bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extranodal-NHL: Outcomeand Comparison with Nodal NHL. Single Institution Experience Year: 1988–2004.
Authors: Lal Amar , Masood Nehal , Adil Salman 
Published: April 2020

Abstract
Background & Objective: Non-Hodgkin’s lymphoma (NHL) arising in an extra nodal (EN) site is not uncommon and its natural history and treatment is clearly characterized in the literature. Data on EN-NHL and comparison with N-NHL with relation to survival and prognostic factors is scarce in our part of the world. The primary objective of this study was to analyze the anatomic distribution, clinical features and outcome of Diffuse large B-cell lymphoma (DLBCL) patients according to the primary site (extra nodal vs nodal) with applicability of International Prognostic Index (IPI).
Methods: From 1988 to 2004, 711 cases of NHL were diagnosed at our Institute. Out of these 145 (20%) patients were excluded as they were other than DLBCL hitopathology. Five hundreds fifty-seven (80%) patients were analyzed for the clinico-pathologic characteristics, treatment outcome and prognostic factors affecting overall survival.
Ann Arbor staging system was used for staging with bone marrow biopsy, chest and abdominal radiography/CT.
Results: Median age was 48.7 ± 15.3 years; the M: F ratio was 2:1. The distribution according to the primary site was: lymph node, 322 cases (58%) of these 145 cases (44%) stage IV, 76 cases (23%) Stage III, 60 cases (18%) stage II and 47 cases(15%) stage I; and EN sites, 235 (42%), including gastro-intestinal tract (44%) followed by upper aerodigestive tract (19%), bones (08%), spine (05%), and unusual sites less than 3% each as breast, CNS, testis, lungs and skin.
The median survival rate was 4.8 and 6.3 years in NL and ENL respectively vary according to primary site/stage of the lymphoma.
In the univariate analysis age less than 60 years, early stage I -II, extra nodal involvement primarily gastric or bone, 0–1 extra nodal site, 0–1 PS, lack of B symptoms, normal LDH level has been associated with good prognosis.
In the multivariate analysis age, PS, stage and level of LDH were the main variables to predict OS; no nodal or extranodal site maintained their prognostic value.
Conclusion: Our data correspond with series from west increasing incidence extranodal lymphoma due to improved diagnostic techniques and superior results with chemotherapy by preserving the organ. Few patients with bowel obstruction or cord compression lymphoma required surgery for diagnosis or relief of symptoms. There is significant difference from western data in histologies DLBC-NHL is the most common histologies in our study. Overall survival patients with EN-NHL were similar to nodal NH-Lymphoma but largely depended on IPI.
Synergic Effects of Proteasome Inhibitor PS-341 and Tyrosine Kinase Inhibitor STI571 on Chronic Myeloid Leukemia Cells and BCR-ABL Oncoprotein In Vitro and In Vivo.
Authors: Zhou Guangbiao , Hu Zheng , Liu Dapeng , Wu Fuqun , Zhu Jiang , Chen Saijuan , Liu Xiaoli , Li Juan , Li Xiaofeng , Zhang Fengxiang 
Published: April 2020

Abstract
STI571/Gleevec/imatinib, a rationally-designed agent that occupies the ATP-binding site of BCR-ABL and stabilizes the protein in its closed, inactive conformation, has been a remarkable success for the treatment of chronic myeloid leukemia (CML). However, a significant proportion of patients chronically treated with STI571 develop resistance because of the acquisition of mutations in the kinase domain of BCR-ABL. Furthermore, the effects of STI571 on CML patients in accelerated phase or blastic crisis are unsatisfactory since many patients relapse after transient remission. Hence, additional drugs or STI571-based combination regimens are desired to circumvent resistance and to improve response rates. Here we reported that PS-341, a proteasome inhibitor which offers great promise to patients with multiple myeloma (MM), significantly enhanced the antileukemia activity of STI571 in vitro and in vivo. We found a synergy exists between low concentrations of PS-341 (5–10 nM) and STI571 (0.1–0.2 μM) in inhibition of cell growth and induction of apoptosis in K562 cell line and CD34+ leukemic cells isolated from CML patients. In K562 cells, combined use of PS-341 and STI571 accelerated activation of caspase-3, 9, and facilitated cleavage of poly-(ADP-ribose) polymerase (PARP) as compared to those in cells treated with PS-341 or STI571 alone. Moreover, PS-341/STI571 combination resulted in potentiated degradation of BCR-ABL and downregulation of phosphorylated BCR-ABL as compared to those in mono treatment. In nude mice inoculated subcutaneously with K562 cells, treatment with PS-341 (injected intraperitoneally, ip) alone (at doses of 0.05, 0.5, 1 mg/kg/d, twice a week for 4 weeks, respectively) decreased tumor growth in a dose-dependent manner. STI571 (ip) at 10 mg/kg/d also inhibited tumor growth. Intriguingly, combinatory administration of low dose PS-341 (0.05 mg/kg/d, twice a week for 4 weeks) and STI571 (10 mg/kg/d) yielded a much more profound inhibition of tumor growth and even clearance of leukemic cells in mice compared to either monotherapy. Taken together, these results demonstrate synergic effects of PS-341 and STI571, and provide the rationale to evaluate PS-341/STI571 combination in treating CML aiming to further improve clinical outcome of patients.
A Prospective Study in Ph+ Chronic Myeloid Leukemia (CML) Patients Showing That Interphase Fluorescence in Situ Hybridization (FISH) Is Effective as Conventional Cytogenetics for Definition of Cytogenetic Response. Correlation with Molecular Response (by the GIMEMA CML WP).
Authors: Testoni Nicoletta , Luatti S. , Marzocchi G. , Amabile M. , Gamberini C. , Buontempo F. , Baldazzi C. , Iacobucci I. , Mancini M. , Cuneo A. , Specchia G. , Kerim S. , Rege-Cambrin G. , Giugliano E. , Giussani U. , Abruzzese E. , Grimoldi M.G. , Modaferri B. , Castagnetti F. , Palandri F. , Mecucci C. , Bernasconi P. , Gozzetti A. , Palka G. , Zanatta L. , Zaccaria A. , Martinelli G. , Rosti G. , Baccarani Michele 
Published: April 2020

Abstract
We planned a prospective analysis involving 3 multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche Adulto) CML Working Party (WP) to evaluate the correlation between conventional cytogenetics (CC) and FISH response in CML pts in chronic phase (CP) treated with Imatinib. Karyotype and FISH analyses were performed on bone marrow (BM) cells in 26 local laboratories and in 12 WP reference labs. Peripheral blood samples for quantitative RT-PCR were centralized in Bologna. The data are reported in Figure 1 and in Table 1. Fig 1 shows the relationship between CC and FISH (r=0.91;p=0.008). Tab 1 shows the demonstration of FISH data according to CC data and the number of metaphases available for CC. Of 217 pts in CCgR by CC and &gt; 20 metaphases studied, 81.6% were FISH negative, 15.2% showed a low rate of FISH positive cells (1–5%) and 3.2% an higher rate. Of 94 pts in CCgR by CC but with &lt; 20 metaphases studied, 71.3% were FISH negative, 21.3% showed a low rate of FISH positive cells (1–5%) and 7.4% an higher rate. Of 43 pts in PCgR by CC and FISH positive, 48.8% showed 1– 5% positive cells. Moreover, 358 samples were performed simultaneously by CC, FISH and quantitative RT-PCR: 179 (50%) samples in CCgR showed major molecular response (MMolR, defined as a BCR-ABL × 100 ratio &lt; 0.1%): 164 (91.6%) were FISH negative and 15 (8.4%) were FISH positive (1.3–10% positive cells). We conclude that interphase FISH is a very releable method of monitoring the CCgR once it has been achieved. The relationship of FISH on BM cells with molecular response is at least as good as the relationship of CC with molecular response. It remains to be shown if the same results can be obtained on peripheral blood cells, that are already widely used for molecular monitoring.
No FISH negative FISH 1–5% FISH &gt; 5% CCgR ≥ 20 met 217 177 (81.6%) 33 (15.2%) 7 (3.2%) CCgR &lt; 20 met 94 67 (71.3%) 20 (21.3%) 7 (7.4%) PCgR ≥ 20 met 43 0 21 (48.8%) 22 (51.2%) CCgR and MMolR 179 164 (91.6%) 12 (6.7%) 3 (1.7%) Figure Figure
Rituximab Is an Alternative to Splenectomy in Adults with Chronic Immune Thrombocytopenic Purpura: Results of a Multicenter Prospective Phase 2 Study.
Authors: Godeau Bertrand , Fain Olivier , Porcher Raphael , Lefrere Francois , Fenaux Pierre , Cheze Stephane , Vekhoff Anne , Chauveheid Marie-Paule , Stirnemann Jerome , Galicier Lionel , Bourgeois Emmanuelle , Haiat Stephanie , Varet Bruno , Leporrier Michel , Papo Thomas , Michel Marc , Bierling Philippe 
Published: April 2020

Abstract
Background : Rituximab, a monoclonal anti-CD20 antibody, is a promising therapeutic agent for adults with immune thrombocytopenic purpura (ITP). Pooling results of the published literature suggest that rituximab achieves an initial response in about 50 % of adults with chronic ITP, with a 25–40% rate of sustained response. However, heterogeneity of patient pre-treatment status, short follow up and bias due to retrospective studies limit the interpretation of the data.
Objective : To assess the safety and efficacy of rituximab in adults with chronic ITP (duration ≥ 6 months) and platelet count ≤ 30x109/L candidate to splenectomy.
Methods : a multicenter prospective open-label single arm phase 2 trial designed according to Fleming’s single stage procedure was conducted. After informed consent, non splenectomized adults received 4 weekly intravenous infusions of rituximab at a dose of 375 mg/m2. All other ITP treatments were stopped. Treatment success was defined as a platelet count ≥ 50 x109/L with at least a 2 fold increase of the initial value at one year after the first rituximab infusion. Patients who received another treatment during follow up were considered as non responders. A sample size of at least 56 patients was calculated by Fleming’s single-stage design to ensure 90 % power for proving lack of efficacy if the true complete response rate was below 25%.
Results : Sixty consecutive patients (40F/20M) were included over a 21 months period. Mean age was 48 years (range 18–84). Mean ITP duration was 4.8 years. Mean platelet count at inclusion was 16±10x109/L. All but one patient, in whom reversible serum sickness disease was diagnosed after 2 infusions, received 4 infusions of rituximab. Fifteen other patients experienced transient side effects that did not lead to treatment discontinuation. No patient was lost to follow up. Success was achieved in 40 % (24/60 patients) (95 % confidence interval 28% to 52%) and was found significantly different from 25% (p=0.007). Among the 24 long term responders, platelet count at one year was ≥ 150x109/L in 18 and between 50 and 150 x109/L in 6. Two other patients (3%) had and incomplete response defined as a platelet count at one year between 30 and 50 x109/L but at least 2 fold the initial value. Thirty four (57%) patients failed to respond and amongst them, 18 have already undergone splenectomy.
Conclusion: rituximab appears to be a safe and good splenectomy-sparing strategy in adults with chronic ITP leading to a significant and durable response in 40% of the cases.
The Clinical Significance of Biphenotypia in Blastic Phase CML.
Authors: Tam Constantine S. , Kantarjian Hagop M. , Verstovsek Srdan , Wierda William G. , Shan Jenny , Otero-Palacios Joselle , Awais Ahmed , Ravandi-Kashani Farhad , Cortes Jorge 
Published: April 2020

Abstract
The characteristics and clinical outcomes of CML blast phase (CML-BP) patients whose blasts express antigens from more than one lineage are currently unknown. We systemically assessed lineage fidelity among patients with CML-BP using the definition of biphenotypic leukemia as proposed by the European Group for the Immunological Characterization of Leukemias (EGIL; Leukemia1995; 9:1783). Briefly, individual antigens are assigned scores based on known specificity for one of three lineages (myeloid, B-lymphoid or T-lymphoid); biphenotypic leukemia is defined by a score of &gt;2 points for two lineages. Between 02/97 and 01/06, 163 patients were treated for CML-BP at the MD Anderson Cancer Center, of which 120 had adequate flow cytometric assessment for calculation of EGIL score. The number of patients by lineages was: 89 myeloid (74%), 21 lymphoid (17.5%; B 14%, T 3.5%), 9 biphenotypic (7.5%), 1 unclassifiable (&lt;1%). Four of nine biphenotypic BP patients had a history of antecedent myeloid BP (n=3) or lymphoid BP (n=1). Lymphoid BP patients had lower mean white cell count (p=0.04), lower mean platelets (p=0.007) and higher mean bone marow blast percentage (p&lt;0.001) than myeloid BP patients; those with biphenotypic BP had values between the lymphoid and myeloid groups. Seven imatinib-naïve biphenotypic patients received imatinib as initial therapy for CML-BP, with six regaining a second chronic phase; however, median time to failure was only 2 months and, with the exception of one patient censored for allogeneic transplantation, all patients progressed within 4 months. The patient who underwent allogeneic transplantation died of transplant-related complications. An additional patient who had previously failed imatinib and nilotinib in chronic phase had no response to dasatinib in biphenotypic BP. The final patient developed biphenotypia during resistant relapse of previous B-lymphoid BP, and received supportive therapy only. Overall survival for lymphoid, myeloid and biphenotypic BP were 13, 8 and 6 months respectively (p=0.04). In order to determine the significance of minor degrees of lineage aberrancy, we examined the survival of myeloid and lymphoid BP patients with EGIL score 1.0 – 2.0 in a second lineage. For lymphoid BP patients, minor expression of myeloid antigens did not affect survival; in contradistinction, myeloid BP patients with minor expression of lymphoid antigens had a trend to inferior survival. Biphenotypic BP may either be de-novo or may emerge from previous unilineage CML-BP, highlighting the trend for lineal infidelity in CML-BP. Responses to tyrosine kinase inhibitors are short-lived, and survival using current therapeutic strategies is very poor.
Overall Survival Overall Survival
Cost-Effectiveness Analysis for Integral Treatment of Chronic Myeloid Leukemia in Chronic Phase at the Instituto Mexicano del Seguro Social (IMSS) Mexico.
Authors: Tenorio Luisa , Vargas E Juan , Baez Enrique , Afanador Carolina , Zapata Leon , Gomez-Morales Enrique 
Published: April 2020

Abstract
The economic analysis has become a priority for health institutions as a result of the increase in medical care costs. Therefore, an analysis model was developed integrating clinical and economic outcomes for the Medical care of chronic myeloid leukemia (CML) in chronic pahse.
Objective: To perform a cost-effectiveness assessment of the therapeutic alternatives for CML at UMAE No.25 IMSS.
Methodology: Economic evaluation of the use of imatinib mesylate (IM) vs. interferon + citarabine (INF/AraC), using as an effectiveness indicator, the number needed for treatment (NNT), to achieve a complete cytogenetic response (CCR) at 24 and 30 months was used. The integral care was obtained from the revision of clinical records in the UMAE 25, and from disease related-costs published by the IMSS.
Results: The NNT reveals the amount of patients that need to be treated with one or the other of the therapies to obtain the desired result (CCR), which means that for every 1.15 patients IC 95% (1.06–1.25) treated with IM for 24 months, one will reach the CCR, with a cost of $867,729 mexican pesos (mx), in comparison to the care cost for 7.14 patients IC 95 % (5.75–8.88) patients that are required to be treated with IFN/AraC for 24 months to obtain the same result, with a cost of mx $4,454,565. This difference is higher when results are assessed at 30 months: A cost of NNT care of 1.27 patients IC 95% (1.07–1.50) of mx $1,178,848 for IM vs. mx $10,182,116 for NNT care of the 13.5 patients, CI 95% (9.40–19.43) required to achieve a CCR with IFN/AraC.
Discussion: Comparing these results with the cost of the main treatment used during the same time, the expense effectiveness is evident. In other words, for each peso spent on IM at 24 months, mx $0.63 are effective, whilst for each peso spent on IFN/AraC, only mx $0.02 are beneficial for the patient. When this same reasoning is applied to the success cost at 30 months, we see that for each peso spent on IM, $0.58 are effective vs mx $0.01 per peso effectiveness spent on IFN/AraC.
Conclusions: The superiority of IM is evident compared to INF/AraC in regards to the effectiveness of achieving CCR at 24 and 30 months. This positive difference in favor of imatinib mesylate is reflected on the cost that Health Institutions have to spend, in order to obtain a successful CCR, due to the decreased number of patients necessary to treat with IM, in order to achieve this success.
High-Sensitivity Mutational Analysis of BCR-ABL Mutations in the Kinase Domain Using Pyrosequencing Could Provides Alternative Methodology for Monitoring the Proportion of Mutant Alleles in Patient with Chronic Myelogenous Leukemia.
Authors: Lee Il-Kwon , Yun Ju Hyun , Kim Yeo-Kyeoung , Kim Hee Nam , Park Kyeong-Soo , Shin Myung Geun , Choi Chan , Kim Hyeoung Joon 
Published: April 2020

Abstract
Imatinib mesylate has substantially changed treatment of chronic myeloid leukemia (CML). But the resistance-conferring mutations in tyrosine KD (Kinase Domain) of BCR-ABL region constitute the leading cause of clinical resistance in CML patients on imatinib or dasatinib monotheray. Therefore early detection and accurate quantification of the common mutations in KD in post-transplantation patient could provide vital information regarding disease progression or prognosis. Here we report results of pyrosequencing to quantify the non-mutated and mutant alleles in 11 CML patients who were treated by imatinib mesylate or dasatinib. Patients were monitored over periods ranging from 24 to 67 months. 11 mutations in the region identified by direct or pyrosequencing and/or pGEMT cloning are Y215F, T253F, E255K, L323P, N336S, A337T, M351T, E355K, F359I, H396R and P480L. Out of 11 mutations, two (F359I and P480L) are found to be novel. Four mutations (L323P, N336S, A337T and E355K) were positioned between P loop and catalytic domain, one (F359I) was in the activation domain and one (P480L) was near to the carboxy terminal of the kinase. One novel mutation (Y215F) located outside (N terminal region of kinase domain) region was also identified. Y215F mutation which lies outside the kinase domain might be sporadic one without affecting kinase activity. We successfully measured proportion of KD mutant cells with greater precision by using pyrosequencing (Fig 1). The dynamics of the mutated clones obtained from pyrosequencing were correlated with RQ-PCR (Fig2) suggesting quantitative pyrosequencing method could be alternative to various methods including allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) and conventional sequencing which have limited sensitivity at low concentrations of mutant allele. Taken together, we established a novel method for early identification of KD mutations and precise monitoring of the proportion of mutant alleles in patient with CML. Most importantly, those results were in correlation with clinical response to imatinib mesylate or dasatinib. Therefore quantitative measurement of mutant cell dynamics could provide early indications of clinically significant disease progression.
T3151 mutation T3151 mutation T3151 Mutation T3151 Mutation
Functional Gfi-1 Is Important for BCR/ABL-Mediated Proliferation and Survival of Myeloid Cells.
Authors: Basu Suchitra , Qiu Yaling , Dong Fan 
Published: April 2020

Abstract
Chronic myelogenous leukemia (CML) is a clonal hematopoietic disorder caused by the BCR/ABL fusion oncogene. CML typically evolves in three distinct clinical stages: chronic and accelerated stages and blast crisis. The progression of CML from chronic phase (CP) to blast crisis (BC) is characterized by the increasing failure of myeloid precursors to differentiate into mature granulocytes and aggressive proliferation of immature myeloid cells. It has been shown that CML progression from CP to BC is associated with downregulation of C/EBPs including C/EBPa and C/EBPe, critical regulators of myeloid development. Forced expression of C/EBPs suppresses transformation and restores granulocytic differentiation of BCR/ABL-expressing myeloid cells, suggesting that downregulation of C/EBPs may be involved in CML transition from CP to BC. The proto-oncogene Gfi-1 encodes a nuclear zinc-finger transcriptional repressor that is required for the survival and proliferation of myeloid cells. We recently showed that expression of a dominant negative Gfi-1 mutant, N382S, led to markedly increased expression of C/EBPe in myeloid cells, suggesting that Cebpe encoding C/EBPe is a Gfi-1 target. We investigated the possibility that inhibition of Gfi-1 function in BCR/ABL-expressing cells may increase C/EBPe expression, thereby exerting a negative effect on BCR/ABL-mediated transformation. Myeloid 32D cells transfected with BCR/ABL (32D/BCR/ABL) are independent of IL-3 for proliferation and survival. Expression of the N382S mutant in 32D/BCR/ABL cells (32D/N382S) had a significant inhibitory effect on proliferation and survival in the absence of IL-3, but only a weak effect in the presence of IL-3, suggesting that the N382S mutant specifically inhibited BCR/ABL-mediated proliferation and survival. The level of C/EBPe protein was markedly augmented in 32D/N382S cells. Interestingly, when cultured in medium containing no growth factors, 32D/N382S cells exhibited certain features of macrophage differentiation including increased cell size, adherence to the surface of culture flasks, spreading and increased surface expression of macrophage differentiation marker F4/80. 32D/N382S cells also became more sensitive to c-ABL kinase inhibitor imatinib. These data indicate that Gfi-1 may play an important role in BCR/ABL-mediated transformation and thus represent a potential therapeutic target in the treatment of CML.