scholarly journals The Impact of Revised Definitions for TACO and TRALI on Hemovigilance Reporting

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3252-3252
Author(s):  
Yin Yuan ◽  
Peta Dennington ◽  
James J. Daly ◽  
John-Paul Tung ◽  
Shoma Baidya
Keyword(s):  
Plasma Volume ◽  
Reporting System ◽  
Conflicts Of Interest ◽  
Antibody Detection ◽  
Validation Data ◽  
Detection Rates ◽  
Significant Difference ◽  
Revised Definitions ◽  
Definition Of ◽  
The Impact

Abstract Introduction Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are serious adverse transfusion reactions. Standardized surveillance definitions are important to ensure consistent and accurate reporting of cases. Recently, revised definitions have been developed for both TACO and TRALI, the latter which have not yet been widely implemented. The primary aim of this study is to assess the impact of the new TACO and TRALI definitions on hemovigilance reporting. The secondary aim is to collate a TRALI case series to describe the epidemiological and laboratory features of this uncommon condition. Methods The Australian Red Cross Lifeblood Adverse Transfusion Reaction database, a passive reporting system, was accessed to identify all cases of suspected or confirmed TACO and TRALI referred from 1 July 2015 to 30 June 2019. Cases were assessed against both the former and new definitions of TACO and TRALI and results compared. For confirmed cases of TRALI the following information was collected: patient demographics, antibody investigation results, type and age of products implicated, donor gender and donor outcomes. Statistical analysis was performed using Fisher's exact test. Results In total 99 cases were identified, of which 12 cases were excluded from analysis due to insufficient clinical details. A further 14 cases were excluded as they were deemed not to be transfusion related. The final number of cases assessed was 73. There were 48 TACO cases identified. Only 26 cases strictly met the former 2011 International Society of Blood Transfusion (ISBT) definition of TACO; 6 cases did not meet the definition and 16 cases lacked sufficient clinical details due to the passive nature of the reporting system. In comparison, 46 cases met the revised 2018 ISBT definition, with only 2 cases having insufficient details. There were 24 cases of TRALI according to the 2004 Canadian Consensus Conference (CCC) definition compared with 25 cases according to the proposed 2019 revised definition. Of the 24 cases of TRALI, 15 were classified as TRALI and 9 as possible TRALI. One case was excluded from having TRALI or possible TRALI under the 2004 CCC definition as the patient had pre-existing acute respiratory distress syndrome from influenza A pneumonia, but could be diagnosed as a TRALI Type II under the revised definition as their respiratory status had been stable for more than 12 hours. A total of 62 components from 81 donors were associated with the 24 TRALI cases. Forty-nine (60%) of these donors were male, 31 (38%) female and 1 (1%) unknown (cadaveric liver). Thirty-three (41%) of these donors were deferred due to the presence of HLA antibodies or being the only donor associated with a case. Sixteen cases (67%) were associated with donor antibodies, most commonly HLA class I and HLA class II antibodies that were non-recipient specific. HNA antibodies were present in 3 cases. There were 8 cases in which an HLA or HNA antibody was not implicated. There was no difference in antibody detection rates between low plasma volume components (red cells, pooled platelets and cryoprecipitate) and high plasma volume components (fresh frozen plasma and apheresis platelets) (45% versus 34%, p=0.44). There was a trend towards higher antibody detection rates in female donors (46%) compared with male donors (29%), however this was not statistically significant (p=0.10). Conclusions The revised TACO definition appears to capture more cases than the former definition. There appears to be no significant difference in the number of TRALI cases under the proposed new definition compared to the definition currently in use. This is the first study to provide validation data for the revised TRALI definition. TRALI is a rare condition and further studies such as these are required to improve our understanding of its pathophysiology and laboratory findings. Disclosures No relevant conflicts of interest to declare.

TIMP-1 and TIMP-2 Levels Are Directly Correlated with Neoangiogenesis and Are Prognostic Factors in Multiple Myeloma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4866-4866
Author(s):  
Luciana Correa Oliveira de Oliveira ◽  
Juliana Alves Uzuelli ◽  
Ana Paula Alencar de Lima Lange ◽  
Barbara Amelia Aparecida Santana-Lemos ◽  
Marcia Sueli Baggio ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Prognostic Factors ◽  
Bone Disease ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4866 Background Multiple myeloma (MM) is an incurable malignant disease, characterized by increased angiogenesis in the bone marrow (BM) microenvironment and aberrant BM metabolism. Matrix metalloproteinases (MMP) are a family of zinc-dependent endopeptidases implicated in tumour progression, invasion, metastasis and angiogenesis, via proteolytic degradation of extracellular matrix. MMPs are inhibited by tissue inhibitors of metalloproteinase (TIMP). Although recent studies have implicated MMP 9 in MM bone disease, little is known about the role of the TIMPs. Objectives a) to compare levels of sRANKL, OPG, MMP-2, MMP-9, TIMP-1, TIMP-2, VEGF, bFGF, microvessel density (MVD) between newly diagnosed MM patients and healthy controls; b) to determine the association of these molecules with disease progression, bone disease and neoangiogenesis and c) to evaluate the impact of these variables on survival. Patients and Methods As of July 2009 38 newly diagnosed and untreated multiple myeloma patients were enrolled in the study. The median age was 61years-old (range 39-91) with 24 (63%) males. Patients were diagnosed and categorized according The International Myeloma Working Group criteria and ISS, respectively. Bone involvement was graded according to standard X-ray: patients with no lesions, or with one/ two bones involved or diffuse osteoporosis were classified as low score, whereas patients with lesions in more than two bones or presence of bone fracture were classified as high score. MMP-2 and MMP-9 were determined by PAGE gelatin zymography from plasma as previously described. MMP-9, TIMP-1 and TIMP-2, OPG and sRANKL concentrations were measured by ELISA. The levels of VEGF, bFGF were obtained using cytometric bead array. Ten healthy volunteers were used as controls. Bone marrow MVD measured in hotspots was evaluated in 26 out of 38 patients at diagnosis and 15 patients with Hodgkin Lymphoma stage IA and IIA (used as controls) by staining immunohistochemically for CD34. Comparisons among groups were analyzed by ANOVA and the correlation by the Spearman's correlation coefficient. Cox regression were performed for overall survival (OS) analysis. Results Patients with MM had elevated TIMP-1, TIMP-2 and OPG values compared with controls. No significant difference was found between plasma sRANKL, pro-MMP2, pro-MMP9 and MMP-9 levels. We found that plasma TIMP-1 levels correlated positively with bFGF, VEGF, MVD, beta-2 microglobulin (B2M) and OPG (r: 0.514, p=0,001, r: 0.350, p=0,031; r: 0.610, p<0.0001; r: 0.760, p<0.0001 and r: 0.701, p<0.0001, respectively) and TIMP-2 levels with bFGF, DMV, B2M and OPG (r: 0.512, p=0.002; r: 0.595, p<0.0001; r: 0.587, p<0.0001 and r: 0.552, p<0.0001, respectively). TIMP-1 and TIMP-2 levels correlated with the ISS stage (p<0.0001, p=0.006, respectively). The only variables that correlated with clinical bone disease staging were hemoglobin, B2M and albumin levels, whereas TIMP-1, TIMP-2, bFGF, VEGF and OPG correlated with DMV. On the univariate analyses, age, gender, proMMP2, TIMP-1, TIMP-2, creatinine, B2M and MVD were significantly associated with overall survival. In Cox regression model, TIMP-1, TIMP-2 and B2M levels remained to be significantly associated with OS. In conclusion, our results suggest that TIMP-1 and TIMP-2 levels are strongly associated with neoangiogenesis and are independent prognostic factors in MM. Disclosures No relevant conflicts of interest to declare.

Association of PML Expression with Chemotherapy-Resistance In Multiple Myeloma Cells

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2959-2959
Author(s):  
Daisuke Ohgiya ◽  
Makoto Onizuka ◽  
Hiromichi Matsushita ◽  
Naoya Nakamura ◽  
Hiroshi Kawada ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cellular Proliferation ◽  
Conflicts Of Interest ◽  
Alkylating Agents ◽  
Chemotherapy Resistance ◽  
Nuclear Body ◽  
Rank Test ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 2959 Background: Although several novel agents have improved the prognosis of patients with multiple myeloma (MM), it still remains an incurable disease because of the difficulty to eradicate MM cells by current therapeutic approaches. Recent studies have revealed that a subset of malignant cells, cancer stem cells, contribute to chemotherapy-resistance in cancer treatment. Promyelocytic leukemia gene product (PML), known as a tumor suppressor through a variety of cellular functions in a nuclear macromolecular structure called the PML nuclear body, has been reported to be responsible for the chemotherapy-resistance by regulating cell cycle in chronic myeloid leukemia. We therefore investigated the impact of PML expression on the cellular proliferation status of MM cells and patients' prognoses. Materials/Methods: Bone marrow clot sections from 48 patients with newly diagnosed MM from Jan 1998 to Dec 2009 before any therapy at diagnosis were obtained, and analyzed, according to appropriate procedure approved by IRB at the Tokai University School of Medicine (Kanagawa, Japan) with written informed consent. They were doubly-stained with a combination of anti-PML/anti-CD138 and anti-Ki67/anti-CD138. For evaluation of the relation between PML status and cellular proliferation, the positive rates of PML and Ki67 in CD138 positive cells were compared. For investigation of the impact of PML expression on the prognosis of MM, the patients were divided into 3 groups, according to the PML positive rates in the CD138 positive cells: negative/low (less than 25 percentile: 12 cases), intermediate (from 25 to 75 percentile: 24 cases) and high (more than 75 percentile: 12 cases). Their overall survivals were compared using log-rank test. Furthermore, the PML positive rates between before and after treatments were compared using paired t-test. Results: The median observation period of 48 cases was 915 days. The median age of the patients was 62.5 (38-76) at diagnosis. All the patients were underwent combination chemotherapies containing alkylating agents as initial therapies. Two and nine patients were underwent allogeneic and autologous stem cell transplantation during the clinical courses, respectively. The numbers of patients of international staging system (ISS) stage I, II and III were 17, 14 and 17 cases. The PML positive rates in each case ranged from 0% to 83.8%. They were not correlated with ISS stages (Spearman r = 0.083) and the Ki67 positive rates (Spearman r = -0.13). The PML positive rates in the negative/low, intermediate and the high groups were less than 22.1%, from 22.1 to 56.6% and more than 56.6%, respectively. No significant difference in overall survival was observed among the 3 groups (p>0.05). However, there were significant differences in two year survival rate when the 3 groups were compared (100%, 85.2% and 54.7%; p=0.015) (Fig. 1). In 13 patients whose bone marrow clot sections were sequentially collected, the PML positive rates after treatments were significantly higher than those at diagnosis (p=0.0042) (Fig. 2). Especially, PML positive rates in all the 3 patients from the negative/low group were progressively increased (0.3 to 82.6%, 14.1 to 100%, 19.0 to 37.5%), and 2 of them died due to disease progression. On the other hand, 2 patients whose PML positive rates decreased after treatment were alive more than 5 years without therapies. Conclusion: Our data indicated that the level of the PML expression at diagnosis was a possible prognostic factor for early course of the disease (2 years after diagnosis). Chemotherapies might induce PML expression in MM cells or select PML positive MM cells. These findings suggest that PML expression presumably reflect chemotherapy-resistance in MM cells. The molecular mechanism of the association is now under investigation. Disclosures: No relevant conflicts of interest to declare.

Cytogenetic Evolution (CE) In Patients (pts) with Low and Intermediate Risk Myelodysplastic Syndromes (MDS) Is Associated with Poor Prognosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2941-2941
Author(s):  
Liunan Li ◽  
Elias Jabbour ◽  
Gautam Borthakur ◽  
Stefan Faderl ◽  
Tapan Kadia ◽  
...  
Keyword(s):  
Disease Progression ◽  
Cytogenetic Analysis ◽  
Conflicts Of Interest ◽  
Myelogenous Leukemia ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Increased Risk ◽  
Significant Difference ◽  
The Impact ◽  
Cytogenetic Evolution

Abstract Abstract 2941 Introduction: MDS is a spectrum of abnormalities in the proliferation and differentiation of hematopoietic stem cells that result in peripheral cytopenias, bone marrow dysplasia and increased risk of transformation to acute myelogenous leukemia (AML). Cytogenetic abnormalities occur in more than 50% of patients (pts) and have an impact on survival and risk of transformation to AML. CE, or acquisition of additional clonal chromosomal abnormalities, has been reported to occur in 30 to 50% of primary MDS pts. Their impact on prognosis and transformation into AML among pts with low and intermediate risk MDS is not known. In this study, we analyzed the impact of CE on prognosis in lower risk MDS. Methods: we reviewed 722 pts clinic records of low and intermediate risk MDS pts at MD Anderson Cancer Center (MDACC) from 2000–2010 and conducted a retrospective analysis of all MDS pts with at least two consecutive cytogenetic analysis (365 patients, 50.6%) and compared the cytogenetic evolution group (CE group) with the group without cytogenetic changes (no CE group). Cytogenetic analysis was performed in the Cytogenetics Laboratory at MDACC. Results: CE was detected in 200 pts (55%). Characteristics of patients with CE are: median age 65 years (23-91), IPSS int-1 79%, diploid CG 42%, excess blasts 25%. Pts with CE were more frequently female (p=0.005), and had more frequently abnormalities of chromosome 5 and 7 (p<0.001) at baseline. There were no statistically significant difference between these two groups (p>0.05) regarding age, WBC, platelet, hgb, ANC, BM blasts percent, diagnosis (RA or RAEB), and IPSS score. There were more chr.-5/-7, insufficient metaphases, and other abnormalities, but less diploid cases in CE group compared with no CE group (p<0.001). History of malignancy (p=0.001) and prior chemotherapy exposure were also associated with CE (p=0.001), but this was not as strong for radiation exposure (p=0.066). Also, more CE patients required therapy for MDS compared to no CE patients (p=0.039). Progression free survival was significantly extended in no CE patients (p=0.02). Overall survival was a longer in no CE (34.1months), compared with CE group (26.2 months), although this was not statistically significant. Conclusion: CE is more commonly observed among pts with high-risk features, and is usually associated with disease progression and resistance. Also, prior malignancy and chemotherapy exposure were associated with CE in this study. This data indicates that genomic instability has a role in disease progression in MDS. Further analysis of CE in MDS is needed. Disclosures: No relevant conflicts of interest to declare.

Evaluation of Enteral Versus Parenteral Feeding As Nutritional Support In Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4576-4576
Author(s):  
Richard Lemal ◽  
Romain Guièze ◽  
Cécile Moluçon-Chabrot ◽  
Eric Hermet ◽  
Aurélie Ravinet ◽  
...  
Keyword(s):  
Stem Cell ◽  
Median Duration ◽  
Nutritional Support ◽  
Conflicts Of Interest ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Early Outcome ◽  
Transfusion Requirements ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4576 Introduction Allo-HSCT procedure is associated with a frequent and potentially severe malnutrition which could highly participate to the transplant-related morbidity (TRM). Optimal nutritional management is still poorly known while both enteral nutrition (EN) and parenteral nutrition (PN) are effective. We proposed to retrospectively evaluate the impact of EN versus PN as nutritional support on early outcome of allo-HSCT. Patients and methods We retrospectively analyzed all the successive patients who needed a nutritional support during their first allo-HSCT in our center from January 2009 to October 2010, excepting whose who had a progressive disease at time of transplant. Datas were compared in an intent to treat analysis according the EN or PN initial nutritional support strategy. Results We analysed early outcome of 56 successive patients. Twenty of them received a myeloablative conditioning regimen and 36 a reduced intensity one. A total of 28 agreed to receive EN via a nasogastric feeding tube and the remaining 28 received PN. No significant difference in terms of age, diagnosis, disease status at transplant, conditioning regimens, stem cell source, GVHD nor antifungal secondary prophylaxis could be observed between the EN and PN groups. We found a lower median duration of fever in EN (2[0–8] vs. 5[0–17] (days); p=0.0026) and a lower need for antifungal therapy in EN group (7/28 vs. 17/28; p=0.0069), with a lower median duration of intravenous antifungal use (0 day [0–99] in EN vs. 7 days [0–93] in PN; p=0.00034) while incidence of bacteriemiae was not different. We observed a lower rate of replacement of central veinous catheter in EN group (3/28 in EN vs. 9/28 in PN; p=0.05) and a lower rate of transfer to ICU in the EN group (2/28 in EN vs. 8/28 in PN, p=0.036) but early death rate (<100 days) was the same in each group (4/28 vs. 4/28, p=NS). Median neutropenia and thrombopenia duration and median transfusion requirements were not significantly different. Fourteen patients in EN group and 18 in PN group presented a grade 3–4 oral mucositis (p=NS). Grade III-IV GVHD incidence was comparable in both groups (4/28 vs. 8/28; p=0.19). Conclusion Compared with PN, EN directly decreases the infectious risk, particularly the fungal risk, and its complications in allo-HSCT, without influencing hematopoietic toxicity nor GVHD incidence. Based on these encouraging results, we are now conducting a prospective, multicentric and randomized trial to confirm EN benefice in allo-HSCT. Disclosures: No relevant conflicts of interest to declare.

Hematopoietic Cell Transplant Co-Morbidity Index (HCTCI) and Multiple Myeloma (MM) Survival After Autologous Hematopoietic Cell Transplantation (AHCT)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4217-4217
Author(s):  
Anuj Mahindra ◽  
Ayman A Saad ◽  
Mei-Jie Zhang ◽  
Xiaobo Zhong ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Risk Groups ◽  
Hematopoietic Cell ◽  
High Dose ◽  
Cell Transplant ◽  
Co Morbidity ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 4217 Background: AHCT improves survival (OS) in newly diagnosed MM patients (pts) in large randomized trials. These trials have limited eligibility to younger, healthier pts. Selection of older pts and those with co-morbid illness for AHCT is problematic. HCT-CI, originally developed as predictor of post-allogeneic transplant outcomes, maybe valuable in stratifying risk of transplant related mortality (TRM) risk and OS in the AHCT setting. We investigated the relative impact of HCT CI along with other patient and MM related variables on outcomes after AHCT in a large cohort of transplant recipients. Methods: Outcomes of 1156 MM pts receiving AHCT after high dose Melphalan (MEL) between 2007 and 2010 reported to the CIBMTR (Center for International Blood and Marrow Transplant Research) were analyzed. HCTCI scores and individual comorbidities were prospectively reported at time of AHCT. Median follow up of survivors was 26 month. The impact of HCTCI and other potential prognostic factors including Karnofsky performance status (KPS) on OS were studied in multivariate Cox regression models. Results: HCTCI score was 0, 1, 2, 3, >3 in 42%, 18%, 13%, 13% and 14% respectively. Most common co-morbidities included pulmonary, diabetes, obesity, psychiatric, cardiac, renal and prior solid tumor. Using consolidated HCTCI scores, patients were stratified initially into 3 risk groups – HCTCI 0 (42%) vs. HCTCI 1–2 (32%) vs. HCTCI >2 (26%). Males and Caucasians were more likely to have greater HCTCI score. Higher HCTCI was associated with lower KPS <90 (33% in HCTCI 0 cohort vs. 50% in HCTCI >2). HCTCI score >2 was associated with MEL dose reduction to 140 mg/m2 (22% vs. 10% in score 0 cohort). Cytogenetic risk and MM related factors were not correlated with HCTCI. TRM at 12 month was 2%, 2%, and 3% for 3 risk groups. With extremely few TRM events, multivariate analysis did not suggest an impact of HCTCI. OS was 95%, 92%, 92% at 1 year and 87%, 81%, 80% at 2 year, respectively. OS was inferior for HCTCI >2 cohort (RR of death 1.48, p=0.02) and HCTCI cohort 1–2 (RR 1.37, p=0.04) compared with HCTCI 0 cohort. There was no significant difference in OS between HCTCI >2 vs. HCTCI 1–2 (p=0.64). Therefore the latter 2 groups were combined as the HCTCI >0 cohort [N=667] and compared with HCTCI=0 [N=489] in multivariate models. HCTCI >0 predicted inferior OS (RR of death= 1.41, p=0.01). Other significant predictors of inferior survival were KPS <90 (RR of death 1.61, p<0.01), IgA subtype (RR 1.64, p<0.01), >1 pretransplant regimen (RR 1.47, p<0.01), resistant MM at AHCT (RR 1.78, p<0.01). Major cause of death in both groups was progressive MM. Conclusion: In clinical practice, higher HCTCI score was associated with MEL dose reduction. Mortality after AHCT is predominantly related to MM progression/relapse with low incidence of TRM. Higher HCTCI scores were independently associated with inferior OS. KPS remains an important tool for risk stratification. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Reciprocal Densities of CXCR4 and CD5 Define Subfractions of Chronic Lymphocytic Leukemia Clones Differing in Phenotype and Response to Environmental Stimuli: Towards a Better Definition of Targetable Components of Leukemic Clones

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3322-3322
Author(s):  
Rajendra N Damle ◽  
Sonal Temburni ◽  
Cristina Sison ◽  
Jaison Jain ◽  
Jacqueline C. Barrientos ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Negative Regulator ◽  
Ki 67 ◽  
Bcr Signaling ◽  
In Vivo Labeling ◽  
Definition Of ◽  
The Impact

Abstract Although chronic lymphocytic leukemia (CLL) is an accumulative disorder of CD5+ B cells, a proliferative fraction exists and the extent of this proliferation correlates with clinical course. We previously demonstrated heterogeneous in vivo labeling kinetics of cells in 3 clonal fractions sorted based on reciprocal densities of chemokine (C-X-C motif) receptor 4 (CXCR4) and CD5 from CLL cases recruited on an in vivo labeling study. In that study, the CXCR4dimCD5br fraction contained more 2H-labeled DNA and hence recently divided cells (proliferative fraction) than the CXCR4brCD5dim(resting) fraction. Here, we have analyzed multiple CXCR4/CD5 based subclonal fractions and characterized their phenotypic differences and ability to respond to signals via the BCR and CXCR4 or a combination of the two. PBMCs from a cohort of 50 untreated IgM+ CLL cases were used for this study. Subclonal fractions marked based on differences in relative densities of CXCR4 and CD5 by CLL cells are referred to as CXCR4br, CXCR4int or CXCR4dim and CD5br, CD5int or CD5dim. Sub-populations adjacent to each other on flow cytometric plots differed at least 5 fold in the densities of both CXCR4 and CD5. When subcategorizing CLL clones based on these markers, 9 subfractions were identified. To permit comparisons between these fractions, each was defined as containing only 2-5% of the total clonal CD19+CD5+population while ensuring no overlap in CXCR4 or CD5 densities among each fraction. Interestingly, certain phenotypic and signaling features consistently clustered with distinct subfractions of the CLL clone. Subfraction analyses confirmed an enrichment of Ki-67+ cells in the CXCR4dimCD5br proliferative fraction of every CLL case. In addition, this subfraction showed the highest percentage of cells expressing smIgM and smIgD (p<0.01). Relative density (RD) of expression was deduced as a ratio of mean fluorescence intensity (MFI) of a molecule expressed by any subfraction compared to that expressed by CXCR4intCD5int cells within the same clone. When considering all cases the CXCR4dim CD5dim cells showed the highest RD of smIgM. However, among U-CLL cases the CXCR4dim CD5br cells expressed the highest RD for smIgM, and the CXCR4dim CD5dim subfraction showed the highest RD of smIgM expression in M-CLLs. Overall, both CXCR4dim CD5br and CXCR4int CD5br showed the highest RD for IgD expression, whereas among U-CLL and M-CLL cases the CXCR4int CD5br and CXCR4dim CD5int subfractions showed the highest RD of smIgD expression respectively. The CXCR4brCD5br subfraction was characterized by the highest % and RD of CD79b, the BCR signaling molecule, and CD22 and CTLA-4, negative regulators of signaling. However, Siglec-10, another negative regulator of BCR signaling, was most highly expressed both in % and RD by the CXCR4dim CD5br subfraction in all CLL cases. Finally, the highest percentages of cells expressing CD21, CD38, CD43, CD69, CD180 associated best with the 3 CD5br subfractions. Of note, CD38 was expressed at highest RD in the CXCR4dim CD5dim in M-CLL cases but in the CXCR4dim CD5brsubfraction in the U-CLL cases. When analyzing phosphorylation of Akt, Erk, p38MAPK and Syk by phosphoflow among all cases, the CXCR4brCD5br fraction exhibited the highest constitutive levels. Constitutive levels of phospho-Btk and - Syk were significantly higher in the CXCR4int CD5br subfraction in M-CLL than in U-CLL cases (p<0.05). Anti-BCR mAbs induced significant increases in phospho-p38MAPK and -Akt in the CXCR4br CD5br subfraction when comparing U-CLL to M-CLL cells. CXCL12 induced significant increases in phospho- Akt and -STAT-5 in CXCR4int CD5br subfraction in U-CLL cases (p<0.01), whereas a combination of signals via BCR and CXCR4 induced increases in phospho-Erk in the CXCR4int CD5br and CXCR4br CD5brpopulations in M-CLL cases. Together, these findings highlight the impact of the molecules expressed by the different subfractions on their ability to relay/inhibit signals elicited via the BCR or CXCR4. They also provide a general frame of reference to further understand functional post-replicative intraclonal heterogeneity of CLL clones and help define aggressive subfractions of the CLL clone as target populations for future therapies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Immunophenotypic Response After Allografting In Multiple Myeloma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3371-3371 ◽  
Author(s):  
Luisa Giaccone ◽  
Lucia Brunello ◽  
Roberto Passera ◽  
Moreno Festuccia ◽  
Milena Gilestro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Flow Cytometry ◽  
Conflicts Of Interest ◽  
Univariate Analysis ◽  
Conditioning Regimen ◽  
First Line ◽  
Significant Difference ◽  
The Impact

Abstract Background Minimal residual disease (MRD) by multiparameter flow-cytometry recently showed a promising role in predicting outcomes in patients with multiple myeloma. However, data on immunophenotypic response (IR) after allografting are lacking. Aim To evaluate the impact of IR and compare it to conventional complete remission (CR) following allografting in myeloma patients. Methods Sixty-six consecutive patients, median age 54 years (35-66), who underwent an allograft between January 2000 and December 2011 with a follow-up of at least 3 months were included. Disease response was evaluated by serum and urine electrophoresis, and bone marrow aspirate at baseline, 3, 6, 12, 18, 24 months after transplant and yearly thereafter. Skeletal survey or MRI were performed yearly or as clinically indicated (overt relapse or complaints of bone pain). Bone marrow aspirates had to contain at least 13000 cells/µL for flow-cytometry studies and IR was defined as absence of monoclonal plasma-cells detected by 4 or 6-colour staining with the following antibodies: CD38, CD138, CD56, CD19, CD45, cyKappa, cyLambda. CR was defined according to standard criteria (Durie et al, Leukemia 2006; 20:1467-73). Results Conditioning regimen was non-myeloablative 2Gy TBI-based in 55 patients, reduced intensity (fludarabine-melphalan-based) in 10 and myeloablative in 1 patient. Post-grafting immunosuppression consisted of cyclosporine with mycophenolate mofetil or methotrexate. Donors were HLA identical siblings in 58 patients and unrelated in 8. Only 1 patient received bone marrow as source of stem cells. Thirty-five/66 (53%) received the allograft as part of the first line treatment, whereas the remaining 31/66, (47%) were transplanted at relapse. At the time of transplant, 5/66 were both in IR and CR, 16 were only in IR and 4 patients were only in clinical CR. All 21 patients in IR at the time of transplant maintained it, while 26/45 (58%) entered IR after the allograft. Among patients surviving at least 3 months, overall treatment related mortality was 10.6% at 3 years. After a median follow-up of 69 months (range 19-147), the incidence of acute and chronic graft-versus-host disease was 45.6% and 49.3% without significant difference between responsive and non-responsive patients. At follow-up, overall, 24 patients achieved CR and IR (CR/IR group), 21 achieved IR but not CR because of persistence of urine/serum M-component (noCR/IR group), and 21 did not achieve either CR or IR (noCR/noIR group). Interestingly, none achieved CR without IR. Median overall survival (OS) and event-free survival (EFS) in patients who achieved IR were 96 and 55 months versus 36 and 7 months in those who did not (p<0.001). Median OS and EFS were not reached and 59 months in the CR/IR group, 77 and 15 months in the noCR/IR, and 30 and 5 months in the noCR/noIR respectively (p<0.001 for both EFS and OS-fig.1). In univariate analysis, being in the CR/IR group was the only significant predictor for prolonged OS and EFS (p<0.001). Of note, cumulative incidence of extra-medullary disease at first relapse after the allograft was 4% in the CR/IR, 32% in the noCR/IR and 15% in the noCR/noIR groups respectively (p<0.001). Receiving the allograft as first line therapy or later during the disease course did not significantly impact on OS and EFS. Conclusion The achievement of IR confers a favorable impact on OS and EFS after allografting. A higher incidence of extra-medullary in the noCR/IR group (some 30% of our patient cohort) may suggest that myeloma cells escape immune control outside the bone marrow. In this group, imaging studies such as positron emission tomography may clinically be indicated during follow-up to detect early relapse. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Significant Increase in Reporting of Transfusion Reactions with the Implementation of an Electronic Reporting System

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4740-4740 ◽  
Author(s):  
Rosanne St. Bernard ◽  
Matthew Yan ◽  
Shuoyan Ning ◽  
Alioska Escorcia ◽  
Jacob M Pendergrast ◽  
...  
Keyword(s):  
Reporting System ◽  
Conflicts Of Interest ◽  
Population Level ◽  
Fold Increase ◽  
Medical Director ◽  
Care Hospital ◽  
Transfusion Reaction ◽  
Reaction Reporting ◽  
Electronic Reporting ◽  
The Impact

Abstract Introduction In robust hospital transfusion services, transfusion reaction reporting triggers a structured response to the assessment, diagnosis, and clinical management of the individual. At a population level, the feedback loop of hemovigilance permits the perception of signals applicable to donors, material production, patterns of use, infusion care, and recipient vulnerabilities. Transfusion reaction reporting therefore aims to improve the quality of patient care and safety in transfusion, which remains one of the most commonly performed procedures in medicine today. Large variations between passive/retrospective or active/prospective systems imply underreporting. Reasons for this may lie in unawareness of, nihilism on, or obstacles to this duty. In 2009, our center transitioned from a paper-based to an electronic reporting system (ERS) for suspected patient reaction events (PREs). This study sought to determine the impact of this change on PRE reporting rates. Methods This study was conducted in Toronto, Canada at the University Health Network, a 4-site, 767-bed, ternary care hospital with high transfusion activity (2014: 60,000 component and 30,000 derivative dispensations). In 05/2009, hardcopy mountsheets for transfusion labels were revised to provide space for recording corresponding vital signs, with instructions on PRE reporting. Medical director PRE review followed with event documentation in a transfusion laboratory database (recording imputability, reaction type, severity, and implicated product(s)). An Acute Transfusion Reaction policy was also developed to protocolize and further streamline the approach to various reactions, but was not implemented across all sites until 11/2009. At this time, electronic PRE reporting went live in the existing electronic medical record, with medical director review hereafter culminating in uploaded case conclusions. Technical tutorials on healthcare worker reporting spanned several months before implementation, without emphasizing the theory or evidence-based value of hemovigilance. The quantity and characteristics of reactions pre-/post-ERS implementation were compared. Results Prior to the ERS option (5/2009-11/2009), the reported PRE rate was 0.26/day. Subsequent to launch (11/2009-12/2009), the reported PRE rate was 0.66/day, representing a 2.54 fold increase (p<0.05) (Figure 1). This nearly-trebled rate has been sustained throughout subsequent years: 01/2010-12/2010: 0.88/day; 01/2011-12/2011: 0.87/day; 01/2012-12/2012: 0.87/day; 01/2013-12/2013: 0.88/day; 01/2014-12/2014: 0.93/day. The distribution of PRE conclusions pre-ERS was: febrile non-hemolytic transfusion reaction (FNHTR) 40%; unrelated to transfusion (UTR) 34%; allergic transfusion reaction (ATR) 7.3%; query bacterial contamination (BaCON) 4.9%; transfusion related acute lung injury (TRALI) 3.6% and transfusion related circulatory overload (TACO) 2.4%. The distribution of PRE conclusions after ERS (11/2009-12/2014) was: ATR 28.8%; UTR 28.7%; FNHTR 19.9%; TACO 8.6%; transfusion associated dyspnea 4.7%; pain 3.2%; query BaCON 2.3% and TRALI 1.7%. Conclusions Our data demonstrate that PRE reporting significantly increased and was sustained after the implementation of an ERS. This finding suggests that despite a dearth of strategies to address underreporting, the solution may lie in removing disincentives while facilitating action in familiar practice platforms. Two other studies investigated the implementation of an ERS for transfusion reaction reporting (Fujihara H. et al. 2015; Yeh, S et al. 2011), with one confounded by a significant increase in transfusion rates in the post-ERS period. In contrast, our denominator of blood utilization has been stable or decreasing across sites over the last five years, with 3% of product recipients nevertheless experiencing a PRE. Despite the significant increase in reported PREs, we did not see an increase in UTRs (34% vs 25%) to account for the difference, arguing against "junk inflations," while rather suggesting that reporter suspicions generally concur with specialist conclusions on transfusion imputability. Given the importance of accurate transfusion reaction reporting for patient safety, we suggest that this strategy be considered by other centers to improve reporting activity with its potential downstream benefits. Disclosures No relevant conflicts of interest to declare.

PS01.196: SHORT-TERM AND MEDIUM-TERM OUTCOMES IN PATIENTS OVER 70 DIAGNOSED WITH OESOPHAGEAL CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 105-105
Author(s):  
Anantha Madhavan ◽  
Nicola Wyatt ◽  
Charlotte Boreham ◽  
Alexander Phillips ◽  
S Michael Griffin
Keyword(s):  
Oesophageal Cancer ◽  
Conflicts Of Interest ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Major Complication ◽  
Radio Therapy ◽  
Significant Difference ◽  
Group A ◽  
Group B ◽  
The Impact

Abstract Background Oesophageal cancer incidence has increased over the last decade in the UK, particularly in older patients. Surgery, with or without perioperative chemotherapy, remains the gold standard treatment for patients with potentially curable disease. Currently, 41% of new cases of oesophageal cancer are in patients aged over 70. However, only 10% underwent surgery compared to 25% of those aged under 70. Concerns exist that advanced age may prejudice treatment decisions. The aim of our review is to evaluate the impact of age on outcomes in those undergoing planned curative treatment for oesophageal cancer. Methods A retrospective review of patients undergoing oesophagectomy for carcinoma between 2006 to 2016 at a single institution was performed. Patients were divided into two cohorts based on age at the time of diagnosis; under 70 years (Group A) and over 70 (Group B). Patients underwent a standardised staging protocol and treatment was decided by a multi-disciplinary team. Oesophagectomy was performed using a transthoracic approach with two field lymphadenectomy and perioperative chemo (radio) therapy used in those patients with locally advanced disease who were fit enough. Results There were 555 patients in Group A and 241 in Group B. Adenocarcinoma was the prevalent histological subtype in both cohorts: 76% (423) in Group A and 68% (165) in Group B. Median age at the time of diagnosis was 62 in Group A versus 74 in Group B. In Group A, 12% (18/343) did not receive neo-adjuvant treatment for locally advanced cancer versus 47% (101/212) in Group B (P < 0.001). Median hospital stay was longer in Group B (18 v 15 days P = 0.02). There was no significant difference in hospital mortality (Group A 1% vs Group B 2.4% P = 0.37) and major complication rate (Group A 14% vs Group B 20% P = 0.31). Two-year survival was 66% (adenocarcinoma) and 78% (SCC) in Group A compared to 60% (adenocarcinoma) and 64% (SCC) in Group B. Conclusion These results demonstrate that patients over 70 can be treated successfully with minimal additional risk to morbidity and mortality. However, these patients are more likely to be denied neoadjuvant treatment which may compromise their long-term outcomes. Disclosure All authors have declared no conflicts of interest.

Alpha-Catenin Is Dispensable for Normal Hematopoietic Stem Cell Function.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1438-1438
Author(s):  
Natallia Mikhalkevich ◽  
Michael W. Becker
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Conflicts Of Interest ◽  
Fusion Product ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Myeloid Neoplasms ◽  
Increased Risk ◽  
Significant Difference ◽  
The Impact

Abstract Abstract 1438 Poster Board I-461 We previously demonstrated the loss of expression of alpha-E-Catenin, the product of the CTNNA1 gene, in primary leukemic stem cells isolated from patients with advanced Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) associated with loss of all or part of the long arm of chromosome 5. To formally assess the impact of loss of Ctnna1 expression on hematopoiesis, we employed a murine model for the hematopoietic specific conditional loss of Ctnna1 expression. We demonstrate that Ctnna1 deficiency is associated with normal hematopoietic maturation and proliferation as assessed by peripheral blood examination and methycellulose colony assays. We assessed stem cell and early progenitor frequencies using both flow cytometry and functional assays. Ctnna1 deficiency was associated with equivalent frequencies of Sca1+C-Kit+CD135-Lineage- HSCs in both experimental animals and controls. Short term HSC and MPP frequencies were likewise unaltered. We assessed HSC function using transplantation studies. In competitive repopulation experiments, HSCs deficient for Ctnna1 maintained stable engraftment of recipient mice for up to 1 year. Limiting dilution analyses detected no significant difference in HSC frequency between wild type and Ctnna1 deficient mice. We examined the potential role of Ctnna1 deficient hematopoietic stem cells in two murine models for myeloid neoplasms 1.) exposure to mutagen ENU and 2.) a model for murine AML driven by the HoxA9-Nup98 fusion product. Following exposure of HSCs to ENU, loss of Ctnna1 was not associated with an increased risk of development of a myeloid neoplasm. Expression of the HoxA9-Nup98 fusion product by retroviral infection of Ctnna1 deficient and wild type Sca1+C-Kit+Lineage- cells resulted in no difference in time to development of the previously characterized myeloproliferative disorder or acute leukemia. Taken together, these data demonstrate that in the absence of specific genetic abnormalities, loss of Ctnna1 expression in primary murine HSCs is not associated with aberrant HSC function or the development of myeloid neoplasms. Further studies are necessary to define a role for of loss of Ctnna1 expression in human myeloid malignancies. Disclosures No relevant conflicts of interest to declare.

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