Transcriptional characterization of immune microenvironment and their prediction role for the prognosis of local advanced lung adenocarcinoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20625-e20625
Author(s):  
Yuqiao Chen ◽  
Xinying Shi ◽  
Xue Song ◽  
Lingling Gao ◽  
Beibei Mao ◽  
...  

e20625 Background: The resection of early stage NSCLC offers patients the best hope of a cure. However, the recurrence rate post-resection remains high. As the mechanisms involved in the process is still not clear due to the unavailability of accurate targets, our study was aimed to integrate the impact of different immune context present in lung adenocarcinoma (LUAD) microenvironment on patients’ prognosis. Methods: RNA targeted sequencing was performed on 24 primary tumor specimens from the resected local advanced LUADs . Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The limma package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the prognosis (PFS, progression free survival) post-resection. Results: 23 DEGs were detected in primary tumor between the better (PFS > 18months, n = 12 ) and worse (PFS≤18months, n = 12 ) prognosis group. The combined prediction model containing MPO, IL-6, CXCR2, FCGR3B, ADGRE5 could identify the favorable prognosis of patients. GSVA and Log Rank test of survival data demonstrated that the antigen processing and lymphocyte activation pathway enrichment may associate with better prognosis (p = 0.01), whereas higher Neutrophils cell infiltration in primary tumor demonstrated a shorter PFS (p = 0.008). Conclusions: In LUAD, the immune related genes such as MPO, IL-6, CXCR2, FCGR3B, ADGRE5, can effectively profile the landscape of tumor immune microenvironment and predict the survival in early stage of lung adenocarcinoma. Accordingly immune pathways were correlated with prognosis of these patients. Our findings suggest that immune-related RNA expression pattern in locally advanced LUAD may provide a potential predictive marker for early recurrence after surgical resection.

2021 ◽  
pp. 021849232110459
Author(s):  
Terrance Peng ◽  
Anita Yau ◽  
Li Ding ◽  
Elizabeth A. David ◽  
Sean C. Wightman ◽  
...  

Introduction Signet ring cell (SRC) histology is considered a poor prognostic factor in various cancers. However, primary SRC lung adenocarcinoma is rare and poorly understood. Methods The National Cancer Database was queried to identify treatment-naïve patients who received lobectomy for primary SRC or non-SRC pT1-2N0 lung adenocarcinoma <4 cm within four months of diagnosis. SRC lung adenocarcinoma was defined by ICD-O-3 code 8490, while non-SRC lung adenocarcinoma was defined by ICD-O-3 codes 8140, 8141, 8143, 8147, 8255, 8260, 8310, 8481, 8560, and 8570–8574. The Kaplan-Meier curve and log-rank test was used to compare five-year OS between SRC versus non-SRC lung adenocarcinoma cohorts. The impact of SRC histology on risk of death was assessed using the Cox proportional hazards regression model. Results 48,399 patients were included in this study: 62 with primary SRC lung adenocarcinoma and 48,337 with non-SRC lung adenocarcinoma. The mean age of the overall cohort was 67.0 ± 9.6 years. Five-year OS following lobectomy did not differ significantly between SRC lung adenocarcinoma and non-SRC lung adenocarcinoma cohorts (SRC 73.9% vs. non-SRC 69.3%, p = 0.64). SRC histology did not significantly impact risk of death within five years after lobectomy (HR 0.89, p = 0.66). Conclusions Following lobectomy for pT1-2N0 tumors <4 cm, patients with primary SRC lung adenocarcinoma do not experience worse five-year OS or increased risk of death within five years relative to those with non-SRC lung adenocarcinoma. Additional study, including exploration of emerging molecular profiling data, may serve to better define optimal treatment for this histopathologic group of lung adenocarcinomas.


2011 ◽  
Vol 29 (20) ◽  
pp. 2773-2780 ◽  
Author(s):  
Carlo Aschele ◽  
Luca Cionini ◽  
Sara Lonardi ◽  
Carmine Pinto ◽  
Stefano Cordio ◽  
...  

Purpose To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Patients and Methods Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m2/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m2 weekly × 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here. Results Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014). Conclusion Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.


2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Pancheng Wu ◽  
Yi Zheng ◽  
Yanyu Wang ◽  
Yadong Wang ◽  
Naixin Liang

Abstract Background The incidence of stage I and stage II lung adenocarcinoma (LUAD) is likely to increase with the introduction of annual screening programs for high-risk individuals. We aimed to identify a reliable prognostic signature with immune-related genes that can predict prognosis and help making individualized management for patients with early-stage LUAD. Methods The public LUAD cohorts were obtained from the large-scale databases including 4 microarray data sets from the Gene Expression Omnibus (GEO) and 1 RNA-seq data set from The Cancer Genome Atlas (TCGA) LUAD cohort. Only early-stage patients with clinical information were included. Cox proportional hazards regression model was performed to identify the candidate prognostic genes in GSE30219, GSE31210 and GSE50081 (training set). The prognostic signature was developed using the overlapped prognostic genes based on a risk score method. Kaplan–Meier curve with log-rank test and time-dependent receiver operating characteristic (ROC) curve were used to evaluate the prognostic value and performance of this signature, respectively. Furthermore, the robustness of this prognostic signature was further validated in TCGA-LUAD and GSE72094 cohorts. Results A prognostic immune signature consisting of 21 immune-related genes was constructed using the training set. The prognostic signature significantly stratified patients into high- and low-risk groups in terms of overall survival (OS) in training data set, including GSE30219 (HR = 4.31, 95% CI 2.29–8.11; P = 6.16E−06), GSE31210 (HR = 11.91, 95% CI 4.15–34.19; P = 4.10E−06), GSE50081 (HR = 3.63, 95% CI 1.90–6.95; P = 9.95E−05), the combined data set (HR = 3.15, 95% CI 1.98–5.02; P = 1.26E−06) and the validation data set, including TCGA-LUAD (HR = 2.16, 95% CI 1.49–3.13; P = 4.54E−05) and GSE72094 (HR = 2.95, 95% CI 1.86–4.70; P = 4.79E−06). Multivariate cox regression analysis demonstrated that the 21-gene signature could serve as an independent prognostic factor for OS after adjusting for other clinical factors. ROC curves revealed that the immune signature achieved good performance in predicting OS for early-stage LUAD. Several biological processes, including regulation of immune effector process, were enriched in the immune signature. Moreover, the combination of the signature with tumor stage showed more precise classification for prognosis prediction and treatment design. Conclusions Our study proposed a robust immune-related prognostic signature for estimating overall survival in early-stage LUAD, which may be contributed to make more accurate survival risk stratification and individualized clinical management for patients with early-stage LUAD.


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15650-e15650
Author(s):  
Kehe Chen ◽  
Haiming Wei ◽  
Tianqi Liu ◽  
Zhenxiang Chen ◽  
Deng Pan ◽  
...  

e15650 Background: Hepatocellular carcinoma (HCC) is one of the most common prevalent fatal cancers worldwide with poor prognosis due to high incidence of recurrence. For patients with HCC, surgical treatment is a potentially cutative therapy. However, the puzzle in the therapy was the rapid recurrence after surgery. The purpose of this study was to integrate the impact of different immune context present in HCC microenvironment on patients’ prognosis, provide the molecular prediction clue of HCC recurrence. Methods: RNA targeted sequencing was performed on 12 primary tumor specimens from HCC patients. Transcripts of 395 immune related genes expressed in FFPE tumor samples were analyzed. The lima package was used to analyze the different expressed genes (DEGs) between patients with different prognosis. The gene set variance analysis (GSVA) analysis was performed to explore gene sets enrichment related to the recurrence post-resection. Results: 15 DEGs were detected in tissue samples between the two groups (group A: patients who relapsed within one year after surgery; group B: patients who hadn't relapsed beyond two years after surgery). The Antigen processing pathway enrichment may associate with the favorable prognosis (p < 0.05). HLA-A gene expression in group A was lower than that in group B; The gene expression of IL23A, TP63, ALOX15B, BUB1, CXCR2, CCL20, CLEC4C, PTK7, MPO, IL1B, MMP9, GAGE2C, GAGE2A, GAGE2E, DMBT1, FOXM1 in group A was higher than that in group B. Additionally, the combination of 3 genes (TP63, IL23A and BUB1) can distinguish the patients recurrent within 1 year or beyond 2 years post-resection. The joint diagnostic equation is logit (Y = 1) = 0.073 +0.740 *(TP63) + 0.589 * (IL23A)+0.959(BUB1), (Optimal threshold: 0.667, specificity: 1, sensitivity: 0.833). Conclusions: Our results suggest that RNA-seq of immune related genes from FFPE sample can effectively profile the specific landscape of tumor immune microenvironment and predict the survival of HCC. 3 genes’ expression (TP63, IL23A and BUB1) might correlate with recurrence in HCC patients after surgery.


2021 ◽  
Vol 23 (Supplement_1) ◽  
pp. i15-i15
Author(s):  
Fenna F. Feenstra ◽  
Friso Calkoen ◽  
Johan M Kros ◽  
Lennart Kester ◽  
Mariëtte Kranendonk ◽  
...  

Abstract Background Ependymomas account for 8–10% of pediatric brain tumors, and the standard therapy of surgery and radiation has not changed for the past two decades. Characterization of the tumor immune microenvironment (TIME) is of great importance in order to find better therapies. However, the TIME of ependymomas is still not defined. In this retrospective observational study we aimed to unravel the TIME of ependymomas at mRNA and protein expression levels. Methods Ependymoma samples from two locations were selected: Posterior Fossa (PF-A, n=8), and supratentorial (ST, n=5). Targeted gene expression profile using the PanCancer immune profile panel of NanoString technology was performed. Data were analyzed using the nSolver software. In addition, 8 samples were subjected to RNA bulk sequencing, and the sequenced data were connected to the expression data of the same samples. To validate some of the findings, immunohistochemistry was performed. Results Unsupervised hierarchical clustering showed that PF-A ependymomas can be divided into two groups based on the expression of their immune-related genes. PF-A that showed high immune-expression clustered closely to the ST ependymomas. Significant expressions of genes related to “antigen-processing” and “adhesion” pathways were found in the immune-active groups. On the contrary, the PF-A that had low expressions of immune-related genes showed a high expression of BMI1 that has a prognostic and therapeutic value. Connecting gene expression to bulk sequence data validated the findings. In addition, immunohistochemical analysis confirmed that protein expression for some of the findings. Conclusion The TIME varies in ependymomas based on the location of the tumor. Moreover, the immune-related expression profiles indicated that PF-A ependymomas can be divided into two groups: immune-active and immune-not active PF-A. The prognostic and therapeutic values of the immune activity of PF-A should be further studied.


2021 ◽  
Vol 11 ◽  
Author(s):  
Giulia Pasello ◽  
Jessica Menis ◽  
Sara Pilotto ◽  
Stefano Frega ◽  
Lorenzo Belluomini ◽  
...  

IntroductionThe COVID-19 pandemic has proved to be a historic challenge for healthcare systems, particularly with regard to cancer patients. So far, very limited data have been presented on the impact on integrated care pathways (ICPs).MethodsWe reviewed the ICPs of lung cancer patients who accessed the Veneto Institute of Oncology (IOV)/University Hospital of Padua (Center 1) and the University Hospital of Verona (Center 2) before and after the COVID-19 pandemic, through sixteen indicators chosen by the members of a multidisciplinary team (MDT).ResultsTwo window periods (March and April 2019 and 2020) were chosen for comparison. Endoscopic diagnostic procedures and major resections for early stage NSCLC patients increased at Center 1, where a priority pathway with dedicated personnel was established for cancer patients. A slight decrease was observed at Center 2 which became part of the COVID unit. Personnel shortage and different processing methods of tumor samples determined a slightly longer time for diagnostic pathway completion at both Centers. Personnel protection strategies led to a MDT reshape on a web basis and to a significant selection of cases to be discussed in both Centers. The optimization of patient access to healthcare units reduced first outpatient oncological visits, patient enrollment in clinical trials, and end-of-life cancer systemic treatments; finally, a higher proportion of hypofractionation was delivered as a radiotherapy approach for early stage and locally advanced NSCLC.ConclusionsBased on the experience of the two Centers, we identified the key steps in ICP that were impacted by the COVID-19 pandemic so as to proactively put in place a robust service provision of thoracic oncology.


2020 ◽  
Author(s):  
Inbar Shlomovitz ◽  
Gali Yanovich-Arad ◽  
Ziv Erlich ◽  
Liat Edry-Botzer ◽  
Sefi Zargarian ◽  
...  

AbstractNecroptosis is a regulated and inflammatory form of cell death. We, and others, have previously reported that necroptotic cells release extracellular vesicles (EVs). We have found that necroptotic EVs are loaded with proteins, including the phosphorylated form of the key necroptosis-executing factor, mixed lineage kinase domain-like kinase (MLKL). However, neither the exact protein composition, nor the impact, of necroptotic EVs have been delineated. To characterize their content, EVs from necroptotic and untreated U937 cells were isolated and analyzed by mass spectrometry-based proteomics. A total of 3337 proteins were identified, sharing a high degree of similarity with exosome proteome databases, and clearly distinguishing necroptotic and control EVs. A total of 352 proteins were significantly upregulated in the necroptotic EVs. Among these were MLKL and caspase-8, as validated by immunoblot. Components of the ESCRTIII machinery and inflammatory signaling were also upregulated in the necroptotic EVs, as well as currently unreported components of vesicle formation and transport, and necroptotic signaling pathways. Moreover, we found that necroptotic EVs can be phagocytosed by macrophages to modulate cytokine and chemokine secretion. Finally, we uncovered that necroptotic EVs contain tumor neoantigens, and are enriched with components of antigen processing and presentation. In summary, our study reveals a new layer of regulation during the early stage of necroptosis, mediated by the secretion of specific EVs that influences the microenvironment and may instigate innate and adaptive immune responses. This study sheds light on new potential players in necroptotic signaling and its related EVs, and uncovers the functional tasks accomplished by the cargo of these necroptotic EVs.


2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 431-431
Author(s):  
Aditya Varnam Shreenivas ◽  
Kaitlin Annunzio ◽  
Mandana Kamgar ◽  
Sakti Chakrabarti ◽  
James P. Thomas ◽  
...  

431 Background: Patients (pts) with localized PC do not routinely undergo comprehensive genomic profiling (CGP) unless they develop recurrent or metastatic disease. KRAS is the most frequently mutated gene in PC, however, the impact of different KRAS mutations in localized PC has not been well characterized. We interrogated our genomic database to analyze the KRAS status in PC pts who presented with localized disease at diagnosis (Dx). Methods: We identified PC pts at our institution who underwent CGP utilizing the Foundation One CDx assay and had localized disease at initial Dx; these pts were categorized into resectable/borderline resectable PC (LPC) and locally advanced PC (LAPC). All pts with LPC and LAPC underwent neoadjuvant chemotherapy and chemoradiation prior to possible surgery (all intended therapy - AIT). Tissue from metastatic sites was used for CGP in pts who developed recurrent/metastatic disease before or after completion of AIT. The primary tumor was used for CGP in pts who completed AIT without subsequent relapse or in the absence of adequate metastatic tissue. Effect of each gene on response and survival outcomes was estimated using proportional odds and Cox regression analysis, respectively, adjusting for stage. Results: 75 pts were identified, median age at Dx was 65 years, 59% were male, 65% had a primary tumor in the pancreatic head. 38 (86%) pts with LPC completed AIT compared to 21 (68%) pts with LAPC (p<0.001). KRAS mutation was detected in 95% (71/75) of pts– 94% (67/71) in codon 12 and 6% (4/71) in codon 61. The various KRAS mutations and their association with completion of AIT is summarized in the table. The likelihood of completing AIT did not differ based on KRAS wildtype (WT) vs mutated status (p =1.00), the mutated codon (codon 12 vs. codon 61; p =1.00) or the individual KRAS point mutations (p = 0.7); however, all patients with G12A (N= 1), G12C (N=1), G12L (N=1) and G12R (N=11) mutations completed AIT. KRAS status (mutated vs. WT) and the individual KRAS mutations were not associated with overall survival (OS) after adjusting for stage (p= 0.13 and p = 0.26 respectively). Median OS for patients with LPC and LAPC, was 39 months (mos) and 29 mos respectively. Conclusions: KRAS status and individual KRAS mutations did not have an impact on completing AIT or mOS; however, these findings need to be interpreted with caution due to the inherent biases involved in such analyses. The clinical significance and functional relevance of KRAS G12A, G12C, G12L and G12R mutations, though relatively rare, needs further characterization as well as mechanistic elucidation. [Table: see text]


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