bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preliminary Results of a Prospective Multicenter Phase III Trial Comparing High-Dose and Standard-Dose Daunorubicin for Induction of Complete Remission (CR) in Acute Myeloid Leukemia (AML).
Authors: Lee Je-Hwan , Joo Young-Don , Park Jae-Hoo , Ryoo Hun Mo , Hyun Myung Soo , Zang Dae Young , Ahn Jin Seok , Lee Junglim , Lee Kyeong Won , Choi Seong-Jun , Lee Jung-Hee , Seol Miee , Kim Keun-Hee , Lee Won-Sik , Min Young Joo , Kim Hawk , Bae Sung-Hwa , Kim Min Kyung , Kim Hyo Jung , Lee Kyoo-Hyung 
Published: April 2020

Abstract
The effectiveness of anthracycline dose intensification for induction of CR in AML has not been studied in a randomized fashion. We conducted a prospective randomized trial to compare the therapeutic efficacy and toxicity of two different doses of daunorubicin in combination with cytarabine in AML. This study began on August 2001 and 293 adult patients (younger than 60 years) with newly diagnosed AML except M3 have been enrolled. Fourteen patients were removed from the study and the remaining 279 patients were analyzed. After random assignments, 135 patients received standard-dose daunorubicin (SD-DN, 45 mg/m2/d × 3 d) and 144 patients received high-dose daunorubicin (HD-DN, 90 mg/m2/d × 3 d) in addition to cytarabine (200 mg/m2/d × 7 d) for induction of CR. Patients with persistent leukemia received the second attempt of induction chemotherapy, consisting of standard-dose daunorubicin (2 d) plus cytarabine (5 d). Patients who attained CR received 4 cycles of high-dose cytarabine (3 g/m2 × 6 doses) and 2 cycles of daunorubicin (1 d) plus cytarabine (5 d). For patients in intermediate- or high-risk cytogenetic groups, allogeneic hematopoietic cell transplantation was performed if there was a suitable donor. CR was induced in 98 of 135 patients (72.6%) in SD-DN arm and 119 of 144 (82.6%) in HD-DN arm (P = 0.044). The impact of daunorubicin dose intensification on the CR rates were different by cytogenetic risk group: the CR rates for SD-DN vs. HD-DN arm were 24/25 (96.0%) vs. 35/36 (97.2%) for good-risk group, 63/88 (71.6%) vs. 64/83 (77.1%) for intermediate-risk group, and 10/20 (50.0%) vs. 19/24 (79.2%) for poor-risk group. With a median follow-up of 596 days for surviving patients, the 4-year probabilities of overall survival, disease-free survival, and relapse-free survival were similar between SD-DN and HD-DN arm. Two different doses of daunorubicin (SD-DN vs. HD-DN) showed similar toxicity profiles regarding recovery times from myelosuppression, transfusion requirements, severe toxicities (grades III to IV) classified by NCI-CTC ver 2.0 including cardiac toxicities, and duration of antibiotics administration. In conclusion, high-dose daunorubicin showed higher CR rates in AML patients of intermediate- and poor- cytogenetic risk groups without increase of toxicities compared to standard-dose daunorubicin.
An Open Label, Dose Escalation Study of AVE9633 Administered as a Single Agent by Intravenous (IV) Infusion Weekly for 2 Weeks in 4-Week Cycle to Patients with Relapsed or Refractory CD33-Positive Acute Myeloid Leukemia (AML).
Authors: Legrand Ollivier , Vidriales Maria B. , Thomas Xavier , Dumontet Charles , Vekhoff Anne , Morariu-Zamfir Rodica , Lambert John , San Miguel Jesus F. , Marie Jean-Pierre 
Published: April 2020

Abstract
AVE9633/huMy9-6-DM4 is an immunoconjugate composed of a humanized monoclonal IgG1 antibody, huMy9-6, which specifically targets the CD33 antigen, conjugated through a disulfide link to the maytansine derivative DM4, a potent tubulin inhibitor. The CD33 antigen is expressed on the surface of myeloid cells. After the conjugate is bound to the CD33 antigen it is internalized and the cytotoxic is released within the target cell. We report preliminary results of the ongoing phase I dose escalation study of AVE9633 in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 and Day 8 of a 28-day cycle. To date, dose levels of 30 (n=1), 50 (n=3), 75 (n=3), 105 (n=3) and 130 (n=3) mg/m2 on Day 1 and Day 8 have been investigated. Patients received 1 (n=2), 2 (n=5), 3 (n=2) and 4 (n=4) cycles of AVE9633. No dose-limiting toxicity was noted so far. Nine patients experienced mild to moderate infusion reactions, mostly on Day1 of Cycle1. One patient at 130 mg/m2 presented grade 3 ALT elevation of 3 days duration. Free DM4, measured by LC/MS/MS was detectable at 105 and 130 mg/m2 in the range of 5 to 10 ng/mL. AVE9633/huMy9-6-DM4 exposure (measuring, by ELISA method, all antibodies containing at least one molecule of DM4) increased proportionally with the administered dose. Using Flow Cytometry Assay, saturation and down regulation of CD33 on peripheral and marrow blasts were observed from the dose of 50 mg/m2. There was one CRp in a 68-year old woman with refractory AML, achieved after 4 cycles of AVE9633 given at 105 mg/m2 × 2, with a 4-month continuing CRp as of 7/07 (she is receiving AVE9633 105 mg/m2 once monthly). One PR occurred in a 81-year old woman with refractory AML after one cycle at 130 mg/m2 × 2, persistent after the second cycle (third cycle is ongoing). Two patients had &gt;50% decrease in bone marrow blasts, at 105 mg/m2 × 2 (from 25% to 8% after two cycles) and at 130 mg/m2 × 2 (from 35% to 9% after one cycle). One additional patient at 75 mg/m2 × 2 presented clearance of peripheral blasts by Day 10 of Cycle1. Mean DM4/IgG on the surface of peripheral blasts (available for one patient at 130 mg/m2) progressively decreased after the infusion, from 3.09 on day 1 to 0.28 on Day 8, and then increased to 2.64 after the second infusion of AVE9633 on Day 8. These preliminary results show that AVE9633 is well tolerated, with manageable safety profile, allowing outpatient treatment. Evidence of anti-leukemia activity was observed in 5 patients. The study is continuing with the evaluation of 150 mg/m2 × 2. Evaluation of closer drug administrations which might enhance efficacy appears warranted.
Safety and Efficacy of Alfimeprase in Subjects with Occluded Central Venous Access Devices: The SONOMA-2 Study.
Authors: Moll Stephan , Gabrail Nashat , Buchanan Jim , Hirmand Mohammad , Levy Michael , Zitnik Ralph 
Published: April 2020

Abstract
Introduction: The infusion of chemotherapy and blood products is facilitated by central venous access devices (CVAD), and the occurrence of thrombotic CVAD occlusion results in delays in these crucial therapies. Alfimeprase is a direct-acting thrombolytic agent with the potential to rapidly re-establish catheter function.
Methods: SONOMA-2 was a multicenter, multinational, randomized, double blind, placebo-controlled phase 3 study evaluating the efficacy and safety of alfimeprase in subjects with occluded CVADs. Subjects were randomized in a 2:1 ratio to receive either intra-luminal alfimeprase (A) at a dose of 3.0 mg or placebo (P). Study drug was delivered in a total volume of 2 mL. If re-establishment of catheter function was not established within 30 minutes, a second dose of the same study drug was instilled and allowed to dwell for an additional 30 minutes. Re-establishment of catheter function was assessed by an attempt to withdraw 3 mL of blood and infuse 5 mL of saline. The primary efficacy endpoint was re-establishment of a functional CVAD at 15 minutes post first infusion. The primary efficacy analysis prespecified a significance level of ≤ 0.00125.
Results: A total of 303 patients (201 (A), 102 (P)) were randomized into the study. Treatment groups were well balanced at baseline with respect to overall demographics, catheter insertion site, and median days since last failed infusion or blood draw. The primary efficacy endpoint, re-establishment of a functional CVAD at 15 minutes post first infusion, was achieved in 34.3% (A) versus 21.6% (P) of subjects (p = 0.022). The cumulative proportion of subjects with re-establishment of a functional CVAD at 30 minutes post first or second infusions was 52.7% (A) versus 30.4% (P) (p = 0.0002). Rates of adverse events (65.8% (A), 59.4% (P)), serious adverse events (15.5% (A), 16.8% (P)), and hemorrhagic adverse events (3.6% (A), 10.9% (P)) were comparable between treatment groups. No intracranial hemorrhages were observed.
Conclusions: Alfimeprase restored CVAD function in a numerically greater fraction of subjects than did placebo; however, the study did not achieve statistical significance for the primary endpoint at the prespecified p-value of ≤ 0.00125 necessary for demonstrating efficacy with a single pivotal study. Alfimeprase was well tolerated. Further clinical studies are underway that evaluate a higher and more concentrated alfimeprase dose which preclinical studies predict will result in greater efficacy. Alfimeprase remains a promising potential candidate for use in patients with CVAD occlusion.
Time of Relapse after Initial Therapy Significantly Adds to the Prognostic Value of the IPI-R in Patients with Relapsed DLBCL Undergoing Autologous HSC Transplantation.
Authors: Costa Luciano J. , Micallef Ivana N. , Inwards David J. , Johnston Patrick B. , Porrata Luis F. , Ansell Stephen M. 
Published: April 2020

Abstract
Background: High-dose chemotherapy and hematopoietic stem cell (HSC) transplantation is curative in about 40% of patients with relapsed chemosensitive diffuse large B cell lymphoma (DLBCL). The international prognostic index obtained at the time of relapse (IPI-R) and the time from initial treatment to relapse (TTR) have been suggested in different series to be predictors of outcome after HSC transplantation. We explored the concomitant effect of IPI-R and TTR on therapeutic outcome in a modern and uniform cohort of patients with relapsed chemosensitive DLBC undergoing high-dose chemotherapy and peripheral HSC transplantation.
Methods: Retrospective analysis of 80 consecutive patients treated at Mayo Clinic, Rochester, MN between 2001 and 2006 who received a peripheral HSC transplant (except for 3 patients who receive bone marrow) after being conditioned with BCNU, etoposide, cytarabine and melphalan (BEAM) for relapsed chemosensitive DLBCL.
Results: Median follow-up of survivors was 31.4 months, Median age at the time of transplant was 62 (interquartile range 53–65; range 26–77), 65% were males; median number of prior chemotherapy regimens was 2. All patients had received at least one previous anthracycline-based regimen, 78% had been previously exposed to rituximab and all achieved at least CRu after the initial treatment. The median time from diagnosis to relapse was 19 months (interquartile range 10–43), 25% of patients had a high or high-intermediate IPI-R. The median survival from the time of transplant for patients with TTR&gt;18 months v. ≤ 18 months was not reached and 50 months respectively (P=0.005). Median survival for patients with high or high-intermediate IPI-R at the time of relapse (IPI score ≥3) was 23.3 months and not reached for patients with low or low-intermediate IPI (P=0.01). These two factors were independent in multivariate analysis with RR for death of 1.8 (1.2–2.9; P=0.004) for TTR ≤ 18 months and 1.7 (1.1–2.5; P=0.017) for high or high-intermediate IPI and therefore combined in a prognostic system were patients with none (n=32), one (n=39) or two (n=9) of these prognostic factors had median disease free survival not reached v. 50 months v. 3.3 months (P=0.001) and overall survival not reached v. 50 months v. 5 months (P=0.0001) (Figure).
Conclusion: TTR and IPI-R provide an easy and powerful prognostic system in patients with DLBCL undergoing modern high-dose chemotherapy with HSC support.
Figure Figure
Multicenter Phase II Trial of 90Y-Ibritumomab Tiuxetan with High-Dose Chemotherapy (Busulfan/Cyclophosphamide/Etoposide) Followed by Autologous Stem Cell Transplantation in Relapsed, Refractoried, or High-Risk B-Cell NHL.
Authors: Kang Byung Woog , Jo Jae-Cheol , Kim Shin , Jang Geundoo , Lee Sung Sook , Sym Sun Jin , Ryu Jin-Sook , Kim Won Seog , Yoon Sung Soo , Suh Cheolwon 
Published: April 2020

Abstract
The need of new effective regimen for high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in aggressive B-cell non-Hodgkin’s lymphoma (NHL) patients and promising results observed so far in trials with 90Y-Ibritumomab tiuxetan containing regimens in ASCT strongly warrants the investigation of 90Y-Ibritumomab tiuxetan combined busulfan/cyclophosphamide/etoposide (Z-BuCyE) high-dose chemotherapy with ASCT for relapsed, refractoried, or high-risk B-cell NHL. We evaluated efficacy and safety of the combination of Z-BuCyE and ASCT in patients with relapsed, refractoried, or high-risk B-cell NHL. Treatment consisted of two doses of Rituximab (250 mg/m2, IV, day -21, -14) and a single dose of 90Y-Ibritumomab (0.4 mCi/kg, IV, day -14). All patients received conditioning regimen: busulfan (3.2 mg/kg, IV, day -7, -6, -5), etoposide (200 mg/m2, IV, day -5, -4), and cytoxan (50 mg/kg, IV, day -3, -2) followed by ASCT (day 0). Thirteen patients were entered the trial. The median age was 46.1 years (range: 25–60), and 6 (46%) patients were male. Histology was diffuse large B-cell (n=10), follicular (n=1), Burkitt (n=1), and mantle cell lymphoma (n=1). The objective overall response rate (ORR) was 76.9% (10/13): continued CR, 38.5% (5/13); induced CR, 23.1% (3/13); continued or induced PR, 15.4% (2/13). Three patients (23.1%) had a PD after transplantation and two of these patients died of progression. Median follow-up duration was 6.0 months. Median progression-free survival (PFS) and median overall survival (OS) has not yet been reached. Toxicity was principally non-hematologic. Grade 2 toxicity included mucositis (53.8%), nausea (61.5%), vomiting (15.4%), diarrhea (23.1%), and elevation of liver enzyme (7.7%). Grade 3 toxicity included mucositis (15.4%), nausea (23.1%), and diarrhea (23.1%). There was no grade 4 toxicity. Infection occurred in ten patients, bleeding in one patient, and there was no treatment related mortality. This preliminary analysis shows that the combination of Z-BuCyE and ASCT has excellent efficacy and is well-tolerated treatments for relapsed, refractoried or high-risk B-cell NHL. This study will be continued till 20 patients enrollment.
Retroviral Vector-Producing Mesenchymal Stem Cells for Tumor Tracking and Therapeutic Gene Amplification in Suicide Cancer Gene Therapy.
Authors: Uchibori Ryosuke , Okada Takashi , Ito Takayuki , Urabe Masashi , Mizukami Hiroaki , Kume Akihiro , Ozawa Keiya 
Published: April 2020

Abstract
Mesenchymal stem cells (MSCs) are known to have a tendency to accumulate at the site of tumors, and therefore can be utilized as a platform for targeted delivery of anti-cancer agents. The MSC-based targeted cancer gene therapy can enhance the therapeutic efficacy, because MSCs are considered to reach tumors including metastatic lesions and to deliver therapeutic molecules in a concentrated fashion. This targeted therapy can also reduce systemic adverse side effects, because the anti-cancer agents act locally at the site of tumors without elevating their systemic concentrations. In the present study, we developed genetically-modified MSCs that produce retroviral vectors encoding HSVtk, aiming at augmenting therapeutic efficacy of systemic suicide cancer gene therapy. The tumor tropism and anti-tumor effects of vector-producing MSCs (VP-MSCs) were examined by intravascular injection in tumor-bearing nude mice. MSCs isolated from the bone marrow of SD rats were transfected with plasmid DNA expressing luciferase alone (=non-VP-MSCs) or whole retroviral vector components (LTR-Luc or LTR-HSVtk with Gag-pol and VSV-G) (=VP-MSCs) by nucleofection. To assess tumor tropism of MSCs, nude mice were subcutaneously inoculated with 9L rat glioma cells or Rat-1 fibroblasts, and were subsequently injected with luciferase-expressing MSCs through the left ventricular cavity. The transgene expression was periodically traced by using an in vivo imaging system. As a result, the transgene expression accumulated at the site of subcutaneous 9L tumors, but undetectable at the site of Rat-1 fibroblasts. In addition, the injection of luciferase-expressing VP-MSCs caused much stronger signal of bioluminescence at the site of 9L tumors compared with luciferease-expressing non-VP-MSCs. Immunostaining study showed that luciferase-positive cells (injected MSCs and transduced glioma cells) were detected at the periphery of tumors. To evaluate the therapeutic efficacy, tumor-bearing nude mice were treated with non-VP-MSCs or VP-MSCs combined with HSVtk/GCV system and then the size of subcutaneous tumors was periodically measured. In this model experiments, tumor growth was more efficiently suppressed by injecting VP-MSCs compared with non-VP-MSCs. The present study suggests the effectiveness of VP-MSCs in suicide cancer gene therapy. The therapeutic benefit of this strategy should be further examined in orthotopic and metastatic tumor models.
Mesenchymal Stromal Cells (MSCs) Acquire Cardiac-Specific Markers but Do Not Become Functional Cardiomyocytes and Retain the Stromal Phenotype.
Authors: Rose Robert A. , Jiang Huije , Wang Xing Hua , Helke Simone , Tsoporis James N. , Gong Nanling , Keating Stephanie C.J. , Parker Thomas G. , Bacx Peter , Keating Armand 
Published: April 2020

Abstract
Although marrow-derived MSCs may be beneficial in treating models of ischemic heart disease, their ability to transdifferentiate into functional cardiomyocytes remains unclear. MSCs from female transgenic mice expressing green fluorescent protein (GFP) under the control of the cardiac-specific α-myosin heavy chain promoter were co-cultured with male rat embryonic cardiomyocytes (rCMs). This novel in vitro model permits identification and functional analysis of putatively transdifferentiated MSCs based on GFP expression. In co-culture, 6.3% of MSCs became GFP+. Quantitative PCR using murine-specific primers revealed that co-cultured MSCs express the cardiac-specific genes atrial natriuretic factor, Nkx2.5 and α-cardiac actin. Furthermore, immunohistochemistry on GFP+ MSCs established co-expression of the sarcomeric proteins troponin I and α-actinin, but without a clear sarcomeric pattern. Despite expression of cardiac genes, patch-clamp experiments illustrate that GFP+ MSCs did not fire action potentials and did not express voltage gated sodium and calcium currents (INa and ICa). In contrast, action potentials, INa and ICa were readily observed in all GFP− rCMs studied in the co-cultures. When investigated using slow voltage ramps, GFP+ MSCs displayed electrical properties typical of non-excitable cells, suggesting retention of a stromal cell phenotype. Indeed, detailed immunophenotyping of GFP+ MSCs demonstrated expression of all antigens used to characterize MSCs as well as the acquisition of additional markers of cardiomyocytes with the phenotype: CD45− CD34+ CD73+ CD105+ CD90+ CD44+ SDF1+ CD134L+ collagen type IV+ vimentin+ troponin T+ troponin I+ a-actinin+ connexin 43+. Although cell fusion between rCMs and MSCs was detectable by fluorescence in situ hybridization, the very low frequency (0.68%) cannot account for the phenotype of the GFP+ MSCs. In conclusion, we have identified a MSC population that shows plasticity towards the cardiomyocyte lineage but that retains mesenchymal stromal cell properties, including a non-excitable electrophysiological phenotype. The demonstration of a MSC-derived population co-expressing cardiac and stromal cell markers may explain the conflicting results in the literature regarding transdifferentiation and indicates the importance of extensive immunophenotypic and functional analysis of the manipulated cells. The data also infer the need to identify mechanisms other than cardiomyocyte differentiation that underlie the effects of MSCs on myocardial injury.
Isolation of Mesenchymal Stem Cells from Human Bone Marrow Using Aldehyde Dehydrogenase as a Marker.
Authors: Nishimoto Eishi , Yamada Yasuhiro , Miyake Hirosada , Mitsuya Hiroaki , Yonemura Yuji 
Published: April 2020

Abstract
Mesenchymal stem cells (MSCs) represent multipotent stem cells that are capable of self-renewal while maintaining their multipotence and can differentiate into a variety of cell types, including osteoblasts, chondrocytes, myocytes, adipocytes, and beta-pancreatic islets cells. However, the origin and properties of human MSCs remain to be elucidated. Aldehyde dehydrogenase (ALDH) is known to be useful for isolation of hematopoietic stem cells as well as neural stem cells and endothelial progenitors. In this study, we attempted to isolate MSCs from human bone marrow (BM) using ALDH as a marker for MSCs. Mononuclear cells (MNCs) in BM were first sorted to ALDHnegative, ALDHlow, and ALDHhigh cell fractions. ALDHnegative and ALDHlow cells had no colony forming units-fibroblast (CFU-F). ALDHhigh cells represented 1.8±0.8% of MNCs in human BM (n=4) and contained CD45 negative cells (9.9±5.3%). When ALDHhigh CD45+ cells and ALDHhighCD45− cells were cultured with MF start® (TOYOBO, Osaka, Japan), CFU-F was found in the latter cells but not in the former cells. The frequency of CFU-F in ALDHhighCD45− cells and MNCs in BM was 1 in 330 and 13,600, respectively. We found that CFU-F differentiated to adipocytes and osteocytes as examined using the human mesenchymal stem cell functional kit (R&D, Minneapolis) and immunological staining with FABP-4- and osteocalsin-specific antibodies. We also tried to isolate MSCs in human cord blood (CB) and granulocyte-colony stimulating factor (G-CSF)-mobilized peripheral blood (PB). Proportion of ALDHhigh cells was 2.1±0.8% in CB (n=3) and 0.6±0.2% in G-CSF-mobilized PB (n=4). CB ALDHhigh cells contained CD45− cells (14.9±2.8%), but G-CSF-mobilized PB ALDHhigh cells contained only few CD45− cells (1.3±0.8%). CFU-F was seen in CB, while no CFU-F was identified in G-CSF-mobilized PB. The current data demonstrate that ALDHhighCD45− cells can differentiate into adipocytes and osteocytes and that ALDH is a useful marker for isolation of human MSCs.