bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4+/bcl-6+ Peripheral T-Cell Lymphoma with Follicular Involvement: A Distinct Type of Nodal Peripheral T-Cell Lymphoma with Multiple T-Cell Clones.
Authors: Munster-Ikonomou Ida , Tierens Anne , Troen Gunhild , Aamodt Hege , Heim Sverre , Lauritzsen Grete , Delabie Jan 
Published: April 2020

Abstract
We studied six cases of a novel type of nodal peripheral T-cell lymphoma. Three cases with this disease were recently described by de Leval et al. (de Leval L, Savilo E, Longtine J, et al. Peripheral T-cell lymphoma with follicular involvement and a CD4+/bcl-6+ phenotype. Am J Surg Pathol2001;25:395–400). The entity was named peripheral T-cell lymphoma with follicular involvement because of its distinctive histological features. We report an additional six well-characterized cases and describe the molecular and cytogenetic findings. The neoplastic T-cells of this lymphoma type express CD4 and Bcl-6, and home to the B-lymphoid follicles. This suggests an origin of the lymphoma from an as yet poorly characterized subset of Bcl-6 expressing intra-follicular T-helper cells. Of interest, the cytogenetic data and/or the study of T-cell receptor gamma gene rearrangements revealed more than one clone in each case. Cytogenetics further revealed complex karyotypes without recurrent chromosomal aberrations. We also studied the presence of somatic mutations in the 5′ untranslated region of the BCL-6 gene in four of the cases but no somatic hypermutation was detected. Clinically, the cases presented with widespread lymph node involvement at diagnosis and multiple relapses occurred after treatment. All patients received a CHOP-based chemotherapy regimen, later followed by high dose chemotherapy with stem cell rescue in five patients. One patient died with lymphoma and hemophagocytic syndrome 24 months after diagnosis, one patient is alive with disease after 27 months from diagnosis, whereas the other four patients are in complete remission 12 to 124 months after diagnosis. In conclusion, we confirm that peripheral T-cell lymphoma with follicular involvement is a distinct lymphoma type and we show that the lymphoma is oligo-clonal. The clinical findings are those of an intermediately aggressive lymphoma type. Although minimal lymph node infiltration with lymphoma cells at diagnosis and oligo-clonality is also characteristic of angio-immunoblastic T-cell lymphoma, we believe that peripheral T-cell lymphoma with follicular involvement is a distinct T-cell lymphoma type. In contrast to angio-immunoblastic T-cell lymphoma it is characterized by the typical infiltration of lymphoma cells in B-lymphoid follicles, coagulation necrosis, the absence of proliferation of high endothelial venules and follicular dendritic cells in T-cell areas, as well as the absence of EBV infection. It is likely that T-cell lymphoma with follicular involvement arises from Bcl-6+ intra-follicular T-cells. No recurrent genetic defects have been identified but the oligo-clonal nature of the lymphoma is intriguing. The latter suggests that the triggering oncogenic factors are external, such as infection.
Rituximab, Bevacizumab (Avastin) and CHOP (RA-CHOP) for Patients with Diffuse Large B-Cell Lymphoma (DLBCL).
Authors: Ganjoo Kristen N. , Gordon Leo , Robertson Michael J. , Horning Sandra J. 
Published: April 2020

Abstract
Introduction
Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF). Non-Hodgkin’s lymphoma (NHL) patients with a high serum VEGF levels have an inferior overall survival compared to patients with low VEGF levels. Rituximab plus CHOP (R-CHOP) prolongs time to treatment failure and survival in patients with DLBCL. But further improvement is needed, particularly with patients with high-intermediate and high risk international index disease. This study was designed to assess the feasibility of the combination of bevacizumab plus R-CHOP (RA-CHOP).
Method
Bevacizumab was administered at 15 mg/kg IV on day 1 of each cycle over 30–90 minutes. R-CHOP was administered on day 2 of cycle 1 and on day 1 of subsequent cycles. Patients were monitored for cardiac function with echocardiogram and for proteinuria. Serum levels of bevacizumab and rituximab were measured to assess pharmacokinetics. Serum and urine samples were also analyzed for circulating VEGF. Tumor samples were stained for VEGF by immunohistochemistry.
Results
Twelve patients (10 males, and 2 females) with newly-diagnosed DLBCL were enrolled. The median age was 48 years (range 29–63). Three patients had stage II primary mediastinal, 2 stage III, and 7 stage IV disease. ECOG performance status ranged from 0–1. Nine patients had an elevated LDH with a median international index score of 2 (range 0–3). Nine patients had an international index score of 2–3. A total of 80 cycles (range 2–8; median 7) of RA-CHOP was administered. Bevacizumab was held in 5 cycles in 3 patients-due to 1) elevated liver enzymes in the setting of positive hepatitis C serology, 2) transient proteinuria, and 3) DVT associated with central line. The following grade 3 toxicities were observed: 4 febrile neutropenia with infection related to central line, 2 DVT (both central line associated), 1 elevated liver enzymes, and 2 transient hypertension. Grade 4 toxicities included 3 absolute neutropenia with 2 febrile neutropenia, and 1 HSV esophagitis. Two patients are too early to assess response. Best response included CR in 3, PR in 4 (2 with normal PET scans), SD in 1. One patient progressed and another achieved a PR after 4 cycles but further treatment was not given due to severe depression.
Conclusion
In this patient population, treatment with RA-CHOP did not result in any grade 3 or 4 proteinuria, heart failure or bleeding. Hypertension was transient and thrombosis was associated with central line placement. Correlative studies and pharmacokinetics are being analyzed and will be available for presentation.
Survivin Expression, Regulation and Biological Role in Multiple Myeloma.
Authors: Romagnoli Mathilde , Bataille Régis , Barillé-Nion Sophie 
Published: April 2020

Abstract
Multiple myeloma (MM) is characterized by the accumulation within the bone marrow of malignant plasma cells with an enhanced survival capacity. Myeloma cells often develop drug resistance leading to treatment failure in patients. Survivin is a member of the inhibitor of apoptosis (IAP) gene family that has been implicated in both cell viability and regulation of mitosis in cancer cells. In this study, we have evaluated survivin expression and its biological involvement in viability, proliferation, cell cycle and drug resistance in myeloma cells. First by western blotting we detected survivin expression in 17 human myeloma cell lines (HMCL) from moderate level in the HMCL XG6 to strong level in the HMCL U266. Survivin was also detectable in primary myeloma cells purified from blood or bone marrow samples of 20 patients in contrast to purified B lymphocytes from tonsil samples or autologous EBV infected B lymphocytes. Survivin expression peaked at G2/M phase as obtained by drug-induced cell-cycle arrest. Second, we demonstrated that both major myeloma growth factors, IL-6 and IGF-1, induced upregulation of survivin expression through JAK/STAT and PI3K/AKT signalling pathways. In order to elucidate survivin role in myeloma cells, we established XG6 stable transfectants overexpressing survivin and extinguished survivin expression by siRNA in U266. Preliminary data suggest that survivin may participate in spontaneous cell death regulation, cell proliferation and drug sensitivity in those HMCL. In summary, our findings tend to show that survivin may be playing an important role in the pathogenesis of MM. A more defined understanding of survivin biology should enhance the rational development of drugs to inhibit its function in myeloma cells.
The Bone Marrow Microenvironment Influences the Differential Chemokine Receptor Expression of Normal and Neoplastic Plasma Cells.
Authors: Davies Faith E. , Al Rayes Mona H. , Child J. Anthony , Morgan Gareth J. , Rawstron Andrew C. 
Published: April 2020

Abstract
The expression of cytokines and chemokines are under control of several factors, including the bone marrow (BM) microenvironment. The aim of this work was to study the chemokine receptor expression on normal and neoplastic PCs and to investigate the relationship between the BM microenvironment and plasma cell behaviour. The study included 20 patients with reactive disorders or normal BM, 20 individuals with MGUS (monoclonal gammopathy of undetermined significance) and 19 patients with multiple myeloma at presentation. A large panel of chemokine receptor-specific antibodies directed against CCR1, CCR2, CCR3, CCR5, CCR6, CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 was characterized employing a four-colour flow cytometry approach. We demonstrate that normal and myeloma PCs have a specific chemokine receptor profile expressing 7/10 of the receptors studied. CCR2, CCR6, and CXCR1 showed decreased expression on myeloma PCs in comparison to normal PCs (average 3.3, 1.5 and 1.8-fold difference in expression level respectively). In contrast CXCR4 was upregulated on myeloma PCs on average 2.2-fold in comparison to normal PCs. There was no significant difference in expression between normal (CD19+) and neoplastic (CD19−) PCs from the same bone marrow environment in MGUS patients with respect to CCR6, CXCR1 and CXCR4. In contrast there was a significant difference in expression of CCR2 between CD19+ and CD19− PCs from the same BM (P=0.002). The level of expression on CD19− PCs was on average 1.6-fold lower than on their CD19+ counterparts (range 1.1 6.8-fold lower). In conclusion these data demonstrate that normal and myeloma PCs have a specific chemokine receptor profile. Myeloma PCs have a reduced level of some chemokine receptors compared to normal PCs which may account for their abnormal localization within the BM. Differences in expression of CXCR1, CXCR4, and CCR6 are not specific to the neoplastic process, as both normal and neoplastic plasma cells from the same marrow in MGUS patients show corresponding levels of expression. It is probable that feedback loops between neoplastic plasma cells and bone marrow stroma also influence normal plasma cell expression of these chemokine receptors. However, differences in CCR2 expression are not influenced by the marrow microenvironment, therefore downregulation of CCR2 expression is either a function of the neoplastic process or of the stage of differentiation of the originating neoplastic cell. Interfering with chemokines and their receptors which are related to the malignant transformation, particularly CCR2, may prove useful as adjunct to chemotherapy approaches.
Rapamycin -- a Potential Mechanistically Targeted Therapeutic for Juvenile Myelomonocytic Leukemia.
Authors: Liu Y. Lucy , Castleberry Robert P. , Emanuel Peter Dean 
Published: April 2020

Abstract
Juvenile myelomonocytic leukemia (JMML) is a mixed myelodysplastic /myeloproliferative disorder (MDS/MPD) of infancy and early childhood. It is characterized by monocytosis, leukocytosis, elevated fetal hemoglobin, hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF), a low percentage of myeloblasts in the bone marrow, and absence of the Philadelphia chromosome or the BCR/ABL fusion gene. The pathogenesis of JMML has been clearly and definitively linked to dysregulated signal transduction through the RAS signaling pathway. A series of studies conducted over the last decade have shown that mutations or other abnormalities in RAS, NF1, and PTPN11, are potentially responsible for the pathogenesis of JMML in up to 75% of cases. Treatment has been very difficult. There is no effective therapy for JMML. Only allogeneic stem cell transplantation (SCT) can extend survival. However, the relapse rate from allogeneic SCT is inordinately high in JMML (28–55%), with 5-year disease-free survival rates of 25-40%. Rapamycin is a macrolide antibiotic with established clinical applications in organ transplantation. Recent studies have proved that the Mammalian Target of Rapamycin (mTOR) plays an important role in cytokine receptor signaling and induction of apoptosis. Numerous studies have suggested that mTOR functions as a nutritional checkpoint and is connected to energy sensing through AMP-dependent kinase (AMPK) which senses the AMP: ATP ratio in cells. Its function is regulated by the RAS/PI3-kinase pathway. In searching for novel mechanistically-targeted reagents to treat JMML, we conducted an in vitro pilot study with JMML cells. The CFU-GM formation assay was used to test the therapeutic sensitivity of rapamycin to JMML cells. Mononuclear cells (MNCs) from peripheral blood of 9 JMML patients were collected and plated on 0.3% agar medium with rapamycin at a concentration of 1-8nM(0.91-7.28μg/L) and carrier (DMSO). Greater than 50% inhibition of spontaneous CFU-GM growth was observed in all cultures in a dose-dependent fashion, with the exception of one patient sample which had colonies resistant to rapamycin. The effective concentrations in our cultures are equivalent to the safe and tolerable whole blood concentrations achieved in organ transplant patients in clinical settings (5-30μg/L). Our data suggests that rapamycin may be considered as a potentially safe and effective reagent to treat JMML, but that in vitro sensitivity testing might be recommended since one patient sample demonstrated complete resistance to rapamycin in vitro. Further studies are ongoing to explore the mechanism of rapamycin in inhibiting hypersensitivity of JMML cells to GM-CSF.
The Macrophage αMβ2 Integrin αM-Lectin Domain Mediates the Phagocytosis of Chilled Platelets.
Authors: Josefsson Emma C. , Gebhard Harry H. , Stossel Thomas P. , Hartwig John H. , Hoffmeister Karin M. 
Published: April 2020

Abstract
αMβ2 integrin receptors on myeloid cells mediate the adhesion or uptake of diverse ligands, and particular sequences on this integrin’s alpha subunit are responsible for recognition specificity. Inhibition of neutrophil adhesion to platelet monolayers by αM-derived peptides has implicated an αM sequence (I-domain) that also binds iC3b, fibrinogen, ICAM-1 and other ligands. However, αMβ2 also recognizes βN-acetylglucosamine (βGlcNAc) residues on the platelet von Willebrand factor receptor (GPIbα) that are clustered after cooling, suggesting that the αM lectin domain is important for this recognition. The phagocytosis of chilled platelets can be reconstituted when CHO cells are transfected with αMβ2. Removal of the N-T portion of GPIbα, containing the exposed βGlcNAc residues, from the chilled platelet surface using the snake venom mocarhagin inhibits this phagocytosis, as does the addition of 1 mM β-methyl-N-acetyl-D-glucosamine. Replacement of the I domain, or the lectin domain of the αM-chain with the corresponding domain from the αx-chain (p150), reveals that the activity of the αMβ2 integrin toward chilled platelets resides within the lectin-domain, and does not require the I domain. Other evidences for this conclusion include: (1) Sf9 cells expressing αM lectin domain but not β2 bind 3-4 x more chilled platelets than control cells; βGlcNAc inhibits this binding. (2) Soluble recombinant αM lectin domain inhibits the phagocytosis of chilled platelets by αMβ2-expressing THP-1 cells while I-domain substrates (fibrinogen or LPM19c), recombinant I-domain protein, or a synthetic peptide that inhibits neutrophil adhesion to platelet monolayers, are without inhibitory effect. We conclude that chilled platelets are removed from blood by an interaction between βGlcNAc residues on clustered GPIbα and the lectin domain of αM-chain of the αMβ2 integrin. Since the phagocytosis and clearance of chilled platelets by hepatic macrophages has precluded refrigeration of platelets procured for transfusion, a more precise molecular definition of the recognition mechanism could inform strategies for its inhibition, thereby accommodating cold platelet storage.
Molecular Characterization of PS-341 (bortezomib) Resistance: Implications for Overcoming Resistance Using Lysophosphatidic Acid Acyltransferase (LPAAT)-β Inhibitors.
Authors: Hideshima Teru , Chauhan Dharminder , Ishitsuka Kenji , Raje Noopur , Kumar Shaji , Podar Klaus , Mitsiades Constantine , Hideshima Hiromasa , Bonham Lynn , Munshi Nikhil C. , Richardson Paul G. , Singer Jack W. , Anderson Kenneth C. 
Published: April 2020

Abstract
PS-341 (bortezomib, Velcade™) is a promising novel agent for treatment of advanced multiple myeloma (MM); however, 65% of patients with relapsed refractory disease in a phase II study did not respond. Lysophosphatidic acid (LPA) is a phospholipid which mediates tumor cell migration and invasion. Recent studies have shown that inhibition of LPAAT-β inhibits both Ras/Raf/Erk and PI3K/Akt signaling cascades. We have previously shown that lysophosphatidic acid acyltransferase (LPAAT)-β inhibitor CT-32615 triggers caspase-dependent apoptosis, and can overcome resistance to conventional therapeutics (ie, dexamethasone, doxorubicin, melphalan) in MM cells. In this study, we determined whether CT-32615 could also overcome resistance to PS-341. We first characterized molecular mechanisms of resistance to PS-341 in DHL-4 lymphoma cells. DHL-4 cells express low levels of caspase-3 and caspase-8; furthermore, no cleavage in caspase-8, caspase-9, caspase-3, poly ADP-ribose polymerase (PARP), or DNA fragmentation factor (DFF) 45 is triggered by PS-341 treatment. We have previously shown that PS-341 treatment triggers phosphorylation of c-Jun NH2-terminal kinase (JNK), which subsequently induces caspase-dependent apoptosis; conversely, JNK inhibition blocks PS-341-induced apoptosis. Here we show that PS-341 does not induce phosphorylation of SEK-1, JNK, and c-Jun in DHL-4 cells, suggesting that it does not trigger a stress response. Importantly, CT-32615 inhibits growth of DHL-4 cells in a time- and dose-dependent fashion: a transient G2/M cell cycle arrest induced by CT-32615 is mediated via downregulation of cdc25c and cdc2. CT-32615 triggers swelling and cell membrane destruction in DHL-4 cells, without caspase/PARP cleavage or TUNEL-positivity, suggesting a necrotic response. Our studies therefore demonstrate that LPAAT-β inhibitor CT-32615 triggers necrosis even in PS-341-resistant DHL-4 cells, providing the framework for its evaluation to overcome clinical PS-341 resistance and improve patient outcome.
A Phase II Trial of Doxil, Vincristine and Reduced Schedule Dexamethasone (DVd) for Patients with Relapsed or Refractory Multiple Myeloma.
Authors: Masci Paul , Karam Mary A. , Platt Luba , Andresen Steven , Lichtin Alan , McGowan Bridget , Hussein Mohamad 
Published: April 2020

Abstract
Patients with newly diagnosed multiple myeloma (MM) typically have responses to initial cytotoxic or steroid based therapy. Disease relapse occurs in all patients. As high as 90% of patients with relapsed or refractory disease will have over-expression of the multi-drug resistance (MDR) gene. Pharmacokinetic data suggest that prolonged exposure to high concentrations of doxorubicin can overcome MDR. Pegylated liposomal doxorubicin can theoretically achieve this goal as the angiogenic activity of the MM bone marrow is significantly increased. We proceeded with a phase II trial to evaluate the response rate of patients with relapsed or refractory MM (R/R-MM) to the DVd regimen. Eligible patients had clinically active R/R-MM following at least one prior cytotoxic based treatment regimen. Patients received intravenous (IV) pegylated liposomal doxorubicin 40 mg/m2 day 1, vincristine 2 mg day 1 and oral or IV dexamethasone 40 mg daily days 1–4. Cycles were repeated every 28 days for a minimum of 6 cycles and 2 cycles after best response. Myeloma parameters were measured at the start of each cycle. SWOG criteria were used to determine response. Thirty-five patients (21 male and 14 female) with R/R-MM clinically active disease were enrolled. Median age was 59 years (range 43–87). Patients received a median of 2 (range 1–4) prior cytotoxic based treatments. All patients received at least one cycle of treatment (median=5; range 1–12) and were evaluable for response. Ten (29%) patients responded to therapy; 5 partial responses (PR &gt; 50%) and 5 responses (R &gt; 75%) were observed after a median of 2 cycles (range 1–9). Median progression free survival of responding patients (PR + R) was 4.5 mos. (range 0.67–44.8). Patients achieving R had a median progression free survival of 32.5 mos. (3.0–44.8). Thirteen (37%) patients had stable disease (SD) for a median of 1.4 mos. (range 0.8–9.9). Twelve (34%) patients had progressive disease after a median of 1 cycle (range 1–5). The most common toxicities were hematologic; there were four occurrences of febrile neutropenia. Three patients experienced grade 3 constipation and one grade 3 palmar-plantar erythrodysethesia was observed. This study suggests that in patients with R/R-MM, DVd alone yields response rates similar to bortezomib with patients achieving an R experiencing a durable plateau phase. Ongoing studies of DVd in combination with thalidomide or CC-5013 in patients with R/R-MM have resulted in higher and better quality response rates (comparable to autologous SCT) translating to a durable progression free survival. We would not recommend the DVd regimen in patients with R/R-MM without the addition of an immune modulator such as thalidomide.
Dysregulated CD4+CD25+ T- Regulatory Cells and TLRs in Myeloma.
Authors: Prabhala Rao , Neri Paola , Tassone Pierfrancesco , Shammas Masood A. , Bae Jooeun , Cumming Virginia M. , Allam Charles K. , Daley John F. , Desarneud Frank , Chauhan Dharminder , Blanchard Elizabeth , Anderson Kenneth , Munshi Nikhil C. 
Published: April 2020

Abstract
Although current vaccine strategies have achieved anti-myeloma immune responses, meaningful clinical responses have not been observed. This may be related with the significant immune dysfunction observed in myeloma that may interfere with the development of effective anti-myeloma immune responses. The initiation of immune response is controlled by CD4+CD25+ T regulatory (Treg) cells, which can suppress anti-tumor immune responses. This property of Treg cells to modulate anti-tumor immune responses may function as a barrier to cancer immunotherapy. In order to overcome such suppression, signaling through Toll-like receptors (TLRs) can induce adjuvant effect by increasing local production of chemokines, and pro-inflammatory cytokines, and by enhancing antigen-presentation by APCs. Here, we have evaluated the role of Treg cells and the effects of TLRs in myeloma. We observed significant increase in CD4+CD25+ Treg cells in MM patient samples compared to normal donors (23±4% vs 6±3%). Proliferation of T cells depleted of Treg cells with anti-CD3 antibody was significantly lower in MGUS (n=9, SI=12±2) and MM (n=9, SI=28±8) compared with normal donors (n=9, SI=74±9, p&lt;0.01). As expected addition of Treg cells was able to suppress T cell proliferation in normal donors (↓31%), however, their effects were less suppressive in MGUS (↓26%), and in fact, they increased T cell proliferation in MM (↑29%). Additionally, LPS which functions through Toll-like receptor 4 (TLR4), is able to overcome suppression of T cell proliferation by Treg cells in normal controls (110%), however, it had significantly limited influence in MGUS (49%) and MM (24%). Expression profile of myeloma cells (n=15) showed up-regulation of TLR4 (7.4 folds) and its related gene MD2 (2.5 folds) in all the MM cells tested compared to normal plasma cells indicating a possible modulation of immune responses by myeloma cells through TLR4 or its soluble agent. This is the first demonstration of dysregulated Treg cells and TLRs in myeloma. Understanding of the molecular basis of Treg cell dysfunction is underway with a view to eventually target these mechanisms to improve immuno-therapeutic strategies in myeloma.