bluuebunny/crossref_metadata_2025_split huggingface dataset:
Extranodal Follicular Lymphoma - a Retrospective Review and Comparison with Localized Nodal Follicular Lymphoma.
Authors: Kukreti Vishal , Petersen Peter , Pintilie Melania , Tsang Richard , Crump Michael , Gospodarowicz Mary 
Published: April 2020

Abstract
Follicular lymphoma arising in an extranodal site is uncommon and its natural history and treatment is poorly characterized in the literature. We retrospectively reviewed a large cohort of patients with stage I and II follicular lymphoma and analyzed the outcomes of patients with extranodal (EN-FL) presentations to identify sites of involvement and treatment outcome, and compared these to patients with nodal follicular lymphoma. From 1967 to 1999, 668 cases of limited stage follicular lymphoma (stage I and II) were treated at the Princess Margaret Hospital. Of these, 157 cases (23.5%) presented in extra-nodal sites. The most common site of presentation was in the head and neck area (42%) followed by gastro-intestinal tract (14.6%) then skin (10.8%). The majority of patients had stage I disease (61.8%). Pathological type was follicular grade I: 22.9%, grade II: 33.1%, and grade III: 43.9%. Treatment consisted of involved field radiation therapy in 72%, combined modality therapy in 22.3% and chemotherapy alone in 3.8%. The treatment changed over time with increased use of combined modality treatment (CMT) [1967–77: 10.5%, vs. 1989–99: 33%] mainly due to the adoption of CMT for follicular grade III lymphoma. Overall complete response rate (CR) to primary treatment was 93%; the CR rate for radiation alone was 97.3%. The cumulative incidence of relapse (RR) was 44% at 10 years. The RR at 10 years was higher for patients age &gt;60 (62% vs. 49%; p =0.059) but did not vary according to stage, tumour bulk, gender or histologic grade. For extranodal lymphoma, the 10-year overall survival (OS) rate was 56% and the 10-year disease free survival (DFS) was 42% and was similar for major sites of presentation.
Comparison of Stage I–II Nodal and Extra-nodal Follicular Lymphoma
Nodal Follicular Lymphoma Extra-nodal Follicular Lymphoma 10 yr Overall Survival 61% 56% (p=0.97) 10 year Disease Free Survival 41% 42% (p=0.27) 10 yr Relapse Rate 50% 44% (p=0.11)
In conclusion, a significant number of patients with localized FL present with extra-nodal disease, involving diverse sites. Patients with EN-FL were more likely to have follicular grade III histology. OS, DFS and RR were similar to nodal follicular lymphoma. These results suggest that the clinical management of stage I and II extra-nodal follicular lymphoma should be the same as for nodal, and that a significant proportion of patients have prolonged DFS with radiation-based therapy.
Non-Hodgkin’s Lymphoma in the Context of Antecedent Rheumatoid Arthritis: A Case Series from the Mayo Clinic and the Nebraska Lymphoma Study Group.
Authors: Endo Justin O. , Ooi Melissa G.M. , Black Natalie A. , Aoun Patricia , Habermann Thomas M. , Stoner Julie A. , Armitage James O. , Mikuls Ted R. 
Published: April 2020

Abstract
PURPOSE: Rheumatoid arthritis (RA) has been associated with an increased risk of non-Hodgkin’s lymphoma (NHL). We describe the characteristics of NHL patients with antecedent RA.
METHODS: Records of the Nebraska Lymphoma Study Group (NLSG) registry between 1982–2004 and the Mayo Clinic lymphoma registry between 1988–1998 were systematically reviewed for RA diagnosis and classified by the quality of supporting evidence. We abstracted available follow-up data through July 1, 2004. Definite cases had either a documented RA diagnosis from a trained rheumatologist or met 4 of 7 American College of Rheumatology criteria. Probable RA cases had a non-rheumatologist diagnosis of RA in addition to one of the following: 1) radiographic joint erosions; 2) disease-modifying anti-rheumatic drug (DMARD) use or; 3) RA-associated deformities (i.e., ulnar drift, swan-neck deformities). Five-year overall survival (OAS), event-free survival (EFS), and rates of treatment response were determined.
RESULTS: We identified 74 RA cases (54 definite and 20 probable) with concomitant NHL. These patients had a mean age of 67 + 8 years and were predominantly Caucasian (82%) and female (64%). Of the probable RA cases, a majority had documented DMARD use (n=17). Approximately half of the cases used methotrexate (55%) and were deceased (52%) by the common closing date. The most common NHL subtypes included B-DLCL (n=31), B-FL-1/B-FL-2 (n=12), B-FL-3 (n=6), and B-BL/B-BLL (n=4). Of the remaining 21 cases, most were of B-cell origin (n=13) and included B-EMZL (n=3), B-LPL (n=3), B-UCL (n=2), B-UCL-LG (n=2), B-DFL-2 (n=1), B-MCL (n=1), and B-SLL (n=1). The remaining NHL subtypes included NHL-NOS (n=7) or T-PTCL-LC (n=1). B-symptoms were present for 6 (19%) patients with B-DLCL and none of the patients with B-FL-1/B-FL-2. Complete response rates to NHL treatment were 48% in B-DLCL and 33% in B-FL-1/B-FL-2. For B-DLCL and B-FL-1/B-FL-2, respectively, the five-year OAS was 54% (95% CI 36%–69%) and 65% (95% CI 31%–85%) while the five-year EFS was 48% (95% CI 36%–69%) and 56% (95% CI 24%–79%). For all NHL cases the 5-year OAS was 58% (95% CI 47%–69%) and the 5-year EFS was 49% (95% CI 37%–59%).
CONCLUSIONS: Lymphomas developing in the context of RA most often include diffuse large B-cell and follicular subtypes. Complete response rates to standard treatment for these major subtypes ranged from 33 to 48%. For RA patients developing NHL, five-year overall- and event-free survival rates are approximately 50%.
Phase I/II Study of Rituxan (R) in Combination with Doxil (D) in Patients (pts) with Relapsing or Refractory B-Cell Lymphoma: Promising Early Results.
Authors: Czuczman Myron S. , Skipper Marion , Mohr Alice , Bernstein Zale P. , McCarthy Philip , Hernandez-Ilizaliturri Francisco , Chanan-Khan Asher Alban 
Published: April 2020

Abstract
In the past, the most common initial combination chemotherapy regimen used by most oncologists to treat B-cell lymphoma was the CHOP regimen. Although doxorubicin (DOX) is a major component of CHOP, it is associated with myelosuppression, alopecia, and potential cardiotoxicity. In vitro data has demonstrated synergistic activity between rituximab and certain drugs, including DOX. Because of D’s unique liposomal encapsulation, delivery, and toxicity profile, it may prove to be a more effective, less toxic anthracycline to combine with R. A formal Phase I/II trial to evaluate the safety and efficacy of R+D in pts with relapsing B-cell lymphoma was undertaken. R (375 mg/m2/dose) was given on day 1 and D (30 mg/m2/dose) on day 3 on q 21 day cycles for 6 cycles. Thirteen pts have completed therapy to date: 9F, 4M; Follicular lymphoma, grade 1 (n=6), grade 2 (n=1), grade 3 (n=3), DLBCL (n=3); med age = 63 (38–78); median number of prior Rx’s = 3 (range 1–8); prior anthracycline exposure (n=8). Overall, the combination of R + D was well-tolerated. Transient grade 3 cytopenias were noted in 3 pts with limited bone marrow reserve and grade 3 palmar/plantar erythrodysesthesia seen in 2 pts. All 13 pts completed the planned 6 courses of Rx. Objective responses were seen in 85% (11 of 13 pts), including 54% CR, 31% PR. Median time-to-progression has not been reached at 7+ months (range 4.5+ to 19+ months). No cardiac toxicity was seen and comparison of pre-Rx to post-Rx LVEF remained unchanged in 9, increased in 2, and decreased in 2 (yet still remaining &gt; 50%). D + R immunochemotherapy is a well-tolerated, unique, non-cardiotoxic, and apparently effective salvage therapy for relapsed B-cell lymphoma. The study will continue until accrual of 42 pts has been reached.
Genetic Abnormalities and Patterns of Antigenic Expression in Multiple Myeloma.
Authors: Mateo G. , Castellanos M. , Rasillo A. , Gutierrez N. C. , Montalban M. A. , Martin M. L. , Hernandez J. M. , Lopez-Berges M. C. , Monteiano L. , Blade Joan , Mateos M. V. , Sureda A. , Rubia J. , Diaz-Mediavilla J. , Lahuerta J. J. , Orfao A. , Miguel J.F. San 
Published: April 2020

Abstract
Myelomatous plasma cells (PC) show a high heterogeneity both in their immunophenotypic characteristics as well as in their cytogenetic features. So far, no extensive studies have been carried out to explore whether such antigenic diversity is associated with specific genetic characteristics. We have investigated the relationship between the immunophenotypic profile at PC and both their DNA ploidy status (evaluated by flow cytometry), and specific genetic features (ascertained by FISH) in a large series of 915 patients with newly diagnosed MM. The non-hyperdiploid MM group (n=454, 52%) was associated with a significantly higher frequency of positivity for CD28 and CD20 as well as a higher incidence of CD56− and CD117− cases (p&lt;0.001). Remarkably, 13q deletion and IGH gen rearrangements, which were significantly more common in non-hyperdiploid MM, showed a strong association with CD117- cases. IGH translocation to 11q13 was associated with reactivity for CD20 (p&lt;0.001), down-regulation of CD56 (p&lt;0.001) and lack of expression of CD117 (p=0.001). By contrast, IGH translocations to other chromosome partners were almost exclusively found among CD20− and CD117− cases (p&lt;0.001). These results suggest that genetic categories in MM exhibit a particular immunophenotypic profiles which in turn are strongly associated with the DNA ploidy status.
Annexin II Mediates Plasminogen-Dependant Matrix Invasion by Adult Human Mesenchymal Stem Cells.
Authors: Bolno Paul B. , Morgan Doris A. , Sharma Mahesh , Lazorik Martin , Wechsler Andrew S. , Kresh J. Yasha 
Published: April 2020

Abstract
Background: Annexin II (ANX2) is a fibrinolytic receptor that serves as a binding site for plasminogen and tissue plasminogen activator, facilitating the generation of plasmin. ANX2 is present on a wide variety of cells including vascular endothelial cells as well as macrophages. ANX2 has been shown to play a key role in extracellular matrix degradation, cellular migration, and invasion. This degradation of extracellular matrix may also cause the release of matrix-bound angiogenic factors such as VEGF and FGF. We hypothesized that adult human mesenchymal stem cells (hMSCs) express ANX2 and utilize this receptor for plasmin generation to facilitate basement membrane invasion.
Methods: Primary hMSCs were isolated from the sternal bone marrow of patients undergoing median sternotomy. Stem cell surface markers were characterized via immuno-fluorescence. The presence of ANX2 protein by hMSCs was established via western blot. ANX2 mediated plasminogen activation and plasmin generation was quantified using chromozyme-P as a colorimetric substrate. Invasion assays were performed in dual-chamber culture wells containing matrigel inserts. hMSCs were plated into upper chambers containing: serum-free medium (SFM), SFM + Plasminogen, or SFM + Plasminogen + epsilon-aminocaproic acid (e-ACA inhibits binding of plasminogen to ANX2). After 24 hours, invasive cells were isolated and counted.
Results: Sternal bone marrow derived hMSCs expressed the membrane phenotype CD34 (−), CD14 (−), CD44 (+), CD105 (+), CD106 (+). The presence of ANX2 was confirmed by western blot analysis. hMSCs generated 1.95 units of plasmin per milligram of protein. There was a 20% (p 0 .004) increase in hMSC invasion in the wells containing plasminogen as compared to SFM alone. When e-ACA was introduced there was a decrease in hMSC invasion back to control values.
Conclusion: Our observations establish for the first time the presence and functional activity of ANX2 in hMSCs. These data suggest that mesenchymal stem cell expression of ANX2 facilitates plasminogen-mediated hMSC trans-endothelial invasion, migration and the release of pro-angiogenic factors from within the extracellular matrix, promoting stem cell directed repair and angiogenesis.
Human Myeloma Cells Express the Bone Regulating Gene Runx2/Cbfa1 and Produce Osteopontin That It Is Involved in Myeloma-Induced Angiogenesis.
Authors: Giuliani Nicola , Colla Simona , Morandi Francesca , Bonomini Sabrina , Crugnola Monica , Rizzoli Vittorio 
Published: April 2020

Abstract
Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that it is involved in angiogenesis, cell survival and tumor progression. OPN gene expression by human cells is mainly regulated by the bone specific trascription factor Runx2 namely also CBFA1 (Runx2/Cbfa1) even if other transcription factors may be also involved in the production of OPN by cancer cells as the CCAAT/enhancer-binding protein alpha (C/EBPα) and AML-1.
In this study we show that human myeloma cell lines (HMCLs): RPMI-8226, U266, XG-1 and XG-6 but not ARH-77 and normal CD19+ cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 in human myeloma cells has been also demonstrated by a gel mobility shift assay. On the other hand we found that all HMCLs tested were negative for C/EBPα mRNA, whereas AML-1A and AML-1B mRNA were expressed in all HMCLs even if any correlation has not been found between OPN expression and AML-1A/AML-1B ratio. In addition we found that OPN production by myeloma was up-regulated at both mRNA and protein level by IL-6 and IGF-I through a Runx2/Cbfa1 mediated mechanism; in turn recombinant human OPN was able to increase myeloma cells proliferation. The potential role of OPN in MM-induced angiogenesis has been also investigated in an experimental model of angiogenesis. rhOPN treatment stimulated vessel formation as compared to control and the conditioned medium (CM) of HMCLs, significantly increased vessel formation in comparison either with control or with VEGF treatment. On the contrary OPN-immunodepleted CM of HMCLs had not a stimulatory effect on vessel formation and the presence of anti OPN Ab inhibited vessel formation induced by HMCLs.
The expression of OPN by purified bone marrow (BM) CD138+ cells has been also investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to control subjects.
A significant higher MVD was observed in the group of patients positive for OPN, (mean±SE: 29.1±0.7 vs. 17.55±0.37; p&lt;0.01) and similarly, the number of microvessels per field was higher in OPN positive patients in comparison with OPN negative ones (mean±SE: 6.7±0.15 vs. 4.28±0.04; p=0.05).
In conclusion our data highlight the direct ectopic production of OPN by human myeloma cells with a Runx2/CBFA1 mediated mechanism and the capacity of myeloma-derived OPN to stimulate angiogenesis in vitro. In addition OPN has been detected in a subset of MM patients with higher BM angiogenesis suggesting its potential involvement in pathophysiology of MM-induced angiogenesis.
Constitutive Expression of CD40L on Bone Marrow Mast Cells Supports the Growth of Lymphoplasmacytic Cells in Patients with Waldenstrom’s Macroglobulinemia.
Authors: Tournilhac Olivier , Santos Daniel Ditzel , Xu Lian , Kutok Jeffery , Tai Yu Tsu , Le Gouill Steven , Hatjiharissi Evdoxia , Catley Laurie , Hunter Zachary , Branagan Andrew , Anderson Kenneth C. , Treon Steven P. 
Published: April 2020

Abstract
CD40 ligand (CD40L) is a potent inducer of normal and malignant B-cell proliferation through interaction with CD40. We and others have observed excess mast cells (MC) in bone marrow (BM) biopsies of WM patients, which are commonly found admixed with tumor aggregates. (Tournilhac et al, JCO 2004, 22:571S). We therefore sought to clarify the role of MC in WM. Co-culture of 0.5% paraformaldehyde fixed, or sublethally irradiated HMC-1, LAD, and KU mast or basophilic cell lines and sorted BM lymphoplasmacytic cells (LPC) from 10 WM patients resulted in MC dose-dependent tumor colony formation and/or proliferation as assessed by 3H-thymidine uptake studies. As demonstrated by immunohistochemical, multicolor flow cytometric (CD117+FceRI+) and/or RT-PCR analysis, CD40L was expressed on BM MC from 29 of 31 (94%), 11 of 13 (85%), and 7 of 9 (78%) of WM patients, respectively. In contrast, cell surface CD40L expression was not detected by immunohistochemistry (p=0.00005) and flow cytometry (p=0.003) in 5 normal donors, and only faint expression for 1 of 5 normal donors by RT-PCR (p=0.09). Moreover, by multicolor flow cytometry, CD40 was expressed on BM tumor cells from 14/17 (83%) patients. CD40 functionality was confirmed either by the G28.5 CD40 agonistic antibody which induced dose dependent proliferation or by the rh-CD40L which partly prevented serum starvation-induced-apoptosis of WM LPC from 4/4 and 3/4 patients respectively. Importantly, expansion of tumor cells from 3 of 4 patients in mixed cultures with paraformaldehyde fixed MC was blocked in a dose dependent manner by use of a CD40L blocking protein (CD40:Fc). These studies demonstrate that CD40L is constitutively expressed on the cell surface of BM MC in WM and support the growth of WM tumor cells, and therefore provide the framework for therapeutic targeting of MC and MC-WM cell interactions in WM.
Evidence for Clonality in Circulating Endothelial Progenitor Cells in Multiple Myeloma.
Authors: Ozcelik Tayfun , Vakil Varsha , Smith Eric , Braunstein Marc , Maroney Justin , Klueppelberg Uwe , Bagislar Sevgi , Akyerli Cemaliye , Batuman Olcay 
Published: April 2020

Abstract
A governing role for neoangiogenesis in the progression of multiple myeloma (MM) is indicated by the finding in patients of increased bone marrow microvascular density that is positively correlated with disease activity and is attenuated by treatment with thalidomide. Bone marrow angiogenesis in MM is largely driven by autocrine and paracrine effects of vascular endothelial growth factor (VEGF) via VEGF receptor-2 (KDR). Elucidation of the role of neovascularization in MM growth and dissemination is likely to result in identification of better therapeutic targets than those currently available as well as provide insight into the pathogenesis of MM. Circulating endothelial cells (CECs) contribute to angiogenesis and comprise mature ECs and endothelial progenitor cells (EPCs). The present study sought to characterize CECs and their relation to disease severity in MM. CECs, identified as CD34+/CD146+/CD105+/CD11− cells, were 6-fold higher in patients compared to controls, and correlated positively with serum M protein and β2-microglobulin (P&lt;.001 for both). In addition, circulating EPCs displayed late colony formation/outgrowth and capillary-like network formation on Matrigel. Effective thalidomide treatment inhibited these characteristics (P&lt;.001). Co-expression of KDR and early vascular antigen CD133 characterized EPCs in MM, and KDR mRNA elevations correlated positively with M protein levels (P&lt;.01). To evaluate the clonality of circulating EPCs, X-chromosome inactivation patterns were quantitated in female patients by human androgen receptor gene (HUMARA) assay. Radioactive (α-[33P] -dCTP) polymerase chain reaction amplification of DNA extracted from peripheral blood mononuclear cells showed that X-chromosome inactivation status was informative in 9 of the 11 MM patients. Distribution of the X-inactivation profiles according to age did not show a shift towards the skewed range in older patients or controls. DNA obtained from confluent EPCs outgrown from 4 informative patients showed an extremely skewed pattern of X-chromosome inactivation, with allele ratios of 90/10% in one patient and 97/3% in another patient, whereas a random pattern of X-chromosome inactivation was observed in two other patients displaying clonal restriction (allele ratios of 55/45% and 54/46%). Collectively, these data underscore the angiogenic aspect of MM and suggest that angioblast-like EPCs are a pathogenic biomarker and a rational treatment target in MM. Furthermore, the clonality of EPCs in MM suggests that the pathogenesis of MM may be tightly related to vascular endothelial cells both at the functional/angiogenic and at the genetic and ontogenic levels.
Pulsed Low Dose Intravenous Melphalan in Patients with AL Amyloidosis, Ineligible for Aggressive Treatment with High-Dose Melphalan and Stem Cell Transplantation.
Authors: Sanchorawala Vaishali , Seldin David C. , Wright Daniel G. , Skinner Martha , Finn Kathleen T. , Falk Rodney H. 
Published: April 2020

Abstract
AL amyloidosis is caused by a clonal plasma cell dyscrasia and characterized by widespread, progressive deposition of Amyloid fibrils derived from monoclonal Ig light chains, leading to multisystem organ failure and death. Aggressive treatment of AL amyloidosis with high-dose melphalan followed by autologous stem cell transplant (HDM/SCT) can induce hematologic and clinical remissions and extend survival. However, not all patients are able to tolerate HDM/SCT, particularly those with severe multisystem disease. Consequently, we investigated an alternative treatment regimen consisting of pulsed low-dose intravenous melphalan (LDM) for a series of patients considered ineligible for HDM/SCT because of severe cardiac involvement and poor performance status. LDM was administered at 17.5–25 mg/m2 every 4–6 weeks for 3–4 cycles depending upon patients’ clinical condition, renal function and performance status. Growth factor support was used with each cycle, and the dose of melphalan was reduced by 20% for white blood cell counts &lt;500/mm3 and/or platelet count &lt;20,000/mm3 during any treatment cycle. Changes in serum free light chain (FLC) levels, as well as toxicity and survival were evaluated. Fifteen patients with AL amyloidosis (11 males, 4 females; median age 55, range 47–69) were treated with this regimen between July 2002 and January 2004. Light chain isotypes were l in 11 cases and k in 4. All patients had clinically significant cardiac involvement with NYHA class III/IV congestive heart failure and/or left ventricular ejection fraction ≤ 45%, and/or ≥ 2 organ systems involved. The median number of LDM cycles given was 3 (maximum; 4), and 3 patients received only 1 cycle. Serum FLC levels were available before and after treatment in 10 patients. Eight of these patients (80%) achieved a &gt; 50% reduction in FLC levels, and 2 (20%) achieved normal FLC levels. One patient achieved a 20–25% reduction in the FLC, and 3 experienced no reduction. Of the15 patients treated, 2 patients survive 6 and 24 months after treatment, while 13 have died (median survival, 2 months; range, 0–10 months). Ten patients (67%) died within 35 days of initiating treatment. Transient myelosuppression was the major treatment-related toxicity with neutrophil and platelet nadirs occurring 12–16 days after melphalan infusions. There was 1 death from sepsis during treatment-induced myelosuppression. In summary, pulsed low-dose intravenous melphalan (LDM) was found to induce hematologic responses in most patients who could be evaluated. However, extended survival ≥ 2 years was observed in only 1 of the 15 patients with severe amyloidosis who were studied. Nonetheless, this regimen may benefit healthier patients, particularly those with less severe cardiac involvement, who are otherwise ineligible or unable to receive HDM/SCT.