Most renal cell carcinoma (RCC) patients die from metastasis or recurrence after the spread of cancer to another organ, but the mechanisms underlying the intravascular survival of circulating tumor cells (CTCs) have not been completely deciphered. Additionally, although elevated plasma C-reactive protein (CRP) levels and thrombocytosis are strongly correlated and both indicate a poor prognosis for RCC patients, the bridge connecting inflammation and coagulation remains poorly understood. To explore the complicated relationship among inflammation, the coagulation system and CTC survival, we obtained viable CTC counts and clinical information from 106 treatment-naïve patients. In addition, we performed RNA sequencing on peripheral blood leukocytes from 21 of these patients. Patients with elevated CRP and fibrinogen (FIB) levels had higher CTC counts than patients with normal levels of these indexes. Each pair of the three variables (CTC count, CRP level and FIB level) was positively correlated. According to transcriptomic analysis of blood leukocytes, the functions of the 257 genes identified as being positively correlated with the CTC count indicated neutrophil extracellular trap (NET) formation. Indeed, gene set enrichment analysis (GSEA) suggested that NET formation or increased levels of NET markers would promote CTC viability. Additionally, the calculated NET score was positively correlated with the plasma FIB concentration, and both of these values were increased in patients with elevated CRP levels. Moreover, immunofluorescence staining showed that NETs were entangled with viable renal cancer cells and that the NET frameworks were decorated with NET-derived tissue factor (TF). Finally, analysis of 533 RCC samples from The Cancer Genome Atlas (TCGA) indicated that the NET score and TF value are independent prognostic factors for RCC patients. Collectively, NETs formed by intravascular neutrophils further activate the coagulation system. Both the DNA scaffold sprouted and fibrin net triggered by NETs anchor and shield CTCs from attack. Thus, degrading this framework maybe could destroy the double shelter of CTCs, the pioneers of metastasis.

The co‐evolving tumour cells and the systemic immune environment are mutually dysregulated. Tumours affect the immune response in a complex manner. For example, although lymphocytes are mobilized in response to tumours, their function is impaired by tumour progression. This study aimed to explore how the baseline and dynamic renal cell carcinoma (RCC) tumour burdens affect the T‐cell repertoire, and whether the baseline T‐cell receptor β‐chain (TCRB) diversity predicts prognosis. To characterise the TCRB repertoire, the baseline and follow‐up peripheral TCRB repertoires of 45 patients with RCC and 2 patients with benign renal disease patients were examined using high‐throughput TCRB sequencing. To explain the significance of TCRB diversity, 56 peripheral leukocyte samples from 28 patients before and after surgery were subjected to transcriptome sequencing. To validate the results, an advanced RCC patient's sample was subjected to single‐cell RNA sequencing (scRNA, 10x Genomics). Higher TCRB diversity was found to be correlated with a higher lymphocyte‐to‐neutrophil ratio, especially indicating more naïve T cells. High‐baseline TCRB diversity predicted a better prognosis for stage IV patients, and different tumour burdens exerted distinct effects on the immune status. The pre‐operative TCRB diversity was significantly higher in benign and stage I (low tumour burden) RCC patients than in stage IV (high tumour burden) patients. After the tumour burden of advanced patients was mostly relieved, we observed that the TCRB diversity was restored, T‐cell exhaustion was reduced, and naïve T‐cells were mobilized. It was demonstrated that the circulating TCRB repertoire could reflect the immune status and predict prognosis, and to some extent that cytoreductive nephrectomy (CN) reduces the burden of the immune system in advanced patients, which might provide a good opportunity for immunotherapy. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

In addition to the anti-infection response, neutrophils are linked to tumor progression through the secretion of inflammation components and neutrophil extracellular traps (NETs) formation. NET is a web-like structure constituted by a chromatin scaffold coated with specific nuclear and cytoplasmic proteins, such as histone and granule peptides. Increasing evidence has demonstrated that NETs are favorable factors to promote tumor growth, invasion, migration, and immunosuppression. However, the cell–cell interaction between NETs and other cells (tumor cells and immune cells) is complicated and poorly studied. This work is the first review to focus on the intercellular communication mediated by NETs in cancer. We summarized the complex cell–cell interaction between NETs and other cells in the tumor microenvironment. We also address the significance of NETs as both prognostic/predictive biomarkers and molecular targets for cancer therapy. Moreover, we presented a comprehensive landscape of cancer immunity, improving the therapeutic efficacy for advanced cancer in the future.

Previous related studies have mainly focused on renal cell carcinoma (RCC) with venous tumor thrombus, specifically inferior vena cava tumor thrombus with renal vein tumor thrombus (RVTT). However, only a few studies have focused on postoperative long-term survival of RCC patients exclusively with RVTT. Our aim was to investigate the independent prognostic factors for locally advanced RCC with RVTT in China. Patients with locally advanced RCC with RVTT were enrolled for the study from January 2000 to December 2015. All patients underwent radical nephrectomy. Survival analysis was estimated using Kaplan-Meier. Univariable and multivariable survival analyses were performed using COX. Patients were divided into high-risk, middle-risk, and low-risk groups based on independent prognostic factors and then analyzed for survival. One hundred twenty-eight consecutive patients (103 men & 25 women) were enrolled with a median age of 61 years. Thrombi were all graded 0 using the Mayo system, of which 23 were friable. None of the thrombi detached during surgery. 121 patients were successfully followed up, with a median follow-up period of 47 months. Median overall survival was 127 months (95%CI: 101–153). The 5-year and 10-year cancer-specific survival (CSS) rate was 67.9 and 57.0%. 59 patients had recurrence with median time of 40 months. Friable thrombus, paraneoplastic syndrome (PNS), modified Fuhrman grade 3/4 and perirenal fat invasion were independent prognostic factors (p < 0.05). The 5-year CSS for the Low-risk group (no factors) was 100%, Middle-risk group (1–2 factors) was 68.6%, while the High-risk group (3–4 factors) was 0%. After radical surgery, RCC patients with RVTT had a relatively fair prognosis except for patients with friable thrombus, PNS, higher modified Fuhrman grade and perirenal fat invasion.

Background: Non-metastatic renal cell carcinoma (RCC) with tumor thrombus showed a greater tendency for developing metastases after surgery. Early identification of patients with high risk of poor prognosis is especially important to explore adjuvant treatment of improving outcomes. Neutrophil-to-lymphocyte ratio (NLR) was a systemic inflammation marker and outcome predictor in RCC, reflecting the chaos in systemic immune status in cancer as myeloid cell expansion and lymphatic cell suppression. Neutrophil extracellular traps (NET) formation (NETosis) is the process of neutrophils generating an extracellular DNA net-like structure. NETosis in tumor was demonstrated to conduce to the subsequent metastases of tumor. However, the role of NLR for systemic immune status and tumor local immune infiltration, especially for neutrophil-associated NETs, in non-metastatic RCC with thrombus remains unclear.Patients and Methods: In our clinical cohort, we enrolled the clinical, pathologic, and preoperative laboratory parameters of 214 RCC patients with tumor thrombus who were treated surgically. The clinical endpoint was defined as cancer-specific survival (CSS). In our basic research cohort, RNA-seq, TCR-seq, and scRNA-seq data were analyzed. Patients who reached the endpoint as recurrence-free survival (RFS) were defined as the “High-risk” group. Otherwise, they were separated into the “Low-risk” group.Results: In the clinical cohort, NLR≥4 was an independent risk factor for 203 localized RCC with tumor thrombus. In the basic research cohort, tumor thrombi were separated into NETosis-thrombi belonging to the “High-risk” group and non-NETosis-thrombi to the “Low-risk” group. NETs induced by tumor-derived G-CSF in tumor thrombus has a mechanistic role in unfavorable prognosis. Besides, NETs-score from single sample GSEA (ssGSEA) algorithm was an independent prognostic factor validated in the TCGA data. Apart from the neutrophils-associated NETosis, systemic immune perturbations of lymphocytes occurred in the “High-risk” group, represented with decreased TCR diversity and increasingly high proportion of CD4-positive effector memory T (Tem) cells, which indirectly represented the state of lymphopenia.Conclusions: Our findings firstly demonstrated that neutrophils-associated NETosis and systemic lymphocytes perturbations were considered as tumor progression in patients of localized RCC with tumor thrombus, which reflected NLR≥4 as an independent risk factor for patients.

Prostate-specific antigen (PSA) testing is limited in identifying prostate cancer (PCa) with modestly elevated PSA levels. Therefore, a robust method for the diagnosis of PCa is urgently needed. A total of 203 men with a PSA level of ≥4 ng/ml were eligible for enrollment in this study from July 2018 to May 2021, and randomly divided into a training set (n=78) and a validation set (n=125). Circulating tumor cells (CTCs) were detected using telomerase-based CTC detection (TBCD), and the diagnostic ability was evaluated using receiver operating characteristic (ROC) and logistic regression analyses. In the training set, the area under the curve (AUC) of CTCs was 0.842 with a sensitivity of 80.33% and specificity of 82.35%. In the validation set, the AUC of CTCs was 0.789, with a sensitivity of 79.31% and specificity of 81.58%. There was no significant difference between CTCs (AUC=0.793) and PSA (AUC=0.697) in the range of 4-50 ng/ml. In the ranges of 4-20 ng/ml and 4-10 ng/ml, the AUC of CTCs were 0.811 and 0.825, respectively, which were superior to the AUC of PSA (0.588 and 0.541). The sensitivity and specificity of CTCs in the three PSA groups were higher than 80%. Moreover, we further established a CTC+PSA combined model, which could significantly improve the diagnostic ability of a PSA level of ‘4-10 ng/ml’. TBCD could be a valuable method for distinguishing PCa and benign prostatic disease, especially in the PSA diagnostic gray area of ‘4-10 ng/ml’.