Objective To define guidelines for the follow-up manage-95%, for pT2 87% and for pT3 tumours 37%. All patients with diploid pT1-2 RCC survived, having a ment of nonmetastatic renal cell carcinoma (RCC), by assessing tumour recurrences and the clinical course survival advantage over those with aneuploid pT1-2 tumours (P=0.018). Also, pT1-2 tumours of < 5 cm in patients who had undergone radical nephrectomy. Patients and methods The records of 187 patients with were associated with better survival rates. Among 74 patients with pT3 tumours, 45 got metastases; DNA pT1-3, N0-X, M0 RCC who underwent radical nephrectomy between 1982 and 1997 were reviewed ploidy in these tumours did not influence survival. Of 30 patients with lung metastases, 28 were diagnosed prospectively. Clinicopathological variables were compared with the time of first recurrence, site of metastaduring follow-up, while 25 of 26 other metastatic sites were diagnosed because of symptoms. sis and reason for diagnosis. Results Metastases were diagnosed in 98 sites in 56 ofConclusions The risk for tumour progression depends mainly on stage; these results indicate no need for the 187 patients (30%). The risk for developing metastases increased with stage; 80% of the patients had follow-up in patients with diploid pT1-2 tumours or with aneuploid pT1 tumours of < 5 cm. For patients their metastases diagnosed within 3 years (median 14.5 months) after nephrectomy. The time to first with aneuploid pT1-2 tumours of > 5 cm and pT3 tumours, follow-up is indicated. diagnosis was longer for patients with pT1 tumours and for those with skeletal metastases. The causeKeywords Renal cell carcinoma, follow-up, surgery, metastasis, stage, prognosis, surveillance specific 5-year survival rate for pT1 tumours was up regimens. However, increasing healthcare costs will Introduction lead to economic decisions to avoid unnecessary followup procedures or those with little eCect. To enhance The only curative treatment for RCC remains surgery; at the time of diagnosis, about a third of patients already eBciency, follow-up eCorts should be directed at patients with a high probability for recurrent disease. Thus, have metastatic disease and of the remaining patients, #40% will have distant metastases during follow-up. In individualized follow-up protocols are desirable and necessary to optimize the use, and justification for, 1963, Robson et al. [1] showed that radical nephrectomy, with complete removal of the perinephric tissue, includfollow-up management.In the present prospective study of RCC, we analysed ing the ipsilateral adrenal gland and the lymphatic field with paracaval or para-aortic lymph nodes, was associthe results of follow-up after radical nephrectomy. Based on these data, an individual patient follow-up protocol ated with a better survival rate than was simple nephrectomy. Radical nephrectomy remains the standard was designed, with the aim of identifying those patients with a high or a low risk for disease recurrence. surgical treatment of resectable RCC. Curren...

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SummaryTissue‐resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty‐three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in‐vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin‐expressing TRM cells. Surprisingly, programmed cell death 1 (PD‐1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin‐15 and T cell receptor stimulation, perforin and T‐bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

Invasive urinary bladder cancer shows high recurrence rates after cystectomy even with apparent complete downstaging at cystectomy. Exosomes are nano-sized vesicles important in cell-cell communication, which have been hypothesized to contribute to cancer dissemination and recurrence. The aim of this study was to investigate if pro-carcinogenic exosomes could be detected in urine from histologically downstaged bladder cancer patients. 13 Patients were included in this study. Paired ureter and urine samples from nine patients underwent mass spectrometry, while samples from the remaining patients were used for exosome characterization. At cystectomy, exosomes were isolated from bladder and ureter urine, whereafter quantitative proteome profiling was performed. Urinary exosomes clustered based on whether they came from the bladder, with tumour contact, or the ureters, without tumour contact, even though all came from completely downstaged patients. Proteins overexpressed in exosomes derived from bladder urine contained several oncogenes and were mainly associated with tumour metabolism pathways. Although patients were histologically tumour-free at cystectomy, the bladder urine contained exosomes with a carcinogenic metabolic profile. This suggests a continuous release of exosomes from the bladder, which may promote recurrence at distant sites through metabolic rewiring, even after apparent complete downstaging. These exosomes, coming from either undetected cancer cells or partly transformed cells, are likely to increase the risk of metastasis and encourages cystectomy even in completely downstaged patients.

Regulatory T cells (Treg) have long been considered one-sided suppressors of antitumor immune responses and hence associated with poor patient outcome in cancer. However, evidence is mounting of a paradoxical positive prognostic effect of Tregs on certain malignancies, including urinary bladder cancer (UBC). This discrepancy has partly been attributed to the shear misidentification of Tregs, but also to the inflammatory profile of the tumor. Our aim was to determine whether tumor-infiltrating Forkhead box P3 (FOXP3) cells confer a stable Treg phenotype and to investigate putative beneficial Treg functions, focusing on tumor-promoting inflammatory pathways in UBC. Patients ( = 52) with suspected UBC were prospectively included. We show, by using a broad range of analytical approaches, that tumor-infiltrating CD4FOXP3 T cells in UBC phenotypically, functionally, and epigenetically represent a true Treg population. At the invasive front of UBC tumors, we found an inverse relationship between Treg frequency and expression of matrix metalloproteinase 2 (MMP2), a key proinvasive factor induced by tumor-promoting inflammation. Correspondingly, a significant, dose-dependent Treg-mediated downregulation of MMP2 protein and mRNA expression was observed in both macrophages and UBC cells. Also, we found that Treg frequency specifically at the invasive front positively correlated with survival. Thus, we identify Treg-mediated suppression of MMP2 in the tumor microenvironment as a mechanism explaining the paradoxical positive prognostic impact of tumor-infiltrating Tregs in UBC. .