Risk factors for postoperative recurrence of cesarean scar endometriosis.

BACKGROUND: The increasing global prevalence of cesarean scar endometriosis necessitates a thorough understanding of the risk factors for postoperative recurrence, as this is crucial for developing preventive strategies and informed decision-making. OBJECTIVE: To obtain insight into the clinical risk factors for postoperative recurrence of cesarean scar endometriosis following open lesion resection. STUDY DESIGN: The cohort for this study comprised 272 women, including 26 patients with postoperative recurrence and 246 without recurrence. Various parameters, including baseline characteristics, preoperative, intraoperative, and postoperative conditions, and follow-up information, were analyzed. A comparison of these parameters was made between patients with and without postoperative recurrence. Time-to-recurrence analyses were conducted using Cox's univariate and multivariate proportional hazard analyses, the Kaplan-Meier method, and the log-rank test. RESULTS: The results revealed significant differences between patients with and without postoperative recurrence in terms of visual analog scale for abdominal pain (P=.008), method of surgery (P<.001), and incision length (P=.002). The Cox proportional hazard model identified the visual analog scale for abdominal pain ≥4 as a significant risk factor for postoperative recurrence (hazard ratio, 3.72 [95% confidence interval, 1.65-8.43]; P=.002). In addition, patients who received removal of scar, excision of mass, and exploration underneath the scar (named as integrated excision) had a lower risk of recurrence than those who received local excision of mass (hazard ratio, 0.14 [95% confidence interval, 0.04-0.48]; P=.002). Furthermore, older patients (aged ≥35 years) were found to have a lower risk of postoperative recurrence than those <35 years (hazard ratio, 0.35 [95% confidence interval, 0.12-1.04]; P=.058). In addition, the depth of involvement was identified as a meaningful factor in postoperative recurrence for patients with local excision of mass, as determined by the log-rank test (P=.018). CONCLUSION: The study highlights that the visual analog scale for abdominal pain ≥4 is a risk factor for the recurrence of cesarean scar endometriosis after open lesion resection. Furthermore, the surgical method of integrated excision was identified as a protective factor.

Align While Fusion: A Generalized Nonaligned Multiview Multilabel Classification Method.

In the task of multiview multilabel (MVML) classification, each object is described by several heterogeneous view features and annotated with multiple relevant labels. Existing MVML methods usually assume that these heterogeneous features are strictly view-aligned, and they directly conduct cross-view information fusion to train a multilabel prediction model. However, in real-world scenarios, such strict view-aligned requirement can be hardly satisfied due to the recurrent spatiotemporal asynchronism when collecting MVML data, which would cause inaccurate multiview fusion results and degrade the classification performance. To address this issue, we propose a generalized nonaligned MVML (GNAM) classification method, which achieves multiview information fusion while aligning cross-view features and accordingly learns a desired multilabel classifier. Specifically, we first introduce a multiorder matching alignment strategy to achieve cross-view feature alignments, where both first-order feature correspondence and second-order structure correspondence are jointly integrated to guarantee the compactness of the view-alignment results. Afterward, a commonality-and individuality-based multiview fusion structure is formulated on the aligned-view features to excavate the consistencies and complementarities across different views, which leads all relevant multiview semantic labels, especially rare labels, to be characterized more comprehensively. Finally, we embed adaptive global label correlations to multilabel classification model to further enhance its semantic expression integrity and develop an alternative algorithm to optimize the whole model. Extensive experimental results have verified that GNAM is significantly superior to other state-of-the-art methods.

Necroptosis-related regulatory pattern and scoring system for predicting therapeutic efficacy and prognosis in ovarian cancer.

BACKGROUND: Ovarian cancer is difficult to treat and is, therefore, associated with a high fatality rate. Although targeted therapy and immunotherapy have been successfully used clinically to improve the diagnosis and treatment of ovarian cancer, most tumors become drug resistant, and patients experience relapse, meaning that the overall survival rate remains low. AIMS: There is currently a lack of effective biomarkers for predicting the prognosis and/or outcomes of patients with ovarian cancer. Therefore, we used published transcriptomic data derived from a large ovarian cancer sample set to establish a molecular subtyping model of the core genes involved in necroptosis in ovarian cancer. METHODS AND RESULTS: Clustering analysis and differential gene expression analyses were performed to establish the genomic subtypes related to necroptosis and to explore the patterns of regulatory gene expression related to necroptosis in ovarian cancer. A necroptosis scoring system (NSS) was established using principal component analysis according to different regulatory patterns of necroptosis. In addition, this study revealed important biological processes with essential roles in the regulation of ovarian tumorigenesis, including external encapsulating structure organization, leukocyte migration, oxidative phosphorylation, and focal adhesion. Patients with high NSS scores had unique immunophenotypes, such as more abundant M2 macrophages, monocytes, CD4+ memory T cells, and regulatory T cells. Immune checkpoint CD274 had a greater expression in patients with high NSS values. CONCLUSION: This NSS could be used as an independent predictor of prognosis to determine the sensitivity of ovarian cancer to various small-molecule inhibitors, immune checkpoint inhibitors, and platinum-based chemotherapy drugs.

LIMD2 promotes tumor proliferation, invasion, and epithelial-mesenchymal transition in clear cell renal cell carcinoma.

LIMD2 was found upregulated in various tumors and metastatic samples and associated with a poor prognosis. But the role of LIMD2 in clear cell renal cell carcinoma (ccRCC) remains elusive. The expression of LIMD2 in ccRCC was analyzed using cohort data downloaded from TCGA and ICGC databases. In vitro and in vivo experiments were then conducted to study the biological role of LIMD2 in ccRCC and explore the possible mechanism. The results indicated that LIMD2 was overexpressed and correlated with a poor outcome in ccRCC. LIMD2 promoted the malignancy of ccRCC both in vitro and in vivo. LIMD2 induced epithelial-mesenchymal transition (EMT) via activating the ILK/Akt pathway in ccRCC. In conclusion, LIMD2 is overexpressed and promotes proliferation, invasion, and EMT in ccRCC, which may serve as a potential novel therapeutic target for ccRCC.

Conditional survival of trimodal therapy for nonmetastatic muscle-invasive bladder cancer: A SEER database analysis.

OBJECTIVE: Conventional survival analysis plays a limited role in patients who have survived a period after initial treatment. The present study analyzed how conditional survival (CS) predicted survival rate over time for nonmetastatic muscle-invasive bladder cancer (MIBC) patients after trimodal treatment. METHOD: This retrospective study from the SEER database included consecutive patients with nonmetastatic MIBC who received trimodal therapy (TMT) between January 2010 and December 2017. Kaplan-Meier analysis was used to estimate overall survival (OS) and cancer-specific survival (CSS). CS was defined as the rate of surviving y years after already surviving for x years. Multivariate Cox regression analysis was used to identify prognostic factors. RESULT: A total of 1110 nonmetastatic MIBC patients treated with TMT were included. Given a 1-, 2-, 3-, and 4-year after TMT, the rate of surviving to 5-year, respectively, improved by +5.0 (20.0%), +17.0 (32.0%), +30.0 (45.0%), and +52.8 (67.8%) from those calculated at baseline (15.0%). The 2-year CS rate of patients who had survived 1-, 2-, or 3-year after TMT improved, respectively, compared to 3-, 4-, or 5-year actual survival. Multivariate Cox regression analysis demonstrated that adverse variables (T stage, age) of OS and CSS lost their prognostic significance over time. DISCUSSION AND CONCLUSION: Conditional survival rate of surviving to 5-year after TMT kept a relatively stable level over time. In addition, those adverse variables were not always the prognostic factors over time. Only age was always the significant prognostic factor for conditional OS from baseline to 5-year survival. Our results provided real-time survival information and prognosis estimates to adjust follow-up plans for nonmetastatic MIBC patients after TMT.

Selection of Optimal Candidates for Cytoreductive Nephrectomy in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Predictive Model Based on SEER Database.

BACKGROUND: Currently, the progress of targeted drugs in the treatment of metastatic clear cell renal cell carcinoma (mccRCC) is limited. Cytoreductive nephrectomy (CN), as an alternative treatment, can improve the prognosis of patients with metastatic renal cell carcinoma to some extent. However, it is unclear which patients would benefit from this tumor reduction operation. As a consequence, we developed a predictive model to identify patients who may well benefit from CN in terms of survival. METHODS: We identified patients with metastatic clear cell renal cell carcinoma retrospectively from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015) and classified them into surgery and non-surgery groups. Propensity score matching (PSM) was performed to balance the baseline characteristics. Patients who survived longer than the median overall survival (OS) of no-surgery group were defined as surgical-benefit patients. Then, we developed a predictive model based on preoperative characteristics using multivariable Logistic regression. Calibration curves and the area under the receiver operating characteristic (AUC) were used to evaluate the efficiency of the predictive model. The clinical value of the nomogram was assessed utilizing decision curve analysis (DCA). RESULTS: Our study collected 5544 patients from the SEER database, with 2352(42.4%) receiving cytoreductive surgery. Overall survival (OS) was longer in the CN group than in the non-surgery group after 1:1 propensity scoring matching (median OS: 19 months vs 7 months; hazard ratio (HR) =0.4106, P< 0.001). In the matched surgery group, 65.7% (367) patients survived more than 7 months after the operation and they were considered to benefit from CN. The predictive model performed well on both the training group (AUC=73.4%) and the validation group (AUC=71.9%) and the calibration curves indicated a high degree of consistency. The decision curve analysis curve demonstrated the clinical utility. We classified surgical patients into the beneficial group and non-beneficial group by using the predictive model, then discovered a substantial difference in OS between the two groups. CONCLUSIONS: We developed a nomogram to select ideal mccRCC patients who might benefit from cytoreductive nephrectomy. Clinicians could make a more precise treatment strategy for mccRCC patients.

Establishment of Sunitinib-Resistant Xenograft Model of Renal Cell Carcinoma and the Identification of Drug-Resistant Hub Genes and Pathways.

INTRODUCTION: Sunitinib is the first-line targeted drug for the treatment of advanced renal cell carcinoma (RCC), but its therapeutic potential is limited by premature drug resistance. In an attempt to overcome this limitation, a sunitinib-resistant cell-derived xenograft (CDX) model of clear cell renal cell carcinoma (ccRCC) in vivo was constructed in this study. The molecular mechanism of drug resistance was analyzed using sequencing and bioinformatics tools. METHODS: First, mice were injected subcutaneously with tumor cells 786-O to create tumors and were simultaneously treated with sunitinib. After three consecutive passages, a drug-resistant xenograft model was obtained. Then, key pathways and genes were identified via second-generation sequencing of the tissue and the examination of differentially expressed genes (DEGs) with bioinformatics tools. RESULTS: Analysis of sequencing data revealed that 646 DEGs were upregulated and 465 were downregulated in the drug-resistant tissues when compared with the sensitive tissues. GO showed that the DEGs were significantly enriched in angiogenesis, cell hypoxia response, and apoptosis. KEGG analysis demonstrated that the main pathways were PI3K-Akt, HIF-1, NF-kappa B, and MAPK. Modular analysis of the PPI network indicated that the GO and KEGG analyses of module 1 with the highest ranking were mainly related to ubiquitinase activity. Similarly, the GO and KEGG analyses of the top 10 hub genes were also chiefly linked to ubiquitinase activity. Then, comprehensive expression analysis of the hub genes, and finally, the genes BTRC and TRIM32 were identified, which were consistent in all observations. CONCLUSION: In this study, through the construction of in vitro models and bioinformatics analysis, the important pathways and key genes related to ccRCC sunitinib resistance were discovered. Among them, ubiquitinase may play an important role in drug resistance and may be a potential therapeutic target and biomarker.

M2 macrophages secrete CXCL13 to promote renal cell carcinoma migration, invasion, and EMT.

OBJECTIVE: M2 macrophages are associated with a poor prognosis in a variety of malignancies. There are, however, few relevant investigations in clear cell renal cell carcinoma (ccRCC). METHODS: The expression of M2 macrophages in ccRCC tissues was first discovered using immunohistochemistry in this study. Then, M2 macrophages were created in vitro to see how they affected the proliferation, migration, invasion, and EMT of ccRCC cells. Using qPCR and prognostic analysis identifies important chemokine. Antibody neutralization tests confirmed the chemokine's involvement and function. Pathway inhibitors confirmed the main pathway of M2 macrophages in ccRCC. Finally, qPCR and IHC were used to confirm the expression of chemokine receptors in ccRCC tissues. RESULTS: The presence of M2 macrophages was linked to a poor outcome in ccRCC. M2 macrophages enhanced the proliferation, migration, invasion, and EMT of ccRCC lines in vitro. CXCL13 was identified as the main chemokine by prognostic analysis and qPCR tests. CXCL13 neutralizing antibodies can inhibit the stimulation of M2 macrophages in ccRCC lines' proliferation, migration, invasion, and EMT. M2 macrophages and CXCL13 may activate the Akt pathway in ccRCC lines, and Akt inhibitors decrease ccRCC lines proliferation, migration, invasion, and EMT. CXCR5 expression is a poor prognostic factor for renal cell carcinoma, according to qPCR and immunohistochemistry. In vivo experiments further proved that CXCL13 secreted by M2 macrophages can promote tumor proliferation. CONCLUSIONS: M2 macrophages in the immunological milieu secrete CXCL13, which promotes ccRCC proliferation, migration, invasion, and EMT. Our findings contribute to a better understanding of the function of the tumor microenvironment in the incidence and progression of ccRCC, and they may point to novel therapeutic targets for ccRCC.

Circular RNA circPPP6R3 upregulates CD44 to promote the progression of clear cell renal cell carcinoma via sponging miR-1238-3p.

Circular RNAs (circRNAs) are a type of covalently closed circular-formed RNAs and play crucial roles in the oncogenesis and progression of various human cancers. Here we identified a novel circRNA, circPPP6R3, to be highly expressed both in clear cell renal cell carcinoma (ccRCC) tissues and cell lines based on analyzing high-throughput sequencing data and qRT-PCR analysis. Highly expressed circPPP6R3 was positively correlated with higher histological grade, T stage, and M stage as well as advanced clinical stage of ccRCC patients. Functionally, knockdown of circPPP6R3 attenuated the proliferation, migration, and invasion of ccRCC cells whereas overexpression had the reverse effects. Mechanistically, the biotin-labeled pull-down assay and dual-luciferase reporter assay revealed that circPPP6R3 directly interacted with miR-1238-3p. miR-1238-3p inhibitors had a rescue effect on the proliferative and metastatic capacities by knockdown of circPPP6R3. Moreover, RNA-sequencing analysis and dual-luciferase reporter assay indicated that circPPP6R3 upregulated CD44, a cell-surface glycoprotein contributed to the cell adhesion and metastasis, via sponging to miR-1238-3p. Further investigation revealed that MMP9 and Vimentin were regulated by CD44 in ccRCC. Our study thus provided evidence that the regulatory network involving circPPP6R3/miR-1238-3p/CD44 axis might provide promising biomarkers as well as a therapeutic approach for ccRCC.

Patterns of Immune Infiltration in Endometriosis and Their Relationship to r-AFS Stages.

Background: Endometriosis (EMS) is an estrogen-dependent disease in which endometrial glands and stroma arise outside the uterus. Current studies have suggested that the number and function of immune cells are abnormal in the abdominal fluid and ectopic lesion tissues of patients with EMS. The developed CIBERSORT method allows immune cell profiling by the deconvolution of gene expression microarray data. Methods: By applying CIBERSORT, we assessed the relative proportions of immune cells in 68 normal endometrial tissues (NO), 112 eutopic endometrial tissues (EU) and 24 ectopic endometrial tissues (EC). The obtained immune cell profiles provided enumeration and activation status of 22 immune cell subtypes. We obtained associations between the immune cell environment and EMS r-AFS stages. Macrophages were evaluated by immunohistochemistry (IHC) in 60 patients with ovarian endometriomas. Results: Total natural killer (NK) cells were significantly decreased in EC, while plasma cells and resting CD4 memory T cells were increased in EC. Total macrophages in EC were significantly increased compared to those of EU and NO, and M2 macrophages were the primary macrophages in EC. Compared to those of EC from patients with r-AFS stage I ~ II, M2 macrophages in EC from patients with stage III ~ IV were significantly increased. IHC experiments showed that total macrophages were increased in EC, with M2 macrophages being the primary subtype. Conclusions: Our data demonstrate that deconvolution of gene expression data by CIBERSORT provides valuable information about immune cell composition in EMS.

Efficacy and safety of immunological checkpoint inhibitors combined with anti-angiogenic drugs in first-line treatment of metastatic renal cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have shown promising results for the second-line treatment of metastatic renal cell carcinoma (mRCC). Several randomized controlled trials have so far also evaluated the efficacy of ICIs for first-line treatment of mRCC. In this study, we conducted a meta-analysis of relevant studies to further clarify the efficacy and safety of ICIs combined with anti-angiogenic drugs for the treatment of mRCC. METHODS: We searched the PubMed, Embase, and Cochrane libraries for RCT trials of ICIs combined with anti-angiogenic drugs for first-line treatment of mRCC published before November 20, 2019. A meta-analysis was conducted based on methodological recommendations by the Cochrane Collaboration. RESULTS: Four articles with a total of 2,967 patients met the inclusion criteria. Our meta-analysis revealed that progression-free survival (PFS) and objective response rate (ORR) were significantly improved in the experimental group while there was no significant difference in overall survival (OS) (HR 0.75, 95% CI: 0.67-0.84; HR 1.43, 95% CI: 1.07-1.91; HR 0.74, 95% CI: 0.53-1.03). After stratification for PD-L1 expression, OS, PFS, and ORR of PD-L1 positive patients were significantly increased in the experimental group (HR 0.74, 95% CI: 0.56-0.96; HR 1.66, 95% CI: 1.11-2.49; HR 0.65, 95% CI: 0.57-0.75). CONCLUSIONS: Immunological checkpoint inhibitors combined with anti-angiogenic drugs as a first-line treatment for mRCC improve PFS and ORR. This effect is more pronounced in PD-L1 positive patients, where ICIs also improve OS. ICIs do not increase the incidence of adverse events.

Development and validation of a CT-based nomogram for preoperative prediction of clear cell renal cell carcinoma grades.

OBJECTIVES: Nuclear grades are proved to be one of the most significant prognostic factors for clear cell renal cell carcinoma (ccRCC). Radiomics nomogram is a widely used noninvasive tool that could predict tumor phenotypes. In this study, we performed radiomics analysis to develop and validate a CT-based nomogram for the preoperative prediction of nuclear grades in ccRCC. METHOD: CT images and clinical data of 258 ccRCC patients were retrieved from the Cancer Imaging Archive (TCIA). Radiomics features were extracted from arterial-phase CT images using 3D Slicer software. LASSO regression model was performed to develop a radiomics signature in the training set (n = 143). A radiomics nomogram was constructed combining radiomics signature and selected clinical predictors. Receiver operating characteristic (ROC) curve and calibration curve were used to determine the performance of the radiomics nomogram in the training and validation set (n = 115). Decision curve analysis was used to assess the clinical usefulness of the CT-based nomogram. RESULTS: One thousand three hundred sixteen radiomics features were extracted from arterial-phase CT images. A radiomics signature, consisting of 20 features, was developed and showed a favorable performance in discriminating nuclear grades with an area under the curve (AUC) of 0.914 and 0.846 in the training and validation set, respectively. The CT-based nomogram, including the radiomics signature and the CT-determined T stage, achieved good calibration and discrimination in the training set (AUC, 0.929; 95% CI, 0.886-0.972) and validation set (AUC, 0.876; 95% CI, 0.812-0.939). Decision curve analysis demonstrated the clinical usefulness of the CT-based nomogram. CONCLUSION: The noninvasive CT-based nomogram, including radiomics signature and CT-determined T stage, could improve the accuracy of preoperative grading of ccRCC and provide individualized treatment for ccRCC patients. KEY POINTS: • Contrast-enhanced CT may help in preoperative grading of ccRCC. • The CT-based nomogram incorporated a radiomics signature and CT-determined T stage could preoperatively predict ccRCC grades. • The CT-based nomogram has the potential to improve individualized treatment and assist clinical decision making of ccRCC patients.

CircPVT1 promotes progression in clear cell renal cell carcinoma by sponging miR-145-5p and regulating TBX15 expression.

Emerging evidence revealed that circular RNAs (circRNAs) play significant roles in regulating tumorigenesis and cancer progression. However, few circRNAs were well characterized in clear cell renal cell carcinoma (ccRCC). We found that circPVT1 was significantly upregulated in ccRCC tissues and positively associated with the clinical stage. The Area Under Curve of tissue and serum circPVT1 expression in ccRCC were 0.93 and 0.86, respectively. Importantly, we demonstrated that circPVT1 promoted ccRCC growth and metastasis in vitro and in vivo. We also found that circPVT1 directly binds to miRNA-145-5p via the Biotin-labelled miRNA pulldown assay and dual-luciferase reporter assay, and miR-145-5p inhibitor significantly attenuated the effect of circPVT1 knockdown on ccRCC cells. Moreover, through RNA sequencing and bioinformatics analysis, we demonstrated that TBX15 was regulated by the circPVT1/miR-145-5p axis and predicted poor prognosis in ccRCC. These findings suggest that circPVT1 promotes ccRCC growth and metastasis through sponging miR-145-5p and regulating downstream target TBX15 expression. The circPVT1/miR-145-5p/TBX15 axis might be a potential diagnostic marker and therapeutic target in ccRCC.

Patterns of Failure and Survival Trends Of 720 Patients with Stage I Nasopharyngeal Carcinoma Diagnosed from 1990-2012: A Large-scale Retrospective Cohort Study.

Objectives: To evaluate the patterns of failure and survival trends of patients with stage I nasopharyngeal carcinoma (NPC) treated with radiotherapy alone over the last 20 years. Materials and Methods: A retrospective cohort study was conducted on 720 patients with stage I NPC who were treated with curative two-dimensional radiotherapy (2DRT), three-dimensional conformal radiotherapy (3DRT), or intensity-modulated radiotherapy (IMRT) between January 1990 and December 2012. The patients were categorized into four calendar periods (1990-1996, 1997-2002, 2003-2007, and 2008-2012) and four age subgroups (18-39, 40-49, 50-59, and >60). We computed overall survival (OS), progression free survival (PFS), locoregional relapse free survival (LRFS) and distant metastasis free survival (DMFS) as measures of patient survival. Results: After a median follow-up period of 105 months (range 1-280 months), we observed the increasing trends in survival and disease control. The 3-, 5-, and 7-year OS rates increased from 97.0%, 86.7%, and 81.7% in the first calendar period (1990-1996) to 100%, 99.3%, and 98.0% in the last calendar period (2008-2012), respectively (P<0.001). Additionally, significant increasing trends could be seen in the PFS and LRFS during the four calendar periods. In the subgroup analysis, the OS, PFS and LRFS in patients diagnosed older than 40 years had greater improvement than the younger patients. However, the rate of distant metastasis was stable and relatively low, as the 5-year distant metastasis rate ranged from 0.2%-2.5% among the four calendar periods. Conclusion: The survival rates in patients with stage I NPC showed increasing trends from 1990 to 2012. The advances of radiotherapy provided excellent locoregional control and enhanced overall survival, and in particular, the IMRT decreased locoregional relapse.

CXCL13/CXCR5 Axis Predicts Poor Prognosis and Promotes Progression Through PI3K/AKT/mTOR Pathway in Clear Cell Renal Cell Carcinoma.

The chemokine ligands and their receptors play critical roles in cancer progression and patients outcomes. We found that CXCL13 was significantly upregulated in ccRCC tissues compared with normal tissues in both The Cancer Genome Atlas (TCGA) cohort and a validated cohort of 90 pairs ccRCC tissues. Statistical analysis showed that high CXCL13 expression related to advanced disease stage and poor prognosis in ccRCC. We also revealed that serum CXCL13 levels in ccRCC patients (n = 50) were significantly higher than in healthy controls (n = 40). Receiver operating characteristic (ROC) curve revealed that tissue and serum CXCL13 expression might be a diagnostic biomarker for ccRCC with an area under curve (AUC) of 0.809 and 0.704, respectively. CXCL13 was significantly associated with its receptor, CXCR5, in ccRCC tissues, and ccRCC patients in high CXCL13 high CXCR5 expression group have a worst prognosis. Functional and mechanistic study revealed that CXCL13 promoted the proliferation and migration of ccRCC cells by binding to CXCR5 and activated PI3K/AKT/mTOR signaling pathway. These results suggested that CXCL13/CXCR5 axis played a significant role in ccRCC and might be a therapeutic target and prognostic biomarker.

Combination of Tumor Volume and Epstein-Barr Virus DNA Improved Prognostic Stratification of Stage II Nasopharyngeal Carcinoma in the Intensity Modulated Radiotherapy Era: A Large-Scale Cohort Study.

PURPOSE: Little is known about combination of the circulating Epstein-Barr viral (EBV) DNA and tumor volume in prognosis of stage II nasopharyngeal carcinoma (NPC) patients in the intensity modulated radiotherapy (IMRT) era. We conducted this cohort study to evaluate the prognostic values of combining these two factors. MATERIALS AND METHODS: By Kaplan-Meier, we compare the differences of survival curves between 385 patients with different EBV DNA or tumor volume levels, or with the combination of two biomarkers mentioned above. RESULTS: Gross tumor volume of cervical lymph nodes (GTVnd, p < 0.001) and total tumor volume (GTVtotal, p < 0.001) were both closely related to pretreatment EBV DNA, while gross tumor volume of nasopharynx (GTVnx, p=0.047) was weakly related to EBV DNA. EBV DNA was significantly correlated with progress-free survival (PFS, p=0.005), locoregional-free survival (LRFS, p=0.039), and distant metastasis-free survival (DMFS, p=0.017), while GTVtotal, regardless of GTVnx and GTVnd, had a significant correlation with PFS and LRFS. The p-values of GTVtotal for PFS and LRFS were 0.008 and 0.001, respectively. According to GTVtotal and pretreatment EBV DNA level, patients were divided into a low-risk group (EBV DNA 0 copy/mL, GTVtotal < 30 cm3; EBV DNA 0 copy/mL, GTVtotal ≥ 30 cm3; or EBV DNA > 0 copy/mL, GTVtotal < 30 cm3) and a high-risk group (EBV DNA > 0 copy/mL, GTVtotal ≥ 30 cm3). When patients in the low-risk group were compared with those in the high-risk group, 3-year PFS (p=0.003), LRFS (p=0.010), and DMFS (p=0.031) rates were statistically significant. CONCLUSION: Pretreatment plasma EBV DNA and tumor volume were both closely correlated with prognosis of stage II NPC patients in the IMRT era. Combination of EBV DNA and tumor volume can refine prognosis and indicate for clinical therapy.