Strong Indicator Of Poor Prognosis Research Articles

Role of cfDNA and ctDNA to improve the risk stratification and the disease follow-up in patients with endometrial cancer: towards the clinical application

BackgroundThere has been a rise in endometrial cancer (EC) incidence leading to increased mortality. To counter this trend, improving the stratification of post-surgery recurrence risk and anticipating disease relapse and treatment resistance is essential. Liquid biopsy analyses offer a promising tool for these clinical challenges, though the best strategy for applying them in EC must be defined. This study was designed to determine the value of cfDNA/ctDNA monitoring in improving the clinical management of patients with localized and recurrent disease.MethodsPlasma samples and uterine aspirates (UA) from 198 EC patients were collected at surgery and over time. The genetic landscape of UAs was characterized using targeted sequencing. Total cfDNA was analyzed for ctDNA presence based on the UA mutational profile.ResultsHigh cfDNA levels and detectable ctDNA at baseline correlated with poor prognosis for DFS (p-value < 0.0001; HR = 9.25) and DSS (p-value < 0.0001; HR = 11.20). This remained clinically significant when stratifying tumors by histopathological risk factors. Of note, cfDNA/ctDNA analyses discriminated patients with early post-surgery relapse and the ctDNA kinetics served to identify patients undergoing relapse before any clinical evidence emerged.ConclusionsThis is the most comprehensive study on cfDNA/ctDNA characterization in EC, demonstrating its value in improving risk stratification and anticipating disease relapse in patients with localized disease. CtDNA kinetics assessment complements current strategies to monitor the disease evolution and the treatment response. Therefore, implementing cfDNA/ctDNA monitoring in clinical routines offers a unique opportunity to improve EC management.Translational relevanceThe study demonstrates that high levels of cfDNA and detectable ctDNA at baseline are strong indicators of poor prognosis. This enables more accurate risk stratification beyond traditional histopathological factors, allowing clinicians to identify high-risk patients who may benefit from more aggressive treatment and closer monitoring. Moreover, longitudinal analysis of cfDNA/ctDNA can detect disease recurrence months before clinical symptoms or imaging evidence appear. This early warning system offers a significant advantage in clinical practice, providing a window of opportunity for early intervention and potentially improving patient outcomes.

UBA2 SUMOylates NQO1 and promotes the proliferation of hepatocellular carcinoma by modulating the MAPK pathway.

In our previous study, we found that small ubiquitin-related modifier (SUMO)-activating enzyme ubiquitin-associated-2 domain (UBA2) was upregulated in hepatocellular carcinoma (HCC) patients who were insensitive to chemoembolization. In this study, we aimed to investigate the role of UBA2 in HCC progression. Three cohorts were used to evaluate the efficacy of UBA2 as a prognostic factor for HCC. Our results indicated that UBA2 was associated with aggressive clinical behaviors and was a strong indicator of poor prognosis in HCC. Invitro experiments demonstrated that UBA2 accelerated cell growth, invasion, and migration. These results were further supported by invivo experiments. RNA-sequencing analysis indicated NQO1 as a target of UBA2, with its levels altering following UBA2 manipulation. The results were verified by western blotting (WB) and quantitative PCR. The SUMOplot Analysis Program predicted lysine residue K240 as a modification target of UBA2, which was confirmed by immunoprecipitation (IP) assays. Subsequent mutation of NQO1 at K240 in HCC cell lines and functional assays revealed the significance of this modification. In addition, the oncogenic effect of UBA2 could be reversed by the SUMO inhibitor ML792 invivo and invitro. In conclusion, our study elucidated the regulatory mechanism of UBA2 in HCC and suggested that the SUMO inhibitor ML792 may be an effective combinatory treatment for patients with aberrant UBA2 expression.

HOXA9 Regulome and Pharmacological Interventions in Leukemia.

HOXA9, an important transcription factor (TF) in hematopoiesis, is aberrantly expressed in numerous cases of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) and is a strong indicator of poor prognosis in patients. HOXA9 is a proto-oncogene which is both sufficient and necessary for leukemia transformation. HOXA9 expression in leukemia correlates with patient survival outcomes and response to therapy. Chromosomal transformations (such as NUP98-HOXA9), mutations, epigenetic dysregulation (e.g., MLL- MENIN -LEDGF complex or DOT1L/KMT4), transcription factors (such as USF1/USF2), and noncoding RNA (such as HOTTIP and HOTAIR) regulate HOXA9 mRNA and protein during leukemia. HOXA9 regulates survival, self-renewal, and progenitor cell cycle through several of its downstream target TFs including LMO2, antiapoptotic BCL2, SOX4, and receptor tyrosine kinase FLT3 and STAT5. This dynamic and multilayered HOXA9 regulome provides new therapeutic opportunities, including inhibitors targeting DOT1L/KMT4, MENIN, NPM1, and ENL proteins. Recent findings also suggest that HOXA9 maintains leukemia by actively repressing myeloid differentiation genes. This chapter summarizes the recent advances understanding biochemical mechanisms underlying HOXA9-mediated leukemogenesis, the clinical significance of its abnormal expression, and pharmacological approaches to treat HOXA9-driven leukemia.

Abstract P2-11-16: Computerized Measurements of Nuclear Morphology Features, Mitosis Rate, and Tubule Formation from H&amp;E Images Predicts Disease-Free Survival in Patients with HR+ &amp; LN+ Invasive Breast Cancer from SWOG S8814

Abstract Background: Lymph node (LN) involvement is a strong indicator of poor prognosis for breast cancer (BC), with adjuvant chemotherapy remaining fundamental to management of these patients. SWOG S8814 was a Phase III randomized trial of postmenopausal patients with pathologic LN-positive BC who were hormone receptor positive (HR+). The objectives of the clinical trial were to compare disease free survival (DFS) and overall survival (OS) of 1) these postoperative patients treated with a combination of cyclophosphamide, doxorubicin, fluorouracil (CAF) plus tamoxifen versus tamoxifen alone; and 2) patients treated with CAF followed by tamoxifen versus CAF plus concurrent tamoxifen. In this study we sought to evaluate the potential of applying computational image analysis on whole slide images (WSI) for predicting DFS and OS in SWOG S8814. Methods: A cohort of 135 patients (N=53 DFS event) diagnosed with HR+ &amp; LN+ BC from clinical trial ECOG 2197 was utilized as training set D1. Validation set D2 comprised 630 patients (N=260 DFS event, N=195 death) with HR+&amp; LN+ BC from SWOG S8814. Three deep learning models were employed to respectively detect nuclei, mitosis, and tubules in WSIs. Subsequently, a total of 1,810 features relating to nuclear morphology (e.g., spatial distribution, shape, texture, orientation), mitotic activity (e.g., mitosis hotspot, mitotic rates) and tubule formation (e.g., tubular nuclei distribution, ratio of tubule to non-tubule area) were extracted from each WSI. A lasso regularized Cox regression model (IbRiS) was trained on D1 to respectively identify four features from each of the feature categories (nuclei morphology, mitotic activity, and tubule formation) most strongly associated with DFS, a continuous risk score based on the selected features was then constructed. An optimal risk threshold was identified on D1 to dichotomize the risk scores into high vs. low risk of recurrence categories. Blinded validation of the machine learning model on SWOG S8814 using Cox regression was performed by SWOG to evaluate its performance in terms of DFS and OS. Results: In D2, patients identified as high risk of recurrence by IbRiS had a significantly worse prognosis in terms of DFS with hazard ratio=1.30 (p=0.039, 95% CI=1.01-1.66). IbRiS was also found to be significantly prognostic of OS with hazard ratio=1.38 (p=0.026, 95% CI=1.04-1.83). IbRiS was however, neither prognostic of DFS (HR = 1.20; 95% CI 0.93-1.54) nor OS (HR = 1.28; 95% CI 0.96-1.71) in multivariable analysis adjusting for treatment, tumor size, and number of positive nodes. IbRiS was also not a significant predictor of chemotherapy benefit (DFS p=0.45; OS p=0.25). Conclusion: We developed a prognostic model (IbRiS) based on the combined features of nuclear morphology, mitosis count, and tubule formation that can help further risk stratify HR+ &amp; LN+ BC patients by only using H&amp;E slides. Citation Format: Yuli Chen, William E. Barlow, Haojia Li, Cheng Lu, Andrew Janowczyk, German Corredor, Shridar Ganesan, Michael Feldman, Pingfu Fu, Hannah Gilmore, Kathy S. Albain, Lajos Pusztai, James Rae, Daniel Hayes, Andrew K. Godwin, Alastair M. Thompson, Anant Madabhushi. Computerized Measurements of Nuclear Morphology Features, Mitosis Rate, and Tubule Formation from H&amp;E Images Predicts Disease-Free Survival in Patients with HR+ &amp; LN+ Invasive Breast Cancer from SWOG S8814 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-16.

Survival of patients with mantle cell lymphoma in the rituximab era: Retrospective binational analysis between 2000 and 2020.

Mantle cell lymphoma (MCL) is a rare peripheral B-cell lymphoma characterised by eventual relapse and progression towards a more aggressive disease biology. With the introduction of rituximab- and cytarabine-based immunochemotherapy regimens, the prognosis of the disease has changed dramatically over the last two decades. To assess the real-world survival of patients with MCL, we used a population-based cohort of 564 patients with MCL who were diagnosed and treated between 2000 and 2020. Patient data were collected from seven Finnish treatment centres and one Spanish treatment centre. For the entire patient population, we report a 2-year overall survival (OS) rate of 77%, a 5-year OS of 58%, and a 10-year OS of 32%. The estimated median OS was 80 months after diagnosis. MCL is associated with increased mortality across the entire patient population. Additionally, we assessed the survival of patients after MCL relapse with the aim of establishing a cut-off point of prognostic significance. Based on our statistical analysis of survival after the first relapse, disease progression within 24 months of the initial diagnosis should be considered as a strong indicator of poor prognosis.

Knockdown of Let-7b in Leukemia Associated Macrophages Inhibit Acute Myeloid Leukemia Progression

As critical components of bone marrow microenvironment, macrophages are significant players in supporting and maintaining hematopoiesis. Macrophages are reported to be remodeled into leukemia-associated macrophages (LAMs) in leukemic microenvironment where they contribute to leukemia development, characterized as M2 macrophages with pro-tumor effects. However, how leukemic microenvironment transforms macrophages into LAMs remains unknown. Here, we analyzed clinical relevance of LAMs and profiled their RNA-Seq from acute myeloid leukemia (AML) patients achieved complete remission (CR) after induction treatment and refractory AML patients. Our results showed that the proportion of LAMs in refractory AML patients was higher than that in CR patients and LAM was a strong indicator of poor prognosis of AML patients. Furthermore, let-7b was a potentially aberrant gene in LAMs contributed to M2-subtype characteristics, which was associated with macrophage polarization. Knockdown of let-7b in LAMs could inhibit the development of AML by repolarizing LAMs towards M1-subtype characteristics through the activation of Toll Like Receptor (TLR) and NF-κB pathway. Our study provides insight for future LAM-based immunotherapy strategies for AML.

Abstract 3744: Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation

Abstract Introduction: Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. Methods: We analyzed publicly available multi-omics data (whole-exome-, whole-genome-, RNA sequencing, Epic-850K-methylation array) of 58 typical-, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K-methylation analysis was cross validated using targeted pyrosequencing on 35 carcinoids. Results: Results showed bimodality of OTP expression in carcinoids (OTPhigh versus OTPlow group, likelihood-ratio test p=1.5x10-2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (fdr&amp;lt;0.05 &amp; β-value effect size&amp;gt;0.2). Overall, OTPlow carcinoids harbor a high DNA methylation level as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (logrank test p=0.0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, i.e., sustaining proliferative signaling, evading growth suppressor, and genome instability and mutation. Conclusion: High OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis. In poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels. Citation Format: Laura Moonen, Lise Mangiante, Daphne J. Leunissen, Lisa M. Lap, Aurelie Gabriel, Lisa M. Hillen, Guido M. Roemen, Alexander Koch, Manon van Engeland, Anne-Marie C. Dingemans, Matthieu Foll, Nicolas Alcala, Lynnette Fernandez-Cuesta, Jules L. Derks, Ernst-Jan M. Speel. Differential Orthopedia Homeobox (OTP) expression in pulmonary carcinoids is associated with changes in DNA methylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3744.

Abstract 4134: Stromal FAP expression is associated with MRI visibility and patient survival in prostate cancer

Abstract Some clinically significant prostate cancers (PCa) are missed by magnetic resonance imaging (MRI). We asked if the tumor stroma in surgically treated primary PCa lesions positive or negative with MRI are different in their cellular and molecular properties, and whether the differences are reflected to the clinical course of the disease. We profiled the stromal and immune cell composition of MRI-classified tumor lesions by applying multiplexed fluorescence immunohistochemistry (mfIHC) and automated image analysis in a clinical cohort of 343 patients (Cohort I). We compared stromal variables between MRI-visible, invisible lesions, and benign tissue and assessed the predictive significance for biochemical recurrence (BCR) and disease-specific survival (DSS) using Cox regression and Log rank analysis. Subsequently, we carried out a prognostic validation of the identified biomarkers in a population-based cohort of 319 patients (Cohort II). MRI true-positive lesions are different from benign tissue and MRI false-negative lesions in their stromal composition. CD163-positive cells and fibroblast activation protein (FAP)-positive cells were more abundant in MRI true-positive than in MRI false-negative lesions or benign areas. In MRI true-visible lesions, a high proportion of stromal FAP-positive cells was associated with PTEN status and increased immune infiltration (CD8+, CD163+), and predicted elevated risk for BCR. High FAP phenotype was confirmed to be a strong indicator of poor prognosis in two independent patient cohorts using also conventional IHC. The molecular composition of the tumor stroma may determine whether early prostate lesions are detectable by MRI and associates with survival after surgical treatment. Citation Format: Teijo Pellinen, Kevin Smith, Sami Blom, Riku Turkki, Annabrita Hemmes, Katja Välimäki, Juho Eineluoto, Anu Kenttämies, Stig Nordling, Olli Kallioniemi, Antti Rannikko, Tuomas Mirtti. Stromal FAP expression is associated with MRI visibility and patient survival in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4134.

Neutrophil Extracellular Traps in ANCA-Associated Vasculitis and Interstitial Lung Disease: A Scoping Review.

Background: Deregulated neutrophil extracellular traps (NETs) formation is implicated in various diseases, including ANCA-associated vasculitis and pulmonary fibrosis (PF). Lung involvement is frequent in AAV, and interstitial lung diseases (ILDs) are strongly related to MPO-ANCA positivity and mainly reported in microscopic polyangiitis. The association between AAV and ILD is a strong indicator of poor prognosis and limited survival. Neutrophils, ANCA and NET interplay in PF development in AAV. This study aimed to review the literature concerning the implications of NET in lung fibrogenesis specifically focused on AAV associated with ILD, and the potential of NET as a theranostic marker. Methods: Through scoping review methodology, we used a descriptive thematic analysis to understand the pathogenic role of NETs in patients with AAV and pulmonary fibrosis and their further role as a theranostic marker of this disease. Results: The implications of NET in the pathogenesis of AAV and ILD, as well as an association between these two diseases, have been identified, but the underlying pathophysiological mechanisms are still unknown. The pharmacological or genetic inhibition of NET release reduces disease severity in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. In this regard, despite the lack of clinical data, we may hypothesise that an optimal management of AAV-ILD patients would require not only B-cells targeted therapy, but also NETs inhibition. Conclusion: Preliminary findings seem to display a lack of efficacy of traditional immunosuppressants, such as Rituximab, in this subset of patients, while to date no patients suffering from a definite ILD have been enrolled in clinical trials. Further insights would be provided by their employment, as a combination treatment, in common clinical practice. Although we can imagine that the inhibition of NETs in patients with AAV-ILD could reduce severity and mortality, we still lack the scientific basis that could improve our understanding of the disease from a molecular point of view.

Differential Orthopedia Homeobox expression in pulmonary carcinoids is associated with changes in DNA methylation.

Limited number of tumor types have been examined for Orthopedia Homeobox (OTP) expression. In pulmonary carcinoids, loss of expression is a strong indicator of poor prognosis. Here, we investigated OTP expression in 37 different tumor types, and the association between OTP expression and DNA methylation levels in lung neuroendocrine neoplasms. We analyzed publicly available multi‐omics data (whole‐exome‐, whole‐genome‐, RNA sequencing and Epic 850K‐methylation array) of 58 typical carcinoids, 27 atypical carcinoids, 69 large cell neuroendocrine carcinoma and 51 small cell lung cancer patients and TCGA (The Cancer Genome Atlas) data of 33 tumor types. 850K‐methylation analysis was cross‐validated using targeted pyrosequencing on 35 carcinoids. We report bimodality of OTP expression in carcinoids (OTPhigh vs OTPlow group, likelihood‐ratio test P = 1.5 × 10−2), with the OTPhigh group specific to pulmonary carcinoids while absent from all other cohorts analyzed. Significantly different DNA methylation levels were observed between OTPhigh and OTPlow carcinoids in 12/34 OTP infinium probes (FDR < 0.05 and β‐value effect size > .2). OTPlow carcinoids harbor high DNA methylation levels as compared to OTPhigh carcinoids. OTPlow carcinoids showed a significantly worse overall survival (log‐rank test P = .0052). Gene set enrichment analysis for somatically mutated genes associated with hallmarks of cancer showed robust enrichment of three hallmarks in the OTPlow group, that is, sustaining proliferative signaling, evading growth suppressor and genome instability and mutation. Together our data suggest that high OTP expression is a unique feature of pulmonary carcinoids with a favorable prognosis and that in poor prognostic patients, OTP expression is lost, most likely due to changes in DNA methylation levels.

Molecular regulators of HOXA9 in acute myeloid leukemia.

Dysregulation of the oncogenic transcription factor HOXA9 is a prominent feature for most aggressive acute myeloid leukemia cases and a strong indicator of poor prognosis in patients. Leukemia subtypes with hallmark overexpression of HOXA9 include those carrying MLL gene rearrangements, NPM1c mutations, and other genetic alternations. A growing body of evidence indicates that HOXA9 dysregulation is both sufficient and necessary for leukemic transformation. The HOXA9 mRNA and protein regulation includes multilayered controls by transcription factors (such as CDX2/4 and USF2/1), epigenetic factors (such as MLL-menin-LEDGF, DOT1L, ENL, HBO1, NPM1c-XPO1, and polycomb proteins), microRNAs (such as miR-126 and miR-196b), long noncoding RNAs (such as HOTTIP), three-dimensional chromatin interactions, and post-translational protein modifications. Recently, insights into the dynamic regulation of HOXA9 have led to an advanced understanding of the HOXA9 regulome and provided new cancer therapeutic opportunities, including developing inhibitors targeting DOT1L, menin, and ENL proteins. This review summarizes recent advances in understanding the molecular mechanisms controlling HOXA9 regulation and the pharmacological approaches that target HOXA9 regulators to treat HOXA9-driven acute myeloid leukemia.

Clinical Significance of and Predictive Risk Factors for the Postoperative Elevation of Carcinoembryonic Antigen in Patients With Non-Metastatic Colorectal Cancer.

BackgroundRecently, a few researches focus on the correlation between postoperative carcinoembryonic antigen (post-CEA) and the outcome of colorectal cancer (CRC), but none investigates the predictive value of post-CEA in a prognostic model. Besides, current recommendations on the frequency of post-CEA surveillance are not individualized and well followed. There is an absence of identification of patients who are more likely to have abnormal post-CEA levels and need more frequent CEA measurements.MethodsConsecutive CRC patients who underwent curative surgery were enrolled and randomly divided into the discovery (n=352) and testing cohort (n=233). Impacts of preoperative CEA (pre-CEA) and post-CEA on prognosis were assessed. Cox regression model was applied to develop prognostic nomograms, which were validated by the concordance index (C-index), calibration curve, and receiver operating characteristic curve (ROC) analysis. And prediction improvement of the nomograms was assessed with net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Logistic regression was used to identify predictive risk factors and construct the prediction model for post-CEA elevation.ResultsPost-CEA independently predicted overall survival (OS) and disease-free survival (DFS), while pre-CEA did not. Post-CEA elevation represented higher risks in patients with normal pre-CEA, compared to those with persistent elevated CEA. The nomograms for OS and DFS were established with body mass index, tumor differentiation, N stage, lymphocyte-to-monocyte ratio, and post-CEA. The nomograms showed good calibration and superior discrimination than pTNM stage, with the C-index of 0.783 and 0.759 in the discovery set and 0.712 and 0.774 in the testing set for OS and DFS, respectively. Comparisons between models using IDI and NRI implied that the nomograms performed better than pTNM stage and the predictive power could be improved with the addition of post-CEA. The prediction model for post-CEA elevation was established with age, platelet-to-lymphocyte ratio, preoperative CA19-9, and pre-CEA. The AUC of the model in the two cohorts was 0.802 and 0.764, respectively.ConclusionsElevated post-CEA was a strong indicator of poor prognosis. The addition of post-CEA significantly enhanced the performance of prognostic nomograms. And the prediction model for post-CEA elevation may help identify patients who ought to reasonably receive more intensive postoperative surveillance of CEA levels.

Tumor-associated macrophage, angiogenesis and lymphangiogenesis markers predict prognosis of non-small cell lung cancer patients

BackgroundThe tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcomes. Tumor-associated macrophages (TAMs) are a well-recognized core element of the TME and generally characterized as M2-like macrophages. TAMs are believed to contribute to tumor progression, but the mechanism behind this remains unclear. We aimed to investigate the clinical, angiogenic, and lymphangiogenic significance of TAMs in non-small cell lung cancer (NSCLC).MethodsUtilizing combined immunohistochemistry and digital image analysis, we assessed CD68, CD163, VEGF-A, and VEGF-C expression in 349 patients with NSCLC. Subsequently, the potential association between M2 TAMs and angiogenic VEGF-A and/or lymphangiogenic VEGF-C was evaluated for its prognostic value. Furthermore, the effects of M2 TAMs on angiogenesis and lymphangiogenesis were explored via an in vitro co-culture system.ResultsCD68 and CD163 expression were found to directly correlate with VEGF-A and/or VEGF-C expression (all p < 0.001). Furthermore, elevated M2 ratio (CD163+/CD68+) was significantly associated with poor overall survival (p = 0.023). Dual expression of M2 ratiohigh and VEGF-Chigh (M2 ratiohighVEGF-Chigh) was correlated with worse overall survival (p = 0.033). Multivariate analysis revealed that M2 ratiohigh [HR (95% CI) = 1.53 (1.01–2.33), p = 0.046] and combined M2 ratiohighVEGF-Chigh expression [HR (95% CI) = 2.01 (1.28–3.16), p = 0.003] were independent predictors of poor overall survival. Notably, we confirmed that M2 macrophages significantly enhanced the protein and mRNA expression of both VEGF-A and VEGF-C, while M1 macrophages induced only mRNA expression of VEGF-A in A549 cells.ConclusionsThis study suggests that TAMs are significantly associated with angiogenesis and lymphangiogenesis, contributing to the progression of NSCLC. Furthermore, elevated M2 ratio, similar to combined high M2 ratio and high VEGF-C expression, is a strong indicator of poor prognosis in patients with NSCLC, providing insight for future TAM-based immunotherapy strategies.

Abstract 3970: Tumor-associated macrophage, angiogenesis and lymphangiogenesis predicts prognosis in patients with non-small cell lung cancer

Abstract Background: The tumor microenvironment (TME) is a critical player in tumor progression, metastasis and therapy outcome. Tumor-associated macrophages (TAMs) are a well-recognized core element of the TME, and are generally characterized as M2-like macrophages. TAMs are believed to contribute to tumor progression, but the mechanism behind this remains unclear. We aimed to investigate the clinical value, angiogenic and lymphangiogenic significance of TAMs in non-small cell lung cancer (NSCLC). Methods: We assessed CD68, CD163, VEGF-A, and VEGF-C expression in 349 patients with NSCLC by combined immunohistochemistry and digital image analysis. Subsequently, the potential association between M2 TAMs and angiogenetic VEGF-A and/or lymphangiogenetic VEGF-C was evaluated for its prognostic value. Furthermore, the effects of M2 TAMs on angiogenesis and lymphangiogenesis were explored in vitro co-culture system. Results: Elevated M2 (CD163+/CD68+) ratio was significantly associated with poor overall survival (p=0.023). Dual high expression of M2 ratio and VEGF-C was correlated with worse overall survival (p=0.033). Furthermore, CD68 and CD163 expression are positively associated with VEGF-A and/or VEGF-C expression. Multivariate analysis revealed that M2 ratio was an independent predictor of poor survival [HR (95% CI) = 1.53 (1.01-2.33), p=0.046]. Combined M2+/VEGF-C+ expression was also an independent predictor of poor survival [HR (95% CI) = 2.01 (1.28-3.16), p=0.003]. Notably, we confirmed that M2 macrophages enhanced the protein and mRNA expression of both VEGF-A and VEGF-C significantly, while M1 macrophages induced only mRNA expression of VEGF-A significantly in A549 cells. Conclusions: This study suggests that TAMs are significantly associated with angiogenesis or lymphangiogenesis in the progression of NSCLC. Furthermore, elevated M2 ratio and combined M2 and VEGF-C high expression are strong indicators of poor prognosis in patients with NSCLC. Citation Format: Ilseon Hwang, Keun Uk Park, Eun Hee Jung, Hun-Mo Ryoo, Kris Ylaya, Joon-Yong Chung, Stephen M. Hewitt. Tumor-associated macrophage, angiogenesis and lymphangiogenesis predicts prognosis in patients with non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3970.

The prognostic and clinicopathological value of tumor-associated macrophages in patients with colorectal cancer: a systematic review and meta-analysis.

There is a growing literature on the significance of tumor-associated macrophages (TAMs) in colorectal cancer (CRC). However, the role of TAMs in predicting the prognosis of CRC remains controversial. The current study aims to determine the prognostic and clinicopathological value of different types and distribution of TAMs in CRC. A comprehensive literature search of PubMed, Embase, and Cochrane Library databases was conducted from the inception to 1 September 2019. The correlations of TAMs with overall survival (OS), disease-free survival (DFS), cancer-specific survival (CSS), and clinicopathological characteristics were analyzed. A total of 5,575 patients from 29 studies were included in this meta-analysis. The pooled hazard ratios (HRs) indicated that high density of pan-macrophages in tumor invasive margin (IM) was associated with better OS (HR = 0.57, 95%CI = 0.38-0.85), DFS (HR = 0.32, 95%CI = 0.19-0.52), and CSS (HR = 0.56, 95%CI = 0.41-0.77). Moreover, the high density of pan-macrophages in tumor center (TC) was correlated with better DFS (HR = 0.66, 95%CI = 0.45-0.96). However, high expression of M2 macrophages in TC was associated with poor DFS (HR = 2.42, 95%CI = 1.45-4.07) and CSS (HR = 1.74, 95%CI = 1.24-2.44). High M2 macrophages density in IM was also associated with short DFS (HR = 2.81, 95%CI = 1.65-4.77). In addition, the results showed that high density of pan-macrophages in IM was associated with no tumor metastasis, while high M2 macrophages density in TC was correlated with poor tumor differentiation. High Pan-TAMs density in IM has a positive effect on the prognosis of CRC patients, while high density M2 macrophage infiltration in TC is a strong indicator of poor prognosis.

Loss of Both USP10 and p14ARF Protein Expression Is an Independent Prognostic Biomarker for Poor Prognosis in Patients With Epithelial Ovarian Cancer.

The prognostic role of USP10 in epithelial ovarian cancer has been studied in various human cancers. Our aim was to evaluate the clinical and pathological significance of USP10 in epithelial ovarian cancer. Immunohistochemical analyses of the expression of USP10 and p14ARF by using tissue microarrays were performed in 336 ovarian tumours and the data were compared with clinicopathological variables. We examined their level of DNA methylation around the putative transcriptional start site in 5' CpG islands in fresh frozen tissues and ovarian cancer cells. Expression of USP10 and p14ARF was significantly lower in cancer tissues than in normal epithelium. Low USP10 expression and a combined USP10/p14ARF low expression were revealed to be independent prognostic factors. A high degree of methylation in USP10 and p14ARF CpG islands was found by methylation specific PCR analysis in cancer than in normal tissues and cells. Decreased expression of USP10 or combined USP10/p14ARF decreased expression is a strong indicator of poor prognosis in patients with ovarian cancer.

Venous thromboembolism in relapsed or refractory multiple myeloma patients treated with lenalidomide plus dexamethasone.

Lenalidomide plus dexamethasone (LD) is currently the mainstay of treatment for both untreated and relapsed or refractory multiple myeloma (RRMM). Although lenalidomide-associated venous thromboembolism (VTE) is a major clinical concern, its incidence and prognostic impact have not been delineated. In this nationwide retrospective cohort study, we aimed to determine the cumulative incidence of VTE and its prognostic value using two consecutive cohorts of LD-treated RRMM patients: the KMM151 cohort (N = 542) and the HIRA cohort (N = 1559). Data were collected from medical records for the KMM151 cohort and healthcare insurance claims database for the HIRA cohort. Throughout the study period, 24 patients (4.4%) in the KMM151 cohort and 80 patients (5.1%) in the HIRA cohort developed VTE. The cumulative incidence reached a plateau approximately 2 years after LD initiation. The 2-year incidence was 4.9% in the KMM151 cohort and 8% in the HIRA cohort. Higher starting dose of lenalidomide, previous history of VTE, and older age were associated significantly with an increased VTE risk. Early-onset VTE was associated significantly with poor survival. In conclusion, VTE occurred in 5-8% of RRMM patients treated with LD over 2 years, and early-onset VTE was a strong indicator of poor prognosis.

CMTM6 overexpression is associated with molecular and clinical characteristics of malignancy and predicts poor prognosis in gliomas.

CMTM6, a previously uncharacterized protein, was identified as a critical regulator of PD-L1, which is reported as an immune checkpoint inhibitor, to modulate the T cell activities both in vitro and in vivo of other tumors. However, the role of CMTM6 has so far remained unclear in glioma. To investigate the role of CMTM6 in gliomas, we analyzed the transcriptome level, genomic profiles and its relationship with clinical practice. 1862 glioma samples with transcriptome data were enrolled in this study, including CGGA RNA-seq, TCGA RNA-seq, CGGA-microarray, GSE16011 and IVY GBM databases. Clinical information and genomic profiles containing somatic mutations and DNA copy numbers were also obtained. We found that CMTM6 expression was highly correlated with major clinical and molecular characteristics. Cases with high CMTM6 expression were more likely to be predicted as malignant entities and frequent with genomic aberrations of driver oncogenes. Moreover, gene ontology analysis based on significantly correlated genes of CMTM6 expression exhibited that CMTM6 was associated with immune responses and inflammatory activities. CMTM6 was synthetic with other immune checkpoint inhibitors. Additionally, CMTM6 was involved in immune functions via modulating T-lymphocyte-mediated anti-tumor immunity. Finally, high CMTM6 expression was associated with reduced survival time and may serve as a strong indicator of poor prognosis in gliomas. In brief, High level of CMTM6 expression is closely related to high malignant gliomas. Meanwhile, CMTM6 plays an important role in regulating T cell activation and antitumor responses. Therefore, CMTM6 is a promising target for developing immunotherapy of gliomas.

Abstract 301: Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric cancer

Abstract Background : Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis and clinical outcomes in a variety of human malignancies. We investigated Cav-1 in primary and metastatic tumor of gastric cancer (GC) and its association with clinical outcomes. Method : All specimens evaluated were obtained from 145 patients with GC who had undergone curative gastrectomy. The primary outcomes measured were the expression levels of Cav-1 by immunohistochemistry and its association with clinicopathologicalparameters and patient survival. Results : Among the 145 patients, the frequency of high expression of stromal Cav-1 within primary tumor and tumoral Cav-1 protein in metastatic lymph node were 22.5% (18/145) and 16.6% (15/91). In the multivariate analysis tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882-8.224; P&amp;lt;0.001) and cancer-specific survival outcome (CSS, HR, 3.985; 95% CI, 1.620 - 8.623; P = 0.002). In addition, it remained as a strong indicator of poor prognosis for RFS (HR, 3.137; 95% CI, 1.445 - 6.810; P = 0.004) and CSS (HR, 2.509; 95% CI, 1.079 - 5.838; P = 0.033). Conclusions : High expression of tumoral Cav-1 protein in metastatic lymph node shows a strong negative association with the clinical outcomes in patients with curatively resected GC, suggesting that this protein have potential uses as novel prognostic markers. Citation Format: Jihyung Hong, Der Sheng Sun, Soon Auck Hong, Hye Sung Won, Han Hong Lee, Okran Kim, Yoon Ho Ko. Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 301. doi:10.1158/1538-7445.AM2017-301

Prognostic value of metastatic tumoral caveolin-1 expression in patients with resected gastric cancer.

83 Background: Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis and clinical outcomes in a variety of human malignancies. We investigated Cav-1 in primary and metastatic tumor of gastric cancer (GC) and its association with clinical outcomes. Methods: All specimens evaluated were obtained from 145 patients with GC who had undergone curative gastrectomy. The primary outcomes measured were the expression levels of Cav-1 by immunohistochemistry and its association with clinicopathological parameters and patient survival. Results: Among the 145 patients, the frequency of high expression of stromal Cav-1 within primary tumor and tumoral Cav-1 protein in metastatic lymph node were 22.5% (18/145) and 16.6% (15/91). In the multivariate analysis tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882–8.224; P &lt; 0.001) and cancer-specific survival outcome (CSS, HR, 3.985; 95% CI, 1.620 – 8.623; P = 0.002). In addition, it remained as a strong indicator of poor prognosis for RFS (HR, 3.137; 95% CI, 1.445 – 6.810; P = 0.004) and CSS (HR, 2.509; 95% CI, 1.079 – 5.838; P = 0.033). Conclusions: High expression of tumoral Cav-1 protein in metastatic lymph node shows a strong negative association with the clinical outcomes in patients with curatively resected GC, suggesting that this protein have potential uses as novel prognostic markers.