bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Dose Melphalan Chemotherapy with Autologous Stem Cell Transplantation in Patients with AL Amyloidosis: No Increased Mortality Using Induction and Mobilization Chemotherapy.
Authors: Schonland Stefan O. , Hegenbart Ute , Dengler Jolanta B. , Benner Axel , Hundemer Michael , Bochtler Tilmann , Ho Anthony D. , Goldschmidt Hartmut 
Published: April 2020

Abstract
High-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (ASCT) is the treatment of choice for patients (pts) with AL amyloidosis (AL) eligible for this therapy. Because of a high treatment-related mortality (TRM), pts admitted for HDC have to be selected by risk analysis. It is unclear whether pts should receive HDC directly after diagnosis or after an intensive pre-treatment with induction and/or mobilization chemotherapy. We have retrospectively analyzed all pts with AL admitted to our centre. The first aim of the study was to analyze the influence of prior chemotherapy on survival. Secondly, pts at high risk not to proceed to HDC should be identified by clinical parameters at first contact.
186 pts have been admitted to our centre since 1998 with the diagnosis of AL. 172 pts were ≤ 70 years of age and were tested regarding eligibility for HDC and ASCT. Major eligibility criteria were cardiac disease &lt; NYHA stage IV and performance status (PS) &lt; 4.
Eighty-three pts (median age 56 years, range 34–69; AL n=71, multiple myeloma &gt;stage I with AL, n=10, NHL with AL, n=2) fulfilled the major eligibility criteria and started either (re-) induction (n=57) or mobilization chemotherapy (n=20) or went directly to HDC after G-CSF stimulated stem cell harvest (n=6). Induction treatment consisted of VAD/AD in 34 pts, pulsed dexamethasone (D) in 24 pts or other regimens in 2 pts. Mobilization chemotherapy included cyclophosphamide (C) in 2 pts, CAD (C/adriamycin/D) in 44 pts, ifosfamide in 13 pts and other regimens in 2 pts. Overall, in 72 pts stem cell mobilization has been performed. Sixty-five pts have been treated with HDC.
The estimated overall survival for the whole group is 60% (last event at 54 months, median follow-up 22 months). Fifty-six out of 65 transplanted pts are alive. Three pts died of TRM (5%), 6 pts died of AL progression. Eighteen pts (22%) have not been transplanted for several reasons which is comparable to the 16% reported by Oran et al. (BMT 2005). These included organ progression after induction chemotherapy in 13 pts and chemotherapy-induced mortality in 5 pts resulting in an overall TRM prior to HDM of 6%. Currently, only 2 out of these 18 pts are still alive, 11 pts died of organ progression after the decision against HDC. Our analysis shows that induction chemotherapy does not result in increased mortality prior to (6%) and after (5%) HDC compared to published data using G-CSF alone for mobilization (4% and 6%, Oran, BMT 2005). Significant factors for prediction not to proceed to HDC were number of organs involved (p=0.04) and NYHA stage (p=0.006) at first contact (multivariate analysis). Whether this intensive approach will finally lead to improved survival might be shown with a longer observation after HDC and ASCT.
High Dose Chemotherapy with Autologous Stem Cell Support Is Effective in Resistant and Refractory Hodgkin Lymphoma. A Single Center Analysis.
Authors: Cocorocchio Emilia , Peccatori Fedro , Bassi Simona , Gigli Federica , Radice Davide , Pruneri Giancarlo , Rabascio Cristina , Calabrese Liliana , Martinelli Giovanni 
Published: April 2020

Abstract
We report retrospective data concerning 49 relapsed or refractory Hodgkin lymphoma pts, treated from 1995 in our institution with high dose chemotherapy (HDCT) with autologous peripheral blood stem cell (aPBSC) support. 41/49 had resistant disease, because presenting an early relapse (14/41), a late relapse (12/41) after CR induced by standard chemotherapy (CT) or persistence of disease (15/41) after initial CT. 8/49 had refractory disease, presenting stable or progressive disease within three months after the end of first line CT. Median age at transplantation time of 32 yrs (range 18–58 yrs). Before high dose chemotherapy, all pts received at least a standard chemotherapy (hybrid regimen for 4–6 cycles ± RT, according to the extension of disease). At the time of transplantation, 13 pts were in complete remission, 31 were in partial or very good partial remission and 5 were in stable /progressive disease. We used as myeloablative regimen mainly HDBEAM. Radiotherapy was performed in 9 pts after transplantation. In the subgroup of the 26 relapsed pts, 21 achieved a CR, 2 a PR and 3 a PD/SD; with a median follow up of 23 months from transplant (range 2 – 112 months), expected DFS and OS at 10 years are 90.5% and 76.9%, respectively. Analyzing separately early versus late relapsed patients, DFS expected at 10 years are 81.8% and 100%, respectively, and the OS expected are 71.4 and 83%, respectively. 11/15 pts with persistence of disease after initial CT achieved a CR, 2 PR, 2 presented SD/PD; with a median follow-up of 32 months from transplant (range 2 – 88 months), expected DFS and OS are 90.9% and 75%, respectively. Finally, 5/8 refractory pts achieved a CR (two of them progressed after transplant), 2 pts a PR (both progressed and died after transplant), 1 patient obtained a SD (progressed and died after transplant). No toxic deaths or second cancer or other severe late toxicity were recorded. Autologous transplantation is a safe procedure, considering the manageable early and late toxic effect; the clinical results achieved indicate that HDCT with aPBSC support is to be considered the first therapeutic option for those pts who present an early or late relapse after standard chemotherapy. The low number of refractory pts doesn’t allow any definitive conclusion about its role in this subgroup, but the relative high number of events observed seems to suggest that further analysis of biological features are warranted in order to better define the best therapeutic option.
Mitoxantrone and Melphalan Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation in Adults with Acute Myelogenous Leukemia.
Authors: Sprague Kellie , Padgaonkar Vaishalee , Klein Andreas K. , Chan Geoffrey W. , Miller Kenneth B. , Klingemann Hans 
Published: April 2020

Abstract
High dose mitoxantrone and melphalan (Mito/Mel) has been reported as an effective and well tolerated conditioning regimen for autologous peripheral blood stem cell transplantation (APBSCT) in patients with lymphoma. We review our experience with Mito/Mel as a conditioning regimen in 18 adults with intermediate or high risk acute myelogenous leukemia (AML) who underwent APBSCT. Median age at time of APBSCT was 51 years (range 19–70). Sixteen patients were transplanted in first complete remission (CR); two in second CR. All patients received mitoxantrone 60mg/m2 IV on day −4 and melphalan 180mg/m2 IV on day −1 followed by infusion of autologous peripheral blood stem cells on day 0. The 100 day survival was 94%. One patient died in CR of suspected pulmonary embolism 3 months post transplant. With a median follow-up of 24 months, 10 patients are alive. The median disease free and overall survival is 40 months and 47 months, respectively. All 18 patients received anthracycline based induction therapy prior to APBSCT. Cardiac toxicity was monitored by echocardiogram. A significant decline in left ventricular function developed in only one patient who had underlying diabetes and hypertension. We conclude that high dose mitoxantrone and melphalan is an easily administered conditioning regimen with a low risk of significant cardiac toxicity despite prior treatment with anthracycline based chemotherapy. This regimen when used for APBSCT in adults with AML results in favorable disease free and overall survival.
RICE/ICE Is an Effective PBSC Mobilising Regime in Patients with Aggressive Lymphoma.
Authors: Wilson Edward , Pawson Rachel , Beston Kathleen , Smyth John , Hatton Chris 
Published: April 2020

Abstract
RICE/ICE is an effective re-induction chemotherapy regime for patients with relapsed or refractory aggressive lymphoma prior to autologous stem cell transplantation. There is however a paucity of data on its effectiveness as a peripheral blood stem cell mobilising regime. We present data on its use in 23 patients, age 50 ± 15 (mean ± SD), with relapsed (n=16) or primary refactory (n=7) lymphoma (DLBCL (n=15), mantle cell (n=1), high grade transformation of follicular lymphoma (n=5), Hodgkins lymphoma (n=1), Anaplastic large cell lymphoma (n=1)). RICE (Rituximab 375mg/m2 (day 1), Etoposide 100mg/m2 (days 1–3), Carboplatin 5x(CrCl+25)mg/m2 (day 2) and Ifosphamide 5000mg/m2 (day 2)) was administered as re-induction chemotherapy (4 patients did not receive Rituximab) along with Filgrastim 10mcg/kg/day from day 5 until collection. Apheresis was attempted on day 15 in those patients (n=18) achieving a peripheral blood CD34+ve cell count greater than 10x103/ml. Peripheral blood stem cells were collected on a Gambro Cobe Spectra cell seperator processing a median of 2.5 blood volumes by standard protocols. Eight patients achieved a successful collection in the first apheresis session, six patients required a single further collection on day 16 and four patients required further collections on days 16 and 17. The median CD34+ve cell dose collected was 5.01x106/kg (range 0.5x106/kg − 17.4x106/kg) with only 2 patients achieving inadequate collections (0.5x106/kg and 1.37x106/kg). In total 70% (16 of 23) of patients successfully achieved PBSC collections of greater than 2.0x106/kg. The group of patients that failed to mobilise was not predictable in terms of known adverse markers such as marrow involvement, underlying low grade lymphoma or previous chemo/radiotherapy. In conclusion successful PBSC collection was achieved in the majority of patients treated with RICE/ICE although the number of patients is small and larger numbers will be required to confirm these results.
The Migratory Activity of Anti-CD19 cTCR-Redirected CIK Cells as a Useful Property for In Vivo Targeting of B-ALL Cells.
Authors: Marin Virna , Dander Erica , Biagi Ettore , Biondi Andrea , D’Amico Giovanna 
Published: April 2020

Abstract
Cytokine induced killer (CIK) cells are a population of ex-vivo expanded cells enriched in CD3+CD56+ natural killer T (NKT) cells with MHC-unrestricted cytotoxicity against several leukemia targets, except B-lineage acute lymphoblastic leukemia (B-ALL) cells. The trafficking machinery of NKT cells reflects their preferential localization in bone marrow, liver and spleen, which are also sites of B-ALL infiltration. In the present study we determined whether CIK cells maintain the original trafficking properties of NKT cells, by analyzing their pattern of expression of adhesion molecules, chemokine receptors and chemotactic activity. Moreover, we investigated the possibility to redirect the cytotoxic activity of CIK cells towards our selected target (B-ALL cells) by transduction with a retroviral vector encoding a chimeric T-cell receptor (cTCR) specific for the CD19 antigen. Similarly to freshly-isolated NKT cells, CIK cells expressed CXCR4, CCR6 and CCR7 (average expression 72%, 60% and 32% respectively), presenting chemotactic activity towards their respective ligands. The adhesion molecules CD49d and CD11a were highly expressed on &gt;99% of CIK cells, potentially reflecting their capacity to adhere to the endothelium in bone marrow and non-lymphoid organs. To induce cytotoxicity against B-ALL cells, we transduced CIK cells with a retroviral vector containing the anti-CD19-ζ chimeric receptor and the GFP as marker gene, and analyzed their phenotypic characteristics (CD3/CD56 and chimeric receptor expression) and cytotoxic activity against REH B-ALL cell line and B-ALL cells in a 51Cr-release assay. Percentage of CD3+/CD56+ was not altered by transduction. CIK cells were efficiently transduced with the retroviral vector (average expression of GFP/chimeric receptor = 15%; n=8). Furthermore, CIK cells expressing the anti-CD19-ζ receptor showed a strong cytotoxic activity against the REH B-ALL cell line (average lysis, 59.9% at an effector:target ratio=30:1, range, 45.7%–69.5%; n=3) and against primary B-ALL blasts (average lysis, 60.2% at an effector:target ratio=30:1, range=39.7%–72.8%; n=3), that was not observed in CIK cells expressing the truncated-nonsignaling form of the receptor. In addition, the migratory capacities of the transduced CIK cells remain unchanged when compared to unmanipulated CIK cells. These findings suggest that CIK cells show a natural capacity to reach sites of B-ALL infiltration and proliferation, and can be redirected with a specific anti-CD19 cTCR, to becoming able to kill leukemic cells without affecting their migratory properties. Based on these preliminary findings we suggest that anti-CD19-modified CIK cells may be an attractive strategy for B-ALL immunotherapy.
A Sensitive Enzyme-Linked Assay of ADAMTS13 Antibodies for Diagnosis of TTP.
Authors: Raoufi Mojgan , Zhou Wenhua , Guinto Enriqueta , Grafos Nick , Ranzurmal Safi , Greenfield Robert S. , Rand Jacob , Tsai Han-Mou 
Published: April 2020

Abstract
Thrombotic thrombocytopenic purpura (TTP), a serious disorder characterized by the development of VWF-platelet rich thrombi in the arterioles and capillaries, requires reliable diagnostic assays for optimal management of the patients. Simple, reliable assays of ADAMTS13 inhibitors or antibodies are not yet widely available. To develop an ELISA for antibodies of ADAMTS13, we analyze the levels of patient IgG bound to immobilized recombinant ADAMTS13 in a microtiter plate format. The mean (±SD) IgG binding value is 5.1 ± 1.5 arbitrary units (AU)/mL among a group of 36 normal subjects and is 5.3 ± 2.7 AU/mL among 31 random patients (P &gt; 0.1). Two (5%) of the normal group and 2 (6%) of the random group are outliers. When applied to patients with thrombotic microangiopathy, this assay yields IgG binding values ranging from 2.0 – 58.3 (median = 5.4) AU/mL in a group of 40 subjects with other thrombotic microangiopathy and 10.1 - &gt; 60.0 (median 49.0) AU/mL in a group of 56 patients with acute TTP. Excluding 2 (5%) outlying samples, the mean (±SD) for the “other TM” group is 5.9 ±2.5 AU/mL, which is not different from the values of the normal and random subjects. In contrast, the IgG binding values are &gt; 10.0 AU/mL in each of the acute TTP patients. Furthermore, heating the plasma samples at 56oC, presumably by dissociating ADAMTS13 from immune complexes, increases IgG binding of 4 weakly positive TTP samples from 10.1 – 12.7 to 28.3 – 154.3 AU/mL. Addition of native ADAMTS13 lacking the tag sequences decreases the binding of TTP IgG to 40% ± 20% of control, but does not affect the binding of 6 outlying non-TTP IgG (120% ± 20% vs. control, P &lt; 0.001), suggesting that the IgG of non-TTP samples do not recognize ADAMTS13. In summary, the ELISA for ADAMTS13 antibodies is highly sensitive for detection of ADAMTS13 antibodies. A subset of the general population contains IgG molecules that react with the recombinant ADAMTS13 fusion protein but not with native ADAMTS13. Blocking with native ADAMTS13 enhances the specificity of the assay for TTP.
Figure Left: Binding of IgG to immobilized rADAMTS13-FLAG/His in four groups of study subjects. Right: Suppression of IgG binding by untagged ADAMTS13 in TTP but not in non-TTP samples. Figure. Left: Binding of IgG to immobilized rADAMTS13-FLAG/His in four groups of study subjects. . / Right: Suppression of IgG binding by untagged ADAMTS13 in TTP but not in non-TTP samples.
A Cyclophilin A-Independent Capsid Motif Renders HIV-1 Derived Vectors More Efficient at Transducing Human Cells.
Authors: Swan Christina H. , Chatterji Udayan , Gallay Philippe , Torbett Bruce E. 
Published: April 2020

Abstract
We recently identified naturally occurring HIV-1 capsid (CA) motifs, which evade both cyclophilin A (CypA)-dependence in human cells and TRIM-5α-CypA (TRIM-Cyp) restriction in owl monkey kidney (OMK) cells (Chatterji, et al. JBC, In press). These HIV-1 capsid motifs contained either one (G89V) or four (V86P/H87Q/I91V/M96I) amino acid substitutions within the CypA binding site, but only the four amino acid mutant was able to bind CypA, yet does not require CypA incorporation to infect human cells. OMK cells are naturally resistant to HIV-1 infection due to TRIM-Cyp, a negative host factor, which efficiently targets incoming wild type HIV-1 capsid and thereby prevents the proper uncoating of the CA core. However, addition of cyclosporine A, which blocks the interaction of CypA and CA, or mutations within the CypA-CA binding site (G89V) yields OMK cells permissive to HIV-1. Interestingly, HIV-1 infection with the V86P/H87Q/I91V/M96I capsid mutant was able to achieve similar levels of infection in OMK cells as does wild type HIV-1 with the addition of cyclosporine A, emphasizing that this motif allows infection despite TRIM-Cyp-CA interactions. Alternatively, the interaction between HIV-1 CA and CypA, is considered as a positive host factor in human cells. It has been proposed that CypA either “protects” the virus from endogenous restriction factors or allows proper CA core uncoating. Human cells lacking CypA or treated with cyclosporine A are highly resistant to infection by wild type HIV-1. Virus is blocked during the early stage of infection, at the pre-reverse transcription step. An important goal of human gene therapy is to efficiently deliver genes to non-dividing or quiescent cells such as hematopoietic stem cells and T-cells, respectively. Improvements on vector design such as self-inactivating LTRs, VSV-G envelope pseudotyping, various viral capsids, and enhancer elements have improved both the safety and efficiency of gene delivery. To identify capsid motifs that enhance transduction, we assessed whether the G89V and V86P/H87Q/I91V/M96I capsid motifs increased transduction efficacy in primary human cells as compared to vectors packaged with wild type HIV-1 gag/pol. Preliminary studies, at low levels of transduction (2000 pg p24 input ~1 MOI) in 293T cells, showed a 3-fold increase in GFP expression using the V86P/H87Q/I91V/M96I-gag/pol packaged vectors as compared to wild type or G89V-gag/pol vectors. Studies with primary PBMC and CD34+ hematopoietic stem cells are underway and will address whether the V86P/H87Q/I91V/M96I capsid motif will allow for greater transduction efficiency for non-cycling, quiescent and/or partially activated cells. Providing a means to enhance uniform vector transduction efficacy should allow for lower levels of vector input during transduction, thereby reducing the probability for insertional mutagenesis.
Can Health Care Plans Afford Hemophilia Costs? Yes.
Authors: Aledort Louis M. , Coates James 
Published: April 2020

Abstract
Hemophilia care has high annual recurring costs. 80–90% of these costs are to cover replacement therapy. Managed care programs have, in general, not recruited specialists to help determine the guidelines of care, the use of hemophilia treatment centers (HTC) by their patients or the multiple sources and charges for acquiring these expensive biologics. Aetna has 700–750 hemophilia patients in a typical year whose medical costs are upward of $60 million. These patients represent only.005% of the total membership, and 0.198% of the health care dollars spent. A hemophilia specialist was asked to evaluate these patients vis-á-vis site of care, optimal treatment plan, and potential savings for covered members, payers and employers.
Methods: working with the Aetna nurse case managers, individual patients were evaluated for the above issues.
Results: From June 2004 to June 2005, 190 patient files were reviewed. Of these, 18% had lifetime caps, and 30% were not treated in an HTC. 16% of these patients decided to transfer to an HTC for either their care or product procurement. The remainder decided not to pursue this path.
Table I Patients Issue 1) 4.5 % Altered regimen, product or product procurement 2) 3 % Contemplating altered regimen, product or product procurement 3) 17 % Physician contacted regarding optimal therapy 4) 9.5 % Prices of product negotiated downward 5) 12 % Product procurement switch to PHS pricing 6) 3 % Adhering to previous regimen Table II $ Savings (using above categories) Real Potential 1) 2,978,028 2) --- 353,972 3) 0 4) 1,157,504 5) 4,334,523 6) --- 1,904,360 Total 8,470,055 2,258,332
The potential savings represent those who are either contemplating change but, in the main, are physicians and/or patients who chose not to accept the recommendations made. Realized annualized savings of more than $8 million affect all aspects of the care system. It is particularly revelant to those with lifetime caps. If this model were expanded for other high cost disorders, medical expenses could diminish and premium inflation could eventually decrease. Hemophilia biologics have continued to increase in costs from cryoprecipitate in the 1960s to current recombinant products. Fostering access to HTCs substantially improves quality of care and reduces medical expenditures. In conclusion, we believe that by using this approach, hemophilia care and its costs can be appropriately managed.
Non-Hemolytic Antibody Induced Loss of RBC Antigen during Transfusion of Crossmatch Incompatible Blood.
Authors: Zimring James C. , Hair Gregory A. , Chadwick Traci E. , Deshpande Seema S. , Anderson Kimberly M. , Hillyer Christopher D. , Roback John D. 
Published: April 2020

Abstract
Background: Transfusion of red blood cells (RBC) into patients with anti-donor RBC antibodies (crossmatch incompatible transfusion) can result in antibody mediated hemolysis. Less well appreciated is the ability of anti-RBC antibodies to specifically remove their target antigen from donor RBCs without compromising cell survival. This phenomenon has now been reported for the major clinically significant blood group antigens, including Rh, Kell, Kidd and Duffy. Although this has been described multiple times in humans, no mechanistic elucidation has been accomplished. In an effort to investigate the mechanism of this process, we describe the first animal model of non-hemolytic antibody induced RBC antigen loss.
Methods: mHEL mice express the model antigen Hen Egg Lysozyme (HEL) as a cell surface protein on RBC. Since mHEL mice are on a C57BL/6 background, the mHEL antigen represents a single antigenic difference between donor RBC and recipient mice. Immunizing C57BL/6 mice with HEL/CFA results in the generation of high titer IgG anti-HEL responses rendering the mice crossmatch incompatible with mHEL RBC. This system was utilized to study the effects of transfusing mHEL RBC into crossmatch incompatible recipients.
Results: Similar to the antibody induced antigen loss observed in humans, transfusion of donor mHEL RBC into crossmatch incompatible mice results in selective loss of HEL antigen from donor RBC without affecting other blood group antigens or reducing the circulatory lifespan of the donor RBC. In addition, recovered RBC that have lost their antigen have normal morphology. This process is antigen specific and occurs in mice that have received passive injections of anti-HEL antisera. A spleen is not required for antigen loss to occur. However, antigen loss does not occur in animals with a targeted deletion of the FcγIII receptor. Although polyclonal anti-HEL antisera consistently causes antigen loss, and IgG1 and IgG2b are the predominant subclasses of anti-HEL IgG in the antisera, no antigen loss is observed in response to purified monoclonal anti-HEL antibodies of the IgG1 and IgG2b subclass.
Conclusion: These studies demonstrate that antibody induced antigen loss is a process that involves interaction of RBC, anti-RBC IgG and FcγIII receptors, thus providing mechanistic insight into the phenomenon of antigen loss during incompatible transfusion. The lack of antigen loss in response to monoclonal anti-HEL IgG1 or IgG2b suggests that antigen loss occurs in response to a minor IgG subtype in antisera, depends upon biological properties of the antibody (such as affinity), or that additional serum cofactors are involved.