bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety, Tolerability, and Pharmacokinetic Assessment of CG53135 Administered Intravenously in Patients with Advanced (Stage 4) Cancer (Single Rising-Dose Tolerance).
Authors: Stephenson Joe , Goel Sanjay , Bhargava Pankaj , Vadhan-Raj Saroj , Annino Vincent , Hawthorne Thomas , Halvorsen Yuan-Di , Hahne William 
Published: October 2019

Abstract
Oral mucositis (OM) is a common complication in cancer patients receiving chemotherapy (CT). OM is characterized by damage to the epithelium of the oral-pharyngeal cavity. CG53135-05, a recombinant human fibroblastic growth factor 20 (rhFGF-20) protein, has demonstrated epithelial and mesenchymal cell proliferation stimulating activity in vitro and reduces OM using single doses in a hamster mucositis model. The goal of this dose-escalating tolerance study was to assess the safety, tolerability and pharmacokinetics of CG53135-05 in cohorts of four patients (pts) at 0.03, 0.1, 0.33, and 1mg/kg (concentrations are determined by the UV method which are equivalent to 0.1, 0.3, 1.0, and 3.0 mg/kg by the Bradford method previously used). Dose escalation was stopped due to tolerability information at 0.33 mg/kg delivered in 15 min (reported in another Phase I study) and the protocol was amended to add a 0.2 mg/kg dose. The World Health Organization (WHO) OM and OMAS scoring systems were used to measure the incidence and severity of OM. The interim results are reported: Ten pts received CG53135-05 at 0.03 mg/kg (n=4) or 0.1 mg/kg (n=6) as a single 100-ml intravenous infusion administered 3 days after completion of the CT. After infusion, CG53135-05 reached maximum plasma concentration within 1h. The mean terminal exponential half-life was 49 min (range: 16.2–87 min, n=5). No pts discontinued the trial due to adverse experiences. Adverse events (number pts) that may be related to the study drug include: nausea (2); chills (2); fever (2); vomiting (1); dizziness (1); vision - “lights flashing” (1) and astigmatism (1); neuropathy (1); tachycardia (1); headache (1); and premature atrial complex (1). All reported incidences were mild to moderate. No grade 3 or 4 laboratory toxicity associated with the study drug was noted. Three serious adverse events deemed unrelated to study drug were noted from two pts including cancer progression, catheter infection, and small intestinal obstruction. Among the treated pts, no grade 3 or 4 OM was observed. Three pts developed Grade 2 mucositis that lasted between 1–5 days. No pts required total parenteral nutrition. Approximately 72–84% of pts receiving CPT-11 experience diarrhea. Of the six pts who received CPT-11 as part of CT in this trial, two pts (both receiving 0.03mg/kg of CG53135-05) experienced mild to moderate diarrhea. Conclusions: CG53135-05 is well tolerated with single dose administration at 0.03 and 0.1 mg/kg. Dosing at 0.2 mg/kg is ongoing. The full results of this study will be presented.
The Suppressive Effect of Bone Marrow Mesenchymal Stem Cells on T Cell Activation, Is Deficient in Patients with Severe Aplastic Anemia.
Authors: Bacigalupo Andrea , Valle Marisa , Podesta’ Marina , Pitto Anna , Zocchi Elena , De Flora Antonio , Pozzi Sarah , Vassallo Franca , Lucchetti Silvia , Figari Osvaldo , Frassoni Francesco , Piaggio Giovanna 
Published: October 2019

Abstract
Normal bone marrow derived mesenchymal stem cells (MSC) suppress T cell function, and may provide an immunoprotected environment for hemopoietic stem cells. In this study we compare the suppressive activity on T cell function of MSC from 23 patients with severe aplastic anemia (SAA) patients, at diagnosis (n=3), following immunosuppressive therapy (IS) (n=16) or after an allogeneic bone marrow transplant (BMT) (n=4), and normal individuals. As shown in Figure 1 increasing numbers of control MSC (25, 50 and 100x10^3 cells) produced a dose dependent suppression of PHA induced T cell proliferation; when MSC were derived from SAA patients, they exhibited significantly less suppressive activity (37% vs 6%, 81% vs 24%, 96% vs 35%). The reduced ability of SAA MSC to suppress mitogen induced T cell proliferation, was seen irrespective of disease phase. Paired experiments on mixed lymphocyte reaction confirmed the inability of SAA MSC to suppress T cell function. Other abnormalities of SAA MSC included: (a) impaired capacity to down regulate CD38 expression on PHA primed T cells, (b) impaired ability to suppress gamma-IFN production in PHA coltures, which resulted in a 11 fold different gamma-IFN concentration in the cultures; (c) no effect on T cell mediated inhibition of hemopietic colony formation. Finally SAA MSC produced significantly (1 log) less adenosin diphosphate -ribosyl cyclase (cADPR), a promoter of in vitro hematopoiesis. MSC mediated suppression of PHA induced T cell proliferation, was restored to control levels in 3 of 4 patients post-BMT. In conclusion, the ability of MSC to down regulate T cell priming, proliferation and cytokine release is deficient in patients with SAA, persists indefinitively after immunosuppressive therapy, but may be restored after BMT. Whether this defect plays a role in the pathogenesis of marrow failure, remains to be determined.
Figure Figure
Results of a Phase I/II Randomized Immunotherapy Trial Testing Adoptive Transfer of Co-Stimulated Autologous T Cells and Pneumococcal Conjugate Vaccine (PCV) Immunization after Autotransplantation for Myeloma (MM).
Authors: Cross Alan , Rapoport Aaron P. , Levine Bruce L. , Stadtmauer Edward A. , June Carl H. , Mann Dean , Frasch Carl , Lynch Christian , Badros Ashraf , Chrisley Lisa , Cotte Julio , Mair Rebecca , Hinkle Joanne , Zhang Lei , Edelman Robert 
Published: October 2019

Abstract
Although immunizations against microbial infections are recommended following autologous stem cell transplantation (ASCT), the antibody responses are often suboptimal. To assess improved immunization strategies, we tested the ability of autologous T cells that were co-stimulated ex vivo with anti-CD3 and -CD28 coated beads as part of their therapy for MM, as well as pre-ASCT immunization to enhance the antibody response to PCV post-ASCT. Subjects were randomized to receive PCV (groups 1 and 2) or no immunization (groups 3 and 4) before T cell harvest, and subsequent mobilization chemotherapy. All subjects received PCV at days 30 and 90 post-ASCT; however, groups 1 and 3 were given T cells before (day 12) post-ASCT PCV immunization, while groups 2 and 4 received T cells after PCV immunization (day 100). Patients receiving adoptive T cell therapy for MM without PCV immunization (group 5) served as controls. The results of the adoptive transfer of T cells on MM therapy are reported elsewhere. Anti-pneumococcal (Pn) antibody levels for serotypes 6B, 14, 23F, 19F were measured in sequential samples for up to 180 days for each patient by ELISA (response defined as ≥ 2-fold increase over baseline and ≥ 0.5 μg/ml) and opsonophagocytosis assay (OPA) (response defined as ≥ 1-log bacterial kill or ≥ 70% kill when ≤ 30% kill at baseline).
Groups 1 2 3 4 5 a Numbers of evaluable subjects per group responding by ELISA to 3 or more of 4 pneumococcal serotypes tested. bNumber of evaluable subjects with OPA response to 19F only. T=T cells; D=day;* P=0.02, and** P=0.05 v. group 5 by Fisher’s Test. No. PCV 3 3 2 2 0 T given at D12 D100 D12 D100 D12 ≥3 types 6/7a 3/8 3/9 3/6 1/4 4 types 6/7* 1/8 1/9 3/6 0/4 OPA 8/9b** 5/8 1/8 3/5 1/4
Responses in group 1 were of longer duration and greater magnitude than in other groups. We conclude that (1) MM patients immunized with PCV pre-ASCT respond better to PCV post-ASCT; (2) T cell administration before PCV immunization enhances protective anti-Pn antibody levels and for a longer duration. Our vaccine schedule that leads to improved PCV responses may also be used to improve the responses of ASCT patients to other microbial and perhaps cancer vaccines. (This study was supported by NIH contract N01-AI-85342 and LSA SCOR #7000-002).
Control of Fulminant Juvenile Myelomonocytic Leukemia (JMML) Relapse and Gut GvHD III° with Purinethol Early after Unrelated Donor BMT.
Authors: Stachel Daniel , Gravou-Apostolatou Chara , Kuhlen Michaela , Leipold Alfred , Bader Peter , Beck Jorn , Holter Wolfgang 
Published: October 2019

Abstract
Juvenile myelomonocytic leukemia (JMML) is a rare disease in childhood which can only be cured by stem cell transplantation. The major complication is relapse in up to half of the patients. The existance and efficacy of graft-versus-leukemia (GvL) in JMML is controversial and often associated with severe graft-versus-host disease (GvHD).
A 1,5 year old boy developed JMML and was transplanted from a 1 antigen mismatched UD (unmanipulated bone marrow, 8.5 Mio CD34/kg) after a CR consisting of Bu 16*1.25 mg/kg), Cy (2*60 mg/kg), Mel (1*140 mg/m2) and ATG (3*20 mg/kg). GvH prophylaxis consisted of CsA and very short MTX. The situation was further complicated by the intermittent presence of CMV, HHV-6 and EBV in the peripheral blood which was treated intermittently by intravenous ganciclovir.
Engraftment occurred on day + 16. GvHD III° of the skin only developed and was treated with corticosteroids, CsA and MMF. Chimerism was complete on day +28.
Beginning on day +45 an increasing autologous chimerism was detected. Therefore, immunosuppression was halted. Despite discontinuation of all immunosuppressants the autologous chimerism increased to 60–80% (d +63) and the peripheral leukocytes increased to approx 30,000/μl together with eosinophilia (d +60). Clinical signs of relapse (hepatomegaly and pulmonary obstruction) were also present. Thereafter, within a week, leukopenia and thrombocytopenia developed and the autologous chimerism decreased to 1–5%.
Coinciding with the apparent GvL effect severe GvHD reappeared. Skin GvHD II–III° developed, than gut GvDH III° with massive life threatening fluid and potassium loss (day +73).
In an attempt to treat both JMML and GvHD the antimetabolite purinethol 50 mg/m2 daily was given orally.
Since day + 98 always an complete chimerism was observed. Gut GvHD gradually improved without further immunosuppression. The boy is now at home without evidence of disease or active GvHD more than 1 year after relapse.
We speculate that in this case purinethol controlled not only the severe gut GvHD after BMT but also JMML.
This antimetabolite may therefore be considered as an immunosuppressant for GvHD when malignat relapse is also present or imminent.
Blood Stream Infection after Reduced- Intensity Unrelated Cord Blood Transplantation for Adults with Hematologic Diseases.
Authors: Narimatsu Hiroto , Kami Masahiro , Matsumura Tomoko , Myojo Tomohiro , Masuoka Kazuhiro , Inokuchi Chiho , Yuji Koichiro , Miura Yuji , Kusumi Eiji , Ueyama Junichi , Wake Atsushi , Miyakoshi Shigesaburo , Yoneyama Akiko , Matsuzaki Michio , Morinaga Shinichi , Muto Yoshitomo , Taniguchi Shuichi 
Published: October 2019

Abstract
<Introduction>
Blood stream infection (BSI) is a major problem after cord blood transplantation (CBT). However we have little information on it after reduced-intensity cord blood transplantation (RICBT).
<Objective>
This study aims to investigate clinical characteristics of BSI within 100 days of RICBT, and to identify its risk factors in the patient who received RICBT between January 2002 and March 2004 in Toranomon hospital.
<Characteristics of patients and cord blood units/ Transplantation>
We reviewed medical records of 77 patients with advanced hematologic diseases who underwent RICBT at Toranomon Hospital between January 2002 and June 2004.
Median age of the patients was 55 years (17-79). Median number of infused cells and CD34+ cells were 0.86 x 10E7 (range; 1.73–4.31) and 0.8x10E7/kg (range; 0.01–46.1), respectively. Conditioning regimen consisted of fludarabine (125–150 mg/m2), melphalan (80–140 mg/m2), and TBI 2–8 Gy. GVHD prophylaxis was cyclosporine or tacrolimus. BSI must have met at least one of the following criteria previously described. (O’Grady, NP et al., Infect Control Hosp Epidemiol 2002)
Mortality was considered to be directly attributable to a bloodstream pathogen if the patient died within 7 day after the last positive blood culture without any other probable cause of death, The patient’s characteristics were compared between those with or without BSI by univariate analysis.
<Results>
149 episodes of BSI were observed in 31 patients. Cumulative incidence within 100 days was 0.40. Median onset was day 13 (1–98) after RICBT.
The causative organisms were P. aeruginosa (47), S. epidermidis (44), E. faecium (13), T. beigelii (6), S. maltophilia (6), E. faecalis (5), E. coli (3), A. xylosoxidans (3) and others (22). 8 patients died of septicemia directly associated with BSI. A mortality rate was 26%. The causative organism included P. aeruginosa, A. xylosoxidans, S. maltophilia, S, aureus and gram-positive rod. Use of corticosteroid (p=0.012) and time to engraftment (p=0.003) were associated with the development of BSI.
<Discussion/ Conclusion >
BSI is a major complication in our series of RICBT. Use of corticosteroid and prolonged neutropenia might have increased the risk of incidence of BSI.
The Zebrafish Hypochromic Mutant [iItalic]Shiraz[/iItalic] Encodes a Novel Mitochondrial Glutaredoxin That Establishes a Link between Heme and Fe/S Production.
Authors: Wingert Rebecca A. , Barut Bruce , Foott Helen , Fraenkel Paula , Dooley Kimberly , Kingsley Paul , Palis Jim , Shubert Heidi , Chen Opal , Kaplan Jerry ,   Tubingen 2000 Screen Consortium, Zon Leonard I. 
Published: October 2019

Abstract
Iron is required in the mitochondria both to produce heme, which is used for hemoglobin synthesis, and to make iron-sulfur (Fe/S) clusters, which confer electron transfer or catalytic functions to proteins. Cellular iron utilization and Fe/S cluster production are thought to occur independently, yet the processes are coordinated through currently uncharacterized pathways. The shiraz (sir) zebrafish mutant manifests a hypochromic, microcytic anemia. Positional cloning of sir discovered a deletion at the locus that included the zebrafish orthologue to glutaredoxin 5 (grx5), a gene required in yeast for Fe/S cluster assembly. We found that grx5 is highly expressed in the developing blood and fetal liver of both zebrafish and mouse embryos. Antisense-mediated morpholino knockdown of grx5 prevented hemoglobin production, and overexpression of zebrafish, yeast, mouse, or human grx5 RNA in sir embryos completely rescued hemoglobin production, indicating that grx5 is the gene responsible for the sir phenotype. Expression of zebrafish grx5 was found to rescue Fe/S protein production in the yeast Δgrx5 strain, demonstrating that the role of grx5 in Fe/S cluster assembly is conserved among eukaryotes. The surprising finding that mutating a gene necessary for Fe/S cluster assembly caused a lack of hemoglobin synthesis suggested that we had discovered a connection between these pathways. In vertebrates, iron regulatory protein 1 (IRP1) acts as a sensor of intracellular iron levels and controls cellular iron homeostasis via posttranscriptional regulation of iron uptake, storage, and utilization genes. For instance, IRP1 binds to the 5′ iron response element (IRE) in the aminolevulinate synthase 2 (ALAS2) mRNA, blocking translation when cellular iron is low. However, when cellular iron is replete, IRP1 binds a Fe/S cluster and its RNA-binding activity is abolished. We hypothesized that the loss of Fe/S cluster assembly in sir would activate IRP1 and block ALAS2 synthesis, resulting in hypochromia. In support of this model, overexpression of ALAS2 RNA without the 5′ IRE rescued sir hypochromia, while overexpression of ALAS2 including the IRE did not facilitate rescue. Furthermore, antisense morpholino knockdowns of IRP1 caused rescue of hemoglobin synthesis in sir embryos. The combination of these data indicate that hemoglobin production in the differentiating red cell is monitored through Fe-S cluster assembly as a mechanism to gauge iron levels and accordingly direct heme synthesis. This finding illustrates a crucial role for the mitochondrial Fe/S cluster assembly machinery during hemoglobin production, and has broad implications for the role of such genes in human hypochromic anemias.
Haploidentical Hematopoietic Cell Transplantation (HCT) Compared with Matched HCT from Family Donors: report of 216 cases.
Authors: Lu Daopei , Han Wei , Dong Lujia , Huang Xiaojun , Liu Kaiyan , Chen Huan , Xu Lanping , Ren Hanyun , Liu Daihong , Chen Yuhong , Wu Tong , Lu Jin , Gao Zhiyong , Wang Jingbo , Jiang Qian , Zhang Yaochen , Wang Jingzhi 
Published: October 2019

Abstract
A total of 216 cases of matched and mismatched-haploidentical HCT from family donors have been performed since May 2002 in our Institute. The purpose of this analysis is to compare the GvHD, relapse rate and their risk factors for complications and survival. The feasibility of the present regimen can then be evaluated. In the arm of mismatched-haploidentical HCT, GIAC regimen (G-CSF priming hematopoietic cells collection; immunosuppression intensified and prolonged; ATG being used; combination use of BM + PB) was used for the first time. It was developed for patients without HLA matched related or unrelated donors. However, in HLA matched HCT, ATG was not used. The two groups were comparable in disease diagnoses, sex, and prophylaxis of GvHD, number of MNC/kg and use of G-CSF post-transplant. The great majority of recruited patients had hematological malignancies. A few were cases of SAA. There were significantly more patients in advanced stage or in high-risk status in mismatched-haploidentical HCT group. After median value of 9(2–260 months follow up, the results are shown in Table 1.
Table 1. Survival and causes of Death (2-year Kaplan-Meire Estimates)
Characteristics and Outcomes Matched Mismatched-haploidentical No. Of Patients 116 100 Age (yr.) 37 (12–62) 23 (3–52) Status of Patients Standard Risk 86 (74.8%) 44 (44%) High Risk 30 (25.2%) 56 (56%) Days post-transplant ANC>0.5x109/L 16.4 12 Platelets>20x109/L 16.9 17 Acute GvHD <100 days 0-I 48.6% 52% II 38.6% 35% III-IV 12.8% 13% Chronic GvHD 62.5% 63.3% Extensive 18.7% 18.3% Overall survival for 1 year 81.2% 72% Relapse related mortality 5.17% 6% Non-relapse related mortality 11.2% 16%
In summary, compared to matched HCT, GIAC regimen for mismatche-haploidentical HCT is sufficiently safe for patients.
Comparison of Outcomes of Unrelated Bone Marrow and Umbilical Cord Blood Transplants in Children with Hematologic Malignancies: Single Center Study in Korea.
Authors: Chung Nak-Gyun , Cho Bin , Park Young-Shil , Jeong Dae-Chul , Jang Pil-Sang , Kim Hack-Ki 
Published: October 2019

Abstract
In order to compare the outcomes of unrelated umbilical cord blood transplants (UCBT) or bone marrow transplants, 102 children with hematologic malignancies transplanted with unrelated umbilical cord blood (n=35, M:F=21:14, median age 4 years) or unrelated bone marrow transplants (UBMT) (n= 67, M:F=49:18, median age 9 years) were analyzed in a retrospective single center study (between Aug. 1997 and Dec. 2003 in the Catholic Hematopoietic Stem Cell Transplantation Center of Korea). HLA mismatches were defined by serology for class I and molecular typing for DRB1. The donor was HLA mismatched in 94% of UCBTs (33 of 35 UCBT) and in 0 % of UBMT. Non-adjusted estimates of 2-year event-free survival rates were 46 % and 57 %, respectively (P > 0.2). Engraftment failures of donor cells occurred in 17 % (6 out of 35) of UCBT and in 6 % (4 out of 67) of UBMT. Grade >= III acute GVHDs developed in 3 out of 29 (10 %) engrafted patients who underwent UCBT and in 17 out of 63 (27 %) engrafted patients who underwent UBMT. Early TRM at day 100 was 31 % (11 out of 35) for UCBT and 22 % (12 out of 67) for UBMTs. Within post-transplant month 3, CMV infections occurred in 37 % of UCBT and 54 % of UBMT, but most of them did not progress to CMV disease due to early ganciclovir treatment. Chronic GVHD developed in 2 out of 22 (9 %) patients who underwent UCBT and in 15 out of 49 (31 %) patients underwent UBMT.
In conclusion, the use of UCBT as a source of hematopoietic stem cells is a reasonable option for children with hematologic malignancies lacking an acceptable, matched unrelated marrow donor.
Myeloablative Conditioning in Myelofibrosis using i.v. Treosulfan and Autologous Peripheral Blood Progenitor Cell Transplantation with High Doses of CD34+ Cells Results in Hematologic Responses - Follow-Up of Three Patients.
Authors: Fruehauf Stefan , Buss Eike C. , Topaly Julian , Kreipe Hans H. , Ho Anthony D. 
Published: October 2019

Abstract
Myelofibrosis with myeloid metaplasia is a chronic myeloproliferative disorder. The only curative therapy to date is myeloablation followed by allogeneic transplantation. This approach, however, is associated with a high morbidity and mortality. Autologous transplantation after myeloablation with high-dose oral busulfan provides a palliative approach which can lead to a long-term relief of symptoms and is associated with acceptable morbidity and mortality (Anderson JE et al. 2001, Blood 98: 586). However, busulfan pharmacokinetics after oral administration can vary between patients and increased toxicity is encountered in some. On the other hand treosulfan, a bi-functional alkylating drug, can be administered safely i.v. with reliable pharmacokinetics up to the myeloablative dose range. In the study presented here, patients were stimulated with G-CSF 16 μg/kg daily for 4 days and subsequent leukapheresis of a minimum of 5 x 106 CD34+ cells/kg was performed. Myeloablation consisted of treosulfan infusions of 14 g/m2 for three consecutive days (total dose 42 g/m2) and subsequent autologous PBPCT. To date we have transplanted 3 patients, all female. Two patients (#1, #3) had symptomatic splenomegaly and severe anemia. Patient #2 had symptomatic splenomegaly and thrombocytopenia (< 100/nl). The WB nadir after treosulfan therapy was 0.06/nl (#1), 0.28/nl (#2) and 0.09/nl (#3). The time to reconstitution of leucocytes > 1/nl post transplantation was 28 days (#1, #2) and 38 days (#3) and the time for reconstitution of thrombocytes > 50/nl was 36 (#1), 22 (#2) and 33 (#3) days. The prolonged reconstitution period may have been due to the myelofibrosis and has also been observed after busulfan conditioning and PBPCT by others. There were no fever or other severe toxicity. Patients did not require total parenteral nutrition. The patients have been followed-up for 18 months post transplantation, now. The first patient (#1), who required erythrocyte transfusions twice weekly pretransplant received her last erythrocyte transfusion on day 56; her Hb-value is 11.2 g/dl at last follow-up. The second patient (#2) recovered to platelet counts higher than pre-transplantation (58/nl) at 3 months.(143/nl) and had 103/nl at last follow-up. Pat. #3 showed a marked reduction of max. spleen size and a rise in Hb from 9 g/dl to 12 g/dl after 12 months, the Hb value at 18 months is 8.7 g/dl and allogeneic transplantation is considered now. We conclude that myeloablation with treosulfan and autologous PBPCT in these three patients with myelofibrosis was safe and useful. Survival of these patients is promising up to date. The results presented warrant further exploration of this approach in a clinical study which has been initiated by our group. (cf. http://leukaemie.krebsinfo.de/kn_home/Studien/studie_101.html).