bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Cyclophosphamide, Fludarabine, Alemtuzumab, and Rituximab (CFAR), an Active Frontline Regimen for High-Risk Patients with CLL.
Authors: Wierda William G. , O’Brien S. , Ferrajoli A. , Faderl S. , Koller C. , Estrov Z. , Garcia-Manero G. , Verstovsek S. , Browning M. , Lerner S. , Keating M. 
Published: October 2019

Abstract
Patients (pts) with CLL have diverse clinical features, including time to first treatment (Rx), response to Rx, remission duration, and outcomes with salvage Rx. We identified serum beta-2 microglobulin (B2M) of 4 mg/L or greater as a high-risk feature, predicting for lower complete remission (CR) rate and shorter progression-free survival (PFS), with frontline chemoimmunotherapy. For pts <70 years old and B2M≥4 treated with the fludarabine (F), cyclophosphamide (C), rituximab (R)-based combination, the CR rate and estimated median PFS were 59% and 60 mo, compared to 81% CR and 80 mo PFS for similar aged pts with B2M<4. We combined FCR with alemtuzumab (A) in the CFAR regimen that was well-tolerated and had activity in treating relapsed/refractory pts. The CFAR regimen is being evaluated in higher-risk pts with an NCI indication for frontline therapy. Frontline CFAR consists of C-200mg/m2 d3–5; F-20mg/m2 d3–5; A-30mg IV d1,3,5, and R-375–500mg/m2 d2, each 28 days for 6 intended courses. Tumor lysis prophylaxis was allopurinol 300 mg/d for 7d, course 1 only. Neulasta 6mg d6 was routine. Antibiotic prophylaxis was TMP-SMZ DS twice daily 2–3 d/wk and valacyclovir (VA) or valgancyclovir (VG) during and for at least 2 months after completion of treatment. CMV antigen in blood was monitored before each course. There currently are 40 pts registered on this trial. The median age for the 21 pts currently evaluable for response was 63 yrs (43–69), B2M was 5.1mg/L (4–9.8), ALC was 72 K/μL (6–355), HGB was 10.9gm/dL (7.9–13.5), and PLT was 158 K/μL (65–390); 13 were Rai high-risk. The median time from diagnosis to Rx was 35 (2–117) mo. The median number of cycles administered was 4 (3–6). Reasons for not completing 6 courses included delayed recovery of counts (6), pt choice (3), AIHA (2), infection (1), and Rx failure (1). CR was achieved in 71%, nPR in 5%, PR in 19%, and 1 pt of 21 did not respond. All pts in CR and nPR and 3 of 4 in PR were free of disease in the bone marrow by 3-color flow cytometry. There was no significant correlation between CR or OR and Rai stage, IgVH mutation status, FISH status, or ZAP70 or CD38 expression. Grade 3 or 4 neutropenia and thrombocytopenia were seen in 27% and 7% of courses, respectively. Major and minor infections were seen in 2% and 8% of courses and FUO in 34% of courses. These FUO included A-infusion related fevers. CMV reactivation occurred in 2/8 pts who received VA and none of 13 pts who received VG prophylaxis during treatment. Two pts developed CMV reactivation 3–6 months after they switched from VG to VA after completing CFAR. In conclusion, CFAR is an active and promising frontline regimen in higher-risk pts with CLL. Accrual and treatment continue on this clinical trial.
Assessment of Psychological Distress in Patients Suffering from Hematological Disorders.
Authors: Cole Craig E. , Ballandby Rebecca , Schroeder Jonean E. , Lee Jennifer A. , Mathiason Michelle A. , Hoeg Rasmus T. , Bottner Wayne A. , Farnen John P. , Ettinger Robert S. , Peters Antoinette M. , Dawson Janette M. , Johnston Kaye L. , Go Ronald 
Published: October 2019

Abstract
Background: Distress is an unpleasant psychosocial response that may impede the capacity of patients to cope successfully with a disease, its physical symptoms, and its treatment. Measurements of distress have been extensively evaluated in patients with solid tumor malignancies. The National Comprehensive Cancer Network (NCCN) has recommend standards of care for distress management. However the degree of distress in patients with hematologic diseases (both malignant and non-malignant) is under-investigated.
Aim: This study was designed to assess and compare distress in patients with malignant or non-malignant hematological disorders.
Methods: Of 617 adult hematology patients enrolled between July 2006 and December 2006, 572 reported distress scores and were prospectively followed, while 45 patients who did not rate their distress were excluded. The NCCN Distress Thermometer (scale of 0–10) accompanied by a modified problem checklist was administered to hematology patients 18 years of age and older seen at the Gundersen Lutheran Center for Cancer and Blood Disorders. Additional demographics, diagnoses, and disease-related information were gathered by chart review. Patients reporting a high score were contacted by a social worker to assess the etiology of distress.
Results: At initial visit during the study period, 572 patients reported a distress score (mean = 3.4 ± 2.7). Patients with malignant (3.2 ± 2.7) or non-malignant (3.6 ± 2.6) disease reported similar distress (p = 0.125). Females (4.0 ± 2.8) were more distressed than males (2.9 ± 2.4; p < 0.001). Other factors significantly associated with distress were history of anxiety (p < 0.001), depression (p < 0.001), younger age (p = 0.001), and time from diagnosis (visit day 3.6 ± 2.4; 1–90 days 4.2 ± 2.9; 3mo-1 year 2.9 ± 2.6; 1+ years 3.4 ± 2.7; p = 0.028). Distress based on disease status was (relapse 5.0 ± 3.1, remission/stable 3.3 ± 2.6, treatment 3.7 ± 2.7) also significantly different (p = 0.009).
Conclusion: We found no significant difference in levels of reported distress between patients with malignant and non-malignant hematologic disorders. Significantly higher distress levels were reported in women, younger patients, those with previous psychiatric disease, date of visit, and those at relapse. Patients with either malignant or non-malignant hematologic disorders should be considered for distress screening and management.
Anti-Idiotype Antibody Response after Vaccination Correlates with Better Overall Survival in Follicular Lymphoma.
Authors: Ai Wei Z. , Tibshirani Robert , Taidi Behnaz , Czerwinski Debra , Levy Ronald 
Published: October 2019

Abstract
Purpose Immunoglobulin idiotype (Id) is a clonal marker expressed by B cells. Lymphoma B cells express a unique Id which serves as an ideal target for immunotherapy. It has been shown that induction of anti-Id immune response through vaccination is associated with many clinical benefits, including tumor regression, molecular remission, and prolonged progression free survival (PFS). However, it is unknown if induced immune response is an independent predictor for overall survival (OS). Patients and Methods We analyzed 91 patients who were uniformly treated with CVP followed by idiotype vaccination as the first-line therapy. The induction of anti-Id immune response was evaluated and correlated with OS. Univariate and multivariate analyses were applied to select independent factors that predicted OS.
Results: Those patients who achieved a CR/CRu to CVP chemotherapy or produced anti-Id antibody after vaccination had longer survival than those who did not. At 10 years, OS was 90% and 68% for patients with or without a CR/CRu after CVP (p = 0.024); 90% and 69% for patients with or without tumor-specific antibody production, respectively (p = 0.027). In contrast, generation of anti-Id cellular response did not correlate with OS. Furthermore, CR/CRu to CVP and generation of anti-Id antibody response were the only two independent factors among those tested that were correlated with longer survival.
Conclusion: Generation of anti-Id antibody after active immunotherapy is an independent predictor for better OS in follicular lymphoma.
TNF-alpha Plays a Crucial Role in the JAK2-V617F Induced Myeloproliferative Disorder.
Authors: Bumm Thomas G.P. , VanDyke Jonathan , Loriaux Marc , Gendron Carolyn , Wood Lisa G. , Druker Brian J. , Deininger Michael W.N. 
Published: October 2019

AbstractBackground: The JAK2 V617F mutation is present in almost all patients with polycythemia vera (PV) and to a large proportion in patients with essential thrombocythemia and idiopathic myelofibrosis. Mice transplanted with JAK2 V617F infected bone marrow develop a myeloproliferative disorder (MPD) resembling PV with secondary myelofibrosis. We have shown that mice with JAK2 V617F induced MPD have significantly higher plasma TNF-alpha levels compared to controls (1). We therefore hypothesized that TNF-alpha may be involved in the pathogenesis of murine JAK2 V617F-induced MPD.Methods: In a side by side experiment 5-FU stimulated murine bone marrow cells from TNF-alpha knock out mice (B6;129S6-Tnftm1Gkl/J, referred to as TNF-alpha null) and wild type F1-hybrid control mice (B6;129S6F1/J, referred to as TNF-alpha WT) were infected with MIGR1-IRES-GFP retroviral vector carrying murine wild type JAK2 (JAK2-WT) or JAK2-V617F or empty vector control (MIGR1). Cells were transplanted into lethally irradiated TNF-alpha null or WT recipients. The mice were monitored by observation and blood counts. At day 90 mice were euthanized for detailed pathologic analysis.Results: TNF-alpha WT mice transplanted with TNF-alpha WT cells infected with JAK2-V617F (but not JAK2 WT or MIGR1) developed a PV-like MPD characterized by plethora and elevated hematocrit (HCT) levels (Figure 1). Autopsy and histology revealed splenomegaly with extramedullary hematopoiesis, while the bone marrow showed trilineage hyperplasia and severe reticulin fibrosis. In contrast TNF-alpha null or WT mice transplanted with JAK2-V617F infected TNF-alpha null marrow retained normal blood counts and their spleen weights were similar to controls (Figure 1). Spleen histology showed only mild to moderate infiltration with myeloid cells, with preservation of splenic architecture. Bone marrow cellularity was only slightly increased, and reticulin fibrosis was absent except in one mouse with focally moderate fibrosis. As expected, recipients of JAK2 WT or MIGR1 infected marrow showed no signs of MPD.Conclusion: TNF-alpha is required for induction of murine JAK2-V617F-positive MPD, at least in the B6;129S6 background. The underlying mechanism is under study. One possibility is that suppression of residual normal hematopoiesis by JAK2-V617F-induced TNF-alpha is required for complete penetrance of the MPD phenotype. This would be in analogy to human PV, where erythroblasts from JAK2 V617F-positive PV patients show increased resistance to CD95-induced apoptosis compared to normal erythroblasts, which may give them a proliferative advantage over normal cells (2).Figure 1. Figure 1.
Addition of Rituximab to CHOP Chemotherapy Significantly Improves Survival of Patients with Transformed Lymphoma.
Authors: Al-Tourah Abdulwahab J. , Savage Kerry J. , Gill Karamjit K. , Klasa Richard J. , Sehn Laurie H. , Shenkier Tamara N. , Gascoyne Randy D. , Connors Joseph M. 
Published: October 2019

Background: Transformation of indolent lymphoma into diffuse large B-cell lymphoma (DLBCL) has been associated with poor survival and the optimal therapy is unknown. The addition of rituximab to CHOP chemotherapy (CHOP-R) has been shown to significantly improve the survival of patients (pts) with de novo DLBCL. However, the impact of rituximab on the survival of patients with transformed DLBCL remains unknown.
Methods: As part of a large retrospective analysis examining the long term natural history of pts initially diagnosed with indolent lymphoma in British Columbia (B.C.) (n=690; follicular 600, small lymphocytic 49, lymphoplasmacytic 41), we have identified those pts who developed transformed lymphoma. The definition of transformation was based on either histological confirmation or clinical features, defined as one or more of the following: rapid discordant nodal or extranodal growth; sudden rise in LDH to > 2 x previous baseline; involvement of unusual extranodal sites; or hypercalcemia. Pts were excluded from this analysis if they received high-dose chemotherapy and stem cell transplant as part of the treatment for their transformed lymphoma (n= 9). Pts who were too frail to be treated with multi-agent chemotherapy were also excluded. The extent of disease at transformation was considered limited in pts with single nodal region involvement, no B symptoms, non-bulky disease (<10 cm) and with limited extranodal involvement. Pts with more extensive disease were considered to have advanced transformation.
Results: 108 pts with transformed lymphoma were identified in the B.C. lymphoid database, the majority of whom had a prior history of follicular lymphoma (n=103, 95%). Median age at transformation was 60 y (22–71). Transformation was histologically confirmed in 74 (69%) pts. The outcome of 23 pts who were treated with CHOP-R was compared to 85 pts who were treated with CHOP-like chemotherapy. None of the 108 pts had received rituximab as part the management of their indolent lymphoma. The median follow-up for all living pts in the CHOP-like cohort was 7 y (3–14) and 3 y (0.5–5) in the CHOP-R cohort. The post-transformation 5 y overall survival following CHOP-like chemotherapy was 33% vs 61% after CHOP-R (P= 0.01). This difference in survival remained significant when pts with clinically diagnosed transformation were excluded from the analysis (P= 0.02). For the 78 pts with advanced disease extent (59, CHOP-like; 19, CHOP-R) there was a significant difference in PT-5yOS (21% vs 57%, respectively; P= 0.005). For pts with limited disease extent (CHOP-like, 26; CHOP-R, 4) no significant difference in PT-5yOS was observed (P= 0.2).
Conclusions: In rituximab-naive patients with indolent lymphoma, the addition of rituximab to CHOP chemotherapy significantly improves overall survival after transformation.
Hydroxyurea Utilization in Nigeria, a Lesson in Public Health.
Authors: Aliyu Zakari Y. , Babadoko Aliyu , Mamman Aisha 
Published: October 2019

Abstract
Hydroxyurea is a successful and cost effective drug therapy for sickle cell disease. Treatment with hydroxyurea is associated with a significant decrease in sickle cell complications, hospitalizations and transfusion requirements by about 50% and mortality reduction by 40% in clinical studies. The drug is unfortunately underutilized in sickle cell disease in the United States despite clear efficacy data and management experience. There is no data on the utilization of hydroxyurea in Africa, a part of the world with the highest global burden of sickle cell disease. We prospectively interviewed 206 consecutive adults and pediatric sickle cell patients as part of the Nigerian pulmonary hypertension screening study and reviewed over 1000 patients followed longitudinally at Ahmadu Bello university teaching hospital in Zaria, Nigeria. We also interviewed 10 hematologists (3 specialists and 7 hematologists in training) at the same university hospital. 65% of the 206 prospectively evaluated patients met the Multicenter Study of Hydroxyurea clinical indications for hydroxyurea treatment. No patient (zero percent) was on hydroxyurea therapy. All hematologists (100%) reported their discomfort with instituting hudroxyurea. Barriers to hydroxyurea utilization identified by practitioners included safety and toxicity profile (100%), patient compliance (100%), effective follow up (100%), drug availability (100%), affordability (100%) and specifically concern for reactivation of latent tuberculosis (50%) and carcinogenesis (100%) and teratogenicity (100%). Only 5% of patients had been informed of or were aware of hydroxyurea as a treatment option in sickle cell disease. Patient related barriers to hydroxyurea identified include lack of awareness (95%), cost (100%), availability (100%), need for frequent follow up (90%), pregnancy restrictions and need for concomitant contraceptive use (98%) and risk of infections (98%). Our study indicates the absolute lack of hydroxyurea utilization in a major health care center in Nigeria. Nigeria has the highest incidence of sickle cell disease in the world with about 150,000 children born with the disease annually. Sickle cell disease accounts for about 9 –16% of under-five mortality rates in the country. The sickle cell disease related morbidity, mortality and health systems financial burden remains very high in Nigeria and most of Africa. Local health care provider education and support and patient counseling and education are needed for the successful introduction of hydroxyurea in Nigeria. Clinical studies designed to assess the safety and efficacy of hydroxyurea in unique African settings is needed to facilitate the introduction and utilization of hydroxyurea in Nigeria and other parts of Africa.
Identification of Candidate Genes Associated with Sensitivity and Resistance to the Histone Deacetylase Inhibitor Valproic Acid in Patients with Acute Myeloid Leukemia.
Authors: Craddock Charles F. , Khanim Farhat , Arrazi Julie , Turner Bryan , Bunce Christopher 
Published: October 2019

Abstract
Histone deacetylases inhibitors (HDIs), such as valproic acid (VPA), demonstrate significant clinical activity in a proportion of patients with high risk acute myeloid leukemia (AML). However the mechanism by which HDIs selectively induce apoptosis in leukemic blasts remains unknown. We have therefore correlated the impact of VPA exposure on gene expression in leukemic cell lines and primary AML blasts with its ability to induce cell death in vitro and induce clinical responses in vivo. 14 hemato-lymphoid cell lines were tested for their sensitivity (IC50) to apoptotic cell killing by VPA. Gene expression array analyses using HGMP chip 6500 gene arrays were performed on the same cell lines prior to HDI exposure. A bioinformatics approach combined the array and IC50 data to generate a score for each gene identifying those whose elevated expression correlated with sensitivity or resistance to VPA in vitro. In a concurrent Phase I/II clinical trial 24 patients with high risk AML (relapsed n=11, newly diagnosed n=6, primary refractory n=3) with a median age of 64 yrs (41–83 yrs) received combination treatment with VPA, all trans-retinoic acid (ATRA) and theophylline. Changes in histone acetylation and expression of HDI responsive genes was measured in leukaemic blasts before and after commencement of VPA therapy. Expression of genes associated with VPA sensitivity in vitro were re-analysed with respect to their expression in pre-treatment blasts from non-responding and responding trial patients. By combining LC50 values to VPA and microarray data generated from pre-treatment RNA in 14 hematolymphoid cell lines we were able to identify candidate genes and signalling networks mediating sensitivity and resistance to VPA in vitro. Genes whose higher expression conferred sensitivity included IL-1β and those associated with VPA resistance included PLOD2, cyclin B1 (CCNB1) and ACVR2A. In the clinical trial 5 patients, all with relapsed AML, achieved clinical responses by Cheson criteria (complete remission n=1, partial remission n=4). Comparison of gene expression, as defined by microarray studies, in responding and non-responding patients with the previously identified in vitro VPA signalling networks identified that similar networks to those defined in vitro appeared to be correlated with clinical response. This study demonstrates induction of pro-apoptotic gene expression by VPA in a clinical context and identifies potential mechanisms through which its anti-leukaemic effect may be mediated in vivo. Furthermore we have identified potential VPA-signalling networks containing novel sensitivity and resistance genes whose expression correlates with VPA-mediated tumour cell killing in vitro and may predict clinical activity.
Hematin Promotes Complement Alternative Pathway-Mediated Deposition of C3 Activation Fragments on Human Erythrocytes: Potential Implications for the Pathogenesis of Anemia in Malaria.
Authors: Taylor Ronald P. , Pawluczkowycz Andrew W. , Lindorfer Margaret A. , Waitumbi John W. 
Published: October 2019

Abstract
Childhood malaria caused by Plasmodium falciparum (pf) is often characterized by severe anemia at low parasite burdens; the mechanism(s) responsible for this pathology remain to be defined. We have reported that erythrocyte (E) CR1, the immune adherence receptor specific for C3b, is reduced during anemia in childhood malaria, suggesting a possible role for complement in E destruction. Intravascular lysis of infected E by pf leads to release of E breakdown products hemoglobin and hematin, which have inflammatory properties. Free hematin can bind to E, and we find that in serum and in whole blood anti-coagulated with lepirudin, moderate concentrations of hematin activate the alternative pathway of complement and promote deposition of C3 activation and breakdown products on E. We documented C3 deposition by flow cytometry, and additional fluorescence microscopy studies revealed that most of the deposited C3 fragments are located in close juxtaposition to CR1. Western blots confirmed that the C3 fragments are indeed covalently bound to the E, and immunoprecipitation experiments indicated that a fraction of the deposited C3 is covalently bound to CR1. The degree of C3 fragment deposition is directly correlated with E CR1 levels, both within a given donor’s E population and when E from different donors are compared. E opsonized with complement in the presence of hematin form rosettes with Raji cells, through interaction with CR2, the C3dg receptor expressed on several types of B cells including splenic marginal zone B cells. Thus, hematin-mediated complement activation and C3 fragment deposition on E may promote accelerated splenic (or liver) clearance of the youngest E, which have the most CR1, leading to sudden onset of anemia along with reduction of mean CR1 on surviving E. A monoclonal antibody specific for C3b, mAb 3E7, previously demonstrated to inhibit the alternative pathway of complement, completely blocks the C3 fragment deposition reaction. Use of this monoclonal antibody in non-human primate models of malaria may provide insight into mechanisms of erythrocyte destruction and thus aid in the development of therapies based on inhibiting the alternative pathway of complement.