bluuebunny/crossref_metadata_2025_split huggingface dataset:
PTEN Gene Deletions in Patients with Multiple Myeloma.
Authors: Qi Xiao Ying , Stewart A. Keith , Chang Hong 
Published: April 2020

Abstract
PTEN, a tumor suppressor gene, negatively regulates the anti-apoptotic action of akt phosphorylation. Allelic loss or mutation of this gene has been detected in many solid tumors and more recently in human myeloma cell lines (HMCLs). Expression of PTEN has resulted in growth inhibition and apoptosis of a HMCL, suggesting that it may play a role in the pathogenesis of multiple myeloma (MM). However, the PTEN status in tumor cells from patients with MM has not been determined. Using a triple staining method combining staining for cytoplasmic light chains and fluorescence in situ hybridization (FISH) with chromosome 10-centromere and PTEN-gene specific probes, we analyzed clonal plasma cells from 71 patients with MM, 10 with plasma cell leukemia (PCL) and 10 HMCLs. Hemizygous PTEN deletions were detected in 4 of 71 (5.6%) MM patients, 2 of 10 (20%) PCLs, and 2 of 10 (20%) HMCLs. The percentages of clonal plasma cells containing PTEN deletions ranged from 21–90% (median, 56%). Three of the 4 patients with PTEN deletions were detected at diagnosis with stage III disease (Duire-Salmon) and 1 was detected at relapse. Two patients had IgG kappa, 1 IgG lambda and 1 free lambda light chain. To correlate the PTEN status with other known genetic abnormalities in MM, we investigated 4 MM and 2 PCLs with PTEN deletions using FISH for chromosome13q, p53 status, translocations t(11;14), t(4;14) and t(14;16). One MM had a 13q deletion, 1 PCL had a t(11;14), and the other PCL had a t(14;16), a 13q deletion and a p53 deletion. All 4 MM patients with hemizygous PTEN deletions received melphalan based high-dose chemotherapy and autologous stem cell support. Their median overall survival (OS) was 48.1months, and progression free survival (PFS) was 42.8 months as compared to patients without PTEN deletions (OS, not reached, PFS, 25.8 months) (p=0.51 for OS, p=0.67 for PFS). Our results indicate that PTEN deletions are uncommon in MM patients and therefore unlikely represent a primary event for MM. PTEN deletions appear to occur in the advance stage of the disease, and are more frequently involved in PCL or HMCLs suggesting that deletions of PTEN may be associated with disease progression in a subset of MM.
t(11;14) Is Infrequent in Long-Term Myeloma Survivors.
Authors: Chang Hong , Samiee Sara , Qi Xiao Ying , Yi Qi Long , Stewart A. Keith 
Published: April 2020

Abstract
The translocation t(11;14) involving immunoglobulin heavy chain gene switch region and cyclin D1 is the most common IgH translocation (15–20%) in multiple myeloma (MM). MM patients with t(11;14) are considered to have a better prognosis when treated with either conventional chemotherapy or autologous stem cell transplant. In contrast, patients with chromosome 13q deletions (40–50% of patients) have a poor prognosis. To address whether long-term survivors of MM more frequently harbor a t(11;14) but not 13q deletions, we used cytoplasmic Ig-enhanced interphase fluorescence in situ hybridization (cIg-FISH) to evaluate clonal plasma cells for t(11;14) and 13q status from 20 long-term survivor MM cases. These patients met the diagnostic criteria for MM before May of 1996 and have survived more than 8 years. The 11 male and 9 female had a median age of 52 (range 39–62) at diagnosis. Eleven had IgG, 6 IgA, 2 free light chains, and 1 non-secretory. Of the 20 patients, 17 received autologous stem cell transplants. The median duration between diagnosis and transplant was 24 months (range 5–149), the median progression free survival (PFS) after transplant was 32 months (range, 1–62). One patient died 3 years after transplant and 10 years after diagnosis. The 19 other patients remain alive. Translocation t(11;14) was detected in only one of 20 patients with 94% of clonal plasma cells involved. This patient had PFS of 20 months after transplant and is alive 3 years post-transplant and 10.5 years after diagnosis. Chromosome 13q deletions were detected in only 3 cases (15%). Despite its association with a better prognosis, our results indicate that t(14;14) is infrequent in long-term myeloma survivors. As anticipated, 13q deletions were infrequent.
No Influence of Previous Thalidomide Administration on Peripheral Blood Stem Cell Collection in Patients with Multiple Myeloma.
Authors: Breitkreutz Iris , Benner Axel , Cremer Friedrich W. , Herrmann Doris , Ho Anthony D. , Goldschmidt Hartmut 
Published: April 2020

Abstract
OBJECTIVES: In a joint study of the GMMG and HOVON groups, induction therapy with Thalidomide (Thal), doxorubicin and dexamethasone (TAD) is currently investigated in comparison with vincristin, doxorubicin and dexamethasone (VAD) followed by mobilisation therapy with cyclophosphamide, doxorubicin and dexamethasone (CAD) and peripheral blood stem cell collection (PBSC). Munshi et al. (Blood 1999, Abstract #2577) described a dampening of PBSC-mobilisation by Thal treatment. We therefore investigated a possible influence of PBSC after previous Thal administration.
METHODS: Altogether, data on 112 patients were analyzed in terms of PBSC-mobilisation. 56 patients were randomized up-front to receive 3 cycles of TAD (Thal 400mg/d orally; doxorubicin 9mg/m2/d, 4 30-min. infusions, day 1–4; dexamethasone 480mg total dose orally). 56 patients received VAD (vincristin 0,4mg/d and doxorubicin 9mg/m2/d, 4 30-min. infusions, day 1–4.; dexamethasone 480mg total dose orally) followed by mobilisation with CAD (cyclophosphamide 1g/m2/d, 1h infusion, day 1; doxorubicin 15mg/m2/d, 4 short infusions, day 1–4; dexamethasone 160mg total dose orally) and G-CSF (Neupogen 600mg/d s.c. or Granocyte 526mg/d s.c., day 5 after the end of chemotherapy until PBSC). Thal was stopped two weeks before CAD. Low dose heparine was administered to prevent deep venous thromboses in the TAD group.
RESULTS: The median time was 14 days after the first day of CAD until PBSC in patients in both the TAD (range 12–18 days) and VAD group (range 10–19 days). In the first leukapheresis, a median total PBSC yield of 8,1x106/kg CD34+ cells in the TAD/CAD (range 0,3–34x106 CD34+ cells) and 8,7x106/kg CD34+ cells in the VAD/CAD (range 0,5–30x106 CD34+ cells) group could be harvested (p=0.31). In the best leukapheresis, a median total PBSC yield of 8,1x106/kg CD34+ cells in the TAD/CAD (range 0,7–34x106 CD34+ cells) and 8,9x106/kg CD34+ cells in the VAD/CAD (range 2–30x106 CD34+ cells) group could be reached (p=0.24).
CONCLUSIONS: No difference was found in stem cell collection and yield after TAD versus VAD. Thalidomide as a part of induction therapy does not seem to have an influence of the peripheral blood stem cell collection of patients with multiple myeloma.
Symptomatic Multiple Myeloma in Young Adults ≤ 40 Years of Age.
Authors: Symeonidis Argiris , Pouli Anastasia , Repoussis Panagiotis , Zervas Konstantinos , Anagnostopoulos Athanasios , Mitsouli Chrysanthi , Gika Dimitra , Maniatis Alice , Dimopoulos Meletios Athanasios 
Published: April 2020

Abstract
Introduction: Multilple myeloma (MM) rarely occurs in patients ≤ 40 years of age. Thus, information regarding disease features and outcome is limited. We performed a retrospective analysis of the database of GMSG which includes 1162 patients with symptomatic MM who were diagnosed since 1987.
Patients and methods: Multiple clinical and laboratory variables were evaluated in patients ≤ 40 years of age and in older patients including the recently proposed International Staging System (ISS) for MM. Furthermore, the same variables were assessed for possible correlation with prognosis in patients ≤ 40 years of age. Patients with asymptomatic MM were not included.
Results: Forty seven (4%) patients were ≤ 40 year old when treatment was initiated. Clinical and laboratory parameters were similar among the two groups of patients with the exception of ISS which was lower in younger patients (p=0.03). Despite a similar response to primary treatment the median survival of younger patients was significantly longer than that of older patients (65 months versus 37 months; p=0.001). Among younger patients, hypercalcemia, thrombocytopenia, bone marrow plasmacytosis and elevated serum LDH were associated with impaired survival on univariate analysis. ISS was not statistically significant (p=0.1) but the median survival of patients with ISS 1,2 and 3 was 154 months, 60 months and 33 months respectively. A Cox regression analysis showed that only elevated serum LDH was significant and was associated with a median survival of 9 months.
Conclusions: Young patients with symptomatic myeloma have similar disease features with older patients but present with a lower ISS. Patients ≤ 40 years of age live twice as long when compared to older patients with symptomatic MM. Elevated serum LDH identified a subgroup of patients (23%) who had an extremely poor outcome. 40% of young patients presented with ISS 1 and survived for more than a decade. This information may be of value when designing therapeutic strategies for young patients with myeloma especially when allogeneic stem cell transplantation is considered.
Campath-1H in Waldenström’s Macroglobulinemia.
Authors: Hunter Zachary R. , Branagan Andrew R. , Treon Steven P. 
Published: April 2020

Abstract
Campath-1H is a humanized monoclonal antibody that targets CD52, a commonly expressed antigen in WM (Treon et al, Semin Oncology 30:248). We therefore initiated this two-stage Phase II study of single agent Campath-1H in patients with WM. WM patients who failed at least one first line regimen (i.e. an alkylator agent, nucleoside analogue or rituximab) were eligible and received Campath-1H by IV for one week on a gradual dose escalation schedule (Day 1, 3 mg; Day 3, 10 mg; Day 5, 30 mg) followed by up to 12 weeks of therapy (30 mg IV TIW) provided therapy was tolerated and patients did not progress. All patients received acyclovir and bactrim prophylaxis while on therapy and for 2 months thereafter. Seven subjects with a median age of 59 (range 43–68) years and 2 (range 1–4) prior therapies have been enrolled, 4 and 7 of whom were relapsed/refractory to nucleoside analogues and rituximab, respectively. Five patients completed the intended therapy. Responses to date are as follows: Partial Response (n=3); Minor Response (n=3); SD (n=1). With a median follow-up of 7 months, no responding patient has progressed. Hematological but not infectious toxicities occurred with reversible grade IV neutropenia (n=3) and thombocytopenia (n=2), and prolonged pancytopenia (n=1) in a patient with systemic amyloidosis. These studies demonstrate that Campath-1H is active in patients with relapsed/refractory WM, with sufficient activity to continue enrollment in this two-stage study.
A Conditional Fibroblast Growth Factor Receptor-1 Derivative Stimulates Extensive Self Renewal of Genetically Modified Primary Hematopoietic Cells.
Authors: Lintmaer Ingrid , Weinreich Michael A. , Blau C. Anthony 
Published: April 2020

Abstract
Fibroblast growth factor receptor-1 (FGFR-1) signaling has been implicated in self renewal and proliferation of hematopoietic stem cells. We have studied the effect of a conditional FGFR-1 in genetically modified primary mouse bone marrow cells. The activity of the conditional FGFR-1 is dependent on the presence of a drug called a chemical inducer of dimerization (CID). For these studies we used a bicistronic vector encoding green fluorescence protein (GFP) as a marker and a fusion protein made up of the intracellular portion of FGFR-1 and the CID binding domain. To test the construct in vitro we plated transduced mouse bone marrow cells in 10% serum with or without the CID, AP20187 (100 nM). While the cells without CID died within two weeks, in the culture with CID the transduced, GFP marked cells proliferated. These hematopoietic cells have proliferated in vitro for over 30 weeks. This makes FGFr-1 only the second CID dependent receptor, other than mpl, that is able to support long-term self renewal of primary hematopoietic cells. By day 28 of culture cells had expanded from 106 to 1.2x1012 cells. The differentiation potential of these cells was tested by transplanting 8 million cells into each of 5 lethally irradiated (1050 cGy) congenic recipients. Four mice are alive 76 days post transplantation, with mean frequencies of GFP positive red cells, platelets, granulocytes, monocytes, B cells and T cells of 55%, 5%, 85%, 98%, 42% and 2%, respectively. These findings indicate that cells expanded under the influence of FGFR-1 signaling retain both lymphoid and myeloid repopulating ability. Additionally, CID-mediated activation of FGFR-1 induced a dramatic rise in genetically modfied red cells, granulocytes and monocytes in vivo. These findings point to a clear difference between CID induced activation of FGFR-1 compared to our previous studies using the thrombopoietin receptor, where effects on neutrophils and monocytes are modest and variable. The CID controlled activation of FGFR-1 may have utility for control of genetically modified hematopoietic cells.
Thalidomide +/− Corticosteroids for the Treatment of Multiple Myeloma Patients ≥ 70 Years of Age.
Authors: Reece Donna E. , Chen Christine , Trudel Suzanne , Mikhael Joseph R. , Chang Hong , Stewart A. Keith 
Published: April 2020

Abstract
Between September 2000 and July 2004, 33 multiple myeloma (MM) patients (pts) ≥ 70 years of age were treated with thalidomide (THAL) alone (4 pts) or THAL plus corticosteroids (CS) (29 pts). Two were treated at diagnosis while 31 received THAL +/− CS after a median of 2 (range 1–5) prior regimens. Prophylactic anticoagulation was not routinely given. In most pts, the THAL dose was slowly increased as tolerated to a maximum of 200 mg/day. Initial CS therapy was pulse dexamethasone (DEX) in 14 and prednisone 50–100 mg every 2 days in 15 pts; in 4, the DEX dose was reduced or changed to prednisone when responses were noted and/or CS toxicity was encountered. Median age was 73 (range 70–88) yrs; median beta2-microglobulin level was 403 (range 153–2120) nmol/L and CRP level 4 (range 1–91) mg/L at referral. MM subtype was IgG kappa:lambda (8:12 pts), IgA kappa:lambda (6:4 pts), light chain kappa:lambda (1:1 pts) and IgD kappa (1pt). Initial stage was IIIA:B in 20:5, IIA:B in 3:1 and IA in 4 pts. Cytogenetic studies were available in 11, of whom 1 had t(4;14), 2 complex changes, 1 monosomy 7 and 1 other abnormalities. Eighteen pts had significant cardiac disease, 3 vascular disease and 4 diabetes at the time therapy was initiated. Four had other hematological malignancies noted before/shortly after THAL +/− CS was started, including MDS in 2, essential thrombocytosis in 1 and AML in 1. The median maximum dose of THAL was 150 (range 50–400) mg and the median duration of therapy was 7 (1.5–19+) mos. To date, 14 (42%) pts have achieved PR and 5 (15%) MR; four (12%) experienced stable disease. The median duration of response was 7 (range 1.5–23+) mos. Fatigue/sleepiness (5), syncope (2), peripheral neuropathy (4) and other reasons (4) necessitated THAL dose reductions in 15 pts; 7 pts stopped THAL due to toxicity. Two TIAs and 1 DVT were observed; 2 of these pts received appropriate medical therapy and continued THAL without further vascular complications. No treatment-related deaths occurred. Eleven of 33 (33%) remain on THAL +/−CS. The actuarial overall survival rate was 80% at 1 year and 55% at 2 yrs after starting THAL +/− CS therapy, while the progression-free survival rate was 42% and 20% at 1 and 2 yrs, respectively. We conclude: 1) THAL +/−CS can be given safely in elderly MM pts, although dose reductions are usually needed; 2) MM response/stabilization was achieved in 69%; 3) THAL +/− CS therapy offers a median benefit of 7 mos in poor prognosis elderly MM pts.
Effect of Rituximab on the Incidence of GVHD in Lymphoma Patients who Received the BEAM-Conditioning and an Allogeneic Stem Cell Transplantation.
Authors: Khouri Issa F. , Saliba Rima M. , Couriel Daniel R. , Okoroji Grace-Julia , Acholonu Sandra , Maadani Farzaneh , Champlin Richard E. 
Published: April 2020

Abstract
It has been postulated that B cells functioning as antigen-presenting cells may have an important role in the pathogenesis of GVHD. Depletion of donor cells from B-cells resulted in a low incidence of GVHD in mouse model (Schultz et al. BMT1995:16:289–289). More recently, we observed a lower incidence of chronic (and to a lesser extent acute GVHD) in patients with CLL who received an allogeneic stem cell transplantation after a non-myeloablative conditioning regimen containing rituximab (Exp Hematol32:28–35, 2004). The purpose of this study is to investigate the effect of rituximab on GVHD in the setting of a more intense chemotherapy with BEAM, in patients who received an allogeneic peripheral blood stem cell from HLA-identical siblings.
To test this hypothesis, we retrospectively studied 11 consecutive patients with non-Hodgkin’s lymphoma who received BEAM/Rituximab at the M. D. Anderson Cancer Center. We attempted to match these patients by age, donor-recipient gender, and donor-recipient CMV reactivity to a historical control of 44 patients with lymphoma, who received BEAM alone as a conditioning regimen, without the Rituximab. Tacrolimus and methotrexate were used for GVHD prophylaxis in both groups. A total of 10 patients in the study group, could be matched with 19 patients in the control group and were included in the final analysis. The outcome of the 2 groups is shown below:
Rituximab-Study Group Control Group -value P No. of patients 10 19 Median age 41 44 0.4     (range) (19–55) (19–60) Patient-Donor sex-matched 9(82%) 18(95%) 0.6 Median # CD34 + cells infused (106/kg) 5.1 4.73 0.1 Patient or Donor CMV+ 9(82%) 18(95%) 0.6 Patient and Donor CMV − 1(10%) 1(5%) Median # prior chemoregimens 3 3 0.9     range (1–8) (1–9) Median follow-up 17 38     range (8–48) (27–77) Acute GVHD 2–4 (n,%) 5(50%) 7(37%) 0.5 Acute GVHD 3–4 (n,%) 3(30%) 5(26%) 0.6 Chronic GVHD (n, % cumulative incidence) 8 (90% + 15) 10 (53% + 12 0.01
Our data suggest that the described protective effect of Rituximab against GVHD in mouse models or in the setting of non-myeloablative allogeneic transplantation, may be overcome by the BEAM. This more intense conditioning regimen may induce more GVHD by enhancing T-cell cytokines release and by causing more gastrointestinal toxicity, thus allowing for a greater antigen presentation.
G-CSF Activated Granulocytes Inhibit Experimental Graft-versus-Host Disease.
Authors: Vasconcelos Zilton F.M. , Farache Julia , Grad Bruna M. Santos , Grad Tereza S. Palmeira , Bouzas Luis Fernando , Bonomo Adriana C. 
Published: April 2020

Abstract
Acute Graft versus host diseas (aGVHD) is a major complication of stem cell transplantation. The disease is mediated by T cells and a higher incidence/severity would be expected when higher numbers of T cells are inoculated. However, the incidence of aGVHD in PBST, which carries about 10 times more T cells then BMT, is not higher than the one found in later. This finding indicates a modulatory role for G-CSF over T cell activity. We had previously shown that T cells from G-CSF treated PBSC donors do not produce g-IFN nor IL-4 and that this inhibition was mediated by low density, G-CSF activated, granulocytes. In order to test if in fact G-CSF activated granulocytes could inhibit disease, we first checked if G-CSF could generate low density granulocytes, in vivo and in vitro. Indeed, either in vivo(21mg /day - 5 days) or in vitro (150 ng -12hs) with G-CSF generates low density granulocytes which co-purify with the mononuclear cells in the ficoll® gradient. Moreover, as we had shown in humans, these low density cells, inhibit the production of g-IFN by anti-CD3 activated T cells on flow cytometry studies (17%-T cells alone versus 3% T cells with granulocytes 1:1).
Radiation quimaeras were set with (B6 X BALB/c)F1 as hosts reconstituted with T cell depleted C57Bl6 bone marrow, in the presence or absence of nylon wool selected spleen cells (NWSC), as T cell source, from normal or G-CSF treated mice. As previously shown by others, NWSC from G-CSF treated mice diminishes the incidence of acute disease on day 20 post-transplant, from 75 to 25%. In order to investigate if this inhibition was dependent on the activated granulocytes present in the NWSC from G-CSF treated mice, granulocytes were depleted with anti-GR1 and complement. In this case, the incidence of disease is the same or even higher (75% experiment#1 and 100% in experiment #2) than the one observed on the control group (NWSC from control mice). These results strongly suggest that activated granulocytes could indeed inhibit aGVHD.
We then generated activated granulocytes in vitro, by treating spleen derived high density granulocytes with 150ng of G-CSF for 12 hs. After the incubation period, a new ficoll® gradient was performed and the low density cells were obtained. T cell contamination on the second gradient was eliminated by anti-CD4 and CD8 complement lysis. These activated granulocytes were inoculated together with NWSC from control mice in the radiation quimaeras at a 1:1 ratio. In this case 100% disease inhibition was observed when compared to the positive control group, where 75% of the animals got sick. Our data indicate that activated granulocytes are the major mediators of the G-CSF immunossupressive effects and that these cells can be used as a novel immune modulator in clinical transplantation to prevent acute GVHD.
Lymphocyte Function and Molecular Mechanisms of Enhanced Immune Reconstitution Following Sex Steroid Ablation and Hemopoietic Stem Cell Transplantation (HSCT).
Authors: Goldberg Gabrielle L. , Alpdogan Önder , Muriglan Stephanie J. , Hammett Maree , Milton Morag K. , Eng Jeffrey M. , Hubbard Vanessa M. , Kochman Adam , Willis Lucy M. , Greenberg Andrew S. , Tjoe Kartono H. , Sutherland Jayne S. , Chidgey Ann , Boyd Richard L. , van den Brink Marcel R.M. 
Published: April 2020

Abstract
Age-related thymic atrophy plays a significant role in delayed immune reconstitution in older recipients after hemopoietic stem cell transplantations (HSCT). Sex steroid ablation has been shown to reverse thymic atrophy and previously we have shown that in syngeneic and allogeneic models of HSCT, sex steroid ablation enhances immune reconstitution. Donor-derived HSC numbers, as well as precursor T and B cells are increased in castrated mice following HSCT. These primary changes lead to an increase in both T and B cells in the periphery. The current study examined both the molecular mechanisms behind this enhanced reconstitution and the function of the lymphocytes produced. Bone marrow (BM) and thymic stromal cell (TSCs) populations were analysed using RT-PCR and were tested for the production of growth factors previously implicated in immune reconstitution. Functional studies including proliferation and cytotoxicity assays and intracellular cytokine production showed that on a per cell basis, there was no difference between the T cells from castrated and sham-castrated mice, following allogeneic HSCT. In vivo immune function was assessed using a delayed type hypersensitivity assay. Six weeks after HSCT the DTH response was enhanced in the castrated mice compared to sham-castrated controls. The combination of a) the increased number of donor-derived lymphocytes and b) intact T cell function, result in an overall increase in immune response (as determined by DTH) in castrated recipients of allogeneic HSCT. This enhanced function may be related to changes seen in growth factor production in the thymus and bone marrow.