bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decitabine and Gemtuzumab Ozogamicin in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome
Authors: Borthakur Gautam , Estrov Zeev , Garcia-Manero Guillermo , Williams Betsy , Wathen Jay K. , Konopleva Marina , Burger Jan , Ferrajoli Alessandra , George Solly , Kantarjian Hagop 
Published: April 2020

Abstract
Background: Hypomethylating agents are approved for the treatment of myelodysplastic syndrome (MDS) and have activity in acute myelogenous leukemia (AML) (Issa, JP et al. Blood. 2004;103:1635–40)(Silverman LR et al. Journal of Clinical Oncology2006; 24: 3895–3903). Exposure of AML cells to hypomethylating agents increase their CD33 expression (Balain and Ball. Leukemia. 2006; 20:2093–2101). This establishes a rationale for the combination of hypomethylating agent with CD33 antibody for treatment of high-risk MDS and AML. A preliminary report of the combination of 5-azacitidine (Aza) and gemtuzumab ozogamicin (GO) in elderly patients with previously untreated AML and MDS showed promise (Nand, S. et al. Blood2006;108: Abstract 1981).
Patients and Method: We have started enrolling patients in a phase 2 study of Decitabine (DAC) with GO in patients with AML and high-risk myelodysplastic syndrome (MDS). Treatment includes DAC 20 mg/m2/day intravenously (IV) × 5 days and GO 3 mg/m2 IV on day 5. GO is repeated on day 15±2 of first cycle if peripheral blood blast count is &gt; 109/L. Six such cycles are planned every 4–8 weeks. Patients achieving clinically relevant response e.g. complete remission (CR), CR with incomplete platelet recovery (CRp), marrow clearance/reduction of blasts etc. can continue on DAC alone approximately every 4–8 weeks for up to 24 cycles of total therapy duration. Based on historical expectations patients are divided into four groups according to study design:
relapsed AML 1st CR duration &lt;= 1 year or beyond first relapse, relapsed AML 1st CR duration &gt; 1 year, untreated AML (not eligible for standard induction)/MDS, previously treated MDS, secondary MDS or AML.
Results: Thirty-seven patients have been treated till date; Group 1=19, group 2=1, Group 3=12 and group 4=5. Median age is 63.5 years (range, 26–82), performance status =1 (range, 0–3), prior therapy =1 (range, 0–7). Eighteen (49%) patients has adverse cytogenetics and 14 (38%) has prior malignancies. Two patients received day 15±2 administration of GO. Median number of treatment cycles is 2 (range, 1–5). Eight patients died while on study. Except for cytopenias, infections, infusion related reactions etc. no significant grade 3/4 toxicities have been encountered. Three patients have achieved CR/CRp and 5 patients achieved other clinically relevant responses with an overall response rate of 22%. Responses according to patient groups are; Group 1=2/19 (4 ongoing), group 2=1/1, group 3=2/12 (3 ongoing), group 4=3/5. Seven additional patients are continuing on study with stable disease. Accrual to the study is ongoing.
Conclusion: The combination of DAC and GO appears promising particularly in less heavily pre-treated patients with high-risk MDS and AML.
Structural Analysis of a BAX-BIM SAHB Complex Reveals a Novel BH3 Interaction Site on BAX for Therapeutic Activation of Apoptosis
Authors: Gavathiotis Evripidis , Suzuki Motoshi , Davis Marguerite L. , Pitter Kenneth , Bird Gregory H. , Katz Samuel G. , Tu Ho-Chou , Kim Hyungjin , Cheng Emily , Tjandra Nico , Walensky Loren D. 
Published: April 2020

Abstract
BAX is a pro-apoptotic protein of the BCL-2 family stationed in the cytosol until activated by a diversity of stress stimuli to induce cell death. Because of its role as a critical gatekeeper of cell death, pharmacologic modulation of BAX has the potential to respectively activate or inhibit apoptosis in hematologic diseases characterized by unrestrained cell survival or pathologic cell death. BAX activation is believed to be a highly regulated, multi-step process involving an interaction-triggered conformational change, mitochondrial translocation, and oligomerization that ultimately leads to mitochondrial dysfunction and apoptosis. Anti-apoptotic proteins, such as BCL-2 and BCL-XL, counteract BAX-mediated apoptosis. Although an interaction site that endows anti-apoptotic proteins with survival functionality has been defined and drugged, an activation site has not been identified for BAX, rendering its explicit trigger mechanism unknown. We previously developed Stabilized Alpha-Helix of BCL-2 domains (SAHBs) that target BCL-2 family proteins in situ, directly initiate BAX-mediated mitochondrial apoptosis in vitro, and suppress leukemia in vivo. Here we demonstrate by NMR analysis that a BIM SAHB peptide binds BAX at an interaction site that is distinct from the canonical binding groove characterized for anti-apoptotic proteins. In five distinct assays that measure ligand-induced BAX activation, BIM SAHB directly and dose-responsively triggers BAX. The specificity of the BAX-BIM SAHB interaction is highlighted by point mutagenesis that abrogates functional activity in vitro and in cells, confirming that BAX activation is initiated at this novel structural location. Thus, we report the first structural analysis of a BH3 death domain alpha-helix bound to a full length pro-apoptotic multi- BH domain protein, unveiling a novel site of protein interaction for direct activation of BAX and pharmacologic modulation of apoptosis.
Presence of Residual Thromboemboli at Least Six Months after a First Episode of Symptomatic Pulmonary Embolism: DO Perfusion Scintigraphy and CT-Angiography Agree?
Authors: Dentali Francesco , Donadini Marco , Cosmi Benilde , Squizzato Alessandro , Bozzato Silvia , Ageno Walter 
Published: April 2020

Abstract
Introduction. The natural history of residual thromboembolic obstructions after pulmonary embolism (PE) and the clinical utility of imaging techniques at follow up are not completely known; in particular, to our knowledge, there are no clinical studies that compared the accuracy of angio-computed tomography (angio-CT) and perfusion scintigraphy (Q scan) in detecting residual thromboemboli after at least 6 months from a first episode of symptomatic PE.
Methods. Consecutive patients on anticoagulant treatment for a first episode of symptomatic PE diagnosed by angio-CT scan and/or Q scan underwent angio-CT and Q scan after 6 to 12 months from the index event. Exclusion criteria were previous PE, recurrent symptomatic PE or deep vein thrombosis (DVT) during the follow-up period. All diagnostic tests were independently assessed by one expert radiologist unaware of the clinical status of the patients. The results of the tests were classified as no signs of recanalization or reperfusion, partial resolution or complete resolution. The agreement beyond chance between tests was assessed by kappa statistics.
Results. Twenty-five patients (14 males, 56%, mean age 59.8) were included after a mean of 7.2 months (217 days, standard deviation 58 days) after acute PE. PE was diagnosed by CT alone in 13 cases, by high probability Q scan alone in 2 cases and by both CT and Q scan in 10 patients. Eleven episodes (44%) were considered idiopathic, 11 (44%) were secondary to transient risk factors, 3 (12%) patients had cancer; concomitant DVT was detected in 17 (68%) patients. At follow-up, Q scan showed no signs of reperfusion in 1 patient (4%), partial resolution in 13 patients (52%) and complete resolution in 11 (44%). Angio-CT showed no signs of recanalization in 0 patient, partial resolution in 17 patients (68%) and complete resolution in 8 (32%). Complete resolution was present in both tests in 1 patient (4%), partial resolution was present in both tests in 6 (24%) patients, with a k agreement between tests &lt; 0.2 (slight).
Conclusions. Partial resolution of thromboemboli after a mean period of 7.2 months from a first episode of PE is present at Q scan or at angio-CT in more than 50% of patients, confirming the results of previous studies. However, the results of our study show for the first time that the agreement between these two tests is low. Thus, caution should be used when interpreting the results of either of these tests to monitor patients with previous PE.
R-FND Followed by Radioimmunotherapy for High-Risk Follicular Lymphoma
Authors: McLaughlin Peter , Neelapu Sattva , Fanale Michelle , Rodriguez Maria , Ayala Ana , Pro Barbara , Hagemeister F.B. , Younes Anas , Neel Susan , Fowler Nathan , Hess Mark , Kwak Larry W. 
Published: April 2020

Abstract
Follicular lymphoma (FL) patients, (pts) with high-risk features using the FL International Prognostic Index (FLIPI) have an expected 5-year survival of only about 50% with conventional therapy. With the incorporation of anti-CD20 monoclonal antibody (mAb) therapy, results are improving (e.g., Buske, Blood2006; 108: 1504). Starting in 2003, we have treated high-risk (FLIPI ≥3) FL pts with R-FND (rituximab, fludarabine, mitoxantrone, dexamethasone) for 4 cycles, followed by radioimmunotherapy (RIT) with ibritumomab tiuxetan, and subsequent rituximab maintenance. Results for the first 35 pts are: complete (CR) and partial (PR) remission 83% and 14%; 3-year overall (OS) and failure-free survival (FFS) 89% and 74% (median follow-up 24 mo.). RIT converted 5 PR pts to CR. Toxicity was mainly hematologic. Five pts did not receive RIT, one because of neutropenia after R-FND. Following RIT, platelet and neutrophil nadirs were 28 and 0.3, occurring at 4–7 weeks. 16 pts required transfusions, and 27 received growth factors. 13 pts had infections, only 2 of which were grade 3. Recovery occurred by 3 weeks in most, with prolonged cytopenias in 6. There has been 1 case of myelodysplasia. In conclusion, the additional complexity of this RIT intensification strategy is warranted in this high-risk FL population, resulting in OS and FFS outcomes that are better than non-mAb therapies, and at least as good as published chemotherapy-rituximab combination therapy.
Long Term Responses to Fludarabine and Rituximab in Waldenstrom’s Macroglobulinemia
Authors: Treon Steven , Branagan Andrew , Ioakimidis Leukothea , Soumerai Jacob , Patterson Christopher , Wasi Parveen , Emmanouilides Christos , Frankel Stanley R. , Lister T. Andrew , Morel Pierre , Matous Jeffrey , Gregory Stephanie A. , Kimby Eva K. 
Published: April 2020

Abstract
Fludarabine and rituximab are commonly used in combination in the treatment of Waldenstrom’s macroglobulinemia (WM), though long term outcome of this regimen remains to be defined. We therefore examined the outcome of 43 WM patients treated on a clinical trial whose eligibility included &lt; 2 prior therapies, and no previous nucleoside analogue or rituximab treatment. Therapy consisted of 6 cycles (25 mg/m2/day for 5 days) of fludarabine and 8 infusions (375 mg/m2/week) of rituximab over 31 weeks. 43 patients were enrolled with a median age of 61, and median prior therapies of 0. Responses were: CR (n=2); VGPR (n=14); PR (n=21); MR (n=4); for an overall and major response rate of 95.3% and 86.0%, respectively. At best response, median bone marrow disease involvement declined from 55% to 5% (p&lt;0.00001), while serum IgM decreased from 3,840 to 443 mg/dL (p&lt;0.00001), and hematocrit rose from 31.2% to 38.0% (p&lt;0.0008). The median time to progression for all patients was 51.2 months, and was longer for untreated versus previously treated patients (77.6 vs. 38.4 months; p=0.017), as well as for those patients who achieved ≥ VGPR versus &lt;VGPR (&gt;88.3 vs. 36.9 months; p=0.049). Grade ≥ 3 toxicities included neutropenia (n=27); thrombocytopenia (n=7); pneumonia (n=6), including two patients who succumbed to non-PCP interstitial pneumonia; peripheral neuropathy (n=2); limbic encephalitis (n=1); hemolytic anemia (n=1). With a median follow-up of 40.3 months, we observed transformation to aggressive lymphoma (n=3); myelodysplasia (n=1); acute myelogenous leukemia (n=2); bladder carcinoma (n=1); and carcinoma of unknown primary (n=1) among 8 patients. The results of this study demonstrate that fludarabine and rituximab is an active regimen in WM, though short and long term toxicities need to be carefully weighed against other available treatment options.
90y Ibritumomab Tiuxetan as Initial Treatment for Follicular Lymphoma (ZEUS Protocol). An Italian Cooperative Study Group
Authors: Carella A. M. , Nati S. , Orcioni G. Fraternali , Petrini M. , Galimberti S. , Vitolo U. , Cascavilla N. , Zinzani P.L. 
Published: April 2020

Abstract
Background: Approximately 80% of patients with Follicular Lymphoma present with disseminated disease, which is consider incurable with standard treatment. Monoclonal antibodies labeled with radionuclides can potentially deliver cytocidal doses of radiation to all sites of disseminated disease. Anti-CD20 radioimmunotherapy has resulted effective in patients who have had relapse after chemotherapy or who have refractory. More recently, radioimmunotherapy (131I-Tositumomab) has been tested also in previously untreated patients with very good results (Kaminsky et al. NEJM, 2005;352:441).
Methods: This study is an open-label, prospective, phase II evaluation of efficacy and safety of a single course of 90Y-ibritumomab tiuxetan at a standard dose of 15 MBq/kg (or 0.4 mCi/kg) in untreated follicular NHL patients. From February 2007, 27 patients with stage III–IV FL received at diagnosis a single course of treatment with 90Y Ibritumomab Tiuxetan (registered as Zevalin). The drug for this study has been suppored by Bayer-Italy. Fifteen patients have enough follow-up for a first evaluation. Eligibility criteria were as follows: CD20 positive follicular lymphoma grade 1 or 2; an age of at least 18 years; no prior therapy, Ann Harbor stage III or IV; at least one bidimensional measurable lesion; involvement of 25% or less of the marrow by lymphoma on trephine biopsy and an absolute neutrophil and platelet count of &gt;1.500×103/ml and 100.000×103/ml, respectively.
Results: Ninety-three percent (14/15 patients) of the patients had any response, and 73% (11/15 patients) had a complete remission. The use of PCR to detect rearrangement of the BCL2 gene was positive at diagnosis in 7/11 remitters patients; six out of these 7 patients developed molecular response and are in continuous complete remission 4–18 months (median, 9 months) after therapy. After a median follow-up of 10 months (range, 4–18 months), 14 patients (93%) are alive, of whom 10 patients in continous complete remission. One remitter patient died of brain stroke; the cause of death was not linked to Zevalin. No patient required hematopoietic growth factors. By week 4, seven patients developed grade 3 thrombocytopenia and 5 of them required platelet transfusions. Until now, no patient developed signs of MDS.
Conclusion: One single dose of 90Y Ibritumomab Tiuxetan as initial treatment can induce clinical and molecular remission in patients with advanced untreated follicular lymphoma; moreover, hematological toxicity was low and quickly reversible.
Efficacy of 90 Y - Ibritumomab Tiuxetan in Relapsed or Refractory Primary Gastric Non Hodgkin Lymphoma
Authors: Vanazzi Anna , Ferrucci Pier Francesco , Grana Chiara Maria , Pruneri Giancarlo , Crosta Cristiano , Pinto Antonello , Chinol Marco , Calabrese Liliana , Paganelli Giovanni , Martinelli Giovanni 
Published: April 2020

Abstract
BACKGROUND: A prospective, single arm, open-label, phase II trial was performed to evaluate efficacy of 90Y-Ibritumomab Tiuxetan at conventional activity of 0,4 mCi/kg in Primary Gastric Non Hodgkin Lymphoma (NHL).
PATIENTS AND METHODS: From May 2004 to May 2008, 13 patients affected by Primary Gastric NHL - either Mucosa Associated Lymphoid Tissue (MALT) or Diffuse Large B Cell (DLBC) NHL, relapsed/refractory disease - were enrolled to receive 90Y-Ibritumomab Tiuxetan at the activity of 0,4 mCi/kg. Median age was 57 ys (range 36–83), 6 female and 7 male. Nine out of 13 patients had gastric MALT NHL, the remaining 4 patients had DLBC NHL. At time of treatment 11 out of 13 patients had stage I/II, 2 patients had stage III/IV disease. Helicobacter Pylori was negative in all patients except one at time of treatment and positive at diagnosis in 5 of them. Median number of previous therapies received was 1 (1–4): all patients except 3 had received prior CT, 7 patients prior Rituximab, no one had received prior RT.
RESULTS: Toxicities were primarily haematological and reversible. All patients had serial testing for HAMA and none developed antibodies to date. MALT-1 gene rearrangement was detected in 3 of the 9 cases analyzed, while none of the cases showed bcl-10 gene rearrangement. All patients are now evaluable for response: 10 out of 13 patients experienced a complete response (CR) (9 MALT, 1 DLBC); progressive disease (PD) was observed in 2 out of 13 patients, both DLBC NHL; finally another patient affected by DLBC NHL did not respond. After a median follow up of 24 months (range 3–50 months) 9 out of 10 CRs are disease free and 5 of them can be considered long term responders at 50, 43, 40, 32 and 31 months, respectively, following radioimmunotherapy (RIT). At the time of the analysis only 1 relapse occurred 17 months after RIT (MALT). Two patients - both DLBC - died due to disease progression. There was no statistically significant associations between response to RIT and the occurrence of the MALT-1 translocation.
CONCLUSIONS: 90Y-Ibritumomab Tiuxetan seems to be very active in patients with primary gastric NHL relapsed or refractory to conventional systemic treatment, especially in gastric MALT NHL. Despite the relative short median follow-up (24 months), we observed durable long-term responses at least in 5 patients. High response rate and durable remissions could be related to the low tumor burden and consequently to higher absorbed doses to tumor, confirming the possible relationship between absorbed doses to tumor, efficacy and duration of response. If preliminary results can be confirmed in larger series, RIT could be offered as valid alternative approach in this setting because of its efficacy and low rate of side effects. These preliminary results warrant further studies.
Antithrombotic Effects of a FXI Antisense Oligonucleotide in Mice
Authors: Zhang Hong , Zhao Chenguang , Crosby Jeff , Mazur Curt , Freier Susan M. , Watt Andy , Siwkowski Andy , Gao Dacao , Black Chris , Monia Brett P. 
Published: April 2020

Abstract
FXI, a component of the intrinsic pathway of coagulation, contributes to the generation of thrombin and is also activated by thrombin on the surface of platelets, resulting in further amplification of the coagulation process. Reports have shown that FXI deficiency in mice or in humans is generally not associated with major bleeding yet is associated with reduced risk for thromboembolic disease. To determine whether targeting FXI with antisense oligonucleotides (ASOs) can produce antithrombotic activity without increasing risk of bleeding, a series of 2nd Generation 2′-O-methoxyethyl modified ASOs were identified that specifically reduce levels of FXI in mice and were evaluated for antithrombotic activity and bleeding potential. Mice were dosed with FXI ASO (ISIS 404071) subcutaneously for three weeks. FXI ASO treatment resulted in a dosedependent and specific reduction in FXI mRNA levels in liver and FXI protein levels in plasma with an ED50 of 3.2 mg/kg. These reductions in FXI levels correlated well with a prolongation of aPTT with no effects on PT prolongation. The anticoagulant effect of FXI ASO treatment also correlated well with antithrombotic activity in a 10% FeCl3 induced IVC thrombosis mouse model across a wide dose range. Furthermore, FXI ASO treatment was generally well tolerated and no prolongation of tail bleeding time was observed at any dose tested, indicating a broad safety margin for FXI ASO targeting. Additional studies using intravital microscopy to study the effects of FXI ASO treatment on thrombosis formation in the mesenteric vein following 10% FeCl3 injury demonstrated that FXI ASO treatment significantly impeded platelet aggregation at the site of vessel injury, thrombus growth and vessel occlusion. Studies to further evaluate the safety of FXI targeting were conducted using a mouse model of intracerebral hemorrhage induced by intracranial injection of collagenase. In this model, FXI ASO treatment had no effect on hemorrhagic size, neurologic deficit score, or mortality at doses well above that needed to produce maximal antithrombotic activity. These results strongly suggest that FXI is an effective and safe target for antithrombotic therapy and that antisense drug technology could be an attractive approach to specifically target FXI for the treatment of thrombotic disorders.
Identification of Hemostatic Modifier Genes Rescuing FVII Deficient Mice
Authors: Rosen Elliot D. , Schroeder Valerie A , Liang Zhong , Suckow Mark 
Published: April 2020

Abstract
FVIItta/− mice are heterozygous for the FVII- null allele and a gene-targeted allele expressing very low levels of FVII. These mice produce very low levels of FVII (&lt;1.0 % of wt levels). FVII+/− and FVIItta/+ mice have each independently been backcrossed into a C57Bl/6 background (thus all the mice in the lineage have had at least 50% of wt FVII levels and there is no selection for compensation for low coagulant activity). The FVII− and FVIItta alleles have similarly been backcrossed extensively into a 129X1/svj background. The FVIItta/− mice were generated in both C57Bl/6 and 129X1/svj backgrounds by crossing FVII+/− and FVIItta/+ animals. In the C57Bl/6 background these low FVII mice suffer intrauterine or perinatal lethality. In contrast FVIItta/− mice generated in a 129X1/svj background survive much longer with 50% surviving more than 6 months. These results indicate there are significant strain differences in the phenotype of mice with a FVIItta/− genotype. To determine the genetic basis of these strain differences we have generated F1 FVIItta/− mice in a 50:50 C57Bl/6 and 129X1/svj background by crossing C57Bl/6J FVII+/tta and 129X1/svj FVII+/− parents. These mice survive long-term similar to FVIItta/− in a pure 129X1/svj background. F1 FVIItta/− males were backcrossed with C57Bl/6J FVII+/− females to generate F1B1 FVIItta/− males. Long-term surviving (&gt;16 weeks) FVIItta/− males were selectively backcrossed with C57Bl/6J FVII+/− females to generate F1B2, F1B3 and then F1B4 FVIItta/− mice. Presumably, the survival of these FVIItta/− mice depends upon the retention of 129X1/svj derived chromosomal regions enabling the survival of low FVII mice. After 4 rounds of backcrossing, the F1B4 FVIItta/− mice retain ~3% of the 129X1/svj genome. DNA from 6 F1B3 FVIItta/− males and all their 81 F1B4 FVIItta/− offspring (total of 87 mice) have been genotyped with a Mouse MD Linkage panel (Illumina) containing 247 informative SNPs distinguishing between 129X1/svj and C57Bl/6J genomes. The initial scan identified 12 chromosomal regions enriched for 129X1/svj derived sequences. To identify putative hemostatic modifier genes, long-term surviving F1B4 low FVII mice have been selectively backcrossed and the DNA of their offspring analyzed with a high density SNP scan in the regions of interest.