bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Dasatinib in Patients with Accelerated-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-A (CA180-005).
Authors: Guilhot Francois , Apperley Jane F. , Kim Dong-Wook , Rosti Gianantonio , Yuan Xiaobin , Van Tornout Jan M.A. , Garzon Felix T. , Cortes Jorge 
Published: October 2019

Abstract
Dasatinib (SPRYCEL®), a potent inhibitor of BCR-ABL and SRC-family kinases, has been shown to be effective and safe for patients with accelerated-phase chronic myelogenous leukemia (AP-CML) who are resistant or intolerant to imatinib. START-A is a 39-center, international study to which patients with AP-CML who failed prior imatinib therapy were enrolled between December 2004 and July 2005. Here we report an update of the efficacy and safety of dasatinib (70 mg BID) from this open-label study of 174 patients with imatinib-resistant (n=161) or -intolerant (n=13) AP-CML after a median follow-up of 14.1 mo (range 0.1–21.7). Dose escalation (100 mg BID) or reduction (50 or 40 mg BID) were allowed for a lack of response or toxicity, respectively. Median time from original diagnosis of CML was 82 mo (range 4–359). Prior therapy included interferon-α in 72% of patients and stem-cell transplantation (SCT) in 13%; 52% had received prior imatinib doses >600 mg/d and 59% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 79% of patients, major cytogenetic response (MCyR) in 33%, and complete cytogenetic response (CCyR) in 21%. CHRs were attained by 45% of patients, while MCyRs and CCyRs were seen in 39% and 32%, respectively. Responses were achieved irrespective of imatinib status (with MCyR of 39% for both imatinib-resistant and -intolerant subgroups), prior stem-cell transplantation (26% MCyR), or the presence of prior BCR-ABL mutations (with the exception of T315I) (40% MCyR for both the mutation-positive and -negative subgroups). Twelve-month progression-free survival and overall survival were 66% and 82%, respectively. Dose interruptions were required for 85% of patients and dose reduction for 65%; the average daily dose administered was 126 mg (range 32–196). Grade 3–4 neutropenia and thrombocytopenia were reported in 76% and 82% of patients. Non-hematologic toxicity was generally mild to moderate and consisted primarily of diarrhea (52% all grades, 8% grade 3–4), headache (29%, <1%), nausea (28%, <1%), pleural effusion (27%, 5%), fatigue (26%, 4%), and superficial edema (22%, 1%). Dasatinib is effective in patients with AP-CML following imatinib treatment failure and the overall benefit-risk evaluation is favorable in this poor prognosis population. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.
Soluble IL-6 Receptor Synergistically Stimulates the Growth of Multiple Myeloma with IL-6 and Confers Resistance to Bortezomib.
Authors: Lee Young Y. , Park Joowon , Yoon Sung-Soo , Choi Jung H. , Park Byoung B. , Kim Byoung K. 
Published: October 2019

Abstract
Proinflammatory cytokines including Interleukin-6 (IL-6), TNFa, and IL-8, involved in a variety of cellular responses including proliferation, differentiation, and inflammatory processes. They play a pivotal role in the pathogenesis of multiple myeloma (MM). Elevated IL-6 and souble IL-6 receptor (sIL-6R) levels have been found in MM patients indicating that its production is not only coordinated as part of a disease progression but also strongly associated with outcome of anti-cancer therapy. Even though Bortezomib, one of proteosome inhibitors, is known to effectively induce the apoptosis of U266 myeloma cells via caspase-dependent pathway and inactivation of NF-kB, these apoptotic effects by Bortezomib could be decreased in U266 myeloma cells exposed to various proinflammatory cytokines. However, roles of IL-6 and sIL-6R in the progression of MM and response to anti-cancer treatment still remain to be explored. In this study, ELISA assay showed higher levels of IL-6, sIL-6R, and IL-8 in bone marrow plasma of MM patients compared to control group, which is the similar results of other investigators. Bortezomib-induced apoptotic effect in U266 myeloma cells was reduced by treatment of IL-6. This Bortezomib-induced apoptotic effect was more reduced in U266 myeloma cells following combined treatment with IL-6 and sIL-6R, although sIL-6R only did not exert on apoptotic effect. Caspase-3 activity by Bortezomib treatment decreased when U266 cells exposed to combined IL-6 and sIL-6R. In addition, U266 cells treated with combined IL-6 and sIL-6R synergically activated the phosphorylation of STAT-3 and ERK resulting in prolong survival of U266 cells. Phosphorylation of STAT-3 and ERK in U266 myeloma cells following combined treatment of IL-6 and sIL-6R did not affect by Bortexomib treatment. These results suggest that the levels of IL-6 and sIL-6R in bone marrow plasma may strongly be associated with clinical outcome of Bortezomib treatment in MM patients.
Transplant Centre Experience and Patient Selection Are the Key Elements Associated with Outcome of RIC and MAC HSCT for CML.
Authors: Crawley Charles R. , Brand Ronald , Olavarria Eduardo , de Witte Theo M. , Apperley Jane F. , Niederwieser Dietger W. , Guglielmi Cesare , Ljungman Per T. , Gratwohl Alois 
Published: October 2019

Abstract
Allogeneic transplantation continues to have a role in the management of high risk CML. However the place of reduced intensity (RIC) versus myeloablative conditioning (MAC) is uncertain in younger patients. A total of 2331 first HSCT’s performed from 1998–2005 were reported to the European Group for Blood and Marrow Transplantation Registry, RIC was used in 276 and MAC in 2055. Overall survivals were similar for the first 9 months. After 9 months the survival curves separated (HR for RIC 1.8, 95% CI 1.2–2.8 p=0.01). All estimates were based on time dependent Cox models and landmark analyses at 9 months. EBMT score was higher in the RIC group (score 0–2, 27% vs 52% p<0.001) and was associated with 5-year survival estimates: EBMT score 0–2, 68% vs 68%, 3–4, 48% vs 56% and 5–7, 27% vs 33% for RIC and MAC respectively. Comparison of RIC and MAC is complicated by differences in patient characteristics. A propensity score was developed to adjust for these differences from a logistic regression model based on the following factors: age, use of PBSC, T cell depletion, disease phase, year, CMV status, sex mismatch, time to transplant and donor type. The propensity score predicts the likelihood of receiving a RIC (high score, RIC more likely). Adjusting for the propensity score compensates for the differences in the underlying covariates. Forty nine percent of RIC allografts were performed in centres reporting ≥5 RIC transplants. There was a significant interaction between propensity score, a centre’s RIC-activity and conditioning intensity on survival. Excluding centres not performing RIC to avoid bias and adjusting for propensity score, survival >9 months was worse in RIC patients with a low propensity score when treated in centres with <5 RICS (HR 2.4 CI 1.3–4.4) whereas survival >9 months was equal in centres treating ≥5 patients with RIC who had a high propensity score (HR 0.8 CI 0.4–1.6). The figures below illustrate this showing the cumulative risk of non-relapse mortality, relapse and death after relapse for these groups estimated in a competing risk setting.
Conclusion: Transplant centre experience and patient selection impact on outcome. Survival with RIC HSCT is inferior to MAC except for the subgroup of patients with a high propensity score transplanted at centres with ≥5 RIC HSCT.
Low Propensity Score and <5 RIC HSCT Low Propensity Score and <5 RIC HSCT High propensity Score and ≥5 RIC HSCT High propensity Score and ≥5 RIC HSCT
Combination of a Spicamycin Analogue KRN5500 and Chemotherapeutic Agents Synergistically Enhances Their Cytotoxicity in Human Myeloma Cells.
Authors: Miki Hirokazu , Ozaki Shuji , Tanaka Osamu , Fujii Shiro , Nakamura Shingen , Mihara Ai , Kagawa Kumiko , Asano Jin , Takeuchi Kyoko , Yata Kenichiro , Hashimoto Toshihiro , Abe Masahiro , Matsumoto Toshio 
Published: October 2019

Abstract
Multiple myeloma (MM) is a plasma cell malignancy characterized by the accumulation of neoplastic plasma cells in the bone marrow. Although new classes of agents such as thalidomide, lenalidomide, and bortezomib have shown marked anti-MM activity in clinical settings, MM remains an incurable disease due to increased resistance to these agents. Therefore, alternative approaches are necessary to overcome drug resistance in MM. KRN5500 is a new derivative of spicamycin produced by Streptomyces alanosinicus (Kirin Pharma, Tokyo, Japan). This drug potently decreases protein synthesis and inhibits cell growth in human tumor cell lines both in vitro and in vivo. Several phase I studies of KRN5500 were conducted in patients with solid tumors, which showed Cmax values of 1000–3000 nM at the maximum tolerated doses. However, no objective anti-tumor response to KRN5500 alone was observed in these patients. In this study, we examined the anti-tumor activity of KRN5500 against MM cells and evaluated its therapeutic potential in combination with other anti-MM agents. MM cell lines and freshly-isolated MM cells were incubated with various concentrations of KRN5500 for 24 hours. Cell proliferation assay showed marked inhibition of cell growth in MM cells such as RPMI 8226, KMS12-BM, and UTMC-2 (IC50 = 10–40 nM), and U266, MM.1S, and primary MM cells (IC50 = 500–1000 nM). Importantly, a chemotherapy-resistant subclone of RPMI 8226 had a similar sensitivity to KRN5500. Annexin V/propidium iodide staining confirmed that KRN5500 induced apoptosis of MM cells in a dose- and time-dependent manner. Moreover, cleavage of poly (ADP-ribose) polymerase (PARP) was detected after 24 hours with only modest activation of caspase-8, -9, and -3 by immunoblotting. Flow cytometric analysis of anti-apoptotic proteins revealed that apoptosis induced by KRN5500 was associated with down-regulation of Mcl-1 and Bcl-2 expression. To determine the effect of KRN5500 on the unfolded protein response (UPR), splicing of XBP-1 mRNA was analyzed by reverse transcription-polymerase chain reaction. In response to stimulation with KRN5500, splicing of XBP-1 mRNA occurred after 24 hours in RPMI 8226 cells, suggesting that KRN5500-induced apoptosis is mediated in part by the inhibition of UPR. Furthermore, synergistic effects on MM cells were observed when KRN5500 was combined with anti-MM agents including melphalan, dexamethasone, and bortezomib. These results suggest that KRN5500 induces apoptosis in MM cells mainly by the caspase-independent pathway and that its unique mechanism of action provides a valuable therapeutic option to overcome drug resistance in patients with MM.
A New Generation XIAP Inhibitor Induces Apoptosis of Human Myeloma Cells and Synergises with Conventional and Novel Anti-Myeloma Therapeutics.
Authors: Khong Tiffany , Spencer Andrew 
Published: October 2019

Abstract
We have demonstrated that a new generation of IAP inhibitor (Novartis) induces apoptosis of a range (n = 8) of genetically heterogeneous human myeloma cell lines (HMCLs) in a dose and time dependent fashion. Dose responsiveness to the IAP inhibitor (IAPI) was determined via MTS assays using IAPI at doses 5 to 50μM for 24 and 72 hours with IC50s of 25 to 50μM evident in 7 out of 8 HMCLs at 72 hours. Mechanistic studies were undertaken utilising 3 HMCLs with high (NCI H929), intermediate (LP-1) or low (OPM2) sensitivity to IAPI with QRT-PCR demonstrating the highest level of XIAP expression in the most IAPI sensitive HMCL NCI H929. Following IAPI exposure immunoblot analyses of all 3 HMCLs exhibited rapid falls in ICAD and CAD as well as cleavage of ROCK-1 and PARP, confirming apoptosis induction. IAPI - induced apoptosis was mediated via both caspase 7 and caspase 3 as demonstrated by rapid cleavage of both caspases following IAPI exposure. Studies combining IAPI with conventional therapies (bortezomib plus doxorubicin) and (bortezomib plus etoposide) against all 3 HMCLs demonstrated synergistic killing with the optimum sequence (IAPI administered 24 hours before or after drug partners) varying between the 3 HMCLs. Similarly, TNF-related-apoptosis-inducing-ligand (TRAIL) and IAPI also demonstrated synergistic killing irrespective of drug sequence. Finally, IAPI combined with LBY135 (Novartis), a chimeric agonistic TRAIL-R2 monoclonal antibody, demonstrated synergistic killing maximally with LBY135 for 24 hours followed by IAPI rather than the reverse sequence. We conclude that IAPI induces down-regulation of both ICAD/CAD signalling as well as ROCK-1 and PARP cleavage via a caspase 3 and 7 dependent process. Furthermore, our data suggest that IAPI is synergistic with a range of conventional and a novel therapeutic agent. While the mechanism of XIAP inhibition in MM warrants further clarification IAPI clearly represents a potentially novel therapeutic approach to MM.
Deficiency of Mannose-Binding Lectin Is a Risk Factor for Invasive Pulmonary Aspergillosis in Patients with Multiple Myeloma: An Analysis of 482 Patients
Authors: Anaissie Elias J. , Zhao Wei-zhi , Wen Yue-Jin , Grazziutti Monica , Ling Wen , Lee Jeanette , van Rhee Frits , Barlogie Bart 
Published: October 2019

Abstract
Invasive pulmonary aspergillosis (IPA) is a major cause of morbidity and mortality in neutropenic cancer patients. Mannose-binding lectin (MBL) is a circulating pattern-recognition molecule that recognizes microbial carbohydrate motifs, leading to complement activation, opsonization, phagocytosis, and cell lysis and is considered an important component of innate immunity. Deficiency of MBL is common due to genetic polymorphisms and has been identified as a risk factor for severe infections among myeloma patients undergoing autologous stem cell transplantation (ASCT). MBL deficiency has also been reported as a predisposing factor for chronic necrotizing pulmonary aspergillosis, a locally invasive infection typically seen in patients with chronic lung disease. The association between MBL deficiency in cancer patients and susceptibility to IPA has never been evaluated.
This study investigated whether MBL deficiency, as measured by serum MBL levels, is associated with the development of IPA in patients with multiple myeloma undergoing multiple cycles of antineoplastic chemotherapy including tandem ASCT and post-transplant consolidation chemotherapy. Baseline serum MBL level was measured using ELISA. The frequency of IPA was assessed retrospectively in 482 adult myeloma patients (2007–2008), 50 of whom developed IPA.
Association between MBL levels and IPA was analyzed using logistic regression analysis (table 1). Patients with normal serum MBL levels (≥ 1000 ng/mL) had significantly fewer episodes of IPA [(21 in 303 patients; 6.9%); Odds ratio, 0.385; 95% CI (0.212–0.699); P = 0.0017] than patients with low (100–999 ng/mL; 18 episodes in 125 patients (14.4%)) and very low (<100 ng/mL) MBL levels (11 episodes in 54 patients; 20.4%) (Table 1). We conclude that MBL deficiency is associated with more frequent episodes of IPA among patients with myeloma undergoing intensive antineoplastic therapy including ASCT and should be added to the list of risk factors for chemotherapy-related IPA. Baseline MBL level may serve as a predictor for the risk of IPA among such patients. This novel finding may have important therapeutic implications because recombinant Human MBL replacement therapy is now available and could therefore be applied prophylactically to decrease the risk of IPA in MBL-deficient patients receiving chemotherapy.
Table 1. Association between serum MBL level and risk of invasive pulmonary aspergillosis (482 pts)
Aspergillosis MBL (ng/mL) No (n=432) Yes (n=50) Rate Odds ratio (95%C.I.) P-value <100 43 (10%) 11 (22%) 11/54 (20% ) Reference Reference 100–1000 107 (25%) 18 (36%) 18/125 (14%) 0.658 (0.287–1.507) 0.3218 1000 282 (65%) 21 (42%) 21/303 (7%) 0.291 (0.131–0.646) 0.0024 MBL <1000 150 (35%) 29 (58%) 29/179 (16%) Reference
Choosing First-Line Therapy for Follicular Lymphoma (FL): A Decision Analysis
Authors: Olin Rebecca L. , Kanetsky Peter A. , Have Thomas Ten , Nasta Sunita Dwivedy , Schuster Stephen J. , Andreadis Charalambos 
Published: October 2019

Abstract
Introduction: There is no standard of care for first-line therapy of low-grade FL. In US practice, the most common strategy is rituximab with combination chemotherapy. However, the optimal choice of regimen remains controversial; options include RCVP, RCHOP and R-Fludarabine-based chemotherapy (RFlu). Because data from randomized clinical trials are not available and unlikely to be generated in the future, we performed a decision analysis comparing RCVP, RCHOP, and RFlu as first-line therapy for FL.
Methods: We constructed a Markov model of sequential first- and second-line therapy based on prescribing patterns in the US. The endpoint of the model was quality-adjusted time to tertiary referral for therapy such as RIT or autologous transplant (≥3rd line). A literature review was performed of the Medline database and international meeting abstracts. Clinical trials of both untreated and previously treated patients were systematically evaluated using explicit eligibility criteria. Data were extracted regarding response rates, treatment-related mortality, and progression-free survival (PFS). Weighted estimates were obtained using a fixed effects meta-analysis. The model also incorporated published data on heath state utilities, risk of anthracycline cardiotoxicity and fludarabine-related delayed cytopenias. Primary and sensitivity analyses were performed using TreeAge software.
Results: The optimal treatment strategy consisted of RCHOP in first-line followed by RFlu in second-line (9.0 quality-adjusted life years; QALYs). Strategies containing RCVP in either first- or second-line were inferior (6.2–7.7 QALYs). The model was sensitive to first-line PFS of RCHOP and RFlu when these were varied over the range of estimates obtained from individual published trials. The model was robust in sensitivity analysis of most other parameters, including rate of delayed cytopenias after RFlu, anthracycline cardiotoxicity, and quality of life adjustments.
Conclusions: Using decision analysis, the optimal first-line therapy for low-grade FL is RCHOP, followed by RFlu in second-line. This strategy maximizes quality-adjusted time to tertiary therapy. Use of RCVP does not improve overall quality-adjusted time relative to more intensive therapies.
TOR Complex 1 and TOR Complex 2 Differentially Regulate Effector and Regulatory T Cell Differentiation
Authors: Delgoffe Greg M , Kole Thomas P. , Zheng Yan , Xiao Bo , Worley Paul F. , Kozma Sara C , Powell Jonathan 
Published: October 2019

Abstract
Effector T cell lineage commitment is determined by the integration of multiple and sometimes opposing signals. Our lab has identified mTOR, an evolutionarily conserved serine/threonine kinase, as a crucial protein dictating the outcome of T cell fate in response to antigen. To do this we utilized a Cre-lox system to conditionally delete mTOR in T cells. In such mice, although mTOR is deleted in the double-positive stage, lymphocyte populations in the spleen and the periphery are comparable to wild-type mice. T cells lacking mTOR proliferate more slowly but secrete appropriate levels of IL-2 upon initial stimulation. However, such cells fail to differentiate into Th1, Th2 or Th17 effector T cells under the appropriate skewing conditions. This failure to differentiate is the result of decreases in appropriate STAT activation and the concomitant lack of upregulation in lineage specific transcription factors. Notably, under normally activating conditions, T cells lacking mTOR preferentially differentiate into Foxp3+ regulatory cells. Supporting this observation, mTOR deficient T cells display hyperactive Smad3 activation, even in the absence of exogenous TGF-β.
mTOR signals through two known signaling complexes, TORC1 and TORC2. TORC1 contains Rheb, mTOR, GβL, and raptor, while TORC2 contains mSin1, mTOR, GβL, and rictor. In order to determine the specific role of TORC1 in T cell lineage commitment we conditionally deleted Rheb in T cells. Upon activation such cells fail to phosphorylate the TORC1 substrate S6K-1 while demonstrating normal TORC2 activity. As was the case for the mTOR−/− T cells, Rheb−/− T cells fail to differentiate into Th1 and Th17 cells when skewed in vitro. However, unlike mTOR−/− T cells, the Rheb deficient T cells are capable of becoming Th2 cells. In spite of lacking TORC1 activity, T cells lacking Rheb do not spontaneously develop into Foxp3+ cells. Such observations implicate a specific and novel role for Rheb in regulating T cell lineage commitment. Overall, our data identify mTOR as a regulator of T cell lineage commitment through which TORC1 and TORC2 signaling differentially regulate T cell fate. These findings support a novel paradigm whereby T cell activation induces a default pathway of differentiation to regulatory T cells and that TORC2 signaling is required to divert differentiation to appropriately programmed effector lineages.