bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unrelated Donor Umbilical Cord Blood Transplantation (UD-UCBT) for Adult Patients with High-Risk Acute Lymphoblastic Leukemia (ALL).
Authors: Sanz Jaime , Lorenzo Ignacio , Montesinos Pau , Senent Leonor , Larrea Luis , Planelles Dolores , Martin Guillermo , Cervera Jose , Jarque Isidro , de la Rubia Javier , Orti Guillermo , Scaff Miguel , Paciello Mari Liz , Moscardo Federico , Romero Monica , Biologist Luis Benlloch , Sanz Miguel A. , Sanz Guillermo 
Published: April 2020

Abstract
BACKGROUND: Adult patients with high-risk ALL can benefit from allogeneic stem cell transplantation but most lack a suitable sibling or unrelated adult donor. Umbilical cord blood has emerged as an alternative source for stem cell transplantation.
OBJECTIVES: The aim of the present study was to evaluate toxicity and efficacy of UD-UCBT for the treatment of high-risk ALL in adults as well as to identify by multivariate analysis factors affecting transplant outcome.
PATIENTS AND METHODS: Thirty-seven consecutive patients (23 males, 14 females) with median age 26 yr (range, 15–47) who underwent UD-UCBT at a single institution from 1999 until 2006 were analyzed. Primary high-risk feature was Philadelphia-positive ALL (12), MLL rearrangement (3), primary refractory disease (3), salvage treatment for patients in second complete remission (CR2, 4) or beyond CR2 (6), and slow response to initial therapy or 2 cycles to achieve CR (9). Conditioning regimen consisted of thiotepa, busulfan (oral, 13; IV, 24), cyclophosphamide (24) or fludarabine (13), and anti-thimocyte globulin. Cyclosporine and prednisone were used for graft-versus-host disease (GVHD) prophylaxis. Most patients (95%) received an HLA-mismatched cord blood unit with 1 (35%) or 2 (60%) HLA disparities. At infusion, the median number of nucleated cells and CD34+ cells was 2.4 × 107/kg and 1.3 × 105/kg, respectively.
RESULTS: Cumulative incidence (CI) of myeloid and platelet engraftment was 92% and 76% at a median time of 21 and 63 days respectively. CI of GVHD acute grades II-IV, III-IV and chronic extensive was 29%, 19% and 19% respectively. Transplant-related mortality at 180 days was 29% and was significantly increased in patients developing severe acute GVHD (96% vs 19%; p &lt; 0.001). With a median follow-up of 23 months (range, 7–88), CI of relapse was 34% at 3 years and was higher in patients beyond CR1 (63% vs 28%; p &lt; 0.001). 3-year event-free survival (EFS) and overall survival (OS) were 33% and 37%, respectively. Patients in CR1/2 had better EFS (41% vs 14%; p = 0.04) and OS (50% vs 14%; p = 0.04) while those who developed severe acute GVHD had a worse EFS (42% vs 0%; p = 0.004) and OS (49% vs 0%; p = 0.004).
CONCLUSIONS: These results show that UD-CBT is a curative alternative for a significant number of patients with high-risk ALL. This option should be offered to patients early in the course of their disease to improve outcomes.
Encouraging Results of Reduced Intensity Conditioning (RIC) Umbilical Cord Blood (UCB) Transplantation for the Treatment of Advanced Lymphoid Malignancies.
Authors: Brunstein Claudio G. , Cantero Susana , Cao Qing , Majhail Navneet , McClune Brian , Burns Linda J. , Tomblyn Marcie , Miller Jeffrey S. , Blazar Bruce R. , McGlave Philip B. , Weisdorf Daniel J. , Wagner John E. 
Published: April 2020

Abstract
We have reported on the safety and efficacy of RIC UCB transplantation for patients with advanced hematologic diseases. Here we report on 65 patients, median age of 46 yrs (range, 6–68), who underwent RIC UCB transplantation for the treatment of advanced lymphoid malignancies between October 2001 and December 2006. Patients received either one (n=9) or two (n=56) UCB unit grafts matched at 4–6/6 HLA loci. Forty were male and 27 CMV seropositive. Diagnoses were follicular lymphoma (FL, n=11), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL, n=9), mantle cell lymphoma (MCL, n=8), large cell lymphoma (LCL, n=14), and Hodgkin’s lymphoma (HL, n=23). Conditioning regimen was cyclophosphamide 50 mg/kg (Day-6), fludarabine 40mg/m2 for 5 days (Day-6 to -2), and single fraction total body irradiation of 200cGy (Day -1), plus cyclosporine A and mycophenolate mofetil (to day +30). At transplantation 53 patients (81%) had chemotherapy sensitive disease, 5 (8%) had bulky adenopathy (≥ 5 cm), 27 (42%) had prior radiation therapy, 26 (40%) had prior autologous transplant, 22 (34%) had an elevated LDH, and 10 (15%) had marrow involvement. The median number of prior treatment courses was 4 (range, 1–9). The median follow-up for survivors is 23 mos. (range, 4–62). Patients were analyzed as indolent (IND=FL+ SLL/CLL), aggressive (AGR=LCL+MCL), and HL. Incidence of acute GVHD grades II–IV was 57% (95%CI, 43–70); grades III–IV 25% (95%CI, 14–35); chronic GVHD 23% (95%CI, 11–35), with similar incidence of acute and chronic GVHD between lymphoma subgroups. The 3-year nonrelapse mortality (NRM) was 15% (95%CI, 5–26) with no significant difference among lymphoma subgroups (IND 5% vs. AGR 24% vs. HL 13%, p=.41). Thirty-five patients (53%) had relapsed or progressive disease with a 3-year progression-free survival (PFS) of 31% (95%CI, 19–44); IND 44% (95%CI, 22–66); AGR 20% (95%CI, 2–39); HL 35% (95%CI, 15–54) (p=.30). Fourteen of these 35 patients were treated with tapering of immunosuppression and rituximab and/or chemotherapy or radiation therapy, and 8 achieved a complete remission. Three-year OS was 55% (95%CI, 42–68); IND 69% (95%CI, 48–90); AGR 54% (95%CI, 33–75); HL 43% (95%CI, 18–69) (p=.37). We conclude that RIC UCB is effective alternative for the treatment of patients with advanced lymphoid malignancy resulting in acceptable NRM and encouraging OS and PFS. Patients with advanced lymphoid malignancies should be considered for a RIC UCBT as a promising alternative for those with no available sibling donor.
Genetic Interaction between PGE2 and the Wnt/β-Catenin Signaling Pathway Regulates Definitive HSC Development and Homeostasis.
Authors: North Trista E. , Goessling Wolfram , Lord Allegra M. , Stoick Cristi , Moon Randall T. , Zon Leonard I. 
Published: April 2020

Abstract
Hematopoietic stem cells (HSC) differentiate throughout the lifetime of the organism to produce each of the definitive blood lineages. Recently, we demonstrated that prostaglandin (PG) E2 regulates vertebrate HSC formation and homeostasis. The mechanism by which PGE2 influences HSCs is currently unknown. Through qPCR analysis and in situ hybridization, we determined that dimethyl (dm) PGE2 regulated expression of the classical wnt targets cyclinD1 and ephrinB2 during embryonic development. As the wnt pathway has been shown to regulate HSC self-renewal, we hypothesized that the two pathways interact genetically to control the production and homeostasis of HSCs. In TOP:dGFP wnt reporter fish, wnt activity was enhanced in vivo following the addition of dmPGE2, whereas indomethacin treatment resulted in the virtual absence of β-catenin/TCF signaling. Activation of wnt signaling in heat-shock (hs) inducible transgenic zebrafish (hs:wnt8) led to enhanced AGM HSC formation, while inhibition of wnt/β-catenin signaling at the membrane level (hs:dickkopf (dkk)), in the cytosol (hs:axin) or in the nucleus (hs:dominant negative (dn) TCF) reduced HSC numbers. Exposure to dmPGE2 rescued HSC inhibition mediated by dkk, but not by axin or dnTCF, implying that PGE2 interacts with the wnt signaling pathway at the level of the β-catenin destruction complex. Furthermore, indomethacin treatment diminished the effects of wnt induction on HSC formation, suggesting that PGE2 activity is required to mediate the full effects of wnt activation. We next sought to determine if PG signaling could regulate wnt-mediated control of hematopoietic recovery in the adult zebrafish following irradiation. As seen with dmPGE2 treatment, wnt induction during marrow recovery led to a significant increase in hematopoietic progenitors by day 10 post injury. Exposure to indomethacin blocked the wnt-mediated increase in kidney marrow precursors. Wnt activation has further been implicated in leukemogenesis. Repetitive activation of wnt signaling in adult fish induced a myeloproliferative disease. Significantly, treatment with indomethacin altered its development and progression. Finally, we investigated the effects of PGE2 modification of wnt activity on hematopoietic homeostasis in the mouse. Following myeloablative 5-FU treatment, PGE2 was capable of modifying wnt-mediated effects on hematopoietic recovery. Compared to wild-type control siblings APCMin mice exhibited elevated numbers of stem and progenitor cells after 2 weeks; treatment with indomethacin every other day prevented this regenerative advantage. These results suggest that pharmacological manipulation of wnt activity through modulation of PGE2 signaling will provide novel therapeutic approaches to regulate HSC homeostasis during bone marrow recovery and leukemogenesis.
“Age” of the Cord Blood (CB) Unit: Impact of Long-Term Cryopreservation and Storage on Transplant Outcome.
Authors: Scaradavou Andromachi , Stevens Cladd E. , Dobrila Ludy , Sung Dorothy , Rubinstein Pablo 
Published: April 2020

Abstract
Cryopreserved, banked CB is being increasingly used for allogeneic bone marrow reconstitution of unrelated transplant recipients. The effect of long-term storage on the viability and function of CB hematopoietic stem cells has been addressed only with in vitro assays and immunodeficient mouse models (Broxmeyer et al, PNAS2003; 100:645–50), but not in clinical transplantation. To evaluate the quality of CB units after prolonged storage in liquid nitrogen freezers, we compared the transplantation outcomes of patients that received CB grafts from the New York Blood Center NCBP stored for 8 years or more (Group 1, N=43, median time from unit collection to transplant: 9.2 years) to those transplanted with units stored &lt; 2 years (Group 2, N=300, median time: 1.1 years). Patients were included in the study if they were transplanted in the period 2001–2006, received a single or double unexpanded unit graft and had no prior transplant in the 6 months preceding the CB graft. Double unit recipients were evaluated if the unit of interest was the one that engrafted, as demonstrated by post-transplant chimerism studies. The two groups were similar with respect to disease category (malignant diseases: 74% in Group 1, 69% in Group 2), location of transplant center (transplant in the US: 60% and 68%, respectively), use of non-myeloablative regimens (19% and 12%, respectively) and double unit transplants (14% and 10%, respectively). More patients in Group 1 were adults (42% and 27%, respectively, p = 0.035). Detailed information on CB thawing was available for all units in Group 1 and 217 in Group 2. Two units of the first Group and 3 of the second were reported to have problems at thawing (clots/leak). No immediate post-infusion complications were reported. Post-transplant ANC recovery was at a median of 25 days in Group 1 and 22 days in Group 2 (multivariate RR = 0.9, p = 0.6). Among patients who survived for 28 days or longer, 8/36 in Group 1 and 42/260 in Group 2 failed to achieve ANC500 (p = 0.3). Overall survival was not different in the two Groups (both 49% at 5 years). These results indicate that “old” CB units can be used effectively in clinical transplantation. Therefore, long-term cryopreservation of CB stem cells is feasible without compromising the quality and engraftment ability of the CB units, supporting the creation of a National Cord Blood Inventory with high quality units. However, these findings need to be viewed with caution: cryopreservation and storage procedures, equipment and devices vary significantly among different Banks. Thus, the results of the NCBP may not apply to all Cord Blood Banks.
Final Results of Lower Dose Fludarabine (F) and Cyclophosphamide (C), and High Dose Rituximab (R), (FCR-Lite) for Patients with Untreated Chronic Lymphocytic Leukemia (CLL).
Authors: Tarhini Ahmad A. , Land S. , Pietragallo L. , Laman A. , Sulecki M. , Marks S. , Meisner D. , Schaefer P.M. , Foon Kenneth A. 
Published: April 2020

Abstract
Introduction Standard FCR therapy in untreated CLL patients (F-25 mg/m2 d1–3 q 4wk; C-250 mg/m2 d 1–3 q 4wk; R-500 mg/m2 d1 q 4wk for 6 cycles) was reported to have complete remissions (CR) of 70% and overall responses (OR) of 95% (J Clin Oncol2005;23:4079). The major toxicity was grade 3/4 neutropenia during 52% of treatment courses. One approach to decrease neutropenia without compromising efficacy could be by reducing the doses of F and C and increasing the dose of R. Methods We conducted a phase II study for previously untreated advanced CLL patients treated with FCR-Lite (F-20mg/m2 d1–3 q 4 wk; C-150 mg/m2 d1–3 q 4 wk; R-500mg/m2 d1 and d14 q 4wks; maintenance R-500 mg/m2 ×1 q 3 months until progression). A Simon two-stage design was used where 15 patients were accrued in the first stage and because of acceptable toxicity and response rate in stage I an additional 35 patients were treated. The primary endpoint was response rate. Results A total of 50 patients were entered into this study and 42 are currently evaluable. There were 29 male and 13 female patients with an age range of 36–85 years (median 58) treated with a total of 236 courses of FCR-Lite. All 42 patients were evaluable for toxicity. Grade 3/4 neutropenia occurred during 29 (12%) courses with two episodes of neutropenic fever. One patient had cellulitis, another had pneumonia (not neutropenic). Grade 3/4 thrombocytopenia occurred during 7 (3%) courses and grade III/IV anemia during 6 (2.5%) courses. Among the 40 evaluable patients for response, the CR rate was 85%, PR rate was 15% with an OR rate of 100%. All of the CR patients were tested by flow cytometry and had &lt;1% CD5+/CD19+ cells in their bone marrow after therapy. One patient with potential CR was excluded due to the absence of follow up bone marrow biopsy. Minimal residual disease (MRD) was tested by four color flow cytometry (sensitivity 0.01%) in 8 patients with CR (Genzyme Genetics Corp.). Seven had no evidence of MRD at 7, 8, 8, 14, 22, 25 and 30 months respectively, post CR, and one patient had 0.03% and 0.06% when tested at 12 and 18 months post CR respectively. Conclusions Our results in 42 patients suggest FCR-Lite is highly effective with considerably less grade 3/4 neutropenia than standard FCR. Complete responders had no detectable CD5+/CD19+ cells in their bone marrow following FCR-Lite. MRD testing is currently underway for all patients.
The Receptor for Hyaluronic Acid Mediated Motility (RHAMM): Characterization as an Immunotherapeutical Target in Chronic Lymphocytic Leukemia (CLL) and First Results of RHAMM-Derived Peptide Vaccination Trial.
Authors: Giannopoulos Krzysztof , Buhler Andreas , Chen Jinfei , Krober Alexander , Kowal Malgorzata , Dmoszynska Anna , Rolinski Jacek , Greiner Jochen , Dohner Hartmut , Stilgenbauer Stephan , Schmitt Michael 
Published: April 2020

Abstract
Background and Aims: The increased expression of receptor of hyaluronic acid mediated motility (RHAMM) was noted in CLL. The defective expression of RHAMM-exon4 splice variant that correlated with chromosomal instability was found to bear negative prognostic value in patients with multiple myeloma. Therefore, here we characterized expression of RHAMM with its splice variants and correlated it with prognosis in CLL. Moreover, based on our previous results we initiated a RHAMM-derived R3 peptide vaccination study for patients with B-CLL in early stages of disease.
Methods: Messenger RNA expression of RHAMM/CD168 was assessed by quantitative RT-PCR in blood samples from 65 B-CLL patients, at the time of diagnosis. The splice variant expression was measured using fluorescence capillary electrophoresis. Three hundred mcg RHAMM R3 peptide (ILSLELMKL) emulsified with the incomplete Freund’s adjuvant (ISA-51) day 3, as well as GM-CSF days 1–5, was administrated four times subcutaneously at a biweekly interval.
Results: The real-time RT-PCR results revealed higher RHAMM/TBP expression rates in patients with unmutated IgVH status compared with mutated CLL cases (0.047 vs. 0.029, p=0.012). Both splice variants RHAMMFL as well as RHAMM-exon4 showed significantly higher expression in unmutated CLL cases. Increased expression of RHAMM/TBP was noted in advanced stages of disease. A tendency towards higher RHAMM/TBP expression ratios was observed in B-CLL cases with del11q. CLL patients with a RHAMM/TBP ratio &gt;0.028 showed a significantly shorter median treatment-free survival (TFS) (16 vs. 38 months, p=0.0019). In a bivariate analysis, patients with VH mutated status and lower amounts of RHAMM presented longer TFS compared to unmutated cases with a high RHAMM expression (110 vs. 8 months, respectively). An enhanced RHAMM expression was observed in bone marrow samples of 5 B-CLL patients compared with the results obtained in blood (RHAMM/TBP 0.102 vs 0.032). Similar tendency to higher RHAMM/TBP ratios was observed after CD40L stimulation (RHAMM/TBP 0.025 vs.0.113). In five patients who completed all four doses of R3 peptide vaccine no toxicity related to vaccine was observed. Reduction of leukemic cells was noted in 3 patients but no clinical responses meeting NCI criteria was observed. Immunological responses were observed in patients who achieved hematological improvement. Conclusion: RHAMM/CD168 is a novel LAA in B-CLL patients, and its expression levels are correlated with the clinical course of the disease. RHAMM expression might indicate the proliferative potential of leukemic cells. First results of peptide vaccination using RHAMM-derived peptide showed limited reduction of tumor burden.
The Frequency of Rheumatic Disease Autoantibodies in Patients with ADAMTS13-Deficient Thrombotic Thrombocytopenia Purpura (TTP).
Authors: Swisher Karen K. , Lewis Qurana F. , James Judith A. , Hovinga Johanna A. Kremer , Lämmle Bernhard , Terrell Deirdra R. , Vesely Sara K. , George James N. 
Published: April 2020

Abstract
Patients who have TTP associated with acquired, severe ADAMTS13 deficiency have an autoimmune etiology and therefore may have increased risk for additional autoimmune disorders. The Oklahoma TTP-HUS Registry enrolled 247 consecutive patients with their first episode of clinically diagnosed TTP from 11-13-1995 (the date of our initial ADAMTS13 measurement) to 6-30-2006 for whom plasma exchange treatment was requested; ADAMTS13 activity was measured in 228 (92%) of patients immediately before their first plasma exchange treatment; 42 (18%) patients had ADAMTS13 activity &lt;10%. Three patients were excluded from this analysis because of preexisting systemic rheumatic disease (systemic lupus erythematosus (SLE), 2, Sjogren’s syndrome, 1). To examine the potential risk for development of autoimmune disorders, we measured screening autoantibodies (ANA, dsDNA, Sm, nRNP, Ro, La, ribosomal P, Jo-1, anti-phospholipid (aPL) IgG and IgM) in 34 of the 39 (87%) remaining patients. The median age at initial presentation was 39 years (range 9–71 years); 27 (79%) patients were women; 13 (41%) patients were black. Autoantibodies were measured by indirect immunofluorescence, immunodiffusion, or ELISA. Measurements were performed only once in 16 patients; in 18 patients 2–3 measures were performed over a period of 13 to 126 months.
Rheumatic disease autoantibodies TTP patients *1 patient had a maximum titer of &gt;1:3240 in 2 samples; 1 patient developed overt SLE and his titer decreased with treatment. ANA ≥1:40 on at least one occasion 33/34 (97%) ANA ≥1:120 on at least one occasion 29/34 (85%) ANA measured ≥2 times, increasing titer 14/16* (88%) Anti-dsDNA ≥1:30 12/34 (35%) Anti-Ro positive 14/29 (48%) Anti-Sm positive 1/34 (3%) Anti-nRNP positive 1/34 (3%) aPL IgG and/or IgM ≥moderate positive 4/34 (12%)
No patients had positive tests for anti-La, anti-Ribo-P, or anti-Jo-1. 23 (68%) of the 34 patients had a positive test for one or more rheumatic disease autoantibodies (dsDNA, nRNP, Ro, La, or moderately positive aPLs). 4 of the 34 patients died during their initial episode; the remaining 30 patients have been followed for a median of 6.4 years (range, 1–11.5 years). During this time only 1 patient has developed clinically evident SLE; no other patients have developed systemic rheumatic diseases.
Conclusions:
A high prevalence of rheumatic disease-associated autoantibodies were found in a cohort of consecutive patients with TTP associated with acquired severe ADAMTS13 deficiency. The presence of dsDNA and Ro autoantibodies and increasing ANA titers suggest that patients with ADAMTS13-deficientTTP may have a potential risk for developing additional autoimmune disorders such as SLE or Sjogren’s syndromes. [3] These serologic observations support clinical observations that presenting features of TTP and SLE may overlap.
Isolation and Characterization of CD4+ T Cells Specific for the HPA 1a Epitope Associated with Neonatal Alloimmune Thrombocytopenia.
Authors: Ahlen Maria T. , Killie Mette K. , Skogen Bjorn , Husebekk Anne , Stuge Tor B. 
Published: April 2020

Abstract
Neonatal alloimmune thrombocytopenia (NAIT) can cause severe complications such as intrauterine death or intracranial hemorrhage (ICH) in the newborn, and is caused by the transfer of platelet-depleting antibodies from the mother to the fetus during pregnancy. These antibodies react with allogeneic epitopes, most commonly human platelet antigen (HPA) 1a, when present on fetal platelets. Although these responses are thought to be a result of a T cell-dependent immune response, HPA 1a specific T cells have not yet been isolated. To examine whether HPA 1a specific T cells could be detected and isolated, we collected PBMC post delivery from an HPA 1a negative mother who gave birth to an HPA 1a positive neonate suffering from severe thrombocytopenia (platelet count &lt;50×109/L). The cells were stimulated with HPA 1a peptides (20aa) in long term cultures supplemented with IL-7 and IL-2, and subsequently, IL-15. After 4 weeks in culture these cells were labeled with CFSE dye and restimulated with HPA 1a or control peptides. After additional 2 weeks in culture supplemented with IL-2 and IL-15, specific proliferative responses were detectable by CFSE dye dilution by flow cytometry. The cells were cloned by fluorescent-activated cell sorting (FACS) and expanded in numbers with anti-CD3 stimulation in the presence of irradiated allogeneic PBMC and IL-2. The resulting clonal T cell lines were characterized in proliferation assays, ELISPOT assays and phenotyped by flow cytometry. All clones were CD3+, CD4+ and CD19−, and the majority of the clones proliferated and secreted cytokines in response to stimulation with HPA 1a peptides, but not control peptides. In ELISPOT assays, peptide-pulsed antigen-presenting cells were required for T cell detection. These clonal HPA 1a specific CD4+ T cell lines represent formal evidence of the existence of HPA 1a specific T cell responses related to NAIT and will serve as important tools for further characterization of maternal immune responses associated with NAIT.