bluuebunny/crossref_metadata_2025_split huggingface dataset:
Peripheral Blood Cytogenetic Studies in Hematological Neoplasms: Predictors of Obtaining Metaphases for Analysis.
Authors: Hussein Kebede , Ketterling Rhett P. , Dewald Gordon W. , Hulshizer Rachael L. , Kuffel Daniel G. , Wiktor Anne E. , Van Dyke Daniel L. , Tefferi Ayalew 
Published: October 2019

Abstract
Background: Peripheral blood (PB) is sometimes used in place of bone marrow (BM) for cytogenetic studies during the evaluation of hematologic malignancies. We looked for clinical or laboratory features that predict success in obtaining analyzable metaphases during PB chromosome studies.
Methods: The Mayo Clinic cytogenetics database was queried to identify adult cases (age > 18 years) with suspected or established hematologic neoplasm in whom PB cytogenetic studies were performed. Success defined as the acquisition of at least two metaphases, was correlated with clinical and laboratory information corresponding to the time of the PB cytogenetic study.
Results: A total of 242 PB cytogenetic studies were performed: clinical diagnosis was a myeloid neoplasm in 169 patients (70%), lymphoid neoplasm in 50 (21%), and unexplained cytopenia or leukocytosis in 23 (9%). The 169 myeloid cases included 59 patients with either primary (n=39) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis (n=20), 42 with acute myeloid leukemia (AML), 15 with chronic myeloid leukemia, 9 with myelodysplastic syndrome (MDS), 8 with ET, 6 with PV, and 30 with other MPDs. The 50 lymphoid cases included 19 with chronic lymphocytic leukemia, 12 with lymphoma, 11 with acute lymphocytic leukemia (ALL), and 8 with plasma cell proliferative disorders. PB cytogenetic studies resulted in at least two analyzable metaphases (median 20, range 2–31) in 142 of the 242 study cases (59%); in univariate analysis, this was predicted by the specific clinical diagnosis (p<0.0001), presence and degree of circulating myeloid progenitor cells (p<0.0001), higher leukocyte count (p<0.001), lower platelet count (p=0.003), lower hemoglobin level (p=0.002), and presence of palpable splenomegaly (p=0.002). In multivariable analysis, only the presence of circulating myeloid progenitor cells sustained its significance and this was consistent with the high yield rates seen in PMF (80%), post-PV/ET MF (85%), AML (76%), and ALL (80%) as opposed to the low rates seen in ET (0%) and PV (2%). In 104 cases, BM cytogenetic studies were performed within one month of the PB cytogenetic studies; an abnormal BM cytogenetic finding was another independent predictor of a successful PB study (p=0.002).
Conclusion: PB cytogenetic studies are most appropriate in diseases characterized by presence of circulating myeloid progenitors or blasts (e.g. PMF, AML, ALL); the yield otherwise is too small to be cost-effective. The current study also suggests a higher likelihood of a successful PB cytogenetic study in the presence of an abnormal bone marrow karyotype.
Regulation of Bim Expression by IGF-1 in the 5T33MM Murine Model for Multiple Myeloma.
Authors: De Bruyne Elke , Bos Tomas , Deleu Sarah , Atadja Peter , Menu Eline , Van Valckenborgh Els , Van Camp Ben , Vanderkerken Karin 
Published: October 2019

Abstract
Insulin-like growth factor-1 (IGF-1) is an important factor in proliferation, cell survival and migration of multiple myeloma (MM) cells. Bcl-2 like 11 (Bim) is a pro-apoptotic protein belonging to the BH3-only group of Bcl-2 family members. Three major forms of Bim are known: BimEL, BimL and BimS. In leukemia, beta1 integrin mediated adhesion has been shown to reduce Bim levels by enhanced proteasome activation. We used the 5T33MM syngeneic, immunocompetent murine model for MM. Both the exclusively in vivo growing 5T33MMvv cells and the stroma independent in vitro growing 5T33MMvt cells were used. The present study showed that Bim levels were reduced in MM cells after IGF-1 treatment. IGF1-mediated regulation of Bim expression in 5T33MMvv cells was demonstrated to be a result of reduced gene expression on the one hand and increased proteasomal-mediated degradation of Bim protein levels on the other hand. Reduced expression was related to activation of the Akt pathway and inactivation of the transcription factor FoxO3a. Increased degradation of Bim was related to activation of the mitogen-activated protein kinase pathway, as IGF-1 treatment resulted in phosphorylation of ERK1/2. Reducing Bim levels by transducing 5T33MMvt cells with a lentiviral vector with a short hairpin RNA cassette inhibited serum starved and the clinical relevant deacetylase inhibitor panobinostat (LBH589, Novartis) induced cell death. Together our data indicate that disrupting IGF-1-mediated regulation of Bim degradation may increase the efficacy of drugs. In the past few years, methylation of DNA and acetylation of histones have been proven to be important regulators of gene expression. Moreover, acetylation of non-histone proteins has emerged as a dynamic posttranslational modification regulating numerous cellular processes. Co-treatment of 5T33MMvv and 5T33MMvt cells for 24h with the demethylation agent 5-Aza-2′deoxycytidine and the deacetylase inhibitor panobinostat resulted in a strong induction of Bim expression at protein level. In the future, we will investigate the contribution of IGF-1 to the epigenetic silencing of Bim by i) comparing the Bim promoter methylation pattern of both human IGF-1 responsive cell lines and murine 5T33MMvv cells treated or not with IGF-1 using bisulfite PCR sequencing and ii) using the epigenetic modulating agents 5-Aza-2′deoxycytidine and panobinostat.
Host Indoleamine 2,3-Dioxygenase Is a Critical Regulator of Acute GVHD Lethality.
Authors: Jasperson Lisa K. , Panoskaltsis-Mortari Angela , Taylor Patricia A. , Bucher Christoph , Mellor Andrew L. , Munn David H. , Blazar Bruce R. 
Published: October 2019

Abstract
Graft versus host disease (GVHD), the major cause of morbidity and mortality after bone marrow transplant (BMT), is initiated following activation of donor T cells by host antigen presenting cells (APCs). The immunosuppressive enzyme indoleamine 2,3-dioxygenase (IDO) is expressed by APCs and parenchymal cells and is further inducible by inflammation. We investigated whether lethal conditioning and GVHD induce IDO and if IDO prevents tissue injury by suppressing immune responses at the induction site. Using a fully MHC-mismatched murine GVHD model, we determined that IDO is a critical regulator of GVHD, most strikingly in the colon, where epithelial cells dramatically upregulated IDO expression during GVHD. No IDO upregulation was detected in mice that received irradiation only or irradiation and T cell-depleted BM without added alloreactive T cells. When mice with a genetic ablation of the IDO gene (IDO−/−) were used as recipients of BM and T cells, they suffered accelerated GVHD lethality compared to wild-type recipients, displaying increased colonic inflammation and T cell infiltration. This was true using grafts of either CD4+ T cells or combined CD4+ and CD8+ T cells. In addition, the IDO inhibitor 1-methyltryptophan caused accelerated GVHD in wild-type recipients. Lethality was not due to increased radiation sensitivity, as sublethally irradiated IDO−/− recipients showed no morbidity, and syngeneic BM was capable of rescuing lethally irradiated IDO−/− recipients. GVHD protection was not mediated by early control of T cell proliferation or apoptosis in lymph nodes or spleen. Furthermore, IDO did not affect expression of T cell effector molecules in lymphoid organs. Though studies have suggested a link between IDO and T regulatory cell (Treg) function, Treg depletion of donor grafts did not abrogate the IDO effect, indicating donor Tregs are not required for the suppressive function of IDO. Conversely, cultured Tregs added to the graft delayed GVHD in IDO−/− recipients, proving Tregs do not require host IDO for their function in this model. Instead, colons from IDO−/− hosts contained more proliferating CD4+ cells than wild-type colons after transplant. Together, this evidence suggests that in GVHD IDO acts primarily at the site of its expression to decrease effector T cell proliferation, diminish colonic inflammation, and reduce disease severity. These studies are the first to identify a function for IDO in GVHD lethality and suggest that modulation of the IDO pathway may be an effective strategy for treatment of this disease.
Bortezomib Protects Osteoblasts from Glucocorticoid-Induced Damage, and Enhances Glucocorticoid-Induced Toxicity Against Osteoclasts and Myeloma Cells.
Authors: Soe Kent , Andersen Thomas L. , Kupisiewicz Katarzyna , Plesner Torben , Delaisse Jean-Marie 
Published: October 2019

Abstract
Introduction: Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow, and leads most often to bone destruction by osteoclasts and prevention of bone repair by osteoblasts. Bortezomib and glucocorticoids are both powerful anti-myeloma drugs that are used for killing malignant plasma cells in the patients. Furthermore bortezomib has direct anti-osteoclastic and pro-osteoblastic properties that may contribute to bone protection in multiple myeloma, while glucocorticoids have more ambiguous effects on these bone cells and are clearly anti-osteoblastic. Recent clinical trials based on the combination of bortezomib and glucocorticoids drew the attention on the very promising anti-myeloma efficiency of this combination. However, the bone cell response of this combination has not been tested. In order to address this question, we performed an in vitro study, and importantly adapted our in vitro model to mimic the pharmacokinetics of bortezomib and glucocorticoid in the patients.
Methods: Myeloma cell lines, primary human osteoclasts and osteoblast-like cells (MC3T3) were pulse-treated or not with clinically relevant doses of bortezomib (12.5, 25 or 50 nM) for 3 hours. Subsequently, the cells were exposed during a 3-day culture to 1.6 μM prednisolone which approximately corresponds to a dose of 50 mg prednisolone in a patient. The impact of the treatment on the cells was determined by survival, activity and gene expression.
Results: Bortezomib as a single treatment was very efficient in killing sensitive myeloma cells (OPM2) whereas the more resistant cells (U266) were more efficiently killed in combination with prednisolone. The release of TRAP from primary human osteoclasts, a marker of osteoclastic activation, was strongly inhibited by bortezomib treatment alone, but only in combination with prednisolone did it result in killing of osteoclasts. Survival of osteoblast like cells was uninfluenced by treatment with bortezomib alone. In contrast, as shown previously, prednisolone strongly reduced osteoblast survival. Most importantly however, a 3 hr pre-treatment with bortezomib protected the osteoblasts against the detrimental effects of glucocorticoids. Ongoing investigations by Q-PCR indicate that important markers of osteoblast maturation remain high if the osteoblasts were pre-treated with bortezomib prior to prednisolone exposure.
Conclusion: Our study demonstrates in conditions relevant to treatment of myeloma patients, that combining bortezomib and glucocorticoids has a direct synergistic effect against myeloma cells and osteoclasts, and that bortezomib protects directly osteoblasts from the negative impact of glucocorticoids. Thus, the combination of bortezomib and glucocorticoids is not only a powerful treatment of multiple myeloma itself, but also shows promise for treating myeloma bone disease.
A Phase I Study of the Proteasome Inhibitor Bortezomib in Patients with Myelofibrosis.
Authors: Barosi Giovanni , Gattoni Elisabetta , Barbui Tiziano , Vannucchi Alessandro M. , Rambaldi Alessandro , Silverman Lewis , Goldberg Judith , Marchioli Roberto , Hoffman Ronald 
Published: October 2019

Abstract
Myelofibrosis (MF) is the most serious myeloproliferative disorder, characterized by clonal myeloproliferation associated with cytokine-mediated bone marrow stromal reaction including fibrosis and osteosclerosis. Because the NF-κB pathway is implicated in the abnormal release of cytokines in MF, the proteasome inhibitor bortezomib might be a potential therapy. We conducted a phase 1 trial of intravenously administered bortezomib (Velcade®) in 12 adults with advanced primary MF (11 patients) or post-PV/post-ET MF (1 patient). Eligibility was defined as refractory or not suitable to first line chemotherapy. Median age was 57 years (range, 22 to 69 years). Three cohorts of patients were treated with bortezomib at day 1, 4, 8, and 11 from 0.8 to 1.3 mg/m2, every 21 days x 6 cycles. Three patients received less than 5 cycles and are not considered evaluable for response (cutaneous vasculitis, respiratory distress syndrome and peripheral neuropathy). Dose-limiting toxicity (DLT) occurred in 1 patient treated with bortezomib in the 1.3 mg/m2 cohort, consisting on respiratory distress syndrome. The patient was hospitalised and improved with corticosteroid therapy. The maximum-tolerated dose was 1.3 mg/m2 for 4 days every 3 weeks. Other frequent non-DLTs were thrombocytopenia (2/12), fatigue (3/12), oedema (1/12), cutaneous rash (2/12). No complete, major or moderate responses according EUMNET response criteria were documented. One minor response was documented due to complete response in platelet count (platelet count 150–400 x 109/L at the end of the sixth cycle of therapy). Our results show that bortezomib in MF is clinically tolerable at the 1.3 mg/m2 every 21 days x 6 cycles. The efficacy of the drug is under examination in a phase II study.
A Single-Center Study To Evaluate the Safety and Efficacy of Intravenous/Oral Fludarabine in Untreated Gastric MALT Lymphoma. Impact of t(11;18)(q21;q21) in Molecular Response Rates.
Authors: Salar Antonio , Bellosillo Beatriz , Seoane Agustín , Martinez Luz , Ferrer Ana , Serrano Sergio , Besses Carlos 
Published: October 2019

Abstract
Background: The treatment of gastric mucosa-associated lymphoid tissue (MALT) lymphoma in the absence of H. pylori infection or when the lymphoma fails to regress after adequate antibiotic treatment remains controversial. Fludarabine (F) is an active agent for indolent lymphoma, however, its clinical activity in gastric MALT lymphoma has not been studied. The aim of the study is to assess the efficacy and safety of single-agent fludarabine in gastric MALT lymphoma and to analyze the molecular response (MR) after this treatment.
Methods: Treatment consisted of fludarabine (25 mg/m2 IV) given on days 1–5, every 4 weeks, for 6 cycles; after the first cycle, oral fludarabine was allowed to be given orally at 40 mg/m2 with the same schedule. Molecular response (MR) was assessed by RT-PCR analysis of t(11;18) or by PCR assays for analysis of IgH gene rearrangements analyzing FR1, FR2 and FR3 in endoscopic biopsies.
Results: Eight consecutive patients were included. Median age: 60 years (range: 45–77); 3 pts were in stage I, 2 stage II-1 and 3 stage IV according to Lugano system. Four out of 5 (80%) pts achieved a CR after three cycles and all eight cases (100%) achieved a CR after six cycles, for an overall response rate of 100%. After a median follow-up of 44 months (range 14.5–58 mo) no patient has shown clinical or endoscopic relapse. Hematological toxicity occurred in 75% of pts, mainly mild neutropenia and generally after the third cycle. Three cases received G-CSF (after the 2nd, 3rd and 6th cycle) and three patients required dose modification or delay (3–7 days) in the delivery of the following cycle. No blood transfusions were required. Only one patient had to be admitted because of non-neutropenic fever. None case of myelodisplasia has been detected at last follow-up. Four out of 8 pts (50%) achieved MR during the study-period (see figure). Four out of 5 (80%) pts without t(11;18) achieved MR. In contrast, no patient carrying t(11;18) achieved MR. Sequencing analysis of monoclonal PCR products will be presented.
Conclusions: Fludarabine, either intravenous or oral, is safe and achieve a high response rate when given in gastric MALT lymphoma, with many pts achieving MR. In those pts carrying t(11;18), residual disease can be detected by PCR but do not determine relapse at present follow-up.
Figure Figure
90Y-Ibritumomab Treatment for Relapsed and/or Refractory B Cell Type Non-Hodgkin’s Lymphoma. Multiinstitutional Argentinian Study.
Authors: Cacchione Roberto , Dupont Juan , Milone Jorge , Bordone Javier , Garay Guy , Ardaiz Maria , Castro-Rios Miguel , Prates Virginia , Basso Alfredo , Iabstrebner Marcelo , Avila Graciela , Diaz Alicia , Argentieri Daniel , Rudoy Silvia , Trouboul Alicia , Palmer Luis , Pombo Gonzalo , Rappaciotti Silvina , Negri Pedro , Lafalse Diana , Riera Leandro , de Tezanos-Pinto Miguel , Riveros Dardo , Arnold Mario Brown , Carrasco Antonio , Bezares Fernando 
Published: October 2019

Abstract
The radionucleid conjugate with monoclonal antibodies (antiCD20/90Y-ibritumomab tiuxetan) have been approved for the treatment of relapsed, refractory and transformed (high grade) follicular lymphomas. Between September 2005 and August 2007, 41 patients with refractory/relapsed lymphoma were enrolled. Median age was 62 yrs old (45–83). Twenty were women and 21 were men. Thirty three were follicular and 5 were mantle cell lymphoma and 3 transformed lymphoma. Eighteen patients had bulky disease, 8 had bone marrow involvement and 21 had stage III-IV disease. Median time from diagnosis was 5 years (0.5–29). Twenty one had received 1–2 previous treatments, and 20 pts had received 3–5 previous treatments including 5 pts with autologous bone marrow transplantation. All had previously received anti-CD20 monoclonal antibody therapy. Six pts received previous radiotherapy. 90Y-Ibritumomab (Zevamab™ Bayer-Schering Argentina) was administered at 0.3 or 0.4 mCi, based on initial platelet count. Seven days before, and on the same day of the immunoconjugate administration, pts received rituximab 250 mg/m2. Thirty eight were evaluable for response. Thirty four (89%) pts responded: 20 CR (53%) and 14 PR (36%). With a median follow-up of 10 months, 60% of pts were expected to continue in CR at 18 months. Overall survival at the same period for the entire group was 89%. Nineteen pts (46%) required filgrastim administration for neutropenia, Ten pts (24%) required platelet transfusions, 10 pts had neutropenia plus fever and they had to be admitted for complicated pancytopenia, 8 pts required red blood cells transfusion. Two patient died 30 and 40 days after treatment with hypoplastic bone marrow complicated with septicemia and in the post autologous bone marrow transplantation period, respectively. Four pts with previous bone marrow transplantation, required filgrastim, transfusions and 2/3 had febrile neutropenia. Our experience with 90Y-ibritumomab in relapsed and refractory folicullar lymphoma shows 53% CR. Even heavily treated pts, that had previous bone marrow transplantation were able to receive the radioimmunoconjugate, although they required extra support. Our experience favours the use of 90Y-Ibritumomab tiuxetan in relapsed and refractory lymphomas even if they had received previous autologous bone marrow transplantation.
Efficacy and Safety of Rituximab+CHOP in IR and Maintenance Therapy with Rituximab vs Observation in De Novo Aggressive Non-Hodgkin Lymphoma.
Authors: Tripp Francisco , Báez Enrique , Ávila Elsa , Baltazar Severiano , Garcés Oscar , Reyes Gustavo , Batista Benjamín , Zaragoza Alva , Vela-Ojeda Jorge , Villela Luis 
Published: October 2019

Abstract
Introduction: Patients with aggressive NHL may respond to treatment, but 4-year DFS is < 40%. Rituximab has shown activity as monotherapy in patients even in refractory or relapsing post-MOT patients. Besides, preliminary results from maintenance therapy studies are promising.
Objective: To determine if maintenance with Rituximab in first complete remission increases disease-free survival and overall survival compared to observation.
Methods: A clinical trial with post-remission randomization was carried out, including patients with Aggressive Non-Hodgkin Lymphoma, stages IIb- III- IV, with ECOG 0–2, and ≥15 years old. All patients received the Rituximab + CHOP/CHOP-Like regimen during induction to remission (IR), and those with Complete Remission (CR) were randomized to receive rituximab-based maintenance therapy biannually (2 x 375 mg/sc) vs observation.
Results: 217 patients have been enrolled to IR, age 52±14 years old, 114 (52.5%) masculine, 174 of them (80.2%) presented remission; 149 CR, 25 PR. Two (0.9%) patients showed stable disease, 25 (11.5%) developed disease progression, and 16 (7.4%) died. Out of the 174 patients with remission, 96 patients have received maintenance therapy for over 6 months, 45 in the rituximab group, and 51 in the observation group, with a median follow-up of 14.4 months (pt 25– 75, 7.74 – 21.88 months). To date only 1 patient per group had a progress and none has died. During IR -considering the maximum toxicity developed per patient -, acute toxicity was remarkable: fever I, II in 13%, III–IV 1%, and chills I, II 8.2%, III 1%. And not acute: anemia I,II 54%, III 1.9, IV 1.4%, neutropenia I,II 46.1%, III 18.4, IV 2.8% and infection I,II 16.4%, III 1.0%, and IV 1.4%.
Discussion: Overall response to Rituximab + CHOP regimen is very good (80.2%), and to date 96 patients included in maintenance therapy with a median follow-up of 14.4 months, the difference between the groups is not evident yet; therefore, surveillance should be continued.
Detection and Follow Up of BCR/ABL Translocation by Cromogen In Situ Hibridization with ABL Centromeric and Telomeric (T/C) Probe Pair. Molecular, Accurate and Inexpensive Assay.
Authors: Barragan Carlos Sergio , Hansson Silvia B. , Cicchini Silvina A. , Tamashiro Monica , Dinardo Pablo G. 
Published: October 2019

Abstract
Objective: To Identify and to standardize a reliable t(9,22) BCR/ABL Molecular diagnosis method for developing countries.
Patients, Materials and method: Nineteen patients: Fourteen newly diagnosed Chronic Myeloid Leukemia confirmed by PCR and Cytogenetic study, one Acute Myeloid Leukemia (AML), one Acute Lymphoblastic leukemia (ALL) Phi positive, two myeloproliferatives Phi negative and a Chronic Lymphocyte Leukemia were studied. Mononuclear cell was obtained by Histopaque separation cell medium (Sigma Aldrich) from Bone Marrow and Blood samples. A translocation probe pair ABL (Chromosome 9 band 9q34) T/C digoxigenin and biotin labeled (Zymed - Invitrogen) were used for hybridization both cellular; blood and bone marrow smear. Immunoassay detection system was applied to localize BCR/ABL under bright field microscope by counting between 200 and 500 cells. We performed fifty assays with these samples.
Result: No differences between cell, blood or bone marrow smear were found. We improved the method fixing the samples with acetone. The assay was performed in fresh and frozen samples after six months without relevant differences. We were able to identify translocation, deletion and trisomy. The assay is semi quantitative and we can see a diminished number of BCR/ABL after five months with Tyrosin Kinase inhibitor, Imatinib (Glivec, Novartis) in six patients. (Table 1 and graphic 1). We detected a BCR/ABL LLA Phi positive and AML. All the cases were tested with RT-PCR, and five of them with QRT- PCR. We established an accuracy cutoff higher than 5 to 8% of positive cells for accepting BCR/ABL presence in the sample.
Conclusion: This low cost method is useful, accurate, easy and fast to diagnose and follow up CML patients treated with Imatinib. Molecular diagnosis is hardly perform in developing countries or in far away towns or cities; training personal with this method in laboratories with basic equipment would solve this critical problem for many people throughout the world.