bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maintenance of Telomere Length in Peripheral Blood CD4+CD25+ Regulatory T-Cells of Cancer Patients Despite Active Proliferation.
Authors: Wolf Dominik , Rumpold Holger , Koppelstaetter Christian , Gastl Guenther , Gunsilius Eberhard , Tilg Herbert , Wolf Anna M. 
Published: April 2020

Abstract
CD4+CD25+ regulatory T-cells (Treg) are increased in the peripheral blood of cancer patients. It remains unclear whether this is due to redistribution or active proliferation. The latter would require the up-regulation of telomerase activity, whose regulation also remains unknown for Treg. We therefore isolated Treg and the respective CD4+CD25− control T-cell population from peripheral blood of cancer patients (n=23) and healthy age-matched controls (n=17). Analysis of their content of T-cell receptor excision circles (TREC) revealed that the observed increase of Treg frequencies in peripheral blood is due to active cycling rather than to redistribution from other compartments (i.e. secondary lymphoid organs or bone-marrow), as Treg from cancer patients are characterized by a significant decrease of TREC content when compared to TREC content of Treg isolated from healthy age-matched controls. Surprisingly, despite their proven in vivo proliferation, telomere length is not further shortened in Treg from peripheral blood of cancer patients as shown by Flow-Fish, Real-Time PCR and Southern Blotting. Accodingly, telomerase activity of Treg was readily inducible in vitro by OKT3 together with IL-2. Notably, sorting of in vitro proliferating Treg using dilution of CFSE revealed a significant telomere shortening in Treg with high proliferative capacity (i.e. CFSElow fraction) under conditions of strong in vitro stimulatory growth conditions despite a high telomerase activity. Thus, under conditions of strong in vitro stimulation induction of telomerase seems to be insufficient to avoid progressive telomere shortening. In contrast, in actively proliferating peripheral blood Treg from patients with epithelial malignancies induction of telomerase activity is likely to compensate for further telomere erosion.
Transcription Factor ICSBP/IRF8 Regulates B Cell Development at Multiple Checkpoints.
Authors: Wang Hongsheng , Lee Chang Hoon , Qi Chen-Feng , Kerrikatte Nishant , Tailor Prafullakumar , Ozato Keiko , Morse Herbert C. 
Published: April 2020

Abstract
The generation of lymphoid and myeloid lineage cells from hematopoietic stem cells is controlled by multiple transcription factors regulating distinct developmental and functional aspects. Interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF8) is a transcription factor known to regulate the differentiation of macrophages, granulocytes, and dendritic cells. Our recent findings that IRF8 transcripts and protein are highly expressed in germinal center (GC) B cells suggest that IFR8 may also play a role in normal B cell development. In IRF8 deficient mice, the number of early B lineage cells (pre-pro-B) was reduced by 5-fold, indicating a defect in early B lineage commitment. While the numbers of late pre-B and immature B cells were moderately reduced (~2-fold), recirculating mature B cells were almost undetectable in the bone marrow of mutant mice. This deficiency in early stage B cells is correlated with increased expression of PU.1, a crucial transcription factor for myeloid and lymphoid lineage specification. Interestingly, the number of splenic transitional 1 (T1) cells was slightly increased but the numbers of T2 and follicular (FO) B-2 cells were moderately decreased in mutant mice. This indicates that positive selection of T2 cells into the mature B-2 pool is regulated by IRF8. The marginal zone (MZ) B cell and peritoneal CD11b+ B-1b cell compartments were also slightly expanded in IRF8 knockout mice. Overall, these results provide compelling evidence that IRF8 regulates B cell differentiation and function at multiple stages.
Murine Embryonic Liver Differentiates Human Stem Cells into a Spectrum of NK Precursors and Polyclonal KIR Expressing NK Cells.
Authors: Miller Jeffrey S. , Brungaard Karen , Oostendorp Robert A.J. , McCullar Valarie 
Published: April 2020

Abstract
We have shown that a murine fetal liver cell line (AFT024) and human cytokines (IL-15, IL-7, IL-3, Flt3-ligand and c-kit ligand) are needed to induce NK cell differentiation and KIR acquisition. To understand the level of maturation where these factors orchestrate NK cell development, a switch culture was designed to separate early and late events. Cord blood CD34+/Lin−/CD38− stem cells were cultured on AFT024 for 28 days. Use of IL-3 or Flt3-L alone resulted in minimal growth. In contrast, we show that NK cell differentiation can occur, albeit at low frequency, with a combination of IL-3 and Flt3-L, in the absence of IL-15. These early NK cells were negative for both CD94 and KIR. These conditions also allowed accumulation of CD56− NK cell precursors. CD34+CD7−, CD34+CD7+ and CD34−CD7+ cells were detected in cultures lacking IL-15. Each precursor was tested in secondary cultures containing AFT024 with IL-15 alone, IL-15+IL-3, or IL15+IL-3+Flt3-L. After an additional 2–4 weeks, NK cells differentiated from each distinct cell population. A few predominantly KIR negative NK cells resulted from IL-15 alone. Addition of IL-3 or IL-3+Flt3-L significantly increased the absolute number of NK cells as well as the acquisition of CD94 heterodimers and KIR. We next explored other stromal cell lines in attempt to identify novel factors important in early NK cell maturation. A novel cell line derived from murine embryonic liver (EL08-1D2), identified for its ability to support expansion of mouse stem cells, was compared to AFT024. To test the differential capacity of these microenvironments, single cord blood stem cells were plated on the two feeders supplemented with all cytokines. After 4 weeks, EL08-1D2 induced 125,852±1400 NK cells from a single stem cell, significantly more than with AFT024 (23,143±8117). KIR+ NK cells were also significantly more frequent with EL08-1D2 (3689±801 vs. 799±491), always in a polyclonal pattern. NK cell development and KIR acquisition were dependent on direct contact with EL08-1D2. Increased development could be from greater differentiation, proliferation or both. Cord blood stem cells were cultured in direct contact with EL08-1D2 under primary culture conditions with IL-3 and Flt3-L but in the absence of IL-15. All CD56− NK cell precursors developed with greater frequency on EL08-1D2 than AFT024. In conclusion, EL08-1D2, derived from a primitive microenvironment during mouse ontogeny, efficiently recapitulates NK cell development by inducing NK cell differentiation and proliferation. IL-3 and Flt3-L, but not IL-15, facilitate the isolation and study of distinct NK cell precursors. Direct contact with EL08-1D2 induces KIR acquisition, suggesting that unique environmental factors conserved between mouse and man contribute to the extrinsic signals which lead to KIR acquisition.
Functional and Molecular Analysis of Maturation of Thymocytes in Bcl10 or Malt1 Deficient Mice.
Authors: Jost Philipp J. , Ferch Uta , Weiss Stephanie , Leeder Stephanie , Gross Olaf , Mak Tak W. , Peschel Christian , Ruland Juergen 
Published: April 2020

Abstract
Development of immature T cells in the thymus requires signals through the clonotypic T cell receptor (TCR). Thymocytes expressing a functionally inactive or autoreactive TCR are deleted via apoptosis (negative selection). Thymocytes expressing a functionally active but not autoreactive TCR are selected through inhibition of cell death (positive selection). Deregulation of this process is likely to result in autoimmunity or lymphomagenesis of T cells. The intracellular mechanisms by which the balance between TCR-dependent survival and apoptosis are regulated are largely unknown. A central regulator of survival and apoptosis in the immune system is the transcription factor NF-κB. Activation of NF-κB in mature T-cells requires the adaptor proteins Bcl10 and Malt1. Using gene-targeted mice deficient for Bcl10 or Malt1, we show that Bcl10 and Malt1 are also required for TCR-induced NF-κB activation in immature T cells. Furthermore, to elucidate the process of T cell selection within the thymus, we have crossed Bcl10 or Malt1 deficient mice into mice with genetic backgrounds expressing defined TCR transgenes. Using specific peptide agonists of these TCR transgenes, we show that neither in vivo nor in vitro development into single positive (SP) CD4 or CD8 positive T cells is altered in Bcl10 or Malt1 deficient mice. Absolute numbers and ratio of SP T cells found within the thymus or in peripheral lymphnodes of transgenic animals are normal. These findings indicate that Bcl10 and Malt1 activate NF-κB in thymocytes but are dispensable for maturation of immature T cells in this model system.
A Prospective Risk Model for Neutropenic Complications in Patients with Malignant Lymphoma.
Authors: Lyman Gary H. , Crawford Jeffrey , Wolff Debra , Culakova Eva , Poniewierski Marek S. , Dale David C. 
Published: April 2020

Abstract
Background: Myelosuppression including severe and febrile neutropenia continues to represent a major cause of dose-limiting toxicity of cancer chemotherapy. Neutropenic complications in cycle 1 have been shown to frequently lead to reduced dose intensity or addition of a myeloid growth factor. A prospective, nationwide study was undertaken to develop and validate risk models for first cycle neutropenic events associated with cancer chemotherapy.
Methods: Patients with malignant lymphoma initiating a new chemotherapy regimen have been prospectively registered at 115 randomly selected practice sites. Data on at least one cycle of chemotherapy were available on 357 patients including 56 with Hodgkin’s disease and 301 with non-Hodgkin’s lymphoma. A logistic regression model for first cycle neutropenic events based on pretreatment characteristics was developed and predictive test performance characteristics examined.
Results: Severe or febrile neutropenia occurred in 81 (22.7%) of patients in cycle 1. Two-thirds of patients with one or more neutropenic events experienced their initial event in cycle 1. Significant independent pretreatment predictive factors for first cycle neutropenic complications were: history of renal disease (OR=33.15, P=.011) or recent infection (OR=12.41, P=.035), Caucasian (OR=4.13, P=.053), use of an anthracycline-based chemotherapy regimen (OR=6.9, P&lt;.001), baseline absolute neutrophil count (OR=0.95, P&lt;.001) and lymphocyte count (OR=0.95, P&lt;.001), anemia (OR=2.14, P=.043), elevated lactate dehydrogenase (OR=2.0, P=.040) and elevated bilirubin (OR=2.25, P=.051). Model fit was excellent (P&lt;.001), R2= 0.503 and c-statistic = 0.769 [95% CL: .71–.83, P&lt;.0001]. Individual predicted risk of cycle 1 events based on the model ranged from 0 to 96% with mean and median probabilities of 0.23 and 0.21, respectively. Two-thirds of patients were classified as high risk with mean risk scores in high and low risk subjects of 32.0% and 5.6%, respectively. Model test performance characteristics [±95% CL] included: sensitivity: 92% [84–96]; specificity: 40% [34–46]; likelihood ratio positive: 1.53 [1.36–1.73]; likelihood ratio negative: 0.19 [0.09–0.42]; positive predictive value: 32% [26–38]; negative predictive value: 94% [88–97] and diagnostic odds ratio: 7.92 [3.32–18.91].
Discussion: The risk model identified lymphoma patients at increased risk for first cycle neutropenic complications using common clinical parameters. Validation of the model in a separate population of patients is in progress.
Phase I Trial of Bortezomib (NSC 681239) and Flavopiridol (NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms.
Authors: Grant Steven , Sullivan Daniel , Roodman David , Stuart Robert , Perkins Edward B. , Ramakrishnan Viswanathan , Wright John , Colevas A. Dimitrios , Roberts John D. 
Published: April 2020

Abstract
Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell-cycle and survival signaling pathways. In accord with this concept, we have shown that flavopiridol (F), a CDK inhibitor, interacts with Bortezomib (B), a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene22:7108, 2003; Dai et al, Blood104,509,2004). These actions were associated with inhibition of NF-kappaB DNA binding, and diminished expression of phospho-JNK, XIAP, and Mcl-1. Based on these findings, we have initiated a phase I trial to identify appropriate doses of B+F for further investigation. Eligible patients (pts) include those with multiple myeloma, indolent B-cell lymphoma, or a related disorder, and must have recurrent or refractory disease following at least 1 prior systemic therapy (excluding allogeneic stem cell transplantation). Pts receive B (iv bolus) immediately followed by F (1 hour infusion) on days 1, 4, 8, and 11; courses are repeated every 21 days. Targeted dose levels are (B/F; mg/m2): 1.0/15, 1.3/15, 1.3/22, 1.3/30, and 1.3/40. Dose limiting toxicity (DLT) is defined as NCI CTCAE grade 4 ANC/platelet for &gt; 1 week or grade ≥ 3 non-heme toxicity. 14 pts have been treated at 4 dose levels. There have been no DLT to date. There have been 3 episodes of herpes zoster (2 disseminated), 4 cases of exacerbation of pre-existing peripheral neuropathy, and 8 pts have discontinued study treatment after 1 to 5 cycles due to non-DLT toxicities. Among 11 patients evaluable for response and who are Bortezomib-naive, there has been 1 complete response (mantle cell lymphoma; MCL), 3 partial responses (2 myeloma, 1 lymphoma), and 5 patients with stable disease (3 myeloma, 1 lymphoma, 1 Waldenstrom’s). The patient with MCL who achieved a CR had previously received CHOP, Rituximab-CHOP, and fludarabine-Rituximab x 2. Correlative laboratory studies involving bone marrow CD138+ cells from patients with myeloma revealed a reduction in post-treatment NF-kappaB nuclear localization in 4/5 evaulable patients. Variable effects on myeloma cell expression of phospho-JNK, Mcl-1, and XIAP have been observed. Additional patients who previously received Bortezomib have now been entered on the study, but it is too early to evaluate their responses. Collectively, these findings indicate that a regimen combining Bortezomib and flavopiridol is well tolerated in patients with progressive B-cell malignancies, and has clear activity in some patients refractory to standard therapy. Pending identification of the MTD and RPTD (recommended phase II dose), Phase II evaluation of this therapeutic strategy should define its activity more definitively.
Phase I Study of Noscapine for Patients with Non-Hodgkin’s Lymphoma or Chronic Lymphocytic Leukemia Refractory to Chemotherapy.
Authors: Tulpule Anil , Levine Alexandra M. , Berman Nancy E. , Smith Lynne , Auerbach Alan , Douer Dan 
Published: April 2020

Abstract
Noscapine is an alkaloid derived from opium, which lacks sedative, euphoric, analgesic or respiratory depressant properties. Antitumor activity of Noscapine has been demonstrated both in vivo, against human lymphoid tumor cells, and in vitro, in human tumors implanted in athymic mice. Noscapine induces conformational changes in tubulin, which results in altered microtubule assembly. In this Phase I trial, cohorts of subjects with relapsed/refractory non-Hodgkin’s lymphoma (NHL) or chronic lymphocytic leukemia (CLL/SLL) were treated at three different dose levels of total daily doses of 1 g, 2 g, and 3 g. At each dose level the drug was administered orally on a three times a day schedule. The total duration of treatment was 49 days. Results: Twelve subjects with a median age of 65 years (range 38–71) have been accrued. Four subjects had CLL/SLL, 2 had mantle cell lymphoma, one had follicular grade III, 4 had DLC, and one had lymphoplasmacytic low grade lymphoma. 10 subjects are evaluable for response. Partial response was seen in 1 subject with follicular grade III disease. The duration of this PR is 56+ months. Stable disease was seen in a case of mantle cell lymphoma (duration 30 days) and a case of DLC (duration 77 days). The remaining 7 subjects had progression of disease. Noscapine has been well tolerated, with no grade 3 or 4 hematological toxicities. One grade 3 neurotoxicity consisting of depressed level of consciousness was experienced at the 3 g dose level. We conclude that a larger study of Noscapine is warranted to evaluate the efficacy of the compound in patients with lymphoma. The oral formulation, suggestion of efficacy and relative lack of toxicity make Noscapine an attractive candidate for further study.
HuMax-CD4 (Zanolimumab), a Fully Human Monoclonal Antibody: Early Results of an Ongoing Clinical Trial in CD4+ Peripheral T-Cell Lymphoma of Non-Cutaneous Type.
Authors: d’Amore Francesco , Relander T. , Hagberg H. , Osterborg A. , Hansen M. , Moeller L. , Johnson P. , Radford J. , Hancock B. , Gramatzki M. , Krause S. , Dreyling M. , Schmitz N. , Lisby S. , Baadsgaard O. 
Published: April 2020

Abstract
HuMax-CD4 (zanolimumab) is a fully human monoclonal IgG1k antibody, targeting the CD4 molecule on T-cells. It exhibits cytotoxic and anti-proliferative effects and has previously shown efficacy in cutaneous T-cell lymphoma. We report initial clinical efficacy and safety of treatment with 980 mg of HuMax-CD4 in 8 patients diagnosed with biopsy-proven, treatment-refractory or relapsed CD4+ peripheral T-cell lymphoma (PTCL) of non-cutaneous type. Patients were enrolled with the following diagnoses; enteropathy-type T-cell lymphoma (n=1), anaplastic large T-cell lymphoma (n=3, 2 ALK− subtype, 1 unknown), angioimmunoblastic T-cell lymphoma (n=1) and PTCL, unspecified (n=3). Primary endpoint was objective tumor response. Responses were based on CT scan and clinical examination and classified according to the Cheson criteria. Out of the 8 patients enrolled, 2 responses have been seen; 1 PR and 1 CRu (verified by CT scan). Further, clinical improvements (marked decrease in the size of peripheral lymph nodes) were recorded by the physicians in 3 other patients. In total, 9 SAEs have been reported. Of these, 1 case of febrile neutropenia was judged related. 8 unrelated SAEs were recorded; knee pain, viremia (n=2), condition aggravated, and disease progression (n=4). Three unrelated deaths have been reported, all due to disease progression. In conclusion, HuMax-CD4 was well tolerated in heavily pre-treated patients and the present results indicate efficacy in the treatment of PTCL.
Primary Gastric T-Cell Lymphoma: Clinicopathologic Features and Treatment Outcome.
Authors: Park Yeon Hee , Kim Won Seog , Bang Soo-Mee , Lee Soon Il , Uhm Ji Eun , Kang Hye Jin , Na Im Il , Ryoo Baek-Yeol , Yang Sung Hyun , Kim Kihyun , Lee Seung Sook , Ko Young H. , Park Keunchil 
Published: April 2020

Abstract
Primary gastric lymphoma is the most frequent type of extranodal malignant lymphoma. The large majority of cases are of B-cell lineage, while primary gastric T-cell lymphomas are exceedingly rare and least well characterized malignancy and the clinical features have been described only in a few case reports. In this study, we conducted a retrospective analysis to investigate the natural history and the clinical outcome after treatment. Between 1990 and 2004, 444 patients with primary gastric lymphoma had been diagnosed at four institutes. Among these 444 patients, 17 patients (3.8%) were identified as primary gastric lymphoma with T-cell immunophenotype. The pathologic review was performed by two experienced hematopathologist to confirm T-cell lymphoma with typical immunohistochemical features including CD3. All of the patients were staged according to the Mushoff system. Among these 17 gastirc T-cell lymphoma patients, 14 patients were treated with combination chemotherapy including CHOP with or without radiotherapy. The two patients were treated with high-dose chemotherapy with autologous peripheral hematopoietic stem cell transplantation. The median age of the 13 male and 4 female patients was 49 years (range 22–76 years). The pathologic subtypes of these patients with T-cell immunophenotype were as follows; precursor T-lymphoblastic lymphoma in 2 patients, peripheral T-cell lymphoma, unspecified in 6 patients, NK/T cell lymphoma in 3 patients, and T-cell others in 5 patients. The many of the patients showed poor performance status (PS), and high LDH level (65%). 12 patients (71%) showed stage III or IV diseases, and 9 patients (53%) showed high or high-risk according to the International Prognostic Index (IPI). A response to treatment was observed in 8 patients (47%), with 6 Complete Response (CR) and 2 Partial Response (PR). The median Progression-Free Survival (PFS) and Overall Survival (OS) were only 5 months (95% C.I.; 4–6 months), and 14 months (95% C.I.; 0–189 months). 5 patients of these 17 patients (29%) presented only in stomach and regional lymph nodes. The patients with localized gastric T-cell lymphoma showed good therapeutic outcome (median PFS; 53 months, median OS; 123 months, p =0.024 by log-rank test). Other clinical factors including PS, age, and LDH did not show clinical significance in this series. Although our series had limitation to interpret due to small population, this study showed that the incidence of this subtype of T-cell gastric lymphoma was very rare, and poor prognosis, like as other T-cell lymphoma. However, about 30% of the patients had localized diseases limited to gastric area and regional lymph nodes with relative good prognosis. New therapeutic strategies need to improve the outcome of patients with gastric T-cell lymphoma.
SGN-30 (Anti-CD30 Monoclonal Antibody) Is Active and Well Tolerated in Patients with Refractory or Recurrent Systemic Anaplastic Large Cell Lymphoma (ALCL).
Authors: Forero-Torres Andres , Bernstein Steven H. , Gopal Ajay K. , Foss Francine , Leonard John P. , Rosenblatt Joseph D. , Bartlett Nancy L. , Cheson Bruce D. , Epner Elliott , Hernandez-Illizaliturri Francisco J. , Proctor Stephen J. , Brice Pauline , Tilly Harve , Haioun Corinne , Jerkeman Mats , Bosly Andre , Lorenz Jennie M. , Barton Jeremy 
Published: April 2020

Abstract
SGN-30 is a chimeric monoclonal antibody (mAb) directed against the CD30 antigen expressed on hematologic malignancies, notably Hodgkin’s disease and ALCL. SGN-30 was well tolerated in phase I studies and objective responses were seen. In this multicenter phase II study, refractory or recurrent CD30-positive ALCL patients, ECOG performance status 0–2, are treated with SGN-30 at 6 mg/kg administered by IV over a 90 minute infusion weekly for 6 consecutive doses. A two stage statistical design provides a 90% power to detect an objective tumor response rate of at least 30%. Twenty patients (11M, 9F) with ALCL have been enrolled, with a median age of 53 (range 33–78) and 3 median prior therapies (range 2–5). Eighteen of 20 patients were Anaplastic Lymphoma Kinase (ALK) negative. Response evaluations demonstrate that one patient achieved a complete response and remains in remission more than one year after therapy. Three patients achieved a partial response, of which two had a lasting response of 27 and 53 days respectively. The third patient is currently still on treatment. Of the other 16 patients, 3 had stable disease, 10 progressed and 3 are not yet evaluable. SGN-30 has been well tolerated. Drug-related adverse events have been typically mild and consistent with the phase I experience. There were 2 grade 3/4 toxicities possibly related to SGN-30. No significant hematological or biochemical toxicities have been observed. One patient had a catheter related infection and another experienced urticaria. There was 1 definitely related grade 3/4 event in a patient who experienced an exacerbation of his cutaneous lesions after 2 doses of SGN-30 and followed by a partial response. The requisite number of responses have now been obtained to allow the study to continue.