bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteomic Analysis of Waldenstrom Macroglobulinemia (WM) and IgM Monoclonal Gammopathy of Undetermined Significance (IgM-MGUS) Identifies Potential Targets for Drug Therapy.
Authors: Ghobrial Irene M. , Leontocich Alexey A. , Eckel Jeanette E. , Timm Michael , Ziesmer Steve , Hoering Antje , Cabanela Miguel , Nehme Alex , Greipp Philip R. , Fonseca Rafael , Gertz Morie A. , Witzig Thomas E. 
Published: October 2019

Abstract
The objective of this study was to analyze molecular changes that occur at the protein level in WM and IgM-MGUS in order to identify proteins dysregulated at disease progression and design new therapies. We employed antibody protein microarrays (BD Clonetech, CA) to measure changes in the patterns of protein expression between WM, IgM-MGUS and normal lymphoplasmacytic cells as control. The antibody array is a novel technique that assays protein differences directly by hybridizing fluorescently labeled protein mixtures from cell extracts onto a glass slide spotted with 512 different monoclonal antibodies specific for human proteins. CD 19+ and CD138+ purified lymphoplasmacytic cells were obtained from cryopreserved bone marrow samples of 5 newly diagnosed patients with WM and 5 patients with IgM-MGUS. Control plasma cells were obtained from 3 pooled CD19+ and CD138+ purified normal donor bone marrow cells. To assess differential expression, the mean of the ratios of Cy5/Cy3 for each sample were analyzed using the Clontech software to calculate an internally normalized ratio. The normalized data were analyzed by the Genespring software and changes of protein expression ≥2 fold in 60% of the samples as compared to normal control were identified in both WM and MGUS groups. There were 20 proteins upregulated in WM and 21 proteins in MGUS as compared to normal control cells These included proteins from the small GTPases such as the Ras, Rho and Ran families (Rab 4, MONA, RCC1, and CDC42GAP), Kinases/signaling proteins (ROK alpha, p62 dok, JAK, 14-3-3e), cyclin dependent kinase (CDK2), fatty acid synthase (HDAC3), NFkB pathway (IKKalpha, IKBe), and histone deacetylase. The WM and IgM MGUS differed in only 3 proteins using the 2-fold threshold. The WM samples showed overexpression of the heat shock protein Hsp90, the Ras family protein CDC25C, and the chemotaxis protein p43/EMAPII as compared to the MGUS samples. This is the first proteomic study of WM and MGUS patients. It identifies novel proteins dysregulated in WM that may serve in future clinical trials as targets for therapy such as Hsp90, NFkB, HDAC and fatty acid synthase. In addition, it identifies 3 proteins that identify disease progression from MGUS to WM, which could be useful for monitoring MGUS patients and designing targeted therapies to prevent progression to WM.
Phase 2 Study of Oblimersen Sodium (G3139; Bcl-2 Antisense; Genasense®) Plus Gemtuzumab Ozogamcin (Mylotarg®) in Elderly Patients with Relapsed Acute Myeloid Leukemia (AML).
Authors: Moore Joseph O. , Seiter Karen , Kolitz Jonathan E. , Stock Wendy , Yu Richard , Frankel Stanley R. 
Published: October 2019

Abstract
Patients with relapsed AML over the age of 60 have a poor prognosis. Gemtuzumab ozogamicin (GO) has been approved for older pts in first relapse, although many pts who attain complete remission (CR) do not fully recover normal platelet count (so-called CRp). In vitro studies have shown that oblimersen down-regulates Bcl-2 in AML cells and enhances apoptotic cell death induced by GO. We conducted a Phase 2 study to evaluate the safety and efficacy of GO combined with oblimersen for older pts with AML. Eligibility requirements included: age ≥ 60 yrs; AML in 1st relapse; ≥ 3 mos 1st CR duration; ≥ 25% CD33-positive AML cells. Pts received oblimersen at a dose of 7 mg/kg/d for 7 days by CIV beginning on days 1 and 15; GO was given at a dose of 9 mg/m2 IV over 2 hrs on days 4 and 18. A total of 48 pts were enrolled (ITT population), all of whom received at least 1 dose of oblimersen; 9 pts failed to receive the required 2 doses of GO (per-protocol population, n=39). The median age was 67 (range, 59 to 88 yrs). Duration of 1st CR: < 6 mos: 7 pts; (15%); 6 to 12 mos: 29 pts (60%); > 12 mos: 12 pts (25%). No. of prior regimens: 1 (17 pts, 35%); 2 or 3 (26 pts, 54%); ≥ 4 (5 pts, 10%). Among treated pts, 79% completed 21 days of protocol therapy. Overall, 12 pts achieved a major response, either CR (n=5) or CRp (n=7), for an ITT response rate of 25% and a per-protocol response rate of 31%. The median time to remission was 52 days. Ten of the 12 responders survived > 6 mos, whereas only 6 non-responders survived ≥ 6 mos. Serious adverse events for the oblimersen/GO combination were qualitatively similar to those reported for GO alone and included among other reactions: Grade 3-4 febrile neutropenia (42%) or thrombocytopenia 33%; nausea; fever; rigors, and dyspnea. Treatment-emergent adverse reactions led to discontinuation of protocol therapy in 10 pts (21%). The most common serious adverse event was febrile neutropenia (25%). One pt (2.1%) died during treatment (sepsis) and 16 pts (33%) died within 30 days of last study medication (infection, bleeding, respiratory failure, progressive AML, and other disease-related complications). No episodes of VOD were observed. Oblimersen can be safely combined with GO; however, pts enrolled in this study appear to have had more unfavorable characteristics at entry compared with prior studies using GO alone in pts with relapsed AML. Therefore, assessment of an incremental benefit from the addition of oblimersen will require a randomized trial.
Midazolam: Significant Pain Reduction in Patients Undergoing Bone Marrow Puncture - a Clinical Trial.
Authors: Naumann Ralph , Schneider Ellen , Einsle Franziska , Kiani Alexander , Jenke Andreas , Lerche Linda , Klut In-Maria , Ehninger Gerhard , Joraschky Peter , Koellner Volker 
Published: October 2019

Abstract
Purpose: Bone marrow puncture with biopsy and aspiration is an everyday routine technique in haematology. The investigation induces substantial pain and fear in many patients. To our knowledge, prospective studies in adults have not yet been published. The aim of our prospective four-arm single-center interventional study was to compare the effect of relaxation (music with facultative instruction on how to relax) with that of an analgetic drug (piritramide), an anxiolytic drug (midazolam) and placebo to reduce pain and anxiety on a double-blind basis.
Methods: 138 patients (60.9% male, 39.1% female, median age 59.5 years, range 21 – 81 years; 26.5% with benign disease, 73.5% with malignant disease) were assigned randomly to one of the four interventional arms taking into consideration the contraindications for piritramide and midazolam before iliac crest puncture. The dose of piritramide administered was 0.05 mg/kg body weight i.v. and that of midazolam 0.035 mg/kg body weight i.v. Local anaesthesia with 1% lidocaine at the puncture site envisaged was administered in each patient. The pain tolerance, pain intensity and fear intensity were measured using visual analogy scales (VAS) from 0 to 10 immediately after puncture (early evaluation) and after two weeks (late evaluation).
Results: 134 patients (97%) could be evaluated. 23% of the patients received relaxation exercise, 26% piritramide, 27% midazolam and 24% placebo. Midazolam was able to increase the pain tolerance and reduce the intensity of pain induced by puncture to a significant extent compared to the other three arms, but there was no difference in the intensity of fear. No differences were found between the early and late evaluation. Subgroup analysis did not show any differences in respect of gender distribution, indication for bone marrow puncture, incidence of complications (e.g. several attempted punctures or wish for a special alleviative treatment).
Conclusions: Midazolam was shown to reduce significantly the pain induced by bone marrow puncture. All subgroups benefited equally from midazolam administration. In accordance with the results of our study, we recommend that midazolam after appropriate information should be offered to every patient before carrying out the bone marrow puncture provided that midazolam is not contraindicated and that there is adequate monitoring of the patients after puncture.
Post-Transplant Positron Emission Tomography Using Fluorine 18-Fluoro-Deoxyglucose ([18F]FDG-PET) Correlates with Outcome in Patients with Aggressive Non-Hodgkin’s Lymphoma Undergoing High Dose Chemotherapy Followed by Autologous Stem-Cell Transplantation (HDC/ASCT).
Authors: Kassim Adetola A. , Mineishi Shin , Greer John P. , McVay Natalie , Koyama Tatsuki , Chinratanalab Wichai , Brandt Stephen J. , Jagasia Madan , Ruffner Katherine , Schuening Friedrich G. , Stein Richard S. , Vusirikala Madhuri , Goodman Stacey , Morgan David S. 
Published: October 2019

Abstract
INTRODUCTION: Compared with standard chemotherapy, treatment of patients with relapsed aggressive lymphoma with high-dose chemotherapy and stem cell transplantation (HDC/ASCT) increases progression-free survival (PFS) and overall survival (OS). [18F]FDG-PET (PET) has been demonstrated to be more precise than conventional radiologic imaging techniques for restaging after chemotherapy [Kostakogu et. al. Euro J Nucl Med. 2000]. However, the value of PET, particularly posttransplant PET to predict clinical outcome after HDC/ASCT has yet to be established.
METHODS: We analyzed 44 patients who had histologically proven non-Hodgkin’s lymphoma (NHL), in first and subsequent relapse, sensitive to conventional-dose salvage chemotherapy, and had HDC/ASCT between April 1999 to June 2004 and PET as part of there disease evaluation, pre (6–8 weeks before) and/or post [early-30 days (D30) and late-100 days (D100)] HDC/ASCT. Thirty (68%) had DLBCL (diffuse large B-cell lymphoma), four (9%) FCCL (follicular center cell lymphoma), four (9%) T-cell lymphoma, three (7%) MCL (mantle cell lymphoma) and three (7%) TCR-BCL (T-cell-rich-B-cell-lymphoma). Log-rank analyses were done to compare PFS of PET positive and negative cases in (a) patients with DLBCL and (b) all histology combined.
RESULTS: Thirty patients (68%) had pretransplant PET and thirty-nine (89%) had posttransplant PET. Fourteen (32%) patients had positive pretransplant scans, while 21 (48%) had positive post-transplant PET-scans. Three patients died and one patient had progressive disease before day 30 and were excluded. Mean observation time of remission cases were 691 days (range 129-1916 days). Among DLBCL patients pre-transplant PET scan did not correlate with PFS (p= 0.1332, figure 1), while posttransplant PET correlated with PFS (D30-PET p=0.0019; D100-PET p=0.007, combined p <0.0001, figure 2). Amongst all histology’s, pretransplant PET-scan did not correlate with PFS, posttransplant PET-scans also showed a positive correlation with PFS (D30 p=0.0001; D100 p=0.0212 and combined p= 0.0001).

CONCLUSION: PET has an important prognostic role in evaluating response of patients following HDC/ASCT. In our analysis, posttransplant PET-scan showed positive correlation with PFS, and may be useful in detecting patients who need additional treatments as early as 30 days post-transplant. This finding however will need to be confirmed in a prospective study.
Aberrant Expression of BAFF System Molecules on B-Cell Precursor Leukemia Modulates Tumor Cell Survival: Novel Targets for Therapeutic Intervention.
Authors: Maia Sara , Rao Sambasiva P. , Sallan Stephen E. , Nadler Lee M. , Cardoso Angelo A. 
Published: October 2019

Abstract
Identification of pathways that support the survival and proliferation of acute lymphoblastic leukemia (ALL) cells will provide novel targets for therapeutic intervention. BAFF and APRIL, with their receptors, BAFF-R, BCMA and TACI are members of the TNF family that play a critical role in the survival of mature B cells but not of normal B cell precursors. We sought to determine whether BAFF/APRIL and their receptors might be aberrantly expressed on B-cell precursor ALL. Surprisingly, tumor cells from 28 of 29 ALL patients expressed mRNA for at least one of these receptors. Using flow cytometric analysis, surface expression of BAFF-R, BCMA, and TACI protein was detected on 89%, 78% and 56% of B-lineage ALL, respectively. Binding assays using a BAFF fusion protein demonstrated that ALL cells expressed high-affinity receptors for BAFF. Stimulation of leukemia cells with BAFF fusion protein triggered the activation of the NFκB pathway with phosphorylation of NFκB2 p100 (Ser864), and its processing to p52. However, BAFF binding did not trigger phosphorylation of IKKα, suggesting that BAFF-mediated activation of NFκB on leukemia cells occurs in an IKK-independent manner. These observations demonstrate that B-cell precursor ALL express functional receptors for BAFF/APRIL ligands. To examine the biological significance of the BAFF system in precursor B-cell ALL, we performed survival and proliferation assays using a myc-tagged BAFF. Our results indicate that while BAFF promoted survival of B-ALL cells, it did not induce their proliferation. Moreover, BAFF binding to leukemia cells was accompanied by increased expression of Bcl-2. To determine the source of BAFF in the leukemic BM, expression of membrane-bound BAFF and APRIL was analyzed in both leukemia cells and cells from the BM microenvironment (BM endothelium, BM mesenchymal stem cells and BM stroma). Surprisingly, leukemia cells expressed BAFF in all patients tested, and APRIL was detected in 94% of the cases. BM microenvironmental cells were found to express membrane-bound BAFF but not APRIL. These findings demonstrate that leukemia B-cell precursors express functional receptors for BAFF system ligands. Importantly, we show that BAFF-mediated stimulation of leukemia cells triggers the activation of the NFκB pathway through an IKK-independent mechanism, and promotes the survival of leukemia cells. The differential expression of BAFF and APRIL on B-ALL cells and the BM microenviromental cells suggests that these ligands may act through both autocrine and juxtacrine mechanisms. Our studies indicate that the BAFF/APRIL ligand-receptor axis might provide new opportunities for therapeutic intervention in B-cell ALL.
Human Herpesvirus 8 K1 Suppresses Fas-Mediated Apoptosis and Binds to the Fas Complex.
Authors: Samaniego Felipe , Wang Shu , Young Daniel , Younes Anas , Wang Suizhao 
Published: October 2019

Abstract
HHV-8 is associated with the development of primary effusion lymphoma (PEL) and Kaposi’s sarcoma. We have previously reported that PEL-derived cell lines constitutively express the HHV-8 K1 gene, which encodes for a transmembrane protein with an immunoreceptor tyrosine-based activation motif (ITAM). ITAMs are present in receptors regulating cell activation and survival. K1 in transgenic mice, driven by a constitutive promoter, is associated with development of lymph node hyperplasia and lymphoma. Given its NF-kB activation inducing properties, we hypothesized that K1 contributes to transformation, in part, by suppression of apoptosis. To study the role of HHV8 K1 gene product, we generated K1 stably expressing cell line BJABK1 and vector alone cell line BJABXS, with retrovirus vector pLXSN, and packaging cell line PT67 NIH 3T3. We also expressed a truncated K1 lacking the ITAM (K1m). Transient transfections were used to expressed epitope tagged K1. Anti-Fas antibody (CH-11) was used to induce apoptosis and cells were monitored for membrane protein Annexin-V, DNA integrity, and morphological features of apoptosis. Caspase 8, cFLIP and Fas were monitored by immunoblot analysis and flow cytometry. K1 was expressed in mouse hepatocytes by intravenous inoculation of plasmids, expressing K1 and green fluorescent protein. K1-Fas complex interactions were analyzed in immunoprecipitation-immunobloting analysis. K1 is expressed in PEL cells and PEL primary cells. Anti-Fas antibody induced apoptosis was suppressed in BJABK1 cells compared with BJABK1m and BJABXS cells. K1 also suppressed apoptosis, which had been induced by Fas ligand but not apoptosis induced by TRAIL or radiation. K1 expressing cells showed consistent lower levels of procaspase 8 cleavage products. Immunoprecipitation-immunoblotting analysis indicated Fas and K1myc were bound to the same complex. Taken together, the data indicate that expression of HHV8 K1 can suppress Fas-mediated apoptosis. K1 and Fas bind to the same complex in several cell types and in vivo. We anticipate K1 regulates apoptosis through binding of the Fas complex and represents a novel form of apoptosis regulation mediated by cellular proteins designated to modulated Fas.
A Multi-Center, Open-Label Study To Evaluate the Safety and Efficacy of Pentostatin, Cytoxan, and Rituxan (PCR) in the Treatment of Previously Untreated or Treated Bulky Stage II or Stage III or IV, Low-Grade B-Cell NHL.
Authors: Mena Raul R. , Christiansen Neal P. , Nyman David W. , Markan Yudhishtra , Chowhan Naveed M. 
Published: October 2019

Abstract
Introduction: The decision to treat indolent B-cell NHL is often based on progressing bulky disease, worsening symptoms, and increasing hematologic derangement. When treatment is indicated, these lymphoproliferative disorders are very sensitive to combination chemotherapies. Combination therapy with pentostatin (P), purine analog, cyclophosphamide (C), alkylator, and rituximab (R), anti-CD20 monoclonal antibody, represents a promising new approach in the treatment of patients with low grade NHL. Most regimens have utilized fludarabine as the purine analog, but the myelosuppression and immunosuppression of these combinations frequently results in severe infections. We have previously reported our experience with pentostatin and rituximab in a cohort of 133 previously treated and untreated patients with Grade III/IV NHL or CLL (2005 Pan-Pacific Lymphoma Conference).
Methods: Fifty-five patients have been enrolled in this study with an expected accrual of 100. Patients are being enrolled through the Pharmatech Research Network. Eligibility criteria allows previously treated and treatment naïve patients diagnosed with bulky stage II or low-grade stage III/IV NHL (REAL classification). Treatment consisted of intravenous infusions of P (4 mg/m2), C (600 mg/m2), and R (375 mg/m2) on day 1 of a 21-day cycle for a total of 8 cycles. Clinical evaluation was performed after even-numbered cycles. Patients were stratified by disease and by prior treatment status.
Results: Forty-seven patients have been eligible for evaluation. NHL patients (median age 64, range 30–84) received a total of 236 cycles (median 6). The ECOG status was 0 (65%) and 1 (33%). The overall objective response rate was 70% (CR 21%, Cru 13%, PR 36%). There were 3 grade 4 neutropenias documented and there was a single grade 4 leukopenia. There were a total of 3 deaths all of which occurred within 30 days of the last dose. The first death was due to a second primary, NSCLC, diagnosed after treatment began. The second death occurred in a 81 year-old female (PR) due to CHF and the last death, due to CAD, occurred in an 84 year-old woman (SD).
Conclusions: This immunochemotherapeutic regimen is very active in indolent Grade III/IV NHL and the incidence of significant toxities was extremely low. Future trials evaluating the use of R as maintenance therapy following this PCR regimen may also be warranted with an eye toward increasing the overall survival of patients with NHL. The use of combination therapy in elderly patients should be used with caution due to associated co-morbidities.
Recent Decrease in Acute GVHD and Increased Relapse in Children with Leukemia Receiving Unrelated Donor Bone Marrow Transplants.
Authors: Davies Stella M. , Wang D. , Wang T. , Arora M. , Ringden O. , Anasetti C. , Pavletic S. , Casper J. , MacMillan M.L. , Sanders J. , Wall D. , Kernan N.A. 
Published: October 2019

Abstract
Unrelated donor (URD) BMT is an effective treatment for leukemia in children, but significant morbidity and mortality occur as a result of acute graft versus host disease (GVHD). In addition, relapse is a major cause of treatment failure in children with otherwise successful transplants. We used the database of the Center for International Blood & Marrow Transplant Research (CIBMTR) to determine whether improved HLA typing and prophylaxis have changed incidence and risk factors for acute GVHD, and the impact of GVHD on treatment-related mortality and relapse. We analyzed outcomes of 638 myeloablative URD BMT performed between 1990 and 2003 for the treatment of AML, ALL, CML or MDS. Peripheral blood stem cell and cord blood recipients were excluded as risk factors for GVHD might differ. All recipients were <18 years of age, and had available high resolution HLA typing for HLA A, B, C and DRB1. Overall, 45% of children developed aGVHD grades II–IV, and 27% aGVHD grades III–IV. The data showed that risk of aGVHD was significantly higher in recipients of T-replete compared with T-depleted grafts (OR 3.12, 95%CI 2.02–4.83; p< 0.0001). Survival was reduced in children with grades II–IV aGVHD compared to those without (OR 1.96, 95% CI 1.46–2.62; p<0.0001). However, the occurrence of aGVHD reduced risk of relapse in children with ALL (OR 0.36 95% CI 0.17–0.75, p=0.004) but not in children with AML (OR 1.23, 95% CI 0.50–2.98; p=0.65). Outcomes have changed significantly over time. The risk of aGVHD was higher in children transplanted in earlier years (1990–1998, n=365) compared to 1999–2003 (n= 220) (OR 1.93 95%CI 1.27–2.91; p=0.002), suggesting that current prophylactic regimens may be more effective. In contrast to this recent improvement in risk of GVHD, risk of relapse was lower in children transplanted 1990–1998 compared with 1999–2003 (OR 0.47, 95% CI 0.28–0.78; p=0.004), possibly reflecting changes in the patient population currently referred for transplant, or perhaps a reduced graft versus leukemia effect with better control of GVHD. As more intense risk adapted chemotherapy has improved outcomes of upfront treatment of leukemia, children who are referred for transplant may have more resistant disease, increasing the difficulty of controlling disease with standard irradiation and chemotherapy preparative regimens. Overall survival of children with URD BMT has not changed over time, although it is possible that current results reflect treatment of children with more resistant disease compared with 10 years ago.