CD56+ NK-like cells. Alternative culture of this purified CD45-CD31+CD34+ hEB population in serum-free, stromal-free cultures supplemented with erythropoietin and VEGF-165 produced an abundant population of embryonic (nucleated gamma, epsilon, zeta chain-hemoglobin-expressing) erythroblasts.
To isolate a clonogenic, expandable human hemangioblastic progenitor of primitive and definitive hematopoieisis as well as endothelial cells in our system, we have prepared transgenic hESC lines expressing a GFP reporter cDNA under the hemato-endothelial regulatory sequences of the human genomic SCL/TAL1 locus. Our hESC model reveals, for the first time, the putative existence of a population of human hEB progenitors capable of both embryonic-type and definitive blood cells depending on the differentiation environment.
Dendritic Cells Reconstitution after Different Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Wu De Pei , Cao Junjie , Li Caixia , Wu Xiaojin 
Published: April 2020

Abstract
Objective: To compare the dendritic cells reconstitution after different allogeneic hematopoietic stem cell transplantation in early time
Methods: From June 2004 to March 2005, Twenty-eight patients undergoing allo-HSCT were enrolled in this study. There were 16 patients who undergone normal HSCT, 8 patients who undergone Haploidentical HSCT and 4 patients who undergone Nonmyeloablative HSCT. Three-colour flow cytometry was applied to study the alteration of the percentage and number in circulating peripheral blood dendritic cells subsets on day 14,day 30,day 60 after transplantation among three distinct type HSCT.
Results: The dendritic cells subsets number of myeloablative HSCT patients were very low. No difference was observed in the kinetics of DC1 (Lin−HLA-DR+CD11c+)and DC2 (Lin−HLA-DR+CD123+) reconstitution between the normal HSCT group and Haploidentical HSCT group patients(p&lt;0.05). There was significant difference between myeloablative HSCT group and normal healthy individuals(p&lt;0.01). There was significantly different between the non-myeloablative HSCT group and the myeloablative HSCT group in the kinetics of DC1 and DC2 reconstitution(p&lt;0.05).
Conclusion: The early reconstitution of dendritic cells in Nonmyeloablative HSCT patients is earlier than the patients who undergone myeloablative HSCT. The early reconstitution of dendritic cells in normal HSCT and Haploidentical HSCT patients were later than others.