bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activity of Tyrosine Kinase Inhibitors in Multiple Myeloma.
Authors: Munker Reinhold , Cordova Cory , Polk Paula , Wendling Charles V. , Sun Amanda W. , Cardelli James A. 
Published: October 2019

Abstract
Tyrosine kinase inhibitors (TKIs) have been successfully introduced for the treatment of cancer. Imatinib, dasatinib and nilotinib target bcr/abl and were found to induce molecular remissions in chronic myeloid leukemia. Imatinib has also been found to be active in other malignancies like gastrointestinal stromal tumors. Sunitinib and sorafenib are multi-targeted tyrosine kinase inhibitors and so far, have shown activity against renal cell carcinoma and other cancers. Gefitinib targets the tyrosine kinase of epidermal growth factor receptor and has been found to be active against some cases of non-small cell lung cancer. There is circumstantial evidence that tyrosine kinases and their receptors (e.g. VEGF, IGF-1 and FGFR3) are active in multiple myeloma. In order to develop new treatments for multiple myeloma (MM), we tested several currently available TKIs for their activity against MM cell lines.
Materials and methods: The a cell lines MC/CAR, ARH77, RPMI 8226, ARP1, JJN3, MM1S, and INA-6 were treated with various concentrations of TKIs and analyzed for cell growth in liquid culture, proliferation, apoptosis, and gene expression pattern screening 14,500 genes using U133A_2 arrays.
Results: Imatinib, nilotinib, dasatinib, gefitinib induced cytotoxicity in most cases at high concentrations (50% inhibitory concentration ≥ 100 μMol), whereas sunitinib and sorafenib were active at lower concentrations (50% IC 1– 5 μMol). The cytoxicity was observed early (within 4 to 24 hours of exposure) and involves apoptosis. Interleukin-6 did not offer protection against the cytotoxicity of sorafenib or sunitinib, however the inhibition of proliferation was more pronounced in low fetal calf serum (2.5 versus 10%). A short-term exposure of the myeloma cell line MM1S to 10 μMol sorafenib resulted in more than 2 fold changes in 283 genes or sequences (175 up, 108 down). If only 10 fold changes are considered, 21 genes or sequences were upregulated (mainly enzymes, regulators and ligands) and 11 downregulated (mainly regulatory proteins, among them IL6 signal transducer).
Conclusion: We found that the multitargeted TKIs sorafenib and sunitinib are active in vitro against multiple myeloma. We plan to investigate patient samples, and to elucidate the targets and the mechanisms of action. Our data will support clinical trials both as single agent and in combination with other drugs like bortezomib, thalidomide, alkylators and ionizing radiation.
Oral Rivaroxaban Compared with Subcutaneous Enoxaparin for Extended Thromboprophylaxis after Total Hip Arthroplasty: The RECORD1 Trial.
Authors: Eriksson Bengt I. , Borris Lars C. , Friedman Richard J. , Haas Sylvia , Huisman Menno V. , Kakkar Ajay K. , Bandel Tiemo J. , Muehlhofer Eva , Misselwitz Frank , Geerts William 
Published: October 2019

Abstract
Background Thromboprophylaxis for at least 10 days and for up to 4–5 weeks is recommended after total hip arthroplasty (THA). Rivaroxaban is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. RECORD1 was a phase III, multinational, randomized, double-blind, double-dummy trial, conducted to determine the efficacy and safety of oral rivaroxaban, compared with subcutaneous enoxaparin, for 5 weeks of thromboprophylaxis in patients undergoing THA.
Methods Patients received rivaroxaban 10 mg beginning 6–8 hours after surgery and once daily (od) thereafter, or enoxaparin 40 mg od, beginning the evening before surgery (restarting 6–8 hours after surgery). Therapy continued for 35±4 days and mandatory, bilateral venography was conducted the next day. The primary efficacy endpoint was the composite of any deep vein thrombosis (DVT), non-fatal pulmonary embolism (PE), and all-cause mortality. The primary efficacy analysis was a test for non-inferiority in the per-protocol (PP) population, followed by a test for superiority in the modified intention-to-treat (mITT) population. The main secondary efficacy endpoint was major venous thromboembolism (VTE): the composite of proximal DVT, non-fatal PE and VTE-related death. Major and non-major bleeding during the active treatment period were the primary and secondary safety endpoints, respectively.
Results A total of 4541 patients were randomized; 4433 were eligible for the safety population, 3153 for the mITT population, and 3029 for the PP population. The criteria for non-inferiority were met and testing for superiority was performed. Rivaroxaban significantly reduced the incidence of the primary efficacy endpoint (p<0.001) and major VTE (p<0.001), compared with enoxaparin, in the mITT population (Table). The incidence of major and non-major bleeding events was similar in both groups (Table). Conclusions Rivaroxaban was significantly more effective than enoxaparin for extended prophylaxis after THA, with a similar safety profile. This is the first pivotal trial to demonstrate the efficacy and safety of a fixed, unmonitored dose of an oral, direct Factor Xa inhibitor - rivaroxaban - for extended thromboprophylaxis after THA.
Rivaroxaban 10mg od % (n/N) Enoxaparin 40 mg od % (n/N) Relative risk reduction % (95% CI) P-value for difference DVT, non-fatal PE, and all-cause mortality 1.1% (18/1595) 3.7% (58/1558) 70% (49–82%) P<0.001 Major VTE 0.2% (4/1686) 2.0% (33/1678) 88% (66–96%) P<0.001 Major bleeding 0.3% (6/2209) 0.1% (2/2224) - P=0.178 Non-major bleeding 5.8% (128/2209) 5.8% (129/2224) - P=1.000
A Randomized Placebo Controlled Phase II Trial of Prevention of Severe Oral Mucositis Using Single Dose Velafermin in Patients Receiving Myeloablative Therapy and Autologous Hematopoietic Stem Cell Transplant (AHSCT).
Authors: Schuster Michael W. , Mehta J. , Waller E.K. , Rifkin R.M. , Micallef I. , Hurd D. , Parekh S. , Hari P. , Skikne B.S. , Shea T.C. , Frei-Lahr D.A. , Abonour R. , Freytes C.O. , Pineiro L. , Halvorsen Y.C. , Anaissie E.J. 
Published: October 2019

Abstract
Oral mucositis (OM) is a commonly occurring side effect in patients (pts) undergoing AHSCT. Velafermin, recombinant human fibroblast growth factor-20, is under investigation for the prevention of severe OM. Previous studies demonstrated that velafermin at 30 mcg/kg was well tolerated and was effective in reducing the incidence of severe mucositis. The primary objective of this multicenter, randomized, double-blind, placebo controlled study was to confirm safety and efficacy of 30 mcg/kg velafermin for prevention of severe OM incidence (grade 3/4 OM based on the WHO grading system). The secondary objective was to evaluate safety and efficacy of 10 and 60 mcg/kg doses to better define the therapeutic range. Pts were randomized to receive placebo or velafermin at 30, 10 or 60 mcg/kg in a 3:3:1:1 ratio 24–36 hrs after stem cell infusion. Randomization was stratified by study center and OM risk factors identified from the previous placebo controlled study in a similar population including conditioning regimen and body mass index (BMI ≥30). Pts with multiple myeloma or lymphoma (≥18 y.o.) receiving ≥2X106 /kg CD34+ cells following chemotherapy with or without Total Body Irradiation (TBI) were eligible. OM status and safety data were collected for 30 days post treatment while mortality and disease progression were followed for 1 yr. An interim analysis by a data monitoring committee (DMC) was planned to assess safety and efficacy after 50% of pts completed the 30 day treatment period. A total of 390 pts who received melphalan (200 mg/m2) (n=239), BEAM (n=129), TBI (n=15), or other (n=7) were randomized and 384 pts were treated. The study drug was well tolerated in general and no pts discontinued study due to drug-related adverse events. There were 93 serious adverse events (SAEs) in 78 (20%) pts and no drug-related death was reported. Five infusion-related SAEs were reported including vasovagal episode (2), syncope (2), and anaphylactoid reaction (1). All 5 episodes occurred on the day of study drug infusion and resolved on the same day with no sequelae. Based on review of the results from the interim analysis, which included safety and efficacy data from 200 pts, the DMC recommended that the study continue to completion as planned. The last pt has completed the 30 day study period. The un-blinded results of the OM efficacy endpoints from velafermin treated groups or placebo as well as 30-day safety information from all pts will be reported.
Allogeneic Stem Cell Transplantation (Allo-SCT) in the Management of Advanced Waldenstrom’s Macroglobulinemia (WM).
Authors: Kyriakou Charalampia , Canals C. , Sureda A. , Taghipour G. , Cornelissen J. , Willemze R. , Socie G. , Greinix H. , Kienast J. , Hamladji R. , Kazmi M. , Jacobs P. , Schmitz N. 
Published: October 2019

Abstract
Despite effectiveness of standard chemotherapy regimens, complete response is infrequent in WM patients and there is no cure. The role of Allo-SCT has not been extensively explored and the available data are limited. In this retrospective European multicenter study we report the outcome of 106 WM patients (69 male) who underwent an Allo-SCT between 1989 and 2005 and were reported to the EBMT Lymphoma Database. The median age at transplant was 49 years (21–65), and the median time from diagnosis to SCT was 34 months (5–310). The median number of treatment lines prior to allo-SCT was 3(1–10) and 19 patients had failed a prior autograft. Ten (10%) patients were in 1st maximum response (MR), 35 (33%) in PR1, 29 (27%) in PR≥2 and 32 (30%) had refractory disease at the time of transplantation. Forty-four patients were treated with conventional (CT) conditioning protocols; [Cy/TBI n=24, Melphalan/TBI, n=6, BuCy n=14] and 62 with a reduced intensity protocol (RIC); [Fludarabine based regimen n=43, Low dose TBI/Cy n=19] With a median follow up of 31 months (3 to 169) 59 (56%) patients, are alive and free of disease. Forty-eight (45%) patients developed aGVHD [Grades I-II (n=34), Grades III-IV (n=14)] with no statistically significant difference between conventional and RIC groups. Five out of nine RIC patients developed aGVHD following the administration of donor lymphocytes for either residual disease or mixed chimerism. Sixteen patients (15%) developed limited and 11 (10%) extensive chronic GVHD. Seventeen (16%) patients relapsed at a median time of 8 (1–89) months after allo-SCT. Thirty-five (33%) patients died, 5 (5%) from disease relapse or progression and 30 (28%) from regimen toxicity. Non-relapse mortality rates were estimated of 30% and 33%, at 1 and 3 years, respectively, for the CT group, and 24% and 30% for the RIC group of patients. Relapse rates at 1 and 3 years were 10%, 12% for the CT group and 14% and 25% for the RIC. Progression free survival (PFS) rates were 60%, 54% and 54% at 1, 3 and 5 years for the CT and 61%, 44% and 39% for the RIC patients. Overall survival was 65%, 59% and 59% for the CT and 71%, 66% and 66% for the RIC at 1, 3 and 5 years, respectively. Multivariate analysis showed that chemorefractory disease at allo-SCT was associated with a significantly higher relapse rate [p<0.03; 95% CI 1.1–8.9] while the use of TBI in the conditioning regimen with a significantly lower relapse rate [p<0.02; 95% CI 1.1–9.3]. There were no differences in outcome when considering the intensity of the conditioning regimen. In conclusion, allo-SCT is a feasible and well-tolerated procedure in this group of elderly patients with advanced disease. In addition, relapse rate after the allogeneic procedure is low resulting in a good long-term outcome.
Treatment Success in Cancer.
Authors: Djulbegovic Benjamin , Kumar Ambuj , Soares Heloisa , Hozo Iztok , Bepler Gerold , Clark Mike , Bennett Charles 
Published: October 2019

Abstract
Background: The evaluation of research output, such as an estimation of the proportion of treatments successes is of ethical, scientific, and public importance. How often experimental cancer treatments that undergo testing in randomized clinical trials (RCTs) result in discovery of successful new interventions has rarely been evaluated systematically.
Methods: We evaluated treatment success in a consecutive cohort of RCTs performed by the National Cancer Institute cooperative groups over the past five decades. We investigated therapeutic success in 3 ways:
assessing the proportion of statistically significant trials favoring new or standard treatments, determining the proportion of the trials in which new treatments were considered to be superior to standard treatments according to the original researchers, quantitatively synthesizing data for overall survival and event-free survival.
Results: Data from 624 trials (781 randomized comparisons) involving 216,451 patients were analyzed. 30% of trials had statistically significant results. Among these, new interventions were superior to established treatments in 80% of trials. The original researchers judged that the risk-benefit profile favored new treatments in 41% trials. Hazard ratio for survival and event-free survival was 0.95 (99% CI 0.93–0.98) and 0.90 (99%CI 0.87– 0.93) respectively, slightly favoring the new treatments. Breakthrough interventions were discovered in 15% of trials. The main advances have occurred in the management of gastro-intestinal cancer and hematological malignancies
Conclusions: When cancer treatments have been tested in RCTs by the NCI cooperatives groups, about one third of the trials lead to the discovery of successful new treatments. On average, the death rate in these trials has been reduced by 5% with the new treatments. Grant support: NIH/ORI (No 1R01NS044417–01; 5 R01 NS052956–02).
High-Resolution Genomic Profiles Identify Novel Genes and/or Chromosomal Regions with Prognostic and Oncogenic Significance in Myeloma Patients.
Authors: Loiseau Herve Avet , Munshi Nikhil C. , Li Cheng , Magrangeas Florence , Gouraud Wilfried , Charbonnel Catherine , Harousseau Jean-Luc , Attal Michel , Marit Gerald , Mathiot Claire , Facon Thierry , Moreau Philippe , Anderson Kenneth C. , Minvielle Stephane 
Published: October 2019

Abstract
Despite major improvements in the treatment of myeloma over the last decade, disease course is variable due to genetic heterogeneity. Even though cytogenetics is a difficult art in myeloma, chromosomal abnormalities are present in 100% of the patients. In order to define the spectrum of unbalanced chromosomal abnormalities in myeloma, we studied a cohort of 200 patients ≤ 65 years of age, homogeneously treated with high dose chemotherapy in the IFM 99 trials, using the Affymetrix 500K SNP arrays. Bone marrow was obtained at diagnosis, and plasma cells were sorted using anti-CD138-coated magnetic beads. In all cases, a plasma cell suspension with a purity > 90% was obtained, and DNA was extracted using standard methods. After labeling, DNA was hybridized on the two Nsp and Sty chips, containing 260,000 SNP each. As expected, copy number variations were observed in all the cases. The most frequently involved chromosomes were chromosomes 13, 16, 1, 8 and 6. We then performed a prognostic analysis to correlate survival and chromosomal abnormalities. Many previously unreported chromosomal regions were identified; for example, 89 deleted chromosomal regions as well as 53 regions present in > 2.5 copies were associated with a survival < 3 years. Among the deleted regions with prognostic impact, the most frequent were 1p, 12p, and 4q. The most frequently gained regions associated with overall survival were 1q, 8q, and chromosomes 7 and 21. A similar analysis was performed for association with event free survival (EFS). Losses at 11q, 4q, and 12p were highly predictive of a short EFS, whereas gains of chromosome 15 predicted a longer EFS. Global analysis revealed a marked heterogeneity in the gains observed in hyperdiploid karyotypes, explaining the inconsistency in the literature regarding the prognostic value of hyperdiploidy. A more detailed analysis identified more than 80 genes presenting a double deletion, suggesting their role as putative tumor suppressor genes. This study represents the largest cohort of patients analyzed with such high-density arrays, enabling the description of a highly confident landscape of chromosomal abnormalities in myeloma. Moreover, since all the 200 patients were treated with a similar high-dose regimen, it allows powerful statistical analysis of the impact of chromosomal gains and losses on response to therapy, event free survival and overall survival. Finally, since all the patients were also annotated for other prognostic parameters such as t(4;14) or beta2-microglobulin, a multivariate prognostic model will be presented.
Serum Uric Acid Is a Novel Prognostic Factor in Patients with Primary Systemic Amyloidosis.
Authors: Kumar Shaji K. , Dispenzieri Angela , Lacy Martha Q. , Hayman Suzanne R. , Leung Nelson , Zeldenrust Steven R. , Buadi Francis K. , Kyle Robert A. , Rajkumar Vincent , Gertz Morie A. 
Published: October 2019

Background: Primary Systemic Amyloidosis (AL) is a fatal disorder characterized by uncontrolled deposition of light chain derived amyloid with variable survival dependent on extent of organ involvement and degree of individual organ dysfunction. We previously demonstrated that troponin T (cTnT) and N-terminal fragment of brain natriuretic peptide (NT-ProBNP) together can allow prognostic stratification in AL. Uric acid (UA) is a marker of increased mortality in congestive heart failure and we examined its prognostic value in AL.
Methods: A cohort 1977 patients with AL seen at our institution and 293 patients with AL undergoing stem cell transplant (PBSCT) were studied retrospectively to examine the value of serum UA.
Results: The median OS for those with UA>8mg/dL was 9 months from diagnosis (95% CI; 7.4, 10.6) compared to 20.3 months for those with UA<=8mg/dL (95% CI; 17.8, 22.7), P<0.001 (Figure 1). As previously demonstrated both cTnT≥0.035μg/L and NT-ProBNP≥332ng/L were prognostic for OS. The median OS for patients (n=617) with a cTnT>0.035g/L was 6.7 months (95% CI; 5.0, 8.4) compared to 35.2months (95% CI; 29.4, 41.0) for those with cTnT<=0.035μg/L, P<0.0001. Similarly, the median OS for patients with NT-ProBNP > 332ng/L was 11.8 months (95% CI; 9.4, 14.2) compared to 36.2 months (95% CI; 26.7, 45.8) for those with NT-ProBNP <=332ng/L; P<0.0001. The prognostic value of UA was independent of cTnT and NT-ProBNP and together with these allowed a novel prognostic classification. Patients with none (Stage-I), 1 (Stage-II), 2 (Stage-III) or 3 (Stage-IV) of these risk factors (UA>8mg/dl, cTnT>0.035μg/L and NT-ProBNP>332ng/L) had a median OS of 36.6, 29.2, 11.1, and 3.6 months respectively (P<0.0001) (Figure 2). We also explored various predictors of OS in this large cohort of patients. The parameters that were significant for a shorter median OS included septal thickness>15mm, ejection fraction<50%, alkaline phosphatase>upper limit of normal, serum creatinine>2.0mg/dL, serum albumin<3.0gm/dl, 24-hour urine albumin>5gm, UA>8 mg/dL, cTnT>0.035μg/L and NT-ProBNP>332ng/L. We then performed a multivariate analysis with all these variables and those predicting for shorter OS were cTnT>0.035μg/L, serum uric acid>8mg/dL, and ejection fraction<50%. The stage determined at the time of PBSCT also predicted outcome with a median OS from PBSCT not reached in stages 1 and 2, 55 months for stage 3 and 16 months for stage 4 patients.
Interpretation: The data confirms the prognostic value of serum UA in AL and allows development of a novel and simple but powerful, reproducible staging system with applicability at all stages of AL.
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JAK2 Activation Stimulates Homologous Recombination and Genetic Instability.
Authors: Plo Isabelle , Nakadake Mayuka , Wiesmuller Lisa , Giraudier Stéphane , Villeval Jean-Luc , Vainchenker William 
Published: October 2019

Abstract
The JAK2 V617F mutation is a recurrent mutation frequently observed in classical myeloproliferatives syndromes such as polycythemia vera (PV) (90%), essential thrombocythemia (ET) and myelofibrosis (MF) (50%). Even if JAK2 V617F is common to these three pathologies, bi-alllic mutation of JAK2V617F have been observed in PV patients due to a loss of heterozygoty following a mitotic recombination event. Moreover, mutations in the receptor of thrombopoietin (c-mpl) have also been identified in MF and in some cases associated with the JAK2V671F mutation. These observations led us to hypothesize that initial mutation of JAK2 can stimulate others abnormalities, in particular genetic abnormalities, which could strengthen the kinase activity of JAK2. The deregulation of the DNA double-strand breaks repair mechanism, homologous recombination (HR), could be involved in the appearance of these new genetic abnormalities. Indeed, mutations in genes controlling HR lead to genomic instability, such as punctual mutation, deletion, loss of heterozygoty and chromosomal rearrangement. As a consequence, we investigated in this study the impact of JAK2 activation either by mutation (JAK2V617F) or by erythropoietin (EPO) on HR and genetic instability. First, we introduced a specific substrate of HR in the genome of Ba/F3 cell line and we measured HR after infecting cells with virus containing either JAK2wt or JAK2V617F. In the presence of EPO, JAK2V617F and at a lesser extend JAK2wt induces a 20 and 5-fold HR increase, respectively, compared to Ba/F3 control cells. In good agreement, in spontaneous condition, we observed an increase in nuclear foci of the key protein involved in this process: RAD51 and in its partner: BRCA1. A spontaneous RAD51 foci formation was also found in CD34+ cells from PV and MF patients compared with CD34+ cells from cytapheresis suggesting that an HR increase also occurs in patients. Consequently, we observed a 40% increased in sister chromatid exchange in JAK2V617F -expressing cells compared to JAK2wt-expressing cells or Ba/F3 control cells. Moreover, increases in centrosome and ploidy abnormalities were also detected in JAK2V617F-expressing cells. Finally, we found a 100-fold and 10 fold increase in mutagenesis at HPRT and Na/K ATPase loci, respectively. This result suggests that JAK2V617F induces more deletion event than punctual mutation. This work highlights a new molecular mechanism of regulation of HR by activation of JAK2 and especially by JAK2V617F. It might also give key to understand how a single mutation can give rise to different pathologies. Further works are currently under investigation to determine how JAK2V617F -induced an hyper-recombination phenotype.