bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of Prophylactic Anticoagulation To Prevent Thalidomide-Related Deep Venous Thrombosis.
Authors: Ikhlaque Nadeem 
Published: October 2019

Abstract
Deep venous thrombosis (DVT) is a known complication of treatment with thalidomide, occurring in up to 25% of patients. Although prophylactic anticoagulation has been recommended by some authors, there are few data available to assess whether this is beneficial. We reviewed the records of 131 patients receiving thalidomide for a variety of indications. Ninety-three patients had multiple myeloma, 12 had MDS or myelofibrosis and 26 had solid tumors. The mean and median dose of thalidomide was 200 mg/day. Fifty-five patients were prescribed warfarin with the intent of preventing DVT. Thirty-seven patients received warfarin at a dose of 1–2 mg per day (low dose) and 18 received a dose intended to raise the INR to 2–3 (high dose). Of 25 patients on single-agent thalidomide; only 4 received warfarin. Twenty-one of the 131 patients developed venous thrombosis during thalidomide treatment. All patients who developed DVT were receiving thalidomide in combination with dexamethasone or some form of chemotherapy. Only one patient who developed DVT was receiving thalidomide at more than 200 mg/day. Eighteen of the 76 patients (23.7%) who were not prescribed prophylactic anticoagulation developed DVT compared to three of the 55 patients (5.5%) who were prescribed any dose of prophylactic warfarin (p=.010). Only one of the 37 patients who received low dose warfarin developed DVT (p=.011). Bleeding complications occurred in 4 patients who were all receiving high dose warfarin. Two previous unrandomized studies suggested that low dose warfarin was not protective of DVT but both used high doses of thalidomide (250–400 mg) in combination with other agents which is no longer recommended. Our study suggests that low dose warfarin prophylaxis may be sufficient and safe for patients receiving thalidomide at a dose of 200 mg/day in combination with other agents.
Clinical Responses to Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Are Associated with Specific Gene Expression Signatures in Patients with Advanced Leukemias: Results of a Phase I Trial.
Authors: Loboda Andrey , Fantin Valeria R. , Bueso-Ramos Carlos E. , Randolph Sophia , Hardwick James S. , Ricker Justin L. , Richon Victoria M. , Issa Jean-Pierre , Kantarjian Hagop M. , Frankel Stanley R. , Garcia-Manero Guillermo 
Published: October 2019

Abstract
Vorinostat is a histone deacetylase inhibitor with potent in vitro and in vivo anti-leukemia activity. Several gene expression signatures were developed from preclinical models as biomarkers for clinical response to vorinostat. The signatures were evaluated in peripheral blood mononuclear cell (PBMC) samples from a Phase I study of oral vorinostat in patients with advanced leukemias or myelodysplastic syndromes (MDS). Of 41 registered patients, 31 had acute myeloid leukemia (AML), 4 had chronic lymphocytic leukemia, 3 had MDS, 2 had acute lymphoblastic leukemia, and 1 had chronic myeloid leukemia. Seven of 41 patients showed improvement with treatment, 2 complete responses, 2 complete responses that were not maintained for 28 days, and 3 with >50% decreases in blast counts without count recovery. All responses occurred in patients with AML at or below the MTD. The following three clinical gene expression signatures were shown to be predictive of clinical response in PBMC samples of AML patients. First, a positive prediction trend was observed when a preclinical 40-gene resistance prediction signature was evaluated in baseline (pre-dose and first day of dosing) AML PBMC samples (8 responder and 21 non-responder samples) or all PBMC samples (14 responder and 56 non-responder samples, including non-AML patients). If this trend is maintained in pretreatment samples of a larger patient population, it may allow for exclusion of up to 50% of non-responders from future clinical trials. Second, a similar prediction of resistance was obtained based on expression levels of known reactive oxygen species scavengers that were upregulated in non-responders relative to responders, indicating that cellular ability to withstand oxidative stress may be protective with respect to vorinostat exposure. This supports the hypotheses that oxidative stress pathways play an important role in the response to vorinostat. Finally, overexpression of p21 and several p53-responsive genes was also associated with resistance, consistent with preclinical observations. These results are being validated at the protein level in a tissue array platform. Post-dose downregulation of genes associated with cellular proliferation was also observed in responders but not in non-responder PBMC samples. This suggests that proliferation may be used as a post-dose efficacy biomarker. Further evaluation of vorinostat in patients with leukemias and MDS, including analysis of a potentially predictive gene expression signature for response to vorinostat, is warranted.
IVIg-Primed Splenocytes Ameliorate Murine ITP in an MHC Class II-Unrestricted Manner.
Authors: Crow Andrew R. , Siragam Vinayakumar , Freedman John , Lazarus Alan H. 
Published: October 2019

Abstract
We have previously demonstrated that IVIg-primed leukocytes can, upon transfer to naïve mice, completley recapitulate the therapeutic effects of IVIg in treating immune thrombocytopenia in a murine model. Dendritic cells (DC) appear to be the primary cellular target of IVIg in this model. The exact pathway by which IVIg-primed DC inhibit platelet clearance remains, however, unknown. DC are professional antigen presenting cells of haematopoietic origin that are specialized for the capture, processing and presentation of antigens to T cells via their MHC Class II. This primary function of DC is absolutely dependent on MHC Class II expression. Herein, we have evaluated the efficacy of action of IVIg-primed splenocytes from MHC mismatched mice in the amelioration of murine ITP. Mice expressing the Class II haplotype I-Ab (C57BL/6) were injected intravenously with IVIg-primed splenocytes from syngeneic mice, or Balb/C mice (Class II haplotype I-Ad /I-Ed) or CD1 mice (outbred, mixed Class II haplotype I-A/E) prior to the induction of thrombocytopenia by an anti-platelet antibody. We found that IVIg-primed splenocytes from all strains of mice tested were able to successfully ameliorate thrombocytopenia in C57BL/6 mice, regardless of Class II haplotype. None of the splenocytes primed with a control protein, BSA, ameliorated thrombocytopenia. To confirm our findings that IVIg-primed splenocytes function independent of MHC haplotype, we next employed IVIg-primed splenocytes from MHC Class II deficient mice and found these splenocytes were also able to successfully ameliorate murine thrombocytopenia. These data demonstrate a non-MHC-restricted function for DC in IVIg function, and suggest that IVIg-primed DC function occurs independent of MHC Class II expression in the amelioration of murine ITP. In addition, since this potential new cell-based therapy for ITP is not MHC-restricted, we speculate that IVIg-primed DC from any donor (including autologous) could theoretically be used to treat individuals with ITP or other autoimmune diseases without the requirement for donor matching.
Importance of Early Intervention with Dasatinib at Cytogenetic Rather Than Hematologic Resistance to Imatinib.
Authors: Kantarjian Hagop M. , Quintas-Cardama Alfonso , O’Brien Susan , Ravandi Farhad , Borthakur Gautam , Liu David , Chen Tai-Tsang , Cortes Jorge 
Published: October 2019

Abstract
Recent data for patients with chronic-phase (CP) CML indicate that development of resistance or intolerance to imatinib and treatment intervention following progression to advanced-phase disease are both associated with poor clinical outcome (with 3-year survival rates of 72% for chronic-phase disease, 30% for accelerated-phase CML, and 7% for blast-phase CML) (Kantarjian et al. Cancer2007;109:1556–60). Results also demonstrate that intervention with a second-generation tyrosine kinase inhibitor is more effective for individuals with chronic-phase CML than for those with advanced-phase disease. Of note, development of hematologic resistance (loss of a complete hematologic response [CHR]) was identified as an independent prognostic factor with a 3-year survival rate of 57% (compared with 92% for patients who experienced cytogenetic resistance [loss of a major cytogenetic response (MCyR)]). The objective of the current data analysis was to assess whether the development of hematologic resistance to imatinib would be a predictor of poor response to dasatinib (SPRYCEL®) relative to the development of cytogenetic resistance. Data from three Phase-II/III dasatinib clinical studies (CA180–013 [70 mg BID], CA180–017 [70 mg BID], and CA180–034 [100mg QD, 50 mg BID, 140 mg QD, 70 mg BID]) in patients with CP CML with resistance to prior imatinib were evaluated. Consistent with our earlier findings, significantly higher complete cytogenetic response (CCyR) rates were reported for patients who had developed secondary or acquried cytogenetic resistance to prior imatinib than for those with hematologic resistance. The improved rates of CCyR in patients with cytogenetic resistance to imatinib were associated with prolongation of progression-free survival compared to patients with hematologic resistance, thereby confirming the importance of early intervention in the event of imatinib resistance and the significance of achieving CCyR with dasatinib.
Loss of MCyR Loss of CHR N n % N n % n = number of patients with [1] complete cytogenetic response or [2] progression Complete cytogenetic response [1] CA180–013 47 34 72 71 27 38 CA180–017 19 12 63 22 5 23 CA180–034     100 mg QD 28 21 75 14 2 14     50 mg BID 17 11 65 12 3 25     140 mg QD 18 9 50 16 8 50     70 mg BID 23 19 83 12 2 17 Progression-free survival at 1 year [2] CA180–013 47 3 95 71 15 84 CA180–017 19 1 94 22 3 85 CA180–034     100 mg QD 28 1 96 14 1 93     50 mg BID 17 0 100 12 6 58     140 mg QD 18 2 87 16 2 93     70 mg BID 23 2 95 12 4 69
These results confirm previous observations and
emphasize the importance of close monitoring of treatment response to imatinib, and argue for early intervention in case of imatinib resistance.
Late intervention, ie waiting for patients to lose a hematologic response, appears to significantly diminish the effectiveness of dasatinib.
Simultaneous Targeting of Aurora Kinases and Bcr-Abl by the Small Molecule Inhibitor PHA-739358 Is Effective in Imatinib-Resistant Mutations Including T315I.
Authors: Gontarewicz Artur , Balabanov Stefan , Keller Gunhild , Colombo Riccardo , Graziano Alessio , Bokemeyer Carsten , Fiedler Walter , Moll Jurgen , Brummendorf Tim 
Published: October 2019

Abstract
The emergence of resistance to Imatinib (IM) mediated by mutations in the BCR-ABL domain became a major challenge in the treatment of chronic myeloid leukemia (CML). Second generation Bcr-Abl inhibitors overcome most mutations except T315I, a frequent cause of clinical resistance, emphasising the importance of developing alternative therapeutic strategies. Here, we report studies performed with a novel small molecule inhibitor, PHA-739358, which selectively targets Bcr-Abl and Aurora kinases. PHA-739358 exhibited strong antiproliferative and pro-apoptotic activity against a broad panel of human BCR-ABL positive and negative cell lines and against mouse BaF3 cells ectopically expressing wild type (wt) or IM-resistant BCR-ABL mutants, including T315I. Pharmacological synergism of IM and PHA-739358 was observed in leukemia cell lines with low-level resistance to IM, whereas no synergistic effects were observed in BCR-ABL negative or highly IM resistant T315I mutated cells. Treatment with PHA-739358 significantly decreased phosphorylation of histone H3-(Ser10), a marker of Aurora B activity and of the small adaptor protein CrkL, an accepted down-stream target of Bcr-Abl. Hence, PHA-739358 acts via combined inhibition of Bcr-Abl and Aurora kinases. Moreover, strong antiproliferative effects of PHA-739358 were observed in CD34+ cells derived from newly diagnosed CML patients and from IM-resistant individuals in chronic phase or blast crisis including those harbouring a T315I mutation. Thus, PHA-739358 represents a promising new strategy for treatment of IM resistant BCR-ABL positive leukemias, including those harbouring the T315I mutation. Clinical trials investigating this compound in IM-resistant CML have recently been initiated.
Elevated Serum Interleukin-7 Levels Precede the Development of Acute Graft-Versus-Host Disease.
Authors: Dean Robert M. , Fry Terry , Mackall Crystal , Steinberg Seth M. , Hakim Frances T. , Fowler Daniel H. , Odom Jeanne , Foley Jason , Gress Ronald E. , Bishop Michael R. 
Published: October 2019

Abstract
BACKGROUND: Despite advances in transplantation immunology, there is no clinically practical tool to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Murine models indicate that aGVHD is promoted by interleukin-7 (IL-7), a homeostatic cytokine for naïve CD4+ and CD8+ T-cells. We hypothesized that serum IL-7 levels might be associated with the development of aGVHD in patients (pts) undergoing allogeneic HSCT, and evaluated this using serum samples obtained for this purpose in a prospective clinical trial.
METHODS: Thirty-one pts underwent allogeneic HSCT from HLA-identical siblings. Pts received 1 to 3 pre-transplant chemotherapy cycles to induce profound, uniform host lymphopenia (CD4<100), followed by fludarabine-based reduced-intensity conditioning. GVHD prophylaxis was cyclosporine & methotrexate. Serum IL-7 was measured by ELISA at baseline and multiple time points from the day of transplant through 1 year after allogeneic HSCT. IL-7 levels were evaluated for associations with blood lymphocyte counts, aGVHD, and survival. Other variables examined for association with aGVHD were pt and donor age; CD3+ and CD34+ cell doses; donor gender; donor-recipient gender mismatch; donor or recipient CMV status, prior rituximab therapy; donor lymphoid or myeloid chimerism >95% at day +14; serum IL-15 levels; and levels of soluble tumor necrosis factor-α receptors 1 and 2 (sTNFR1 and sTNFR2).
RESULTS: Grades I, II, and III aGVHD occurred in 3%, 23%, and 19%, respectively; none had grade IV. Median (range) IL-7 levels rose from baseline 12.1 (0–46.9) pg/ml to 37 (13.3–79.2) pg/ml on day 0 before allografting, then fell to 12.0 (1.3–74.7) pg/ml by day +14; these changes were inversely correlated with absolute lymphocyte counts, CD3, CD4, and CD8 counts at baseline and day +7. The development of aGVHD was associated with IL-7 levels at day +7 (p=0.01) and day +14 (p=0.000033) post-transplant (Figure), along with the allograft CD34+ cell dose (p=0.012). Higher IL-7 levels at day +14 corresponded to more severe grades of aGVHD (p<0.0001).
Figure Figure
In logistic regression models, these factors jointly classified pts according to development or avoidance of aGVHD with a maximum sensitivity of 86% and a specificity of 100%. IL-7 levels were more strongly associated with aGVHD than were sTNFR levels or other parameters.
CONCLUSIONS: Determination of serum IL-7 levels in the early post-transplant period accurately predicted the risk of developing aGVHD after allogeneic HSCT and holds promise as a simple, reproducible test to select pts for pre-emptive therapy. These data support preclinical observations that demonstrate a critical role for IL-7 in inducing aGVHD and provide a rational basis for novel approaches to GVHD prophylaxis through modulation of the IL-7 homeostatic pathway.
Stem Cell Transplantation (SCT) Improves Survival in Acute Biphenotypic (ABL) and Acute Undifferentiated Leukemia (AUL): A Single Centre Experience.
Authors: Narayanan Sujaatha , Barnett Michael J. , Mourad Yasser R. Abou , Forrest Donna L. , Hogge Donna E. , Lavoie Julye C. , Nantel Stephen H. , Shepherd John D. , Song Kevin W. , Sutherland Heather J. , Toze Cynthia L. , Smith Clayton A. , Power Maryse , Nevill Thomas J. 
Published: October 2019

Background: ABL and AUL are associated with an unfavourable outcome for patients (pts) treated with standard-dose therapy alone. Although high-dose therapy has been used successfully in this population, the optimal management of pts with ABL/AUL remains unclear.
Methods: A retrospective review was performed involving 24 adult pts with ABL or AUL who were treated in Vancouver between 1984 and 2006. Kaplan-Meier estimates were utilized for event-free survival (EFS) and overall survival (OAS) and a multivariate analysis was performed to determine factors predictive of outcome.
Characteristics: Utilizing the WHO criteria, 18 pts had ABL and 6 pts had AUL. There were 17 males and 7 females with a median age of 37 (range 22–75) years. Median white cell count (WCC) at presentation was 10.1 × 109(range: 0.9–196 × 109)/L. Seven pts had poor-risk karyotypes (3 pts complex, 3 pts with t(9,22), 2 pts with11q23 rearrangement, and 1 pt with monosomy 7),12 pts had standard-risk karyotypes, and 5 pts had an unknown karyotype. Induction chemotherapy consisted of Cytosine arabinoside (3–6/m2/day), Daunorubicin, Vincristine and Prednisone with one pt with t(9,22) also having received Imatinib Mesylate. Thirteen pts went on to receive high-dose therapy and SCT. Stem cell source was autologous in 3 pts (all with AUL) or a related (6 pts) or an unrelated donor (4 pts). Eight of 10 pts were in complete remission at the time of SCT, one was in relapse and one had primary refractory ABL. Conditioning was TBI-based in 10 pts and Busulfan-based in 3 pts.
Results: EFS and OAS estimates for all 24 patients at 3 years were 25% (95% CI 13%–50%) and 32% (95% CI 17%–58%), respectively. The non-relapse mortality (NRM) for the whole group at 3 years was 43% (95%CI 15%–61%). On multivariate analysis, when compared to pts receiving only standard-dose chemotherapy, pts who underwent high-dose therapy had significantly improved EFS [39% (95% CI 19%–77%) vs. 9% (95% CI 1%–59%), p=.03] and OAS [46% (95% CI 26%–83%) vs.14% (95% CI 3–74%), p=0.01], respectively. Age, WCC at presentation and cytogenetic risk group were not found to significantly influence outcome.
Conclusion: Although patient numbers are limited, this experience would suggest that patients with ABL/AUL who achieve complete remission with standard chemotherapy should be considered for high-dose therapy and stem cell transplantation. This approach provides them with the greatest probability of long-term event- free and overall survival.
Imatinib Mesilate Versus Allogeneic Bone Marrow Transplantation for Patients with Chronic Myeloid Leukemia in First Chronic Phase - A Brazilian Point of View.
Authors: Bittencourt Henrique , Funke Vaneuza , Fogliatto Laura , Magalhaes Simone , Setubal Daniela , Paz Alessandra , Macedo Antonio V. , Ruiz Jefferson , Azambuja Ana Paula , Silla Lucia M.R. , Clementino Nelma , Pasquini Ricardo 
Published: October 2019

Abstract
Imatinib has profoundly change indication of allogeneic bone marrow transplantation (alloBMT) worldwide for CML and is now the first line of treatment in most countries. However, in Brazil, Imatinib for CML in first chronic phase is provided by Federal Health Agency only for patients refractory/intolerant to interferon (IFN). In order to study results of treatment with imatinib and alloBMT in this particular scenario we retrospectively analyzed 266 patients treated for CML in first chronic phase (less than 60 years-old) in three different institutions in Brazil. End points were event free survival (EFS = absence of hematological response, lost of hematological/cytogenetic response, relapse in accelerated phase/blast crisis or death) and overall survival (OS). From jan/2001 to dec/2006, 176 patients received imatinib 400 mg after failure or intolerance to IFN. Median time from diagnosis to imatinib treatment was 19 months (range: 2 to 205). At the same period of time, 90 patients received an allo-BMT from an HLA-matched sibling (n=83) or an unrelated donor (n=7). Patients receiving peripheral blood stem cell or umbilical cord blood were excluded. Eighty-two patients received busulfan+cyclophsphamide as conditioning regimen and all patients received cyclosporin+methotrexate±steroids as GVHD prophylaxis. Median time from diagnosis to allo-BMT was 16 (range: 5 to 104) months. Gender distribution was similar between groups. Imatinib group had a higher median age (40.7 vs. 32.8 years, P<0.001). With a median follow up of 3 years, 5-year estimate EFS was 67.6% for patients receiving imatinib and 51.8% for patients receiving an allo-BMT (P=0.0002). Estimate overall survival at 5 years was 92.7% for patients treated with imatinib and 58.8% for patients receiving an allo-BMT (P<0.0001). Allo-BMT should be no more recommended as a first line alternative treatment, even if imatinib is available only for patients refractory/intolerant to IFN. Impressively, OS in Imatinib group were quite similar to those seen at the imatinib arm of IRIS study (Druker BJ et al. N Engl J Med2006; 355: 2408).
Human Leukocyte Antigens of A33, B58 or DR7 Decrease the Treatment-Related Mortality in HLA-Matched Sibling Hematopoietic Stem Cell Transplantation in Association with Heat Shock Protein 70-Hom Polymorphisms.
Authors: Kim Jin Won , Oh So Yeon , Kim Hye Jin , Yi Hyeon Gyu , Lee Kyung-Hun , Rhee Ji Young , Shin Eun-Soon , Piao Cheng Zhe , Kim Inho , Yoon Sung-Soo , Park Myoung Hee , Park Seonyang , Kim Byoung Kook 
Published: October 2019

Abstract
Human leukocyte antigens(HLA) are expected to influence outcomes or adverse effects in allogeneic hematopoietic stem cell transplantation through its immunologic function. However, the types of HLA and its mechanism to affect clinical outcomes are not well defined. In the other hand, heat shock protein 70-hom (HSP70-hom) plays an important role in protein folding and immune responses and was reported to influence the incidence of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. And it was also reported that HLA types were associated with polymorphisms of HSP70-hom in several diseases. So, we evaluated the association between HLA types and HSP70-hom polymorphisms and identified the specific HLA types to affect clinical outcomes in allogeneic hematopoietic stem cell transplantation. We analyzed the DNA of patients and donors who underwent allogeneic hematopoietic stem cell transplantation from HLA-matched sibling donors at single institute between 1998 and 2005 for malignancy or aplastic anemia. The HSP70-hom polymorphisms, rs2227956 and rs2075800, were genotyped and HLA typing was conducted in 141 patients and their donors. Individual haplotypes were estimated from genotype data of the two HSP70-hom polymorphisms using the expectation maximization algorithm. The HSP70-hom polymorphisms of patients were completely identical to those of their donors. Patients(101) with TG haplotype (TG/TA, TG/TG or TG/CG) did not only show less treatment-related mortality but also had longer overall survival compared with those(40) with non-TG haplotype (TA/TA or TA/CG). (P=0.011, P=0.013,respectively) TG haplotype was associated with HLA types of A33, B58 and DR7.(P<0.001, P=0.002, P=0.039, respectively) Patients with HLA types of A33, B58 or DR7 showed less treatment-related mortality compared with patients without the these HLA types in multivariate analyses with age, sex, transplant method, stem cell source and risk group.(P=0.034, HR=0.397, 95% CI: 0.169–0.931) In conclusion, HLA types of A33, B58 or DR7 in HLA-matched sibling hematopoietic stem cell transplantation were protective for treatment-related mortality in association with HSP70-hom polymorphisms.
Figure Figure