bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expanded Access Program (EAP) for Lenalidomide (Revlimid®) Plus Dexamethasone in over 1400 Subjects with Relapsed or Refractory Multiple Myeloma.
Authors: Chen Christine , Reece Donna E. , Siegel David , Niesvizky Ruben , Boccia Ralph Vincent , Stadtmauer Edward A. , Abonour Rafat , Irwin David , Polikoff Jonathan , Kumar Shaji , Gams Richard A. , Kenvin Laurie , McElveen Dale , Hu Angela , Pietronigro Dennis , Knight Robert D. , Zeldis Jerome B. 
Published: October 2019

Abstract
Background: Lenalidomide (Revlimid®) in combination with dexamethasone was approved in the US on June 29, 2006 for the treatment of subjects with multiple myeloma who had received at least one prior therapy. On February 28, 2005 based upon a positive interim analysis of two pivotal placebo-controlled Phase III studies, an independent Data Safety Monitoring Board recommended the studies be unblinded and all subjects in both studies be given access to lenalidomide. In April 2005, the FDA in association with myeloma patient advocacy groups requested Celgene establish an expanded access program to make lenalidomide plus dexamethasone available to subjects with relapsed or refractory multiple myeloma while the treatment was awaiting approval.
Aim: To provide lenalidomide to multiple myeloma subjects with a high likelihood of benefit and to obtain additional safety data.
Methods: Subjects with relapsed or refractory multiple myeloma that received at least 1 prior therapy were eligible. Subjects received 25 mg lenalidomide plus high-dose dexamethasone in 4-week cycles until disease progression was documented, study drug was discontinued, or lenalidomide became commercially available for this indication.
Results: Between September 8, 2005 and July 25, 2006, approximately 1400 subjects in the US and Canada were enrolled into the study. A data snapshot taken March 17, 2006 demonstrated that 746 subjects had been enrolled, median age was 63 years, 60% were male, and 66.5% had Stage III disease. Median time on study was 7.1 weeks (0.1–24.4) and median daily dose was 20.5 mg. At least one Grade 3 or 4 adverse event was reported in 261 (35%) of the 746 subjects. Most commonly reported Grade 3–4 events were neutropenia (7.9% of subjects), thrombocytopenia (6.0%), fatigue (3.6%), anemia (3.5%), pneumonia (3.1%) and hyperglycemia (2.0%). These most commonly reported Grade 3–4 adverse events were the same as those found in the previous pivotal studies, however, their frequencies of occurrence were lower in the current study probably due to ongoing data collection and differences in study maturity. Likewise, the most commonly reported adverse events (all grades) were the same as those reported in the two previous pivotal studies.
Conclusion: Preliminary data from this expanded access program in over 1400 subjects with multiple myeloma are consistent with results from two earlier Phase III pivotal studies. The EAP of lenalidomide plus dexamethasone in multiple myeloma represents a model of how government, advocacy groups, healthcare providers and industry can work together to quickly provide treatment to subjects in need while a clearly active treatment regimen is awaiting approval.
A Randomized Comparison of Dexamethasone + Thalidomide (Dex/Thal) vs Dex + Placebo (Dex/P) in Patients (pts) with Relapsing Multiple Myeloma (MM).
Authors: Fermand Jean-Paul , Jaccard Arnaud , Macro Margaret , Uzunhan Yurdagul , Allard Christian , Castaigne Sylvie , Divine Marine , Mariette Xavier , Leblond Veronique , Chevret Sylvie 
Published: October 2019

Abstract
We randomly compared a Dex/Thal and a Dex/placebo combination as treatment of MM pts in first or second relapse after high dose therapy (HDT) or conventional chemotherapy (CCT). 116 pts, aged 41 to 81 (med. 63 yrs), were enrolled between July 2001 and December 2004. Dex was given orally during 4 days at a dose of 40 mg/day every other week for 4 cycles and then monthly. Thal or placebo were given blindly at the initial dose of 100 mg, escalated up to 400 mg daily according to tolerance, and maintained for a maximum of 12 mths. In both arms, treatment initially included continuous infusions of Doxorubicin (9 mg/m2/d for 4 days 4–5 wk apart). In July 2002, because of a high incidence of thrombotic event (TE), the study was interrupted during a six-mth period, before restarting without Doxorubicin administration. Anticoagulation prophylaxis wasn’t systematically given at any time.
Main characteristics of pts included in both arms were similar, including age above 65 yrs (43% in the Dex/Thal arm, 44 % in the Dex/P arm), previous therapy (HDT 57% vs 56%), MM isotype (IgA: 26% vs 21%), serum β2m (≥3 mg/L, 48% vs 55%), serum creatinine (≤ 300 μmol/L in all pts) and albumin levels. Data were analyzed in an intent to treat basis, regarding EFS as the primary objective.
A partial response (defined by a 50% or more reduction of MM protein in serum) was achieved in 46% of all pts, in 65% of pts treated by Dex/Thal and in 28% of pts treated by Dex/P (p<.0001). At one year post randomization, 46.5% of pts in the Dex/Thal arm were alive and free of progression, compared to 31% in the Dex/P arm (p=.009). Death rates were 7% (n=4) and 5% (n=3), respectively.
Median dose of actually tolerated Thal was 150 mg daily. At least one ≥ grade II WHO adverse event was reported in 90% of pts who received Thal, as compared with 42% of pts who received the placebo (p<.0001). A TE was recorded in 12 (22%) of pts in the Dex/Thal arm, as compared to 4 (7%) of pts in the Dex/P arm (p= .02). Other frequent side effects were somnolence/mood changes (58% vs 21%), constipation/nausea (43% vs 11%), skin/mucosal dryness (26% vs 9%) and tremor (19% vs 4%). A symptomatic peripheral neuropathy was observed in 28% and 7% of pts, respectively. Besides the 25 pts who completed the trial (16 and 9 in both arms, respectively), toxicity was the main cause of treatment discontinuation in 21 (55%) pts of the Dex/Thal arm and in 3 (6%) pts of the Dex/P arm.
This randomized study demonstrates that the adjunction of Thal to Dex, although it increases toxicity, is a valuable therapeutic option for pts with relapsing MM since it produces higher response rate and longer remission duration than Dex alone.
Generation of CD8+ Viral Specific T Cells from EBV and CMV Naive Individuals.
Authors: Bao Lei , Niyazova-Brewer Nargisa , Dunham Kimberly , Kenneth Kenneth , Sun Qi 
Published: October 2019

Abstract
Adoptive T cell immunotherapy (ATCI) with viral specific T cells, as exemplified by ATCI against Epstein-Bar virus (EBV) and Cytomegalovirus (CMV) with viral specific T cells generated from virus-experienced individuals, is efficacious against viral reactivation in immuno-compromised hosts. EBV-seronegative solid organ transplant recipients and CMV-seropositive stem cell transplant patients receiving CMV-seronegative grafts are at high risk of EBV-driven lymphoproliferation and CMV reactivation, respectively. However, due to the absence of virus-specific memory T cells, ex vivo techniques for generating virus-specific CD8+ CTL from virus-naive individuals remain to be developed for reproducibility and efficiency. To extend ATCI to the above patients, we are developing novel ex vivo systems to expand virus specific CD8+ CTL from seronegative individuals. We designed a two step stimulation for the naive T cells to develop into specific T cells. The first step, “de-naiviation”, involves non-specific but high-affinity stimulation of CD45RO/CD25/CD56/CD14 depleted peripheral blood mononuclear cells with anti-CD3 and -CD28 antibodies. The “de-naiviated” T cells were then antigen-specifically stimulated by antigen presenting cells expressing both EBV and CMV antigens. Peripheral blood mononuclear cells from an EBV/CMV seronegative individual were depleted for two rounds with micro-beads conjugated with antibodies against CD45RO, CD25, CD14 and CD56. The resultant cells were a homogenous population of cells mostly CD45RO−/CD45RA+/CD3+/CD25−, the phenotype for naïve T cells. After a period of expansion stimulated by a cocktail containing anti-CD3 (OKT3) and -CD28, 90% of the RO-T cells became RO+/RA−, the phenotype of memory T cells. Nearly all the CD4+ cells and most the CD8 cells became CD25+, suggesting recent activation. Then the “de-naiviated” T cells were stimulated with autologous EBV immortalized B lymphoblastoid cells transduced and expressing the CMV pp65 (CMVpp65) antigen. After three rounds of stimulation, the T cells were screened for specific production of interferon-gamma (IFNg) by ELISA. Clones were isolated from the primed T cells, and FACS analysis showed that the T cell clones produced IFNg in response to EBV BLCL expressing CMVpp65. These T cells also antigen-specificly expressed IL2 and GMCSF. Interestingly, while the cells were predominantly CD8+/CD3+, some of the cells were also positive for CD56, suggesting newly differentiated effector T cells. Work is ongoing to further characterize the T cell clones for antigen specificity, functionality and differentiation status. The novel approach we are developing has the potential to generate EBV and CMV specific CD8+ CTL from virus naive individuals for adoptive T cell immunotherapy against viral infections.
Sensitive In Vivo Detection of Primary T Cells Expressing Membrane-Anchored Gaussia Luciferase for the Study of Adoptive T Cell Immunotherapy in Murine Models of Malignancy.
Authors: Brentjens Renier J. , Santos Elmer , Yeh Raymond , La Perle Krista , Toledo-Crow Ricardo , Nikhamin Yan , Punzalan Blesida , Entenberg David , Aranda Iana , Punzalan Bleserene , Larson Steven , Sadelain Michel 
Published: October 2019

Abstract
Current approaches to in vivo bioluminescent imaging (BLI) of T cells utilizing luciferase enzymes may be compromised by poor transduction efficiencies in primary T cells, and low photon emissions. Here we describe a novel and widely applicable approach to in vivo BLI of primary T cells utilizing a membrane-anchored form of the naturally secreted Guassia luciferase (GLuc) enzyme, termed exGLuc. We constructed exGLuc by fusion of the GLuc gene to the coding region of the CD8 transmembrane domain. The resulting exGLuc enzyme is anchored to the cell surface of retrovirally transduced cells. In vitro, cells which expressed the exGLuc enzyme demonstrated a markedly (>9 fold) increased bioluminescent signal when compared to cells which expressed the native GLuc (GLuc), the related Rhenilla luciferase (RLuc), a membrane-anchored form of RLuc (exRLuc), or a green fluorescent protein (GFP)-fire fly luciferase fusion protein. Following injection into SCID-Beige mice, MHC-mismatched C57BL6 T cells transduced to express exGLuc were detected by BLI generating graft versus host disease at an earlier time point and demonstrated a >10 fold increased bioluminescent signal when compared to infused C57BL6 T cells expressing GLuc, RLuc, or exRLuc. We further demonstrate homing of OVA-specific DO11.10 exGLuc+ T cells to A20(OVA) but not A20(GFP) subcutaneous tumors in both SCID-Beige and Balb/c mice. We further successfully applied this strategy to the study of in vivo human T cell homing using a xenogeneic SCID-Beige tumor model. Specifically, we demonstrate that human T cells, retrovirally co-transduced to express both a CD19-specific chimeric antigen receptor (CAR), 19z1, and exGLuc, could be monitored over time, and that these T cells quite rapidly home to subcutaneous CD19+ acute lymphoblastic leukemia (NALM-6) tumors when compared to T cells co-expressing an irrelevant CAR with exGLuc. Furthermore, we were able to demonstrate for the first time specific homing of 19z1/exGLuc+ human T cells to systemic NALM-6 tumor, detecting exGLuc+ T cells in deep tissues including the bone marrow, spleen, and liver. We conclude that the exGLuc enzyme emits a superior bioluminescent signal when compared to other commonly utilized luciferase enzymes; that primary T cells are readily transduced to express the exGLuc enzyme; and that exGLuc+ T cells may be accurately monitored in vivo over time by BLI. Based on these data, we believe that this novel approach to primary T cell in vivo imaging will significantly enhance the study of adoptive T cell immunotherapy in murine models of leukemia and other malignancies.
Redirecting Human T Lymphocytes toward Tumor-Associated Antigens by T Cell Receptor (TCR) Replacement.
Authors: Neudorfer Julia , Sommermeyer Daniel , Peschel Christian , Blankenstein Thomas , Uckert Wolfgang , Bernhard Helga 
Published: October 2019

Abstract
The gene transfer of alpha and beta chains derived from a defined TCR has been successfully applied to endow T cells with specificities directed against tumor-associated antigens. However, it is still unclear if the transfer of TCR genes into T cells that already express an endogenous TCRalpha and beta chain leads to engineered T cells expressing four different TCR complexes on their cell surface. Mixed TCR heterodimers composed of endogenous and exogenous TCR chains may acquire new specificities, which may cause unwanted reactions in patients following adoptive T cell transfer. We examined the possibility of mixed TCR heterodimer formation using defined conditions of single TCR chain transfer into human cytotoxic T cell (CTL) clones specific for CMV and Melan-A, respectively. After stimulation for three days CTLs were retrovirally transduced with the beta chain derived from a gp100-specific TCR. The expression of the exogenous (transduced) and the endogenous beta chain was distinguished by flow cytometry using antibodies against the different Vbeta motives. Indeed, CTLs that had been transduced with the single beta chain expressed this chain on the cell surface indicating the formation of mixed TCRs, because the expression of the exogenous TCRbeta chain requires the pairing with the endogenous TCRalpha chain. Furthermore, we transduced the CTL clones with both the TCRalpha and beta chain derived from a gp100-specific TCR. The transduced T cells were positively stained with an A2/gp100 multimer documenting the correct formation of the exogenous TCR chains. Functionality of transduced CTL clones was tested by antigen-specific IFN-gamma release and cytolytic activity. The TCR-transduced T cells were sorted with the A2/gp100 multimer and expanded for two weeks. Double staining with HLA multimers for the endogenous and the transduced TCRs showed the downregulation of the endogenous TCRs in three different CTL clones. In one CTL clone, the endogenous TCR was even replaced by the exogenous TCR as documented by flowcytometry and antigen-specific T cell function. In conclusion, transfer of single TCR chains in CTL clones can result in the formation of TCR heterodimers. However, our results also show that complete TCRs are predominantly expressed or can even replace other TCRs following transfer. The development of dominant TCRs will facilitate the therapeutical approaches of adoptive transfer regimens based on TCR-transduced T cells, because dominant TCRs can be selected or TCRs can be modified to be more dominant.
Alloreactivity as a Source of High Avidity T Cell Clones Specific for Cancer Testis-Antigens Associated with Multiple Myeloma: Prospects for Adoptive Immunotherapy with Primary T Cells Redirected toward Multiple Myeloma by T Cell Receptor Gene Transfer.
Authors: Kronig Holger , Hofer Kathrin , Neudorfer Julia , Peschel Christian , Bernhard Helga 
Published: October 2019

Abstract
Cancer testis (CT)-antigens belong to a class of tumor antigens that are aberrantly expressed in a variety of hematological malignancies including multiple myeloma. Owing to their restricted gene expression, CT-antigens represent potential target antigens for immunotherapeutical approaches such as vaccination and adoptive T cell transfer. As the CT-antigens are self antigens, the majority of CT-antigen-specific autologous T cells display a low avidity T cell receptor (TCR), which often results in a weak tumor recognition efficiency.
Our group has been focusing on the isolation of highly avid T cells against CT-antigens that are expressed in multiple myeloma, in particular MAGE-C1, MAGE-C2, and NY-ESO-1. The experimental approach was based on the stimulation of allo-restricted cytotoxic T cells, because highly avid T cells recognizing peptide epitopes in context with foreign HLA-alleles are not depleted in the thymus. HLA-A2-negative T cells were stimulated with HLA-A2-positive allogeneic dendritic cells that had been exogenously loaded with HLA-A2-binding peptides derived from NY-ESO-1, MAGE-C1 or MAGE-C2. Using this technique we were able to isolate allo-HLA-A2-restricted cytotoxic T lymphocyte (CTL) clones with peptide-dominant binding against known and novel peptide epitopes derived from NY-ESO-1, MAGE-C1 and MAGE-C2. The expanded peptide-specific CTL clones lysed HLA-A2-positive myeloma cell lines expressing NY-ESO-1, MAGE-C1 and MAGE-C2, respectively. Of note, the MAGE-C1-specific T cells crossreacted with the corresponding MAGE-C2 peptide due to the existing sequence homology between MAGE-C1 and MAGE-C2. Current experiments focus on redirecting primary T cells toward myeloma cells by retroviral gene transfer of CT-antigen-specific TCRs.
The establishment of a set of high avidity TCRs specific for CT-antigens facilitates the development of adoptive transfer regimens based on TCR-transduced T cells for the treatment of multiple myeloma.
Iron Does Not Cause Arrhythmias in the Guinea Pig Model of Transfusional Iron Overload.
Authors: Kaiser Lana , Davis John , Patterson Jon , Olivier N. Bari , Bohart George , Schwartz Kenneth 
Published: October 2019

Abstract
Cardiac events, including heart failure and arrhythmias, are the major cause of death in patients with b-thalassemia. Although cardiac arrhythmias in humans are believed to result from iron overload, excluding confounding factors in the human population is difficult. The purpose of these studies was to evaluate the development of cardiac arrhythmias using the guinea pig model of secondary iron overload. Electrocardiograms were recorded via surgically implanted telemetry devices in guinea pigs loaded intraperitoneally with iron dextran and controls. Cardiac and liver iron concentrations were significantly elevated in the iron loaded animals when compared to control, and were in the range of those reported for humans with thalassemia. Arrhythmias were noted infrequently in both iron loaded and control guinea pigs. No life threatening arrhythmias were detected in either group. These data suggest that iron alone may be insufficient to cause cardiac arrhythmias, and that arrhythmias detected in individuals with iron overload may be the result of a complex interplay of factors.
A Novel Parameter for the Diagnosis of Iron Deficiency: The Transferrin/Albumin Ratio.
Authors: Pieroni Laurence , Jardel Claude , Merle-Beral Helene , Azgui Zahia , Baudet Sylvie , Tostivint Isabelle , Hainque Bernard , Maloum Karim 
Published: October 2019

Abstract
Iron deficiency (ID) is generally easily diagnosed by a serum ferritin concentration less than 12 μg/L. However, in patients with concomitant pathologies, sensitivity of ferritin for diagnosing ID is low, since inflammation or liver disease can lead to normal or increased ferritin values, even when iron deficiency. In this study, we propose a new marker for diagnosing ID in patients with chronic disease: the Transferrin/Albumin ratio (Tf/A ratio). Indeed, the synthesis and the elimination of albumin and transferrin are regulated by similar processes, excepted in ID. In the latter, the synthesis of transferrin is stimulated, whereas that of albumin is not. Therefore, the Tranferrin/Albumin ratio increases in case of ID, even when transferrin values are within the normal range. To determine the accuracy of this novel parameter, we studied 75 patients with chronic disease who were submitted to bone marrow aspirates and iron staining. Iron stores depletion was defined by less than 10% sideroblasts, without extra-cellular iron nor siderocytes. Blood samples were routinely undertaken at the time of the medullar sampling for determination of hematological and biochemical parameters. Iron status including ferritin, Tranferrin Saturation (TfSat), soluble Transferrin Receptor (sTfR), sTfR/log ferritin and Tf/A ratio, was determined. The diagnostic accuracy of the Tf/A ratio was compared to previously described parameters of iron status that we cited above. Receiver Operating Characteristics (ROC) curves were built to determine the best cut-off values for the prediction of iron deficiency. According to the Perls’ reaction, 25 of the 75 patients (33%) had depleted iron stores and 50 had normal or increased iron stores. Sixteen iron-depleted patients (67%) had anemia. Mann and Whitney U test showed that parameters significantly associated with ID were: Tf, Tf/A ratio, ferritin, TfSat, sTfR, sTfR/log ferritin, mean corpuscular volume, mean corpuscular hemoglobin, red blood cell and reticulocyte counts. In a multivariate analysis, the only significant, independent predictor of iron depletion was the Tf/A ratio (r = 0.637, p < 0.005). The sensitivity/specificity of Tf/A ratio at a cut-off point of 6.4% as given by ROC curve were 80%/88%. In conclusion, the Tf/A ratio is useful in the detection of iron depletion in patients with chronic disease and could dispense with bone marrow aspirate and Perls’ reaction in more than 80% of cases.
Liver Status in a Cohort of Polytransfused B-Thalassemia Major (BTM) on Long Term Desferrioxamine (DfO) or Deferiprone (L1).
Authors: Elalfy Mohsen Saleh , Abdin Iman 
Published: October 2019

Abstract
The liver is the main body site for iron storage. Iron chelators as DFo and L1 had problems of compliance and intolerance respectively. This prospective study enrolled 76 BTM patients aged from 9–33 years, mean of 14±4.4 to evaluate the effectiveness of both chelators judged by serum ferritin (sf) and liver iron content (LIC) using repeated liver biopsies. Fifty patients were on DFo 35 mg/kg/day 5 days per week and twenty-six were on L1 75 mg/kg/day on daily bases. Mean baseline sf values were 3678±1922 and 3573±1879 ng/ml while mean baseline LIC was 19.2±7.9 and 18.9±8.1 mg fe/g dw, while 12% and 14% showed evidence of liver fibrosis (score ≥ 3) respectively. Twenty-four months later; a decline in sf by 287±837 in Dfo (In Dfo compliant group [number = 30]who had received ≥ 75% of planned dose; sf dropped by 890±437 while increased in DFo non compliant by 621±513). While falling by 729±633 in L1 group. A decrease in LIC by 3.9±2.8 mg fe/g dw (−5.8±3.1 in Dfo compliant,+2.6±3.3 in Dfo non compliant) and falling by 2.2±3.4 mg fe/g dw in L1 group, the difference was statistically significant P< 0.05 between compliant and non compliant DFo and insignificant difference between Dfo and L1.The mean iron excretion: intake was 1.61,0.86 and 1.48 in Dfo compliant, non compliant and L1 respectively. A positive correlation was found between sf and LIC in both groups. Fibrosis was improved in Dfo compliant group better than L1 but no statistically significant difference was observed, while progressive fibrosis in 10% of Dfo non compliant group. All Dfo compliant group completed study, 18 out of 20 Dfo non compliant while six L1 patients discontinued the drug prematurely (3 severe gastrointestinal disturbances, 2 severe arthralgia and one repeated neutropenia). Conclusion: Both Dfo and L1 are effective iron chelators evident by drop in sf, LIC and improved fibrosis, however compliance and intolerance are still troublesome.