bluuebunny/crossref_metadata_2025_split huggingface dataset:
L-Asparaginase in the Treatment of Relapsing Nasal/Nasal Type NK-T-Cell Lymphoma.
Authors: Jaccard Arnaud , Suarez Felipe , Zini Jean-Marc , Turlure Pascal , Trimoreau Franck , Petit Barbara , Bordessoule Dominique , Hermine Olivier 
Published: April 2020

Abstract
Nasal/nasal type NK-T-cell lymphoma is a rare and severe type of non Hodgkin’s lymphoma (NHL) more frequent in asia than in western countries. When localised, radiotherapy seems to be the best treatment. When radiotherapy cannot be used because of dissemination or relapse, chemotherapy protocols used for other types of NHL give poor results. Recently some papers from China and Japan, (Yong W et al: L-asparaginase-based regimen in the treatment of refractory midline nasal/nasal-type T/NK-cell lymphoma. Int J Hematol. 2003 Aug;78(2):163–7), reported the efficacy of a drug: L-asparaginase, usually used to treat acute lymphoblastic leukemia. Few patients have been treated in Asia and no patient from western countries have been reported.
We used this drug in 3 french centers to treat 7 patients with relapsed nasal/nasal type NK-T-cell lymphoma.
There were 4 men and 3 women, median age was 52 (39 to 81), the primary site of disease was the nasal cavity in 3 patients, the nasopharynx in 2, the gastrointestinal tract in 1 and the bone marrow in 1. Pathological diagnosis was confirmed by biopsy, showing typical aspect of necrosis and angioinvasion. Tumoral cells were usually CD20 negative, SCD3 positive, CD56 positive. EBV was found by in situ hybridisation in all but one case.
When L-asparaginase was given 5 patients were refractory to CHOP and/or DHAP regimen, 5 patients were in stage IV with bone marrow involvment (n=2), cerebral involvment (n=2), gastrointestinal tract involvment (n=1). Hemophagocytosis was seen in 3 patients with typical biological anomalies.
L-asparaginase 6000 UI / m2 (1 to 3 courses) was given for 5 to 10 days associated with Dexamethasone 40 mg for 4 days (n=4), methotrexate 3 gr/m2 (n=1) or velbe 6 mg (n=1). 2 patients who had a severe anaphylactic reaction with L-asparaginase received further courses of PEG-asparaginase.
Treatment efficacy was evident in all patients with 4 patients in complete remission (CR) and 3 patients in partial remission (PR) after treatment with L-asparaginase. 2 patients died, one of acute GVH after allotransplantation and a second 1 month after the second course of L-asparaginase, probably of pulmonary embolism. Apart from this case toxicity related to L-asparaginase was mild, mainly brief leucopenia and elevation of alanine aminotransferase. With antithrombine III transfusions when its level was below 60% no other thrombotic event was noted.
5 patients are still alive with a median follow-up of 7 months (3 to 13), 4 patients are in persistent CR, 2 had received high dose therapy with autologous stem cell transplant.
The efficacy of L-asparaginase to treat nasal and nasal type NK-T-cell lymphoma must be known because of the very poor prognosis of relapsing patients with conventionnal chemotherapy. Prospective studies using L-asparaginase for de novo patients are warranted.
Extreme Effectiveness of Operative Resection with or without Radiotherapy as a First Line Treatment for Localized Orbital Malt Lymphoma.
Authors: Yakushijin Yoshihiro , Kodama Toshio , Takaoka Ikue , Otsuka Masaki , Hato Takaaki , Yasukawa Masaki , Fujita Shigeru 
Published: April 2020

Abstract
Localized orbital extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are predominately low-grade, small B cell types and are associated with systemic occurrence either sequentially or concurrently in some cases. The risk of future relapse and the original lymphomas’ transformation to diffuse large B-cell lymphomas are great concerns for the treatment of patients with MALT lymphoma. Several groups have reported on the efficacy and complications related to radiotherapy with orbital MALT lymphoma, however, the efficacy of surgical operation for local control has not been well documented. We have studied series of orbital MALT lymphoma cases treated using operative resection, and analyzed the procedure’s efficacy as a first line treatment. We treated a total of twenty-three patients with orbital MALT lymphoma (median follow-up was 3.0 years). Pathological diagnoses of all cases were reviewed by hematopathologists, and the B cell monoclonality of twenty-two cases was confirmed by immunoglobulin heavy chain (IgH) rearrangement using Southern blot. There were three cases which occurred on both sides (right and left) of the ocular adnexa. In the surgically removed sections, a large component of pathological cells which seemed to be transforming into large cell lymphomas was found in two cases. All patients were treated using surgical operations as a first line therapy, and six (26%) cases needed additional adjuvant treatments such as radiotherapy and/or chemotherapy because of incomplete tumor resection. There was 100% freedom from local relapse or relapse in any sites among seventeen patients treated only with surgical operations. Two patients (12%) out of seventeen had xerophthalmia or strabismus as complications after the operations. Two patients (33%) among the six cases who needed adjuvant treatment had radiation-induced cataracts within three years. We conclude that operative resection as a treatment for orbital MALT lymphoma is very effective and well tolerated as a first line treatment. In addition, if the tumor resection is not complete, additional radiotherapy should be considered.
BL22, a Recombinant Anti-CD22 Immunotoxin, Induces Cell Cycle Arrest and Apoptosis in B-Cell Lymphoma.
Authors: Decker Thomas , Wagner Michaela , Oelsner Madlene , Kreitman Robert J. , Pastan Ira , Peschel Christian , Licht Thomas 
Published: April 2020

Abstract
A recombinant immunotoxin, BL22 has shown clinical efficacy against hairy cell leukemia and other B-cell non-Hodgkin’s lymphomas. BL22 contains an antibody-derived domain that recognizes CD22, and PE38, a truncated Pseudomonas exotoxin A domain, for inhibition of protein synthesis. Previous studies have shown that Pseudomonas exotoxin A-based immunotoxins exert their cytotoxicity by apoptosis and additional, yet uncharacterized mechanisms. We investigated the cytotoxicity of BL22 in two mantle cell lymphoma lines, NCEB-1 and Granta-519, and in the diffuse, large-cell lymphoma line SU-DHL-4. Presence of the CD22 target was confirmed by flow cytometry. Treatment of NCEB-1 cells to 1 μg/ml BL22 for 24-32h reduced the numbers of viable cells in comparison to cells exposed to a non-binding immunotoxin. Induction of apoptosis, determined by activation of caspase-3 and exposure of phosphatidylserine, was not detected before 48h of exposure. Incorporation of bromo-deoxyuridine into DNA was, however, almost completely inhibited after 24h. Correspondingly, the numbers of G1 phase cells were increased upon treatment with BL22 as determined by flow cytometry. G1-arrest resulted from decreased enzyme activities of cyclin-dependent kinases (cdk)-2 and 4 as assessed in vitro with respective substrates, histone H1 and the retinoblastoma susceptibility (RB) protein. Immunoblotting revealed markedly reduced amounts of cyclins A, E, D1 and D3 whereas cdk2 and cdk4 protein expression levels remained unchanged. Expression of the RB protein was decreased, and the protein was hypophosphorylated in immunotoxin-treated cells. Pulse-labeling with [35S]-labeled amino acids, followed by immunoprecitation of cyclins E and D1 confirmed that BL22 inhibited synthesis of these cyclins. Thus, immunotoxin-induced cell cycle arrest results from insufficient synthesis of regulatory cyclins required for progression through G1 into S-phase. Similar results were obtained in Granta-519 cells. SU-DHL-4 diffuse, large-cell lymphoma cells were highly sensitive to BL22, and G1 arrest was observed as early as after 8–24h in these cells. Expression of cyclins A, D3 and E was decreased while cyclin D1 was not expressed in SU-DHL-4 cells. Interestingly, cell cycle arrest did not prevent from subsequent induction of apoptosis in lymphoma cells continuously exposed to the immunotoxin. In conclusion, we have characterized cell cycle arrest as a previously unknown mechanism that contributes to the cytotoxicity of Pseudomonas exotoxin-based immunotoxins.
Refractory Autoimmune Cytopenias, Either Associated with Lymphoproliferative Diseases or Idiopathic in Adult Patients, Treated with Anti-CD20 Monoclonal Antibody (Rituximab).
Authors: Garay Guy , Riveros Dardo , Milone Jorge , Fernandez Jose , Duarte Patricio , Cacchione Roberto , Dupont Juan 
Published: April 2020

Abstract
Immune cytopenias (IC) frequently require prolongued administration of immunosupressors, especially when associated with lymphoproliferative disorders (LPD). Rituximab causes in vivo selective destruction of B lymphocytes and supresses the production of antibodies. Three mechanisms are involved; complement dependent cytotoxicity, antibody dependent cellular citotoxicity and the induction of apoptosis. We present 10 patients with IC: 8 autoimmune hemolytic anemia (AIHA), and 2 AIHA plus immune thombocytopenia (Evans’ syndrome). Seven patients had IC associated with LPD, and 3 were idiopathic. LPD were: 3 follicular lymphoma (1 Grade 1, 1 Grade 2, 1 Grade 3), 1 small lymphocytic lymphoma, 3 chronic lymphocytic leukemia. Three patients with idiopathic cytopenias had a long history of recurrent AIHA (2) and Evans’ syndrome (1). Ages ranged between 43 and 81 (median 63 yrs); 6 were female gender and 4 male. All AIHA cases, except 1 pts with cryogrobulins, presented with warm IgG antibodies. Previous evolution included splenectomy in 2 pts and all pts received multiple courses of immunosupression with steroids and others, like azathioprine and cyclophosphamide. All patients with LPD received one or more chemotherapeutic regimens with alkylating agents, fludarabine or CHOP combination. Median time to IC in 7 pts with LPD was 75 months (2–228). Idiopathic cases had 12, 132 and 204 months of previous evolution. Rituximab was administered at 375 mg/m2 every 1 to 3 weeks for 3 to 8 doses (median 4). Six pts received rituximab as monotherapy and 4 pts in combination with chemotherapy. Toxicity was mainly related to the first cycle of rituximab and consisted in chills and fever grade I-II in three pts. Clinical resolution of cytopenia occured in 9/10 pts (90%). 4 of them (44%) resolved with negative direct antiglobuline test. Median time to response was 4 weeks (2–8). One AHIA died with hemolysis progression, six months after rituximab, and 1 pts with AHIA and follicular lymphoma died 8 months after rituximab treatment with progression of LPD without evidence of hemolysis. The rest of the patients remained without IC for 2–42 months (median 18). Rituximab, originally designed to treat B-cell neoplasms, is an active immunosupressive agent in either lymphoproliferative associated or idiopathic autoimmune cytopenias even in non splectomized pts. Its use may avoid the secondary effects of long term administration of steroids, alkylating agents or transfusions.
All-Trans Retinoic Acid Can Reduce Proviral DNA of Human T-Cell Leukemia Virus as a Reverse Transcriptase Inhibitor.
Authors: Yamaguchi Terufumi , Maeda Yasuhiro , Ueda Satomi , Hijikata Yasuki , Matsuda Mitsuhiro , Kanamaru Akihisa 
Published: April 2020

Abstract
We previously reported that all-trans retinoic acid (ATRA) inhibits growth in HTLV-1-positive T-cell lines and fresh cells from patients with adult T-cell leukemia. However, the mechanism of this inhibition is not clear. In the present study, we observed the NF-κB transcriptional activity as well as cell growth in HTLV-1-positive T-cell lines decreased significantly in these cells in the presence of ATRA. However, no significant growth inhibition was observed after treatment with IFN-γ, TNF-α, and TGF-β of growth inhibitory cytokines induced by ATRA. Thereafter, we observed that ATRA reduced HTLV-1 proviral DNA, gag and tax mRNA load using a real time quantitative polymerase chain reaction and soluble IL-2 receptor in the culture supernatant using ELISA in HTLV-1-positive T-cell lines. Interestingly, ATRA significantly inhibited reverse transcriptase activity similar to azidothymidine in HTLV-1-positive T-cell lines. These results suggested that ATRA could inhibit reverse transcriptase activity in the growth inhibition of ATL cells. Additionally, an effect of ATRA on replication of the human immunodeficiency virus (HIV) was also observed. ATRA significantly reduced the HIV proviral DNA load of both a HIV-1-positive cell line and HIV-1-infected patients. These results indicated that ATRA may be useful for HIV treatment in a clinical setting.
The Change of Vascular Endothelial Growth Factor and Microvessel Density Following Imatinib Mesylate Therapy and Allogeneic Bone Marrow Transplantation in Chronic Myeolid Leukemia.
Authors: Kwak Jae-Yong , Lee Na-Ri , Song Eun-Gi , Yim Chang-Yeol , Chung Myoung-Ja , Jo Yong-Gon , Choi Sam-Im 
Published: April 2020

Abstract
Chronic myeloid leukemia(CML) is a clonal myeloproliferative disorder and increased angiogenesis in bone marrow is a feature of CML. Vascular endothelial growth factor(VEGF) is a potent angiogenic peptide and microvessel density(MVD) is increased in bone marrow of CML. In this study, the effect of imatinib mesylate therapy on angiogeneisis was investigated and compared with allogeneic bone marrow transplantation(BMT) with philadelphia chromosome positive/BCR-ABL+ CML in first chronic phase. Immunohistochemical staining for detecting VEGF protein was performed by labeled avidin-biotin method on the formalin-fixed and paraffin embedded bone marrow biopsy samples of 10patients of allogeneic BMT, 20patients of imatinib mesylate therapy and 10normal control. Initial and sequential, after at least 12 months of therapy, bone marrow biopsy examed and all patients achieved complete cytogenetic remission. Microvessel was scored in at least 3 areas(*200 fields) of the highest MVD in representative sections of each bone marrow biopsy specimen using immunohistochemistry for CD32 antigen. Patients with Imatinib mesylate therapy and allogeneic BMT induced a significant reduction of MVD (normalization in comparison with controls). MVD was no significant difference between the patients with imatinib therapy and allogeneic BMT. VEGF was mainly expressed myeloid progenitors and less abundantly megakaryocytes and mature granulomonocytic cells. Expression of VEGF, it was significantly decreased in patients with Imatinib mesylate therapy and allogeneic BMT(normalization in comparison with controls). VEGF expression was no significant difference between the patients with imatinib therapy and allogeneic BMT. First line therapy with imatinib mesylate was normalization of bone marrow vascularity compared with allogeneic bone marrow transplantation of CML in first chronic phase.
Circulating Myeloperoxidase (MPO) as a Tumor Marker in Patients with Chronic Myeloid Leukemia (CML).
Authors: Jilani Iman , Vincente Ted , Faraji Homan , Giles Francis J. , Cortes Jorge , Kantarjian Hagop M. , Albitar Maher 
Published: April 2020

Abstract
MPO is a hemoprotein expressed in polymorphonuclear neutrophils and their precursors. Free circulating MPO in the plasma or serum is an important indicator of inflammation in various inflammatory diseases, whereas cellular expression levels of MPO, assessed by cytochemical staining, are used extensively for the diagnosis and subtyping of various leukemias. The role of circulating MPO levels in the evaluation of CML has not been assessed. In this study, we examined the association of plasma MPO levels with hematologic characteristics and clinical outcome in 107 patients with Philadelphia chromosome-positive CML: 74 in chronic phase (CP) and 33 in accelerated/blastic (ACC/BC) phase). 100 apparently healthy individuals were included as a control group. All patients received imatinib mesylate therapy, with a median follow-up period of 18.6 months (range, 2.1–31.1 months). Overall, MPO levels did not differ significantly between CP and ACC/BC patients (Wilcoxon test, P=0.34). However, both CP (median, 38.2; range, 4.9–11421.6 ng/mL) and ACC/BC (median, 47.00; range, 3.4–1423.6 ng/mL) groups had significantly higher levels than control subjects (median, 4.9; range, 3.5–20.6 ng/mL). Response rates were 77% for CP patients and 57% for ACC/CP patients. When both groups were considered together, nonresponders had significantly higher MPO levels than responders (P = 0.03). In separate analyses, this association held true for ACC/BC patients (P = 0.04) but not for the CP group. MPO levels correlated strongly with WBC, LDH, percent basophiles, and percent Philadelphia chromosome-positive metaphases (all P &lt;0.001). These data suggest that plasma MPO levels are elevated in CML and may be useful in predicting response to imatinib mesylate therapy for patients in ACC/BC phase; whether the association of MPO levels with response reflects an underlying association with tumor burden requires further study. Longer follow-up with larger samples sizes may be needed to accurately evaluate the relationship between plasma MPO levels with response and overall survival for patients in CP.
Increased IL-6 Receptor Proteolytic Cleavage in Mononuclear Cells from Patients with Essential Thrombocythemia.
Authors: Goette Nora P. , Marta Rosana F. , Chazarreta Daniel C. , Molinas Felisa C. 
Published: April 2020

Abstract
Recently we described increased IL-6 soluble receptor (IL-6sR) levels in plasma of essential thrombocythemia (ET) patients as well as elevated IL-6sR release by cultured mononuclear cells. IL-6sR can be generated by two different mechanisms: alternative splicing and proteolytic cleavage. Here we evaluated the participation of metalloproteases responsible for the proteolytic cleavage in the increase of IL-6sR levels produced by cultured cells. We studied expression changes in anchored IL-6 receptor (IL-6R) in CD3 lymphocytes as well as monocytes before and after cell culture. We also assessed the IL-6sR levels in the supernatant of cell culture in the presence and absence of a metalloprotease inhibitor, TAPI, that prevents most of the IL-6sR shedding from the anchored receptor. Seventeen patients with ET were studied, 14 without treatment and 3 under anagrelide treatment. Blood samples were obtained under sterility conditions and mononuclear cells were separated by Ficoll-Hypaque gradient. Afterwards, cells were cultured during 24 hs in IMDM supplemented with 10% FCS in the presence and absence of 150 mMol/L TAPI and IL-6sR released to culture media was measured by ELISA technique. Anchored IL-6R was evaluated before and after cell culture by flow cytometry using anti-CD126-PE. Monocyte and lymphocyte populations were selected using anti-CD14 and anti-CD3 respectively. IL-6sR levels in supernatant of mononuclear cells from 10 untreated ET patients were found increased, 122.5pg/ml (74–248 pg/ml) (median and range), compared to 9 normal controls, 83 pg/ml (22–130 pg/ml), p=0.011. In the presence of TAPI, patients and normal controls showed similar results, 54.95 pg/ml (18–137 pg/ml) and 48 pg/ml (18–96 pg/ml), respectively, p=NS. The difference between the amount of IL-6sR released in the absence and the presence of TAPI (D) would correspond to IL-6sR generated by proteolytic cleavage. This D was statistically higher in ET patients (61 pg/ml, 18–111 pg/ml) than in normal controls (28 pg/ml, 2–87 pg/ml), p=0.034. Expression of IL-6R on monocyte and lymphocytes from 5 untreated and 3 anagrelide treated ET patients before and after cell culture was similar to that of normal controls as shown by flow cytometry analysis. In conclusion, we found that proteolytic cleavage of IL-6R is increased in cultured mononuclear cells from patients with ET although the steady-state of IL-6R on monocytes and lymphocytes membrane is not altered.
Serum Insulinlike Growth Factor Is Not Elevated in Patients with Early B-Cell Chronic Lymphocytic Leukemia but Is Still a Prognostic Factor for Disease-Progression.
Authors: Molica Stefano , Vitelli Gaetano , Mirabelli Rosanna , Digiesu Giovanna , Giannarelli Diana , Iorfida Antonella 
Published: April 2020

Abstract
Insulin like growth factor 1 (IGF-1) is an important growth and antiapoptotic factor for the cancer cells in several malignancies and in multiple myeloma recent studies support the hypotesis of a role for IGF-1 in disease progression. Clinico-biological relevance of IGF-1 was never studied in B-cell chronic lymphocytic leukemia (CLL). Using a quantitative sandwich immunoassay technique (ELISA)(QUANTIKINE®, Human IGF-1 and IGFBP-3, R & D Systems), we measured the concentration of IGF-1 and its major binding protein IGF-binding protein 3 (IGFBP-3) in serum drawn at the time of diagnosis from 77 Binet stage A CLL patients. Either IGF-1 or IGFBP-3 were significantly decreased compared to healthy age- and sex-matched controls (P&lt;0.0001 for both; Mann-Whitney test).
Serum levels of IGF-1 and IGFBP-3 paralleled each other (P=0.002); in contrast, no significant correlation was found between serum levels of IGF-1 and clinico-hematological variables including age (P=0.253), sex (P=0.270), Rai clinical substages (P=0.140), LDH (P=0.956), β2-microglobulin (P=0.368), lymphocyte count (P=0.703) and lymphocyte doubling time [LDT](P=0.233). When correlation were attempted with circulating levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF)(P=0.971), basic fibroblastic growth factor (FGF-2)(P=0.695), angiogenin (P=0.282) or adhesion molecules such as vascular cell adhesion molecule-1 [VCAM-1] (P=0.318), intercellular adhesion molecule-1 [ICAM-1] (P=0.883) and platelet endothelial cell adhesion-1 [PECAM-1] (P=0.772) similar results were found. Serum levels of IGF-1 were further evaluated as a dichotomous variable with respect to progression-free survival (PFS), an endpoint surrogate for overall survival in early B-cell CLL. The best separation of curves was seen with the cutoff point at the 75th percentile of IGF-1 levels (i.e., 93 pg/ml). Median PFS was 63 months in the patient group with low IGF-1, compared to a median PFS of 40 months in the remaining patients (P=0.002; HR, 0.311, 95% C.I, 0.085–0.630). In the multivariate analysis performed including variables significant at univariate analysis [i.e., Rai substage (P=0.002); LDT (P=0.004), IGF-1 (P=0.01)], only Rai substage retained prognostic significance (P=0.006). However, after removing from analysis LDT (only 6 out of 77 had an LDT&lt; 12 months), either IGF-1 or Rai substage entered the model at a significant level ((P=0.03 and P=0.01, respectively).
In conclusion, IGF-1 did not correlate with markers of tumor burden or clinical status in CLL thus suggesting that levels of this cytokine do not reflect the intrinsic malignancy of disease. Results of the present study highlight, however, its involvement in mechanisms of disease-progression in early CLL.