bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of TW-37, a pan Bcl-2 Proteins Small-Molecule Inhibitor, Against Spectrum of Human B-Cell Lines and Patient-Derived Samples.
Authors: Mohammad Ramzi M. , Sun Yuan , Wang Shaomeng , Aboukameel Amro , Al-Katib Ayad M. 
Published: November 2019

Abstract
Non-Hodgkin’s lymphoma (NHL) tumors include a group of heterogeneous diseases with varying natural histories and responsiveness to therapy; nonetheless, overexpression of Bcl-2 protein is seen in more than 80% of NHL. Throughout the years our laboratory succeeded in establishing a panel of B-cell lines representing various maturational stages of NHL. In this study, we have utilized a structure-based strategy to design a new class of potent nonpeptidic small-molecule inhibitor (SMI) of Bcl-2 family. TW-37, a lead compound that was designed to target the BH3 binding groove of antiapopototic Bcl-2 proteins. It binds to Bcl-2, Bcl-XL and Mcl-1 with Ki values of 290 nM, 1110 nM and 260 nM, respectively. TW-37 showed significant antiproliferative effect against Pre-B-Acute Lymphoblastic Leukemia (WSU-pre-B-ALL), Diffuse Large Cell Lymphoma (WSU-DLCL2), Follicular Small Cleaved Cell Lymphoma (WSU-FSCCL), Waldenstrom’s Macroglobulinemia (WSU-WM) and primary cells obtained from lymphoma patients, despite variations in their anti- and pro-apoptotic Bcl-2 proteins (Bcl-2, Bcl-XL, Mcl-1, Bax, Bak, Bim, Bad, BUMA and Bok). The IC50 for TW-37 varied from 165 nM in the WSU-FSCCL to 300 nM in WSU-DLCL2 cells. Apoptosis was independent of proliferative status or pathological classification of B-cell tumor. TW-37 was able to block Bim-Bcl-XL and Bim-Mcl-1 eterodimerization and induces apoptosis via activation of caspases -9, -3, PARP and DNA fragmentation. Although cell lines and patient samples expressed multiple Bcl-2 family proteins at various levels, TW-37 induced apoptosis was only strongly associated with Bax:Mcl-1 ratio. TW-37 administered to tumor-bearing SCID mice led to significant tumor growth inhibition (T/C), tumor growth delay (T-C) and Log10kill, when used at its maximum tolerated dose (40 mg/kg x 3days) via tail vein. failed to induce changes in the Bcl-2 proteins levels suggests that assessment of baseline Bcl-2 family proteins can be used to prognosticate the response to drug. These findings indicate activity of TW-37 across the spectrum of human B-cell tumors and support the concept of targeting the Bcl-2 system as a therapeutic strategy in the treatment of B-cell lymphoma.
Red Blood Cell Alloimmunization Is Affected by Depletion of Donor White Cell Subsets.
Authors: Campbell-Lee Sally A. , Liu Jinhuan , Ness Paul M. , Baldwin William M. 
Published: November 2019

Abstract
Red blood cell (RBC) alloimmunization leads to therapeutic limitations due to difficulties in obtaining compatible RBC components. Better understanding of immune mechanisms responsible for alloantibody formation are necessary in order to develop ways of preventing or treating alloimmunization in high risk patients. A murine model of RBC alloimmunization was developed using B6CBA-F1-Tg Fyb mice that express the human Fyb blood group as donors, and recipient mice of the B6CBA-F1 strain. RBC were obtained from donor mice that were anesthetized and exsanguinated by cardiac puncture. Donor whole blood was collected into sterile syringes containing CPDA-1 (Sigma Aldrich, St. Louis, MO) and was then centrifuged to produce packed RBCs. Recipient mice were transfused 0.3 mL via the tail vein once a week for two weeks with donor RBC that had 108 spleen cells added which were then depleted of either CD4, CD8, CD19 or natural killer (NK) cell subsets (n=6 in each group). Depletions were performed using immunodensity negative selection with murine anti-CD4, CD8, CD19 and DX5 antibodies (StemCell Technologies, Vancouver, BC). Two control groups were transfused with either washed buffy coat depleted RBC (leukodepletion to fewer than 5 × 106 remaining white blood cells (WBC)) or RBC with spleen cells added that was processed through immunodensity negative selection without the addition of antibody (no leukodepletion with 1 × 108 WBC). Serum was collected from recipient mice once a week for four weeks post-transfusion. Circulating IgG anti-Fyb titers were measured by flow cytometry using donor RBC and staining with fluorescein isothiocyanate conjugated rat anti-mouse IgG (Jackson ImmunoResearch, West Grove, PA); target cells were gated on by size and side scatter parameters using a FACScan flow cytometer (Becton Dickenson, Franklin Lakes, NJ). Serum samples from week 4 post transfusion demonstrated a mean anti-Fyb titer of 64 in the CD4 depleted group. Mean titers of 256, 512 and 512 were observed in the CD8, CD19 and NK depletion groups, respectively. The leukodepletion control group had a mean anti-Fyb titer of 16, and the non-leukodepletion control group showed a mean titer of 64. These results indicate that donor contaminating WBC affect RBC alloimmunization. CD4 cell removal led to an anti-Fyb titer that was the same as the non-leukodepletion control group. CD8, CD19 and NK cell removal increases anti-Fyb titer and may indicate a variety of inhibitory roles of these cell types.
Compassionate Use Experience with Dasatinib Therapy in Patients after Imatinib and/or Nilotinib Failure.
Authors: Gunawardena Bettina A. , Schlief Sarah , Dempke Wolfram , Wnterhalter Bernd 
Published: November 2019

Abstract
Background: Dasatinib is a potent orally active, multi-targeted tyrosine kinase inhibitor that blocks signal transduction pathways implicated in the proliferation and survival of tumor cells. A European compassionate use trial was conducted to provide dasatinib to patients (pts) who were ineligible to be enrolled into the START-trials.
Methods: From April 2006 to February 2007, 26 pts were included in Germany. Diagnosis at inclusion: 9 Ph+ALL, 6 CML in accelerated phase, 5 CML in myeloid blast crisis, 2 biphenotypic Ph+ALL and 1 chronic phase CML. Additionally, 3 pts with systemic mastocytosis (SM), refractory to imatinib due to D816V mutation were also included. Pts had previously failed several chemotherapy regimens, including imatinib and/or nilotinib. Sixty-one percent were resistant, 35% were refractory and 4% intolerant to imatinib/nilotinib.
Results: Of 26 patients, there were 17 male and 9 female pts. The median age was 56 years (range, 22–80 years). The average daily dose of dasatinib was 137 mg with a median duration of therapy of 69.5d (range 3–252d). Six (23%) pts required transient treatment interruption, 2 (8%) due to non-haematological toxicity (dyspnea and increased hepatic values), 4 (15%) due to haematological toxicities. Twenty-one pts discontinued therapy for the following reasons: study related toxicity (23%), SCT (15%), death (8%), lost to follow-up (11%) and patient’s wish (4%). Two patients still remain on therapy. The response rate was CHR in 42%, complete (CCyR) cytogenetic response in 19%, and PCyR in 4% of the pts. For patients with diagnosed SM one partial HR, one stable disease and one progression have been recorded. Disease progression occurred in 19% of cases. Adverse events were transient and generally mild to moderate in severity. Generally, the observed AE profile was similar to that seen in previous research trials. For all pts, the most common hematological side-effects Grade 3/4 AEs reported were thrombocytopenia (23%), neutropenia (4%), and anemia (4%). Most frequent non-hematological side-effects included dyspnea in 23% of pts (no grade 3–4), edema in 23% (grade 3, 8%), diarrhea in 15% (grade 3, 4%), headache in 15% (no grade 3–4), bone and neck pain in 11% (grade 3, 8%) and pleural effusion in 8% (grade 3, 4%).
Conclusions: Dasatinib therapy appeared to be effective and was well tolerated in this difficult to treat patient population.
Myelodisplastic Syndrome: Is It Associated or Is It a Precursor of Myeloid Malignancies?.
Authors: Corinaldesi Giorgio , Corinaldesi Christian 
Published: November 2019

Abstract
Myelodisplastic syndrome (MDS) is a clonal haematopoietic stem cells disorder considered a pre-leukemic disease (about 30% of MDS turn into acute myeloid leukaemia (AML)) which is frequently associated with cytogenetic abnormalities and chromosomal instability: monosomy 7 or 7q - syndrome, 5q- syndrome, trisomy 8, inv(16), t (8;21), t (15;17), t (12;21), t (9;11), or sub microscopic DNA mutation of gene such as RAS, p53, FLT3, HSPA9, FMS and refractory cytopenias, with dysmyelopoiesis and increased apoptosis. We have identified 15 people aged between 54/67 years with MDS and we have examined their clinical presentation and their associated disorders.
RA: refractory anaemia (7 patients) RARS: refractory anaemia with ringed sideroblasts (1 patient) 5q-syndrome (1 patient) RAEB refractory anaemia with excess blast: type 1 (5–10%) (3 patients); type 2 (11–20%) (1 patient) E) RAEB-T refractory anaemia in transformation (1 patient) F) CMML chronic myelomonocytic leukemia (1 patient)
The disease is characterized by chronic tiredness, headache, shortness of breath, increased susceptibility to infection especially in the lung with a prolonged fever, easy bruising, nosebleeds, pinpoint red spots, bleeding, splenomegaly, hepatomegaly, abdominal distress and pain are also common. VEGFR-1 and VEGFR-2 are strongly expressed in megakaryocytes, HLA-DR2 and HLA-DR15 are higher, immune dysfunction in MDS increases activated cytotoxic T-cells with higher percentage of CD8+CD28-, CD8+CD28- CD57+ with an increased level of CD4, and Fas ligand/Apo-1 (CD95). The RA, RARS, 5q-syndrome are more indolent disease with a lower rate of progression to AML and a prolonged clinical course; the RAEB, RAEB-T are slightly more advanced with a short course; in the CMML the progression is faster and it is frequently associated with the secondary chromosomal perturbation t(5;12), (q33;p13), or with the loss of specific portion 3p-, 7q- (7q22-7q33-). The goals of the therapy are to control symptoms and to decrease the progression to myelogenous leukaemia; our results show that a low intensity treatment in the low and intermediate groups with 5-azacitidine 75 mg/m2/day produces a high rate of response (72%, of which: complete remission: 18%, partial remission: 34%, improved: 20%), relapse 24%, disease-free survival at 3 years of 64%; with a low incidence of side effects (nausea 68%, vomiting 60%, chest pain 28%); on the other hand in the high risk group the 5-azacitidine with gentuzumab reverted to normal about 90% of the patients (complete remission: 6%, partial remission: 28%, improved: 56%), disease free survival at 3 years 52%, relapse 48%; however, the only curative treatment is stem cells transplantation from a tissue matching donor. Finally, it is very important to provide a supportive care with erythropoietin, G-CSF or GM-CSF, red cells transfusions, administration of broad-spectrum antibodies mostly for controlling symptoms, but also for preventing or treating complications.
Clinical and Prognostic Relevance of Magnetic Resonance Imaging of the Spine in Newly Diagnosed Multiple Myeloma Patients Receiving Autologous Stem Cell Transplantation.
Authors: Tosi Patrizia , Zamagni Elena , Tacchetti Paola , Salizzoni Eugenio , Perrone Giulia , Ceccolini Michela , Brioli Annamaria , Pallotti Maria C. , Pantani Lucia , de Vivo Antonio , Baccarani Michele , Cavo Michele 
Published: November 2019

Abstract
Magnetic resonance imaging (MRI) of the spine has demonstrated to be a useful tool for correct staging of multiple myeloma (MM), as it is more sensitive than plain x-rays in detecting vertebral lesions. Furthermore, different patterns of bone marrow involvement (focal, diffuse or normal) can be depicted, and this could contribute to better define the prognosis in newly diagnosed patients. In the present study we prospectively evaluated the clinical and prognostic role of spinal MRI in 120 newly diagnosed MM patients (68M, 52F, median age = 56yrs) that subsequently received high-dose chemotherapy and autologous stem cell transplantion, either single (n=28) or double (n=92). Pattern of marrow involvement was focal in 72 cases (60%), diffuse in 29 (24%) and negative in 19 (16%). Patients with a diffuse pattern showed a significantly higher bone marrow plasma cell infiltration (p=0.05) and beta2 microglobulin values (p= 0.04) as compared to patients with a focal pattern; stage III disease according to ISS was observed in 29%, 8% and 1% of patients with a diffuse, focal or negative pattern, respectively. Response rate to treatment program was similar in the three groups of patients, with a stringently defined CR obtained in 34% of patients with a focal pattern, 29% in those with a diffuse pattern and 35% in patients with a negative MRI. Median progression-free survival showed a trend in favor of patients with a negative MRI (54 months) as compared to those with a focal or diffuse pattern (42 and 38 months, respectively). A focal pattern of bone marrow involvement was associated with a significantly higher probability of experiencing an overt vertebral lesion (73% vs 48% in patients with diffuse pattern, p=0.03), including either a compression fracture or a vertebral mass. Consistently with this finding, also extra-spinal bone lesions were more common in patients with a focal pattern (66%) as compared to patients with a diffuse or negative pattern (42% and 6% respectively) (p=0.05). Serum crosslaps were significantly increased in patients with a focal pattern (7032 pmol/L±635SE vs 5431pmol/L±812SE in those with a diffuse pattern, p=0.04). According to our data, a diffuse pattern of bone marrow involvement could be predictive of a more aggressive disease, even though these data needs to be confirmed in a larger series of patients. A focal pattern of bone marrow involvement at diagnosis could help to identify MM patients more prone to develop skeletal complications, so that a careful monitoring and bisphosphonate therapy should be recommended.
Stroke in a Multiple Myeloma Cohort.
Authors: Keyrouz Salah G. , Saba Sadia , Zangari Maurizio , Schmidley James W. 
Published: November 2019

Abstract
Background: Neurologic complications of multiple myeloma (MM) are numerous, however little is known about strokes occurring in the course of MM and its treatment.
Methods: 2877 MM patients were seen for an initial evaluation at our institution over a 5-year period (1998–2002). Patients were identified using discharge summaries by combining ICD-9 codes for MM and stroke. They were included if they had clinical and radiological features of acute stroke. Ischemic stroke was defined as a new acute neurologic deficit lasting > 24 hours, irrespective of diffusion-weighted MRI results. Diagnosis of hemorrhagic stroke was made in patients with new acute neurologic deficit plus evidence of hemorrhage on CT scan. We retrospectively reviewed medical records for demographics, type of MM and treatment, stroke type, clinical features, relevant imaging and laboratory data, and outcomes.
Results: The 11 patients that we identified included eight with ischemic strokes and three with subarachnoid hemorrhages (SAH). There were no patients with intraparenchymal hemorrhage. The overall incidence of stroke in this cohort was 76/100,000 per year, whereas the incidence of ischemic stroke was 56/100,000 per year. The mean age of patients with ischemic stroke was 59 years. Seven had one or more stroke risk factors and an equal number had received thalidomide. The latter were given small doses of coumadin as part of the treatment protocol; at the time of the stroke, INR range was 0.9–1.4. Based on clinical, radiological and other laboratory features, of the eight patients with ischemic strokes, two were presumed cardio-embolic (one had infective endocarditis), five were thrombotic, and one was caused by hypoperfusion. Two patients had findings of severe stenosis/occlusion in vessels corresponding to the infracted brain territory (internal carotid and basilar arteries). Two patients had documented normal plasma viscosity and three had evidence of extra-cranial thrombosis at the time of the stroke. In the three patients with SAH, hemorrhage occurred in the setting of trauma and thrombocytopenia, although one patient had an incidental anterior communicating artery aneurysm. Seven patients were left with minor or no deficits and four died, two in each of the groups.
Conclusion: Overall, strokes did not appear to be more common in MM patients than in the general population, and the pathophysiology was likewise, not different than in patients without MM, with the exception of one patient with infective endocarditis, which is probably directly related to MM or its treatment. The highly selected referral population at our myeloma institute, and the retrospective nature of the study probably underestimate the incidence of stroke. The role of thalidomide in stroke remains unknown. Thrombocytopenia and trauma are probable risk factors for subarachnoid hemorrhage in MM patients. Fatal outcomes were frequent, but when death did not occur, the deficits were minor.
Update of Experience with Fludarabine, Cyclophosphamide, Mitoxantrone Plus Rituximab (FCM-R) in Frontline Therapy for Chronic Lymphocytic Leukemia (CLL).
Authors: Faderl Stefan , Wierda William , Ferrajoli Alessandra , O’Brien Susan , Ravandi Farhad , Kantarjian Hagop M. , Showalter Brandi L. , Lerner Susan , Keating Michael J. 
Published: November 2019

Abstract
Combination therapy has developed into a gold standard of CLL therapy. Chemoimmunotherapy combinations currently achieve the highest rates of complete remission (CR) and molecular responses. Various combinations have been tried to maximize outcome. Based on our previous results with fludarabine, cyclophosphamide, rituximab (FCR) and more recent reports of favorable results with FC + mitoxantrone (M), we have designed an FCM-R (plus pegfilgrastim) combination for pts with previously untreated and symptomatic CLL. All patients were younger than 70 years with b2M levels < 4 mg/L. Pts received F 25 mg/m2 i.v. d2–4, C 250 mg/m2 i.v. d2–4, M 6 mg/m2 i.v. d2, R 375 mg/m2 i.v. d1, and pegfilgrastim 6 mg s.c. d4. For courses 2–6, FCM started day 1 together with R 500 mg/m2, and pegfilgrastim on d3. Courses were repeated q4–6 wks. The primary objective was assessment of clinical responses (NCI-WG criteria) and flow cytometry (CD5/CD19) response rate at 3 and 6 months as well as toxicity. Thirty-one pts were enrolled of whom 30 were treated. The median age was 57 yrs (range 38–69). Fourteen pts (48%) were male. Four pts (14%) had Rai stage ≥ 3. Median b2M was 2.6 mg/L (1.4–4) and the median WBC 59.9 × 109/L (5.6–355). Two pts had 11q23 and 17p- abnormalities by cytogenetics/FISH. Unmutated IgVH occurred in 12/17 (71%) pts; ZAP-70 immunohistochemistry was positive in 11/19 (58%) pts. Twenty-nine pts were evaluable for response at 3 months and 30 at completion of therapy. Twenty-eight pts (97%) responded at 3 mos (41% CR, 17% nPR, 39% PR); 10 pts (34%) had <1% CD5/CD19+ cells in the marrow. Response rates at completion of therapy: 77% CR, 10% nPR, 10% PR for an OR rate of 97%. Seventeen pts (57%) had < 1% CD5/CD19+ cells in the marrow at the end of therapy. Grade >/= 3 neutropenia occurred in 19 (63)% of the pts, thrombocytopenia in 2 (7%). Infectious episodes were seen in 13 pts (45%). Seven (23%) did not complete 6 courses because of ongoing cytopenias. In conclusion, FCM-R has a high CR rate in symptomatic frontline patients with CLL. Time-to-event parameters and a comparison with FCR will be presented.
A Long-Term (5-Year) Sustained Efficacy of Tocilizumab for Multicentric Castleman’s Disease and the Effect on Pulmonary Complications.
Authors: Nishimoto Norihiro , Honda Osamu , Sumikawa Hiromitsu , Johkoh Takeshi , Aozasa Katsuyuki , Kanakura Yuzuru ,   Japanese MRA Study Group on MCD
Published: November 2019

Abstract
Multicentric Castleman’s disease (MCD) is an atypical lymphoproliferative disease, which is closely associated with dysregulated overproduction of interleukin-6 (IL-6). These patients have numerous complications including secondary amyloidosis, paraneoplastic mucocutaneous disease, renal failure, and pulmonary manifestations such as diffuse lymphoid hyperplasia. We previously reported on a 60 weeks study of the humanized anti-human IL-6 receptor monoclonal antibody tocilizumab (TCZ) in patients with MCD and showed that TCZ provides rapid clinical improvement in constitutional symptoms as well as biochemical markers such as c-reactive protein, erythrocyte sedimentation rate, serum amyloid A, hemoglobin, and albumin levels. In this long-term follow-up over 5 years, we investigated the efficacy and safety of TCZ. Patients received TCZ monotherapy at 8 mg/kg intravenously every 2 weeks for 5 years. The dose and dosing interval were allowed to be adjusted according to disease activity. Pulmonary diffuse lymphoid hyperplasia was examined by high resolution computed tomography (HRCT) and evaluated and scored by 2 independent radiologists who were blinded to the time sequence of the images and clinical response of each patient. This study complied with all provisions of the Declaration of Helsinki and was conducted in accordance with Good Clinical Practice guidelines. Thirty-five patients were enrolled in this clinical trial and 30 patients (86%) continued TCZ treatment over the period of 5 years. The reduction in size of enlarged lymph nodes as reported previously was sustained. Clinical improvement in constitutional symptoms as well as the improvement of laboratory markers was maintained. Twenty-two patients had received corticosteroids at baseline (mean corticosteroid dose was 16.5 mg/day prednisolone equivalent), and 11 patients (50%) were able to discontinue corticosteroid therapy without flare. Pulmonary diffuse lymphoid hyperplasia was identified in 31 patients at baseline. Significant improvement was observed in the scores of centrilobular nodules, interlobular septal thickening, bronchovascular bundle thickening and ground glass attenuation with 50 to 60% reductions evaluated by HRCT over the 5 year period. No statistically significant change was observed in scores of cyst and airspace consolidation. TCZ was generally well tolerated during this 5 years treatment. The majority of adverse events (AEs) were mild to moderate in severity. Most frequently reported AEs were mild to moderate infections such as common cold and urinary tract infections (2.3 AEs / patient year). In conclusion, in this 5 years extension study tocilizumab demonstrated an excellent long term efficacy on inflammatory manifestations and pulmonary diffuse lymphoid hyperplasia. Tocilizumab treatment also showed a very good safety profile.