Integrative Radiogenomics Approach for Risk Assessment of Postoperative and Adjuvant Chemotherapy Benefits for Gastric Cancer Patients.
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ABSTRACT:
SUBMITTER: Jin Y
PROVIDER: S-EPMC8602567 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aims: TBX2 is related to tumor progression and drug resistance. However, the roles of TBX2 in gastric cancer (GC) remain unclear. Our study aims at investigating the clinical roles of TBX2 in GC. Methods: The protein expression levels of TBX2 in fresh GC tissue (n=20) were investigated with Western blotting analyses. The correlation between TBX2 expression and its prognostic significance was evaluated by immunohistochemical analyses of 401 patients. The survival benefit of postoperative adjuvant chemotherapy (PAC) for patients was evaluated. Results: The expression of TBX2 was increased in GC tissue compared with adjacent paracancerous tissue (p=0.020). Immunohistochemistry demonstrated that TBX2 expression was significantly associated with lymphovascular invasion (p=0.024) and lymph node metastasis (p=0.044). A high level of TBX2 expression was an independent indicator of unfavorable recurrence-free and overall survival (p=0.002 and p=0.033, respectively). The prognostic model incorporating TBX2 expression exhibited greater predictive accuracy than the primary model. More importantly, the benefit of PAC noted in stage II/III GC patients with low TBX2 expression was superior to high TBX2 expression. Conclusion: TBX2 may be not only a useful prognostic marker for GC but also a predictive biomarker of response to PAC in stage II/III GC patients. The current findings warrant further verification.
| S-EPMC7097955 | biostudies-literature
Project description:Purpose: There is currently a lack of validated predictors for adjuvant chemotherapy efficacy in patients with gastric cancer (GC). Perineural invasion (PNI) is the process of neoplastic invasion of the nerves, accompanied by tumor microenvironment (TME) changes. TME can determine treatment outcome while the impact of PNI on chemotherapy efficacy remains unknown in GC. We investigated the association between PNI and the efficacy of postoperative adjuvant chemotherapy in patients with resected GC. Methods: Patients who underwent radical resection of stage IB-III GC with or without fluoropyrimidine (FU)-based adjuvant chemotherapy were retrospectively selected from two separate patient cohorts. PNI was confirmed with S100 immunohistochemistry (IHC). Tumor hypoxia and activity of selected pathways were quantified by mRNA-based signature scoring based on publicly available data. A hypoxia biomarker, ERO1A, and a FU resistance biomarker, thymidylate synthase (TS), were assessed by IHC, respectively. Results: Two cohorts included 223 and 599 patients, respectively. Adjuvant chemotherapy significantly improved overall survival (OS) and disease-free survival (DFS) in PNI-positive but not in PNI-negative patients, which was not impacted by stages. Multivariate models showed that adjuvant chemotherapy was an independent predictor for OS and DFS in PNI-positive patients in both cohorts. For TME, PNI-negative tumors were more hypoxic than were PNI-positive tumors, and displayed relative up-regulation of signaling along the pathways that are important in FU metabolism or resistance. Expressions of ERO1A and TS significantly decreased in PNI-positive compared to PNI-negative tumors. Conclusions: PNI might help predict adjuvant chemotherapy benefit in patients with resected GC. Validation in prospective studies is required. Novel treatment strategies need to be developed in PNI-negative patients.
| S-EPMC7186485 | biostudies-literature
Project description:Despite the increasing incidence of pathological stage T1 renal cell carcinoma (pT1 RCC), postoperative distant metastases develop in many surgically treated patients, causing death in certain cases. Therefore, this study aimed to create a radiomics model using imaging features from multiphase computed tomography (CT) to more accurately predict the postoperative metastasis of pT1 RCC and further investigate the possible link between radiomics parameters and gene expression profiles generated by whole transcriptome sequencing (WTS). Four radiomic features, including the minimum value of a histogram feature from inner regions of interest (ROIs) (INNER_Min_hist), the histogram of the energy feature from outer ROIs (OUTER_Energy_Hist), the maximum probability of gray-level co-occurrence matrix (GLCM) feature from inner ROIs (INNER_MaxProb_GLCM), and the ratio of voxels under 80 Hounsfield units (Hus) in the nephrographic phase of postcontrast CT (Under80HURatio), were detected to predict the postsurgical metastasis of patients with pathological stage T1 RCC, and the clinical outcomes of patients could be successfully stratified based on their radiomic risk scores. Furthermore, we identified heterogenous-trait-associated gene signatures correlated with these four radiomic features, which captured clinically relevant molecular pathways, tumor immune microenvironment, and potential treatment strategies. Our results of accurate surrogates using radiogenomics could lead to additional benefit from adjuvant therapy or postsurgical metastases in pT1 RCC.
| S-EPMC7226068 | biostudies-literature
Project description:ImportanceThe current TNM staging system provides limited information for prognosis prediction and adjuvant chemotherapy benefits for patients with gastric cancer (GC).ObjectiveTo develop a tumor-associated collagen signature of GC (TACSGC) in the tumor microenvironment to predict prognosis and adjuvant chemotherapy benefits in patients with GC.Design, setting, and participantsThis retrospective cohort study included a training cohort of 294 consecutive patients treated between January 1, 2012, and December 31, 2013, from Nanfang Hospital, Southern Medical University, People's Republic of China, and a validation cohort of 225 consecutive patients treated between October 1, 2010, and December 31, 2012, from Fujian Provincial Cancer Hospital, Fujian Medical University, People's Republic of China. In total, 146 collagen features in the tumor microenvironment were extracted with multiphoton imaging. A TACSGC was then constructed using the least absolute shrinkage and selection operator Cox proportional hazards regression model in the training cohort. Data analysis was conducted from October 1, 2020, to April 30, 2021.Main outcomes and measuresThe association of TACSGC with disease-free survival (DFS) and overall survival (OS) was assessed. An independent external cohort was included to validate the results. Interactions between TACSGC and adjuvant chemotherapy were calculated.ResultsThis study included 519 patients (median age, 57 years [IQR, 49-65 years]; 360 [69.4%] male). A 9 feature-based TACSGC was built. A higher TACSGC level was significantly associated with worse DFS and OS in both the training (DFS: hazard ratio [HR], 3.57 [95% CI, 2.45-5.20]; OS: HR, 3.54 [95% CI, 2.41-5.20]) and validation (DFS: HR, 3.10 [95% CI, 2.26-4.27]; OS: HR, 3.24 [95% CI, 2.33-4.50]) cohorts (continuous variable, P < .001 for all comparisons). Multivariable analyses found that carbohydrate antigen 19-9, depth of invasion, lymph node metastasis, distant metastasis, and TACSGC were independent prognostic predictors of GC, and 2 integrated nomograms that included the 5 predictors were established for predicting DFS and OS. Compared with clinicopathological models that included only the 4 clinicopathological predictors, the integrated nomograms yielded an improved discrimination for prognosis prediction in a C index comparison (training cohort: DFS, 0.80 [95% CI, 0.73-0.88] vs 0.78 [95% CI, 0.71-0.85], P = .03; OS, 0.81 [95% CI, 0.75-0.88] vs 0.80 [95% CI, 0.73-0.86], P = .03; validation cohort: DFS, 0.78 [95% CI, 0.70-0.87] vs 0.76 [95% CI, 0.67-0.84], P = .006; OS, 0.78 [95% CI, 0.69-0.86] vs 0.75 [95% CI, 0.67-0.84], P = .002). Patients with stage II and III GC and low TACSGC levels rather than high TACSGC levels had a favorable response to adjuvant chemotherapy (DFS: HR, 0.65 [95% CI, 0.43-0.96]; P = .03; OS: HR, 0.55 [95% CI, 0.36-0.82]; P = .004; dichotomized variable, P < .001 for interaction for both comparisons).Conclusions and relevanceThe findings suggest that TACSGC provides additional prognostic information for patients with GC and may distinguish patients with stage II and III disease who are more likely to derive benefits from adjuvant chemotherapy.
| S-EPMC8634059 | biostudies-literature
Project description:Immune molecules, which have been found to be important in tumor microenvironment, seem prospective in tumor therapy, but they are still not effective enough to use in clinical practice. C-C motif chemokine 22 (CCL22) exists in various malignancies and correlates with migration of regulatory T cells, but its clinical significance in gastric cancer is still unclear. In this study, a combined data set of 466 patients with gastric cancer after surgical resection, comprised of a discovery (n = 319) and a validation data set (n = 147), was enrolled. CCL22 expression was assessed by immunohistochemical staining and we evaluated prognostic values of CCL22 staining and clinical outcomes with use of Kaplan-Meier curve and Multivariate Cox regression analysis. Positive CCL22 expression predicted adverse overall survival independent of traditional pathological grade. Multivariate analysis defined CCL22 and TNM stage as two independent prognostic factors for overall survival. Besides, in patients with TNM stage II/III disease, the rate of overall survival was higher among patients with CCL22-positive tumors who were treated with 5-fluorouracil based adjuvant chemotherapy than that among those who were not (P = 0.012, P < 0.001 and P < 0.001, in discovery, validation and combined data set). But for these with CCL22-negative tumors, whether to undergo adjuvant chemotherapy showed no statistical significance (P = 0.595, P = 0.085 and P = 0.252, respectively). To conclude, CCL22 was identified as an independent adverse prognostic immunobiomarker for patients with gastric cancer after surgery, which is associated with tumor-infiltrating immunocytes and could be incorporated into TNM staging system to redefine a high-risk subgroup who were more likely to benefit from 5-fluorouracil based adjuvant chemotherapy.
| S-EPMC5980413 | biostudies-literature
Project description:Gastric cancer is among the leading causes of cancer death worldwide. Surgery is the only curative modality, but mortality remains high because a significant number of patients have recurrence after complete surgical resection. Chemotherapy, radiation, and chemoradiotherapy have all been studied in an attempt to reduce the risk for relapse and improve survival. There is no globally accepted standard of care for resectable gastric cancer, and treatment strategies vary across the world. Postoperative chemoradiation with 5-fluorouracil/leucovorin is most commonly practiced in the United States; however, recent clinical trials from Asia have shown benefit of adjuvant chemotherapy alone and have questioned the role of radiation. In this review, we examine the current literature on adjuvant treatment of gastric cancer and discuss the roles of radiation and chemotherapy, particularly in light of these new data and their applicability to the Western population. We highlight some of the ongoing and planned clinical trials in resectable gastric cancer and identify future directions as well as areas where further research is needed.
| S-EPMC3780633 | biostudies-other
Project description:Postoperative/adjuvant radiotherapy of advanced gastric cancer involves a large planning target volume (PTV) with multi-concave shapes which presents a challenge for volumetric modulated arc therapy (VMAT) planning. This study investigates the advantages of automated VMAT planning for this site compared to manual VMAT planning by expert planners.For 20 gastric cancer patients in the postoperative/adjuvant setting, dual-arc VMAT plans were generated using fully automated multi-criterial treatment planning (autoVMAT), and compared to manually generated VMAT plans (manVMAT). Both automated and manual plans were created to deliver a median dose of 45 Gy to the PTV using identical planning and segmentation parameters. Plans were evaluated by two expert radiation oncologists for clinical acceptability. AutoVMAT and manVMAT plans were also compared based on dose-volume histogram (DVH) and predicted normal tissue complication probability (NTCP) analysis.Both manVMAT and autoVMAT plans were considered clinically acceptable. Target coverage was similar (manVMAT: 96.6?±?1.6%, autoVMAT: 97.4?±?1.0%, p?=?0.085). With autoVMAT, median kidney dose was reduced on average by >?25%; (for left kidney from 11.3?±?2.1 Gy to 8.9?±?3.5 Gy (p?=?0.002); for right kidney from 9.2?±?2.2 Gy to 6.1?±?1.3 Gy (p?<? 0.001)). Median dose to the liver was lower as well (18.8?±?2.3 Gy vs. 17.1?±?3.6 Gy, p?=?0.048). In addition, Dmax of the spinal cord was significantly reduced (38.3?±?3.7 Gy vs. 31.6?±?2.6 Gy, p?<? 0.001). Substantial improvements in dose conformity and integral dose were achieved with autoVMAT plans (4.2% and 9.1%, respectively; p?<? 0.001). Due to the better OAR sparing in the autoVMAT plans compared to manVMAT plans, the predicted NTCPs for the left and right kidney and the liver-PTV were significantly reduced by 11.3%, 12.8%, 7%, respectively (p???0.001). Delivery time and total number of monitor units were increased in autoVMAT plans (from 168?±?19 s to 207?±?26 s, p?=?0.006) and (from 781?±?168 MU to 1001?±?134 MU, p?=?0.003), respectively.For postoperative/adjuvant radiotherapy of advanced gastric cancer, involving a complex target shape, automated VMAT planning is feasible and can substantially reduce the dose to the kidneys and the liver, without compromising the target dose delivery.
| S-EPMC5913894 | biostudies-other
Project description:Adverse reactions in normal tissue after radiotherapy (RT) limit the dose that can be given to tumour cells. Since 80% of individual variation in clinical response is estimated to be caused by patient-related factors, identifying these factors might allow prediction of patients with increased risk of developing severe reactions. While inactivation of cell renewal is considered a major cause of toxicity in early-reacting normal tissues, complex interactions involving multiple cell types, cytokines, and hypoxia seem important for late reactions. Here, we review 'omics' approaches such as screening of genetic polymorphisms or gene expression analysis, and assess the potential of epigenetic factors, posttranslational modification, signal transduction, and metabolism. Furthermore, functional assays have suggested possible associations with clinical risk of adverse reaction. Pathway analysis incorporating different 'omics' approaches may be more efficient in identifying critical pathways than pathway analysis based on single 'omics' data sets. Integrating these pathways with functional assays may be powerful in identifying multiple subgroups of RT patients characterised by different mechanisms. Thus 'omics' and functional approaches may synergise if they are integrated into radiogenomics 'systems biology' to facilitate the goal of individualised radiotherapy.
| S-EPMC5016239 | biostudies-other
Project description:Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e., limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that disease-free survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment.
| S-EPMC4000488 | biostudies-literature
Project description:ImportanceLoss of O6-methylguanine-DNA methyltransferase (MGMT) protein expression has been reported in several malignant tumors and predicts dismal survival outcomes. In gastric cancer, existing studies on this topic are limited and the association between MGMT and fluorouracil-based adjuvant chemotherapy remains obscure.ObjectiveTo investigate the postoperative prognostic significance of MGMT in patients with resectable gastric cancer and its responsiveness to fluorouracil-based adjuvant chemotherapy.Design, setting, and participantsThis study recruited 445 consecutive patients with resectable gastric cancer who underwent radical gastrectomy between August 1, 2007, and December 30, 2008, at Zhongshan Hospital at Fudan University in Shanghai, China. Patients were randomly divided into a discovery data set (n = 200) and a validation data set (n = 245), and the range of follow-up time was from 2 to 76 months for the discovery group and 2 to 79 months for the validation group. The immunoreactivity for MGMT in cancer cells was reviewed under a light microscope by 2 pathologists who were blinded to the clinicopathological data. The association of MGMT expression with clinicopathological characteristics and measures and prognosis was inspected. Data and specimens were collected from patients from the date of surgery to April 25, 2014. Data analysis took place from May 9, 2016, to July 15, 2016.Main outcomes and measuresEstimates of overall survival on the basis of MGMT expression and hazard ratio (HR) for estimates of overall mortality risk.ResultsOf the 445 patients included in the study, 315 (70.8%) were men, and the mean (SD) age of all patients was 60 (12) years. Positive expression of MGMT indicated better overall survival for patients with stage II or III gastric cancer in both the discovery data set (HR, 0.52; 95% CI, 0.32-0.84; P = .003) and the validation data set (HR, 0.63; 95% CI, 0.43-0.93; P = .01). Multivariate analysis identified MGMT expression and TNM stage as 2 independent prognostic factors for overall survival. In stage II disease, the benefit from fluorouracil-based adjuvant chemotherapy was superior among MGMT-positive patients (HR, 0.35; 95% CI, 0.13-0.95; P = .007 for interaction) compared with MGMT-negative patients.Conclusions and relevancePositive expression of MGMT in gastric cancer was identified as an independent, favorable prognostic factor. Incorporating MGMT expression into the current TNM staging system could lead to better prognostic accuracy. These findings should be confirmed within the framework of randomized clinical trials associated with genomic DNA sequencing studies.
| S-EPMC5831425 | biostudies-literature