bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-DKK1 mAb (BHQ880) as a Potential Therapeutic for Multiple Myeloma.
Authors: Fulciniti Mariateresa , Tassone Pierfrancesco , Hideshima Teru , Vallet Sonia , Ettenberg Seth , Stover David , Blotta Simona , Shen Zhenxin , Dimartino Maria Teresa , Neri Paola , Prabhala Rao , Nopur Raje , Goldring Steven R. , Anderson Kenneth C. , Munshi Nikhil C. 
Published: October 2019

Abstract
Decreased activity of osteoblasts (OB) contributes to osteolytic lesions in multiple myeloma (MM). Dickkopf-1 (DKK1) is a soluble Wnt inhibitor produced by MM cells that inhibits osteoblastogenesis in the bone marrow (BM) microenvironment. DKK1, also present in MM patient plasma, has been shown to inhibit the differentiation of osteoblast precursor cells in vitro, and its plasma level correlates with focal bone lesions in MM. Therefore, we have evaluated DKK1 as a target in MM in the context of the BM microenvironment. We first analyzed the effects of a DKK1 neutralizing antibody (BHQ880) on OB differentiation. Anti-DKK1 Ab was able to increase differentiation of mesenchymal stem cells (MSCs) to OB and reduce IL-6 levels following MSC differentiation to OB. While OB activity in MSCs cultured with osteoblast differentiation media was reduced in the presence of INA-6 MM cells, treatment with DKK1 neutralizing antibody was able to restore OB activity in a dose-dependent manner, overcoming the negative effect of MM cells. We did not observe a direct effect of this Ab on growth or survival of human MM cell lines. However, when a panel of MM cell lines was cultured with BM stromal cells (BMSC), the Ab induced significant growth inhibitory effects on MM cells, associated with downregulation of IL-6 produced by MSCs. To evaluate the in vivo bone and antitumor effects of anti-DKK1 Ab treatment on MM cells in the human microenvironment, we used a SCID-hu murine model, using INA-6 MM cells. In this model we observed a direct correlation between the level of soluble human DKK1 in murine blood and the tumor growth. Following treatment with BHQ880, by bone histology analysis, we observed increased trabecular bone and numbers of OBs in the retrieved bone chip from BHQ880 treated mice compared to control mice, one month after initial dose. We also found an increase in human osteocalcin in the serum of BHQ880-treated mice compared to the controls, suggesting an increase in OB activity. Interestingly, we observed suppression of myeloma growth, measured by changes in serum level of soluble huIL6sR, 4 weeks following BHQ880 treatment of the mice. These results support DKK1 as an important therapeutic target in myeloma and provide the rationale for clinical evaluation of this molecule in MM to improve bone disease and to inhibit MM growth.
The In Vitro and In Vivo Antioxidant Effects of Erythropoietin in Thalassemia.
Authors: Fibach Eitan , Amer Johnny 
Published: October 2019

Abstract
Erythropoietin (EPO), a hormone produced on hypoxia mainly in the kidneys, enhances red blood cell (RBC) production (erythropoiesis) by stimulating the proliferation of erythroid progenitors and precursors in the bone marrow. This effect is mediated by the homodimeric EPO receptor, a class 1 cytokine receptor. Recombinant human EPO is widely used for the treatment of anemia, e.g., in patients on dialysis, patients with myelodysplastic syndrome and oncology patients undergoing chemotherapy. Treatment with EPO was also tried experimentally in patients with thalassemia. In these patients, in spite the state of chronic anemia, the levels of EPO is usually low relative to the degree of anemia. Administration of EPO to thalassemic patients have been shown to increase erythropoiesis and in some cases to elevate fetal hemoglobin production. In addition, EPO has been suggested to have cardio- and neuro-protecting effects and to increase RBC survival in dialysis patients. We have previously shown that RBC and platelets derived from patients with beta-thalassemia and sickle cell disease are under oxidative stress; they have elevated potential to generate reactive oxygen species (ROS) and membrane lipid peroxides, and have lower content of reduced glutathione (GSH) than normal RBC. This oxidative stress resulted in high exposure of phosphatidylserine (PS) that is considered a major factor in shortening the life span of thalassemic RBC, and in the tendency of platelets to undergo activation and thus contributes to the high incidence of thromboembolic complications in thalassemia. In the present study, we investigated the in vitro and in vivo effects of EPO as an antioxidant on RBC and platelets from beta-thalassemic patients and mice. Using flow-cytometry methodology, we showed that in vitro treatment of blood cells from beta-thalassemic patients with 1–4 U/ml of EPO for 2 hours increased the GSH content of RBC (2.1-fold) and platelets (1.7-fold) and reduced their ROS (1.5-fold), membrane lipid peroxidation and externalization of PS. Intraperitoneal injection of EPO to heterozygotes (Hbbth3/+) beta-thalassemic mice (3,000U/kg) significantly reduced ROS and increased GSH in their RBC within 3 hours. The in vitro effects of EPO on oxidative stress resulted in reduced sensitivity of thalassemic RBC to undergo hemolysis and phagocytosis by macrophages, and reduced tendency of platelets to undergo activation, as reflected by fewer platelets carrying external PS. Our results suggest that in addition to its effect on erythropoiesis and fetal hemoglobin production, EPO might alleviate symptoms in thalassemia and other hemolytic anemias as a potent antioxidant.
Outcomes of Second Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Children.
Authors: Schechter Tal , Avila Laura , Dupuis L.Lee , Pollock-BarZiv Stacey , Gassas Adam , Finkelstein Yaron , Armstrong Christine , Doyle John J. 
Published: October 2019

Abstract
Introduction: Relapse of the malignancy, secondary malignancy and rejection of the graft (GF) remain important risk factors for mortality after HSCT. The optimal treatment strategy for GF is second HSCT, but for recurrent malignancy it has yet to be determined; however, second HSCT provides a chance for long term survival. This study reports outcomes and clinical experience of HSCT retransplantation in pediatric patients with GF, relapse or secondary malignancy after primary HSCT.
Methods: Outcomes of all pediatric recipients of second HSCT for recurrent malignancy or GF between June 1, 1996 and June 30, 2006 at SickKids Hospital were reviewed. Demographic data, the conditioning regimen chosen, morbidity and mortality after second HSCT were described. EFS was defined as evidence of relapse of malignancy or failure to engraft. Univariate analysis was utilized to assess factors that may influence survival.
Results: Forty-one children (25 male; median age 7.8yrs (range 0.6–17.5yrs)) received a second HSCT during the study period. Initial diagnosis was malignancy in 25 (AML/MDS-11, ALL-6, lymphoma-4, CML-3, JMML-1) and nonmalignant disease in 16 (SAA-4, SCID-4, inherited marrow failure symdrome-5, HLH- 1, MPS-1, thalasemia-1). Indications for second HSCT were: malignancy (recurrent/ secondary) in 21 and GF in 20. Mean time to second HSCT in children with GF was 10.5 months (range: 0.8–57.2 months) compared to 22.7 months (range: 10.1–58.1months) for malignancy (p=0.004). All patients transplanted for malignancy received the second HSCT ≥ 6 months from the first HSCT and only 5 (24%) were transplanted within a year from first HSCT. 8 patients (40%) receiving a second HSCT for GF were retransplanted within the first 6 months. Conditioning regimens at second HSCT included myeloablative treatment (23); reduced intensity (RIC) (16) and none (2). The following factors were not statistically associated with survival: underlying disease, type of conditioning regimen (myeloablative vs reduced intensity) and indication for second HSCT (GF vs. malignancy). Overall survival (OS) and EFS rates are summarized below. Non-relapse related mortality was 45%; 9 patients died from infections.
parameters OS EFS Underlying disease Malignant 0.37±0.1 Non-Malignant 0.49±0.13 p=0.64 Reason for second HSCT Recurrent/secondary malignancy 0.43±0.11 Graft failure 0.42±0.12 p=0.69 Conditioning regimen Myeloablative 0.48±0.1 Reduce-intensity 0.33±0.13 p=0.3 All patients 0.425 0.44
Discussion and conclusion: Children who underwent second HSCT had an OS of 43%. We conclude that a second HSCT can result in prolonged EFS in children relapsing more than 6months after first HSCT and provides an acceptable therapeutic option for patients with GF.
Defibrotide in Prevention of Liver Toxicity in Patients at High Risk of VOD after HSC Transplantation.
Authors: Milone G. , Poidomani M. , Coppoletta S. , Mauro E. , Marturano E. , Crispi F. , Spadaro A. , Di Marco A. , Leotta S. 
Published: October 2019

Abstract
Defibrotide has been proposed as preventive treatment of Veno Occlusive Disease (VOD), data on its use are, however, limited and its effectiveness not yet demonstrated. We have administered Defibrotide as prevention of VOD in pts treated with HSC transplantation because of haematological malignancies, all patients were at high VOD risk because of hyper-ferritinemia (>800 ng/ml) or because not in CR of their underlying disease at time of transplant or being overweight (Actual BW>20% of Ideal BW) or because Hepatitis virus B or C sero-positive. 120 pts were treated with Defibrotide, 77 pts received allogeneic HSC tx and 43 autologous HSC tx, 105 received a myeloablative conditioning (55 pts it was based on busulfan) and 15 pts received a RIC. 48% of patients were affected with Acute leukemia, 23% with Lymphomas, 17% with Multiple Myeloma, 12% by other malignancies. Defibrotide was administered i.v. at dosage of 600 mg/d. from the day of conditioning was started to day +25 together with heparin at low dose (100 IU/Kg c.i.).
RESULTS: after prophylaxis with Defibrotide a bilirubin value above 2.5 mg/dl during the first 30 days was observed in 16/120 pts (13%), 7/120 pts (5%) reached Seattle’s VOD criteria but had spontaneous resolution of liver toxicity, only 1 patient (0.8%) had a severe VOD and MOF. Overall survival at 3 years was 60% and it was 54% in allo-transplanted patients. We compared results with those obtained in a group of 78 pts treated by allogeneic or autologous transplants and who received low dose heparin only and not Defibrotide because they were considered at low risk of VOD. Percentage of pts who developed a bilirubin level > 2.5 mg/dl (p=0.12) and percentage of patients that reached criteria for VOD were not different (p= 0.08) in these two groups, numbers of red blood cell transfusions were comparable (p=0.07). When all the 198 studied patients were analyzed using logistic regression for factors important in the development of a bilirubinemia above 2.5 mg/dl we found to be important: use of MTX as prophylaxis of GVHD (P=0.004; Odds ratio 5,153), allogeneic transplant (P=0.007; Odds ratio 7,127) and baseline value of bilirubin (P=0.02; Odds Ratio 4,690).
Conclusions: Use of Defibrotide in prophylaxis of VOD after HSC transplantation is safe and when employed in patients at high risk of VOD, it leads to an incidence of severe VOD below 1% with a frequency of liver toxicity equivalent to that found in patients having low risk features. To conclude on efficacy of Defibrotide in comparison to low dose heparin alone, a large randomised comparison is warranted.
Outcomes for Unrelated Donor Hematopoietic Cell Transplantation (URD-HCT) for Patients with Acute Lymphoblastic Leukemia (ALL) Using Fractionated Total Body Irradiation (FTBI) and Etoposide (VP16).
Authors: O’Donnell Margaret , Parker P , Dagis A , Slovak ML , Snyder D , Stein A , Spielberger R. , Pawlowska A , Rosenthal J , Palmer J , Kogut N. , Forman S. J 
Published: October 2019

Abstract
Although treatment outcomes for adult ALL remain stagnant at 35–40% 5 yr event free survival (EFS), allogeneic transplant particularly from unrelated donors has frequently been reserved for patient beyond first complete remission (CR1) with the exception of patients with a t(9;22) or Philadelphia (Ph+) cytogenetic abnormality. Between 4/1/2001 and 11/14/2007, 67 patients with ALL received URD-HCT; disease status at HCT was (CR1) in 27 pts (40%), CR2 in 20 pts (30%) and advanced disease (AD) which included induction failure, relapse or CR3 in 20 pts (30%). Age ranged from 2–58 yrs with median age of 29.5 yr. One third of the patients were Ph+. An additional 18 pts had high or very high risk cytogenetics abnormalities. The majority (≥75%) of Ph+ patients had received Gleevec prior to HCT. The conditioning regimen was FTBI 1320 Gy given as 11 fractions over four days followed by VP-16 60 mg/kg. Graft vs. host disease (GVHD) prophylaxis was tacrolimus (FK) and methotrexate (MTX) in 20 pts; sirolimus (Siro) was added to this regimen in 15 pts. Other GVHD regimens used were FK, MTX and Cellcept (12 pts) FK and siro (4 pts) and anti thymocyte globulin was added in 11 pts. Graft source was marrow in 12 pts and peripheral blood stem cells in 55 pts. Median time to ANC > 500 was 17 days (range 11–36d) and for platelets was 24 days (range 15–218d). Three patients died prior to day 18 of infectious complications and were considered unevaluable for engraftment. The incidence of acute GVHD Grade II-IV was 57% with Grade III-IV in 18%. Chronic GVHD occurred in 52% of 56 patients at risk. Treatment related mortality was 16% at 100 days and 28% at 1yr. At two years the event free survival (EFS) was 58% for CR1 pts vs 23% for CR2 and 17% for AD. Relapse rates were 18%, 24% and 40% respectively EFS was 62% at 2 yrs for Ph- pts and 50% for Ph+ in CR1 vs 19% for pt > CR1 who were Ph-and 40% for Ph+ (p=0.31). Remission status (CR1 vs > CR1) was a significant predictor of survival (p=0.01) and EFS (p=0.03) in multivariate analysis while age and Ph+ status had no impact on survival end points.
Conclusion: The preparative regimen of FTBI and VP16 offers 2 yr EFS rates of 50–60% in patients receiving URD-HCT in CR1, including patients with Ph+ and other high risk cytogenetic risk groups. These results are comparable to those reported with sibling donor transplants and provide a curative option for patients in CR1 lacking a family donor.
Figure Figure
Reduced-Intensity Conditioning for Allograft (RICT) after Cytoreductive Autograft (ASCT) in Relapsed/Resistant Hodgkin’s Lymphoma (HL)
Authors: Carella A. M. , Todisco E. , Castagna L. , Santoro A. , Catania G. , Nati S , Congiu A , Vimercati R , Rossi E , Spriano M , Varaldo R 
Published: October 2019

Abstract
Reduced-intensity conditioning for transplant (RICT) aims to exploit graft vs lymphoma (GvLy) effects while reducing conditioning-related toxicity. Because GvLy responses might be insufficient when HL are bulky and lymphoma growth is rapid, we pionered that intensive cytoreduction prior to RICT may allow GvLy reaction to be exploited (Carella et al. JCO2000; 18:3918). Thirty-eight patients with relapsed (n=26) or refractory (n=12) HL underwent RICT from an HLA-identical sibling preceeded by ASCT. Previous therapy consisted of 2–6 lines. High-dose therapy with ASCT consisted of BEAM protocol (n=29) or melphalan 200 mg/m2 (n=9). RICT consisted of fludarabine-cyclophosphamide (n=30) or fludarabine-melphalan (n=8). The two groups had similar prognostic factors. The median time to neutrophils and platelets recovery was 10 days and 16 days, respectively. Chimerism studies indicated 100% donor-derived engraftment. Day 100 and cumulative (2 yrs) TRM were 5,3 % (2 pts) and 18% (7 pts), respectively. Seventeen patients (44%) are alive (12 in complete remission and 5 with stable disease) with a median follow-up of 41 months (7–110 months). Twenty-one patients expired (TRM n=7, disease progression n=14). In conclusion, tandem ASCT/RICT is feasible and effective salvage therapy for patients with advanced HL. The long-term results obtained appear encouraging.
Higher Incidence of Relapse with Peripheral Blood Rather Than Marrow as a Source of Stem Cells in Adults with Acute Myelocytic Leukemia, but Not in Adults with Acute Lymphocytic Leukemia Autografted during the First Remission
Authors: Gorin Norbert C , Labopin Myriam , Polge Emmanuelle , Samey Benedicte , Rocha Vanderson 
Published: October 2019

Abstract
The cell source for autologous stem cell transplantation has shifted since 1994 from bone marrow (BM) to peripheral blood (PB). However, no study has compared outcomes. We analyzed 2165 adults with acute myelocytic leukemia (AML) and 1545 adults with acute lymphocytic leukemia (ALL) in first complete remission (CR1) who received autografts (AML: 1607 PB and 558 BM, ALL: 1126 PB and 416 BM) from 1994 to 2006.
AML: Relative to the time of CR1, PB transplants were performed earlier than BM transplants. Since a poorer outcome was associated with a shorter interval from CR1 to PB transplantation, patients were divided into three groups: BM, early PB (≤ 80 days after CR1) and late PB transplants. BM recipients were younger, and more received total body irradiation. In multivariate analysis, transplant-related mortality was not different among groups, but relapse incidence (RI) was higher for early PB (p = .0006) and late PB (p = .01) compared to BM (56 ± 3%,.46 ± 2%, 39 ± 2% respectively). Earlier PB (p= .02) and later PB transplants (p= .06) were associated with a lower three year LFS rate than marrow (36± 3%, 46 ± 2%, 52± 2% respectively).
ALL:: In multi variate analysis the only poor prognostic factors were a high white cell count at diagnosis and cytogenetics (presence of the Phi/bcr-abl). The RI and LFS at 2 years were identical in patients receiving BM and PB ( 45 ± 3% vs 47 ± 2% and 47 ± 3% vs 46 ± 2% respectively)
In conclusion, in AML patients autografted in CR1 but not in ALL, risk of relapse was lower with BM than with PB, independent of the CR1 to transplantation interval.
Double Transplantation with Melphalan (200 mg/m2) Compared with Triple Transplantation with Intermediate Dose Melphalan (100 mg/m2) in Patients with Multiple Myeloma
Authors: Ludwig Heinz , Spicka Ivan , Linkesch Werner , Greil Richard , Kasparu Hedwig , Gunsilius Eberhard , Thaler Josef , Drach Johannes , Kuhn Ingrid , Weiβmann Adalbert , Hinke Axel 
Published: October 2019

Abstract
Previous studies showed a survival advantage of double over single transplantation in proportion of patients. In this study we aimed to explore whether triple transplantation with intermediate melphalan 100mg/m2 (M100) yields at least similar treatment results with less toxicity than double transplantation with melphalan 200mg/m2 (M200). 219 Patients were entered in the study and started on 3 cycles of VAD induction therapy followed by IEV (ifosfamide (2g/m2)-etoposide (150mg/m2), d1-3; epirubicin (50mg/m2) d1) and G-CSF (5mg/kg) from d4 for stem cell priming and collection. Thereafter, 178 patients were randomized to either double or triple transplantation with M200 or M100. Reasons for non-randomization were PD (n=21), toxic side effects during induction or insufficient mobilization (n=9), withdrawal of consent (n=3), too early (n=1), death (n=1), second neoplasia (n=1), protocol violation (n=2), other (n=3). Patients achieving better than PD had subsequently been randomized to prednisolone plus interferon-a2b (Schering Plough) 3MU TIW or to interferon only maintenance therapy. Median age was 58 years (range: 27–71 years, n=172). DS stage I: 7%, stage II: 18%, stage III: 75%, M-component: IgG: 60%, IgA: 24%, IgD: 1%, IgM: 1%, light chain: 11%, non-secretory:1%. QoL was assessed with the EORTC QLQ C30 instrument. Chi2 test for trend was used for comparison of response and survival endpoints were estimated by the Kaplan-Meier product limit method. Median follow up is 34 months. Response rates in 186 patients evaluable for response after VAD (≥ 2 cycles of VAD) were: CR: 10%, PR: 58%, SD: 21% and PD: 11%. Median time from start of VAD to start of transplantation was 141 in the double and 144 days in the triple transplantation arm. Response rates after transplantation did not differ between pts treated with double or triple transplantation (CR: 41% vs. 41%, PR: 50% vs. 49%, SD 8% vs. 8%, PD: 1% vs. 3%, p=0.91. Median PFS for both groups combined was 39 mos, but showed a tendency for shorter PFS in pts on triple transplantation (median 44 mos. vs. 38 mos; HR 1.18, 95% CI: 0.77–1.81, p=0.22). Median OS has not been reached as yet, but did not differ between both groups with 3-year rates of 85% and 81%, respectively, and a HR of 1.01. Except for more cases of grade 1 and 2 anemia in the triple transplantation arm, hematological toxicity was similar in both groups. There was a tendency for more grade 2–3 mucositis and grade 3–4 vomiting, nausea in the double transplantation group. In conclusion, triple transplantation with intermediate dose M resulted in similar response rates, slightly shorter PFS but similar OS and was associated with less mucositis and slightly less vomiting, and nausea.
Figure Figure
Superior Incidence of Progression-Free Survival (PFS) Following High- Dose Melphalan (HDM) and Autologous Stem Cell Transplant (ASCT) for Multiple Myeloma (MM) Patients Receiving Pre-Transplant Induction with IMiDs Versus Conventional VAD Induction Chemotherapy.
Authors: Holland H. Kent , Solomon Scott R. , Bashey Asad , Morris Lawrence E. 
Published: October 2019

Abstract
Previous randomized trials evaluating the benefit of high-dose Melphalan and ASCT for MM patients receiving conventional induction chemotherapy have demonstrated that patients who achieve either a CR or VgPR post transplant have a superior PFS and overall survival (OS) compared to those who do not. We report on our 6-year experience comparing the outcome benefit of newly diagnosed MM patients who received either conventional VAD versus IMiDs based induction pre-transplant therapy and the impact on response on 112 consecutive patients transplanted between 5/2002 through 2/2008. The median age was 58 years (33–74). Disease status was Stage III in 92 (82%), Stage II in 11 (10%) and Stage in 9 (8%) patients. Conventional VAD induction chemotherapy was administered pre-transplant in 36 patients and IMiDs (thalidomide, lenalidomide) based therapy in 76 patients. Single ASCT was administered in 78 patients and Tandem ASCT in 34 patients (8 received conventional therapy and 26 received IMiDs, p=NS). Pre-transplant achievement of CR/VgPR was observed in 1/36 (1%) of patients receiving VAD chemotherapy and in 15/76 (20%) of patients receiving IMiDs (p=.017). Post-transplant, 5/36 (14%) patients that received VAD conventional therapy and 39/76 (51%) that received IMiDs achieved CR/VgPR (p=.002). Patients that entered into a CR/VgPR had both a superior PFS and OS (Median PFS 1,118 days vs. 670 days, p=.02/HR.49; Median OS “Not achieved” vs. 1,387 days, p=.05/HR 0.36). Single vs. Tandem transplant had no impact on outcome. These observations support the use of IMiDs as pre-transplant induction therapy over historical VAD chemotherapy.
Figure Figure