bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reduced Intensity Conditioning in Acute Leukemias: Long Term Follow-Up Confirms Sustained Complete Remissions.
Authors: Massenkeil Gero , Neuburger Stefan , Tamm Ingo , Lutz Christoph , Nagy Marion , Le Coutre Philipp , Doerken Bernd , Arnold Renate 
Published: April 2020

Abstract
Introduction:
Reduced intensity conditioning (RIC) now accounts for approximately one fourth of all allogeneic stem cell transplantations (SCT) worldwide (IBMTR database 2002). A reduction of transplant-related mortality has been observed in uncontrolled trials of patients with MDS, CLL, NHL and M. Hodgkin, but at the same time some of these trials revealed an increased relapse rate. Long term follow-up of acute leukemias after RIC has not been reported so far. Own results have demonstrated continuous complete remissions in patients with ALL transplanted early in the course of disease (Arnold 2002).
Patients and Methods:
Between August 1998 and December 2003, 40 pts with high-risk ALL (n = 11) or AML (n = 29) received allogeneic SCT after RIC with fludarabine, busulfan and ATG because of contraindications against standard high-dose conditioning (age &gt; 50 years, prior allogeneic SCT, fungal infections, low performance status). 8/40 had already relapsed prior standard SCT. 13 pts were in CR-1, 7 were in subsequent CR and 20 had uncontrolled disease. Median age was 48 years (range 19 – 67), 24 were male and 16 were female. All but one patient with 1 HLA-class I mismatch were transplanted from HLA-identical related (n = 23) or unrelated (n = 17) donors. Stem cell sources were mobilized peripheral blood in 37 and bone marrow in 3 patients. Patients received 5.0 x 10E6 CD34+ cells/kg bw in median (range 2.1 – 19.8). GvHD-prophylaxis was performed with cyclosporine A (CSA) alone (n = 23) or CSA + mycophenolate mofetil (n = 17).
Results:
37/40 pts reconstituted and reached CR including 17/20 patients with uncontrolled disease before SCT. 1/40 had a primary graft failure and was successfully retransplanted; two patients had refractory disease. After a median follow-up of 14 months (range 2 – 64 months), cumulative transplant-related mortality is 8 % ( 3/40 patients). 9/40 patients had developed acute GvHD III–IV and 11/24 patients had chronic extensive disease. 19 patients relapsed (including 2 refractory patients and 7/8 patients with salvage transplantation). Probability of disease-free survival at 3 years is 49 %. Overall survival at 3-year is 37 %. Median survival for patients with ALL is 13 months (95% C.I., 1 – 26) and for AML 14 months (95% C.I. 4 – 24) (n.s.). Among 18 survivors in CR, 8 were transplanted in CR-1 and 10 with advanced disease.
Discussion:
RIC results in sustained complete remissions in patients with high-risk acute leukemias. Even advanced diseases can be cured by allogeneic SCT after RIC. The high relapse rate is worrisome and calls for effective post-transplant strategies like prophylactic DLI or maintenance therapy to reduce relapse risk. TRM is comparably low in this group despite intensive pre-treatment and high rates of GvHD.
Characterization of the Binding Interaction between ADAMTS13 and von Willebrand Factor (VWF).
Authors: Majerus Elaine M. , Anderson Patricia J. , Sadler J. Evan 
Published: April 2020

Abstract
VWF multimers are cleaved into smaller less thrombogenic fragments in plasma by ADAMTS13. Deficiency of ADAMTS13 activity leads to thombotic thrombocytopenic purpura (TTP), a disease characterized by thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological decline, and renal insufficiency. ADAMTS13 is a member of the A Disintegrin and Metalloprotease with ThromboSpondin repeats family that has characteristic motifs including a signal sequence, a propeptide, a catalytic metalloprotease domain, a disintegrin domain, a thrombospondin-1 (TSP1) repeat, a cysteine-rich region, and a spacer domain. These domains are followed in ADAMTS13 by seven additional TSP1 repeats and two C-terminal CUB domains. Previous work has shown that ADAMTS13 truncated after the spacer domain retains proteolytic activity towards VWF, but little is known about the potential role of the additional C-terminal TSP1 and CUB domains in VWF binding or cleavage. We therefore developed an enzyme-linked immunosorbent assay (ELISA)-based system to study ADAMTS13-VWF binding. VWF was immobilized in microtiter wells and incubated with plasma or recombinant ADAMTS13 variants. Bound ADAMTS13 was detected directly by solubilization and Western blotting, or indirectly by ELISA. ADAMTS13 proteolytic activity towards VWF is enhanced by denaturation of VWF with urea or guanidine, but ADAMTS13 bound specifically to VWF without prior denaturation. EDTA increased the binding of ADAMTS13 to VWF and prevented proteolysis of the immobilized VWF. Binding was saturable and time-dependent with maximal binding in two hours. Binding was reversible with a half-time for dissociation of four hours. ADAMTS13 in normal human plasma but not in plasma from a patient with TTP bound immobilized VWF. The stoichiometry of VWF monomers to ADAMTS13 at saturation was approximately 2 (range 1–4) and the Kd of recombinant ADAMTS13 binding to VWF was 12 nM (range 5–26 nM). This Kd for binding is similar to the Km for VWF cleavage of 16 nM determined independently, and both are comparable to the estimated plasma ADAMTS13 concentration of 8 nM. The properties of C-terminally truncated ADAMTS13 constructs suggest a regulatory function for certain domains. Truncation after the 8th TSP1 domain decreased the Kd 2-fold. Further truncation after either the 6th or 7th TSP1 domain increased the Kd 2-fold relative to full-length ADAMTS13. Truncation after the spacer domain gave binding properties indistinguishable from full-length ADAMTS13. Truncation after the metalloprotease domain gave no detectable binding to VWF. Therefore, binding of ADAMTS13 to VWF requires sequences in the cysteine-rich or spacer domains, and is modulated by sequences in at least the 8th TSP1 repeat and the CUB domains.
Allogeneic BMT Followed by Substrate Deprivation Therapy with N-butyldeoxynojirimycin in a Child with Tay-Sachs Disease.
Authors: Jacobs Hans J.F.M. , Willemsen Michel M.A.A.P. , Groot-Loonen Jacqueline J.J. , Wevers Ron R.A. , Hoogerbrugge Peter P.M. 
Published: April 2020

Abstract
Introduction: Tay-Sachs Disease (GM2 gangliosidosis) is a lysosomal storage disorder caused by beta-hexosaminidase A (Hex-A) deficiency, which leads to severe and progressive neurological damage. BMT has been used successfully as treatment strategy in some storage disorders. GM2 gangliosidosis mouse models demonstrate that after BMT donor-derived metabolically competent cells infiltrate the CNS leading to delayed onset of symptoms and prolonged survival. Further enhancement of survival has been reported in mice receiving a combination of substrate deprivation therapy and BMT. To our knowledge data on the effects of BMT in children with Tay-Sachs disease are lacking.
Patient: A three-year-old girl was diagnosed with Tay-Sachs disease with minimal clinical symptoms, after the same diagnosis was made in her symptomatic older sister. Pre-BMT conditioning consisted of busulfan, cyclophosphamide and ATG. She received T-cell depleted marrow from an HLA identical unrelated donor. Ciclosporin-A (CsA) was given as GvHD prophylaxis. Follow-up is 2.5 years.
Results: Hex-A levels in leukocytes increased initially to donor levels and decreased to a steady level of 30% of controls for the last 1.5 years, indicating stable mixed chimerism. Also the enzyme levels in serum increased to 10% of controls, indicating release of enzyme into serum. Shortly after BMT, rapid progression of neurological symptoms occurred (MRI, EEG and neuro-psychological tests). Some neurological symptoms partially improved, others stabilized after CsA was stopped, suggesting that CsA had contributed to the neurological deterioration. Experimental substrate deprivation therapy with N-butyldeoxynojirimycin was started 1.5 years after BMT. No adverse effects of this drug were observed.
Conclusion: BMT followed by substrate deprivation therapy in our patient with early stage of Tay-Sachs disease resulted in Hex-A enzyme levels in leukocytes and serum of 30% and 10% of normal levels respectively. Neurological deterioration occurred shortly after BMT and seemed to stabilize thereafter, but follow-up is too short to draw firm conclusions yet.
A Pilot Study for Haploidentical Transplant Using a Chemotherapy only Preparative Regimen eith T-Cell Depleted Haploidentical Transplant and Intensive Antibiotic Prophylaxis To Treat Advanced Leukemia Patients (pts).
Authors: Gajewski James L. , Saliba Rima , McMannis John D. , Shpall Elizabeth J. , Ippoliti Cindy , Giralt Sergio A. , Jones Roy B. , Khouri Issa F. , Hosing Chitra M. , Korbling Martin J. , Donato Michele L. , Champlin Richard E. 
Published: April 2020

Abstract
We present preliminary data of haploidentical transplant for 12 patients (pts) with relapse of refractory acute leukemia using a chemotherapy only preparative regimen of 140 mg/m2 Melphalan on day −8; 10 mg/kg Thiotepa on day −7; 160 mg/m2 Fludarabine on days −6, −5, −4, −3; 1.5 mg/kg of rabbit ATG/day days −6, −5, −4, −3 and T-cell depleted peripheral blood progenitor cells, processed using the CliniMACS® device. All products had &lt;1 x 104 CD3+ T-cells/kg recipient body weight and needed a minimum of 5 x 106 CD34+ cells/kg but preferably &gt;1 x 107 CD34+ cells/kg recipient body weight. Pts received: intensive PCP prophylaxis with bactrim and pentamidine prior to transplant and during pancytopenia; CMV prophylaxis with valcyte during the BMT prep and foscarnet while pancytopenic; and with ambisone for fungus. The last 4 pts enrolled were treated with cancidas prophylactically instead of ambisome. 10 of 12 pts engrafted (83%). 2 pts had protocol deviations and primary graft failure - 1 survived disease free and 1 relapsed. Median time to engraftment was 14 days (range, 9–26) to 500 neutrophils and 13 days to platelets 20,000 (range, 10–25). Among engrafting patients, two died within 100 days due to disease progression and multiple organ failure. Six-month overall survival is 50% (21–74). One year overall and progression-free survival is 33% (95% CI 10–59). 7 pts had disease relapse at a median of 10 months (range 2–13 months). Two of 10 pts who engrafted developed grade 1 acute graft-versus-host disease (GVHD) and 4/8 pts who engrafted and survived beyond day 100 had chronic GVHD. The 2 patients who engrafted and survived beyond 1 year post transplant had chronic GVHD. This report for haploidentical transplant demonstrates that a chemotherapy only preparative regimen achieved a high rate of engraftment. Infectious complications were minimal. 25% of patients survived progression free. If these results are sustained in a larger study, haploidentical transplant may offer hope of allogeneic transplant for every individual needing such therapy.
Biology-Driven Classification of Childhood Acute Lymphoblastic Leukemia: A Combined Analysis of Prognostic Markers from the Pediatric Oncology Group (POG) and Children’s Cancer Group (CCG).
Authors: Schultz Kirk R. , Pullen Jeanette , Sather Harland , Shuster Jonathan , Borowitz Michael J. , Heerema Nyla A. , Carroll Andrew J. , Gaynon Paul S. , Camitta Bruce M. 
Published: April 2020

Abstract
Risk adapted therapy, tailoring treatment to the likelihood of relapse, has constituted a significant advance in the treatment of childhood ALL. The recent merger of the POG and CCG provided an opportunity to reassess previous approaches and to develop a new biology driven classification system based on data from both legacy groups. All children (age 12 months to 21.99 years) with newly diagnosed B-precursor (ALL), consecutively enrolled on CCG (December 1988 to August 1995, N = 3056) and POG (January 1986 to November 1999, N = 6800) protocols, were evaluated for the impact of numerous clinical and laboratory variables on event free survival at 5 and 8 years in each group separately, thereby superseding differences in treatment approaches. Infants and patients with a T- cell phenotype were excluded from the analyses. Very high risk was defined as the group for which myeloablative therapy might be indicated with an anticipated 5 year EFS &lt;45%, while a reduction in therapy could be justified for the lowest risk patients with a &gt;85% 5 year EFS. Patients identified as being at very high risk for relapse had hypodiploidy (&lt;45 chromosomes) (CCG 34.8%, POG 46.5% - 5 year EFS), induction failure (CCG 11.3% 5 year EFS) or t(9;22) or BCR/ABL (POG 27.5%, CCG 29.6% 5 year EFS). Patients identified as low risk for relapse were NCI standard risk patients with either t(12;21) (TEL-AML1) (CCG 86%, POG 85% 5 year EFS) or all three trisomies of 4, 10, and 17 (CCG 91.5%, POG 89.3% 5 year EFS). Certain NCI high risk patients were identified as having a higher risk for relapse but did not fall into the VHR category: t(4;11)(POG 49.9%, CCG 50.0% 5 year EFS),CNS3 (CCG 59.3%, POG 67.8% 5 year EFS) and slow early response (SER) defined by M2/3 at day 14 (Standard risk 66% SER versus 84% and for high risk ALL 63% SER versus 75%). Other potential VHR factors that require confirmation included, slow early responder t(4;11) (CCG 11.1% 5 year EFS) and monosomy 7 (CCG 44%, POG 66.6% 5 year EFS). A balanced t(1;19) had only a minor unfavorable effect on EFS. The COG has identified a risk classification system that builds on the previous NCI risk classification system for childhood ALL, incorporating the cytogenetic and molecular genetic features of the blasts, as well as rapidity of clinical response. The division of B-precursor ALL patients into low risk (18%), standard risk (49%), high risk (30%) and very high risk (3%) groups will : 1) identify those patients for whom therapy might be reduced without sacrificing overall cure rates, 2) determine those patients who will require intensified therapy and 3) suggest underlying biological pathways that mediate cure or treatment failure.
Autologous Hematopoietic Stem Cell Transplantation without Total Body Irradiation for Diffuse Scleroderma. Rapid Improvement of Skin Score.
Authors: Oyama Yu , Burt Richard K. , Traynor Ann E. , Statkute Laisvyde , Barr Walter G. 
Published: April 2020

Abstract
Background & Aims
Scleroderma is an immune mediated vasculopathy of unknown etiology. There is no known therapy that could alter the natural course of the disease. Patients with diffuse cutaneous disease or visceral involvement has an overall 10-year survival of 35 to 68%. Hematopoietic stem cell transplantation (HSCT) has been performed in the US, but with substantial toxicity, may be due to regimens that utilize total body irradiation (TBI). We performed autologous HSCT without TBI.
Methods
We conducted a phase I HSCT study in 5 patients with diffuse scleroderma with poor clinical features. Candidates were less than 65 years old with modified Rodnan skin score (mRSS) of more than 14 or lung diffusion capacity (DLCO) less than 80%, interstitial lung disease, elevated ESR, renal involvement, or abnormal electrocardiogram. Patients with irreversible end-stage organ involvement were excluded. Peripheral blood stem cells were mobilized with cyclophosphamide and granulocyte colony-stimulating factor. The graft was not manipulated. The conditioning regimen consisted of 200mg/kg cyclophosphamide (CY), and 7.5mg/kg rabbit antithymocyte globulin (ATG).
Results
The procedure was well tolerated with anticipated cytopenias, neutropenic fever, and fluid overload that were easy to manage and without mortality. The median days for neutrophil and platelet engraftment were 8 (range 7–9) and 8 (range 0–10), respectively. The median infused CD34+ and CD3+ cell counts were 9.27 x 106/kg (range 2.35–14.7) and 2.34 x 108/kg (range 1.48–6.83), respectively. Improvement of mRSS and changes of pulmonary function {DLCO, total lung capacity (TLC)}, cardiac function {left ventricular ejection fraction (LVEF), pulmonary artery pressure (PA pressure)} and renal function (creatinine) pre-HSCT, at 6 months and at 12 months post-HSCT are in table 1. After median follow-up of 19 months (range 8–20), all patients had improvement of skin score while pulmonary, cardiac and renal function remained stable.
Conclusion
Autologous HSCT with CY/ATG is safe and may be effective. Randomized studies will be needed to confirm the efficacy of this therapy.
table 1
patient skin score (mRSS) DLCO % TLC % LVEF % PA pressure mmHg Creatinine mg/dl 1 pre HSCT 26 48 71 60 23 0.7 6 months 13 39 73 63 normal 0.7 12 months 6 44 74 64 20 1 2 pre HSCT 31 86 114 58 33 0.7 6 months 17 62 106 60 unable to obtain 0.8 12 months 17 118 112 60 28 1 3 pre HSCT 31 57 73 70 36 0.8 6 months 18 55 64 60 35 0.7 12 months 18 48 69 65 43 0.7 4 pre HSCT 24 59 83 55 unable to obtain 0.5 6 months 8 52 79 55 26 0.5 12 months 5 45 73 50 unable to obtain 0.4 5 pre HSCT 30 48 94 55 25 0.6 6 months 8 54 80 55 normal 0.7
Extreme Regression: A Statistical Technique for Finding Good or Poor Prognostic Groups, Illustrated Using Myeloma Patient Data from Intergroup Trial S9321.
Authors: Crowley John J. , McCoy Jason , LeBlanc Michael , Barlogie Bart 
Published: April 2020

Abstract
Extreme Regression (LeBlanc, Moon and Kooperberg, manuscript submitted) is a statistical technique for finding patient subsets with either very good or very poor prognosis. In contrast to Cox regression, which generates predictions based on linear combinations of variables, Extreme Regression results in groups based on intersections or unions of simple statements involving single covariates (eg sb2m &gt; 3.5 and albumin &lt; 3.5; sb2m &gt; 3.5 or LDH &gt; ULN). Thus, Extreme Regression is similar in spirit to tree-based regression methods, except that the goal is not to develop a complete staging system (like the new International Staging System, ISS, for myeloma, which was derived using tress-based methods) but rather to define subsets of a given size (eg 10%) with extreme prognosis. Here prognosis may be defined in terms of any type of outcome such as response, one-year mortality, overall survival, etc. To illustrate we use survival data from the Intergroup Trial S9321, which tested high dose therapy with melphalan and TBI versus a standard dose regimen of VBMCP (both after VAD induction) for newly diagnosed patients with multiple myeloma. We used as potential predictors serum beta-2 microglobulin (sb2m), LDH, albumin and creatinine as measured at baseline. There were 682 eligible patients with complete data on these four covariates. We asked the algorithm to identify roughly 10% of the patients representing a poor prognosis group, and then another 25% representing a good prognosis group. The results are shown in Figure 1, along with the intermediate group of all other patients. The poor risk group comprised 77 patients (11% of the total) and was defined by those patients with sb2m &gt; 9 and LDH &gt; ULN; or patients with creatinine &gt; 5; or patients with albumin &lt; 2. These patients had a median survival of 19 months, a one year survival of 66%, and a five year survival of 19%. The good risk group included 181 patients (27%) defined by LDH &lt;= 67% of ULN and creatinine &lt;= 2 and albumin &gt;= 3.5. This group had a median survival of 67 months, a one year survival of 96%, and a five year survival of 57%. Extreme regression appears to be a promising exploratory tool when the goal is the identification of simple, interpretable subsets of patients with extreme prognosis.
Figure Figure
Autologous Hematopoietic Stem Cell Transplantation for Type I Diabetes Mellitus.
Authors: Voltarelli Julio C. , Couri Carlos E.B. , Oliveira Maria-Carolina B. , Stracieri Ana-Beatriz P.L. , Moraes Daniela A. , Godoi Dannielle F. , Coutinho Marina A. , Malmegrim Kelen C.R. , Foss-Freitas Maria-Cristina , Foss Milton C. , Simoes Belinda P. , Squiers Elizabeth C. , Burt Richard K. 
Published: April 2020

Abstract
Insulin-dependent type I diabetes mellitus (IDDM) is caused by autoimmune destruction of pancreatic β-islet cells mediated by inflammatory T cells. The pathogenic process evolves gradually for several years and becomes symptomatic when most Langerhans islands are destroyed. Antibodies against β-cell antigens (like anti-glutamic acid decarboxylase, GAD) are markers of the autoimmune reaction and levels of proinsulin C-peptide correlate with endogenous insulin secretion. Several immunosuppressive regimens have demonstrated clinical and laboratorial benefit in early onset IDDM, presumably sparing islets reserve, but most responses were transient and long term toxicity limited their continuous use. In view of durable remissions observed in various autoimmune diseases treated with high-dose immunosuppression and autologous hematopoietic stem cell transplantation (AHSCT), we started in December/03 a phase I/II trial of AHSCT in early-onset IDDM. Patients from 12–35 years old with &lt;6 weeks from diagnosis have their peripheral blood stem cells mobilized with 2 g/m2 cyclophosphamide and 10 mcg/kg G-CSF, cryopreserved and reinfused (&gt;2 million/kg) after conditioning with 200 mg/kg cyclophosphamide and 4,5 mg/kg rabbit antithymocyte globulin- ATG (Thymoglobuline, SangStat). End points of the study are insulin needs (U/kg/d), glycosilated hemoglobin levels, anti-GAD titers and C-peptide levels. Four patients have been transplanted and the insulin usage of the first three patients is shown in the Figure. The first patient received high dose of steroids to prevent ATG hypersensitivity and showed increasing needs of insulin after mobilization. The other two patients received minimal (#2) or no (#3) steroid dose during conditioning and showed decreasing needs of insulin after mobilization (Figure). Patient #2 presented bilateral pneumonia while pancytopenic, recovered after treatment with antibiotics and Amphotericin-B but did not require insulin therapy. A fourth patient has just been discharged from the BMT Unit. Immunologic studies in the three patients with longer follow-up showed a progressive shift from Th1 to Th2 cytokine profile after transplantation which could provide a mechanism for the modulation of the autoimmune process by high dose immunosuppression and autologous HSC. In conclusion, the preliminary results are encouraging but must be validated with a larger number of patients (12 planned in this phase) and a longer followup (5 years).
Figure Figure
Intratumoral Expression of MIP-1b Induces Antitumor Responses in a Pre-Established Tumor Model through Chemoattracting T Cells and NK Cells.
Authors: Yu Yizhi , Luo Xiaoling , Liu Shuxun , Xie Yuan , Cao Xuetao 
Published: April 2020

Abstract
Direct intratumoral introduction of therapeutic or regulatory genes is a developing technology with potential application for cancer gene therapy. Macrophage inflammatory protein-1 beta (MIP-1b) is a chemokine which can chemoattract immune cells such as T cells. In the present study, murine colorectal adenocarcinoma CT26 cells were transfected with a recombinant adenovirus (AdhMIP-1b) carrying the human MIP-1b gene. 24h post-transfection, hMIP-1b levels reached approximately 980 pg/ml in supernatants of 106 hMIP-1b-transfected CT26 cells. Moreover, the supernatants exhibited chemotactic activity for CD8+ T cells, CD4+ T cells, NK cells and immature DCs. Intratumoral injection of AdhMIP-1b significantly inhibited tumor growth and prolonged the survival time of tumor-bearing mice. Intratumoral hMIP-1b gene transfer also induced powerful tumor-specific CTL responses in vivo. The therapeutic effects of hMIP-1b gene therapy were greatly reduced following in vivo depletion of both CD4+ and CD8+ T cells, but were unaffected by depletion of single T cell subsets. Immune cell depletion experiments also revealed that NK cells played an important role in hMIP-1b-induced anti-tumor responses. These results suggest that intratumoral expression of hMIP-1b has the potential effect to induce host anti-tumor immunity and may prove to be a useful form of cancer gene therapy.