bluuebunny/crossref_metadata_2025_split huggingface dataset:
Allogeneic Stem Cell Transplantation for Patients with Acute Leukemia Transformed from Myelofibrosis
Authors: Ciurea Stefan O , De Lima Marcos , Giralt Sergio , Qazilbash Muzaffar H. , Alousi Amin , Kebriaei Partow , Khouri Issa F. , Anderlini Paolo , Andersson Borje , Hosing Chitra , Verstovsek Srdan , Kantarjian Hagop , Champlin Richard , Popat Uday 
Published: October 2019

Abstract
Background and Rationale: Transformation of myelofibrosis (MF) to acute leukemia (>20% blasts) portends a grave prognosis. Allogeneic stem cell transplantation (ASCT) is a curative approach for patients with acute leukemia; however, the outcomes of ASCT in patients with MF transformed to acute leukemia are currently unknown.
Methods: Fifty-one consecutive patients with either primary (PMF) or secondary (SMF) were transplanted at UTMDACC after 1994. Thirteen patients who developed AML (25%), 10 arising from PMF and 3 with SMF, received an ASCT from a sibling or matched unrelated donor. Median age was 59 years. Five patients (38%) had prior splenectomy. JAK2V617F mutation analysis was performed in 7, and was present in 5 patients. Cytogenetics were intermediate in 10 and poor-risk in 3 patients. Seven patients (54%) were not in remission at the time of transplant. Eleven of 13 patients received induction chemotherapy; 6 achieved remission, while 7 had persistent disease at the time of transplant. One patient had a prior autologous transplant and 2 patients had prior allogeneic transplant for myelofibrosis. The donors were matched siblings (7 patients), matched unrelated (4 patients) and 1 antigen mismatched relatives (2 patients). The stem cell source was peripheral blood in 9 and bone marrow in 4 patients. Nine patients received a reduced-intensity conditioning regimen with a fludrabine-melphalan-based regimen, and 4 myeloablative conditioning (3 fludarabine-busulfan, 1 busulfan-cyclophosphamide).
Results: All patients engrafted, 75% achieved full donor chimerism, on day 30. Neutrophil and platelet engraftment occurred after a median of 13 and 21.5 days. Twelve evaluable patients achieved remission; 3 subsequently relapsed. JAK2V617F mutation became negative after transplant in all tested patients and reappeared in 1 patient who later relapsed. Grade 2–4 aGVHD developed in 3 patients (grade 3–4 in one) and cGVHD in 4/11 evaluable patients (extensive in two). After a median follow-up of 17.2 months (range 7.2–128.6 mo), OS and EFS were 49% (SE 15%) and 44% (SE 14%), respectively (Figure1). Six patients died, related to disease relapse (2), pneumonia (2), GVHD (1), and hepatic failure (1).
Conclusion: Patients with acute leukemia transformed from myelofibrosis with good performance status can achieve durable complete remissions with ASCT.
Figure 1. Overall survival (continuous line) and disease-free survival (interrupted line) in 13 patients with acute leukemia transformed from MF post ASCT after a median follow-up of 17.2 months. Figure 1. Overall survival (continuous line) and disease-free survival (interrupted line) in 13 patients with acute leukemia transformed from MF post ASCT after a median follow-up of 17.2 months.
Evaluation of Serum Free Light Chains and Outcome in Multiple Myeloma Patients with an Intact Monoclonal Immunoglobulin Treated with Autologous Stem Cell Transplantation.
Authors: Trieu Young , Xu Wei , Anglin Peter , Chen Christine , Kukreti Vishal , Trudel Suzanne , Reece Donna E. 
Published: October 2019

Abstract
Introduction: The serum free light chain (FLC) assay is a useful tool in diagnosing and monitoring multiple myeloma (MM) patients (pts) with non-secretory and light chain only disease. In addition, the detection of an abnormal serum FLC ratio is an adverse prognostic factor in pts with monoclonal gammopathy of undetermined significance. However, the relationship of the FLC assay to the outcome of patients with an intact monoclonal immunoglobulin following a single autologous stem cell transplantation (ASCT) has not been studied. Thus, the objective of this single centre, retrospective review study was to evaluate the usefulness of the FLC assay as a predictor for response rate and progression free survival (PFS) in this category of pts.
Patients & Methods: We identified in our Princess Margaret Hospital MM database a total of 290 pts who underwent a single ASCT between June 2003 and May 2006. Of these, 65 had an intact monoclonal immunoglobulin (IgG in 47, IgA in 16 and IgD in 2) detected at diagnosis plus FLCs measured at referral. Normal range for FLC measurements is as follows: kappa 3.3–13.1 mg/L, lambda 5.7–26.3 mg/L, and kappa/lambda ratio of 0.26–1.65.
Results: The median age at diagnosis was 59 years (range, 34–73); 33 (51%) were male. The median time from diagnosis to ASCT was 9.0 months (range, 5.0–29), with a median follow-up time of 27 months (range, 1.0–58.0). Assessment of best response following ASCT revealed that 20 (31%) pts achieved CR/nCR, 21 (32%) VGPR, 21 (32%) PR, 2 (3%) MR, and 1 (2%) was not evaluable for response. No prognostic factors for response were identified. To date, only 9 pts have died and the median overall survival is not yet reached. The median PFS is 25.4 months, with 36 patients progressing after ASCT. An elevated kappa and lambda light chain was detected in 30 (46%) and 22 (34%) of the 65 pts, respectively. Additionally, 52 (82%) of the 65 pts were found to have an abnormal kappa/lambda ratio. There was no significant difference in the PFS of patients with abnormal vs. normal free kappa light chains or FLC ratio. However, a decreased PFS was associated with elevated levels of serum free lambda light chains (p=0.01), β-2 microglobulin (p=0.007) and LDH (p=0.01).
Conclusions:
The majority of pts with an intact monoclonal immunoglobulin also have an abnormally high level of the corresponding serum FLC and an abnormal FLC ratio; an elevated serum free lambda level as well as increased β-2 microglobulin and LDH levels, as previously described, were identified as adverse prognostic factors for PFS in this population; we continue to routinely assess serum FLC for all pts at referral; however, longer follow-up is needed to further evaluate the prognostic significance of this parameter on the clinical outcome of pts.
Molecular Signatures to Improve Diagnosis, Prognostication and Identification of Oncogenic Pathways in Peripheral T and NK Cell Lymphoma.
Authors: Iqbal Javeed , Weisenburger Dennis , Greiner Timothy C. , Nakamura Shigeo , Vose Julie M. , Seto Masao , Delabie Jan , Berger Francoise , Loong Florence , Au Wing-Yan , Ko Young-Hyeh , Sng Ivy , Smith Lynette M , Kucuk Can , Geng Huimin , Armitage James , Chan Wing C. 
Published: October 2019

Abstract
Background: Peripheral T-cell lymphoma (PTCL) consists of an uncommon and heterogeneous group of lymphomas that are often challenging to diagnose and classify. Since most patients also have a poor survival with standard multiagent chemotherapy, more effective therapeutic approaches are needed to improve patient outcome.
Table1:
Pathological diagnosis Number of cases profiled AITL 36 ALK(+)ALCL 19 ALK (−)ALCL 08 ATLL 12 T/NK 14 PTCLU 44 Other rare entities 10
Methods: A mRNA profiling study using Affymetrix HGU133+2 arrays on 143 cases of PTCL and NK-cell lymphoma (NKCL) from the International Peripheral T-cell Lymphoma Project, was conducted on pre-treatment biopsies. These included the following pathologically classified cases (Table 1). In addition, we also profiled nine NK cell lines, seven T cell lines, normal resting and activated CD4+ and CD8+ T cells and resting and IL2- activated NK cells from healthy individuals. BRB-ArrayTools was used to develop gene classifiers for the major PTCL entities and survival predictors for AITL based on gene expression data.
Results: We have identified key molecular signatures for PTCL and NKCL that have allowed us to construct a robust classifier for AITL (207 transcripts), ALK+ ALCL (94), ATLL (225) and NKCL (127). PTCL-U group may have 3 or 4 molecular subgroups and additional studies with more cases, are necessary to further define this group. Misclassified cases were identified and re-assigned to the molecularly defined entities, including re-assigning of 9/44 PTCL-U to AITL. We have confirmed the enriched expression of genes identified in follicular helper T-cells in AITL, suggesting that AITL is derived from this T-cell subset. A number of oncogenic pathways (e.g. NF-κB, HIF-a,VEGF, IL6) and tumor/host interactions that contributed to local tumor-induced immunosuppression (e.g. TGF-b), were identified in AITL. A molecular predictor of outcome was developed for AITL and validated by leave one-out-cross validation. Since PTCL is an uncommon disease, future studies will require the collaboration of multiple large clinical groups with tissue resources for both discovery and validation.
Conclusion: This study has demonstrated that GEP will allow the construction of robust and biologically-meaningful classifiers for PTCL, and prognosticators can be derived for well-defined entities with a sufficient number of cases. GEP will also allow us to identify therapeutically-relevant oncogenic pathways and tumor/host interactions that may lead to improvement in the therapy and outcome of patients with PTCL and NKCL. (This study is a part of the International T-cell Lymphoma Project)
Limitations of Current Plasma VonWillebrand Factor (VWF) Activity Tests: A Comprehensive Comparison of Five VWF Activity Assays.
Authors: Chen Dong , Pruthi Rajiv , Nichols William L. , Heit John A. 
Published: October 2019

Abstract
Accurate measurement of plasma von Willebrand factor (VWF) activity is essential for the laboratory diagnosis and treatment monitoring of von Willebrand disease (VWD).
Currently available VWF activity assays include VWF ristocetin cofactor activity by manual light transmission platelet aggregometry (VWF:RCo–Agg) or flow cytometry (VWF:RCo–FL), collagen I and III binding activity (VWF:Co–I and –III) (Technozym), and platelet activity by latex agglutination (VWF:Lx) (Instrumental Laboratory). In this study we evaluated and compared the accuracy and precision of these 5 assay methods. Plasma samples from 11 normal donors and 41 patients categorized as type 1 (n=20) or type 2 (n=21) VWD based on clinical evaluation, fVIII:C activity, VWF:RCo–Agg, VWF antigen (VWF:Ag) level and plasma VWF multimer analysis by agarose gel electrophoresis were assayed for VWF activity by VWF:RCo–FL, VWF:Co–I, VWF:Co–III and VWF:Lx methods. The VWF:Ag/VWF activity ratio by VWF activity assay method was calculated for each sample. For normal donors and type I VWD patients, VWF:RCo–FL and VWF:Lx correlated well with VWF:RCo–Agg (R2=0.87, and 0.97, respectively), while VWF:Co–I and –III were lower compared to VWF:RCo-Agg. For type 2 VWD patients, different VWF:Ag/VWF activity ratio cutoffs (range 0.3–0.7) were used (Figure). Both VWF:RCo–Agg and –FL were sensitive (95%) and specific (97%) for type 2 VWD while the VWF:Lx was slightly less sensitive (81%) but was very specific (100%). VWF:Co–I and –III were the least sensitive (<90%) and specific (<90%); both methods had high false positive and negative rates for type 2 VWD. In Summary, for normals and type 1 VWD patients, VWF:RCo–FL and VWF:Lx correlate well with VWF:RCo–Agg and have similar sensitivities and specificities for type 2 VWD. VWF:Co–I and –III are unreliable for assessing plasma VWF activity.
Cell-Based Immunotherapy with Different Subsets of Tolerogenic Dendritic Cell in Idiopathic Thrombocytopenic Purpura.
Authors: Zhang Xiao-Lin , Peng Jun , Xu Shu-Qian , Liu Xin-Guang , Yu Yuan , Qin Ping , Shi Yan , Wang Lin , Hou Ming 
Published: October 2019

Abstract
There is growing evidence that tolerogenic dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction of anergic or regulatory T cells. However, in humans, little is known about the ability of tolerogenic DCs to induce tolerance to autoantigens in autoimmune patients. Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disease in which platelets are destroyed by antiplatelet autoantibodies. Here, we explored in vitro the ability of four subsets of tolerogenic DCs (i.e., immature DCs (imDCs), IL-10-modulated DCs (IL-10-DCs), vasoactive intestinal peptide-modulated DCs (VIP-DCs) or plasmacytoid DCs (pDCs)) derived from patients with ITP, to induce an anergic state or regulatory T cells in autologous platelet glycoprotein (GP)-specific T cells. GPIIb/IIIa-reactive T cells were preincubated with GPIIb/IIIa-loaded imDCs, IL- 10-DCs, pDCs or VIP-DCs, and then rechallenged with autologous mature DCs (mDCs) in the presence of GPIIb/IIIa. Only when T cells were cultured with GPIIb/IIIa-loaded VIP-DCs in primary incubation, inhibited proliferation of GPIIb/IIIa-reactive T cells could be observed at rechallenge with GPIIb/IIIa-loaded mDCs. The anergic state of VIPDC- primed GPIIb/IIIa-reactive T cells could be reversed when rechallenged with GPIIb/ IIIa-loaded mDCs in the presence of a high concentration of exogenous IL-2. Meanwhile, GPIIb/IIIa-reactive T cells were also cultured with VIP-DCs loaded with tetanus toxoid (TT). In contrast to T cells pretreated with GPIIb/IIIa-loaded VIP-DCs, GPIIb/IIIareactive T cells pretreated with TT-loaded VIP-DCs proliferated when rechallenged with GPIIb/IIIa-loaded mDCs, which demonstrated that the induced anergy of autoreactive T cells is antigen specific. Additionally, functional analysis showed that VIP-DC-modulated T cells could not suppress the proliferation of newly induced GPIIb/IIIa-reactive T cells when cocultured with GPIIb/IIIa-loaded mDCs. These results indicated that VIP-DCs could induce autoreactive T cells anergic but not functionally suppressive. Moreover, we found that coculture of VIP-DCs with autologous PBMCs resulted in reduced production of anti-GPIIb/IIIa antibodies, suggesting that GPIIb/IIIa-reactive T cells lost their helper function for inducing autoantibody production by B cells. In contrast, reduced antibody production could not be found when autologous PBMCs were cocultured with imDCs, IL-10-DCs or pDCs. In conclusion, our studies revealed the therapeutic potential of VIPDCs, compared with imDCs, IL-10-DCs or pDCs, to induce autoreactive T-cell anergy to GP antigens, which would in turn facilitate the reestablishment of autoantigen-specific tolerance in patients with ITP.
Changing Trends in ITP Management from 1995 to 2007: An Interim Report from the UK Paediatric ITP Registry.
Authors: Grainger John D. , Rees Joanne L , Reeves Marie , Bolton-Maggs Paula HB 
Published: October 2019

Abstract
A UK national paediatric ITP registry (www.uk-itp.org) was set up in January 2007 designed to collect data from all newly diagnosed ITP over at least a subsequent 10 year period. By May 2008, 62 hospitals had recruited 114 children. Details about epidemiology, presentation and management were entered into the registry. The preliminary data presented was compared with results from two national UK audits in 1995 and 2000.
In this first analysis, 68% children had mild, 29% had moderate and 3% had severe disease as defined by a modified Buchanan bleeding score. The mean platelet counts at diagnosis for the groups were 18.3, 10.1 and 8.0 respectively. Bruising (mean 86.7%) and purpura (mean 73.0%) were the most common bleeding manifestations in ITP followed by epistaxis (mean 22.0%) and oral bleeding (mean 18.7%). Other bleeding sites such as bleeding from the gastrointestinal tract and menorrhagia are much less common and there were no intracranial bleeds. Children with mild disease have fewer bleeding sites (mean 1.3), compared to 2.3 with moderate and 3.0 for severe disease. These data are very similar to those reported in the previous national audits.
The proportion of children receiving platelet raising treatment was noted to decrease from 60.5% in 1995 to 37.8% in 2000. The current 2007 registry data shows a continued decrease in treatment to 20% of all the children. In the mild category 11.8% were treated, compared to 31% of the moderate and all of the severe. Of those receiving treatment 75% were treated with steroids alone, 15% IVIG alone and 10% received combination IVIG and steroids. Forty seven percent were admitted to hospital with a median duration of stay at 2 days. In summary the current UK Paediatric ITP Registry data shows similar epidemiological data to the previous UK audits. The previous observed decrease in treatment and adoption of a “watch and monitor” policy has increased to the extent that 80% of children do not receive platelet raising therapy. Continued recruitment and analysis is required to provide more data on which patients can safely avoid platelet raising therapy and which patients require prompt treatment to raise their platelet count.
PTPN22 Mutation Is Present in An Increased Proportion of ITP Patients.
Authors: D’Silva Karl , Zamora Mathew , Gerlach John , Schwartz Kenneth A. 
Published: October 2019

Abstract
Immune-mediated thrombocytopenic purpura (ITP) is an autoimmune disorder characterized by low platelet count and antibody mediated platelet destruction. ITP may be due to a failure of T-cell tolerance. Protein tyrosine phosphatase non receptor type 22 (PTPN22) is an important negative regulator of signal transduction from the T cell receptor. A single nucleotide polymorphism 1858C>T in the PTPN22 gene has been associated with various autoimmune disorders. We hypothesize that the PTPN22 mutation 1858C>T would be present in a higher proportion of ITP patients and patients who carry the mutation would have an increased concentration of autologous antiplatelet IgG on their platelet surface. We genotyped 45 patients with ITP by a PCR based restriction length polymorphism(RFLP) to identify the mutation 1858C>T in the gene PTPN22. Ten patients (22%) were heterozygous for the PTPN22 mutation and 2 were homozygous for the mutation (4.4%). This compares with a frequency of 8.6% observed in a published population study of 960 controls who did not have autoimmune disease (p<0.0001) (Am. J. Hu. Genetics2004:75:330). All of the 12 ITP patients who carried the PTPN22 mutation had an increase in autologous platelet surface IgG (≥1250 molecules IgG/platelet)(Schwartz Am. J. Heme1990;33:167). We conclude that the PTPN22 1858C>T mutation is present in an increased proportion of ITP patients and that all 12 of the PTPN22 mutation positive patients were also positive for autologous antiplatelet IgG. Our results indicate that PTPN22 increases the probability of developing ITP.
Drug Dependent Immune Destruction of Human Platelets in the NOD/SCID Mouse.
Authors: Bougie Daniel W. , Boylan Brian , Nayak Dhirendra , Newman Peter J. , Aster Richard H. 
Published: October 2019

Abstract
Animal models have been of limited value for studying survival and immune destruction of human blood cells because of xenoantibodies that mediate rapid elimination of the transfused cells. The NOD/SCID mouse is a genetic variant that lacks immunoglobulins, including xenoantibodies, and may therefore be useful for studying survival and immune destruction of human blood cells (Newman, PJ et al. J Thromb Haemost.2007; 5 Suppl 1:305–9). Human platelets, infused into the retroorbital plexus of NOD/SCID mice survive about three days, nearly as long as mouse platelets themselves. Injection of IgG from a patient with quinine-induced immune thrombocytopenia (TP) and a newly developed quinine-dependent murine monoclonal antibody (mAb) were without effect on platelet survival. However, both antibodies caused rapid platelet clearance after IP injection of quinine. 500 μg, but not 50 μg, of IgG from serum containing an anti-HPA-1a (PlA1) antibody also caused rapid clearance of HPA-1a positive platelets. These findings indicate that the NOD/SCID mouse can be valuable for the study of immune clearance of human platelets and perhaps other unresolved problems in transfusion medicine. However, it is not known whether mice recognize cells opsonized with human IgG or mouse IgG equally well. To examine this, we compared the survival of human platelets sensitized with 1) mAb 7E3 (IgG1) specific for an epitope in the beta A domain of GPIIIa or 2) c7E3 (from Centocor Inc), which recognizes the same epitope but possesses a human IgG1 Fc. In titration studies, we found that about four times as much c7E3 as 7E3 is needed to produce equivalent clearance of human platelets, indicating that mouse IgG is a more efficient opsonin than human IgG. However, this difference should not limit use of the model for studies of antibody-mediated blood cell destruction, since mg quantities of IgG can easily be isolated from small amounts (0.1– 0.2 ml) of human serum.
Rare SOX13 Sequence Variations in Pediatric Idiopathic Thrombocytopenic Purpura Patients.
Authors: Rischewski Johannes R , Wyss Johanna , Stocker Sylvie , Hergersberg Martin , Huber Andreas R , Kühne Thomas 
Published: October 2019

Abstract
Introduction: Idiopathic or immune-thrombocytopenic purpura (ITP) is defined as a bleeding disorder with the hallmark of autoimmune mediated thrombocytopenia. ITP is a diagnosis of exclusion. Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver. Many nonhepatic autoimmune diseases are found in association with PBC, and may prompt initial presentation. Several case reports described the co-occurrence of ITP and PBC. In some PBC patients, autoantibodies against SOX13 can be detected. SOX13 has been identified as a transcription factor promoting gamma-delta T-cell development while opposing alpha-beta T cell differentiation. As ITP has been linked to the autoimmune bicytopenic Evans syndrome, which may present as autoimmune lymphoproliferative syndrome (ALPS) with the hallmark of increased alpha-beta double negative T-cells, we are interested in a potentially etiological role of molecular SOX13 sequence variations in ITP patients.
Material and methods: After obtaining informed consent from ITP patients (n=34) and their legal guardians to participate in the IRB approved study genomic DNA was extracted from peripheral blood samples. The complete coding region of SOX13 including the classical non-coding splice sites was amplified by PCR. The amplicons were screened for sequence variations by Denaturing High Performance Liquid Chromatography (DHPLC) after heteroduplex induction. All samples with aberrant DHPLC retention patterns were directly sequenced.
Results: Two rare heterozygous sequence variations in the coding region of SOX13 were detected in a total of 4 patients (12%): c.1603C>T (Pro534Ser) and c.1836 C>T (synonymous). Discussion: In a healthy cohort with European ancestry the heterozygous c.1603C>T (Pro534Ser) genotype was detected in 1.7% of individuals. In our cohort 6% of the ITP patients were heterozygous. 2.6% of individuals in a cohort of African-Americans and Caucasians carried the heterozygous genotype c.1836C>T (synonymous). 6% of the investigated ITP patients were heterozygous. A surprising high proportion (12%) of pediatric ITP patients carries one of two rare SOX13 sequence variations. The rare heterozygous genotypes are 3.5 (c.1603C>T) respectively 2.3 times (c.1836C>T) more common than in published non-ITP cohorts.
Conclusion: It seems possible, that rare alleles of SOX13 accumulate in pediatric ITP cohorts. Larger case-control sample studies are needed to verify the results. The rare genotypes could influence the alpha-beta versus gamma-delta T-cell balance in the studied pediatric ITP patients. Immunological studies of our cohort are necessary to evaluate this suggested association.