bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pattern of Relapse in Localized Gastric Lymphoma Registered within the Prospective German Multicenter Study GIT NHL 01/92.
Authors: Liersch Ruediger , Berdel Wolfgang E. , Willich Normann A. , Reinartz Gabriele , Tiemann Markus , Koch Peter 
Published: October 2019

Abstract
Introduction: In 2001 (Koch et al.,JCO) we published the treatment results of 185 patients (pts) with localized primary gastric lymphoma (PGL) registered within the GIT NHL 01/92 German multicenter study. After a median time of observation of 130 months we present clinical and pathological features of relapsed patients.
Methods: We compared treatment results in PGL after combined surgery and conservative (S/CM) versus conservative management (CM). Radiotherapy (Rx) and chemotherapy were stratified according to histological grading, stage, and the inclusion or omission of surgery as follows: PGL pts with indolent lymphomas in stage I received an extended field (EF) Rx with total abdominal irradiation and in stage II additionally a T-field preceded by 6 cycles of COP. The dose was 30 Gy for EF followed by a boost of 10 Gy on sites of tumor. All pts with aggressive PGL were treated with four (stage I) or six (stage II) cycles of CHOP-14 followed by EF Rx (stage I) or involved field Rx (stage II), dosage of Rx corresponded to Rx for indolent NHL.
Results: Between the years 1992 and 1996, a total of 185 pts were registered. Recurrence of NHL occurred in 17 cases during follow-up. Analysis revealed no specific features of relapsed pts with respect to initial symptoms, clinical features (except stage II2 - more than regional lymph nodes involved) and initial treatment. DLBCL was the most common histological subtype seen in relapsed pts (58.8%). Indolent lymphoma relapsed in 41.2% pts. Interestingly 70% of the DLBCL initially had an additional small-cell component, and 56% relapsed as marginal zone B-cell lymphoma, particularly at primary site independent of the initial treatment.
Conclusion: In this non-randomized study there was no disadvantage for a stomach preserving approach in the context of tumor recurrence. Patients with distant nodal involvement (Stage II2) and DLBCL relapsed more often than pts. with localized stages (Stage I/II1) and indolent lymphomas. Interestingly, aggressive lymphomas, with an initial small-cell component, predominantly relapsed as marginal zone B-cell lymphomas at primary site, while indolent lymphomas relapsed also generalized.
Immunosuppression (IST) Can Be Safely Ceased during Chemotherapy for PTLD in Renal Transplant Patients.
Authors: Mollee Peter , Hourigan Matthew , Johnson David , Jones Mark , Isbel Nikki , Hawley Carmel , Marlton Paula , Gandhi Maher , Campbell Scott , Gill Devinder 
Published: October 2019

Abstract
Aim. The optimal management of IST in renal transplant patients with PTLD is uncertain. As chemotherapy regimens used for PTLD are in themselves immunosuppressive, IST may not be required during this phase of treatment. Subsequent long-term reduction in IST is important to prevent relapse. We examined whether a protocol (instituted in 1994) of ceasing IST during chemotherapy for PTLD and recommencing IST at reduced doses after chemotherapy (calcineurin inhibitor at 50%, prednisolone <6mg daily and no third agent) was associated with deleterious effects on renal graft function.
Methods. We performed a retrospective audit of adult renal transplant patients with PTLD requiring chemotherapy who were managed according to this protocol. Outcomes were compared (matched 1 case to 2 controls) to renal transplant patients without PTLD matched for age, gender, diabetes, graft type (cadaveric or live donor) and year of transplant. Matching was performed blinded to outcome.
Results. 20 cases were identified: median age at PTLD diagnosis 39yrs; 85% male; 17 late onset PTLD; median time to onset of PTLD post-transplant 110 months (range, 5–276). 18 patients received prior triple combination IST (cyclosporine/tacrolimus plus azathioprine/mycophenolate mofetil plus prednisone). All patients received anthracycline-based chemotherapy with additional therapies of rituximab in 6 and radiation therapy in 4. 85% attained complete remission. 4 patients have relapsed. The 5yr OS was 75% with a median follow-up of 67 months from PTLD diagnosis. 6 cases (30%) had died (5 due to PTLD, 1 unknown) compared to 1 control (2.5%). Of the surviving 14 cases, 2 patients had failed renal allografts at 14 and 19yrs post-transplant and recommenced haemodialysis compared to 18 controls; neither case was retransplanted compared to 8 controls. 2 cases had >25% increment in serum creatinine but not requiring dialysis (assumed secondary to chronic allograft nephropathy) compared to 4 controls. 10 cases had normal functional allografts with no significant decrement in renal function. The cumulative rate of renal allograft failure requiring change of treatment to dialysis at 22yrs post-transplant was 34% vs 63% for cases and controls, respectively (p<0.05).
Figure Figure
Conclusions. IST can be safely ceased during chemotherapy for PTLD in renal transplant patients and recommenced at reduced doses after chemotherapy, without deleterious effects on renal graft function.
GS-9219 - A Novel Prodrug of the Acyclic Nucleotide PMEG Demonstrates Significant Therapeutic Activity Against Spontaneous Non-Hodgkin’s Lymphoma as Modeled in Pet Dogs.
Authors: Vail David M. , Thamm Douglas H. , Tumas Daniel B. , Reiser Hans , Ray Adrian S. , Wolfgang Grushenka H.I. , Babusis Darius , Kurzman Ilene D. , Jeraj Robert , Plaza Susan , Anderson Christie , Wessel Mackenzie A. , Robat Cecilia , Lawrence Jessica 
Published: October 2019

Abstract
Non-Hodgkin’s lymphoma (NHL) is the fifth leading cause of cancer deaths and the second fastest growing form of cancer in the United States. While clinical remission can be induced using currently available antineoplastic agents, drug resistant relapse is common. Canine NHL has proven to be a relevant model for preclinical testing of novel therapeutics prior to human trials. GS-9219, a novel double prodrug of the anti-proliferative nucleotide analog 9-(2-phosphonylmethoxyethyl) guanine (PMEG), has been shown to have potent cytotoxic activity in lymphoblasts and leukemia cell lines and was designed to load and functionally target malignant lymphoid cell populations upon intravenous administration. To generate proof-of-concept, activity and safety data in lymphoid malignancies, a dose-finding and activity trial with GS-9219 monotherapy was initiated in pet dogs (N = 38) with naturally occurring chemotherapy naïve or refractory NHL. Dose cohorts of 3 to 6 dogs were treated using several schedules including daily treatments for 5 consecutive days out of every 21 days, once weekly, once biweekly and once every 3 weeks. Adverse events, when observed, were manageable and reversible, dose- and regimen-dependent and included predominantly Grade 1 to 2 transient neutropenia, gastrointestinal signs, lethargy, dermatopathy and proteinuria. Major antitumor responses were noted in 79% of dogs treated with GS-9219 monotherapy (61% complete and 18% partial responses) as measured by tumor size (RECIST criteria). Responses were similar across the different treatment regimens evaluated. Importantly, responses were noted in both previously untreated dogs (N=16) and dogs with chemotherapy-refractory NHL (N=22), implying a role both in induction therapy and in the rescue of drug resistant disease. B and T cell phenotypes were both found to respond to GS-9219 therapy; however, first remission durations were significantly longer in dogs with B cell NHL. The overall median first remission duration of 4.5 months observed compares favorably to other monotherapies reported in dogs with NHL. Furthermore, in dogs retreated with GS-9219 after recrudescence of their NHL, 78% achieved a second remission. A subset of nine dogs were further evaluated with 18F-fluorothymidine (FLT) PET/CT imaging prior to and after their first treatment with GS-9219; 8 of 9 displayed initially high FLT uptake (mean standardized uptake values [SUV] of 81.55) prior to treatment which decreased significantly after GS-9219 monotherapy (SUV of 13.39; p < 0.05). Given these very promising results in this relevant preclinical model, a Phase I study of GS-9219 in humans with NHL has been initiated.
Marked Therapeutic Efficacy of a Novel Polyethyleneglycol-SN38 Conjugate, EZN-2208, in Xenograft Models of Non-Hodgkin’s Lymphoma.
Authors: Sapra Puja , Mehlig Mary , Malaby Jennifer , Kraft Patricia , Longley Clifford , Zhao Hong , Greenberger Lee M. , Horak Ivan D. 
Published: October 2019

Abstract
Background: The clinical utility of SN38 (10-hydroxy-7-ethyl-camptothecin), the active moiety of CPT-11 (Camptosar®), has been severely compromised due to its poor solubility. EZN-2208 is a novel, water-soluble, polyethyleneglycol (PEG)-SN38 conjugate generated by linking SN38 with a multi-arm high molecular weight PEG, 40k 4-arm-PEG, via a glycine linker. Here, we compare the efficacy of EZN-2208 and CPT-11 in the treatment of animals bearing non-Hodgkin’s lymphomas.
Methods: The in vitro cytotoxicity of EZN-2208 and CPT-11 were tested in human lymphoma (Raji, Daudi, DoHH2) cancer cell lines using the tetrazolium assay. The pharmacokinetics and maximum tolerated dose (MTD) of EZN-2208 and CPT-11 were evaluated in tumor-free severe combined immunodeficient (SCID) mice and the therapeutic efficacy was evaluated in xenograft models of non-Hodgkin’s lymphoma (Raji and Daudi).
Results: In vitro, the IC50 of EZN-2208 ranged from 2–20nM and the in vitro potency of EZN-2208 was 30 to 50-fold more than CPT-11. The MTDs of EZN-2208 and CPT-11 in SCID mice were 30 and 60 mg/kg, respectively, when injected as a single dose. When administered in a multiple dose regimen (q2d x 5), the MTDs of EZN-2208 and CPT-11 were 10- and 40 mg/kg respectively. The pharmacokinetic profile of EZN-2208 was biphasic showing a rapid distribution phase (t1/2a =0.6h) and a slow elimination phase (t1/2b =19.3h for conjugate and 14.2h for SN38). In the Raji xenograft model, treatment with a single MTD of EZN-2208 resulted in a 500% improvement in life span (ILS) and 50% cures of animals compared with 19% ILS observed for mice treated with a single MTD of CPT-11. Multiple dose treatment of EZN-2208 resulted in 90% cures of animals compared with 63% ILS and no cures observed for the CPT-11 group. In the Daudi xenograft model, a single injection of EZN-2208 given as early treatment resulted in cures of 100% of animals in contrast to 66% ILS and no cures observed for CPT-11 group. When treatment was delayed, a single MTD of EZN-2208 caused 90% cures of animals, whereas CPT-11 treatment was completely ineffective.
Conclusions: EZN-2208 demonstrated excellent efficacy in preclinical models of non-Hodgkin’s lymphoma. Ongoing Phase I studies will determine the optimal dose and schedule of EZN-2208.
Notch Signaling Pathway in Hematopoietic Stem Cells Is Activated through Interactive Communication with Mesenchymal Stem Cells.
Authors: Kikuchi Yuji , Kume Akihiro , Urabe Masashi , Mizukami Hiroaki , Suzuki Takahiro , Ozaki Katsutoshi , Nagai Tadashi , Ozawa Keiya 
Published: October 2019

Abstract
Mesenchymal stem cells (MSCs), which are key elements of hematopoietic microenvironment in bone marrow, are known to play a critical role in supporting hematopoiesis. A variety of hematopoietic growth factors are produced from MSCs, and cell-to-cell contact is also believed to be crucial in the interaction between hematopoietic stem cells (HSCs) and MSCs. However, the molecular mechanisms of hematopoiesis-supporting ability of MSCs are still unclear. In particular, there is little information regarding the effects of HSCs on MSC function. In the present study, we investigated the cellular and molecular events in the interactive communication between HSCs and MSCs using a differentiation-inducible MSC model; i.e. parent C3H10T1/2 cells and 10T1/2-derived cell lines, A54 preadipocytes and M1601 myoblasts. These cells were co-cultured with murine HSCs (Lin-Sca1+) isolated from bone marrow. There was 9-fold increase in the number of hematopoietic progenitors after co-culture with A54 preadipocytes, whereas there was no increase when co-cultured with parent 10T1/2 or M1601 cells. More intriguingly, cobblestone areas were observed only when HSCs were co-cultured with A54 cells. Quantitative RT-PCR showed that A54 cells express significantly higher levels of SCF, SDF-1, and angiopoietin-1 (Ang-1) compared with parent 10T1/2 cells and M1601 cells, although these cytokines were not up-regulated when co-cultured with HSCs. To search for the genes involved in the interaction between HSCs and MSCs, we compared gene expression profiles before and after the co-culture by using a microarray analysis. Among the candidate genes with up-regulation after the co-culture, we paid attention to the Notch system, because Notch ligands are considered to play an important role in nurturing HSCs within the hematopoietic microenvironment. As a result, the expression of Notch ligands, Jagged1 and Dll3, increased in A54 cells after the coculture with HSCs. On the other hand, the expression of Notch1 and Hes-1 also increased in HSCs upon co-culture with A54 cells. These data were confirmed by quantitative RT-PCR. Moreover, when HSCs were co-cultured with A54 cells without cell-to-cell contact using Transwell permeable supports, there was neither increase in the number of progenitors in the upper wells, nor the up-regulation of Notch ligands in A54 cells in the lower wells. These findings support the idea that HSCs act on MSCs to induce the expression of Notch ligands via direct cell-to-cell contact and that the Notch ligands derived from MSCs act on HSCs in turn to activate Notch signaling pathway, possibly leading to the cobblestone formation with the maintenance of immature state of HSCs. The Notch system may be one of the critical elements in the interactive communication between HSCs and MSCs.
Prospective In Vivo Identification of Osteogenic Stem/Progenitor Cells from Bone Marrow-Derived Lin−/Sca-1+/CD45− Cells.
Authors: Wang Zhuo , Jung Junghun , Kucia Magdalena , Song Junhui , Shiozawa Yusuke , Ratajczak Mariusz Z. , Krebsbach Paul H. , Taichman Russell S. 
Published: October 2019

Abstract
We previously developed an in vivo prospective assay for identification of non-cultured cells with MSC potential. Using this assay we identified a population of cells that were slowly cycling and of low density that were capable of multilineage differentiation both in vitro and in vivo (Z. Wang et al, Stem Cells. 2006 24(6):1573). Further characterization of these cells suggested that they resemble a homogenous population of rare Lin−/Sca-1+/CD45− cells that have the morphology and express several markers of undifferentiated embryonic-like stem cells. In vitro the Lin−/Sca-1+/CD45− cells may differentiate into cells from all three germ-layers (M. Kucia et al, Leukemia. 2007 21(2):297). To determine the in vivo fate of this population, we transplanted 500 or 5,000 Lin−/Sca-1+/CD45− cells from a GFP mouse into SCID mice in each group (n=3) immediately after cell sorting to evaluate tissue generation in vivo. At 4 weeks the regenerative potential of these populations was evaluated by micro-CT and histology, and cells were tracked by gross examination of the harvested tissues by fluorescent microscopy. The results showed that a large number of GFP+ cells are located in the implants, indicating that the transplanted cells maintain the ability to contribute to the generation of new tissue. Bone-like tissue was observed in the Lin−/Sca-1+/CD45− group with as low as 500-cells/implant, while 5,000 Lin−/Sca-1+/CD45− cells generated significantly larger mineralized tissue volume, which was confirmed by micro-CT. Lin−/Sca-1+/CD45+ cell only implantation did not form any mineralized tissue, however, while mixed with 2x106 whole bone morrow cells, positive mineralized tissue occurred. Whole bone marrow mixture also improve bone formation in Lin−/Sca-1+/CD45− cell implants compared the actual bone volumes measured by micro-CT. This study demonstrates that non-cultured BM-derived Lin−/Sca-1+/CD45− cells exhibit the capacity to form bone in vivo with as low as 500 cells/implant. Whole bone marrow mixtures can enhance the bone formation, presumably through the interaction of other populations cells. Based on these findings, it is proposed that non-cultured BM-derived Lin−/Sca-1+/CD45− cells are enriched osteogenic cells that can be applied to bone regeneration in vivo.
Artificial Hematopoietic Stem Cell Niche Sustains Growth and Differentiation of Human ES-Derived Early Hematopoietic Progenitors.
Authors: Esmaeli-Azad Babak , Srivastava Anand S. , Frederico Cybele , Martinez Geraldo , Yasukawa Satoshi , Carrier Ewa 
Published: October 2019

Abstract
Using a novel Microplate Biomaterial Microarray (MBM™) technology, we have created an artificial hematopoietic stem cell niche that can sustain growth and differentiation of human embryonic stem cells-derived (hES) early hematopoietic progenitors. This hydrogel based ex-vivo niche allows uploading of human embryonal stem cells, human mesenchymal stem cells (MSC), genes (bcl-2 preventing apoptosis and HoxB4 enhancing hematopoiesis) and extracellular matrices to support growth and differentiation of human ES cells. These experiments were done using NIH-approved hES cell lines H1 and H9. Serum-free, feeder-free culture conditions were established and early hematopoietic progenitors grown using SCF, TPO, VEGF and IL-3 with high efficiency. At day 3–5 dual CD34+/CD31+ progenitors were identified, while on day 7–8 CD34+ hematopoietic progenitors were isolated, which formed typical hematopoietic colonies. These progenitors expressed genes related to early hematopoiesis, such as TAL1/SCL, FLT1, GATA2, GATA1, EPOR and TPOR. The early dual endothelio-hematopoietic progenitor (hemangioblast) expressed PECAM-1 and CD34 and showed typical blast-like morphology. Based on mathematical simulations, various micro-niches were designed to establish optimal differentiation conditions for this progenitor using IL-3, IL-6, TPO, EPO, VEGF, SFC, Flt-3 ligand and various extracellular matrices. Specific micro-niches were created for generation of CFU-E, BFU-E, CFU-GM, CFU-GEMM, CFU-M, CFU-G, and CFU-MK progenitors from human ES-derived hemangioblast. Kinetic uploading of TPO, EPO, SCF and VEGF created a niche-sustaining growth of ES-derived hemangioblast with high efficiency and low apoptosis rate. These niches used pulse -delivery of anti-apoptotic bcl-2 gene and hematopoiesis-enhancing Hoxb4 gene. The model of artifical niche sustaing growth and differentiation of human ES-derived hemangioblast was established. In the future, this system will allow optimized and upscaled generation of early hematopoietic progenitors from human ES cells, as a first step towards clinical applications of human embryonic stem cells.
Figure Figure
Elevated Red Cell Microparticles (RMP) as Risk Factor for Thrombosis in Patients with Renal Failure.
Authors: Fontana Vincenzo , Jy Wenche , Horstman Lawrence , Pamela Dudkiewicz , Carina Fernandez , Bidot Carlos , Ahn Ahn S. 
Published: October 2019

Abstract
BACKGROUND: Cell-derived microparticles (MP) are microvesicles released during activation or apoptosis from endothelial cells (EMP), platelets (PMP), leukocytes (LMP) and red cells (RMP). Their roles in hemostasis and inflammation are increasingly coming to light. Chronic and acute renal failure (RF) is associated with increased risk of bleeding as well as thrombosis but the pathogenesis is unclear. Platelet hyperaggregation, elevated clotting factors, deficiency in natural anticoagulants, impaired fibrinolysis and hyperhomocysteinemia have all been implicated in thrombosis in RF. Recently high levels of EMP, PMP and LMP have been reported in RF but their clinical significance is obscure. We investigated these MP as well as RMP in patients with RF.
METHODS: Twenty-seven patients (14M/13F, mean age 53yr) with RF were investigated. Incidence of thrombosis was assessed. Healthy controls were n=109. Flow cytometry was used to assay LMP by anti CD45, PMP by anti CD41, RMP by anti-glycophorin, and EMP by CD31+/CD41−.
RESULTS: The RF patients were divided into groups with thrombosis (TB) and without (NTB). Nine patients (33%) had thrombosis, most often venous. When MP were compared between controls and all RF patients, EMP (p=0.0004) and RMP (P=0.01) were elevated in RF. However, PMP and LMP in RF did not differ from controls (FIG. 1). On the other hand, when we compared MP between TB and NTB, only RMP was significantly greater in TB (mean 2064/uL) than NTB (mean 972/uL), p=0.001. Mean levels of EMP, PMP and LMP did not differ significantly between TB and NTB in RF (FIG. 2).
CONCLUSION / DISCUSSION: First, we confirm elevated EMP in RF compared to normal controls, and also report for the first time elevated RMP in RF. This indicates activation of endothelium and and red cells. Elevation of procoagulant MP likely contribute to risk of thrombosis in RF. Interestingly, PMP and LMP were not significantly increased in RF. Secondly, in comparing MP between the two groups of RF patients, only RMP, not other MP, were significantly higher in TB than NTB. The potential role of RMP in hemostasis and thrombosis is unknown, but the present study demonstrates a unique association of elevated RMP with thrombosis. Specifically, only RMP discriminate the TB from the NTB group in RF. This may suggest a role of RMP in thrombosis. RMP carry procoagulant phosphatidylserine (PS). Expression of PS was increased in RBC of patients with RF. The mechanism of increased RMP in RF is not known. Increased membrane fragility and decreased deformability of RBC seen in uremic patients, together with enhanced membrane lipid peroxidation from oxidative stress would contribute to increased hemolysis and RMP in RF. Thus, the present findings should further stimulate investigation into the causes and significance of RMP in RF and other TB disorders.
Figure 1 Figure 1. Figure 2 Figure 2.