bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transfusion of Red Blood Cells under Shock Conditions in the Rat Microvasculature.
Authors: Chin-Yee Ian , Statchuk Leslie , Milkovich Stephanie , Xenocostas Anargyros , Ellis Christopher 
Published: April 2020

Abstract
Background RBC transfusion is the mainstay of therapy for resuscitation of patients with hemorrhagic shock. Ex-vivo storage of RBCs for transfusions is associated with a storage lesion which decreases erythrocyte deformability and increases their adhesiveness to vascular endothelium. This may impair microcirculatory flow with deleterious effects on oxygen delivery post-transfusion. The objective of this study was to determine whether transfused stored rat blood impairs the microcirculation following resuscitation from hemorrhagic shock
Methods Donor Sprague Dawley rat RBCs were collected and stored in CPDA-1 under standard blood bank conditions. RBCs were labelled with FITC (fluorescein isothiocyanate) 24 hours before the experiment. RBCs stored for less than 24 hours (fresh) RBCs (n=3) were compared to RBCs stored for 7 days (n=3). To induce shock, forty percent of blood volume was removed from male Sprague Dawley rats. Animals were then resuscitated by injecting 1.5mL of labelled packed RBCs and sufficient saline to restore blood volume via arterial line. The number of adherent labelled RBCs in the extensor digitorum longus muscle (EDL) was detected using intravital video microscopy (20X magnification). RBC velocity, capillary diameters, capillary Hct (hematocrit), arterial Hct, and lactate data was collected at three time points (baseline, shock and resuscitation).
Results Lactate levels increased significantly during shock in both the fresh and stored groups. Arterial Hct decreased in shock and was restored to baseline levels with resuscitation. The stored group had an increased number of stopped cells in the microcirculation compared to their fresh counterparts (p=0.004). There was no statistical significant difference in capillary diameters between groups or time points. Both groups showed an increase in RBC velocity from baseline to resuscitation (stored group doubled, fresh group tripled). Capillary Hct did not change in the fresh group but doubled in the old group from baseline to resuscitation.
Conclusion In our shock model, transfusion of stored RBCs resulted in an increased number of stopped cells and lower RBC velocity in capillaries as compared to fresh RBCs. Stored RBCs also had an increased capillary Hct from baseline to resuscitation and a diminished hyperemic response as compared to fresh RBCs. We conclude that stored RBCs following transfusion behave differently than native or fresh transfused cells in the microcirculation. Further studies are needed to determine the impact of these microcirculatory changes on oxygen availability in transfusion.
Anti-CD20 Monoclonal Antibody in the Treatment of Refractory Autoimmune Cytopenias in Adults.
Authors: Narat Santhosh , Gandla Jagdish , Mehta Atul B. 
Published: April 2020

Abstract
Anti-CD20 monoclonal antibody (rituximab) has been used in autoimmune cytopenia with variable success.We report 13 patients with chronic refractory autoimmune hemolytic anemia (AIHA) and idiopathic thrombocytopenic purpura (ITP) who each received 4 cycles of rituximab 375mg/m2 weekly. All 8 AIHA patients (6 idiopathic,2 secondary to a lymphoproliferative disorder, 5 splenectomised) had warm antibody type. Response was seen in 4(50%) of 8 patients (3 CR,1PR) and 3 patients remain in CR at 5,7,14 months post-therapy. Median time to maximum response (TMR) in responders was 9 weeks(range 6 – 18 weeks). In 5 ITP patients (4 splenectomised), 4(80%) responded (3CR) and one continues in CR 50 weeks after completion of rituximab treatment Median time to maximum response was 4 weeks (range 4 – 12 weeks). No pre-treatment clinical or laboratory parameters that predict response could be identifird in the AIHA or ITP groups.Our data indicate that rituximab is a relatively safe and effective treatment option in patients with refractory autoimmune hemolytic anemia and thrombocytopenia.
Table 1
Number of patients Mean age (Years) Sex Overall response Complete response No response Time to maximal response AIHA 8 47.75 (26– 73) 3M:4F 4 (50%) 3 (37.5%) 4 (50%) 9 weeks ITP 5 58.6 (28–89) 4M:1F 5 (80%) 3 (60%) 2 (40%) 4 weeks
Strain Variation in the Immune Response to Human Factor VIII in Normal and Hemophilic Mice.
Authors: Jin Linda X. , Soukhareva Nadejda N. , Scott David W. 
Published: April 2020

Abstract
Approximately 25–30% of Hemophilia A patients make inhibitors after treatment with therapeutic Factor VIII (fVIII). The ability to predict which patients may respond with inhibitors would be important in order to identify suitable patients for tolerance therapies prior to exposure to fVIII and the development of high inhibitor titers. Advances in identifying the nature of the fVIII mutations (inversion, stop codons, etc), HLA linkage and other factors have suggested these as important predictors of inhibitor responsiveness. As a step toward identifying other genetic factors that may predispose for inhibitor formation, we immunized both fVIII−/ − (knockout; C57Bl background) and fVIII sufficient mice of different MHC backgrounds with human fVIII (i.e. therapeutic doses, intravenously in saline with no adjuvant). Our hypothesis was that fVIII sufficient mice would only respond to epitope differences between human and mouse fVIII and that this response would be more sensitive to genetic variation. Our results showed a clear hierarchy of responsiveness both in terms of T-cell proliferation and ELISA titers in the following order: CAST/Ei&gt;BALB/c&gt;B10.A; CBA&gt;C57Bl/6. Despite being bred on a C57Bl (low responder) background, knockout mice made the strongest response to human fVIII, presumably due to the lack of tolerance to mouse epitopes. These results suggest that MHC plays a role in fVIII responsiveness, as it does in the response to fIX or fVIII delivered via an adenovirus vector (http://www.abstracts-on-line.com/abstracts/hemphiladelphia03; Lozier, 2003; Brown et alia, J. Thromb. Haemost.2:111–118, 2004). Thus, it may be possible to map additional loci responsible for inhibitor formation in future studies. Moreover, the fact that fVIII sufficient mice respond to intravenous fVIII points out a unique immunogenic quality of this molecule that appears to be unlike most other plasma proteins. This offers the additional possibility of developing mutated fVIII molecules that lack this inherent immunogenicity.
Dramatic Improvement in CR Rate and CR Duration with Imatinib in Adult and Elderly Ph+ ALL Patients: Results of the GIMEMA Prospective Study LAL0201.
Authors: Vignetti Marco , Fazi Paola , Meloni Giovanna , Chiarenza Annalisa , Malagola Michele , Fabbiano Francesco , Recchia Anna , Kropp Maria G. , Offidani Massimo , Palmieri Salvatore , Cilloni Daniela , Torelli Giuseppe , Cimino Giuseppe , Foà Roberto , Baccarani Michele , Mandelli Franco 
Published: April 2020

Abstract
In 2001, the GIMEMA Group started a phase II study to evaluate Imatinib both in adult (study A, 18–60 years) and elderly (Study B, &gt;61 years) patients with Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL).
In study A, adult patients with Ph+ ALL received the standard GIMEMA induction (VCR, DNR, PDN, L-ASP) and consolidation (MTZ and high-dose Ara-C) treatments, without imatinib. All patients in hematological complete remission (HCR) after the consolidation, either with or withouth a donor, received imatinib p.o. at the dosage of 800 mg/day for 6 months. After completing the 6-months therapy, in the absence of safety concerns, if the investigator considered the patient eligible for treatment, the therapy with imatinib was continued. A total of 22 patients have been enrolled [7 in molecular complete remission (MCR) and 15 still BCR/ABL+]: 18 are still in HCR after a median follow up of 20 months (2 – 26). In particular, all the 7 patients PCR- when started imatinib are still in HCR (6 PCR- and 1 becoming PCR+), after a median follow-up of 19 months (7.6 – 24) and eleven of the 15 PCR+ patients are in CHR after a median follow-up of 19 months (1.2 – 26). Of the remaining 4 PCR+ patients, 1 died in CR after an alloSCT and 3 patients relapsed at 4, 9 and 11 months, respectively. The probability of disease-free survival at 2 years is 79% (C.I. 95%: 58,4 – 100,3).
Figure Figure
In study B, planned for elderly patients usually not eligible for intensive treatments, the induction therapy consisted of imatinib 800 mg/day p.o. associated to prednisone 40 mg/sqm/day for 30 days, withouth any other chemotherapy. Up to date only 12 patients have been enrolled. Median age was 67.5 yrs (61–78), 9 were females. Eleven (92%) obtained a CR with the prednisone-Imatinib association induction treatment, 1 patient discontinued the treatment for toxicity. The post-remissional treatment mainly consisted of imatinib alone: 8 patients are still in CR, after a median follow up of 7 months (4 – 15), 2 relapsed at 4 and 4 months and 1 died in CR due to a 2nd neoplasia. In conclusion, these studies, planned 3 years ago to verify the feasibility and toxicity of imatinib in adult and elderly Ph+ ALL patients, clearly suggest a strong activity of Imatinib also in this disease, not only giving the possibility of inducing a CR as monotherapy, but even of maintaining long-lasting hematological and molecular CR withouth allogeneic stem cell transplantation. Further studies are mandatory to finally identify the best way to integrate imatinib in the entire treatment strategy of this disease.
Treatment of Philadelphia-Positive Acute Lymphocytic Leukemia (Ph+ ALL) in the Elderly with Imatinib Mesylate (STI571) and Chemotherapy. an Interim Analysis of the GRAALL AFR09 Trial.
Authors: Delannoy Andre , Lhéritier Véronique , Thomas Xavier , Castaigne Sylvie , Farhat Hassan , Rigal-Huguet Françoise , Raffoux Emmanuel , Gressin Remy , Legrand Ollivier , Witz Francis , Dubruille Viviane , Turlure Pascal , Troussard Xavier , Delain Martine , Bilhou-Nabera Chrystele , Macintyre Elizabeth , Delabesse Eric , Vernant Jean-Paul , Dombret Hervé , Fière Denis 
Published: April 2020

Abstract
Ph+ ALL accounts for approximately one third of ALL cases in patients aged 55 years or older. The median survival of older Ph+ ALL patients is one year, with practically no long-term survivor (Blood, 98, Supp1 p319a, 2001). Imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Ph+ ALL, which prompted the GRAALL to implement a treatment protocol associating imatinib and chemotherapy in previously untreated elderly patients: ALL patients aged 55 years or older are treated with steroids during one week and Ph+ve cases are then offered a specific therapy including an induction treatment with steroids, cyclophosphamide, daunorubicin and vincristine, followed, irrespective of response to induction chemotherapy, by imatinib, 600 mg daily, combined with intermittent steroids during 2 months. Patients in complete response are then given 10 blocks of alternating chemotherapy, including 2 additional two-month blocks of imatinib, for a total treatment duration of 2 years. Therapy of occult central nervous system leukemia includes 5 intrathecal injections of methotrexate and cranial irradiation. The study is intended to include 30 patients and its main objective is to improve overall one-year survival to 70%. Results are compared with those obtained in 21 Ph+ ALL elderly patients treated according to our previous protocol. Since January 2003, 21 patients aged 58 to 78 years (median: 64.7 years) were included in the AFR09 protocol. Their median follow-up is 3 months. 15/19 patients are in complete response after induction chemotherapy vs 6/21 in the historical controls given similar induction regimen but with no steroids before chemotherapy (p=0.002). The projected overall survival is 95% at 9 months vs 62% in the control group (p=0.08, log-rank test). The 9-month projected event-free survival is 83% vs 10% (p&lt;0.0001) and the projected 6-month relapse-free survival is 79% vs 22% (p=0.006, log-rank test). In conclusion, although preliminary, this interim analysis suggests that the use of imatinib in elderly patients with Ph+-ALL is very likely to dramatically improve prognosis. Of note, an unexpected high proportion of patients accrued in this study achieved a CR after induction chemotherapy possibly denoting a beneficial impact of steroids given before starting chemotherapy.
Pharmacokinetics and Pharmacodynamics of Three Asparaginases in Pediatric Patients with Higher Risk Acute Lymphoblastic Leukemia: A Report from CCG-1961.
Authors: Panosyan Eduard H. , Seibel Nita L. , Grigoryan Rita S. , Avramis Ioannis A. , Jaques Jon D. , Ettinger Lawrence J. , Gaynon Paul S. , Sather Harland N. , Franklin Janet , Cecilia Fu , Siegel Stuart E. , Fingert Howard J. , Avramis Vassilios I. 
Published: April 2020

Abstract
Deamination of asparagine (Asn) and glutamine (Gln) by asparaginase (ASNase) induces apoptosis of ALL lymphoblasts, which lack ability to synthesize Asn de-novo. Early treatment intensification after Induction, including PEG-ASNase instead of native E.Coli-ASNase, in addition to more vincristine and intravenous methotrexate, improves outcome in pediatric ALL patients presenting with unfavorable features, who show rapid early response to Induction chemotherapy (Seibel NL, et al., Blood, 2003;102:224a). Erwinase was used for patients with overt clinical allergy to E.Coli-ASNase. We evaluated the population pharmacokinetics and pharmacodynamics (PK-PD) of the three ASNase formulations employed on CCG-1961. The PK-PD parameters of native and PEG-ASNase in this group of HR ALL patients were similar to those reported from SR ALL patients from CCG-1962 (Avramis VI, et al., Blood, 2002;99:1986–1994). Population PK (NONMEM) showed the expected half-lives of native E.Coli-ASNase (6000 IU/m2): 1.3 days; PEG-ASNase (2500 IU/m2): 6.5 days; and Erwinase (6000 IU/m2): 0.8 days. Repeated doses resulted in an accumulation of activity with moderate prolongation of elimination half-lives for all formulations. PEG-ASNase provided &gt; 0.3 IU/ml activity for &gt; 21 days for most patients in Delayed Intensification. We measured simultaneous amino acid levels in 430 sera samples obtained from various phases of CCG-1961 from these 187 fully evaluable patients with detectable post-treatment ASNase activity. The averages of pre-treatment control serum levels for Asn and Gln were 44.8 ± 3.0 μM (mean ± SE) and 363.8 ± 23.9 μM, respectively. There were no statistical differences between the PD effects of ASNase formulations on serum Asn deamination, although the lowest Asn levels averaging 2.6 ± 0.4 μM were obtained on 11–14 days post-PEG-ASNase samples (n=14). Glutamine deamination enhanced Asn depletion, and deamination correlated with ASNase activity. At levels &gt;0.4 IU/ml, PEG-ASNase and native ASNase provided 95 ± 8% and 85 ± 26% Gln deamination, respectively (p=0.04). Eleven to 14 days after PEG-ASNase, Gln levels averaged 13 ± 5 μM (n=14). In general, Erwinase provided greater Gln deamination (94 ± 5%, n=19) 2–3 days post administration, than either native or PEG-ASNases at comparable activity levels, which were 70–80% (p&lt;0.001). Greater Gln deamination yielded lower Asn levels after Erwinase. These PD results provide insight into the benefit of PEG-ASNase intensification and possibly Erwinase substitution in the treatment of patients with high risk ALL treated with augmented BFM therapy and need to be further explored.
Non-Myeloablative Allogeneic Transplantation in Patients with Relapsed or Refractory Multiple Myeloma.
Authors: Gerull Sabine , Hegenbart Ute , Goerner Martin , Benner Axel , Moehler Thomas , Goldschmidt Hartmut , Ho Anthony D. 
Published: April 2020

Abstract
Patients with recurrent and refractory multiple myeloma have a very limited survival expectance. Allogeneic transplantation might offer an option for cure in myeloma and the recent development of non-myeloablative conditioning regimens has reduced transplant related morbidity and mortality and rendered this treatment feasible in elderly patients.
The role of non-myeloablative allogeneic transplantation for multiple myeloma however, has not yet been defined. We have analyzed the results of patients with relapsed or refractory multiple myeloma treated at our institution.
Between 08/1999 and 02/2004, 56 patients with relapsed (n=54) or refractory (n=2) myeloma were treated with non-myeloablative allogeneic transplantation. The median beta2microglobulin at the time of diagnosis was 2.75 mg/l, and median age at the time of transplant was 54.5 years (39.2–67.8). The median time from diagnosis to transplant was 3.6 years. Prior to allogeneic transplantation, patients received reinduction chemotherapy which included an autologous transplantation for 30 patients. The median number of previous cycles of conventional chemotherapy was 9. The conditioning regimen was 2 Gy TBI with (n=43) or without (n=3) fludarabin 3 x 30 mg/m² for 46 patients, the remaining 10 patients received a melphalan containing regimen.
Acute toxicity was low with a WBC &lt; 500/μl and platelets &lt; 50/μl for a median of 0 days. Engraftment was prompt with 90 % of patients having achieved &gt; 90 % donor chimerism by day 56. Acute GvHD Grade II-IV occurred in 36 % of patients with 22 % Grade III-IV, and 61 % experienced chronic GvHD. Total transplant related mortality reached 20 %, with a day 100 TRM of 5 %. 32 patients experienced relapse or progressive disease, and 32 % of patients died due to relapse. The Kaplan-Meier estimate of overall survival and progression free survival at 18 months was 40 % and 25 %, respectively, with a median follow up of survivors of 21 months. Patients who experienced cGvHD had a significantly higher overall survival estimate (60 % vs. 20 % at 18 months, p=0.03). The number of cycles of pretreatment before allogeneic transplantation had a statistically significant negative influence on overall (p=0.02) and progression free survival (p=0.006).
We conclude that non-myeloablative allogeneic transplantation is feasible in patients with relapsed multiple myeloma. The significant poor prognostic factors we identified were absence of chronic GvHD and number of cycles of pretreatment. Allogeneic transplantion should therefore be considered as an option earlier in the course of the disease.
Successful Treatment of Advanced and Refractory AML with Sirolimus Based Non-Myeloablative Allogeneic Stem Cell Transplantation.
Authors: Claxton David F. , Ehmann Christopher , Rybka Witold 
Published: April 2020

Abstract
Non-myeloablative conditioning has extended the use of allogeneic hematopoietic transplant to many previously ineligible patients but has to date been disappointing in patients with advanced acute myelogenous leukemia (AML). We added the immunosuppressive and antitumor agent sirolimus (rapamycin) to an established transplant regimen of fludarabine 25 mg/M2 days -7 through -3 and cyclophosphamide 1000mg/M2 days −7 and −6, with tacrolimus and methotrexate immunoprophyllaxis. 23 patients with AML were treated, with median age 59 (range 28–72) at transplant. 6 patients received matched sibling, 11–unrelated donor, 1–5/6 matched and 5-haploidentical (“haplo” −3/6 or 4/6 matched) transplants. The haplo recipients also received antithymocyte globulin on days −1, 1, 3, and 5. Only 7 patients in total were in CR, but all of these were at high risk for relapse because of prior MDS, chromosome status, or other features. 9 patients were in chemotherapy refractory progression, and 7 were primarily refractory to induction therapy. All patients engrafted. In patients without graft versus host disease by day 30 (9 patients) tacrolimus was discontinued between days 45 and 100 while sirolimus was continued. 12/23 patients survive at 61–903 days of followup post transplant (median 525) and 11/12 survivors are currently free of detectable leukemia. 3 of these 12 relapsed at 83, 88, and 243 days, but the first 2 of these have received chemotherapy and DLI and are in CR 771 and 311 days from relapse. The figure below shows overall and progression free survival (PFS). All survivors but the single patient undergoing therapy for progression have performance status 0 or 1 and are free of need for transfusion. 9/12 survivors continue on sirolimus therapy. Only 2 patients, both recipients of haploidentical cells, have died from transplant related causes. Non-myeloablative hematopoietic cell transplantation with sirolimus (rapamycin) based immunosuppression effectively treats many patients with advanced and poor prognosis AML. Given the very limited anti-leukemic activity of the conditioning chemotherapy, this suggests that disease control has been via graft versus leukemic effects alone or combined with anti-leukemic activity of the sirolimus.
Figure Figure
Improved Long Term Survival with Minimal GVHD after Myeloablative Unrelated Donor Stem Cell Transplantation Using In Vitro and In Vivo T Cell Depletion with CAMPATH-1H.
Authors: von dem Borne Peter A. , Beaumont Floor , Starrenburg Ingrid , Oudshoorn Machteld A. , Hale Geoff , Falkenburg J.H. Frederik , Fibbe Willem E. , Willemze Roel , Barge Renee M.Y. 
Published: April 2020

Abstract
In allogeneic stem cell transplantation (SCT) T-cell depletion reduces transplant related mortality by diminishing GVHD. We have investigated a myeloablative regimen for matched unrelated donor SCT using both in vivo and in vitro CAMPATH-1H for effective T-cell depletion, utilising DLI at a later time point for graft versus tumor effect if necessary.
Thirty patients (median age 33 years, range 18–48) were transplanted from January 1997 to June 2002. Diagnoses were: CML CP (n=9), CML AP (n=2), AML/MDS (n=9), ALL (n=8), NHL (n=1) and Fanconi anemia (n=1). Six patients had one HLA mismatch, the others were identical for HLA A, B, C, DR and DQ. Conditioning consisted of CAMPATH-1H 5mg/d on days −8 to −4, TBI 6 Gy on days −8 and −7 and cyclofosfamide 60 mg/kg on days −6 and −5. T-cell depletion was performed by in vitro incubation of the graft with 20 mg CAMPATH-1H for 30 minutes (Campath “in the bag”). Post-transplant GVHD prophylaxis consisted of cyclosporine A and methotrexate. The stem cell source was bone marrow in 19 patients (63%) and peripheral blood in 11 patients.
One graft failure was observed, all other patients had sustained engraftment of donor cells. Acute GVHD was observed in 12 patients (40%), maximally grade I-II skin. No severe acute GVHD (grade III-IV) was experienced. Limited chronic GVHD developed in 2 patients, resolving after treatment. Only in one patient extensive chronic GVHD developed, which did not resolve. CMV reactivation occurred in 23% of patients, one patient developed CMV disease. No EBV disease was observed. Ten patients received donor lymphocyte infusion (DLI) at a median of 17.4 months after SCT (8 patients with relapsed CML, one patient with relapsed ALL, one patient with autoimmune hemolytic anemia). After DLI acute GVHD grade I-II developed in 4 patients, and GVHD grade III-IV in 3. Chronic GVHD developed in 5 patients, of which 2 extensive, resolving in all except one patient. With a median follow up of 37 (range 21–84) months 17 patients are alive (57%). One of the CML patients shows persistence of molecular disease not responding to increasing doses of DLI. All other patients are in CR with the CML patients in molecular remission. Five patients (17%) died because of relapsed disease (2 AML/MDS and 3 ALL). Treatment related mortality was 26% (1 rejection, 2 GVHD, 1 myocardial infarction, 4 infections).
In conclusion, matched unrelated donor SCT following myeloablative conditioning using T-cell depletion with CAMPATH-1H in vivo as well as in vitro results in good engraftment, minimal grade I-II GVHD and an overall survival of 57%. Relapse rate was not increased with this strategy. This regimen appears to be successful for young adults with high-risk malignancies.