bluuebunny/crossref_metadata_2025_split huggingface dataset:
A New Prognostic Index In Diffuse Large B-Cell Lymphoma Using Serum Albumin: A Pilot Study Evaluating The Albumin Adjusted-International Prognostic Index (A-IPI)
Authors: Dalia Samir , Chavez Julio C , Bello Celeste M. , Chervenick Paul A. , Little Bryan J , Al Ali Najla H , Sokol Lubomir , Sotomayor Eduardo M. , Lee Ji-Hyun , Fisher Kate , Thompson Zachary , Choi Bong-jin , Shah Bijal D. 
Published: October 2019

Abstract

Introduction
Low serum albumin (SA) has been identified as a prognostic marker in multiple hematological malignancies including diffuse large B-cell lymphoma (DLBCL). Low SA may be an indicator of worsening disease biology, increased inflammation, or increased co-morbidities. Changing demographics and improved care of the elderly may abrogate some of the risk attributable to age. SA, however, may not be influenced by such changes. Currently the Revised International Prognostic Index (R-IPI), the currently best accepted model for prognosis in DLBCL, does not account for albumin. We therefore explored the use of albumin as a prognostic variable in conjunction with the covariates included in the R-IPI.

Methods
Patients with DLBCL treated between 2007-2010 with RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) were retrospectively identified using the Moffitt Total Cancer Care platform. Age, ECOG performance status, LDH, extrandoal sites of disease, stage, and albumin were collected and analyzed using Random Forest Modeling. Both age and extranodal involvement failed to retain statistical significance and were dropped from the model, leading to the generation of a new algorithm, the Albumin Adjusted IPI (A-IPI). This score assigned a point for SA<3.7g/dL, LDH >the upper limit of normal, ECOG performance status >=2, and Ann Arbor stage III-IV. Progression free and overall survival was compared by the risk groups using Kaplan-Meier curves along with the log rank test. Statistical analysis was done using R statistical software.

Results
A total of 124 patients were identified. Median age was 58 years with 62% male. 46% were over the age of 60 at diagnosis and 63% were Ann Arbor stage 3 or 4. The A-IPI score identified three groups of patients (Very good: A-IPI=0, Good: A-IPI=1-2, Poor: A-IPI=3-4), similar to the R-IPI. PFS and OS at 4 years were compared using the A-IPI and R-IPI (Table 1).

Conclusions
In comparison to the R-IPI, the A-IPI appears to better define poor risk patients while retaining the ability to discriminate well between low (“Very Good”) and intermediate (“Good”) risk groups. Confirmation in a larger and prospective cohort is indicated, however, these preliminary data suggest SA may be a better surrogate for co-morbid status, pro-inflammatory states, and worse disease biology than age in patients with DLBCL.

Disclosures:
No relevant conflicts of interest to declare.
A “Universal” Lectin-Mediated Interaction Drives B-Cell Receptor Signaling In Primary Follicular Lymphoma Cells
Authors: Packham Graham , Krysov Serge , Coelho Vania , Johnson Peter , Stevenson Freda K. 
Published: October 2019

Abstract
B-cell receptor (BCR) signaling has been identified as a critical driver of B-cell malignancies and as a target for therapeutic attack. Clinical responses to novel inhibitors of BCR-associated kinases have been relatively modest in follicular lymphoma (FL) and a more detailed knowledge of BCR function in these cells is required. Surface Ig (sIg) is unusual in FL since variable regions contain N-linked glycosylation sites which are introduced by somatic mutation. These are rarely found in normal B cells, indicating strong positive selective pressure in malignant cells. Remarkably, added sugars terminate with high mannose suggesting a novel function for FL BCRs in binding to, and perhaps receiving stimulation via, microenvironmental mannose-binding lectins. In previous studies we demonstrated that candidate mannose-binding lectins, including DC-SIGN, promote intracellular calcium mobilization in primary FL cells, but not normal B cells. In this work, we characterized in more detail the response of FL cells to DC-SIGN and its inhibition by BCR-targeted kinase inhibitors.
Initial studies using immunoblotting demonstrated that, like anti-Ig antibodies, DC-SIGN caused increased phosphorylation of the downstream kinases AKT and ERK in primary FL samples. DC-SIGN treatment also resulted in increased expression of the MYC oncoprotein in a subset of samples. In contrast to FL samples, DC-SIGN did not increase AKT or ERK phosphorylation in normal B cells although anti-IgM induced strong responses in these cells. Overall, responses to DC-SIGN were similar in IgM+ and IgG+ FL samples. Flow cytometry demonstrated that DC-SIGN also increased phosphorylation of proximal signaling kinases (SYK and BTK), as well as phosphorylation of PLCγ2 in FL samples, and that DC-SIGN-induced signaling occurred within the CD19+BCL2+ malignant cells. Flow cytometry also revealed intraclonal variation in responses to DC-SIGN and, like responses to anti-Ig, DC-SIGN responses were strongest in a sub-population of malignant cells with high CD20 expression. Finally, we demonstrated that tamatinib, the active form of the SYK inhibitor pro-drug fostamatinib, significantly inhibited phosphorylation of ERK and PLCγ2 induced by either anti-Ig or DC-SIGN.
Overall our results are consistent with the hypothesis that N-linked glycosylation sites, introduced into BCRs by somatic mutation, are selected for in FL since they confer signaling responsiveness following binding of environmental lectins. Like canonical antigen signaling, lectin-mediated signaling via the BCR appears to be susceptible to therapeutic blockade using kinase inhibitors. However, further analysis of this novel lectin-mediated pathway may reveal novel targets for optimal therapeutic attack.

Disclosures:
No relevant conflicts of interest to declare.
Lack Of Clinical Benefit For Routine Surveillance Imaging For Diffuse Large B-Cell Lymphoma In First Complete Remission
Authors: Vose Julie M , Pingali Ravi , Wagner-Johnson Nina , Loberiza Fausto R. , Fenske Timothy S. , Jewell Sarah , Bast Martin , Bartlett Nancy L. , Armitage James O. 
Published: October 2019

Abstract

Background
The use of routine surveillance imaging (RSI) for patients in first complete remission (CR1) following front-line rituximab (R) based anthracycline therapy remains controversial. We compared patients with diffuse large B-cell lymphoma (DLBCL) who received an R-CHOP or a similar regimen, obtained a CR and then were followed by either RSI or clinical surveillance (CS) in which scans were only performed for signs or symptoms.

Methods
Patients from three tertiary care center from 2001-2011, who achieved a CR1 with frontline R-CHOP or similar therapy for DLBCL, and had a minimum follow up of 1 year were analyzed. Patients with HIV-related lymphoma, transformed lymphoma, and post-transplant lymphoproliferative disorders were excluded. Patients with composite lymphoma were included only if the DLBCL component was >50%. Patients were stratified into two groups based on the surveillance strategy employed. Baseline patient characteristics, prognostic features, treatment type, and outcomes were compared.

Results
391 patients with DLBCL treated with R-CHOP or similar regimens who obtained CR1 were analyzed. There were 129 patients in the CS group and 262 in the RSI group. Patient characteristics (age, gender, stage, and IPI) were similar in the two groups. The median follow up is 5 years (range 1 – 12). Relapse after CR1 was detected in 26 (20%) of patients in the CS group and 46 (18%) of the RSI group. The median number of images in the CS group was 0 (range 0-14) and 4 (range 1-27) in the RSI group, p<0.0001. The median average number of images per year of follow up in the CS group was 0 (range 0-6) and 1 (range 1-13) in the RSI group, p<0.0001. Relapses were detected through clinical manifestations in 100 % of CS cases versus 43% in RSI cases, p=0.01. The 5 year progression-free survival (PFS) was 76% in the CS group and 82 % in the RSI group (p = 0.31). The 5 year overall survival (OS) was 87% in the CS group and 92 % in the RSI group (p=0.15). The table shows an analysis of OS by IPI and type of surveillance.

Conclusions
The majority of relapses in patients with DLBCL after achieving CR1 to an R-CHOP or similar regimen occur when signs or symptoms of the disease lead to evaluation and are not detected by RSI. Although asymptomatic relapses are occasionally detected by RSI, in this large cohort of patients neither a PFS nor OS benefit could be demonstrated in favor of RSI. Given the additional cost, radiation exposure and risk of additional procedures, we conclude that the use of RSI in patients with DLBCL in CR1 has limited clinical utility.

Disclosures:
No relevant conflicts of interest to declare.
The Role Of Modified Glasgow Prognostic Score As Predictor In Diffuse Large B Cell Lymphoma Treated With The R-CHOP Regimen
Authors: Kim Yundeok , Kim Yu Ri , Kim Soo Jeong , Jieun Jang , Shin-Young Hyun , Dohyu Hwang , Kim Jin Seok , Hong Min Yoo , Cheong June-Won , Hyun Lee Jung 
Published: October 2019

Abstract

Background
The modified Glasgow Prognostic Score (mGPS), an inflammation-based prognostic score consisting of serum C-reactive protein (CRP) levels and serum albumin levels, shows significant prognostic value in several types of tumors. However, the prognostic value of GPS in lymphoma remains unclear. In this study, we evaluated the prognostic significance of mGPS in patients with diffuse large B cell lymphoma (DLBCL).

Methods
The medical records of 285 DLBCL patients (156 males, 128 females) who were treated with R-CHOP chemotherapy at Yonsei University Severance Hospital were retrospectively reviewed. Patients with an elevated CRP level (³10 mg/L) and hypoalbuminemia (<3.5 g/dL) were given a score of 2, patients with CRP elevated were assigned a score of 1, and patients with neither of these abnormalities were scored 0.

Results
The study population included 285 patients with a median age of 58 years (range, 21-87 years). According to mGPS classification, 204 patients (71.5%) had an mGPS of 0, 57 patients (20%) had an mGPS of 1, and 24 patients (8.5%) had an mGPS of 2. Our study found that high mGPS were associated with poor prognostic factors including older age (>60 years), extranodal (EN) involvement, advanced disease stage, unfavorable IPI scores, and the presence of B symptoms. After 3 cycles of R-CHOP chemotherapy, 144 of the 285 treated patients (50.5%) achieved complete response (CR) or CR unconfirmed (CRu). The CR rate after 3 cycles of R-CHOP chemotherapy was significantly higher in patients with mGPS of 0 (53.8%) compared to those with mGPS of 1 (33.3%) or 2 (25.0%) (P=0.001). Fifty-four (30.2%) patients eventually died. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates for 285 patients were 77.2% and 72.8%, respectively. Patients with mGPS of 0 had significantly better OS than those with scores of 1 (5-year PFS, vs. 74.1%) or 2 (80.9% vs. 54.7; P=0.036). Patients with mGPS of 0 also displayed significantly better OS than patients with mGPS of 2 (P<0.001). The 5-year PFS rate was 76.1% in patients with mGPS scores of 0, 62.3% in patients with scores of 1, and 66.4% in those with scores of 2. Patients with lower mGPS scores tended to have longer PFS compared to patients with higher mGPS, although it was statistically insignificant (P=0.112). Multivariate analyses revealed that the GPS score was a prognostic factor for the CR rate of 3 cycle R-CHOP therapy (P=0.044) as well as OS (P=0.037).

Conclusion
Similar to several other cancers, GPS can be an independent predictor of survival outcomes in DLBCL patients treated with R-CHOP therapy.

Disclosures:
No relevant conflicts of interest to declare.
Interactions Between PD-1 and PD-L1 and PD-L2 Promote Malignant B-Cell Growth in Waldenstrom Macroglobulinemia
Authors: Grote Deanna M. , Ziesmer Steven C. , Hodge Lucy S. , Price-Troska Tammy L. , Novak Anne J. , Yang Zhi-Zhang , Ansell Stephen M 
Published: October 2019

Abstract
Programmed death 1 (PD-1) is a T cell co-inhibitory receptor with two ligands, PD-L1 and PD-L2. In B-cell malignancies, this pathway plays a major role in immune resistance in the tumor environment by promoting the differentiation of regulatory T-cells and inducing T-cell exhaustion. Recent data have shown that blockade of this pathway can enhance antitumor immune responses. While interactions between PD-1 and its ligands have been studied in various lymphoid tissues, little data exist regarding these interactions in the bone marrow, particularly in patients with Waldenstrom macroglobulinemia (WM). The goal of this study was therefore to determine the expression of PD-1 and its ligands in the bone marrow of patients with WM and to assess the functional role of PD-1 signaling in this disease.
Using immunohistochemistry, the expression of PD-1, PD-L1 and PD-L2 in bone marrow (BM) specimens from patients with WM (n=6) was compared to normal control BM. PD-1 expression was modest and the pattern of staining in WM was similar to normal BM. In contrast however, intense staining for PD-L1 and PD-L2 was seen in WM compared to controls. When analyzed by flow cytometry, PD-L1 and PD-L2 expression was seen on malignant B-cells and also on dendritic cells, monocytes and macrophages isolated from the bone marrow. To determine the functional effect of PD-1 signaling in WM, we stably transfected PD-L1 and PD-L2 into the HEK-293 cell line. The WM cell lines, MWCL-1, BCWM.1 and RPCI-WM1 as well as patient specimens, were then cocultured with either the PD-L1 or PD-L2 expressing HEK-293 cells. When compared to cells expressing an empty vector control, proliferation and viability of WM cells was increased when they were cocultured with cells expressing PD-L1 or PD-L2. Addition of blocking antibodies abrogated the increase in proliferation.
These results show that PD-L1 and PD-L2 are highly expressed on both malignant B-cells and non-malignant cells within the BM microenvironment in WM and promote malignant B-cell growth. Inhibition of PD-1 signaling may therefore be a promising therapeutic strategy in patients with WM.

Disclosures:
No relevant conflicts of interest to declare.
Oral Arsenic Trioxide Based Regimen As Salvage Treatment For Relapsed Or Refractory Mantle Cell Lymphoma
Authors: Gill Harinder , Au Wing-Yan , Cheung Winnie W.W. , Kwong Yok Lam 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoproliferative disorder, and relapsed/refractory disease has a poor prognosis. In patients with relapsed / refractory MCL, optimal treatment strategy remains undefined. Oral arsenic trioxide (As2O3) was initially developed for the treatment of relapsed acute promyelocytic leukemia (APL). As2O3 inhibits neoplastic cellular proliferation by a wide array of mechanisms, including induction of apoptosis, targeting of signaling pathways, and down-regulation of BCL-2. Evidence in vitro also suggested that As2O3 might be effective in lymphoma, but clinical data are hitherto not available. In this study, we investigated the use of an oral-As2O3-based regimen for the treatment of patients with relapsed / refractory MCL. Thirty-nine patients (men=34, women=5) at 64 (41–82) years of age with relapsed/refractory MCL, who had received 2 (1–5) prior regimens and were ineligible for high-dose chemotherapy, were treated with a continuous oral regimen, comprising oral arsenic trioxide (oral-As2O3), chlorambucil and ascorbic acid. The overall response rate was 49% (complete response: 28%; partial response: 21%). Only grade 1/2 toxicities were observed (hematologic: 56%, hepatic: 8%). Independent prognostic factors for response were increased lactate dehydrogenase (P=0.04) and unfavorable MCL international prognostic index (P=0.04). At a median follow up of 21(range:1-118) months, the median progression-free-survival (PFS) was 16 months, and overall-survival (OS) 38 months. The 2-year and 5-year PFS were 41% and 29% respectively. The 2-year and 5-year OS were 56% and 43% respectively. Independent prognostic factors for PFS were female gender (P=0.002), Eastern Cooperative Oncology Group (ECOG) performance score of 2 (P=0.009), and non-response to treatment (P<0.001). Independent prognostic factors for OS were female gender (P<0.001), ECOG performance score of 2 (P=0.03), non-response to treatment (P<0.001), and disease progression while on treatment (P=0.05). These findings showed that an oral regimen of oral-As2O3, chlorambucil and ascorbic acid was an active regimen with minimal toxicity in relapsed/refractory MCL, achieving durable responses in some cases.

Disclosures:
No relevant conflicts of interest to declare.
Real World Data On Primary Treatment For Mantle Cell Lymphoma 2000-2011 – a Nordic Lymphoma Group Observational Study
Authors: Abrahamsson Anna , Lindblad Alexandra Albertsson , Brown Peter de Nully , Wennerholm Stefanie Baumgartner , Pedersen Lars Moller , d'Amore Francesco , Nilsson-Ehle Herman , Jensen Paw , Pedersen Michael , Geisler Christian H. , Jerkeman Mats 
Published: October 2019

Abstract

Background
There is a consensus that younger patients with mantle cell lymphoma (MCL) should receive intensive immunochemotherapy regimens including high-dose cytarabine, rituximab and high-dose chemotherapy with stem cell support, but the optimization of treatment for elderly or unfit patients, as well as patients with localized or indolent disease, remains a challenge.

Methods
Our study is based on data from the Swedish and Danish Lymphoma Registries from the period of 2000-2011, in Sweden supplemented by review of patients´ records. The Lymphoma Registries comprise >95% of all diagnosed lymphoma patients in Sweden and Denmark.

Results
1389 patients were diagnosed with MCL, confirmed by positive cyclin-D1 and CD5 staining, in Sweden and Denmark between 2000 and 2011. In this population based cohort, we could confirm the prognostic impact of MIPI, but in addition, male sex was associated with inferior overall survival (OS) in multivariate analysis (HR 1.4, p<0.001). Treatment with the Nordic MCL2 regimen (n=324) was associated with superior outcome compared to the majority of other regimens (3-year OS: 80%). In patients >65 years, chlorambucil (n=132) was superior to CVP (n=35) (HR 1.8, p=0.003), when adjusted for MIPI and rituximab, but there was no significant difference between CHOP (n=311) and CHOP+Cytarabine (n=84). Rituximab (HR 1.5, p<0.001) and autologous stem cell transplantation (HR 1.9, p<0.001 ) per se were both associated with prolonged OS in multivariate analysis. Forty-three (3.1%) patients with stage I-II disease received radiotherapy as primary treatment with curative intent showing an estimated 3-year OS of 93%. A small proportion, 29 patients (2.1%), were followed without treatment. Estimated 3-year OS for this group of patients was 79%.

Conclusion
By a population-based approach, we were able to provide novel data on prognostic factors and primary treatment of MCL, applicable to routine clinical practice.

Disclosures:
No relevant conflicts of interest to declare.
Network Analysis Of Single Cells Identifies DDIT3 As a Nucleator Of Erythroid Signatures In Early Erythro-Myelopoiesis
Authors: Pina Cristina , Teles Jose , Fugazza Cristina , Guo Yanping , May Gillian , Peterson Carsten , Enver Tariq 
Published: October 2019

Abstract
Analysis of individual cells within phenotypically-uniform stem and progenitor populations reveals heterogeneity of cell states and affords exploration of their differential contribution to fate transitions. Herein, we investigate the transcriptional composition of lineage commitment transitions in the mouse hematopoietic system, obtained either spontaneously or driven by individual transcription factors (TF), to define alternative molecular states at the emergence of erythroid and myeloid lineage identity.
To this end, we transcriptionally profile hundreds of individual cells across a spectrum of lineage states by quantitative RT-PCR on a Fluidigm platform. We explore the dual binary (on-off) vs. continuous (expression level) nature of PCR data and respectively calculate odds ratio, and Spearman correlation on co-expressing cells, for any pair of genes, in order to infer the circuitry underlying alternative routes to lineage commitment. This approach identifies Ddit3 as a specific target of GATA-driven networks that antagonizes Cebpa transcriptionally at the emergence of myeloid fate.
Knockdown and knockout approaches indicate a requirement for Ddit3 in early erythroid decisions from stem cells. Enforced expression of Ddit3 in granulocytic-monocytic progenitors (GMP) results in down-regulation of individual Cebpfamily members and their downstream transcriptional programmes, including myelo-monocytic cytokine receptors. Notably, the resulting cells have robust self-renewal potential and express an early erythroid signature that is augmented in the presence of interleukin-3 and erythropoietin.
Taken together, the data suggest that Ddit3 can nucleate incipient erythroid-affiliated programmes in early erythro-myelopoiesis, and may contribute to fate choice through antagonism with Cebp networks. Interestingly, ex-vivo culture and expression profiling of individual wild-type and DDIT3-enforced GMP suggest that the erythroid-primed state captured through Ddit3 expression may be found in a small proportion of native GMP, suggesting some fluidity of lineage identity in early progenitors.

Disclosures:
No relevant conflicts of interest to declare.