Aberrant Expression of the MLL5, BAALC, ID1, and WT1 Genes Is Associated with Higher Induction Mortality and Poorer Overall Survival in Acute Promyelocytic Leukemia Patients Treated with ATRA and Anthracycline-Based Chemotherapy: An International Consortium On Acute Promyelocytic Leukemia Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1407-1407
Author(s):  
Antonio R Lucena-Araujo ◽  
Rafael Henriques Jacomo ◽  
Haesook T Kim ◽  
Raul A Melo ◽  
Rosane Bittencourt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Board Of Directors ◽  
Acute Promyelocytic Leukemia ◽  
Outcome Prediction ◽  
Promyelocytic Leukemia ◽  
Advisory Committees ◽  
Aberrant Expression ◽  
Expression Levels ◽  
Gene Expression Levels

Abstract Abstract 1407 Background: Aberrant expression of MLL5, BAALC, ID1, and WT1 genes is frequently associated with inferior outcome in cytogenetically normal acute myeloid leukemia patients (Damm et al. Blood 2011; 117(17):4561–8). The expression levels of these genes vary in patients with acute promyelocytic leukemia (APL), but the clinical significance of these findings remains unclear. Objective: (1) to determine if the gene expression levels of MLL5, BAALC, ID1, and WT1 are associated with clinical outcome of APL patients treated with ATRA and anthracycline-based chemotherapy, (2) to generate an integrative score (IS) based on these potential prognostic factors and clinical parameters and (3) to use this score for outcome prediction in APL. Design and Methods: One hundred and fifty APL patients (age, 15–73y) from seven different Brazilian institutions and treated according to the IC-APL protocol were included. The treatment schedule was identical to the PETHEMA-LPA 2005, except for the replacement of idarubicin by daunorubicin; ATRA treatment was initiated immediately in all cases in which the diagnosis of APL was suspected based on morphology. Gene expression profile was analyzed by Real-time PCR. Integer weights for the IS were derived from Cox proportional hazard model, using overall survival (OS) as outcome parameter. Hazard ratios (HR) for OS were calculated for each variable separately (Table 1). Variables with P<0.05 in univariate analyses were included in the model. Variables considered for the model inclusion consisted in 2 clinical (WBC counts, albumin levels) and 5 molecular markers (FLT3-ITD status and gene expression levels of MLL5, BAALC, ID1, and WT1). Other candidates, such as age, platelet count, gender, ECOG performance status, PML breakpoint and FAB subtype were not significant and not included in the score. The HR were converted to integer weights according to the following: variables with HR < 1 were excluded from analyses; variables with HR 3 1 and < 1.5 were assigned a weight of 1; variables with HR 3 1.5 and < 2.5 were assigned a weight of 2; variables with HR 3 2.5 were assigned a weight of 3. The final score was the sum of these integer weights. Based on maximally selected rank statistics, the scores were grouped into 3 risk-groups: 0–5 (low-IS), 6–9 (intermediate-IS), and > 9 (high-IS). Results: The integrative weights of variables analyzed are summarized in Table 1. The IS was modeled in 137 patients (median score: 6; range, 1–17). According to PETHEMA-GIMEMA relapse risk criteria, 22%, 23% and 70% of patients assigned in the low-IS (n=46), intermediate-IS (n=57) and high-IS (n=34) groups were deemed high-risk of relapse (P<0.001). Overall, 118 (86%) patients achieved CR; the remaining 19 patients (14%) experienced early death due to hemorrhage (n=12), therapy-related infection (n=6) and differentiation syndrome (n=1). Induction mortality was significantly higher in the high-IS group (low: 2%; intermediate: 15%; high: 26%) (P=0.001). CR was achieved in the low-, intermediate-, and high-IS group in 98%, 84%, and 73% of the patients, respectively (P=0.007). With a follow-up of 24 months among survivors, patients assigned in the high-IS group had a lower 2-y OS rate (63%) compared with those in the intermediate- (80%) and low-IS groups (97%; P<0.001). Eight relapses were recorded. The IS was not predictive of relapses (P=0.351). Conclusions: Our results suggest that MLL5, BAALC, ID1, and WT1 expression levels are associated with clinical outcome and that the IS may become a useful tool for outcome prediction in APL. Disclosures: Lo-Coco: Cephalon: Speakers Bureau; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees. Löwenberg:Skyline Diagnostics: Membership on an entity's Board of Directors or advisory committees.

Expression of the Wilms’ Tumor 1 (WT1) Gene Renders Acute Promyelocytic Leukemia Cells Resistant to All-Trans-Retinoic-Acid-Induced Differentiation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4385-4385
Author(s):  
Aschwin L. Menke ◽  
Ruth H.J.N. Knops ◽  
Jurgen A.F. Marteijn ◽  
Willemijn Wissink ◽  
Josie Smeets ◽  
...  
Keyword(s):  
Overall Survival ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Wilms Tumor ◽  
Promyelocytic Leukemia ◽  
Induced Differentiation ◽  
Expression Levels ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Wilms Tumor 1

Abstract Acute myeloid leukemia is characterized by the uncontrolled proliferation of immature cells that have lost their ability to differentiate. In the case of acute promyelocytic leukemia (AML-M3), the cells can be forced to differentiate by pharmacological dosages of all-trans retinoic acid (ATRA), a phenomenon that is successfully used in the treatment of APL patients. About 70% of the patients, suffering from PML-RARa -positive acute promyelocytic leukemia, can be cured with a combination of ATRA and anthracycline - based chemotherapy. However, relapse remains a major problem. The molecular mechanisms by which the retinoic acid receptors mediate their biological functions have been studied extensively and although various retinoic acid-responsive genes have been identified, the target genes that are crucially involved in leukemogenesis are unknown. The Wilms’ Tumor 1 gene, has been implicated in the development of leukemia. WT1 overexpression can be detected in most acute leukemias and is particularly highly expressed in APL cells. Several groups have found an inverse correlation between the expression levels of WT1 and the overall survival of leukemia patients. The underlying mechanism, however, remains to be elucidated. We have shown that the Wilms’ Tumor 1 (WT1) is strongly downregulated in APL cells, during ATRA-induced differentiation. Using a newly developed realtime RT-PCR method we have found that the expression levels of all four major WT1 isoforms are downregulated. To study the biological activity of each WT1-isoform, we have retrovirally transduced the APL cell line NB4, with the 4 major WT1 isoforms and analyzed the effect on ATRA-induced differentiation. Using flowcytometry and NBT staining, we show that ectopic expression of the different WT1-isoform inhibited ATRA-induced differentiation and subsequently, the apoptosis of APL cells, albeit with different potential. WT1-transduced cells survived pharmacological dosages of ATRA for more than 14 days and in some cases even continued to grow. These data indicate that downregulation of WT1 is essential for ATRA-induced differentiation of APL cells and provide an explanation why AML patients with high WT1 expression levels have worse overall survival in comparison to patients with low WT1 expression levels.

scholarly journals Biomarkers of Overall Survival and Response to Glasdegib and Intensive or Non-Intensive Chemotherapy in Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2733-2733 ◽  
Author(s):  
Jorge E. Cortes ◽  
Akil Merchant ◽  
Catriona Jamieson ◽  
Daniel A Pollyea ◽  
Michael Heuser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Board Of Directors ◽  
Research Funding ◽  
Intensive Therapy ◽  
Employment Equity ◽  
Advisory Committees ◽  
Expression Levels ◽  
Biomarker Analysis ◽  
Cytokine Levels ◽  
Equity Ownership

Abstract Background: In a previously reported Phase 2 randomized study of patients with acute myeloid leukemia (AML), addition of the investigational agent glasdegib (PF-04449913) to low-dose cytarabine (LDAC) improved overall survival (OS) when compared with LDAC alone. In a non-randomized study arm, glasdegib together with 7+3 chemotherapy was well tolerated and associated with clinical activity. We used a comprehensive biomarker analysis, evaluating gene expression, circulating cytokine levels, and gene mutations, to identify molecular drivers that predict overall response (OR) and OS. Methods: In this Phase 2 multicenter study (NCT01546038), patients with AML who were suitable for non-intensive therapy were randomized (2:1) to LDAC + glasdegib 100 mg QD or LDAC alone, and patients suitable for intensive therapy were assigned 7+3 plus glasdegib 100 mg QD. Whole blood, serum, and bone marrow aspirate samples were collected at baseline, and used to assess 19 genes for expression analysis, 38 analytes for circulating cytokine levels, and 109 genes for mutation analysis. Gene expression was analyzed using TaqMan Low Density Array Cards (TLDCs), cytokine levels were analyzed using quantitative, multiplexed immunoassays (Myriad RBM), and mutation analysis was performed using the Illumina® MiSeq instrument (San Diego, CA). All correlations were performed either for OS or for OR. For gene expression and cytokine analysis, a cut-off value above or below the median expression level for each treatment arm was used to separate samples into two subgroups (< or ≥ the median value) to explore the relationship of expression levels with OS data. Criteria for significance in the non-intensive cohort required one subgroup to have a p-value of <0.05 in the between-treatment arms comparison and the HR difference between the two subgroups to be ≥2 fold. Responses were defined as patients with a complete remission (CR), CR with incomplete blood count recovery (CRi), morphologic leukemia-free state, partial remission (PR), or PRi. For response correlations, genes or cytokines were considered to be differentially expressed if they had a p-value <0.05 and were differentially expressed by ≥2-fold. Results: Within the non-intensive arm (LDAC + glasdegib, n=68; LDAC alone, n=30), expression levels of several genes correlated with improved OS with glasdegib plus LDAC. Lower levels of expression of FOXM1 and MSI2, and higher expression levels of BCL2 and CCND2 correlated with improved OS with the combination. Additionally, lower levels of the cytokines 6CKINE (CCL21), ICAM-1, MIP-1α, and MMP-3 correlated with improved OS. An analysis of correlations of gene expression and cytokine levels with OR could not be completed due to the low number of responders in the LDAC only group (n=2). In the intensive treatment arm (glasdegib and 7+3, n=59), higher PTCH1 expression correlated with improved OS (p=0.0219, median OS 10.8 versus 39.5 months). In this cohort, lower levels of IL-8 (p=0.0225) and MIP-3β (p=0.0403) correlated with lower OS. Expression levels of no genes or cytokines significantly correlated with OR in this arm. We also examined correlations between gene mutation status and OS in both study arms. In the non-intensive arm (LDAC + glasdegib, n=58; LDAC alone, n=25), no genes mutated in at least 5 patients correlated with OS. In the intensive treatment arm (n=47), mutations in FLT3, TP53, CEP170, NPM1, and ANKRD26 correlated with OS (all p<0.05). Patients in this arm with FLT3 mutations responded better than patients with wild type FLT3 (p=0.0336, median OS of 13.1 months versus unreached for FLT3 mutant). Conclusions: In this biomarker analysis, we found that expression levels of a select number of genes and circulating cytokines implicated in AML correlated with OS in the non-intensive and the intensive arms. The improved response for patients with FLT3 mutations and high PTCH1 expression levels in the intensive arm deserves further investigation. These findings need to be verified in larger controlled studies, which are ongoing. Disclosures Cortes: Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding. Pollyea:Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; Curis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Heuser:Astellas: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding; Bayer Pharma AG: Consultancy, Research Funding; StemLine Therapeutics: Consultancy; Janssen: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BergenBio: Research Funding; Karyopharm: Research Funding. Chan:Pfizer: Employment, Equity Ownership. Wang:Pfizer: Employment, Equity Ownership. Ching:Pfizer Inc: Employment, Equity Ownership. Johnson:Pfizer Inc: Employment, Equity Ownership. O'Brien:Pfizer Inc: Employment, Equity Ownership.

scholarly journals The Effect of 8-Weeks of Low-Intensity Swimming Training on Promyelocytic Leukemia Zinc Finger Protein and Spermatid Transition Nuclear Protein Gene Expression in Azoospermic Rats Model

2020 ◽  
Vol 26 (4) ◽  
pp. 332-347
Author(s):  
Leila Zohrabi Karani ◽  
◽  
Parvin Farzanegi ◽  
Mohammad Ali Azarbayjani ◽  
◽  
...  
Keyword(s):  
Gene Expression ◽  
Zinc Finger ◽  
Nuclear Protein ◽  
Promyelocytic Leukemia ◽  
Swimming Exercise ◽  
Promyelocytic Leukemia Zinc Finger ◽  
Expression Levels ◽  
Low Intensity ◽  
Healthy Control ◽  
Gene Expression Levels

Aims: One of the causes of infertility in men is the azoospermia disease, which is attributed to the lack of sperm in each sperm. The primary function of spermatogenesis is the maintenance, proliferation, and differentiation of spermatogonial cells. Thus, the present study aimed to investigate the changes in Promyelocytic Leukemia Zinc Finger (PLZF) and spermatid Transition Nuclear Protein (TNP) gene expression levels in an azoospermic rat model after 8 weeks of low-intensity aerobic training. Methods & Materials: In this experimental study, 15 adult male Wistar rats were randomly divided into three groups of healthy control, with azoospermia, and exercise plus azoospermia after creating an azoospermia model. The patient plus exercise group performed a low-intensity swimming exercise 30 minutes a day, five days a week for 8 weeks, after the creation of the azoospermic rats. A One-way ANOVA test was used for data analysis. Findings: The results showed that a period of swimming exercise program in the exercise plus azoospermia group significantly reduced PLZF gene expression compared to the healthy control groups (P=0.001) and no significant increase to the azoospermia group (P=0.06). There was also a significant decrease in TNP gene expression levels in the exercise plus azoospermia group compared to the healthy control group (P=0.001) and a significant increase in the azoospermia group (P=0.057). Conclusion: Based on these Findings, it can be stated that the alteration of key molecules or signaling pathways and expression of the PLZF and TNP genes in the spermatogenesis process may increase infertility, but regular aerobic exercise, such as low-intensity swimming, helps to control the effects of infertility by increasing the maintenance and development of spermatogonial stem cells.

scholarly journals Inotuzumab Ozogamicin (Ino) May Overcome the Impact of Philadelphia Chromosome (Ph)-like Phenotype in Adult Patients (pts) with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1641-1641 ◽  
Author(s):  
Elias Jabbour ◽  
Kathryn G. Roberts ◽  
Koji Sasaki ◽  
Yaqi Zhao ◽  
Chunxu Qu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Advisory Committees ◽  
The Impact

Background: Ino showed significant activity in phase II trials in pts with R/R ALL, that was subsequently confirmed in Phase III trial where Ino demonstrated higher response rates and superior overall survival vs standard of care chemotherapy (SOC) in adults with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R ALL).Ph-like or BCR-ABL1-like ALL possesses a gene expression profile similar to that of BCR-ABL1 ALL but lacks the BCR-ABL1 fusion protein. It is characterized by increased expression of hematopoietic stem-cell genes, deletion of B-cell lineage genes and kinase-activating alterations. Ph-like ALL is associated with refractoriness to standard induction/consolidation chemotherapy and poor prognosis. Aim: To evaluate the outcomes of pts with R/R Ph-like ALL treated in phase II trial with Ino monotherapy. Methods: We performed an integrated analysis of whole genome sequencing (to identify sequence mutations, structural variations and DNA copy number alterations), and transcriptome sequencing (RNAseq; to quantify gene expression, determine Ph-like gene expression profile and identify fusions) on 53 patients' samples treated with Ino between June 2010 and September 2012. Results: Fifty-three evaluable pts with R/R ALL with stored baseline samples were analyzed. Pts characteristics are summarized in Table 1. Median age was 50 years. Ino was given as Salvage 1, Salvage 2, and Salvage 3 and beyond in 20 (38%), 18 (34%), and 15 (28%) pts, respectively. Figure 1 reflects the different genomic subgroups identified among 53 evaluable pts. Ph-like gene signature was found in 12 pts (22.6%). Among these 12 pts, 6 had IGH-CRLF2, 2 IGH-EPOR, 1 SNX2-ABL1, and 3 had no fusions identified. The overall response rates (ORR) were 54% [complete remission (CR) 20%, CR with partial hematologic recovery (CRh) 32%, and marrow CR (CRi) 2%]. Among pts with morphologic remission, 46% and 82% achieved minimal residual disease (MRD) negativity at CR and at any time, respectively. The ORR for pts with Ph-like ALL, Ph-positive ALL, ALL with KMT2A, and others were 58% (CR=25%; CRh=33%), 42% (CR=8%; CRh=33%), 57% (CR=14%; CRh=29%; CRi=14%), and 56% (CR=26%; CRh=30%), respectively. The respective overall MRD negativity rates were 71%, 100%, 75%, and 83% (Table 1). The median follow-up was 60 months. The median event-free (EFS) and overall survival (OS) were 3.3 and 5.4 months, respectively. There was no difference in EFS and OS between the subgroups analyzed (P=0.464; P=0.824). The median EFS and OS were 4.5 and 4.5 months for pts with Ph-like, 3.1 and 7.2 months for those with Ph-positive ALL, 2.8 and 4.4 months for those with KMT2A, and 2.2 and 4.6 months for others (Table 1). 21 (40%) pts had subsequent allogeneic stem cell transplant; 6 (50%), 3 (25%), 4 (57%), and 8 (36%) in each subgroup, respectively. The rate of VOD was 3 (6%) with no difference among different subgroups. Conclusion: The current analysis suggest that Ino therapy may overcome the impact of Ph-like phenotype in pts with ALL. Confirmation of these findings in a larger cohort and in frontline ALL patients is needed. Disclosures Jabbour: Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Sasaki:Pfizer: Consultancy; Otsuka: Honoraria. Jain:Precision Biosciences: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, an AbbVie company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Adaptive Biotechnologies: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Research Funding; Amgen: Honoraria. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Konopleva:Cellectis: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria; Ablynx: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding. Mullighan:Illumina: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored travel; Pfizer: Honoraria, Other: speaker, sponsored travel, Research Funding; AbbVie: Research Funding; Loxo Oncology: Research Funding; Amgen: Honoraria, Other: speaker, sponsored travel. Kantarjian:Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Jazz Pharma: Research Funding; Takeda: Honoraria.

Molecular detection of occult nodal metastases in esophageal adenocarcinoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4540-4540
Author(s):  
I. Altomare ◽  
A. Pennathur ◽  
L. Xi ◽  
W. E. Gooding ◽  
V. R. Litle ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Lymph Nodes ◽  
Esophageal Adenocarcinoma ◽  
Molecular Analysis ◽  
Expression Levels ◽  
Qrt Pcr ◽  
Positive Expression ◽  
Disease Free ◽  
Gene Expression Levels

4540 Introduction: Esophageal adenocarcinoma (EAC) is an aggressive malignancy whose incidence is on the rise. Approximately 40% of patients with N0 disease will recur after theoretically curative surgery, suggesting that in early stage disease, metastatic spread is often undetected by routine pathology. Molecular techniques may more accurately detect micrometastatic spread of EAC, but the correlation between molecular analysis of nodes and prognosis is unknown. Our lab has previously identified and validated 4 markers whose gene expression levels are able to distinguish benign nodes from nodes with metastatic EAC: CK19, CK20, CEA and TACSTD1. We used quantitative real-time RT-PCR to evaluate the expression of these 4 markers in lymph nodes from 68 N0 and 62 N1 EAC patients to see if molecular staging is predictive of a worse clinical outcome. Methods: RNA was isolated from 1456 lymph nodes obtained from 130 patients who underwent resection of EAC. QRT-PCR was used to analyze gene expression for each of the 4 markers. Relative expression of each marker was compared with expression in 53 benign esophageal lymph nodes previously analyzed. Results: Analysis of 778 lymph nodes from 68 pN0 patients identified 71 nodes (9%) from 30 patients (44%) which showed positive expression of at least one marker, indicating occult metastases (and molecular upstaging). Analysis of 678 lymph nodes from 62 pN1 patients revealed 141 nodes (21%) from 40 patients (65%) which had positive expression of at least one marker in nodes that were pathologically negative. In the pathologically positive nodes from N1 patients, there was an encouraging 88% concordance between pathological and molecular analysis. After a median follow-up of 2 years, 13 N0 patients had recurrence of their cancer. Gene expression levels of 3 of the 4 markers (CK20, CEA and TACSTD1) correlated with significantly worse disease-free and overall survival among these N0 patients, with p values <0.05. Conclusion: We have shown that QRT-PCR of 3 independent genetic markers is predictive of significantly worse disease-free and overall survival among node-negative EAC patients by identifying lymph nodes with occult metastatic disease. Further analysis will reveal if the N1 patients with molecularly positive lymph nodes had significantly worse outcomes as well. No significant financial relationships to disclose.

scholarly journals Combining gene mutation with gene expression analysis improves outcome prediction in acute promyelocytic leukemia

Blood ◽  
2019 ◽  
Vol 134 (12) ◽  
pp. 951-959 ◽  
Author(s):  
Antonio R. Lucena-Araujo ◽  
Juan L. Coelho-Silva ◽  
Diego A. Pereira-Martins ◽  
Douglas R. Silveira ◽  
Luisa C. Koury ◽  
...  
Keyword(s):  
Gene Expression ◽  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Gene Expression Analysis ◽  
Outcome Prediction ◽  
Prognostic Score ◽  
Promyelocytic Leukemia ◽  
Alternative Therapies ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Abstract Luceno-Araujo et al use assays of mutations associated with myeloid malignancy to propose an integrative prognostic score for acute promyelocytic leukemia (ISAPL) in patients treated with all-trans retinoic acid and anthracycline-based therapy. They demonstrate that the ISAPL is superior for predicting outcomes and identifying patients who may benefit from alternative therapies to maximize their chance of a cure.

scholarly journals An IDO1-Related 3-Gene Signature Predicts Overall Survival in Intermediate-Risk Acute Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5193-5193
Author(s):  
Simone Ragaini ◽  
Sarah Wagner ◽  
Giovanni Marconi ◽  
Sarah Parisi ◽  
Chiara Sartor ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Mrna Expression ◽  
Board Of Directors ◽  
Research Funding ◽  
Gene Signature ◽  
Intermediate Risk ◽  
Advisory Committees ◽  
Expression Score ◽  
Gene Expression Score

Introduction: ELN intermediate-risk AML poses considerable challenges to clinicians both in terms of accurate prognostication and optimal treatment. Indoleamine 2,3-dioxygenase 1 (IDO1) plays a central role as a mediator of immune tolerance in AML through the increase of Treg cells. IDO1 activity is negatively regulated by the BIN1 proto-oncogene. Herein, we analyzed the correlation between BIN1 and IDO1 expression in AML, also focusing on IDO1-interacting genes, with the aim to identify a predictive gene signature for OS. Methods: Biological and clinical data of 732 patients with de novo AML were retrieved from public TCGA and HOVON datasets. Since details on chemotherapy regimens were not available in the HOVON dataset, we decided to exclude patients >= 65 years from survival analyses. IDO1-interacting genes were selected through a co-expression analysis performed on TCGA RNA-sequencing data accessed through cBioPortal. The best genes combination predicting overall survival was plotted in a gene expression score. Patients were split in three different groups using score quartiles as cut-off. Results: In the HOVON dataset, IDO1 and BIN1 mRNA expression were negatively correlated (r = -0.40, P<0.0001). Our analysis of TCGA data identified PLXNC1 as an IDO1-interacting gene and a predictor of patient survival (median split of mRNA expression, P<0.001, survival analysis performed on the BloodSpot online portal). The correlation between PLXNC1 and IDO1 was validated in the HOVON dataset (r=-0.24, P<0.0001). PLXNC1 expression was combined with IDO1 and BIN1 expression to obtain the gene expression score. The 3-gene score predicted survival in ELN intermediate-risk patients who did not receive allogeneic HSCT both in the HOVON dataset (P<0.0001) and the TCGA dataset (P<0.05). In particular, the highest score values predicted the shortest OS. Conclusions: Our study shows a negative correlation between IDO1 and BIN1 in AML, suggesting IDO1 inhibition by BIN1, and identifies for the first time PLXNC1, a receptor for semaphorines, as an IDO1-interacting gene potentially implicated in immune response regulation. This finding corroborates the role of IDO1 and its interacting genes in the promotion of a tolerogenic microenvironment in AML. Lastly, our gene expression score predicted OS in intermediate-risk AML patients not undergoing HSCT, a finding which has clinical implications for accurate patient stratification and for clinical decision making, i.e., bridging these patients to transplant. Figure Disclosures Papayannidis: Pfizer: Honoraria; Amgen: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Shire: Honoraria; Teva: Honoraria. Cavo:celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel accommodations, Speakers Bureau; bms: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; novartis: Honoraria; takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rutella:MacroGenics, Inc.: Research Funding; NanoString Technologies, Inc.: Research Funding; Kura Oncology: Research Funding.

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