High Cereblon Protein Expression Correlates with Improved Response and Survival in Myeloma Patients Treated with Lenalidomide

Abstract Abstract 931 Background: Cereblon (CRBN), an adaptor protein of the Cul4A-DDB1-ROC1 ubiquitin E3 ligase complex was recently identified as a primary target of thalidomide teratogenicity and as essential requirement for IMiDs mediated cytotoxicity in multiple myeloma (MM) cells in vitro (Zhu YX et al, 2011). We have undertaken the current study to confirm the association between cereblon protein expression and the clinical response to lenalidomide. Methods: We constructed tissue microarrays (TMA) using bone marrow biopsies collected immediately prior to initiating therapy with lenalidomide. Fluorescence immunohistochemistry was performed using a polyclonal anti-CRBN antibody (HDA045910, Sigma-Aldrich) at a dilution of 1:4000, with 3 minutes of antigen retrieval at 121°C in a decloaking chamber in a pH=9 Tris/EDTA-based buffer (S2367, Dako). Tissue microarray slides were scanned on a HistoRx PM-2000 and digital images where analyzed with AQUA analysis software to determine the CRBN AQUA scores (protein expression = AQUA scores defined as the average CRBN pixel intensity within CD138 positive cells). CRBN AQUA scores where standardized on the Z-distribution (Z= X-μ/σ). The clinical parameters, response criteria and survival outcomes (PFS and OS) of these patients were defined according to the international uniform response criteria. The Kaplan-Meier method was used to estimate OS and PFS. Multivariate analysis was performed using the Cox regression method. Results: 42 patients with newly diagnosed (71.4%) or relapsed / refractory (28.6%) MM patients treated with lenalidomide and dexamethasone (MM009, MM016 or MM020 trials) and available pre-treatment bone marrow biopsies were included in this analysis. In this cohort, median age was 68 (range 46–88), median Hb 114 g/L (range 77–145), median Calcium 2.35 mmol/L (range 1.62–2.82), median creatinine 91.5 μmoles/L (range 44–500), high LDH in 21.4%, median albumin 35.5 g/L (range 23–47), β2 microglobulin 4.66 mg/L (range 1.2–35.19), ISS I 19%, II 35.7% and III 45.3% and high-risk cytogenetics (del17p13, t(4;14) by FISH) in 26.6%. Response CR/nCR was observed in 13/42 (31 %), PR in 21/42 (50%), MR in 4/42 (9.5%) and PD in 4/42 (9.5%). With a median follow-up of 22.4 months (range 0.72–65.6), 28/42 (67%) progressed with mPFS 19.53 months (95% CI 8.57–30.496) and mOS 28.733 months (95% CI 24.061–33.406). Cereblon expression or AQUA normalized Z scores ranged from -1.419 to 3.895. Kaplan Meier log-rank survival analysis were generated based on CRBN normalized AQUA Z scores with the bottom (Q4) and top quartiles (Q1-3) defined as CRBN-low or CRBN-high groups respectively. PFS was significantly shorter in CRBN-low (5.633 months) versus CRBN-high (19.733 months; p= 0.008). Similarly, OS was also reduced in CRBN-low patients (11.4 versus 30.467 months; p=0.033). In univariate Cox regression analysis, cereblon protein expression was significantly associated with PFS (HR 0.322; 95% CI 0.133–0.780; p=0.012) and OS (HR 0.323; 95% CI 0.108–0.970; p=0.044). Cereblon expression remained an independent predictor of PFS (HR 0.161; p=0.01) but not for OS when ISS and cytogenetics were included in multivariate regression analysis. In the CRBN-high group only 5/31 patients (16.1%), compared to 54.5% (6/11) in the CRBN-low group, failed to respond (≤MR) to lenalidomide. Similar to the protein tissue array analysis, low CRBN mRNA was also significantly associated with shorter PFS (p=0.008) in a chip microarray analysis of CRBN expression (Affymetrix probe 222533_at) in a cohort of 32 MM patients treated with lenalidomide and dexamethasone. Cereblon protein expression (AQUA normalized Z score) significantly correlated with CRBN mRNA microarray values (Affymetrix probe 222533_at) in 17 patients with matching protein and mRNA samples (Spearman's rho 0.417; p= 0.048). In contrast, and confirming the specificity of cereblon for response to IMiDs, no association between cereblon protein expression and response to therapy or survival outcomes (PFS/OS) was observed in a independent cohort of newly diagnosed MM patients (n=37) treated with bortezomib induction therapy and ASCT. Conclusion: Using an automated, observer-independent and fully quantitative approach, our studies confirm the association between cereblon protein expression and response to lenalidomide in MM. Disclosures: Neri: Johnson ans Johnson: Research Funding. Bahlis:Johnson and Johnson: Honoraria, Research Funding; Celgene: Honoraria.

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Prognostic Impact of Bone Marrow Erythropoiesis on Newly Diagnosed Plasma Cell Myeloma: A Single Institutional Analyses

Blood ◽

10.1182/blood-2018-99-116619 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5579-5579

Author(s):

Daniel E Ezekwudo ◽

Rohit Singh ◽

Bolanle Gbadamosi ◽

Mark Micale ◽

Ishmael Jaiyesimi ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Outcome ◽

Plasma Cell ◽

Prognostic Impact ◽

Plasma Cell Myeloma ◽

Newly Diagnosed ◽

Bone Marrow Biopsies ◽

Kaplan Meier ◽

Significant Difference ◽

The Impact

Abstract Introduction: In plasma cell myeloma (PCM), tumor burden and activity plays an important role in diagnosis and prognosis (e.g. circulating plasma cells), however very little attention has been directed to the impact of the non-plasma cell component of the bone marrow. The presence of anemia has been used to distinguish PCM from smoldering myeloma; however this can be a non-specific finding as there are many potential causes of anemia besides PCM. We sought to determine if the level of erythropoiesis in bone marrow biopsies may be a more reliable prognostic factor. In the study herein, we assessed the level of bone marrow erythropoiesis in patients with newly diagnosed PCM, and compared those findings with cytogenetic results (CGs), other prognostic factors and overall clinical outcome. We hypothesized that patients with adequate erythropoiesis (AEp) are likely to have favorable cytogenetics and better outcome compared to those with decreased erythropoiesis (DEp). Methods: We retrospectively reviewed pathology database for bone marrow biopsies in patients with diagnosis of plasma cell myeloma (PCM) at Beaumont Hospital, an academic community center from 2012 and 2014. Biopsy cases without anemia were excluded. A total of 91 patients with plasma cell myeloma and anemia were identified. Each biopsy was re-examined to determine the level of erythropoiesis. The level of erythropoiesis was calculated by multiplying erythroid fraction (obtained from M:E ratio) with non-plasma cell bone marrow cellularity. Cases were separated into AEp and DEp using an erythroid compartment cut-off of 7.5% based on already established data. Kaplan-Meier analysis was used to compare survival between groups. Results: Demographic distribution of studied patients were 46 (50.1%) white, 39 (43%) African Americans and 6 (6.6%) others. Out of 91 cases analyzed, 38 (42%) had AEp whereas 53 (58%) had DEp. Among those with AEp, 23 (62%) had favorable CGs (defined as those without t (4, 14), t (14, 16), t (14, 20) or 17 p deletion); 15 (38%) had unfavorable CGs. Among those with DEp, 14 (26%) had favorable CGs whereas 39 (74%) had unfavorable cytogenetics. The vast majority of patients with favorable CGs were alive whether they had AEp (87%) or DEp (79%), thus CGs remained significant even after controlling for erythroid compartment (p = 0.03). Overall, those with AEp were noted to have significantly lower β-2 microglobulin (AEp median =2.42 mg/dL, DEp median = 4.50 mg/dL, p = 0.02). Kaplan-Meier analysis showed a significant difference in survival curves among the four groups (AEp with favorable CGs, AEp with unfavorable CGs, DEp with favorable CGs, DEp with unfavorable CGs, p<.0001). While the two groups with favorable CGs showed no significant difference (p=.6050), the two groups with unfavorable CGs did (p=.0027). Conclusion: Our findings suggest that patients with PCM and anemia are not a homogenous population. Assessment of the erythroid compartment in these patients reveals a population with AEp that has more favorable CGs and lower β-2 microglobulin than patients with DEp. Despite this finding, patients with favorable CGs had a favorable clinical outcome whether they had AEp or not, indicating that current therapies can overcome differences in erythropoiesis in that group. For patients with unfavorable CGs, however, those with AEp had superior survival outcome compared to those with DEp, indicating that there may be some prognostic or diagnostic utility to assessing erythropoiesis in patients who meet current criteria for PCM, and possibly, incorporating erythropoietic activity into diagnostic/prognostic schema. Disclosures No relevant conflicts of interest to declare.

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Relation Between Cereblon Expression and Survival in Patients with Newly Diagnosed Multiple Myeloma Treated with Thalidomide

Blood ◽

10.1182/blood.v120.21.3973.3973 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3973-3973

Author(s):

Annemiek Broyl ◽

Rowan Kuiper ◽

Mark van Duin ◽

Bronno van der Holt ◽

Laila el Jarari ◽

...

Keyword(s):

High Risk ◽

Research Funding ◽

Cox Regression ◽

Progression Free Survival ◽

Hazard Ratio ◽

Phase Iii ◽

Newly Diagnosed ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Hazard Ratios

Abstract Abstract 3973 Introduction: Cereblon (CRBN) expression has been described to be essential for the activity of Thalidomide and Lenalidomide. This suggests that presence and possibly increased level of CRBN expression would be associated with better outcome in Thalidomide/Lenalidomide treated patients. The aim of this study was to evaluate CRBN expression in relation to outcome in patients receiving Thalidomide maintenance. Patients and methods: The HOVON-65/GMMG-HD4 trial is a multi-center, phase III trial, comparing Bortezomib in induction and post-intensification vs. conventional chemotherapy and daily Thalidomide 50 mg for 2 years post-intensification in newly diagnosed MM patients. This trial demonstrated that Bortezomib during induction and maintenance improved CR and achieved superior PFS and OS (Sonneveld et al., JCO, July 16, 2012). Gene expression profiling was performed at the start of the trial by Affymetrix U133 Plus 2.0 GeneChip, and was available for 96 patients which started Thalidomide maintenance. CRBN expression levels were based on a combined value of probe sets 218142_s_at and 222533_at. CRBN expression was validated using real-time PCR. All survival analyses were performed in SPSS, with survival time taken from the start of maintenance. Results: In patients receiving Thalidomide maintenance, increased CRBN expression was significantly associated with longer progression free survival (p=0.005, hazard ratio = 0.7) and longer overall survival (p=0.04, hazard ratio= 0.7). Using Kaplan-Meier analysis for visualization and using the median expression to define high and low expression, a significant separation was found for PFS (Log rank p=0.009) but not for OS (Log rank p=0.13). No association was observed between CRBN expression and PFS/OS after Bortezomib maintenance (PFS, p=0.4, hazard ratio=1.1; OS, p=0.7, hazard ratio=1.1). Multivariate Cox regression analysis was performed using the covariates ISS, CRBN and high-risk cytogenetics, defined as having del(17p) and/or 1q gain and/or t(4;14). Higher CRBN levels remained significantly related to longer PFS (hazard ratio 0.7, p=0.03), but not OS (hazard ratio of 0.8, p=0.3). High-risk cytogenetics and ISS were both significant in both PFS and OS multivariate models, with hazard ratios of 2.8 and 3.6, for high-risk cytogenetics and 2.5 and 5.5, for ISS stage 3, respectively (p=0.0004, p=0.003, high-risk cytogenetics and p=0.01 and p=0.005, ISS stage 3, respectively). Conclusion: These data suggest use of CRBN as a biomarker for thalidomide outcome, but further analysis in other Thalidomide trials is required to validate this finding. Disclosures: Lokhorst: Genmab: Consultancy. Sonneveld:Onyx: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; celgene: Honoraria, Research Funding.

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Outcomes of Patients With Advanced Gastrointestinal Cancer in Relationship to Opioid Use: Findings From Eight Clinical Trials

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2019.7382 ◽

2020 ◽

Vol 18 (5) ◽

pp. 575-581

Author(s):

Omar Abdel-Rahman ◽

Hatim Karachiwala ◽

Jacob C. Easaw

Keyword(s):

Clinical Trials ◽

Regression Analysis ◽

Cox Regression ◽

Survival Outcomes ◽

Disease Entity ◽

Gastrointestinal Cancers ◽

Opioid Use ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

The Impact

Background: This study assessed the patterns of opioid use among patients with advanced gastrointestinal cancers who were included in 8 clinical trials and evaluated the impact of opioid use on survival outcomes of included patients. Methods: Deidentified datasets from 8 clinical trials evaluating first-line systemic treatment of advanced gastrointestinal cancers were accessed from the Project Data Sphere platform (ClinicalTrial.gov identifiers: NCT01124786, NCT00844649, NCT00290966, NCT00678535, NCT00699374, NCT00272051, NCT00305188, and NCT00384176). These trials evaluated patients with pancreatic carcinoma, gastric carcinoma, hepatocellular carcinoma (HCC), and colorectal carcinoma. Multivariable logistic regression analysis was used to evaluate factors predicting the use of opioids. Kaplan-Meier survival estimates were used to compare survival outcomes in each disease entity among patients who did or did not receive opioid treatment. Multivariable Cox regression analysis was then used to further assess the impact of opioid use on survival outcomes in each disease entity. Results: A total of 3,441 participants were included in the current analysis. The following factors predicted a higher probability of opioid use within logistic regression analysis: younger age at diagnosis (odds ratio [OR], 0.990; 95% CI, 0.984–0.997; P=.004), nonwhite race (OR for white vs nonwhite, 0.749; 95% CI, 0.600–0.933; P=.010), higher ECOG score (OR for 1 vs 0, 1.751; 95% CI, 1.490–2.058; P<.001), and pancreatic primary site (OR for colorectal vs pancreatic, 0.241; 95% CI, 0.198–0.295; P<.001). Use of opioids was consistently associated with worse overall survival (OS) in Kaplan-Meier survival estimates of each disease entity (P=.008 for pancreatic cancer; P<.001 for gastric cancer, HCC, and colorectal cancer). In multivariable Cox regression analysis, opioid use was associated with worse OS among patients with pancreatic cancer (hazard ratio [HR], 1.245; 95% CI, 1.063–1.459; P=.007), gastric cancer (HR, 1.725; 95% CI, 1.403–2.122; P<.001), HCC (HR, 1.841; 95% CI, 1.480–2.290; P<.001), and colorectal cancer (HR, 1.651; 95% CI, 1.380–1.975; P<.001). Conclusions: Study findings suggest that opioid use is consistently associated with worse OS among patients with different gastrointestinal cancers. Further studies are needed to understand the underlying mechanisms of this observation and its potential implications.

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Cisplatin-Based versus Carboplatin-Based Chemotherapy for Extra-Pulmonary Neuroendocrine Carcinomas; A Real-World Study.

Neuroendocrinology ◽

10.1159/000520193 ◽

2021 ◽

Author(s):

Omar Abdel-Rahman ◽

Sheryl L. Koski

Keyword(s):

Overall Survival ◽

Regression Analysis ◽

Cox Regression ◽

Survival Outcomes ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Platinum Agent ◽

Extra Pulmonary ◽

The Impact ◽

Neuroendocrine Carcinomas

Objective: To assess the survival differences between cisplatin/etoposide versus carboplatin/etoposide chemotherapy regimens in the management of extra-pulmonary neuroendocrine carcinomas (NECs). Methods: Administrative cancer care databases in the province of Alberta, Canada were reviewed, and patients with extra-pulmonary NECs (including those with small cell and large cell neuroendocrine carcinomas) who were treated with either cisplatin/ etoposide or carboplatin/ etoposide, 2004-2019, were reviewed. Kaplan-Meier survival estimates were used to compare the survival outcomes according to the type of platinum agent, and multivariable Cox regression analysis was used to assess the impact of the type of platinum agent on overall survival outcomes. Results: A total of 263 eligible patients were included in this analysis. These include 176 patients who received cisplatin/ etoposide and 87 patients who received carboplatin/etoposide. Using Kaplan-Meier survival estimates, patients treated with cisplatin have better overall survival compared to patients treated with carboplatin (P=0.005). Multivariable Cox regression analysis suggested that the following factors were associated with worse overall survival: higher Charlson comorbidity index (HR: 1.17; 95% CI: 1.05-1.30), gastrointestinal primary site (HR: 1.55; 95% CI: 1.12-2.14), stage IV disease (HR: 1.75; 95% CI: 1.28-2.38) and use of carboplatin (HR: 1.40; 95% CI: 1.02-1.92). Conclusions: The current study suggested that cisplatin/etoposide might be associated with better overall survival compared to carboplatin/etoposide among patients with extra-pulmonary NECs. It is unclear if this is related to differences in inherent responsiveness to the two platinum agents, or due to differences in comorbidity burden between the two treatment groups.

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Impact of Body Mass Index on Survival Outcome in Patients with Newly Diagnosed Glioblastoma: A Retrospective Single-Center Study

Integrative Cancer Therapies ◽

10.1177/1534735421991233 ◽

2021 ◽

Vol 20 ◽

pp. 153473542199123

Author(s):

Jun-Yong Cha ◽

Jae-Sung Park ◽

Yong-Kil Hong ◽

Sin-Soo Jeun ◽

Stephen Ahn

Keyword(s):

Cox Regression ◽

Survival Outcomes ◽

Newly Diagnosed ◽

Eligibility Criteria ◽

Cox Regression Analysis ◽

Asian Populations ◽

Kaplan Meier ◽

Single Center Study ◽

Newly Diagnosed Glioblastoma ◽

The Impact

Introduction: The impact of obesity on survival outcomes in patients with glioblastoma (GBM) has not been well reported and the results for patients are currently unclear. We investigated the effect of obesity on survival outcomes in patients with newly diagnosed GBM. Methods: Using electronic medical records, all GBM patients that visited the Seoul St. Mary’s Hospital between 2008 and 2018 were reviewed. A total of 177 patients met our eligibility criteria. The cut-off point for BMI was 23.0 kg/m2 based on previous studies which focused on Asian populations. Results: A total of 177 patients met our eligibility criteria. The overall median BMI of patients was 24.5 kg/m2 (range 15.82-39.26). About 62 patients who had a BMI less than the cut-off value were assigned to the “lower BMI” group, while 115 patients who had a BMI greater than the cut-off value were assigned to the “higher BMI” group. In Kaplan-Meier survival analysis, the median OS of the higher BMI group was longer than that of the lower BMI group (21.3 months vs 15.3 months, P = .002). In multivariate Cox regression analysis for OS, lower BMI was associated with inferior OS (HR 1.48 CI 1.06-2.08, P = .002). Conclusion: Our findings suggest that elevated BMI may be associated with better survival in patients with newly diagnosed GBM. Additional larger prospective studies could help validate our findings to confirm the effect of body composition and survival outcomes in GBM patients.

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The Presence of SETBP1, RUNX1 or EZH2 Mutation in MDS/MPN Is Associated with Absence of Response to Hypo-Methylating Agents

Blood ◽

10.1182/blood-2021-151624 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1520-1520

Author(s):

Theodoros Karantanos ◽

Hua-Ling Tsai ◽

Mark Levis ◽

Ravi Varadhan ◽

Richard J. Jones ◽

...

Keyword(s):

Overall Survival ◽

Logistic Regression ◽

Regression Analysis ◽

Research Funding ◽

Cox Regression ◽

Univariate Analysis ◽

Median Number ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Methylating Agents

Abstract INTRODUCTION: The management of myelodysplastic syndrome/myeloproliferative overlap neoplasms (MDS/MPN) remains challenging due to their molecular complexity. Hypo-methylating agents (HMA) have been used for cytoreduction and preparation of patients for allogeneic blood or marrow transplantation (BMT). However, less than 50% patients have a meaningful response to HMA and predictive factors for response remain unknown. The aim of our study is to examine molecular predictors of response to HMA in patients with MDS/MPN. PATIENTS AND METHODS: We performed a retrospective analysis of 150 patients evaluated at our center for chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) and unclassifiable MDS/MPN (MDS/MPN-U) between 1/1/2010 and 12/31/2020. Forty-three individuals who were treated with HMA during chronic phase and had next generation sequencing (NGS) using the established 63-genes panel were identified. Complete and partial remission (CR and PR), and marrow response (MR) were assessed based on the MDS/MPN International Working Group response criteria. Univariate logistic regression analysis was used to associate the number of somatic mutations or high-risk (HR) mutations (NRAS, SETBP1, RUNX1, EZH2, TP53, ASXL1, STAG2), and other disease specific factors at the time of the initiation of HMA with response categories. Multivariable analysis for modeling response were conducted via Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression approach, where the predictors were selected based on 5-fold cross validation with turning parameter selected to minimize deviance of logistic regression model. Kaplan-Meier was used to assess the overall survival based on the CR/PR status at 6 months from the initiation of HMA in landmark analysis. Cox-regression analysis considering the occurrence of CR/PR as a time-varying covariate was used to assess the impact of CR/PR on overall survival. RESULTS: Fifteen women and 28 men with a median age 67 years (range: 45 - 85 years) and a median follow up of 1.5 years (range: 91 days - 5.2 years) were included. Twenty five (58.1%) had CMML, 15 (34.9%) had MDS/MPN-U and 3 (7%) had aCML. Thirty-four patients (79.1%) received azacitidine (median number of cycles: 4.5, range: 1 - 65) and 9 patients (20.9%) received decitabine (median number of cycles: 4, range: 3 - 21). Seventeen patients (39.5%) underwent BMT following HMA therapy. The incidence of AML transformation was 16%. No patients had CR while 56% achieved a PR and 42% had an MR. Univariate analysis showed that ≥2 HR mutations (OR 0.19, 95% CI 0.05-0.67), SETBP1 mutation (OR 0.16, 95% CI 0.02-0.76), RUNX1 mutation (OR 0.1, 95% CI 0.01-0.48) and a mutation in at least one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.05, 95% CI 0.01-0.21) were associated with absence of PR. ≥2 HR mutations (OR 0.23, 95% CI 0.05-0.9), and the presence of a mutation in one out of the SETBP1, RUNX1 and EZH2 genes (OR 0.16, 95% CI 0.03-0.62) were associated with absence of MR on univariate analysis. Finally, older age as a continuous variable was associated with PR (OR 1.09, 95% CI 1.01-1.19) and MR (OR 1.12, 95% CI 1.03-1.24). Presence of a mutation in one of the SETBP1, RUNX1 and EZH2 genes with age adjusted was selected from LASSO approach and significantly predicted the absence of PR (OR 0.05, 95% CI 0.01-0.27), and MR (OR 0.19, 95% CI 0.04-0.91) (Table 1). Using the landmark of 6 months after the initiation of treatment, Kaplan-Meier analysis showed that PR at 6 months was associated with superior overall survival (P=0.010) compared to patients with no response (Figure 1). Similarly, Cox-regression analysis revealed that the occurrence of PR following the initiation of treatment was associated with better overall survival (HR 0.26, 95% CI 0.9-0.13, P=0.010). CONCLUSIONS: Mutations in SETBP1, RUNX1 or EZH2 genes predicted absence of response to HMA among patients with MDS/MPN independent of other factors including karyotype, blast percentage and R-IPSS. These findings suggest that the molecular profile of MDS/MPN patients can potentially identify patients with HMA-refractory phenotype. Multi-institutional studies of larger cohorts are required to verify these results and develop novel treatment strategies especially for patients with high-risk mutations in MDS/MPN. Figure 1. Kaplan-Meier estimates of OS by PR status at 6 months in landmark analysis. P-value was based on log-rank test. Figure 1 Figure 1. Disclosures Levis: BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Honoraria; Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas and FujiFilm: Research Funding; Pfizer: Consultancy, Honoraria; Takeda: Honoraria. Jain: Syneos Health: Research Funding; CTI Biopharma: Research Funding; CareDx: Other: for advisory board participation; Bristol Myers Squibb: Other: for advisory board participation; Targeted Healthcare Communications: Consultancy.

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Interleukin-9 Promotes Chemoresistance in B-ALL Which Correlates with Decreased Bim and c-Raf Protein Expression

Blood ◽

10.1182/blood-2021-153010 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2386-2386

Author(s):

Jamie A.G. Hamilton ◽

Miyoung Lee ◽

Claire E. Pillsbury ◽

Curtis J Henry

Keyword(s):

Protein Expression ◽

Children And Adolescents ◽

Health Research ◽

Research Funding ◽

Survival Outcomes ◽

Obese Patients ◽

Obese Mice ◽

Chemotherapy Treatment ◽

Interleukin 9

Abstract Background: According to the National Cancer Institute, B-cell acute lymphoblastic leukemia (B-ALL) is the most common cancer of children and adolescents (ALL, NCI, PDQ, accessed 8/2/2021). Recently, obesity has been identified as a risk factor which is associated with poor survival outcomes (Butturini et al., 2007; Eissa et al., 2017; Ethier et al., 2012) which is concerning due to the obesity rates in children and adolescents having tripled since the 1970's (Ogden et al., 2006; Ogden et al., 2020). Indeed, survival rates in obese pediatric patients with B-ALL can decline by as much as 30% relative to outcomes observed in lean patients, with obese patients more commonly presenting with treatment-related adverse events (Butturini et al., 2007; Eissa et al., 2017; Ethier et al., 2012). A hallmark of obesity is the accumulation of adipocytes, an endocrine cell type which can promote chemoresistance (Ehsanipour et al., 2013; Sheng et al., 2016; Mittelman., 2021). The mechanistic understanding of how adipocytes promote chemoresistance in B-ALL is still under investigation and further insight into this relationship could lead to the rational design of effective therapeutic strategies for obese patients with limited treatment options. Methods: A cytokine/chemokine array was performed on adipocyte and stromal cell secretomes to identify potential adipocyte-secreted inflammatory mediators, which may promote chemoresistance in human B-ALL cells. Once candidate cytokines were identified, we performed in vitro assays to measure how the addition or neutralization of proteins of interest impacted the proliferation, activation of signaling pathways, steady-state mitochondrial protein levels, and survival of human B-ALL cells in the absence or presence of chemotherapy treatment. Additionally, we mined publicly available databases to determine how protein-coding genes of interest were associated with patient survival. Furthermore, we have used the diet-induced murine model of obesity to determine how targeting candidate cytokines impact B-ALL pathogenesis. Results: We have made the novel finding that interleukin-9 (IL-9) levels are higher in adipose-rich microenvironments and activates pro-survival pathways that promote chemoresistance in human B-ALL cells. We have found that obese mice lacking IL-9 are more resistant to B-ALL development due to significant increases in survival outcomes compared to lean mice transplanted with B-ALL cells. Furthermore, we have discovered that human B-ALL cells upregulate the interleukin-9 receptors (IL-9R) when exposed to the adipocyte secretome. This potential feedback loop may increase the responsiveness of leukemia cells to local IL-9 levels. These observations were supported by our data mining results, which revealed that IL-9R gene expression levels were higher in more aggressive subtypes of B-ALL, including Ph-like B-ALL. When human B-ALL cells were treated with recombinant IL-9 (rIL-9), chemoresistance to methotrexate and doxorubicin was observed. Mechanistically, rIL-9 treatment of human B-ALL cells also downregulated the protein expression of the pro-apoptotic mitochondrial-associated protein Bim and pro-proliferative protein Raf. In all, our experiments have identified IL-9 as an adipocyte-enriched cytokine, which promotes pan-chemoresistance in human B-ALL cells. Furthermore, we have shown that this effect maybe mediated in part by suppressing the protein of expression of pro-apoptotic and proliferative proteins. Conclusions: To our knowledge, our results represent the first reports of IL-9 mediated chemoresistance in human B-ALL and the first to demonstrate that IL-9 regulates the protein homeostasis of anti- and pro-apoptotic mitochondrial proteins. In ongoing studies, we are conducting in vitro and murine studies with parental and IL-9R-deficient B-ALL cells to determine how B-ALL pathogenesis and chemosensitivity are impacted. Subsequent studies will be conducted in lean and obese mice transplanted with B-ALL cells who receive chemotherapy treatment alone or in combination with IL-9 neutralizing antibody administration. Disclosures Lee: PureTech Health: Research Funding. Henry: PureTech Health: Research Funding.

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Identification and Analysis of Three Hub Prognostic Genes Related to Osteosarcoma Metastasis

Journal of Oncology ◽

10.1155/2021/6646459 ◽

2021 ◽

Vol 2021 ◽

pp. 1-16

Author(s):

Jianye Tan ◽

Haofeng Liang ◽

Bingsheng Yang ◽

Shuang Zhu ◽

Guofeng Wu ◽

...

Keyword(s):

Regression Analysis ◽

Cox Regression ◽

Survival Rates ◽

Prognostic Biomarkers ◽

Messenger Rnas ◽

Hub Genes ◽

Cox Regression Analysis ◽

Expression Levels ◽

Kaplan Meier ◽

Before And After

Osteosarcoma (OS) often occurs in children and often undergoes metastasis, resulting in lower survival rates. Information on the complexity and pathogenic mechanism of OS is limited, and thus, the development of treatments involving alternative molecular and genetic targets is hampered. We categorized transcriptome data into metastasis and nonmetastasis groups, and 400 differential RNAs (230 messenger RNAs (mRNAs) and 170 long noncoding RNAs (lncRNAs)) were obtained by the edgeR package. Prognostic genes were identified by performing univariate Cox regression analysis and the Kaplan–Meier (KM) survival analysis. We then examined the correlation between the expression level of prognostic lncRNAs and mRNAs. Furthermore, microRNAs (miRNAs) corresponding to the coexpression of lncRNA-mRNA was predicted, which was used to construct a competitive endogenous RNA (ceRNA) regulatory network. Finally, multivariate Cox proportional risk regression analysis was used to identify hub prognostic genes. Three hub prognostic genes (ABCG8, LOXL4, and PDE1B) were identified as potential prognostic biomarkers and therapeutic targets for OS. Furthermore, transcriptions factors (TFs) (DBP, ESX1, FOS, FOXI1, MEF2C, NFE2, and OTX2) and lncRNAs (RP11-357H14.16, RP11-284N8.3, and RP11-629G13.1) that were able to affect the expression levels of genes before and after transcription were found to regulate the prognostic hub genes. In addition, we identified drugs related to the prognostic hub genes, which may have potential clinical applications. Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction (qRT-PCR) confirmed that the expression levels of ABCG8, LOXL4, and PDE1B coincided with the results of bioinformatics analysis. Moreover, the relationship between the hub prognostic gene expression and patient prognosis was also validated. Our study elucidated the roles of three novel prognostic biomarkers in the pathogenesis of OS as well as presenting a potential clinical treatment for OS.

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Bioinformatic Analysis: The Role of LINC00634 in Colorectal Carcinoma

10.21203/rs.3.rs-801188/v1 ◽

2021 ◽

Author(s):

Fang Liu ◽

Fengyihuan Fu ◽

Yuqiang Nie

Keyword(s):

Esophageal Cancer ◽

Regression Analysis ◽

Prognostic Factors ◽

Colorectal Carcinoma ◽

Roc Curve ◽

Cox Regression ◽

Survival Outcomes ◽

Immune Infiltration ◽

The Relationship

Abstract Background: LINC00634 is highly expressed in esophageal cancer, and its depletion can suppress the viability and induce the apoptosis of esophageal cancer cells. However, there is a lack of studies that examine the relationship between LINC00634 expression and the clinicopathological features, survival outcomes, prognostic factors and tumor immune cell infiltration of colorectal carcinoma (CRC) patients.Objective: We aim at investigating the role of LINC00634 in colorectal carcinoma.Methods: We obtained data from the TCGA (The Cancer Genome Atlas) public database, GTEx (Genotype-Tissue Expression) database and clinical samples. Wilcoxon rank-sum test, Kruskal-Wallis test and logistic regression analysis were employed to assess the relationship between LINC00634 expression and the clinicopathological characteristics of CRC patients. Receiver operating characteristic (ROC) curve was constructed to evaluate the ability of LINC00634 for distinguishing between CRC patients and normal subjects based on the area under the curve (AUC) score. Univariate and multivariate analyses were conducted to evaluate the association between prognostic factors and survival outcomes. Kaplan-Meier curves and Cox regression analysis were employed to determine the contribution of LINC00634 expression to the prognosis of colorectal carcinoma patients. Immune infiltration analysis and Gene Set Enrichment Analysis (GSEA) were conducted to identify the significantly involved functions of LINC00634. Finally, a nomogram was constructed for internal verification based on the Cox regression data.Results: The expression of LINC00634 was upregulated in CRC patients, and markedly associated with N stage, residual tumor, pathological stage, and overall survival (OS) event. ROC curve showed that LINC00634 had strong diagnostic and prognostic abilities (AUC=0.74). The high expression of LINC00634 could predict poor disease specific survival (DSS; P=0.008) and poor overroll survival (OS;P<0.01). The expression of LINC00634 was independently associated with OS in CRC patients (P=0.019). GSEA and immune infiltration analysis demonstrated that LINC00634 expression was involved in gene transcription, epigenetic regulation and the functions of certain types of immune infiltrating cells. The c-index of the nomogram was 0.772 (95％CI: 0.744-0.799).Conclusions: Our study reveals that LINC00634 can serve as a potential prognostic biomarker for CRC patients.

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Predictive Value of Atrial Electromechanical Delay on Long-Term Cardiovascular Outcomes in Hemodialysis Patients

American Journal of Nephrology ◽

10.1159/000441099 ◽

2015 ◽

Vol 42 (3) ◽

pp. 239-249 ◽

Cited By ~ 2

Author(s):

Kultigin Turkmen ◽

Levent Demirtas ◽

Ergun Topal ◽

Abduzhappar Gaipov ◽

Ismail Kocyigit ◽

...

Keyword(s):

Regression Analysis ◽

Total Cholesterol ◽

Cox Regression ◽

Healthy Individuals ◽

Electromechanical Delay ◽

Cox Regression Analysis ◽

Atrial Electromechanical Delay ◽

Kaplan Meier ◽

All Cause Mortality ◽

Spearman Test

Background: Atrial electromechanical delay (AEMD) times were considered independent predictors of cardiovascular morbidity among the general population. We aimed at evaluating AEMD times and other risk factors associated with 2-year combined cardiovascular (CV) events in HD patients. Material and Methods: Sixty hemodialysis (HD) and 44 healthy individuals were enrolled in this prospective study. Echocardiography was performed before the mid-week dialysis session for HD patients. Data were expressed as mean ± SD. Spearman test was used to assess linear associations. Survival was examined with the Kaplan-Meier method. Multivariate Cox regression analysis was used to determine the predictors of combined CV events in this cohort. Results: At the beginning of the study, left intra-atrial-AEMD times were significantly longer in HD patients compared to the left intra-atrial-AEMD times in healthy individuals. After 24 months, 41 patients were still on HD treatment and 19 (31.6%) had died. Serum triglyceride, total cholesterol and albumin were found to be higher and C-reactive protein (CRP) levels, left intra-atrial EMD time (LIAT) and interatrial EMD times were found to be lower in survived HD patients. With the cut-off median values of 3.5 g/dl for albumin, 0.87 mg/dl for CRP, 157 mg/dl for total cholesterol and 151 mg/dl for triglyceride, the Kaplan-Meier curves demonstrated significant differences in terms of all-cause mortality. We also demonstrated the Kaplan-Meier survival curves of HD patients according to tertile values of LIAT. Cox regression analysis revealed that increased CRP and higher LIAT were found to be independent predictors of combined CV events. Conclusions: Increased LIAT and inflammation were found to be closely associated with 2 years combined CV events and all-cause mortality in HD patients.

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