Factor In non-Hodgkin Lymphoma Research Articles

Semi-automated 18F-FDG PET segmentation methods for tumor volume determination in Non-Hodgkin lymphoma patients: a literature review, implementation and multi-threshold evaluation

In the treatment of Non-Hodgkin lymphoma (NHL), multiple therapeutic options are available. Improving outcome predictions are essential to optimize treatment. The metabolic active tumor volume (MATV) has shown to be a prognostic factor in NHL. It is usually retrieved using semi-automated thresholding methods based on standardized uptake values (SUV), calculated from 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) images. However, there is currently no consensus method for NHL. The aim of this study was to review literature on different segmentation methods used, and to evaluate selected methods by using an in house created software tool.A software tool, MUltiple SUV Threshold (MUST)-segmenter was developed where tumor locations are identified by placing seed-points on the PET images, followed by subsequent region growing. Based on a literature review, 9 SUV thresholding methods were selected and MATVs were extracted. The MUST-segmenter was utilized in a cohort of 68 patients with NHL. Differences in MATVs were assessed with paired t-tests, and correlations and distributions figures.High variability and significant differences between the MATVs based on different segmentation methods (p < 0.05) were observed in the NHL patients. Median MATVs ranged from 35 to 211 cc.No consensus for determining MATV is available based on the literature. Using the MUST-segmenter with 9 selected SUV thresholding methods, we demonstrated a large and significant variation in MATVs. Identifying the most optimal segmentation method for patients with NHL is essential to further improve predictions of toxicity, response, and treatment outcomes, which can be facilitated by the MUST-segmenter.

Diagnosis of a plasmoblastic lymphoma of the mandible after renal transplantation: a case report

Introduction: Post-transplant lymphoproliferations (PTL) are a severe complication of solid organ transplants. Their locations can be extra-nodal. Observation: The diagnosis and management of a non-Hodgkin's plasmablastic lymphoma of mandibular localization affecting a 66-year-old kidney transplanted patient are reported here. Comment: The main risk factors for non-Hodgkin lymphoma are immunosuppression and infection with Epstein-Barr virus. Clinical and radiographic examinations, which are not specific, must be supplemented by a histological examination. Treatment which is not consensual will most often consist of a reduction in immunosuppression coupled with chemotherapy. Conclusion: Despite a constant evolution in the incidence and clinical picture of post-transplant lymphomas, the role of the dentist remains essential in the early detection of lesions.

Abstract CT133: Targeting BCL-2 and MCL-1 overcomes treatment resistance in relapsed and refractory non-Hodgkin lymphoma: Pre-clinical rationale and results from an open-label phase 1b study

Abstract Purpose: Treatment of patients with relapsed or refractory lymphoid neoplasms represents a significant clinical challenge, largely due to the genetic heterogeneity of these malignancies. Our study goal was to design a rational treatment strategy that simultaneously targets multiple disease drivers to provide safe, efficacious, and durable responses in patients with relapsed or refractory non-Hodgkin lymphoma (NHL). Experimental procedures and data summary: Venetoclax is a selective BCL-2 inhibitor that induces apoptosis and is efficacious in chronic lymphocytic leukemia; however, single-agent efficacy in other lymphoid neoplasms is limited. Using pharmacologic and genetic studies, we identified the pro-survival BCL-2 protein family member MCL-1 as a venetoclax resistance factor in NHL cell lines. We found that the monomethyl auristatin E (MMAE) payload of the antibody-drug conjugate polatuzumab vedotin promotes MCL-1 degradation via the ubiquitin/proteasome system, thus providing a strong rationale for combination with venetoclax. Mechanistically, polatuzumab vedotin combined with venetoclax promoted apoptotic NHL cell death. In NHL animal models, venetoclax, polatuzumab vedotin, and the anti-CD20 antibody obinutuzumab, that activates targeted antibody- and complement-dependent cell cytotoxicity, produced durable tumor regressions. In a phase 1b clinical trial, 33 patients with relapsed or refractory follicular lymphoma were evaluable for response over 6 dose levels with 19 complete responses and 6 partial responses (overall response rate 76%). All patients (8 of 8) treated with the recommended phase 2 regimen (venetoclax 800mg + polatuzumab vedotin 1.8mg/kg + obinutuzumab 1000mg) achieved complete responses at end of induction. The median duration of follow-up for all dose levels was 17.7 months. This triplet combination was well-tolerated by most patients and had an expected and acceptable safety profile. Conclusions: Our studies implicate MCL-1 as a key venetoclax resistance factor in NHL that can be overcome by polatuzumab vedotin, which promotes MCL-1 degradation. Pre-clinical NHL animal models and early clinical data confirmed that the combination of venetoclax, polatuzumab vedotin, and obinutuzumab is safe and promotes durable responses. Because MMAE and other anti-tubulin agents are likely not the only therapeutics that antagonize MCL-1, our study provides scientific rationale to pursue the broader strategy of identifying other therapeutics that similarly neutralize MCL-1 function. Such agents could be used in combination with venetoclax in other malignancies where MCL-1 is a venetoclax resistance factor. Our mechanism-based treatment regimen that directly targets oncogenic drivers in NHL patients may serve as a framework for treating other malignancies with complex etiologies. Citation Format: Dhara N. Amin, Rajat Bannerji, Raghuveer Singh Mali, Jason Oeh, Eva Lin, Anuradha Zindal, MaryAnn Go, Shang-Fan Yu, Maxwell Krem, Chris Arthur, Uwe Hahn, Anna M. Johnston, Vinit G. Karur, Nadia Khan, Paula Marlton, Tycel Phillips, Giuseppe Gritti, John F. Seymour, Monica Tani, Sam Yuen Yuen, Scott Martin, Matthew T. Chang, Christopher M. Rose, Victoria C. Pham, Elizabeth A. Lasater, Andrew G. Polson, YiMeng Chang, Jamie Hirata, Lisa Musick, Deepak Sampath, Christopher R. Flowers, Ingrid E. Wertz. Targeting BCL-2 and MCL-1 overcomes treatment resistance in relapsed and refractory non-Hodgkin lymphoma: Pre-clinical rationale and results from an open-label phase 1b study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT133.

Prophylactic antibiotic treatment with TMP-SMX decreased the incidence of interstitial pneumonia in patients with B-cell lymphoma on chemotherapy

BackgroundSeveral studies have reported the incidence of interstitial pneumonia (IP) among patients with non-Hodgkin lymphoma (NHL) that are undergoing combination chemotherapy plus rituximab; however, the effective prophylactic treatment for IP remains unclear. This study aims to explore the prophylactic effect of trimethoprim-sulfamethoxazole (TMP-SMX) on IP and identify IP-associated risk factors in NHL patients.MethodsBetween March 2013 and April 2018, 498 patients (264 males, 53%) with B-cell NHL undergoing first-line RCHOP-like chemotherapy treatment with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone were enrolled in this study.ResultsThese patients had a median age of 56 years, and 311 of the 498 patients (62.4%) were administered once daily with the prophylactic treatment of TMP-SMX. IP occurred in 65 patients (13.1%), indicating a significant reduction in the IP incidence rate (21.4% vs. 8.0%; p < 0.001). Among patients treated with TMP-SMX, 2 (1.2%) exhibited rashes, 38 (12.2%) suffered from nausea and vomiting, 52 (16.7%) showed signs of neutropenia, and 18 (5.8%) suffered from kidney dysfunction. Both univariate and multivariate analysis showed that gender (male), history of diabetes, and absence of prophylactic TMP-SMX treatment were significant risk factors associated with IP. Disease progression was observed in 55/311 (17.7%) patients that underwent prophylactic TMP-SMX treatment and in 63/187 (33.7%) patients that did not (p < 0.001).ConclusionsThis study revealed that the occurrence of IP was common in B-cell NHL patients undergoing combined chemotherapy plus rituximab treatment. IP could be reduced with prophylactic treatment of once-daily oral TMP-SMX.

Expression and clinical significance of neuropilin-1 in Epstein-Barr virus-associated lymphomas.

The expression of neuropilin-1 (NRP-1) in Epstein-Barr virus (EBV)-associated lymphomas and its relationships with clinicopathological parameters was investigated. The researchers compared 111 cases of patients with lymphoma to 20 cases of reactive lymphoid hyperplasia. In situ hybridization was applied to observe the expression of EBV-encoded RNA (EBER) in lymphomas, and immunohistochemistry was used to detect the NRP-1 expression in lymphoma tissues and lymph node tissues with reactive hyperplasia. In these 111 cases, the EBER of 62 cases (55.9%) appeared positive. NRP-1 was relatively highly expressed in lymphomas (P= 0.019). Further, NRP-1 showed higher expression in lymphomas with positive EBER than in negative ones. A comprehensive analysis revealed that NRP-1 was differently expressed in NK/T-cell lymphoma, Hodgkin's lymphoma, diffuse large B-cell lymphoma, and anaplastic large cell lymphoma (P= 0.027). Moreover, highly expressed NRP-1 was found to be a useful independent prognostic factor in assessing overall survival and progression-free survival rates in cases of non-Hodgkin's lymphoma (NHL). NRP-1 exhibited higher expression in lymphomas, and it was positively expressed in EBV-positive lymphomas. Moreover, highly expressed NRP-1 can be used as an undesirable independent prognostic factor in NHL.

A multivariable approach for risk markers from pooled molecular data with only partial overlap

BackgroundIncreasingly, molecular measurements from multiple studies are pooled to identify risk scores, with only partial overlap of measurements available from different studies. Univariate analyses of such markers have routinely been performed in such settings using meta-analysis techniques in genome-wide association studies for identifying genetic risk scores. In contrast, multivariable techniques such as regularized regression, which might potentially be more powerful, are hampered by only partial overlap of available markers even when the pooling of individual level data is feasible for analysis. This cannot easily be addressed at a preprocessing level, as quality criteria in the different studies may result in differential availability of markers – even after imputation.MethodsMotivated by data from the InterLymph Consortium on risk factors for non-Hodgkin lymphoma, which exhibits these challenges, we adapted a regularized regression approach, componentwise boosting, for dealing with partial overlap in SNPs. This synthesis regression approach is combined with resampling to determine stable sets of single nucleotide polymorphisms, which could feed into a genetic risk score. The proposed approach is contrasted with univariate analyses, an application of the lasso, and with an analysis that discards studies causing the partial overlap. The question of statistical significance is faced with an approach called stability selection.ResultsUsing an excerpt of the data from the InterLymph Consortium on two specific subtypes of non-Hodgkin lymphoma, it is shown that componentwise boosting can take into account all applicable information from different SNPs, irrespective of whether they are covered by all investigated studies and for all individuals in the single studies. The results indicate increased power, even when studies that would be discarded in a complete case analysis only comprise a small proportion of individuals.ConclusionsGiven the observed gains in power, the proposed approach can be recommended more generally whenever there is only partial overlap of molecular measurements obtained from pooled studies and/or missing data in single studies. A corresponding software implementation is available upon request.Trial registrationAll involved studies have provided signed GWAS data submission certifications to the U.S. National Institute of Health and have been retrospectively registered.

The relation of vitamin D level to adverse prognostic factors in Non Hodgkin lymphoma: A single center analysis

Vitamin D insufficiency has been found to be associated with higher incidence of NHL, besides the lower levels are linked with poor prognosis. The current study was conducted to assess vitamin D level in newly diagnosed chronic lymphocytic leukemia (CLL) and diffuse large B- cell lymphoma (DLBC) patients. In addition, grade of lymphoma was evaluated with the relation of hypo-vitaminosis D and adverse prognostic parameters. 74 patients (50% CLL and 50% DLBCL) were enrolled in this study. All patients with CLL had vitamin D insufficiency which correlated with advanced Rai and Binet stage. About 91.8% of DLBCL patients had vitamin D insufficiency which correlated with bad ECOG performance, advanced Ann-Arbor staging, high LDH and extranodal involvement. Vitamin D levels in the CLL group were significantly lower than DLBCL group. However, we could not detect an impact of the severity of deficiency on the lymphoma grade.

Vascular endothelial growth factor &amp; basic fibroblast growth factor polymorphism as prognostic factors in Non-Hodgkin Lymphoma

Vascular endothelial growth factor &amp; basic fibroblast growth factor polymorphism as prognostic factors in Non-Hodgkin Lymphoma

Correlation of Patterns of Bone Marrow Infiltration and Biochemical factors in Non-Hodgkin Lymphoma.

Objectives:To investigate the patterns of bone marrow involvement in in Non-Hodgkin’s Lymphoma (NHL) patients and to correlate the patterns with β2 microglobulin (β2m) and lactate dehydrogenase 2 (LD2) levels in these patients.Methods:It was a cross sectional study which was conducted in two years at Post Graduate Medical Institute, Lahore and at Centre of Excellence in Molecular Biology (CEMB), Lahore. The study was conducted on 50 subjects irrespective of age and sex divided into two groups i.e. Group-A comprising 20 normal healthy controls while Group-B consisted of 30 patients of NHL with bone marrow infiltration. Bilateral bone marrow trephine biopsy was done to assess the patterns of bone marrow infiltration. Serum β2m and LD2 isoenzyme levels were determined in already diagnosed 30 patients of NHL. The values were compared with 20 healthy age and sex matched controls. Correlation coefficients were determined using Pearson’s Correlation Coefficient. The estimations were made prior to the institution of chemotherapy.Results:β2m and LD2 levels were significantly (p-Value < 0.05) raised in NHL patients with disease advancement and were compared with controls. These serological markers showed negative correlation (-0.235 for β2m and -0.133 for LD2) with the spread of disease and patterns of involvement in NHL patients.Conclusion:By observing the patterns of bone marrow involvement in NHL patients possible guidelines about prognosis and treatment protocols can be obtained as the serological markers levels correlate well with the spread of disease and patterns of involvement in NHL patients.

Sustained Natural Killer Cell Recovery Post-Autologous Peripheral Blood Hematopoietic Stem Cell Transplantation Predicts Survival in Non-Hodgkin's Lymphoma

AbstractOur group recently reported a Phase III clinical trial (Porrata et al. Biology of Blood and Marrow Transplantation 2016; 22: 1017-1023) demonstrating that the infusion of the autograft-absolute lymphocyte count (A-ALC) and autograft natural killer cells (A-NKC) are survival prognostic factors in non-Hodgkin lymphoma (NHL) patients treated with autologous peripheral blood hematopoietic stem cell transplantation (APBHSCT). A limitation of our Phase III clinical trial was the short-term follow-up of just two years. Therefore, we evaluated longer follow-up and assessed the role of the infused A-ALC, infused A-NKC, and peripheral blood absolute natural killer cell count (ANKC) recovery on survival post-APBHSCT. Of the 122 patients that participated in the Phase III trial, 111 patients were able to complete APBHSCT and included in the current study. With a median follow-up of 57.2 months (range: 2.1-84.6 months), superior overall survival (OS) and progression-free survival (PFS) was observed in patients infused with an A-ALC ≥ 0.5 x 109 lymphocytes/kg [OS: HR = 0.429, 95%CI, 0.128-0.828, p < 0.01; and PFS: HR = 0.456, 95% CI, 0.177-0.863, p < 0.01] and an A-NKC ≥ 0.09 x 109 cells/kg [OS: HR = 1.58e-3, 95% CI, 1.046e-6-0.179, p < 0.003; and PFS: HR= 1.58e-3, 95% CI, 7.81e-7-0.064, p < 0.003]. Furthermore, patients that maintained an ANKC ≥ 250 cells/µl at 3 months, 6 months, 9 months and 12 months post-APBHSCT also experienced superior OS (Figure 1A) and PFS (Figure 1B)[OS and PFS times in months were evaluated from infusion date of stem cells]. In the multivariate analysis a sustained ANKC ≥ 250 cells/µl was an independent predictor for OS (HR = 0.013, 95% CI, 0.001-0.063, p < 0.0001) and PFS (HR = 0.014, 95% CI, 0.001-0.067, p < 0.0001). This study is an extension of our Phase III clinical trial showing that sustained innate immunity by measuring the ANKC correlated with superior clinical outcomes; thus providing a platform to develop innate immunity immunotherapeutic strategists directing to improve clinical outcomes post-APBHSCT in NHL patients. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Inhibiting IL-2 Signaling and the Regulatory T-Cell Pathway Using Computationally Designed Novel Peptides

Regulatory T-cells (TREG) are the gateway to immune function and typically regulate immune cell activation. Cytokines, including interleukin-2 (IL-2), induce T-cell differentiation and promote a regulatory phenotype. Once activated via the IL-2 receptor (IL-2R), a cascade of events in T-cells initiate signal transducer and activator of transcription 5 (STAT5) and Forkhead box P3 (FOXP3) activation which appear to function as important regulators of this immunologic pathway and promote the development and function of TREG cells. In non-Hodgkin lymphoma (NHL), we have found that intratumoral TREG cells are increased in number and suppress immune function. In previous work, we have found that TREG cells inhibit T-cell proliferation, suppress cytokine production and limit effector cell cytotoxicity. We have also shown that increased serum levels of soluble sIL-2Rα is a prognostic factor in NHL and that sIL-2Rα can bind to IL-2 and promote its signaling thereby increasing TREG cell numbers. In this study, we developed a strategy to inhibit the binding of IL-2 to sIL-2Rα with the goal of suppressing the induction of FOXP3 and decreasing TREG cell numbers. To do this, we developed peptides designed to disrupt the interaction between IL2 and sILRα.In collaboration with CMDBioscienceSM, we developed and analyzed 22 peptide compounds derived by structure-based computational design. Initially, we screened each peptide at increasing concentrations using an ELISA assay to test the inhibition of IL-2/IL-2Rα binding by the solubilized peptide. Candidate peptides were then further tested using upregulation of pSTAT5 and FOXP3 in T-cells measured by flow cytometry as a measure of inhibition of IL-2 signaling. The peptides were developed according to different design hypotheses and grouped into different families; the screening ELISA results indicated 4 promising peptides that inhibited IL2/IL2Rα binding (up to 100% inhibition; max peptide concentration of 100uM). These peptides were then used to determine their effect on STAT5 and FOXP3 expression. A lead candidate peptide consistently reduced the expression of FOXP3 and STAT5 expression compared to cells not exposed to peptide. Use of the peptide to disrupt IL-2 signaling inhibited the development of cells with a TREG phenotype.We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/IL-2Rα signaling and inhibit STAT5 and FOXP3 upregulation. These peptides could be used as new therapeutic agents to limit immune suppression by TREG cells and promote a more effective anti-tumor immune response in NHL. DisclosuresNo relevant conflicts of interest to declare.

Non-Hodgkin lymphoma in adults: a guide for practice nurses

Practice nurses have a valuable role to play in instigating earlier diagnosis in patients with possible symptoms of non-Hodgkin lymphoma, and supporting those undergoing treatment, writes Margaret Perry Non-Hodgkin lymphoma is an uncommon cancer that develops in the lymphatic system and accounts for approximately 85% of cancers of this type. This article—part one in a two-part series, the second part of which will consider Hodgkin lymphoma—outlines the causes and possible risk factors for non-Hodgkin lymphoma, diagnosis, treatment and management and prognosis. It aims to provide nurses with insight into the disease, to enhance their knowledge of a complex condition and increase their confidence in treating patients in primary care. Practice nurses can play a vital role in instigating earlier diagnosis and treatment when they encounter patients with suspicious symptoms, and can offer support to those undergoing treatment.

KLF4 and YY1 Are Resistant Factors in NHL and Potential Therapeutic Targets: The New Resistant NF-κb/YY1/KLF4/BclxL/Mcl-1 Axis

Introduction: We have recently reported that the expression of Krüppel-like factor 4 (KLF4) is upregulated in pediatric Burkitt lymphoma and it was suggested to be a prognostic biomarker for survival (Valencia-Hipolito et al., 2014)*. In addition, preliminary findings have demonstrated that KLF4 is also a resistant factor for drug-induced apoptosis.Rationale: Analysis of the role of KLF4 in resistance may have prognostic and therapeutic implications.Objective: To investigate the molecular mechanism underlying KLF4-induced resistance.Hypothesis: We have reported that the transcription factor Yin Yang 1 (YY1) is overexpressed in hematological malignancies and regulates both drug resistance and immune resistance. In Non-Hodgkin lymphoma (NHL), KLF4 is overexpressed and is under the transcriptional regulation of YY1. Hence, we hypothesized that KLF4 may also regulate drug/immune resistance and its inhibition would reverse the resistance of tumor cells to drug-induced apoptosis.Methods: We have used the NHL cell lines Ramos and DHL4 as models. The expression of KLF4 was assessed by Real Time-PCR and Western. KLF4 inhibition was achieved using the inhibitor Kenpaullone and the inhibition of YY1 and KLF4 was induced by transfection with corresponding siRNAs. Apoptosis was determined by activation of caspase 3 by flow cytometry. Tumor biopsies from pediatric NHL patients were analyzed by IHC.Results: Several NHL human tumor cell lines showed overexpression of KLF4, although at different levels. Treatment with the KLF4 inhibitor, Kenpaullone, resulted in the inhibition of KLF4 expression and the cells were sensitized to Doxorubicin-induced apoptosis. Treatment of tumor cells with YY1 siRNA inhibited both YY1 and KLF4 expressions and the cells were sensitized to drugs-induced apoptosis. Tumor biopsies from patients were divided into two groups, namely, one group with high KLF4 and YY1 and the other group with low levels of KLF4 and YY1. Kaplan Meier analysis revealed that patients with low expression of KLF4 and YY1 responded subsequently to CHOP, whereas patients with high KLF4 and YY1 did not respond to CHOP.Conclusions: The findings revealed the followings: (1) KLF4 overexpression is under the transcriptional regulation of YY1 (2) Inhibition of KLF4 by the chemical inhibitor Kenpaullone, or by YY1 siRNA resulted in the sensitization of tumor cells to drug-induced apoptosis and (3) Patients with NHL whose tumors overexpressed KLF4 and YY1 did not respond to CHOP treatment.Implications: We suggest that the overexpression of KLF4 in NHL may be a novel prognostic biomarker for response to chemotherapy and may also be a therapeutic target. In addition, a recent report by Farrugia M et al (2015)** reported that KLF4 is associated with both BclxL and Mcl-1 and, thus, drug resistance is primarily under the influence of the overexpression of BclxL and Mcl-1. Consequently, since KLF4 is regulated by YY1 and YY1 is in turn, regulated by NF-κB, we suggest the presence of an NF-κB/YY1/KLF4/BclxL/Mcl-1 resistant axis in NHL and gene products in this axis maybe potential novel prognostic biomarkers and therapeutic targets.

VEGF overexpression is a valuable prognostic factor for non-Hodgkin's lymphoma evidence from a systemic meta-analysis.

Vascular endothelial growth factor (VEGF) plays a vital role in the progression of Non-Hodgkin's lymphoma (NHL). Although multiple studies have investigated the relationship between VEGF expression and prognosis of NHL, these studies have yielded conflicting results. Therefore, we performed a meta-analysis to evaluate the role of VEGF in the prognosis of NHL patients. We systematically searched eligible studies from databases and determined that there was a significant correlation between VEGF overexpression and overall survival (HR (hazard ratio) = 1.66, 95% CI: 1.25–2.22, P = 0.001). Based on subgroup analysis by study location, number of patients, the source of VEGF expression, and study design, we found that VEGF overexpression in surgically resected tissue (HR = 1.95, 95% CI: 1.41–2.69, P = 0.000), but not in serum (HR = 1.37, 95% CI: 0.96–1.95, P = 0.087), was associated with poorer prognosis. Additionally, VEGF overexpression did not correlate with performance status, LDH level, IPI score, tumor staging, B symptoms, or NHL relapse. In summary, overexpression of VEGF in lymphoma tissue represents a promising potential prognostic factor in NHL.

Α-tubulin nuclear overexpression is an indicator of poor prognosis in patients with non-Hodgkin's lymphoma.

In the present study, the newly established mouse monoclonal antibody, Y-49, binding to a specific epitope of α-tubulin, was used to examine immunohistochemical reactivity in 116 patients with non-Hodgkin's lymphoma (NHL). The protein was detected at elevated levels in the nuclei of human proliferating cells by western blot analysis, flow cytometry and immunohistochemical analysis. The relatively weak binding in the cytoplasm was evident in almost all cases. The investigation of the correlation between immuno-histochemical positivity and clinicopathological variables revealed links with the MIB-1 proliferation index and poor survival. Nuclear positivity with Y-49 was more frequent in older-aged patients, those with nodal NHL and in those who harbored the diffuse large B-cell histological subtype, and was strongly associated with high MIB-1 labeling indices (LIs). Survival analysis by the Kaplan-Meier method revealed statistically significant differences between patients with high and low Y-49 LIs (p=0.0181), even in the group with advanced (stage III/IV) disease (p=0.0327). Multivariate analysis revealed that overexpression of α-tubulin is an independent prognostic factor in NHL with a relative risk of 2.786.

Clinical characteristics, pathological distribution, and prognostic factors in non-Hodgkin lymphoma of Waldeyer's ring: nationwide Korean study.

Background/AimsIn Asia, the incidence of non-Hodgkin lymphoma (NHL) has increased in recent decades. Waldeyer's ring (WR) is the most common site of NHL involving the head and neck. In this study, the pathological distribution of WR-NHL and its clinical features were analyzed retrospectively.MethodsFrom January 2000 through December 2010, we analyzed the medical records of 328 patients from nine Korean institutions who were diagnosed with WR-NHL.ResultsThe study group comprised 197 male and 131 female patients with a median age of 58 years (range, 14 to 89). The rate of localized disease (stage I/II) was 64.9%, and that of low-risk disease (low/low-intermediate, as defined by the International Prognostic Index) was 76.8%. Diffuse large B-cell lymphoma (DLBCL; 240 patients, 73.2%) was the most common pathologic subtype, followed by peripheral T-cell lymphoma (14 patients, 4.3%) and nasal NK/T-cell lymphoma (14 patients, 4.3%). WR-NHL occurred most frequently in the tonsils (199 patients, 60.6%). Extranodal involvement was greater with the T-cell subtype (20 patients, 42.5%) compared with the B-cell subtype (69 patients, 24.5%). Multivariate analyses showed that age ≥ 62 years, T-cell subtype, and failure to achieve complete remission were significant risk factors for overall survival.ConclusionsDLBCL was found to have a higher incidence in Korea than those incidences reported by other WR-NHL studies. T-cell lymphoma occurred more frequently than did follicular lymphoma. T-cell subtype, age ≥ 62 years, and complete remission failure after first-line treatment were significant poor prognostic factors for overall survival according to the multivariate analysis.

Expression and possible significance of vascular endothelial growth factor in non-Hodgkin lymphoma

There is little information about the exact trigger mechanisms of vascular endothelial growth factor (VEGF) expression in hematolymphoid malignancies. The aim of this study was to investigate the expression of VEGF in malignant non-Hodgkin lymphoma (NHL), in terms of its immunohistochemical distribution and clinicopathological significance. We evaluated the distribution in tumor cells, macrophages and in non-tumoral cells. VEGF immunoreactivity was esti- mated according to this score: 0 (0% positive cells); 1 ( 30%). Histopathological evaluation revealed 18 cases of diffuse type lymphoma and 3 cases of follicular type lymphoma. VEGF was positive in 95.23% of cases and in one case, VEGF was negative in all cell types. We noticed a significant correlation in VEGF expression between tumor cells and macrophages (p=0,001), tumor cells and non-tumoral cells (p=0,002). In non-Hodgkin lymphoma, the main mecha- nism of angiogenesis seems to be dependent on the VEGF pathway and its expression particularly by stromal cells.

Serum IL-10 and IL-8 Among Variable Cytokines Derived From Helper T Cells Might Be Associated with Prognoses for Malignant Lymphoma Patients

Abstract 5107 Background:Over the past few decades, investigators have worked to identify prognostic factors in non-Hodgkin lymphoma (NHL) so an appropriate therapeutic plan can be put in action. In addition to conventional prognostic factors such as the international prognostic index (IPI), many biomarkers including cytokines, chemokines, enzymes, or gene profiling have known. Recently, many researchers reported that tumor-infiltrating immune cells played an important role in host immune reaction against variable tumor cells including malignant lymphoma (ML). Variable tumor-infiltrating cells such as helper T cell, cytotoxic T cell, macrophage and mast cell were reported to give an influence for prognosis. These microenvironmental cells are influenced from variable cytokines. Purpose:We measured the some cytokines derived from helper T cells (Th1 and Th2) and discussed their prognostic significance for ML. Patients and Methods:This study was approved by our institutional review board. Consecutive 115 previously untreated patients with ML (diffuse large B-cell lymphoma (DLBCL) 56, Follicular lymphoma (FL) 19, peripheral T-cell lymphoma (PTCL-NOS) 14, mucosa associated lymphoid tissue lymphoma (MALT) 6, Hodgkin's lymphoma (HL) 5 and others 15) who were histologically diagnosed according to the WHO classification prospectively participated in this study between 2009 and 2011. We measured serum cytokines which were related with helper T cells (Th1 and Th2), such as interleukin (IL)-12p70, IFN-gamma, IL-2, IL-10, IL-6, IL-8, IL-4, IL-5, IL-1 beta, TNF alpha, and TNF beta using Flow Cytomix from eBioscience company. Patients with DLBCL received R-CHOP regimen consisted of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone with standard doses. Result:No significant differences were observed for serum levels between healthy control donors (HCD) and patients with ML, except for IL-10 and IL-8. The median serum level of IL-10 in ML was higher than that of HCD (ML: 0. 02 pg/ml, HCD: 0 pg/ml, p=0. 0003), and the median serum level of IL-8 was also higher in ML (ML: 49. 18 pg/ml, HCD: 0 pg/ml, p=0. 01). No significant differences were observed between B cell lymphoma and T cell lymphoma. Among DLBCL patients, higher IL-10 level group (> 0 pg/ml, detectable level) had poor prognosis than lower IL-10 level group (0 pg/ml) for overall survival (OS) and progression free survival (PFS) (3-year OS 100%, PFS 84. 0% in low IL10 group, 3-year OS 56. 3%, PFS 45. 1% in high IL10 group; OS p=0. 01; PFS p=0. 01). In addition, in low grade lymphoma including MALT, FL, mantle cell lymphoma (MCL), and small lymphocytic lymphoma (SLL), higher IL-10 level group also had poor prognoses than lower IL-10 level group in PFS (3-year PFS 83. 9%, vs. 30%, p=0. 003). Conclusion:IL-10 and IL-8 among variable cytokines derived from helper T cells significantly increased in the serum of untreated patients with ML and they might be associated with their prognoses. Especially, for patients with DLBCL, their cytokines might be a significant prognostic factor and a useful tool for selecting an appropriate therapeutic strategy. Further clinical investigations with a larger number of cases should be considered in future. Disclosures:No relevant conflicts of interest to declare.

Association of serum B7-H1 level and lymphopenia in diffuse large B-cell non-Hodgkin lymphoma.

8080 Background: Activation of the adaptive immune response plays an important role in tumor immune surveillance. Not surprisingly then, lymphopenia has emerged as an adverse prognostic factor in non-Hodgkin lymphoma (NHL). The factors which may contribute to the development of lymphopenia in NHL are incompletely understood. B7-H1, a member of the B7 family of costimulatory/coinhibitory ligands, inhibits T-cell proliferation and promotes the induction of cell death in tumor-specific T cells. We recently described its expression on malignant cells, tumor-infiltrating dendritic cells, and circulating CD14+HLA-DRlo myeloid-derived suppressor cells in NHL (Blood. 2009;114(10): 2149- 58.). Therefore, we have hypothesized that B7-H1 may contribute to the development of lymphopenia in NHL. Methods: Serum samples were collected from normal donors (n=25) and patients with cutaneous T-cell NHL (CTCL, n=24), peripheral T-cell NHL (PTCL, n=29) and diffuse large B-cell lymphoma (DLBCL, n=31) and levels of soluble B7-H1 (sB7-H1) determined by ELISA. Results: Soluble B7-H1 was detected in serum of both normal donors (mean 0.29 ng/mL; 0.09-0.50 95% CI) and CTCL patients (mean 0.44 ng/mL; 0.25-0.63 95% CI), but was found to be significantly elevated in both PTCL (mean 0.84 ng/mL, 0.49-1.20 95% CI, p<0.001) and DLBCL (mean 0.62 ng/mL, 0.49-0.75 95% CI, p<0.001), when compared with that observed in normal donors. In order to determinewhether sB7-H1 may be associated with the development of lymphopenia, sB7-H1 levels at diagnosis were correlated with matched absolute lymphocyte counts (ALC) obtained from DLBCL patients (n=31). An inverse correlation was noted between sB7-H1 and the ALC. Forty-two percent of patients with elevated sB7-H1 (defined as greater than the mean sB7-H1) were lymphopenic (ALC <900/uL) at diagnosis, whereas 16% of the remaining patients were lymphopenic at diagnosis (p=0.1). Following therapy with anthracycline-based chemotherapy, a 39% reduction in sB7-H1 was observed (n=29, p<0.00001, paired t-test) and was associated with an 18% increase in the ALC. Conclusions: Collectively, the data presented demonstrates that sB7-H1 may represent a novel biomarker in NHL that's associated with lymphopenia. No significant financial relationships to disclose.

A distinct profile of serum levels of soluble intercellular adhesion molecule-1 and intercellular adhesion molecule-3 in mycosis fungoides and Sézary syndrome

Cell adhesion molecules (CAMs) play a pivotal role in cutaneous localization of T cells. Tissue-selective localization of T lymphocytes to the skin is crucial for immune surveillance and in the pathogenesis of skin disorders. To detect the profile of soluble CAMs in patients with cutaneous T-cell lymphoma (CTCL), we investigated the levels of intercellular adhesion molecule-1 (ICAM-1, soluble ICAM-1 [sICAM-1]); intercellular adhesion molecule-3 (sICAM-3); vascular cell adhesion molecule-1 (sVCAM-1); and E-selectin (sE-selectin) in sera from patients with T-cell-mediated skin diseases. Serum levels of the 4 CAMs were measured by enzyme-linked immunosorbent assay in 42 participants including 11 patients with early stages of CTCL; 7 with advanced stages of CTCL including Sézary syndrome; 12 with inflammatory skin diseases (psoriasis and atopic dermatitis); 8 with skin diseases that may evolve into CTCL; and healthy individuals. Levels were correlated with biological parameters known as prognostic factors in non-Hodgkin lymphomas. In patients with CTCL, significantly increased levels of sICAM-1 and sICAM-3 were found when compared with healthy individuals and patients with inflammatory dermatosis. Soluble E-selectin and sVCAM-1 levels were not increased. There were significant positive correlations between sICAM-1 and sICAM-3 levels and each of them with beta2-microglobulin levels. Limited number of patients was a limitation. There is a distinct profile of soluble CAMs in patients with CTCL. However, future studies with a larger group of patients are needed to confirm these findings. We propose that high sICAM-1 and sICAM-3 levels have important implications in the context of immune response and immune surveillance in these patients.