bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequential Treatment with Rituximab and CHOP Chemotherapy in B-Cell PTLD - A New Standard in Therapy?.
Authors: Trappe Ralf , Choquet Sylvain , Oertel Stephan , LeBlond Veronique , Ekman Tor , Sender Monica , Molle Peter , Reinke Petra , Lehmkuhl Hans , Hummel Manfred , Jonas Sven , Neuhaus Ruth , Salles Gilles , Morschhauser Franck , Jaccard Arnaud , Dierickx Daan , Anagnostopoulos Ionannis , Raphael Martine , Riess Hanno 
Published: October 2019

Abstract
Purpose: This trial aimed to investigate the efficacy and safety of sequential treatment with rituximab and CHOP-21 in patients with PTLD unresponsive to reduction of immunosuppression.
Methods: An ongoing prospective multicenter phase II trial was initiated in January 2003. Patients were treated sequentially with rituximab at days 1, 8, 15 and 22 followed by four cycles of CHOP-21 combined with G-CSF support starting 4 weeks after the last dose of rituximab.
Results: In this 3rd interim analysis after enrolment of 75 patients 64 patients have finished the protocol. The median follow up is 19.6 months. 58 patients were diagnosed with monomorphic PTLD, 6 with polymorphic PTLD. 23 patients were kidney, 15 liver, 12 heart, 3 lung, 2 heart+lung, 3 kidney+pancreas, 1 bone marrow transplant recipients (5 others). Median age was 53 years (range 16 to 74). 59% had stage III or IV disease. 48% of tumors were EBV positive. 79% of patients had late PTLD (i.e. later than 1 year after transplantation). LDH was elevated in 67% of patients. The overall response rate of sequential therapy was 90% (CR 65%, PR 25%). Progression free survival (PFS) and disease free survival (DFS) were 71.4% and 81.2% at two years, respectively. Treatment response to rituximab (CR/PR versus SD/PD) was a significant factor predicting overall survival (OS) with OS rates of 91.3% and 56.5% at 1 year, respectively (p=0.0107). Following chemotherapy, WHO °3/4 leukopenia was observed in 38% of cycles and 16% of patients suffered from WHO °3/4 infections. There were four early therapy-associated deaths due to infections (7%). Fatal bleeding complications occurred in 3% and 5% of patients died from primary refractory disease.
Conclusions: This is one of the largest prospective studies in PTLD. Sequential treatment with rituximab and CHOP-21 + G-CSF is well tolerated and highly effective. Treatment response to rituximab is predictive for overall survival. As compared to rituximab monotherapy more patients achieve a CR with sequential therapy and PFS is very much prolonged.
Figure Figure
Disruption of Bcl-2 Heterodimerization by the BH3 Mimetic ABT-737 Restores Spontaneous Apoptosis and Induces Differentiation in High Risk MDS and AML.
Authors: Ades L. , Boehrer S. , Braun T. , Grosjean J. , Fabre C. , Fenaux Pierre , Kroemer Guido 
Published: October 2019

Abstract
Background : Increased spontaneous apoptosis is a hallmark of low risk MDS and its suppression by secondary events favors progression to AML. The ratio of Bcl-2 family members is related to progression in MDS, and high expression of proapoptotic Bax is associated with favorable outcome while high expression of antiapoptotic Bcl-2 is linked to poor prognosis.
Methods : we investigated the potential of ABT-737 - known to disrupt the Bcl-2/Bax heterodimer - on cell death, cell cycle progression and differentiation of AML and MDS cells, including AML and MDS cell lines (HL 60, U 937, P39) and cells from MDS and AML patients.
Results : In the cell lines studied
ABT-737 induced cell death in a time- (from 24 to 72 hours) and dose-dependent (from 100 nM to 1 mM) manner as evidenced by the loss of the mitochondrial transmembrane potential and expression of phosphatidylserine residues on the cell surface. In addition, incubation of HL60 and P39 cell lines with ABT-737 increased apoptosis (up to 80% at 48h with 500 nM of ABT 737) while U937 cells were resistant ; ABT-737 promoted concomittant release of mitochondrial protein cytochrome c and subsequent activation of caspase-3 ABT-737 caused caspase-dependent cell death, which was prevented by the pan-caspase inhibitor zVAD-fmk.
Evaluating the underlying molecular mechanisms by small interfering RNA, we found that knockdown of Bcl-2 recapitulated the apoptosis-inducing effect of ABT-737, whereas abrogation of its proapoptotic counterpart Bax remained without effect. Moreover, down-regulation of Mcl-1 rendered otherwise ABT-737-resistant blasts (U937 cells) sensitive to the drug. Noteworthy, although ABT-737 had no impact on the cell cycle distribution of blasts, it nevertheless enabled them to overcome the differentiation block. Indeed, incubation of HL60, P39 cells with ABT-737 increased cell surface expression of the differentiation marker CD11b, an event that could also be prevented by caspase inhibition. Finally, CD34-positive cells from 12 MDS and AML patients were treated ex vivo with ABT-737. ABT-737 induced apoptosis in the 8 samples of high risk MDS and AML (20–60% increase in cell death with 200 nM of ABT737, as compared to controls), whereas the 4 samples of low risk MDS proved to be resistant.
Conclusion, we provide novel evidence that ABT-737 is able to restore apoptosis and to overcome the differentiation block that characterizes malignant cells of high risk MDS and AML, suggesting potential therapeutic activity in those disorders.
Comparison of Cytochemistry, Flow Cytometry and Immunohistochemistry for the Detection of Myeloperoxidase in Acute Myeloid Leukemia.
Authors: Saravanan Linda , Juneja Surender 
Published: October 2019

Abstract
Myeloperoxidase (MPO) is an unequivocal marker of myeloid differentiation and is used routinely in the diagnosis of acute myeloid leukaemia (AML). Cytochemistry (CC), flow cytometry (FCM) and immunohistochemistry (IH) are three routine techniques used to demonstrate MPO positivity. As FCM techniques have improved, IH and CC are being performed less frequently. However, very few reports comparing combinations of these modalities have been published, and to our knowledge none comparing all three. We have reviewed 158 bone marrow biopsies of patients diagnosed with AML between 2000 and 2007 at the Royal Melbourne Hospital, Victoria, Australia. A comparison of MPO positivity using CC, FCM and IH was performed. In 101/158 biopsies all three methods were performed, while the remaining 59 cases had only 2 of the 3 performed. 76 (75%) of these 101 cases showed MPO positivity by all three modalities, defined as at least 3% MPO positive cells on cytochemistry or IH, and at least 10% MPO positive cells by FCM. A further 2 biopsies were negative for MPO by all three techniques. In 23/101 (23%) biopsies in which all three methods were performed, discrepancies occurred between the different modalities (Table 1). The largest group (11/23, 48%) was positive by FCM and IH but negative by CC. A further 7/23 (30%) cases were positive by IH only. Four (17%) cases were positive by CC and IH in the presence of negative FCM, and there was a single case in which FCM was positive when CC and IH were negative. In three cases of AML minimally differentiated (FAB-M0), IH was the only modality able to identify MPO positivity. CC was the least sensitive with no cases of detection of MPO positivity in the presence of negative results by FCM and IH. However there were still 4 cases where FCM was negative in the presence of a positive CC result. These results confirm the importance of employing more than one method of detecting MPO, particularly in cases where FCM and CC are negative or discrepant. In our study, IH was the most sensitive marker for demonstration of MPO. Despite the widespread use of FCM for typing AML, CC and IH still have an important role to play in the demonstration of MPO positivity in these cases.
Table 1. Detection of MPO by cytochemistry, flow cytometry and immunohistochemistry in discrepant cases. Cytochemistry Flow Cytometry Immunohistochemistry Number of cases (n=23) + MPO positive, − MPO negative − + + 11 − − + 7 + − + 4 − + − 1
Wilms Tumor 1 Gene (WT1) Isoforms in Leukemia and Lymphoma.
Authors: Li Aihong , Westman Ulla-Britt , Golovleva Irina , Kutok Jeffery L. , Silverman Lewis B. , Sallan Stephen E. , Roos Goran 
Published: October 2019

Abstract
The Wilms tumor 1 gene (WT1) acts as a transcriptional activator or repressor and is important for normal development. Evidence has accumulated to show that WT1 is oncogenic in acute leukemia and in some solid tumors. WT1 has 4 major isoforms and each encoded polypeptide is thought to make a contribution to normal gene function, but no data are available on their expression in hematologic malignancies. We have analyzed the expression of WT1 and its four isoforms (A, B, C, and D) in 187 diagnostic samples from patients with leukemia or lymphoma. WT1 RNA expression was detected in 9/10 (90%) chronic myeloid leukemias (CML), in 41/47 (87%) of acute myeloid leukemias (AML), in 38/56 (68%) acute lymphoblastic leukemias (ALL) and in 22/74 (30%) of malignant lymphomas. The highest expression levels were found in pre-B ALL and in AML samples. Aggressive lymphomas were more often WT1 positive and with higher levels compared to indolent cases (p < 0.01). Only 9% of AML and ALL bone marrows in complete remission (n=22) showed detectable WT1 expression and all benign lymph nodes studied (n=11) were WT1 negative. The different WT1 isoforms demonstrated highly variable expression levels with isoform A as the most common form in all tumor types. There was no difference in isoform expression between T-ALL and B-lineage ALL. However, AML-M3 demonstrated a significantly higher expression of isoform A compared to other AML subtypes (p<0.01). T-cell lymphoma had a higher level of all isoforms than other lymphoma types (p<0.01). We observed a high concordance regarding WT1 expression levels between matched samples from peripheral blood and bone marrow in T-ALL (R=0.982, P<0.01). A significant reduction in WT1 levels was demonstrated during chemotherapy in two pediatric AML patients. In conclusion, WT1 expression was coupled to malignancy in both bone marrow and lymph node samples and thus could be considered as a potential molecular marker for minimal residual disease detection in acute leukemia. All four WT1 isoforms could be detected in most WT1 positive samples, but their functional significance remains to be clarified.
Sodium Gluconate Containing Parenteral Nutrition Solution as a Cause of False Positive Aspergillus Galactomannan Assay in Paediatric Patients with Hematological Malignancies.
Authors: Ribaud Patricia , Sulahian Annie , Touratier Sophie , Brethon Benoit , de Latour Regis Peffault , Socie Gerard , Menotti Jean , Derouin Francis 
Published: October 2019

Abstract
Background: The detection of Aspergillus galactomannan antigenemia (GM-Ag) is a contributive method in the diagnosis of invasive aspergillosis (IA). Herein, we report 3 cases of false positive GM-Ag in paediatric patients (pts) receiving NP2 Enfants AP-HP® parenteral nutrition (Fresenius, France), and none of them had or developed IA.
Methods: In December 2006, the sera of these 3 pts (1 allogeneic transplant recipient and 2 neutropenic acute leukaemia pts) taken before, during, and after cessation of NP2 solution were tested for the presence of GM-Ag using the Platelia® Aspergillus kit. This solution, its 30 components and 8 other commercially available solutions for parenteral nutrition were tested for the presence of GM.
Results: GM became detectable within 1 day after IV administration of NP2 with indices up to 9.25, remained positive throughout treatment, and became negative (≤0.5) within 48 hours in 2/3 pts. The NP2 solution and a single one of its components, sodium gluconate (SG), tested positive with GM estimated at 55.4ng/ml. No Aspergillus DNA was detected by real-time PCR. Three NP2 and 6 SG batches from different origins yielded similar results. On the other hand, 6 different batches of calcium gluconate and 8 other commercially available SG-free parenteral nutrition solutions tested negative.
Conclusions: These results suggest a strong cross reactivity of Platelia® kit with SG-containing NP2, as recently described with Plasma-Lyte® (Baxter Distribution Centre Europe). We estimate that clinicians and biologists should become aware of this problem which might lead to inappropriate invasive investigations and/or treatments.
Effects of Anemia on the Rehabilitation Outcomes in Elderly Patients in the Post-Acute Care Setting.
Authors: Witkos Maciej , Uttaburanont Michelle , Vicenio Myra , Lang Christopher , Haddad Rami Y. 
Published: October 2019

Abstract
Background - More than 3 million people in the United States over the age of 65 are anemic. The evidence indicates that older people with anemia suffer hospitalizations, physical decline and disability more than people without anemia. Additionally there are reports that anemia is an independent risk factor for this decline in physical performance in those over the age of 65.
Objective - The goal of this study was to detail if anemia significantly affects patient’s rehabilitation outcomes by focusing on the ability to perform activities of daily living (ADL) as assessed by the physical therapist, the disposition upon discharge (meeting the therapy goals) and an analysis of length of stay (LOS) in relation to anemia.
Methods - We conducted a chart review of 260 medical records of patients who underwent rehabilitation therapy at the North Chicago Veterans Affairs Medical Center, and detailed the progress of 69 of these patients who received ADL therapy. The study is ongoing with a projected chart review of 437 medical records, and with an estimated final sample size of 150. Univariate and multivariate analysis was conducted in relation to our outcome measures.
Results - The anemic group had 43 patients and the non-anemic 26. Average values for anemic patients were: Hgb 11 Hct 32, MCV 88, MCH 29.2, RDW 15.6, Platelets 259, the non-anemic patients values were: Hgb 13.4, Hct 39, MCV 89, MCH 33.3, RDW 14.3, platelets 229. The patients with anemia had a median change in ADL scores of 9 versus non-anemic patients’ median change in scores of 12 (p=0.154). Length of stay was 51 days (median) for anemic patients and 36 days (median) for non-anemic patients (p=0.108) Of the non-anemic patients, 19 out of 26 (73%) met the goals of therapy and 21 out of 43 (49%) of the anemic patients met the goals of therapy (p=0.055). Surprisingly, only 3 out of the 43 (7%) anemic patients were treated for their anemia or had work up done to identify the cause of the anemia. The multivariate model for length of stay indicated that anemia was not significant (p=0.842), the morbidity of the patient was marginally not significant (p=0.089), however, the patients’ age was statistically significant at p=0.05. For the multivariate model of ADL improvement the results were: anemia p=0.186, sex p=0.298, Charlson index p=0.50.
Conclusion - There is a definite lack in the identification and treatment of anemia in patients undergoing rehabilitation. Anemia exerts an influence on the course of patient therapy/recovery and should be addressed as an individual problem. Anemic patients undergoing rehabilitation are scoring lower, and are admitted longer to the hospital.
Outcomes in Subcutaneous Panniculitis-Like T-Cell Lymphoma (STCL)
Authors: Alpdogan Onder , Ornstein Deborah , Subtil Tony , Seropian Stuart , Cooper Dennis L. , Foss Francine 
Published: October 2019

Abstract
Subcutanous panniculitis–like T cell lymphoma (STCL) is a rare clinical entity which simulates panniculitis and can present with an aggressive clinical course. STCL is divided two major subgroups (αβ-STCL and γδ-STCL), according the T cell receptor expression on the malignant T cells. γδ-STCL is often associated with a more aggressive course and poor prognosis with an 11% 5-yr survival in a retrospective study of 20 cases, only 6 of which were confirmed by TCRδ -1 staining.1 We report our results from 10 patients with STCL, 2 BetaF1+ (αβ-STCL), 8 γδ-STCL. The median age at presentation was 43 (25–63); 7 of 10 were female. Immunohistochemical studies and TCR gene rearrangements (TCRR) were performed on all patients. Cytotoxic T-cell markers were expressed in all pts (TIA-1 in 8 of 10 and Granzyme B in 5). Six were CD8+ and 3 were CD3+CD4−CD8−. CD56 expression was detected in 3. All demonstrated clonal TCRR. All pts presented with skin nodules or ulcerations, and 3 had visceral involvement (blood/bone marrow in 2, liver in 1). Three patients (2αβ-STCL and γδ-STCL) were treated initially with denileukin diftitox; one each with αβ- and γδ- disease had PR on therapy and have been maintained without PD. Seven patients were treated with cytotoxic chemotherapy regimens. Four of 7 achieved a remission after EPOCH (2), denileukin diftitox-CHOP (1) or pentostatin/cyclophosphamide followed by alemtuzumab (1). Four pts (1 with refractory ab-STCL, 2 with refractory gd-STCL, and 1 with γδ-STCL in first CR after denileukin diftitox-CHOP) underwent allogeneic hematopoietic stem cell (HSCT) from matched-related donors. Two patients are alive 6 and 13 months after HSCT with no evidence of disease; 1 patient died in CR from infectious complications of HSCT, and 1 relapsed 6 mo after HSCT and died from PD. At a median follow up of 3 yrs from diagnosis, 8 pts (80%) are alive, including the 2 pts with αβ-STCL and 6 of 8 pts with γδ-STCL. In summary, while γδ-STCL is reported in retrospective studies to have a poor prognosis, we demonstrate that aggressive therapies along with the incorporation of novel T-cell directed agents such as denileukin diftitox and alemtuzumab into treatment regimens and the use of allogeneic HSCT as a potentially curative therapy are promising approaches for these patients.
Is Diabetes Mellitus An Independent Risk Factor for Incident Venous Thromboembolism (VTE)? a Population-Based Case-Control Study
Authors: Heit John A. , Leibson Cynthia L. , Ashrani Aneel A. , Petterson Tanya M. , Bailey Kent R. , Melton L. Joseph 
Published: October 2019

Abstract
Introduction: Diabetes mellitus is often cited as a VTE risk factor. However, persons with diabetes are frequently hospitalized for medical illness or undergo surgery, both major VTE risk factors. Thus, the association of VTE with diabetes independent of surgery or hospitalization is uncertain.
Methods: Using longitudinal, population-based Rochester Epidemiology Project resources, we identified all Olmsted County, MN residents who met objective criteria for incident VTE over the 25-year period, 1976–2000 (n=1922), and one to two controls per case, matched on age, gender, Olmsted County residency, and length of medical history (n=2115). For cases and controls, we reviewed their complete medical history in the community for baseline characteristics previously identified as independent VTE risk factors, including clinically-diagnosed diabetes mellitus. We tested diabetes as a potential VTE risk factor both alone and after adjusting for other baseline characteristics, and in the subset of cases with idiopathic VTE, using conditional logistic regression.
Results: Among all cases and controls, 231 (12%) and 199 (9.4%) had diabetes, respectively. Univariately, diabetes was associated with overall VTE (odds ratio [OR]=1.32; 95% CI: 1.07, 1.62; p=0.009). However, after controlling for body mass index (OR=1.04, p<0.001), hospitalization with major surgery (OR=25.2, p<0.001) or hospitalization for medical illness (OR=7.3, p<0.001), active cancer (OR=8.3, p<0.001) and varicose veins (OR=1.3, p=0.003), diabetes was no longer associated with VTE (OR=1.09; 95% CI: 0.85, 1.41; p=0.49). Among 458 idiopathic VTE cases and 518 matched controls, 43 (9.4%) and 46 (8.9%) had diabetes, respectively. Diabetes was not associated with idiopathic VTE (OR=1.07, 95% CI: 0.69, 1.67; p=0.76).
Conclusions: Diabetes mellitus is not an independent risk factor for overall or idiopathic incident VTE.
Hemoglobin Blocks Von Willebrand Factor Proteolysis by ADAMTS-13: A Mechanism Associated with Acquired ADAMTS-13 Deficiency in Patients with Sickle Cell Disease
Authors: Zhou Zhou , Hyojeong Han , Cruz Miguel A. , Lopez Jose A. , Dong Jing-fei , Guchhait Prasenjit 
Published: October 2019

Abstract
One of the hallmark events of sickle cell disease (SCD) is vasoocclusion and episodic pain crisis. Although the mechanism of vascular occlusion is very complicated, processes like thrombosis and thromboembolism have been recognized to play an important role in the development of such clinical manifestation in SCD. Studies have shown that the von Willebrand factor (VWF), especially the ultra-large (UL) multimers play a major role in vasoocclusion, which clearly indicates a possible impairment of the VWF-cleaving metalloproteae ADAMTS-13 in these patients with SCD. In a recent work, indeed we have mentioned that the plasma ADAMTS-13 in patients with SCD having normal antigen level showed 35% less protease activity than the normal. There may be several plasma factors responsible for the acquired deficiency of ADAMTS-13 in SCD. Since, the increasing evidences suggest that the elevated level of extracellular hemoglobin (Hb) in plasma parallely associated with the pathogenesis of SCD, we investigated the effects of extracellular Hb on VWF proteolysis by ADAMTS-13. We observed that purified Hb dose-dependently inhibited the ADAMTS-13 cleavage of recombinant(r) VWF and endothelial ULVWF multimers under static and flow conditions. Hb bound to VWF multimers in a saturation-dependent manner and more potently to the rVWFA2 domain (affinity Kd~24nM), which contains the cleavage site for ADAMTS-13. Hb bound also to the ADAMTS-13 (Kd~65nM), with 2.7 times less affinity than to VWFA2. The bindings were neither calcium-dependent nor affected by haptoglobin. However, it is the Hb-binding to VWF that prevented the substrate from being cleaved by ADAMTS-13. These in vitro findings are consistent with the in vivo observations in patients with SCD. An elevated level of extracellular Hb in plasma was inversely correlated (linear regression, r2 =0.6354) with the low activity of ADAMTS-13 in a cohort of ten adult patients with SCD (mean±SE, Hb 346±138 mg/l; activity 33.3±30%) compared to age and gender-matched normal individuals (n=10; Hb 24±8 mg/l; activity 76.2±16%). The data together suggest that patients with SCD suffer from acquired ADAMTS-13 deficiency, primarily because Hb competitively binds and inhibits the proteolysis of VWF multimers, leading to ULVWF accumulation on vascular endothelium and in circulation. The Hb-VWF interaction may therefore be considered as a therapeutic target for reducing thrombotic and vasoocclusive complications in patients with severe hemolysis such as those with SCD.