bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter Phase II Trial of Patients with Refractory or Recurrent Multiple Myeloma with Oral Treatment of Thalidomide Combined with Oral Cyclophosphamide, Idarubicin and Dexamethasone.
Authors: Glasmacher Axel , Moehler Thomas , Goldschmidt Hartmut , Geer Thomas , Kleinschmidt Rolf , Gaska Tobias , Uwe Janssens , Schubert Jorg , Bruck Patrick , Clemens Michael R. , Bair Wolfgang , Seipelt Gernot , Schleuning Michael , Hahn-Ast Corinna , Herz Susanne , von Lilienfeld-Toal Marie , Naumann Ralf , Gorschluter Marcus , Schmidt-Wolf Ingo G.H. 
Published: October 2019

Abstract
Introduction and rationale: The aim of our study is to evaluate the role of thalidomide in combination with oral CID therapy in order to improve treatment wit an all oral regime.
Patients and methods: Patients with refractory or relapsed myeloma were included into this trial. Concerning inclusion criteria, 10 patients had progressive disease after standard chemotherapy, 12 no change after standard chemotherapy and required further therapy, 6 recurrent disease after standard therapy and 22 recurrence after high dose chemotherapy. At start of the treatment patients were in stages IIA (16 patients), IIB (1), IIIA (34) and IIIB (1). Idarubicin was given in capsules at 8–10 mg/m2/day for days 1–4, 40 mg dexamethasone were given on days 1–4 and 15–18, cyclophosphamide at 200 mg/m2/d d1–4 and thalidomide 100mg daily with scheduled increase to 400mg. Treatment cycles were repeated every 28 days. 3–8 cycles were applied. Supportive therapy consisted of PEG-filgrastim, cotrimoxazol, dalteparin and ibandronate. In addition, after the induction phase patients were randomized between thalidomide and thalidomide / idarubicin maintenance treatment.
Results: At this interim analysis, 66 patients have been entered into the ongoing trial; 6 patients had to be excluded for violation of unclusion criteria. Of the 60 included patients, 52 patients have been documented so far and are evaluable for toxicity. In total, 187 cycles have been applied. Median cycle number was 3 (1–8). There was one death during treatment due to progressive myeloma at cycle 1. The median age was 62 years (interquartile range 57–67). The following toxicities were observed: FUO (2 patients), pneumonia (4), pulmonary embolism (1), exsiccosis after diarrhea (1), constipation (1), sepsis (1), severe nausea (2), syncope (1), collaps after bleeding (1, not related to TCID treatment) and mucositis grade 4 (1). Hematologic toxicity grade IV was reported in 35% of the patients, mainly in cycles 1 and 2. Concerning response to treatment 41 patients are evaluable for response so far. Of these 31 (76%) achieved a PR (24 patients) or MR (7 patients) according to EBMT criteria, 4 patients a stable disease and 3 patients a PD. Three patients were not evaluable and scorded as failures.
Conclusions: T-CID is feasible and highly effective in relapsed or refractory myeloma patients. Toxicity seems to be acceptable and mainly hematologic and infectiologic. The remission rate of 76% is encouraging.
Combination Therapy with Lenalidomide, Bortezomib, Liposomal Doxorubicin and Dexamethasone (LBlipDD) May Overcome Resistance to Prior Treatment with Doxorubicin, Lenalidomide, and Bortezomib in High-Risk Multiple Myeloma (MM).
Authors: Ruckser Reinhard , Tatzreiter Georg , Kitzweger Elvira , Strecker Karin , Hraby Stefan , Buxhofer Veronika , Stampfl Margarete , Kier Peter , Habertheuer Karl H. , Hejtman Milos , Hinterberger Wolfgang 
Published: October 2019

Abstract
Introduction: Lenalidomide (Revlimid®) plus dexamethasone therapy and single-agent bortezomib therapy are approved for the treatment of relapsed/refractory multiple myeloma (MM) patients. A recent phase II trial has shown activity of lenalidomide/bortezomib/dexamethasone in patients with relapsed/refractory MM (Richardson, IMW 2007). Here, we present a case report on the efficacy of combination therapy with lenalidomide, bortezomib, liposomal doxorubicin, and dexamethasone in a patient who was refractory to prior treatments with bortezomib, lenalidomide, and doxorubicin.
Methods and Results: A male patient (58 years) presented with IgG-lambda MM in June 2006. Laboratory tests at diagnosis showed total protein of 123g/L (normal value, 66–87 g/L) and a serum IgG of 87.3g/l (normal value, 7–16 g/L). The patient had t(11;14)(q13;q32) translocation and a del13q14, and bone marrow aspirate showed >90% plasma cells. From July 2006 to March 2007, the patient received 3 different chemotherapy treatment regimens (VAD: vincristine, Adriamycin® [doxorubicin], dexamethasone; VDD: Velcade® [bortezomib], doxorubicin, dexamethasone; and LD: lenalidomide, dexamethasone). He showed primary resistance to VAD treatment and developed resistance after 3 and 5 cycles of VDD and LD, respectively. At that point, the patient’s free light chain (fLCh) concentration was 2,320 mg/L (normal value, 5.7–26.3 mg/L). We changed the patient’s treatment regimen to the 4-fold combination of lenalidomide plus bortezomib plus liposomal doxorubicin (lipD) plus dexamethasone (LBlipDD), (lenalidomide 25 mg day 1–21, bortezomib 1mg/m2 day 1+4+8+11, lipD 50 mg/m2 day 4, dexamethasone 40 mg day 1+2+4+5+8+9+11+12; q28 days). The patient received 3 cycles of LBlipDD from May 2007 to July 2007. This treatment combination was well tolerated with no WHO grade 3 or 4 adverse events. The patient was reassessed after 3 treatment cycles. FISH showed a complete eradication of the former cytogenetic abnormalities, bone marrow aspirate showed <5% plasma cells and serum analysis demonstrated a normalized serum IgG value, and a decrease in the fLCh from 2,320 to 173 mg/L. The patient is for the first time transfusion independent and in very good clinical condition. High-dose melphalan with autologous stem cell support is currently planned.
Conclusion: Treatment with LBlipDD leads to a good remission in a VAD-, VDD- and LD-resistant patient. The present observation suggests that the use of 4-fold combination of lenalidomide, bortezomib, liposomal doxorubicin, and dexamethasone can be effective in high-risk MM patients and warrants further investigation.
Combination Therapy of Bortezomib with Bendamustin in Elderly Patients with Advanced Multiple Myeloma. Clinical Observation.
Authors: Hrusovsky Irena , Heidtmann Hans-Heinrich 
Published: October 2019

Bortezomib(Bo) was approved for therapy of relapsed Multiple Myeloma (MM) in 2003-for use in Germany 2004. There is growing evidence that combination of Bo with conventional chemotharapy agents could improve MM patients’ (pts) outcome(P.Richardson ASCO 2004). Bendamustin(Ben) is widely used for MM chemotherapy in Germany. In weekly low dose regimen it is well tolerated and highly effective in therapy of low grade lymphoma in elderly (K.Bremer ASCO2003, Abstract 2410). Ben has no cross resistances with other cytostatic drugs used in MM therapy, in low dose regimen it is well tolerated, has low bone marrow toxicity and no renal toxicity. We reported results of the combination therapy of the first 17 pts 2 years ago. Because of very good tolerability and high response rates we established the combination in our institution as a salvage-therapy for pts with relapsed MM after at least 2 previous chemotherapies. Till now we treated 40 pts - all white European-21 women, 19 men- median age 66 years (range 51–86). All pts had relapsed MM with clinical symptoms such as anemia, bone pain, progressive bone disease, several of the pts had renal failure (1 on hemodialysis). Previous therapies - median 4-(range 2–10)- included Melphalan, Dexamethason, VAD and sim. combinations, Cyclophosphamide, Bendamustin, Thalidomide, Bortezomib mono and in 3 pts tandem HD Melphalan. Therapy-regimen: Bortezomib 1–1,3 m/sqm d 1,4,8,11, Bendamustin 60mg/sqm d 1,8, Dexamethason 3x8mmg p.o. d 1–3 and 8–10 if tolerated, Ondansetron 8 mg i.v. d 1,4,8,11- q3w until best response- median number of cycles 4 (range 2–6). Early responses with symptom relief at begin of second cycle were frequently observed. Results (outcome according to SWOG criteria): ORR 85%, very good PR 25%(normal electrophoresis, normal level of free light chains in serum and urine), PR 47,5%, MR 12,5%. Remission duration in pts with at least PR- 8 Months (range 2–26 months)-19 pts are still alive. Toxicity: comprised fatigue and mostly mild thrombocytopenia without bleeding, reversible within 1 week. 8 pts had neuropathy and required symptomatic therapy with Gabapentine- most of them pretreated with Thalidomide. 9 pts had herpes zoster before aciclovir 3x400 mg daily was administered as prophylactic therapy.
Conclusion: The therapy with combination Bortezomib- Bendamustin is highly effective, safe and well tolerated. The therapy is feasible in out-patient setting. The response rates suggest that the drugs act at least additive. We think therefore that further studies are warranted.
CD38 Gene Polymorphisms Contribute to Genetic Predisposition to B-Cell Chronic Lymphocytic Leukemia.
Authors: Jamroziak Krzysztof , Szemraj Zofia , Grzybowska-Izydorczyk Olga , Szemraj Janusz , Cebula Barbara , Balcerczak Ewa , Wawrzyniak Ewa , Mirowski Marek , Robak Tadeusz 
Published: October 2019

Abstract
Genetic background and abnormal immune response are supposed to play a role in the pathogenesis of B-cell chronic lymphocytic leukaemia (B-CLL). CD38 is a leukocyte activation antigen and ectoenzyme involved in numerous immune functions as well as important prognostic factor in B-CLL. The aim of this study was to investigate potential association of two single nucleotide polymorphism (SNPs) located in CD38 gene at position 182 (C/G) in intron 1 and at position 418 (C/T) in exon 3 with genetic susceptibility to B-CLL. Furthermore, we wanted to verify whether these SNPs influence CD38 expression or clinical outcome of B-CLL patients. Genotyping of 365 Caucasian individuals (163 B-CLL patients and 202 healthy controls) was performed by restriction fragment length polymorphism (RFLP) and allele-specific polymerase chain reaction (ASPCR) assays. CD38 gene expression was quantified by real-time RT-PCR and CD38 protein expression was measured by flow cytometry in circulating B-CLL cells from 50 patients and normal B and T lymphocytes from 30 healthy controls. We found that allele frequency and distribution for both CD38 SNPs differed significantly in patients and controls with increased prevalence of alternative alleles detected in B-CLL (allele 182G found in 34.7% B-CLL patients vs. 13.4% controls, p<0.0001, and allele 418T found in 4.6% B-CLL patients vs. 0.5% controls, p=0.0002). Logistic regression analysis regarding SNP at position 128 showed that the 182CG heterozygotic genotype conferred risk of B-CLL (odds ratio, OR=3.8, 95% confidence interval, CI=2.4–6.1) that was further increased in alternative allele homozygotes (OR=7.3, 95%CI=2.8–19.1), p<0.0001. Similarly, compared to the individuals with wild-type 418CC genotype, carriers of heterozygotic 418CT genotype and alternative allele 418TT homozygotes were at higher risk of B-CLL (OR=7.3 and OR=240, respectively, p=0.032). Interestingly, we did not observe any differences in CD38 gene or protein expression in B-CLL or normal lymphocytes related to genotypes at position 128 or 418, however, this could be due to low numbers of rare genotypes found among patients included to the expression tests. Finally, the survival analysis showed that SNP at position 128 of CD38 gene influenced overall survival (OS) of B-CLL patients, with the best prognosis observed in carriers of 128CG genotype (p=0.05). In conclusion, our data indicate that inherited SNPs located in the CD38 gene are associated with genetic susceptibility to B-CLL in Caucasian patients, and may have some impact on prognosis of this malignancy.
Capture and Enrichment of CD34-Positive Haematopoietic Stem and Progenitor Cells from Blood Circulation Using P-Selectin in an Implantable Device.
Authors: Narasipura Srinivasa D. , Wojciechowski Joel C. , Charles Nichola , Mickelsen Deanne , Blair Martha L. , King Michael R. 
Published: October 2019

Abstract
Clinical infusion of haematopoietic stem and progenitor cells (HSPCs) is vital for restoration of haematopoietic function in many cancer patients. Previously we have demonstrated an ability to mimic physiologic cell trafficking in order to capture CD34-positive (CD34+) HSPCs using a monolayer of P-selectin in flow chambers. The aim of the current study was to determine if HSPCs could be captured directly from circulating blood in vivo. Vascular shunt prototypes, coated internally with P-selectin, were inserted into the femoral artery of rats. After one-hour blood perfusion, successful capture of mononuclear cells was achieved and analysis of these cells revealed a significant enrichment for CD34+ HSPCs. Blood flow through the cell capture device resulted in a wall shear stress of 4–6 dynes/cm2. Purity of captured CD34+ cells showed 7-fold enrichment (average purity = 28 ± 4%) over levels found in the control mobilized peripheral blood mononuclear cells (average purity = 3 ± 0.5%). Robust cell capture and HSPC enrichment were also observed in devices that were implanted in a closed-loop arterio-venous shunt conformation for two hours. Adherent cells were viable and were able to differentiate into burst forming units in culture. This study demonstrates an ability to mimic the physiologic arrest of HSPCs from blood in an implantable device and may represent a practical alternative for adult stem cell capture and enrichment.
Interleukin 11 Induced Capillary Leakage Syndrome and Deteriorated Hemorrhagic Cystitis in an Acute Myelogenous Leukemia Patient after Allo-HSCT.
Authors: Sun Xuemei , Yang Yonggong , Guan Chaoyang , Li Xiaohui 
Published: October 2019

Abstract
Interleukin 11 (IL11) has been approved for clinical utilization by Chinese Drug and Food Administration in the treatment of thrombopenia post chemo/radio therapy. It has been proved a safe cytokine in previous clinical trials. We however found a case who presented with a severe syndrome which was suspected in relation with IL 11. A 38- year-old male was undertaken a matched unrelated peripheral blood stem cell transplantation after an ablative BuCy conditioning for the treatment of acute myelogenous leukemia. He suffered from hemorrhagic cystitis(HC) on day 40 and was managed well with aggressive hydration and diuresis as well as administration of anti-virus regimen. After a resultant pancytopenia occurred, he was given IL11 for the amelioration of the thrombocytopenia in aid of controlling the bladder bleeding. His HC was in good control initially, but two days after the IL-11 administering, the patient manifested with generalized edema, hypotension with hemoconcentration and hypoalbuminemia without albuminuria. The diagnosis of capillary leakage syndrome (CLS) was under consideration. Interleukin 11 was ceased immediately and 6% hydroxyethly starch(HES) was added to improve the symptoms of CLS. In the following day the 24 hour- urinary volume of the patient reduced sharply accompanying by dysuresia. Ultrasonic examination displayed a clumping mass measured 50 mm×75mm ×63mm. Three days later, he was diagnosed as acute renal failure owing to combination factors of the renal and/or postrenal damage of the kidney. Meanwhile continuous renal replacement therapy (CRRT) was started and patient got well 5 days later with normal urinary volume. And symptoms from HC and CLS were improved dramatically. We concluded here that interleukin 11 could play the pivotal role in inducing a CLS and resultant acute renal failure. And it thus deteriorated HC in this patient. The patient’s renal function could recover well rapidly with the infusion of HES and CRRT. We suggested a comprehensive clinical study of Interleukin 11 be conducted to optimize its clinical usage for the sake of safe medication.
Tacrolimus and Short-Term Methotrexate (mini-MTX) for Graft Versus Host Disease (GVHD) Prophylaxis after Unrelated Single Unit Cord Blood Transplant (CBT) in Pediatric Patients.
Authors: Petropoulos Demetrios , Worth Laura L. , Koontz Susannah E. , Choroszy Mary S. , Chan Ka Wah , Shpall Elizabeth J. , Champlin Richard E. , Cooper Laurence J. 
Published: October 2019

Abstract
CBT is increasingly used in the management of patients with a variety of hematologic and neoplastic conditions. We investigated the use of Tacrolimus with MTX for the prevention of GVHD. Sixty consecutive pediatric patients (37 males, median age 6.8 years, range 0.4–20 y) underwent 63 single unit CBT. Sixty-two units were mismatched with the patients (1 Antigen mismatch [Ag MM]: 20; 2 Ag MM: 39; 3 Ag MM: 3). Five patients had non-malignant conditions (severe aplastic anemia [SAA] 2, Wiskott-Aldrich 2, Hunter 1). Thirty-one of the 55 patients with malignant diseases (ALL 30, AML 16, CML 2, NHL 2, MDS 2, JMML 2, neuroblastoma 1) had high-risk disease. The conditioning regimen was chemotherapy-only in 34 (Thiotepa, Busulfan[Bu], Cyclophosphamide[Cy] for 28 children younger than 5 years or with prior irradiation; Bu-Cy in the patient with Hunter and a patient with AML and trisomy 21; Fludarabine[Flu], Cy, Lymphoglobulin in one patient with SAA; Bu-Flu:3) transplants. Radiochemotherapy was implemented in 29 patients (Flu, Melphalan[Mel], TBI: 26; Etoposide, Mel, TBI:1; Etoposide, Mel, TBI:1; Flu, Cy, ATG, 200cGy TBI:1 SAA patient). The median pre-cryopreservation total nucleated cell dose was 4.3 x 107 / kg recipient weight (range 1.8–12 x 107/ kg). The combination of Tacrolimus and mini-MTX (5 mg/m2 on days 1, 3 and 6) was used in 60 transplants (Tacrolimus alone in 3). ATG or steroids were not routinely used.
Results: Forty-six of the 52 transplants evaluable for acute GVHD did not have severe GVHD (Grade 0:11 patients; I: 10 patients; II: 25 with 22 limited to skin only; III: 3; IV: 3 patients). Eight patients had primary graft failure (2 with persistent disease). There were 3 early deaths. Chronic GVHD was diagnosed in 8/42 evaluable patients. With a median follow-up of 1,757 days (range 512–3,731) 27 patients are alive without disease.
Conclusion: Tacrolimus with mini-MTX should be considered for the prevention of GVHD after mismatched unrelated cord blood transplants in pediatric patients with malignant or non-malignant diseases.
Nonmyeloablative Peripheral Blood Stem Cell Transplantation for Chronic Myeloid Leukemia in Chronic and Advanced Phases.
Authors: Ding Jia-Hua , Ma Yan , Chen Bao-An , Zhao Gang , Wang Jun , Sun Yun-yu , Cheng Jian 
Published: October 2019

Abstract
Objective: To study the effect of nonmyeloablative peripheral blood stem cell transplantation(PBSCT) for chronic myelogenous leukemia(CML) in chronic phase(CML-CP) and advanced phase(CML-AP).
Methods: Twenty-four CML patients, 16 in CML-CP and 4 in CML-AP underwent nonmyeloablative peripheral blood stem cell transplantation(NST). The conditioning regimen included fludarabine 30mg.m−2.d−1, intravenously(i.v.)×6d, busulphan 4mg.m−2.d−1×2d and CTX 350mg.m−2.d−1×2d combined with or without Ara-C. The donors were HLA-identical (n=20) and 5/6 antigen-matched (n=4).
Results: All the patients were successfully engrafted. The mean time needed for increase of the number of neutrophils to more than 0.5×109/L and platelet more than 20×109/L were 13 days and 11.5 days respectively. Among 12 patients, 9 showed complete donor chimerism(CDC) and 3 showed mixed chimerism(MC) at +day 30. At +day 180, 18 patients still alive showed CDC and remained alive after a median follow-up of 24 months (4∼48months). 3 cases died of severe acute GVHD(aGVHD), 1 case of chronic GVHD(cGVHD), 2 cases of interstitial pneumonia(IP) and 1 case of relapse.
Conclusion: Nonmyeloablative PBSCT is an effective method for CML patients in chronic phase and advanced phase.
Characteristics of 24 CML patients and their donors Patient Age Gender Diagnosis Donor HLA *: unrelated donor 1 40 male CML-AP brother HLA-identical 2 32 male CML-AP brother HLA-identical 3 40 male CML-CP brother HLA-identical 4 40 male CML-CP brother HLA-identical 5 42 male CML-AP brother HLA-identical 6 24 male CML-AP sister HLA-identical 7 55 male CML-CP sister HLA-identical 8 32 male CML-CP brother HLA-identical 9 36 male CML-CP brother HLA-identical 10 46 female CML-AP sister HLA-identical 11 52 female CML-CP brother HLA-identical 12 60 male CML-CP sister HLA-identical 13 45 female CML-CP brother HLA-identical 14 48 male CML-CP brother HLA-identical 15 33 male CML-CP URD* HLA-identical 16 35 female CML-CP URD HLA-identical 17 40 male CML-CP brother HLA-identical 18 34 female CML-AP sister HLA-identical twin 19 54 female CML-CP brother HLA-identical 20 33 male CML-AP URD Subtype mismatched 21 32 male CML-CP URD Subtype mismatched 22 42 male CML-CP URD mismatched 23 50 female CML-CP URD HLA-identical 24 46 male CML-CP brother HLA-identical
An In Vivo Evidence That the CD45negative Adult Marrow-Derived CXCR4+ SSEA-1+ OCT-4+ Very Small Embryonic-Like (VSEL) Stem Cells May Differentiate into CD45positive Long Term Repopulating Hematopoietic Stem Cells.
Authors: Wysoczynski Marcin , Kucia Magda , Zuba-Surma Ewa K. , Wan Wu , Ratajczak Mariusz Z. , Ratajczak Janina 
Published: October 2019

Abstract
Mounting evidence accumulates that bone marrow (BM) contains a population of pluripotent stem cells (PSC) that give rise to long-term repopulating hematopoietic stem cells (HSC). Recently we identified in murine BM a homogenous population of rare (∼0.01% of BMMNC) and very small (2–4 μm) Sca-1+ lin− CD45− cells that express by RQ-PCR and immunhistochemistry markers of PSC such as SSEA-1, Oct-4, Nanog and Rex-1 and highly express Rif-1 telomerase protein (Leukemia2006;20,857–869). Direct electronmicroscopical analysis revealed that these cells display several features typical for primary epiblast-derived embryonic stem cells such as i) a large nuclei surrounded by a narrow rim of cytoplasm, and ii) open-type chromatin (euchromatin). In co-cultures with C2C12 murine sarcoma supportive feeder-layer, these cells grow spheres that are composed of immature CXCR4+SSEA-1+Oct-4+ cells that have large nuclei containing euchromatin and, if plated into cultures promoting tissue differentiation, show pluripotency and expand into cells from all three germ-cell layers. Based on this, we called them very small embryonic like (VSEL) stem cells. However, VSEL isolated freshly from the BM do not posses immediate hematopoietic activity - they neither grow hematopoietic colonies nor radioprotect lethally irradiated recipients. Recently, however, we noticed that if plated over supportive OP9 cell line, these CD45− VSEL give rise to colonies of CD45+CD41+Gr-1−Ter119− cells where their phenotype resembles those of the earliest hematopoietic cells that are derived in vitro from established embryonic cell lines. This hematopoietic differentiation of VSEL was accompanied by upregulation of mRNA for several genes regulating hematopoiesis (e.g. PU-1, c-myb, LMO2, Ikaros). More importantly, the CD45+CD41−Gr-1−Ter119− cells expanded from VSEL isolated from GFP+ mice if transplanted into wild-type animals protected them from lethal irradiation and differentiated in vivo into all major hematopoietic lineages (e.g., Gr-1+, B220+ and CD3+ cells). This hematopoietic activity was maintained after transplantation into secondary recipients. Based on this, we postulate that i) VSEL are PSC that give rise to HSC and ii) that CD45+ cells may derive from a CD45− population. Thus we propose that VSEL are a population of BM-residing PSC that may give rise to long-term engrafting hematopoietic stem cells.