Several Immune Cell Subsets Are Associated with Outcome in the Microenvironment of Follicular Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3953-3953
Author(s):  
Björn Engelbrekt Wahlin ◽  
Mohit Aggarwal ◽  
Santiago Montes-Moreno ◽  
Luis Francisco Gonzalez ◽  
Giovanna Roncador ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Immune Cell ◽  
Univariate Analysis ◽  
Cd4 Cells ◽  
Cell Stimulation ◽  
Cd8 Cells ◽  
Good Outcome ◽  
Immune Cell Subsets

Abstract Abstract 3953 Poster Board III-889 AIMS Several studies concur that the microenvironment determines outcome in follicular lymphoma (FL), but they disagree regarding which components thereof are important. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should be demonstrable in the same analysis and in competition with clinical factors. Specifically, we hypothesized that (1) CD8+ cells are associated with good prognosis (presumably due to tumor cell killing), as are (2) cells positive for programmed death-1 (PD-1) or FOXP3 (due to diminished B-cell stimulation), while (3) CD4+ cells are associated with poor prognosis (due to B-cell stimulation). PATIENTS AND METHODS Seventy FL patients with extreme clinical outcome (“poor” and “good” cases) were identified in a cohort of 197 patients. The criterion for poor outcome was death from lymphoma <5 years after diagnosis (n=33). The general criteria for good outcome were absence of a lymphoma-related death and/or transplantation and one of the following three statements had to be true: (1) never treated against lymphoma and followed for ≥5 years (n=11); (2) never relapsed after first-line anti-lymphoma treatment and followed for ≥8 years (n=14); (3) relapsed but never received intensive or frequent (≥3 years between) treatments and followed for ≥10 years (n=12), rendering totally 37 good-outcome patients. A tissue microarray was constructed from diagnostic and relapse biopsies of these 70 patients. Sections of the microarray were stained for CD3, CD7, CD4, FOXP3, PD-1, CD8, TIA-1, granzyme B, perforin, CD57, CD56, CD68, and tryptase. The number of positive cells for each staining were quantified using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). RESULTS Between the two clinical extreme groups there were great differences in the FL International Prognostic Index (FLIPI), as expected (P<0.0001). In univariate analysis, the amounts of several immune subsets were different between the two groups with borderline or stronger significance. These subsets were taken to multivariate analysis together with the FLIPI. Independently of the FLIPI, CD4+ cells were associated with poor (Odds Ratio [OR] 1.26; P=0.025) but PD-1+ (OR 0.58; P=0.020) and CD8+ (OR 0.94; P=0.024) cells with good outcome. In a second multivariate analysis, where the subsets in the follicular and interfollicular comparments were analyzed (again in competition with the FLIPI), the prognostic values of CD4+ and PD-1+ cells were accentuated when they were follicular (OR 2.16; P=0.010 and OR 0.34; P=0.019, respectively), and that of CD8+ cells when interfollicular (OR 0.86; P=0.014). Follicular FOXP3+ cells were also associated with good outcome (OR 0.09; P=0.018) and interfollicular CD68+ cells with poor (OR 1.36; P=0.040). CONCLUSION We conclude that there are many important immune cell subsets in the microenvironment of FL. Independently of the FLIPI, and of each other, PD-1+, FOXP3+, CD4+, CD8+, and CD68+ cells correlate with outcome. This suggests several different but not mutually exclusive mechanisms which all affect the course of the disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Characterization of Immune Cell Subsets of Tumor Infiltrating Lymphocytes in Brain Metastases

Biology ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 425
Author(s):  
Priyakshi Kalita-de Croft ◽  
Haarika Chittoory ◽  
Tam H. Nguyen ◽  
Jodi M. Saunus ◽  
Woo Gyeong Kim ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Tumor Infiltrating Lymphocytes ◽  
Cd8 Cells ◽  
Targeted Analysis ◽  
Immune Cell Subsets ◽  
Checkpoint Molecule ◽  
Formalin Fixed Paraffin Embedded ◽  
Infiltrating Lymphocytes

The heterogeneity of tumor infiltrating lymphocytes (TILs) is not well characterized in brain metastasis. To address this, we performed a targeted analysis of immune-cell subsets in brain metastasis tissues to test immunosuppressive routes involved in brain metastasis. We performed multiplex immunofluorescence (mIF), using commercially available validated antibodies on formalin-fixed paraffin embedded whole sections. We quantitated the subsets of immune-cells utilizing a targeted panel of proteins including PanCK, CD8, CD4, VISTA and IBA-1, and analyzed an average of 15,000 cells per sample. Classifying tumors as either high (>30%) or low (<30%) TILs, we found that increased TILs density correlated with survival. Phenotyping these TILs we found tumors with low TILs had significantly higher expression of the immune-checkpoint molecule VISTA in tumor cells (p < 0.01) as well as in their microenvironment (p < 0.001). Contrastingly, the tumors with high TILs displayed higher levels of microglia, as measured by IBA-1 expression. Low TILs-tumors displayed CD8+ T-cells that co-express VISTA (p < 0.01) significantly more compared to high TILs group, where CD8+cells significantly co-express IBA-11 (p < 0.05). These results were supported by RNA analysis of a publicly available, independent cohort. Our work contributes to a growing understanding of the immune surveillance escape routes active in brain metastasis.

scholarly journals Absolute B cell counts in blood predict long-term response in follicular lymphoma patients treated with rituximab without chemotherapy

2020 ◽  
Vol 99 (10) ◽  
pp. 2357-2366
Author(s):  
Henna-Riikka Junlén ◽  
Sandra Lockmer ◽  
Eva Kimby ◽  
Björn Engelbrekt Wahlin
Keyword(s):  
T Cell ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Cell Subset ◽  
Response Duration ◽  
Cell Counts ◽  
Pre Treatment

Abstract Rituximab monotherapy is widely used for follicular lymphoma. However, there are no established predictors for response or response duration. We analyzed the long-term prognostic relevance of pre-treatment absolute blood counts of lymphocytes with subsets and monocytes in 265 follicular lymphoma patients, uniformly treated with rituximab without chemotherapy, in two Nordic Lymphoma Group trials. There were 265 previously untreated, stage II–IV follicular lymphoma patients with a median follow-up of over 10 years. Absolute B cell counts ≥ median (0.09 × 109/L) were an independent predictor for shorter time to next treatment or death (multivariable analysis P = 0.010). In univariate analysis, absolute monocyte counts ≥ median (0.5 × 109/L) did not correlate with time to next treatment or death, but with inferior overall survival (P = 0.034). Absolute T cell or T cell subset counts were not predictive for outcome. High absolute B cell counts, possibly reflecting circulating lymphoma cells, have an unfavorable impact on time to next treatment or death in patients treated with rituximab without chemotherapy.

scholarly journals Life Expectancy in Follicular Lymphoma Is Mainly Determined By Response to First LINE Treatment: A LONG-TERM Survey on 597 Patients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3989-3989
Author(s):  
Corrado Tarella ◽  
Angela Gueli ◽  
Federica Delaini ◽  
Anna Maria Barbui ◽  
Riccardo Bruna ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Follicular Lymphoma ◽  
Progressive Disease ◽  
Histological Grade ◽  
Univariate Analysis ◽  
Primary Treatment ◽  
Refractory Disease ◽  
Front Line

Abstract BACKGROUND Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin's lymphoma. However, FL is a heterogeneous disorder and in a proportion of patients, the disease is very resistant to standard frontline therapies. In the current analysis clinical features and outcome to primary treatment were evaluated in a large series of FL patients who were consecutively treated at the Hematology Centers of Bergamo and Torino, Italy between 1976 and 2012. The aim of the study was to define the rate of refractory disease and the long term survival of patients according to response to their primary treatment. METHODS Medical records of 597 FL patients were reviewed. In front line therapy, rituximab was employed in 330 patients (55%), front-line high dose therapy with autograft (HDS) was administered in 58 patients (9.7%). Primary refractory disease was defined as full refractoriness (stable or progressive disease) or progressive disease within six months after initial response. Univariate analysis was done for prognostic factors including gender, age at diagnosis (age≤60 and >60 years), histological grade, IPI score (low=0-2 versus high=3-5), bone marrow (BM) involvement, rituximab administration in 1st line treatment, lymphocyte to monocyte ratio at diagnosis (>2.6 vs ≤2.6), presence of primary refractory disease, and the administration of front-line HDS. Cox model was also used for multivariate analysis. RESULTS: A total of 375 patients (63%) were older than 60 years (range: 18-88) and 49% were males. There were 476 patients (79.7%) with stage III-IV, 286 patients (48%) with BM involvement, 185 (31%) had a high IPI score and 28 patients (5%) presented with high histological grade. Eighty-seven patients (13%) displayed primary refractory disease. At a median follow-up of 8 years, median overall survival (OS) was 25 years for all patients, 32.6 years for responsive patients compared to 5 years for primary refractory patients (p=<0.0001). Among primary refractory patients, those with fully refractory disease had a shorter survival (median OS: 2.7 years) compared to patients with early progressive disease (median OS: 5 years). The strikingly different outcome of primary refractory vs. responsive patients is shown in the Figure 1. A significant prolonged survival was observed in patients who were treated with rituximab in primary therapy. The median OS is not reached for rituximab treated patients compared to 19 years for those who did not receive rituximab. Median OS was 25 years for patients with low IPI and 14.6 years for the high risk group. By univariate analysis, age and BM involvement were also significant prognostic factors for OS. Median OS for patients 60 years old or younger compared to older patients were 32.6 versus 13 years, respectively. The median survival was not reached for patients without BM involvement vs 19 years for patients with BM involvement (p=0.001). By multivariate analysis high IPI, refractory disease and not receiving rituximab in first line regimens were independent negative prognostic factors for OS, as detailed in Table 1. CONCLUSION: FL patients who display responsive disease to their primary treatment have a very long life expectancy with median survival of 32.6 yrs. Similarly to the aggressive lymphoma subtypes, primary refractory disease is of major concern also for FL. Research studies should be focused on the early identification of primary refractory patients to promptly institute adapted therapy for this unfavorable subgroup, and possibly optimize treatment strategies for patients with high-risk FL. Table 1. Multivariate analysis for overall survival Parameter Hazard Ratio (95% Confidence interval) p-value Age (yrs): >60 vs. ≤ 60 1.54 (1.5-2.3) .03 Histologic grade: 1-2 vs 3 2.25 (0.5-9.1) .3 IPI *Score: low (0-2) vs high(3-5) 0.59 (0.4-0.9) .009 Primary Refractory: yes vs no 4.40 (3.0-6.5) < .0001 Rituximab 1st line: yes vs no 0.56 (0.4-0.8) .005 BM# involvement: yes vs no 1.44 (1.0-2.1) .06 *International prognostic index was used to have a uniform prognostic factors scoring system for patients treated over the three decades of the survey. # Bone marrow Figure 1. Overall Survival in 597 follicular lymphoma patients according to response to primary treatment Figure 1. Overall Survival in 597 follicular lymphoma patients according to response to primary treatment Disclosures No relevant conflicts of interest to declare.

scholarly journals Selective B cell depletion upon intravenous infusion of replication-incompetent anti-CD19 CAR lentivirus

2020 ◽  
Author(s):  
Craig M. Rive ◽  
Eric Yung ◽  
Lisa Dreolini ◽  
Daniel J. Woodsworth ◽  
Robert A. Holt
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Immune Cell ◽  
Wild Type ◽  
Immune Cell Subsets ◽  
Car T

AbstractAnti-CD19 CAR-T therapy for B cell malignancies has shown clinical success, but a major limitation is the logistical complexity and high cost of manufacturing autologous cell products. Direct infusion of viral gene transfer vectors to initiate in vivo CAR-T transduction, expansion and anti-tumor activity could provide an alternative, universal approach for CAR-T and related immune effector cell therapies that circumvents ex vivo cell manufacturing. To explore the potential of this approach we first evaluated human and murine CD8+ T cells transduced with VSV-G pseudotyped lentivectors carrying an anti-CD19CAR-2A-GFP transgene comprising either an FMC63 (human) or 1D3 (murine) anti-CD19 binding domain. To evaluate CD19 antigen-driven CAR-T proliferation in vitro we co-cultured transduced murine T cells with an excess of irradiated splenocytes and observed robust expansion over a 9 week period relative to control T cells transduced with a GFP transgene (mean fold expansion +/- SD: ID3-CD19CAR-GFP modified T cells, 12.2 +/- 0.09 (p < 0.001); FMC63-CD19CAR-GFP modified T cells 8.8 +/- 0.03 (p < 0.001). CAR-T cells isolated at the end of the expansion period showed potent B cell directed cytolytic activity in vitro. Next, we administered approximately 20 million replication-incompetent lentiviral particles carrying either ID3-CD19CAR-GFP, FMC63-CD19CAR-GFP, or GFP-only transgene to to wild-type C57BL/6 mice by tail vein infusion and monitored the dynamics of immune cell subsets isolated from peripheral blood at weekly intervals. We saw emergence of a persistent CAR-transduced CD3+ T cell population beginning week 3-4 that reaching a maximum of 13.5 +/- 0.58 % (mean +/- SD) and 7.8 +/- 0.76% of the peripheral blood CD3+ T cell population in mice infused with ID3-CD19CAR-GFP lentivector or FMC63-CD19CAR-GFP lentivector, respectively, followed by a rapid decline, in each case of, the B cell content of peripheral blood. Complete B cell aplasia was apparent by week 5 and was sustained until the end of the protocol (week 8). None of these changes were observed in mice infused with GFP-only control lentivector, and significant CAR positive populations were not observed within other immune cell subsets, including macrophage, natural killer, or B cells. Within the T cell compartment, CD8+ effector memory cells were the predominant CAR-positive subset. Modest weight loss of 5.5 +/- 2.97 % (mean +/- SD) observed in some animals receiving an anti-CD19CAR-GFP transgene during the protocol. These results indicate that direct IV infusion of lentiviral particles carrying an anti-CD19 CAR transgene can transduce T cells that then fully ablate endogenous B cells in wild type mice. Based on these results it may be useful to further explore, using currently available vectors, the feasibility of systemic gene therapy as a modality for CAR-T intervention.

scholarly journals Hematopoietic Stem Cell Transplantation (HSCT) with Omidubicel Is Associated with Robust Immune Reconstitution and Lower Rates of Severe Infection Compared to Standard Umbilical Cord Blood Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 333-333
Author(s):  
Paul Szabolcs ◽  
Stuart Levy ◽  
Dima Yackoubov ◽  
Aviad Pato ◽  
Einat Galamidi-Cohen ◽  
...  
Keyword(s):  
B Cell ◽  
Viral Infections ◽  
Immune Cell ◽  
Nk Cell ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Cell Counts ◽  
Immune Cell Subsets ◽  
Cell Current ◽  
One Year

Abstract Introduction Omidubicel is an advanced cell therapy for allogeneic hematopoietic stem cell transplantation (HSCT), derived from appropriately HLA-matched umbilical cord blood (UCB) and comprised of ex-vivo expanded CD133+ cells and a non-cultured lymphocyte-containing fraction. Recent results of a global phase III trial of omidubicel vs standard UCB showed more rapid hematopoietic recovery, reduced rates of infection, and shorter hospitalizations in patients (pts) randomized to omidubicel (Horwitz et al, Blood, 2021). We now report results of correlative immune reconstitution (IR) studies in this trial (NCT02730299). Methods A total of 125 pts aged 13-65 with hematologic malignancies were randomized to allogeneic transplantation with omidubicel or standard UCB following myeloablative conditioning; 108 pts were transplanted per protocol. An optional IR sub-study was conducted and blood was collected at intervals from Day 7 through one year post-transplant. Cryopreserved samples were analyzed in a central laboratory (Covance) using 16-color and 14-color panels and flow cytometric assays to explore T cell, NK cell, B cell, monocyte, and dendritic cell (DC) subsets. Means, medians, ranges, and standard errors were used to summarize cell counts, and one-tailed t-tests were used to compare counts in the two treatment arms. Results A total of 37 pts from 15 sites consented to the IR sub-study, representing 34% of the per protocol population; 17 pts were transplanted with omidubicel and 20 pts with control (15 [75%] of control with double UCB). Median age was 30 (range: 13-62) years for omidubicel pts and 43 (range: 19-55) years for controls in the sub-study. Median CD3+ content of omidubicel prior to cryopreservation was lower (180 x 10^6; range: 71-580 cells) than that of controls post-thaw (516 x 10^6, range: 183-990 cells). Omidubicel pts achieved neutrophil engraftment at a median of 10 (range: 6-28) days post-transplant compared to a median of 18.5 (range: 14-40) days in controls. Omidubicel pts had fewer BMT-CTN Grade 3 viral infections in the first-year post-transplant than controls (6% vs. 25%, respectively). At Day 7 post-transplant, CD4+ T cell counts were significantly higher in omidubicel pts (37x10^3 cells/ml) than in controls (17x10^3 cells/ml, p=0.011). B cells (12x10^3 vs 1x10^3 cells/ml, p=0.013) and NK cells (6x10^3 vs 3 x10^3 cells/ml, p=0.016), as well as monocyte and DC subsets, were also significantly higher in omidubicel pts (Table). Day 14 results similarly demonstrated higher counts of circulating immune cell subsets in omidubicel pts than in controls (Table). Higher B cell counts were observed in omidubicel pts than in controls at 6 months ([863±463] x10^3 vs. [543±221] x10^3 cells/ml, p=0.03) and one year ([1492±370] x10^3 vs [763±150] x10^3, p=0.02) following transplant (Figure). Conclusions Circulating immune cell subsets were consistently higher in omidubicel pts than controls as early as one week after transplant, and higher B cell counts persisted through one year. These findings correlated with the clinical observation of fewer severe bacterial, fungal, and viral infections in pts treated with omidubicel compared to standard UCB. These results demonstrate that rapid hematopoietic recovery in pts transplanted with omidubicel is accompanied by the early and robust appearance of a broad array of lymphocyte, monocyte, DC, and NK cell subsets, despite substantially fewer numbers of these cells infused, suggesting a facilitator effect of omidubicel on their in vivo expansion. Figure 1 Figure 1. Disclosures Szabolcs: Gamida Cell: Consultancy; Prevail Therapeutics: Consultancy; Sotiria/Forge Biologics: Current equity holder in publicly-traded company. Levy: Gamida Cell: Current Employment. Yackoubov: Gamida Cell: Current Employment. Pato: Gamida Cell: Current Employment. Galamidi-Cohen: Gamida Cell, Ltd: Current Employment. Horwitz: Gamida Cell: Research Funding.

scholarly journals Cachexia at Diagnosis adversely predicts outcomes in patients with Aggressive B-Cell NHL receiving standard of care treatment: A Prospective Observational Study from India

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2907-2907
Author(s):  
Vivek S Radhakrishnan ◽  
Reena Nair ◽  
Anwesha Patra ◽  
Saurabh Jayant Bhave ◽  
Jeevan Kumar Garg ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Observational Study ◽  
B Cell ◽  
Research Funding ◽  
Prospective Observational Study ◽  
Univariate Analysis ◽  
Standard Of Care ◽  
High Grade ◽  
Actuarial Survival

Background and Objectives:Cancer associated malnutrition and cachexia is an important determinant of the patient's short and long term outcomes. This prospective study was conducted to determine the association between cachexia at diagnosis and overall survival of patients with aggressive B-cell non-Hodgkin's Lymphoma (ABNHL) Methods:This investigator initiated single centre prospective observational study was conducted at the Tata Medical Center, Kolkata, India between Jan 2015 and Mar 2019 after IRB approval. Patients diagnosed with ABNHL receiving standard of care chemo-immunotherapy were eligible. This study was supported by an educational research grant from Baxter to our institution. All patients who consented to participate were screened for cachexia at entry using a modified Subjective Global Assessment (SGA) tool (1). Baseline clinical factors of prognostic importance including stage, IPI score, etc. were recorded. All statistical analysis was carried out using EpiInfo-ver.7 software. Results:239 patients diagnosed with high grade B-NHL were recruited. The study group included 89 women and 150 men, and 77 (32.1%) were older than 65 years. 130 (54.3%) patients received private care. 88(36.8%) had IPI stage high-intermediate plus high grade; 136 (56.9%) had Ann Arbor stage III plus IV disease; 40 (16.7%) had extra-nodal NHL; 96 (40.1%) had weight loss and 107(44.7%) had reduced food intake. Cachexia scores estimated by the modified SGA tool was SGA-A in 101, SGA-B in 120 and SGA-C in 18 patients. Only 37 (15.4%) had been subjected to screening for malnutrition prior to cancer treatment. 44 (20.5%) patients experienced neutropenic sepsis during treatment. At a median follow up of 457 days, 69% achieved complete remission at the end of initial therapy, 50 (20.9%) patients died during the study period. In univariate analysis, SGA, IPI, Stage and age groups were statistically significant prognostic markers. The 2-year actuarial survival of all patients adjusted for SGA, IPI and Stage was 72%. The two-year actuarial survival in the SGA-A, SGA-B, and SGA-C groups were respectively 80%, 68% and 45% (p<0.001). In a multivariate analysis using cox proportional hazards method the hazard ratio for SGA B was 1.67 (0.94-2.97), and SGA-C was 3.65, after adjusting for IPI and stage groups (p=0.0137).The follow up is continuing and final multivariate analysis will be done when sufficient events have occurred. Conclusions:Cachexia at diagnosis is an important independent prognostic biomarker in patients with ABNHL. The role of routine screening for cachexia before initiating treatments and providing individualized medical nutrition therapy along with physical therapy during chemotherapy to prevent worsening of cachexia and improve survival needs evaluation. References: 1.Shirodkar M etal, Indian J Gastroenterol.2005; 24:246-50 Figure Disclosures Patra: Baxter: Research Funding. Mallath:Otsuka Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau; GlaxoSmithKline: Research Funding; Baxter: Research Funding; Otsuka Pharmaceuticals: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer-Zydus Pharma: Honoraria; Sayre-Therapeutics: Honoraria.

Abstract P414: Outcomes of Incident Hemorrhage From Cranial Dural Arteriovenous Fistulae: Analysis of the Multi-Center International Condor Registry

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Matthew Koch ◽  
Christopher Stapleton ◽  
Ridhima Guniganti ◽  
Gregory J Zipfel ◽  
Sepideh Amin-hanjani
Keyword(s):  
Multivariate Analysis ◽  
Statistical Significance ◽  
Univariate Analysis ◽  
Case Series ◽  
Patient Characteristics ◽  
Chi Square ◽  
Exact Test ◽  
Good Outcome ◽  
Secondary Hemorrhage

Introduction: Dural artertiovenous fistulae (dAVF) are rare causes of secondary intracranial hemorrhage (ICH) and there remains a paucity of knowledge regarding their natural history. To date our knowledge comes from small case series. CONDOR, (Consortium for Dural Arteriovenous Fistula Outcomes Research), a large multi-institutional retrospective registry, provides a unique opportunity to evaluate the outcomes of patients presenting with dAVF related hemorrhages. Methods: We performed a retrospective review of 1077 dAVF patients from the CONDOR registry and selected those patients who presented with hemorrhage secondary to the dAVF. Patient characteristics, clinical presentation/follow-up, and radiographic details were analyzed for associations with patient outcomes. An outcome of mRS 0-2 was categorized as a “good” outcome and 3-6 as “poor”. Statistics were performed in SAS 9.4 with chi square, fisher’s exact test, and stepwise select variable multivariate analysis; P<.05 was marked as the level for statistical significance. Results: Evaluation of the CONDOR dataset yielded 267 patients who presented with hemorrhage. The mean age of the population was 59 ±13y.o, 30% were female, 40% had a history of smoking and 93% were not on anticoagulants. The median follow-up was 1.4 years. The mortality was 4.0 % at follow-up, and 83% of patients had a good outcome (mRS 0-2). Univariate analysis found age (p=0.001), anticoagulant use (p=0.006), and presentation mRS (p=0.03) were associated with poor outcome at follow-up. Subtype of hemorrhage (parenchymal hemorrhage or subarachnoid hemorrhage), smoking, and cortical venous shunting of the lesion, (i.e. Cognard grade IIb and greater) did not reach statistical significance. On multivariate analysis age (p=0.023) and mRS (p=0.035) at presentation but not anti-coagulant use (p=0.11) was associated with follow-up mRS. Conclusion: Within the largest individual patient series to date, we found that dAVF presenting with hemorrhage was associated with a relatively low risk of mortality. Age and mRS at presentation were most strongly predictive of outcome. Our results suggest that dAVF hemorrhage may be associated with a less morbid outcome than other forms of secondary hemorrhage.

High Expression of the Endoplasmic Reticulum Protein MZB1 predicts Inferior Prognosis in Chronic Lymphocytic Leukemia, Follicular Lymphoma and Diffuse Large B-Cell Lymphoma and Is Associated with a Unique Gene Expression Profile,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3657-3657
Author(s):  
Tobias Herold ◽  
Medhanie A Mulaw ◽  
Vindi Jurinovic ◽  
Till M Seiler ◽  
Klaus H. Metzeler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multivariate Analysis ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Data Sets ◽  
Expression Levels ◽  
Large B Cell Lymphoma

Abstract Abstract 3657 Introduction: The marginal zone B and B1 cell-specific protein (MZB1) was recently described as a key regulator of the secretion of IgM molecules, the control of calcium homeostasis and integrin-mediated adhesion in B-lymphocytes. We recently identified MZB1 gene expression as a novel prognostic factor being part of a highly significant 8 gene expression signature in chronic lymphocytic leukemia (CLL). Since several neoplasm's derive from mature B-lymphocytes and differ in clinical behavior and prognosis, but share unique functions like immunoglobulin production and secretion we asked whether these different diseases share common molecular mechanisms and prognostic factors. Here, we show that MZB1 expression is a novel, strong prognostic factor in a variety of B-cell neoplasm's. Methods: We analyzed 106 previously untreated and 33 relapsed CLL patients by quantitative PCR and correlated the MZB1 gene expression with overall survival (OS), time to treatment (TTT) and known risk factors of CLL. To expand the study on other hematological malignancies we additionally analyzed the public available gene expression data sets of follicular lymphoma (FL; GSE16131; n=184), diffuse large B-cell lymphoma (DLBCL; GSE10846; n=414), multiple myeloma (MM; GSE2658, n=559), and acute myeloid leukemia (AML; GSE12417; n=306). To adjust for clinical variables, multivariate Cox model were fitted to the respective data sets. To identify genes strongly correlated with MZB1 expression levels, we compared the CLL, DLBCL, FL and AML datasets and performed a multistep correlation analysis. Results: High MZB1 expression was a significant parameter of inferior prognosis in previously untreated (OS: HR: 1.63 (CI: 1.14–2.33), p=0.007; TTT: HR: 1.43 (CI: 1.13–1.81), p=0.003) and relapsed CLL patients (OS: not significant; TTT: HR: 1.48 (CI: 1.12–1.95), p=0.005) and was associated with known clinical and molecular parameters including unmutated IGVH status (p<0.001) and advanced Binet stage (Binet A vs. C p=0.001). Thus, due to the high correlation with IGVH status, MZB1 expression remained not an independent factor in multivariate models including both factors. In addition, MZB1 expression was also a predictor of OS in FL (221286_s_at HR: 1.16 (CI: 0.98–1.37) p=0.086; 223565_at: HR: 1.3 (CI: 1.1–1.61) p=0.015) and DLBCL (221286_s_at: HR: 1.17 (CI: 1.06–1.3) p=0.003; 223565_at: HR: 1.21 (CI: 1.08–1.35) p=0.001) but not in other hematologic malignancies like MM or AML. Again, high MZB1 expression levels correlated with prognostic markers in both, FL and DLBCL. However, a multivariate analysis in DLBCL including the International Prognostic Index (IPI), the gene expression subtype of DLBCL and MZB1 expression (continuous) confirmed MZB1 as an independent predictor of OS. Similar results were obtained from a multivariate analysis in follicular lymphoma including MZB1 expression (continuous) and IPI. We also identified genes that closely correlated with MZB1 expression in CLL, FL, DLBCL and AML based on the multistep correlation analysis. We compared the four datasets using these genes and observed that FL, DLBCL, and CLL show stronger similarity to each other than to the AML group. Interestingly, the ratio of probesets positively correlated to MZB1 expression levels to negatively correlated probesets was the highest in the AML group (CLL=3.69; FL=3.4; DLBCL=0.60; AML=78.7). The similarity of the lymphoma subsets was further strengthened by the analysis of the deregulated pathways based on these genes. Among the top seven pathways deregulated only in CLL, FL, and DLBCL were protein processing in endoplasmic reticulum, endocytosis, MAPK signaling pathway and Fc gamma R-mediated phagocytosis. Discussion: In conclusion we discovered a novel prognostic marker that predicted OS in all analyzed malignancies of mature B-cell origin and showed additional prognostic value in multivariate analysis in both, FL and DLBCL. The differential analysis of genes co-expressed with MZB1 further strengthened the prognostic relevance of MZB1 across different mature B-cell diseases. Due to its biological function in neoplasm's of mature B-cell origin and the potential involvement in known oncogenic pathways MZB1 may represent a target for future therapeutic interventions. Disclosures: No relevant conflicts of interest to declare.

Genomic Alterations Important for the Prognosis in Patients with Follicular Lymphoma Treated on SWOG Study S0016

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2678-2678
Author(s):  
Xiaoyu Qu ◽  
Hongli Li ◽  
Oliver W Press ◽  
Lisa M. Rimsza ◽  
Rita M. Braziel ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Univariate Analysis ◽  
Bulky Disease ◽  
Therapeutic Decisions ◽  
Genomic Array ◽  
Genomic Aberrations ◽  
Tissue Specimens ◽  
Array Testing

Abstract Background: FL is a common, indolent, yet typically incurable disease characterized by clinical and genetic heterogeneity. Recent studies suggested that TNFRSF14 mutation and 1p36 deletion were associated with worse outcome in FL and that TNFAIP3 mutation on 6q occurred at FL transformation. However, no genomic biomarkers are currently in clinical use for prognostic and therapeutic decisions. We aimed to identify novel genomic aberrations associated with prognosis of patients with FL in the context of a randomized cooperative group trial (Press 2013 JCO). Patients and Methods: We employed a comprehensive genomic array testing strategy to assess the common genomic abnormalities, including copy number aberrations (CNAs), copy-neutral loss-of-heterozygosity (cnLOH), and common cancer gene mutations. Our study set includes all patients enrolled in the SWOG FL study S0016 with available pre-treatment tissue specimens (n=250). To date, chromosome genomic array testing (CGAT) has been performed on archived formalin-fixed, paraffin embedded (FFPE) lymphoma tissue specimens from 158 patients. A SWOG pathologist reviewed all tissues prior to CGAT to ensure that each sample met the diagnostic criteria for FL and had at least 30% tumor content. The OncoScan platform was used for CGAT with data analysis performed by Nexus Express. Statistical analysis was performed using the Cox-proportional hazard regression model. Hazard ratio (HR) and 95% confidence interval (CI) were estimated from the multivariate model. For this exploratory analysis, statistical significance was determined at an alpha-level of 0.05 without adjustment for multiple comparisons. Results: Most samples (>90%) showed multiple chromosome abnormalities (median 10, range 1-65). The most frequently affected chromosome arms were: 1p (49.3%), 6q (41.7%), 6p (40.5%), 1q (38.6%), 16p or 22q (36%), and 18q (35.4%). Specific common CNAs were deletions of 1p, 6q, and 10q, gains of X, 1q, 2p, 7, 8q, 12q, 17q, and 18, and cnLOH of 1p, 6p, and 16p. Point mutations were not identified. Univariate analysis for progression free survival (PFS) identified several aberrations (of the 94 aberrations assessed) significantly associated with prognosis at unadjusted .05 level; these include gain of 12p, 17q, 18q, and Yp, deletions of 2q, 6q, 8q, 9p, and Yq, and deletion or cnLOH of 9p and 10q. Multivariate analysis adjusting for FLIPI risk, bulky disease, and combined serum β2M and LDH levels demonstrated that selected markers, including deletion or cnLOH of 9p and 10q and gain of 12p and 17q, remained significant for PFS (HR 2.0 for 9p, 0.5 for 10q, 2.8 for 12p, and 2.0 for 17q), while FLIPI risk and serum β2M/LDH levels were no longer significant. In particular, estimated two-year PFS was lower in patients with 9p deletion or cnLOH (60% vs 77%), gain of 12p (62% vs 78%), and gain of 17q (59% vs 80%) compared with those without. Conclusion: We confirmed the frequent 1p and 6q deletions in FL reported in literature. In addition, we identified several genomic aberrations that may be prognostic of FL patients. Among these, deletions and cnLOH of CDKN2A (9p), PTEN (10q) and CREBBP (16p) are of significant interest for their known tumor suppressor functions. Gain of 12p, 17q, and 18q may also help identify oncogenes and other activating tumorigenic processes relevant to disease progression and survival. Multivariate analysis suggested that the genomic aberrations might add to currently utilized clinical risk stratification as a means to identify high risk patients at diagnosis of follicular lymphoma. Support: This work was supported by Affymetrix Inc., NIH/NCI National Clinical Trials Network (NCTN) grants CA180888 and CA180819, and in part by GlaxoSmithKline. Disclosures Hsi: Abbvie: Research Funding; Cellerent Therapeutics: Research Funding; Eli Lilly: Research Funding; Onyx: Honoraria; Seattle Genetics: Honoraria. Smith:Pharmacyclics: Consultancy; Celgene: Consultancy. Fang:Affymetrix: Research Funding.

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