bluuebunny/crossref_metadata_2025_split huggingface dataset:
Erythropoietic Agents and Venous Thromboembolic Events in Multiple Myeloma Patients Treated with Anthracycline Based Chemotherapy and Immunomodulators.
Authors: Baz Rachid , Fruchtman Steven M. , Zeldis Jerome B. , Walker Esteban , Hussein Mohamad A. 
Published: April 2020

Abstract
Background: Erythropoietic agents (EPO) have recently been implicated with higher rates of thromboembolic events (VTE) in multiple myeloma (MM) patients receiving lenalidomide (R) and dexamethasone (Knight et al. NEJM 2006). Uncontrolled erythrocytosis, a recognized risk factor for VTE, may complicate therapy with EPO, but was not evaluated as a causative factor for VTE in the above report. We sought to evaluate the putative interactions between erythrocytosis, immunomodulator therapy, EPO and VTE.
Patients and Methods: We retrospectively reviewed patients’ records from 2 studies of anthracycline-based chemotherapy with immunomodulators: pegylated liposomal doxorubicin, vincristine, dexamethasone and thalidomide (T) (study A) or lenalidomide (study B) in MM. Demographic variables, aspirin therapy, EPO therapy, immunomodulator therapy (T vs R), as well as laboratory variables (which included all hemoglobin values while on study) were reviewed.
Results: From August 2001 to December 2005, 184 multiple myeloma patients with active disease were treated on study A (105) and B (79). The median age for patients was 63 and 62 years on study A and B respectively. Aspirin prophylaxis (81mg daily) was administered for all patients on study B and for all but 19 patients on study A. Among all patients, 113 patients (61%) received EPO. Twenty-six patients on study A and 7 patients on study B developed a VTE. Treatment with EPO was not associated with a higher rate of VTE compared to no treatment with EPO (19% versus 22%, Fisher exact test, p=0.8). The mean peak hemoglobin for patients with a VTE was not statistically different from patients without a VTE (14.2 vs. 13.8 g/dL, p=0.3). Similarly, the mean on study hemoglobin was not different among patients with a VTE and those without a VTE (11.7 vs. 11.6 g/dL, p=0.8). The mean hemoglobin at the time of the VTE was 12.0 g/dL (S.D. 1.5g/dL).
Conclusion: Our results do not indicate an association between EPO and VTE in MM patients receiving anthracycline-based chemotherapy with an immunomodulator and aspirin prophylaxis. Uncontrolled erythrocytosis does not appear to be associated with VTE in this patient population. Of note, target hemoglobins were not commonly exceeded. Low dose Aspirin (81mg) is an effective prophylaxis for VTE in multiple myeloma patients receiving anthracycline based therapy with thalidomide or lenalidomide in conjunction with the use of erythropoietin therapy.
Osteonecrosis of the Jaw (ONJ) in Patients with Multiple Myeloma, Receiving Bisphosphonate Therapy, Is Independent of Renal Function: Single Institute Experience of an Emerging Clinical Problem.
Authors: Manochakian Rami , Coignet Jean-Gabriel , Padmanabhan Swaminathan , Sullivan Maureen , Miller Kena C. , Chanan-Khan Asher Alban 
Published: April 2020

Abstract
Introduction: Use of bisphosphonate (zoledronic acid and pamidronate) for prevention of pathological fractures is standard of care in multiple myeloma (MM) patients with osteolytic bone lesions. While clinical trials have investigated effectiveness of these agents for up to 2 years of use, clinical practice has incorporated their use indefinitely. With improvement in survival through availability of novel agents in MM patients, the use of bisphosphonate therapy has also prolonged. Recent reports unveiled a new side effect of Bisphosphonate therapy i.e., ONJ, characterized by necrosis of the jawbone with antecedent subluxation or loss of the teeth and ulceration of the gum mucosa. The underlying etiology remains elusive, and in the absence of effective remedy ONJ has raised significant concerns upon the duration of treatment with Bisphosphonate. We investigated the magnitude of this problem among MM patients receiving Biphosphonate therapy at our institute.
Methods: We conducted a retrospective review of all patients diagnosed with MM at our institute since 2001 who received bisphosphonate treatment and developed ONJ. Clinical characteristics, prior treatments and renal function prior to development of ONJ were evaluated.
Results: Records of 20 pts who developed ONJ were reviewed.
The median age of these pts was 57 (range 45–69).
Among these, 9 were males, 11 were females. All pts (100%) had stage III MM.
11 patients (55%) received 2 or more antimyeloma treatment.
14 pts (70%) were on Zoledronic acid, 5 pts (25%) were on Pamidronate, and 1 pt (5%) was first on Zoledronic acid then switched to Pamidronate.
Out of those 20 patients, 19 (95%) had normal renal function prior to and after development of ONJ, with Creatinine level range of (0.5–1). Only 1 patient (5%) had decreased renal function prior to development of ONJ, with Creatinine level of 6.6
Conclusion: Although the number of patients reported are small, experience at our center with ONJ in MM patients who were on Bisphosphonate failed to show any association with renal function. Interestingly all patients who developed ONJ were stage III MM.
There are currently no established guidelines for prevention or treatment of this disorder.
Effect of Chemotherapy Treatment on Fetal-Maternal Microchimerism in Parous Cancer Patients.
Authors: Gilmore Gary L. , Holm Melissa M. , Anikanova Yuliya , Haq Bushra , Jasthy Sri Lakshmi , Lister John , Rossetti James M. , Shadduck Richard K. 
Published: April 2020

Abstract
Fetal-maternal microchimerism [MC] is a benign condition arising from cross-trafficking of circulating cells between the fetus and the mother during gestation. It is known that MC persists for decades post-partum. The reported incidence of MC is 33% in normal parous women, but the MC status of cancer patients has not been examined. We have completed our study of 200 parous cancer patients, using a sensitive two-round PCR technique with nested primer sets specific for the Y-chromosome specific sequence, DSY14, to detect male DNA in blood samples from female patients.
Exhaustive analysis of samples from parous cancer patients gave a frequency of 34% MC+ [68 of 200], which is significantly lower than the 57% MC+ [114 of 200] we found in normal parous women [p&lt;.0001]. We reported an apparent dichotomy based on diagnosis, in that patients with hematologic malignancies had a greater frequency of MC than solid tumor patients [46% vs 29%; p&lt;.0001]. Both groups received similar numbers of chemotherapy cycles [3.4 cycles for solid tumor patients; 3.2 for hem/onc patients], suggesting this difference was not due to less intensive treatment.
When we separated the untreated patients from each population, we found that only 25% [3 of 12] untreated patients with hematologic malignancies were MC, whereas 32% of untreated solid tumor patients were MC+ [12 of 38; p=.66, ns]. Therapy appeared to increase the frequency of MC in hematologic patients to 52% [25 of 48; p=.09, ns], but MC was essentially unaffected in solid tumor patients [27%, 28 of 104; p = .18, ns]. The difference between treated solid tumor patients and those with hematologic malignancies was significant [p=.0001]. Thus, one side effect of chemotherapy may be to increase MC in hematologic malignancy, but in solid tumor patients, MC is not affected.
The reason for the increased MC in treated hematologic patients in unclear, but we speculate the reduced frequency in untreated patients is due to dilution by the malignant clone, and that chemotherapy restores the normal balance of blood cells in these patients. The reason for reduced MC in solid tumor patients is also not obvious, as DNA yields are roughly equivalent between the two groups of cancer patients. Further analysis of the data is underway to see if an underlying cause can be determined.
The Balance in Chimerism between T Cells and Blood Dendritic Cells in Relapsed CML Patients Influences the Induction of Alloreactivity Following Donor Lymphocyte Infusion.
Authors: Levenga Henriette , Woestenenk Rob , Schattenberg Antonius V.M.B. , Maas Frans , Jansen Joop H. , Raymakers Reinier , De Mulder Pieter H.M. , Schaap Nicolaas , de Witte T.M. , Dolstra Harry 
Published: April 2020

Abstract
Donor lymphocyte infusions (DLI) after allogeneic stem cell transplantation induce complete remissions in 70 to 80% of patients with relapsed CML in chronic phase, but some patients do not respond sufficiently to DLI. We studied chimerism in subsets of immune cells in relation to the induction of alloreactivity. T cells and two subsets of DC (blood precursor myeloid dendritic cells [MDC] and blood precursor plasmacytoid dendritic cells [PDC]) were isolated from 15 relapsed CML-patients shortly before DLI for chimerism analysis. Furthermore, the absolute blood counts of DC-subsets were determined. Based on chimerism we identified three groups. Group 1 (4 patients) was complete donor chimeric in T cells and DC-subsets. These patients had an early stage of relapse and 3 of 4 patients attained a complete molecular remission (mCR) without significant GVHD. Group 2 (6 patients) was complete donor in T cells and mixed chimeric in DC-subsets. Median percentage of recipient MDC in 4 patients with mixed chimerism was 67% (range, 36%–72%). One patient was complete donor and one patient complete recipient chimeric in MDC. Median percentage of recipient PDC was 37% (range, 18%–58%) in 5 patients with mixed chimerism and in 1 patient PDC were complete recipient derived. All patients entered mCR, however in combination with GVHD in 4 and bone marrow hypoplasia in 3 patients. Group 3 (5 patients) had mixed chimerism in T cells and complete recipient chimerism in MDC in 4 of 5 patients. Only 2 patients entered mCR. Absolute DC numbers at the time of DLI did not predict the induction of an allo-immune response, however very low numbers of MDC and PDC were associated with progressive disease and a poor outcome. The combination of donor chimerism in T cells and mixed chimerism in DC-subsets in advanced relapse is associated with the most potent GVL effect following DLI. GVL and GVHD are separated in patients with an early relapse and donor chimerism in both T cells and DC-subsets. Finally, absolute DC numbers do not predict the strength of the alloresponse.
The Role of CD4+CD25+ T Cell and FOXP3 in Acute Graft Versus Host Disease.
Authors: Liu Yue-jun , Wu De Pei , Li Cai-xia , He Jun , Qiu Qiao-cheng 
Published: April 2020

Abstract
Objective To explore the relationship among CD4+CD25+ regulatory T cell, the expression of FOXP3 mRNA levels of donor bone marrow (BM) and graft versus host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT).
Methods
Thirty patients undergoing allo-HSCT were enrolled in this study. The levels of donor CD4+CD25+ regulatory T cell were compared in the patients with GVHD and those without GVHD by immnofluorescence and flowcytometry. The donor BM expressions of Foxp3 mRNA levels were analyzed by using reverse transcriptase polymerase chain reaction (RT-PCR).
Results
All patients achieved engraftment. ANC ≥0.5×109/L and PLT ≥ 20×109/L were at day 14(range, 12–15)and day 18 (range, 15–25) respectively. With a median follow-up of 12.8 (8–16) months, Acute GVHD occurred in 15 of 30 patients(50.0%) with gradeII–IV Acute GVHD (40.0%). Chronic GVHD developed in 6 (extensive 2, limited 4) out of 30 patients (20.0%). The levels of donor CD4+CD25+ regulatory T cell pre-and pro-mobilization were (2.67±0.38)% and (5.01±1.33)% respectively, no difference were observed (P&gt;0.05). Patients with I–II aGVHD demonstrated higher donor-type CD4+CD25+ immune regulatory T cell level than those with III–IV aGVHD; Patients with III–IV aGVHD showed much lower donor-type CD4+CD25+ immune regulatory T cell level than those without GVHD; no difference were observed between patients withI–II aGVHD and those without aGVHD. The transcripts of FOXP3 donor BM were detected in seven donors of thirty recipients who received allo-HSCT. Five patients had no GVHD after transplantation;two developedIaGVHD. Donor BM Foxp3 transcripts were never detected in patients with II–IV aGVHD.
Conclusion
Donor-type CD4+CD25+ immune regulatory T cell level was relative to recipient II–IV aGVHD. Up-grade donor-type CD4+CD25+ immune regulatory T cell level could reduce the incidence of aGVHD. Donor BM FOXP3 transcripts were detected in patients without serious aGVHD after transplantation.
Enhanced Human Hematopoietic Cell Engraftment and T Lymphocyte Development in NOD/Scid/Jak-3 Null Mice.
Authors: Okada Seiji , Harada Hideki , Suzu Shinya 
Published: April 2020

Abstract
Xenotransplantation of human cells into immunodeficient mice has been used to develop models of human hematopoiesis and immune function. In this study, we generated the NOD/Scid mice with null mutation of Jak-3 (NOD/Scid/Jak-3 null) by 10 backcross mating of C57/BL6-Jak-3 null mice and NOD/Scid mice. NOD/Scid/Jak-3 null mice had NK and NKT cells as well as mature T and B lymphocytes. NK activity was not also detected in this mice.
Intrahepatic injection of CD34+ human cord blood cells into irradiated (2.0Gy) newborn NOD/Scid/Jak-3 null mice led to de novo development of B and T lymphocytes. In addition to the high engraftment rate of human hematopoietic cells, multilineage cell differentiation including T cell lineage was obserbed. T lymphocyte appeared in peripheral blood as early as 8 weeks after transplantation and it was increased in number thereafter. Both naive and memory phenotype CD4 and CD8 T lymphocytes were detected 12 weeks after transplantation. Plasma cells were detected in the bone marrow 20 weeks after transplantation.
Furthermore the engrafted mice were infected with HIV. Our model mice provide a valuable model to study not only development and function of human hematopoeitic and immune system but also the immune response to the cancer and infectious disease such as HIV.
Rapid Generation of Cytomegalovirus Specific T Lymphocytes Using Commercially Available CMV pp65 Peptides.
Authors: Lucas Kenneth G. , Sun Qi , Niyazova-Brewer Nargisa , Bao Lei 
Published: April 2020

Abstract
Adoptive immunotherapy with cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) can result in resolution of viremia and reconstiution of CMV specific immunity following allogeneic stem cell transplantation. Most recipients of allogeneic transplants who develop CMV reactivation are successfully treated with anti-viral agents, however some have persistent viremia or develop CMV disease despite these medications. In these situations the development of CMV specific T cells may be impractical due to time contraints or institutional limitations. We have expanded CMV pp65 specific CTL from 5/6 normal blood donors of diverse HLA backgrounds in 10–15 days using adherent cells (monocytes) as antigen presenting cells, pulsed with a commercially available source of CMV pp65 peptides, which includes 138 CMV pp65 15mers. These pulsed monocytes are incubated at a 1:5 ratio with non-adherent peripheral blood lymphocytes, resulting in a population of CD4 and CD8+ CMV pp65 specific T cells after 2 weekly stimulations. While &gt;80% of these cells were CD3+, 29–78% were CD4+, and 15–55% were CD8+. These CTL have specific cytotoxicity against CMV pp65, and intracellular cytokine analysis showed specific interferon-gamma production in response to CMV pp65 target cells. Table I depicts the phenotype as well as interferon-gamma production and specific cytotoxicity in response to stimulation with B lymphoblastoid cell lines (BLCL) expressing pp65. There was no reactivity to allogeneic targets by cytokine analysis or in chromium release assays. CTL sufficient for a dose of 30–50 × 106 CTL were routinely generated from 40–50 cc of whole blood. Considering the short time frame and relative ease with which these CTL can be expanded, this methodology could be readily adopted in clinical situations of persistent or therapy refractory CMV infections in allogeneic stem cell transplant patients as an adjuvant to anti-viral therapy.
Characteristics of CMVpp65 CTL Interferon production Cytotoxicity Donor CD4 CD8 BLCL-pp65 BLCL Allo BLCL 1 1% 23% 57% 1% 1% 2 2% 3% 75% 22% 6% 3 6% 1% 31% 7% 7% 4 9% 29% 47% 0% 0% 5 7% 15% 69% 1% 5% 6 24% 3% 10% 1% 6%
Transfection of Bone Marrow Cells In Vitro or In Vivo Prior to Cryopreservation with Manganese Superoxide Dismutase (MnSOD-PL) Protects Frozen Cells from Ionizing Irradiation.
Authors: Epperly Michael W. , Epperly Laura D. , Franicola Darcy , Zhang Xicheng , Smith Tracey , Greenberger Joel S. 
Published: April 2020

Abstract
Overexpression of MnSOD in IL-3 dependent murine hematopoietic progenitor cell line 32D cl 3 protects against apoptosis induced by ionizing irradiation, TNF-α, IL-3 withdrawal or other inducers of cytotoxic stress. Cryopreservaton of bone marrow is routinely used in clinical marrow transplantation with the necessary cytotoxic loss of a fraction of cells from the stress of thawing. To determine if overexpression of MnSOD protected marrow from the stress of thawing and also whether frozen cells resisted ionizing irradiation, 32D cl 3 and subclone 2C6 stably transfected and overexpressing MnSOD were tested. Exponentially growing cells 2C6 cells demonstrate increased irradiation survival with an increased shoulder on the survival curve n = 4.95 ± 0.1 compared to 32D cl 3 n = 2.77 ± 0.1 (p = 0.011), with no significant change in the Do = 2.11 ± 0.08 vs. Do = 2.36 ± 0.10 Gy. Cells from 32D cl 3 and 2C6 were frozen in liquid nitrogen in 50% DMSO and stored at a −140°C for a minimum of 24 hrs and irradiated to doses ranging from 0 to 800 cGy while frozen. The cells were thawed 24 hr later, plated in methylcellulose and colonies of greater than 50 cells counted seven days later. The data was analyzed using linear quadratic and single-hit, multi-target models. Cells from 2C6 were more resistant to thawing with survival of 24.3 ± 0.6% compared to 20.9 ± 0.8% for 32D cl 3 (p = 0.018) and to irradiation as shown by an increase in the Do of 2.036 ± 0.225 compared to 1.455 ± 0.149 Gy for frozen 32D cl 3 cells (p= 0.0287). The frozen 2C6 cells resisted the stress of thawing with an increased plating efficiency compared to the frozen 32D cl 3 cells (121.4 ± 3.2 colonies for 2C6 cells and 104.3 ± 3.9 colonies for 32D cl 3 per 500 cells plated, p=0.0018). To determine whether fresh bone marrow transfected in vivo, or in vitro, then frozen and irradiated, also was protected, C57BL/6NHsd mice were injected with MnSOD-PL (100 ug plasmid DNA in 100 μl). Twenty-four hours later, bone marrow was isolated from MnSOD-PL injected mice as well as control mice (a subpopulation transfected with MnSOD-PL in vitro) and frozen in aliquots of 1 × 106 cells. The cells were irradiated while frozen to doses ranging from 0 to 800 cGy, plated in methylcellulose and colonies of greater than 50 cells counted 7 days later. The colonies were divided between nonadherent and adherent in the methylcellulose. The Do was calculated for the adherent colonies, nonadherent colonies and total colonies. In all three cases the Do for the bone marrow treated with MnSOD-PL in vitro or in vivo was higher than the Do of the control bone marrow. The percent HA-epitope tagged total transfected cells was 22.1 ± 3.7%. The data indicates that MnSOD overexpression protects frozen bone marrow perhaps important to increasing preservation efficiency.
Amplification of Graft vs Malignancy (GVM) Effects by Using Intentionally Mismatched Donor Lymphocytes While Avoiding Graft-vs-Host Disease in Conjunction with Haploidentically Mismatched Stem Cell Allografts in Patients with Hematological Malignances.
Authors: Slavin Shimon , Shapira Michael Y. , Resnick Igor B. , Bitan Menachem , Aker Memet , Samuel Simcha , Morecki Shoshana , Or Reuven 
Published: April 2020

Abstract
Alloreactive donor lymphocytes can induce potent graft vs malignancy (GVM) effects in conjunction with allogenenic stem cell transplantation or when given as donor lymphocyte infusion (DLI) following allogeneic stem cell transplantation. Unfortunately GVM effects are frequently accompanied by graft vs host disease (GVHD) and in many cases, despite severe GVHD, no adequate control of tumor progression can be achieved. In order to improve GVM effects while avoiding GVHD, we have attempted to use natural killer (NK) cells activated with rIL-2 isolated from the blood of haploidentically mismatched donors following engraftment of T-cell depleted donor stem cells. A pilot trial was conducted in patients with hematological malignancies 3 MDS; 2 AML; 1 ALL; 1 biphenotypic leukemia; 5 lymphoma (2 Burkitt’s; 1 anaplastic (ALK) & 1 Hodgkin’s), all resistant to chemotherapy, 4 failing autologous and 1 allogeneic transplant. Eleven received haploidentically mismatched graft. Prevention of rejection was accomplished by activation-induced clonal deletion following infusion of donor buffy coat 24 hours before administration of cytoxan 120–180mg/kg to eliminate host anti-donor T lymphocytes or by using total body irradiation 750cGy following conditioning that was fludarabine based. Positively selected CD34+ cells or CD3 depleted stem cells mobilized with G-CSF were infused on day 0. Based on our murine data, mismatched rIL-2 activated NK cells cause no GVHD. Consequently, 22 procedures were done involving administration of purified NK cells 1–15 months post transplantation. Donor mononuclear cells were activated 4 days at 37°C in 5% CO2 in air with rIL-2 (6,000 IU/ml) and administered on day 4. NK cells were positively selected with anti-CD56, or by negative selection of anti-CD3 using Miltenyi’s immunomagnetic beads. Using this procedure engraftment of mismatched allografts can be accomplished with no or minimal GVHD. Of 11 treated recipients, 5 entered CR. The first patient failing 2 prior transplants from a matched sibling is alive and well 4 years out. Out of 10 patients, 3 died from unrelated causes with no evidence of disease, but no GVHD developed. In conclusion, following engraftment of haploidentically mismatched related stem cell, donor-derived rIL-2 activated NK cells positively selected with anti-CD56 or negatively selected anti-CD3 immunomagnetic beads can be used to induce GVM effects while avoiding GVHD.