bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Mechanism of Transfusion-Related Immunomodulation Is Related to the Transfusion of Dendritic Cells Expressing the CD200 (OX-2) Tolerance Signal and Alloantigen: Evidence from a Murine Tumor Model.
Authors: Blajchman Morris A. , Gorczynski Reginald M. , Clark David A. 
Published: October 2019

Abstract
Background: The transfusion of blood products containing allogeneic leukocytes can alter recipient resistance to infection and stimulate the growth of some types of tumors in animal models of transfusion-induced tumor growth. Transfusion related immunomodulation (TRIM) represents a credible mechanism for the altered resistance to infection seen clinically, but cannot explain the growth of non-immunogenic tumors in syngeneic hosts seen regularly in the various transfusion-related animal models of tumor growth.
Methods and Results: In this study the transfusion of 50–200 μL of unmodified anticoagulated allogeneic BALB/c (H-2d) mouse blood into C57B1/6 (H-2b) mice, four days before being intravenously injected with syngeneic (H-2b) FSL10 fibrosarcoma cells (1–2 x 106 cells per mouse) resulted in a significant increase in the number of pulmonary nodules observed at 3 weeks compared to that seen in control mice. The median number of pulmonary nodules increased in an allogeneic blood transfusion dose-dependent manner, as did the proportion of mice without pulmonary nodules. This tumor growth-promoting effect of the allogeneic blood transfusions required the presence in the transfused blood of allogeneic CD11c+ dendritic cells bearing the CD200 co-stimulatory tolerance signal. This tumor growth-promoting effect of allogeneic blood could be blocked by specific monoclonal antibodies to either CD11c or to CD200. CD200 receptor-mediated signaling alone, in the absence of alloantigen, failed to augment the number of TRIM-induced pulmonary tumor nodules. Physiological concentrations of TGFβ, but not IL-10, were shown to stimulate proliferation of FSL10 cells in vitro in these studies. In this context, it is known that CD200 together with alloantigens are known to stimulate development of suppressor cells acting via IL-10 and TGFβ in vivo. Allogeneic blood also caused a significant CD200-dependent accumulation of TGFβ+ suppressor cells in the spleen, 12 days after transfusion, when the spleen cells could be shown to adoptively transfer the TRIM effect to naive animals.
Conclusions: These data support the hypothesis that allogeneic transfusions in an allogeneic blood transfusion mouse tumor model results in tumor growth promotion in recipient mice. This effect appears to result in both the induction of TGFβ-producing suppressor cells as well as requiring the transfusion of allogeneic CD11c+ dendritic cells, bearing both CD200 tolerance signaling molecules and alloantigens.
Nitrosylation of Platelet MHC Class I Molecules Directs Their Movement into the Immunosuppressive MHC Class I Processing Pathway within Antigen Presenting Cells.
Authors: Semple John W. , Speck Edwin R. , Freedman John 
Published: October 2019

Abstract
Previous studies have demonstrated that recipient mice require the production of nitric oxide (NO) within their antigen presenting cells (APC) in order to generate IgG anti-donor immunity against allogeneic platelet transfusions. NO has a complex biochemistry and several of its conjurors could be involved in this response; the most obvious is peroxynitrite (ONOO-) generated by the spontaneous combination of NO and superoxide (O2•−). ONOO- is a potent oxidant that can spontaneously nitrosylate lysine and tyrosine residues in proteins within the phagolysosome. To address the role of ONOO- in platelet immunity, we transfused GP91 PHOX knockout mice that lack the ability to produce O2•− and thus ONOO-. Results show that when wild type C57BL/6 mice were transfused with allogeneic BALB/c platelets, they developed a weak IgG anti-donor antibody response by the fifth transfusion. In contrast, PHOX KO mice generated IgG anti-donor antibodies by the 2nd transfusion and their IgG anti-donor antibody titres were significantly higher than the WT recipients. This suggested that ONOO- and protein nitrosylation may be linked with an immunosuppressive event within the recipient. This was confirmed by demonstrating that in vitro nitrosylation of platelet antigens with the ONOO- donor SIN-1 inhibited the ability of the platelets to mount an IgG immune response when transfused into allogeneic recipients. Nitrosylated platelet antigen trafficking within recipient APC was assessed by using adherent macrophages and various inhibitors of processing. When adherent APC were pulsed with nitrosylated platelet antigens in the presence of either Brefeldin A or proteosome inhibitors, IgG anti-platelet immunity against the platelets was restored. Furthermore, the IgG immunity could also be rescued against the nitrsosylated platelets if the recipients were first depleted of CD8+ T cells by injection of a monoclonal antibody. These results suggest that if platelet antigens are nitrosylated within antigen presenting cells, they are preferentially shunted to the MHC class I processing pathway and presented to CD8+ T cells that suppress the IgG immune response. Thus, it appears that reactive oxygen species act as intracellular regulators that determine whether a productive IgG immune response against platelet transfusions will occur.
Therapeutic Plasma Exchange (TPE) for Thrombotic Thrombocytopenic Purpura (TTP) Using Plasma Prepared with Photochemical Treatment (INTERCEPT Plasma).
Authors: Mintz Paul D. , Neff A. , MacKenzie M. , Hillyer C. , Goodnough L. T. , Kessler C. , McCrae K. , Menitove J. , Damon L. , Lopez I. , Roualt C. , Crookston K. , Benjamin R. J. , George J. , Van Doren S. , Lin J. S. , Corash L. 
Published: October 2019

Abstract
INTERCEPT Plasma (I-FFP) uses amotosalen (S-59, 150μM ) and UVA light (3 J/cm2 to inactivate pathogens in single plasma units. TPE is the mainstay therapy for TTP. Efficacy and safety of I-FFP for TPE of TTP were evaluated in a double-blinded, randomized, controlled trial. Eligible patients (pts) with TTP unrelated to cancer, cancer therapy, transplantation, AIDS, HUS, or SLE received daily TPE (1.0 to 1.5 blood volumes) with either I-FFP or conventional plasma (C-FFP) for up to 2 TPE cycles, each with a maximum of 35 days (d) of TPE. Treated pts were followed for 7 d after the last TPE to detect overall adverse events (AE) and for 60 d after achieving remission to detect relapse and serious adverse events (SAE). The primary endpoint was the proportion of pts in remission (platelet count ≥ 150,000/μL for 2 consecutive d without neurologic progression) within 30 d after the 1st TPE. Secondary endpoints were: time to 1st remission, volume of plasma used, number of TPEs, relapse rates after remission, vWF cleaving protease (vWF-CP) activity and inhibitor levels, antibodies to potential S-59 neoantigens, and safety. 35 pts (17 I-FFP, 18 C-FFP), mean age of 40 yr, 80% female were treated. TPE with I-FFP was comparable to C-FFP in remission rates (82% I-FFP, 89% C-FFP:p=0.66), median time to remission (6 d I-FFP, 6 d C-FFP:p=0.58), mean total volume of plasma exchanged (40.6 L I-FFP, 41.3 L C-FFP:p=0.86), mean number TPEs (11.3 I-FFP, 10.3 C-FFP:p=0.68), and relapse rates (36% I-FFP, 38% C-FFP:p=1.00). Baseline and post TPE vWF-CP activity and inhibitor levels were similar between groups. Overall AEs, serious AEs, deaths (1 I-FFP and 1 C-FFP: neither attributed to TPE), rates of discontinuation from study, laboratory abnormalities, and vital signs (VS) during TPE were comparable between groups. 1 C-FFP pt had TRALI. Five I-FFP pts had AEs coded to the cardiac system organ class compared to no C-FFP pts (p=0.02). In 4 of the I-FFP pts, these AEs were non-serious and did not interrupt TPE. One I-FFP pt with relapsing TTP had a serious AE after 12d of TPE, recovered without sequelae, was withdrawn from study, and continued on non-study FFP TPE with recurrent relapse. No antibodies to potential S-59 neoantigens were detected in any pts. In this trial, efficacy endpoints and safety profiles of TTP pts treated with I-FFP TPE were similar to those for TTP pts treated with C-FFP TPE.
High Shear Stress and Immobilization of Von Willebrand Factor Promotes the VWF-Cleaving Protease Activity as Assessed by the Cone and Plate(let) Analyzer.
Authors: Varon David , Shenkman Boris , Budde Ulrich , Angerhaus Dorothea , Schneppenheim Reinhard , Savion Naphtali , Seligsohn Uri 
Published: October 2019

Abstract
The metalloprotease ADAMTS-13 cleaves von Willebrand factor (VWF) that is released from endothelial cells as a large multimeric protein. However, the specific physiological conditions required for the function of this von Willebrand factor-cleaving protease (VWF-CP) are not yet established. In this study we determined the optimal conditions for the VWF-CP activity using the Cone and Plate(let) Analyzer (CPA). Proteolysis of a soluble recombinant VWF by a recombinant VWF-CP in the absence or the presence of BaCl2 (for induction of VWF-CP) was performed under static and flow (2050 s−1) conditions. The resulted fragments of the soluble VWF were immobilized on a polystyrene surface and non-adhering sites were blocked with 1% BSA. In parallel, polystyrene surface immobilized VWF was similarly treated by VWF-CP. The immobilized cleaved VWF fragments by the above protocols served as a substrate for citrated whole blood platelet adhesion under flow (2050 s−1). Reduction of platelet adhesion (surface coverage, SC) in BaCl2 treated compared to untrerated sample reflects the degree of VWF-CP activity.
Platelet adhesion (SC, %) to VWF proteolytic products generated under the indicated conditions:
Static w/o BaCl2 Static + BaCl2 Flow w/o BaCl2 Flow + BaCl2 Soluble VWF 15.0 ± 3.4 11.1 ± 2.7 13.6 ± 2.2 8.0 ± 2.1 Immobil. VWF 19.1 ± 3.0 12.0 ± 4.1 6.5 ± 1.1 1.0 ± 0.6
Maximal VWF-CP activity as reflected by maximal reduction (85%) of platelet adhesion was observed when immobilized VWF was treated by VWF-CP under flow. Minimal effect of VWF-CP activity was observed when soluble VWF was treated under static condition (26% reduction). Intermediate effect was observed with soluble VWF under flow (41%) and with immobilized VWF under static condition (37%). It should be noted that in the case of immobilized VWF application of flow alone (without BaCl2) was sufficient to induce a remarkable decrease of platelet adhesion (66%). In conclusion, both immobilization of VWF and high shear stress are important conditions for VWF-CP function, suggesting that stretching of immobilized VWF under flow exposes the VWF-cleavage site and thereby may serve as a control mechanism of platelet adhesion at the site of thrombus formation.
Clofarabine Plus Cytarabine (ARA-C) Combination Is Active in Newly Diagnosed Patients (PTS) ≥ Age 50 with Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS).
Authors: Faderl Stefan , Gandhi Varsha , Verstovsek Srdan , Cortes Jorge , Ravandi-Kashani Farhad , Beran Miloslav , Garcia-Manero Guillermo , Koller Charles , O’Brien Susan , Ferrajoli Alessandra , Estrov Zeev , Kwari Monica , Plunkett William , Kantarjian Hagop M. 
Published: October 2019

Abstract
Clofarabine is a next-generation deoxynucleoside analog with activity in acute leukemias. As clofarabine effectively inhibits ribonucleotide reductase, it is also suited for biochemical modulation strategies with other nucleoside analogs. In a previous study of clofarabine plus ara-C in pts with relapsed/refractory AML/MDS, we reported a CR rate of 24% (41% OR) (Blood 102:615a, 2003). Cellular pharmacology studies suggested that accumulation of intracellular clofarabine triphosphate resulted in higher ara-CTP accumulation of the leukemia blasts. We conducted a phase II study to investigate the efficacy and safety of clofarabine plus ara-C in pts ≥ 50 yrs with newly diagnosed AML and MDS (≥ 10% marrow blasts). Pts were excluded for ECOG PS > 2, age ≥ 75, and good prognosis karyotypes [t(8;21), inv(16), t(15;17)]. Clofarabine was given at 40mg/m2/d over 1-hour (hr) i.v. daily for 5 days (d2-6) followed 4 hrs later by ara-C at 1g/m2/d over 2-hrs i.v. daily for 5 days (d1-5). Sixty pts (53 AML, 7 RAEB-2 incl. 1 CMML-2) were enrolled and are evaluable. Median age: 61 yrs (range 50–74). Twenty-eight pts (47%) had secondary AML (17 AHD, 11 other malignancies) and 30 pts (50%) had abnormal cytogenetics (−5/−7 in 15, +8 in 10, del(11)(q23) in 3). 31 pts (52%) achieved CR; another 5 pts (8%) achieved CRp. Of 11 pts who received a second induction course, 4 pts (36%) responded (2 CR, 2 CRp). The CR rate was 60% (18/30 pts) in the diploid and 43% (13/30) in the abnormal karyotype group. Median time to CR: 29 days (20–98). 9 deaths (15%) occurred on study of which 4 pts (7%) died during the first course (d10 to d42). Adverse events included transient facial flushing and headaches (< gr. 3) during the infusion, and hyperbilirubinemia (gr. 3 in 3 pts), skin rashes, ↑ SGPT/SGOT, palmoplantar dyserysthesias, pancreatitis (1 pt) and renal failure (1 pt). Our data suggest that clofarabine + ara-C is active in older pts with newly diagnosed AML/high-risk MDS. The toxicity profile is acceptable. An update of time-to-event parameters will be presented.
Autologous vs Allogeneic Cell Transplantation for Mantle Cell Lymphoma (MCL): Outcomes over a 10-Year Period at City of Hope.
Authors: Popplewell Leslie L. , Nademanee A. , Carter Nora , Zain Jasmine , Krishnan Amrita , Rodriguez Roberto , Kogut Neil M. , Vora Nayana , Molina Arturo , Forman Stephen J. 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) carries a poor prognosis with standard therapy. Both allogeneic (ALLO) and autologous stem cell transplant (ASCT) approaches have been used to intensify therapy in an attempt to achieve lasting remissions. 77 patients were transplanted at City of Hope over a 10-year period (1994–2003), including 13 ALLO and 64 ASCT.
Demographics: The majority of patients were male (92% ALLO, and 73% ASCT). Median age was significantly younger for the ALLO, 47 years vs. 55 years for ASCT (p=0.003). ALLO patients had received more prior regimens than ASCTs-- avg 3 in ALLO and 1 in ASCT (p-value 0.0031). Median time from diagnosis to transplantation was 1.3 years for ALLO, 0.81 for ASCT. For ALLO patients, 8% were in first complete remission (CR1), 62% in second or subsequent remission, 23% in relapse, and 8% in unknown status. For ASCT patients, 47% were in CR1, 31% in second or subsequent remission, 14% in relapse, 2% in unknown status.
Methods: Conditioning regimens for ASCT include FTBI/VP16/CTX (36), BCNU/VP16/CY (14), BEAM (2), Zevalin/BEAM (4), and other (8). One patient received an ASCT transplant, then received a reduced intensity ALLO transplant at the time of second relapse. Conditioning for ALLO included FTBI/CTX (9), Flu/Mel (3), or BU/CY (1),
Results: Median follow-up was 57 months for ALLO, and 26 months for ASCT. 3-year Overall Survival (OS), progression free survival (PFS), and relapse rate was 51%, 53%, and 14% , respectively, for ALLO, and 66%, 57%, and 27% for ASCT. Patients transplanted in 1st CR had a significantly higher 3-year OS (85% vs. 52%, p = 0.0153) and PFS (78% vs. 44%, p = 0.027) a trend to a lower RR than patients transplanted in more advanced disease status.
Conclusions: MCL patients transplanted in CR1 fared better than those transplanted with more advanced disease status, regardless of transplant approach. While relapse rates were lower in ALLO patients, this did not translate into improvement in OS or PFS, possibly due to a higher transplant related mortality (TRM). Analysis of PFS curves suggests no plateau on the ASCT curve, while late relapses were uncommon in ALLO patients.
Intense Immunochemotherapy (IC) and Autologous Stem Cell Transplant (ASCT) for Untreated Patients (pts) with Mantle Cell Lymphoma (MCL): CALGB 59909. A Preliminary Report.
Authors: Damon Lloyd , Niedzwiecki Donna , Johnson Jeff , Cheson Bruce , Hurd David , Barlett Nancy , Kelly Michael , Linker Charles , Canellos George 
Published: October 2019

Abstract
We evaluated the feasibility, safety, and effectiveness of an intense IC regimen including ASCT in pts with untreated MCL up to age 70. Pts with MCL confirmed by central pathology review plus one additional feature (compatible immunophenotype, cyclin D1 over-expression, t(11;14) or Bcl-1/IgH rearrangement) were treated with 2–3 cycles of R-M-augmented CHOP (Rituximab [R] 375 mg/m2 d1, Methotrexate 3000 or 300 mg/m2 d2, CHOP d3 [cyclophosphamide {C} 2 g/m2]) followed by consolidation and stem cell collection with EAR (Etoposide [E] 40 mg/kg continuous d1-4, Cytarabine 2 g/m2 Q12h d1-4, R d6 and d13, and filgrastim 10 mcg/kg/d beginning d14 until completion of stem cell collection). EAR was followed by ASCT using CBV (Carmustine 15 mg/kg d-6, E 60 mg/kg d-4, C 100 mg/kg d-2) followed by R 6 and 7 weeks after ASCT. 69 pts have been enrolled in 36 months.
Patient demographics: median age 57 (38–68); 84% stage IV; 47% serum LDH elevated; 78% bone marrow (+); 5% cerebrospinal fluid (+). To date, 38 pts have completed all therapy, 6 have completed EAR, and10 are still receiving RM-CHOP. Stem cell collection was excellent, with a median CD34+ cell dose of 11.8x106/kg in median1 apheresis. 4 pts were unable to receive the full intended therapy due to adverse events (2 treatment related deaths, 2 early progressions). 5 pts withdrew from study because of personal preference (2), lack of insurance approval (2) or allogeneic stem cell transplant (1). With a median follow-up of 7 months, the projected 2-year progression-free survival is 70±21%. We conclude that intense IC plus ASCT is feasible and safe in pts with MCL up to age 70 with a high percentage of pts able to receive the planned therapy.
Early Dose Intensity Is Critical in Patients with Aggressive Lymphoma: A Randomized study Comparing Identical Doses of Cyclophosphamide, Adriamycin, Vincristine, Etoposide, and Prednisolone given as 4 or 6 cycles followed by Repetitive Transplantation of Stem Cells (Mega-CHOEP).
Authors: Glass Bertram , Kloess Marita , Reiser Marcel , Berdel Wolfgang E. , Ho Anthony D. , Truemper Lorenz , Loeffler Marcus , Pfreundschuh Michael , Schmitz Norbert 
Published: October 2019

Abstract
The German Study Group for High-Grade NHL (DSHNHL) investigated the efficacy of CHOP + Etoposide (Mega-CHOEP) at high doses for treatment of younger patients (pts) (<60y) with aggressive NHL and LDH > N. Autologous stem cells (ASC) were administered after the last 3 courses of therapy for hematopoietic rescue. At dose level (DL) 1 and 2 four courses of treatment were given: while doses of adriamycin (70 mg/m²), vincristine (2 mg), and prednisolon remained identical at all dose levels, the doses of Cyclophosphamide (C) and Etoposid (E) were set at 1500, 4500, 4500 6000 mg/m² (C), and 600, 600 (960), 600 (960), 1480 mg/m² (E) during courses 1, 2, 3 and 4 of therapy at DL1 (2). At DL 3 pts were randomized to receive either 4 (DL 3/4) or 6 courses of therapy (DL 3/6). While the cumulative doses of C and E were highest at DL 3 (C 19.5 g/m²; E 5.04 g/m²) as compared to DL 1 (C 16.5 g/m²; E 2.8 g/m²) or DL 2 (C 16.5 g/m²; E 4.0 g/m²) the administration of Mega-CHOEP with 6 courses of chemotherapy resulted in substantial prolongation of treatment (65 to 124 days) and thus loss of dose intensity (Table). From February 1997 to June 2001, 208 consecutive pts. were enrolled at DL 1–3, 31 of whom were excluded mostly due to incorrect histopathologie diagnosis. Therapy was given as per protocol in 81.8 % of pts. at DL 1 and 2, 90.2 % at DL 3/4 , and 69.2 % at DL 3/6, respectively, with treatment delays at DL 3/6 mostly due to extramedullary toxicity and, or poor performance status. Results were as follows: see table 1.
Late events were very rare with 5 relapses beyond 2 years in the whole population. Dose escalation without higher dose intensity (DL1+2 vs DL3/4) did not improve results. Dose escalation with loss of dose intensity (DL1+2 and DL 3/4 vs DL3/6) resulted in loss of efficacy. Mega-CHOEP DL2 was selected for comparison with non-transplant therapy in an ongoing phase III trial. These data underscore the importance of early dose intensity for successful treatment of aggressive NHL with high risk features.
Table 1
Therapy n IPI1/2/3(%) Duration of therapy (days) CRandCRu (%) TTTF2y (%) OS2y (%) DL 1+2 110 31/49/20 65 74 67 75 DL 3/4 41 20/46/34 80 68 53 70 DL 3/6 26 15/62/23 124 50 23 46
Autologous Transplantation for Diffuse Large B Cell Lymphoma: Pre-Transplant Hypogammaglobulinemia Is a Predictor for Early Toxicities.
Authors: Bolwell Brian J. , Kalaycio Matt , Sobecks Ronald , Andresen Steven , Rybicki Lisa , Kuczkowski Elizabeth , Bates Jennifer , Summers Kristie , Bernhard Laura , Cherni Kelly , Baker Janet , Brown Stacey , Pohlman Brad 
Published: October 2019

Abstract
Response to chemotherapy and LDH level at the time of transplant are generally accepted as two variables predictive of clinical outcome in autologous peripheral blood progenitor cell (PBPC) transplantation (ABMT) for diffuse large B cell lymphoma (DLBCL). Several years ago we anecdotally noted that some patients suffered ongoing hypogammaglobulinemia after ABMT. We therefore embarked on a study examining pre and post ABMT IgG levels to determine possible prognostic volume of immunoglobulin levels. This study focuses on 68 patients with relapsed/refractory chemosensitive DLBCL undergoing autologous transplant from 4/2000 to 1/2004. All received PBPCs alone for hematopoietic support, and all received a preparative regimen consisting of Bu/Cy/VP. Median age was 55; patients received a median of 2 courses of prior chemotherapy; 44% received prior radiation therapy; 60% were male; 25% had tumor bulk greater than 10 cm in greatest diameter; 22% had elevated LDH at the time of transplant. Median PBPC dose infused was 7.5 x 106 CD34+ cells/kg. Median pre-transplant IgG level was 689 mg/dL (institutional normal range 717–1411 mg/dL). Six weeks post transplant the median IgG level had fallen to 587 mg/dL. There is a statistically significant difference in survival stratified by baseline IgG: 43% of patients with an IgG level less than 600 mg/dL were alive 18 months post transplant, as compared with 72% with a baseline IgG greater than 600 mg/dL (p=0.011). This is shown graphically below:
Figure Figure
18 month relapse-free survival was 44% in the less than 600 mg/dL group versus 63% in the greater than 600 mg/dL group. 13 of 24 in the less than 600 mg/dL group have died (54%) versus 13 of 44 (30%) in the greater than 600 mg/dL group. The majority of these deaths are from disease relapse, however, the relapses occurred faster in the less than 600 mg/dL group. 5 of 7 relapse related deaths occurred by day +200 in the less than 600 mg/dL group, compared to 1 of 10 in the greater than 600 mg/dL group (p=0.009). Additionally, 4 patients in the less than 600 mg/dL group died of diffuse interstitial pulmonary toxicity between day 100 and 165 post chemotherapy. We conclude that pre-transplant hypogammaglobulinemia may be related to a more refractory underlying disease and is associated with the potential for rapid relapse after ABMT. Additionally, those patients entering an autologous transplant with hypogammaglobulinemia are at risk for later non-specific pulmonary toxicity.