bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphisms and Lack of or Aberrant Expression of HLA Class I and II May Influence Antigen Presentation in Classical Hodgkin Lymphoma.
Authors: Diepstra Arjan , Poppema Sibrand , te Meerman Gerard , Niens Marijke , Nolte Ilja , Vellenga Edo , van Imhoff Gustaaf , Kluiver Joost , van den Berg Anke 
Published: October 2019

Abstract
In a previously performed population-based genetic screening analysis we found that polymorphisms in the HLA class I region are specifically associated with EBV-positive classical Hodgkin lymphoma(cHL)(Diepstra et al., Lancet2005;365:2216). We now studied the expression of HLA class I and HLA class II in this population (n=450) by immunohistochemistry. HLA-B/C, HLA-G, beta-2-microglobulin and HLA-DP/DQ/DR staining was performed on formalin fixed paraffin embedded tissue sections, and HLA-DM and HLA-DO staining on frozen sections. Hodgkin-Reed Sternberg (HRS) cells showed cell surface expression of HLA class I in 37.5% (159/424) of cHL tumors and expression was observed predominantly in EBV-positive cases (73%; 103/141). Expression of HLA-G, a molecule known to enable evasion from natural killer cell responses, was found in 67% of the cases and was associated with absence of MHC class I and EBV. Only 58% of cHL cases showed HLA class II positive staining in more than 50% of the HRS cells (224/387). The non-classical HLA class II protein HLA-DM, essential for the loading of HLA class II with antigenic peptides was reduced or absent in HRS cells in 7 out of 10 HLA class II positive cases, whereas HLA-DO, the natural repressor of HLA-DM, was not or minimally expressed. Impaired expression of HLA-DM may prevent presentation of antigens at the level of individual HRS cells. Reanalysis of the genotyping data revealed an association of HLA class I positive cases with the known susceptibility polymorphisms in the HLA class I region. However, this association was stronger for the EBV-positive cases than for the HLA class I positive cases. Within the group of EBV-positive cHL patients, the same predisposing alleles were present in both HLA class I negative and positive cases, suggesting that the negative cases probably did express HLA class I during early pathogenesis. Finally, in cases with HLA class II expression on the HRS cells, a genetic association with the HLA class II region was found. These changes may influence (EBV) antigen presentation by HRS cells in cHL.
Prediction of Relapse Risk by Day 100 BCR-ABL Quantification after Allogeneic Stem Cell Transplantation for Chronic Myeloid Leukaemia.
Authors: Rubio Marie T. , Asnafi Vahid , Delabesse Eric , Damaj Gandhi , Dhedin Nathalie , Varet Bruno R. , Buzyn Agnes , Macintyre Elizabeth A. 
Published: October 2019

Abstract
CML relapse after allogeneic SCT is a relatively frequent situation and is clearly correlated to disease status, time from diagnosis to transplant and T cell depletion. Defining other risk factors could help modulate post transplant immunosuppression. We evaluated the value of early minimal residual disease (MRD) quantification to predict relapse of CML patients receiving standard allogeneic SCT. MRD was analysed by RQ-PCR at Day 100 in 38 patients with a follow up after transplant > 1 year and was expressed as BCR-ABL/ABL, qualified by objective evaluation of RNA amplifiability relative to local normal values for MRD samples (the Quality Index or QI). This QI allows objective evaluation of the degree of correction for positive results and modification of the limits of detection for negative results. Thirty six of 38 patients received conventional conditioning regimen with either BU/CY or TBI/CY and classical prevention of GVHD based on cyclosporin and methotrexate. The median time from diagnosis to transplant was 21 months and median follow up of the cohort was 76.8 months. Patients were allocated to two groups according to their Day 100 RQ PCR level. We compared the characteristics and evolution of the 14 patients with a high MRD level (Day 100 RQ PCR >10−4) to that of the 24 patients with a low MRD level (Day 100 RQ PCR <10−4). There were no significant differences in terms of disease status at transplant, median age at transplant, time from diagnosis to transplant, type of conditioning regimen, source of stem cells, sex mismatch, grade of acute GVHD or incidence of chronic GVHD between the two groups. We show that Day 100 BCR-ABL transcript levels >10−4 by RQ-PCR represents an independent risk factor of relapse after conventional non T cell depleted SCT. These data should favour risk-adapted post transplant immunosuppression based on a single time point early evaluation of MRD.
Transplant Outcomes and Stabilization of Neurological Function in Young Children with MPS III (Sanfilippo Syndrome) after Unrelated Donor Umbilical Cord Blood Transplantation.
Authors: Lakshminarayanan Sonali , Szabolcs Paul , Prasad Vinod K. , Parikh Suhag , Allison June , Wood Susan J. , Escolar Maria , Kurtzberg Joanne 
Published: October 2019

Abstract
Between September 1998 and June 2004, 15 children, ages 10 – 55 months, 60% males, 14 Caucasian, 1 mixed racial background, underwent unrelated donor umbilical cord blood transplantation for treatment MPS III (Sanfilippo Syndrome, types A or B) Grafts were mismatched at 0 (n = 1), 1 (n = 10) or 2 (n = 4) HLA loci. All children were prepared for transplant with busulfan 40mg/m2/dose PO or 1mg/kg/dose IV targeting a Css of 600–900ng/ml), cyclophosphamide 50mg/kg/dose daily x 4, and equine ATG 30mg/kg/dose daily x 3. Cyclosporine and solumedrol were used for prophylaxis against GvHD. Engraftment with donor cells occurred in 10/15 patients, although one additional patient engrafted after a second transplant. Five patients, including the one transplanted a second time, died within 8 months of transplant of graft failure with respiratory failure and viral infections (Adenovirus, HSV). Six patients developed mild to moderate acute GvHD and 4 patients had limited (2) or extensive (2) chronic GvHD. All children were tested with baseline neurophysiologic, imaging and neurocognitive tests. These were then followed in surviving children every 6 months for 2 years and yearly thereafter. All children demonstrated deficits in hearing and mild to moderate developmental delays at the time of initial evaluation. MRIs showed varying degrees of volume loss generally increasing with the age of the patient at initial evaluation. EEGs were normal in the younger patients, but showed slowing and signs of generalized encephalopathy in the older patients. Two patients developed hydrocephalus requiring VP shunt placement within 1 year of transplant and one patient experienced subdural hematomas after minor head trauma. MRIs of all surviving patients stabilized for the first 4 years post transplant. One patient, now almost 5 years post transplant showed volume loss on the latest study. Patients transplanted at <3 years of age appear to have better neurocognitive outcomes than those over 3 since the younger patients continue to learn, albeit at a slower pace than typically developing children, while the older patients appear to have stabilized at their pretransplant level of functioning. All patients, however, show improvement in adaptive behaviors and general well being. Parents report less aggression, autistic like behaviors and improved sleep. We conclude that UCBT has a role in the therapy of children with MPS III. Effects of transplantation under the age of 2 years should be explored in a larger group of patients.
Mutational Status of Chronic Lymphocytic Leukemia (CLL) Determines Clonlal Evolution in Classical Hodgkin’s Lymphoma Variant of Richter’s Transformation.
Authors: Chen Wayne W. , Raffeld Mark , Pittaluga Stefania , Sorbara Lynn , Jaffe Elaine S. 
Published: October 2019

Abstract
Approximately 5% of CLL patients transform during their clinical course into a high grade lymphoma, referred to as Richter’s transformation, most commonly DLBCL, rarely (0.4%) classical Hodgkin’s lymphoma (cHL). Most cases of cHL transformation are Epstein-Barr virus positive and are often related to fludarabine treatment. Only a handful of cases in the literature, most of them EBV positive, have been studied for their clonal relationship with the pre-existing CLL. EBV negative cHL cases in CLL patients are rare and have not been well investigated. We have studied 2 EBV positive and 8 EBV negative cHL cases using single cell laser microdissection combined with PCR analysis for the IgH gene rearrangement. ZAP-70 immunohistochemical staining was used as a surrogate for Ig gene mutational status. Three cases of EBV negative and 1 EBV positive cHL case arose in ZAP-70 negative (mutated) CLL while 5 EBV negative and 1 EBV positve cHL cases arose in ZAP-70 positive (unmutated) CLL. Surprisingly, regardless of the EBV status, all 4 cHL cases from ZAP-70 negative (mutated) CLL shared the same clonal origin with the pre-existing CLL. In contrast, all 6 cHL cases from ZAP-70 positive (unmutated) CLL exhibited a different clonal origin. These results demonstrate that the mutational status of the CLL, and not the EBV status of the cHL, determines the nature of the evolution to cHL. Additional EBV positive cHL cases are currently under investigation. Passage through the germinal center may predict the ability of a CLL B-cell to transform to a Hodgkin’s cell.
Highly Efficient Gene-Transfer into Chronic Lymphocytic Leukemia Cells Using Adenovirus Type 35 Genetic Vectors.
Authors: Whitacre David C. , Hedjran Farah , Schmidt-Wolf Ingo , Prussak Charles , Reid Tony , Kipps Thomas J. , Whitacre David 
Published: October 2019

Abstract
Adenovirus (Ad) vectors have been used to introduce genetic material into mammalian cells for gene-expression studies and/or gene therapy. Ad serotypes 2 and 5, the most widely used Ad virus vectors, belong to the group C adenoviruses, which bind to the coxsakie/adenovirus receptor (CAR) present on cells that are most susceptible to virus infection. Because lymphoid cells generally do not express CAR, high-titer virus and optimal conditions are required to infect lymphocytes, including the neoplastic cells of most lymphoid malignancies. Ad35, on the other hand, is a member of the group B adenoviruses that infect cells by binding CD46, a receptor expressed on most cell types. We found chronic lymphocytic leukemia B cells (n = 10) expressed high-levels of CD46 by flow cytometry, whereas none of the CLL samples expressed CAR by immunoblot analyses. We examined and compared the relative susceptibility of CLL cells to infection by Ad5 versus Ad35 vectors at various multiplicity of infection (MOI). These studies revealed that CLL cells were 100-fold more sensitive to infection with Ad35 than with Ad5. To examine whether this improved tropism of Ad35 for CLL cells was due to the adenovirus receptor for CD46, we examined the relative susceptibility of CLL cells to infection by Ad5 vectors that had been engineered to express the Ad35 knob fiber protein (Shayakhmetov DM, et al., J Virol 2000, vol 74, pp. 2567-83) responsible for binding CD46, designated Ad5F35. Titration studies evaluating for expression of a reporter transgene in infected CLL cells (e.g. the gene encoding green fluorescence protein (GFP)), found that Ad5F35 vectors also were > 100-fold more effective than Ad5 vectors at transducing CLL B cells. These studies reveal that Ad5F35 is a highly efficient vector for transducing CLL cells, a quality that should make these vectors better suited than Ad5 virus vectors for studies requiring gene transfer and/or gene therapy of this and related lymphoid malignancies.
Quality of Life in the LRF CLL4 Trial.
Authors: Else Monica , Smith Alastair G. , Hawkins Kim , Crofts Shirley , Course Margaret , Richards Susan , Catovsky Daniel 
Published: October 2019

Abstract
The UK CLL4 trial randomised 777 previously untreated patients between 1999–2004 to chlorambucil (Chl) or fludarabine +/− cyclophosphamide (F v. FC). Other trial endpoints are reported elsewhere in this meeting (Catovsky et al). The current study seeks to determine whether there is any difference in the quality of life (QoL) of patients according to treatment arm; and whether QoL correlates with baseline patient characteristics and/or with treatment outcomes. All patients were asked to complete the validated EORTC QLQ-C30 (version 2.0) at start of therapy (baseline), at 3, 6 and 12 months, and annually thereafter. Scores (0–100) within each of 15 different measures of QoL (5 functional scales, 3 symptom scales, 1 global health/QoL scale, and 6 single items) were calculated at each point in time (currently up to 1 year), and analysed according to the EORTC QLQ-C30 Scoring Manual. Statistical significance was determined by the use of ANOVA. Patient compliance was high: 599 questionnaires were completed at baseline, 557 at 3 months, 559 at 6 months and 470 at 12 months, respectively 77%, 74%, 77% and 78% of those who had so far reached the time-period and remained alive. Analysis of baseline and 12 month QoL assessment by treatment group and response is presented. QOL results were the same for each treatment group at baseline and at 12 months (Table 1). Quality of response to treatment correlated with QoL at 12 months (Table 2). With treatment approaches having potentially different risk and side effect profiles, and perhaps limited impact on overall survival, QOL forms an important component of treatment outcome assessment. Further analysis of QoL parameters (in particular their relationship to prognostic factors and further follow-up) will be forthcoming within the next year.
Table 1: Mean QoL Scores by Treatment Group* Functioning Scales Physical Role Emotional Cognitive Social Global Health No. B 12M B 12M B 12M B 12M B 12M B 12M Abbreviations: B = baseline; 12M = 12 months. Chl 175 81 78 74 75 75 78 83 82 79 77 66 69 F 92 82 82 72 74 80 81 82 82 80 79 64 68 FC 94 80 77 77 73 78 81 85 82 82 76 66 68 361 Table 2: Mean QoL Scores by Response to Treatment* Functioning Scales Physical Role Emotional Cognitive Social Global Health No. B 12M B 12M B 12M B 12M B 12M B 12M Abbreviations: B = baseline; 12M = 12 months; CR/NPR = complete/nodular partial response; PR = partial response; NR/PD = no response/disease progression. P-values compare response groups with respect to the change in scores from baseline to 12 months. (* Only those patients are shown in the Tables for whom data is available at both time-points.) CR/NPR 159 84 84 76 80 78 84 86 85 82 83 67 73 PR 125 79 76 73 73 78 78 82 79 80 77 63 68 NR/PD 56 77 74 71 61 74 74 81 79 74 65 65 60 340 p=0.02 p=0.03 p=0.002
Follow-Up Results of a Prospective, Multicenter, Open-Label Study of Oral Fludarabine Phosphate in Patients with Previously Untreated B-CLL.
Authors: Rossi Jean-Francois , Van Hoof A. , De Boeck K. , Johnson S. A. , Bron D. , Foussard C. , Lister T. A. , Kramer M. H.H. , Littlewood T. J. , Marcus R. E. , Deconinck E. , Guibon O. , Montillo M. , Tollerfield S. M. 
Published: October 2019

Abstract
The IV formulation of fludarabine phosphate is an effective treatment in patients with B-cell chronic lymphocytic leukemia (B-CLL), yielding overall response rates of 60% to 80%. An oral formulation of fludarabine phosphate has been developed. In a previously published multicenter, open-label, phase II clinical trial, 81 previously untreated B-CLL patients received 10-mg tablets of fludarabine phosphate (Fludara® oral) 40 mg/m2/day for 5 days, repeated every 4 weeks. The primary endpoint of the trial was response rate, and secondary endpoints included safety and quality of life assessments. Of 81 patients (mean age, 61.2 years; range, 30–75 years) with previously untreated B-CLL, 81.5% were classified as Binet stage B or C. The overall response rate (complete response [CR] + partial response [PR]) using National Cancer Institute (NCI) criteria was 80.2% (12.3% CR and 67.9% PR) and the median time to progression was 841 days (range, 28–1,146 days) (Rossi JF, et al. J Clin Oncol2004;22:1260–1267). The most frequently reported grade 3/4 adverse event was myelosuppression: WHO grade 3/4 hematologic toxicities included granulocytopenia (32.1%), anemia (9.9%), and thrombocytopenia (4.9%). This analysis reports on the long-term follow-up of this cohort during the period from November 2001 to November 2004. Of the 74 patients eligible for the survival analysis, 61 were also assessed for duration of response using NCI criteria: 9 CR (14.8%) and 52 PR (82.2%). During the 3-year follow-up period, 22 (29.7%) patients did not progress. For those who progressed, median time to progression was 29.7 months, and median duration of response was 22.9 months. In 41 (80.4%) of these patients, an increase in circulating lymphocytes was reported as evidence of disease progression. In 23 patients (45.1%), an increase in the sum of the products of at least 2 lymph nodes and/or appearance of new palpable nodes was reported as evidence of disease progression. During the indicated follow-up period, 37 patients (50%) received subsequent treatment. Twelve patients (16.2%) died during the follow-up period: 7 patients (58.3%) due to disease progression, 3 patients (25.0%) due to adverse events, and 2 patients (16.7%) due to other causes. Results from this study suggest that oral fludarabine phosphate is clinically effective and well tolerated by patients with previously untreated B-CLL. Moreover, these data demonstrate that oral fludarabine phosphate achieves response rates and duration of response comparable to those achieved with first-line fludarabine phosphate IV therapy.
Genetic Aberrations and Response to Fludarabine as First Line Treatment in a Serie of B-CLL Patients.
Authors: Giraldo Pilar , Rubio-Martinez Araceli , Recasens Valle , Valganon Mikel , Latre Paz , Rubio-Felix Daniel , Calasanz Maria J. , Odero Maria D. 
Published: October 2019

Abstract
Background: Genetic factors have been established in the recent years as the most important independent predictors of disease progression and survival in patients with B-chronic lymphocytic leukaemia (B-CLL). Fludarabine is an approved first-line treatment for B-CLL, which achieves superior remission rates than traditional therapies. The drug is equally effective in early and advanced disease and in younger and elderly patients with B-CLL but different results have been found in patients with cytogenetic aberrations as methylation in the TP53 promoter
Aims: To evaluate the response to Fludarabine as first-line therapy in B-CLL patients with advanced stages.
Patients and methods: In the study 55 B-CLL patients were enrolled. The diagnosis was established based on standard morphologic and immunophenotypic criteria, and classified on high clinical risk category Rai stage III/IV treated with Fludarabine (25 mg/m2 daily for 5 days IV in a 28-day cycle) as first-line therapy from January 00 to December 03. Response was evaluated after 4 cycles of therapy and in those patients which had not achieved complete remission (CR) two additional cycles were administrated. Criteria for response were established using the revised 1996 NCIWG. FISH studies were performed using the probes LSI p53 (17p13), LSI D13S25 (13q14), CEP 12 and ATM gene (11q22). The sequences of the IGVH genes were determined in cDNA of the patients. Responses to therapy, time to progression disease and overall survival were available to analyse in 41 patients. Association was studied using contingence tables followed by Fisher exact test and to evaluate survival by acturial method of Kaplan Meier and Cox regression.
Results: Mean age 64 (36.9–83.9), female 53.7%. 75% of patients presented genetic aberrations associated with worse prognosis: del (17p) and/or del (11q) (45%). No-mutated IGVH genes (57%). Response: 83.5% of patients achieved response (CR 47.8%). Related to genetic aberrations the responses were: 55.5% in patients with del(17p), 75.0% del(11q), 100% +12, 88.8% del(13q) and 100% of patients without genetic alterations showed response to Fludarabine. The 48.8 % of patients developed progression of disease with mean duration of the response of 15.1 months. Related to genetic aberrations the progression was over 81% of patients with genetic aberrations versus 55.5% without genetic alterations (p=0.044). The overall survival was 68.0 months. 34.1% of patients are alive in CR, 36.6% are alive with stable disease 7.3 % are alive with disease in progression and 22.0 % have died.
Conclusions: A high response to Fludarabine in first line therapy was observed, however only 55.5% of patients with del(17p) showed response. Patients with genetic aberrations had higher significant rate of progression in comparison with those containing normal genotypes.
A Reduced Capacity To Generate Activated Protein C and the Role of PAI-1 Deficiency on Coagulation Activation and Fibrin Formation during Murine Influenza Pneumonia.
Authors: Keller Tymen , van Wissen Matthijs , van der Sluijs Koen , van Gorp Eric , Meijers Joost , van der Poll Tom , Buller Harry , Brandjes Dees , Levi Marcel , Gerdes Victor 
Published: October 2019

Abstract
Background: Recent studies have shown that influenza activates coagulation in vitro. We aimed to study influenza and post-influenza pneumonia induced hemostatic changes in vitro and to study the role a reduced capacity to generate activated protein C (APC) and PAI-1 deficiency on the prothrombotic state.
Methods: C57BL/6 mice were inoculated with influenza or PBS (control). After 14 days these mice received S. pneumoniae. PAI-1−/− , TM pro/pro and control mice were inoculated with influenza. Controls for the influenza-infected PAI-1−/− and TM pro/pro mice were C57BL/6 mice and wild-type littermates, respectively. TATc, PAI-1, D-dimer levels, fibrin deposition and pro-inflammatory cytokines were studied on day 0, 2, 4, 8, 14, 15 and 16.
Results: Influenza-infected C57BL/6 mice showed a dose dependent increase in TATc, PAI-1 and fibrin deposition compared to non-infected controls. Median TATc levels increased from 5.3 at baseline to 12.8 ng/ml at day 4 and PAI-1 levels increased from 4.0 to 16.0 IU/ml (both p<0.05). TATc and PAI-1 levels remained unchanged in non infected controls. Mice recovered from influenza infection were highly susceptible to pneumococcal pneumonia as reflected by a 3-fold increase in cytokines compared to non-influenza infected controls. In addition, an increase in TATc and PAI-1 levels was seen (both p<0.05). Furthermore, influenza-infected TM pro/pro mice showed higher TATc levels (16.2 vs. 12.0 ng/ml, p<0.05) and higher D-dimer levels (2.6 vs. 2.0 μg/l, p<0.05) compared to infected controls 4 days after infection. In influenza-infected PAI-1−/− mice TATc levels were similar as in infected controls, but D-dimer levels were increased (4.0 vs. 2.2 μg/l, p< 0.05).
Conclusion: This study demonstrates that influenza and post-influenza pneumonia exert a prothrombotic state in vivo. Mice with a reduced capacity to generate APC show increased thrombin generation. PAI-1 deficiency does not effect coagulation activation but results in a hyperfibrinolytic state.