BACKGROUND AND PURPOSE:Clinical tools to optimally select real-world metastatic renal cell carcinoma (mRCC) patients for treatment with ipilimumab-nivolumab remain to be identified. PATIENT AND METHODS:Medical records of the first 100 mRCC patients treated with ipilimumab-nivolumab at three Swedish centers were retrospectively analyzed. Data on International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, baseline levels of routine blood markers, and tumor burden were collected. Outcome variables were progression-free survival (PFS), overall survival (OS), and radiological response (RR) according to clinical routine imaging. RESULTS:At a median follow-up of 22 months, 65% had progressed or died with a median PFS of 7 months and an estimated median OS of 28 months. The RR rate was 45%, including 11% complete responses (CR). 29% had progressive disease as best response. IMDC poor-risk patients had shorter mPFS (4 vs 14 months; HR [hazard ratio] 1.90; P = 0.009), shorter mOS (12.5 months vs not reached; HR 4.27; P < 0.0001), and lower CR rate (3% vs 16%, P = 0.06) than IMDC intermediate/favorable patients. C-reactive protein (aHR 2.67; P = 0.040), albumin (aHR, 2.13; P = 0.039), neutrophil-lymphocyte-ratio (aHR, 2.8; P = 0.009), and > 2 metastatic sites (aHR, 2.13; P = 0.024) were associated with OS after adjusting for IMDC risk. Prior nephrectomy was not (aHR, 0.84; P = 0.62). A normal C-reactive protein was associated with an increased likelihood of CR (OR 7.2; P = 0.017). INTERPRETATION:Baseline blood markers and number of metastatic sites add prognostic value independently of IMDC risk in real-word mRCC patients treated with ipililmumab-nivolumab.

Renal cell carcinoma (RCC) is recognized as an immunogenic tumor, yet tumor-infiltrating lymphocytes often exhibit diminished effector function. However, the mechanisms underlying reduced T and NK cell activity in RCC remain unclear. Here, we examined the immune contexture in RCC patients undergoing nephrectomy to identify immune-related biomarkers associated with disease progression. Immune cell phenotypes and secretion profiles were assessed using flow cytometry and Luminex multiplex analysis. Supervised multivariate analysis revealed several changes of which frequencies of T and NK cells expressing CCR5, CXCR3, and PD-1 were elevated within tumors compared with peripheral blood. In addition, higher levels of regulatory T cells, PD-1+, and CXCR3+ T and NK cells were observed in patients with relapse following nephrectomy. With regards to soluble factors, tumor-derived CXCL8 was associated with higher Fuhrman grade and increased frequency of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). These biomarkers demonstrate potential relevance in the progression of RCC and merit further investigation in prospective studies.

Objectives:This study aimed to identify clinical and socioeconomic factors associated with treatment selection and survival in patients diagnosed with synchronous metastatic renal cell carcinoma (mRCC). Patients and Methods:The Renal Cell Cancer Database Sweden (RCCBaSe2.0), linking the National Swedish Kidney Cancer Register with other national quality registers, was used to identify all patients with synchronous mRCC diagnosed 1 January 2014-1 July 2019 (n = 951); thus, it was performed during the tyrosine kinase inhibitor era. Logistic and Cox regression were used to evaluate associations with treatment selection, overall survival (OS) and cancer-specific survival (CSS). Results:Upfront cytoreductive nephrectomy (uCN) was the primary treatment in 56% of patients and was associated with larger primaries and treatment at university hospitals. Immediate systemic treatment (IST) was chosen in 32% and associated with multidisciplinary team (MDT) discussions, cN1 disease, more metastatic sites and higher comorbidity index. Gender, income, education level or marital status were not associated with upfront treatment. Patients selected for uCN had longer OS and CSS compared with those allocated to IST. This association remained when adjusting for selection factors. Socioeconomic factors were not linked to survival. Limitations include the retrospective design and the lack of detailed data on the International mRCC Database Consortium risk factors. Conclusion:Tumour-related factors had significant effects on the choice to perform uCN or not. Patients with more advanced disease, higher comorbidity index and those discussed at MDT were more likely to be offered immediate systemic treatment. Socioeconomic status did not affect treatment allocation or survival, indicating equal healthcare access for Swedish mRCC patients.

One third of patients with clear cell renal cell carcinoma (CCRCC) eventually develop metastasis. The introduction of anti-angiogenic therapy and immunotherapy in metastatic CCRCC (mCCRCC) has significantly improved outcomes for many patients. Among vascular endothelial growth factor tyrosine kinase inhibitors (TKIs), sunitinib is the most commonly used first-line drug. However, treatment is administered without specific patient selection criteria and relapse occurs in approximately 40% of cases. Given the lack of clinical stratification of these patients, predictive and prognostic biomarkers are needed to improve their clinical outcome. This work explored the clinical impact of perivascular (PV) characteristics in RCC by performing multiplex-based tissue profiling in a population-based cohort (N = 70) and a sunitinib-treated mCCRCC cohort (N = 61). Vessel features and tumor PV cell subsets were characterized based on multimarker (CD34, PDGFRα, PDGFRβ, αSMA and pSMAD2) expression combinations. In both cohorts, patients were categorized using a tertile-based dichotomization of the variables, with the upper tertile compared against the combined lower and middle tertiles to explore associations. Two PV cell subsets, PER4 (PDGFRB+/ASMA+/PDGFRA-/pSMASD2-) and PER5 (PDGFRB+/ASMA-/PDGFRA-/pSMASD2-), showed statistically significant survival associations using multiple endpoints in both cohorts. In the sunitinib-treated cohort (OS from treatment), PER4 (log-rank p < 0.001) and PER5 (log-rank p = 0.002) were associated with poor survival. Similarly, in the population-based cohort (OS), PER4 (log-rank p = 0.043) and PER5 (log-rank p = 0.001) were also linked to worse survival. Univariate and multivariate analyses confirmed robust survival associations for the identified PV cell subsets PER4 and PER5. Collectively, this study identified candidate prognostic or TKI predictive response markers in RCC. These data provided in-depth characterization of PV cell subsets associated with clinical outcome in RCC. These data could be further explored to find clinically useful patient selection to improve the accuracy of anti-angiogenic therapy administration in RCC. Alfonso Martín-Bernabé, Víctor Sánchez-Miñarro, Philipp Schmucker, Magnus Lindskog, Ulrika Harmenberg, Martin Johansson, Lars Egevad, Arne Östman. Identification of outcome-associated tumor perivascular features in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3357.

Dear Editor, The activating receptor DNAX accessory molecule-1 (DNAM-1) plays an important role in T and natural killer (NK) cell-mediated cytotoxicity via the interaction with its ligands poliovirus receptor (PVR, CD155) and Nectin-2 (CD112). Compared with peripheral blood NK cells, tumor-infiltrating NK cells show reduced expression of DNAM-1 across several solid tumors, including ovarian and breast cancer resulting in impaired NK cell function. Early studies reported an inverse correlation between DNAM-1 expression and its ligands in leukemic blasts and ovarian cancer [1]. It was recently reported that engagement of the PVR results in reduced DNAM-1 expression in murine T cells [2]. In contrast to several other solid tumors, the frequency of tumor-infiltrating T cells is associated with poor prognosis in patients with renal cell carcinoma (RCC) [3]. Instead, high frequencies of NK cells have been associated with improved prognosis in RCC [4]. However, the underlying mechanisms that regulate NK cell activity in RCC are poorly understood. Here we explored the DNAM-1 – PVR axis in RCC and propose a strategy to maintain DNAM-1 expression in NK cells. Analysis of The Cancer Genome Atlas (TCGA) data revealed that high DNAM-1 expression is associated with increased overall survival and progression-free survival in patients with RCC. Conversely, high PVR expression is associated with a worse prognosis (Figure 1A and Supplementary Figure S1A). PVRhigh tumors showed increased neutrophil, M0 and M2 macrophage, and resting memory CD4 T cell signatures and reduced signatures for CD8 T cells, activated NK cells, gamma delta T cells and resting dendritic cells (Supplementary Figure S1B). The detailed methods are described in the Supplementary Materials. RCC tumors induce DNAM-1 downregulation on NK cells and attenuate their activity via PVR. (A) Overall survival in RCC patients stratified by high and low DNAM-1 or PVR expression. P values were calculated by log-rank test. (B) Frequencies of DNAM-1+ NK cells and mean fluorescence intensity (MFI) of NK cells in blood and tumor of RCC patients (n = 14 patients). (C) Inverse correlation of PVR expression on tumor tissue and frequencies of DNAM-1+ NK cells in RCC tumor tissue (Spearman correlation) (n = 14 patients). (D) Frequencies of DNAM-1+ NK cells after 2-day co-culture of NK cells and WT Caki-1 or PVR-KO Caki-1 cells (n = 7 biological replicates). Data are depicted as mean ± SD. Fold change in the frequency of DNAM-1+ NK cells between co-culture with WT and PVR-KO Caki-1 is 6.5. (E) Specific killing of WT Caki-1 target by tumor-experienced NK cells (n = 4 biological replicates). Data are depicted as mean ± SD. (F) t-distributed stochastic neighbor embedding (t-SNE) of different NK cell clusters origin in PBMC and tumor. (G) GO and KEGG pathway enrichment of different NK clusters. (H) Expression of CBLB on NK cells from different clusters in PBMC and tumor. (I) Frequencies of DNAM-1+ NK after co-culture with Caki-1 in the absence or presence of warfarin (n = 4 biological replicates). Abbreviations: RCC, renal cell carcinoma; DNAM-1, DNAX accessory molecule-1; NK, natural killer; PVR, poliovirus receptor; MFI, mean fluorescence intensity; WT, wild type; KO, knockout; eNK, experienced NK; t-SNE, t-distributed stochastic neighbor embedding; PBMC, peripheral blood mononuclear cell; GO, gene ontology; KEGG, Kyoto encyclopedia of genes and genomes; CBLB, Casitas B-Lineage Lymphoma Proto-Oncogene B. The expression of PVR has shown to be a negative prognostic marker in several cancers, including urothelial carcinoma, hepatocellular carcinoma, and head and neck squamous cell carcinoma. Although PVR is expressed in RCC, its prognostic value has not been well-studied in patients with RCC. Analysis of PVR expression levels in the TCGA RCC cohort (KIRC) revealed that PVR expression correlated with Fuhrman grade, where the highest expression of PVR was observed in Fuhrman grade 4 tumors (data not shown). Compared with peripheral blood, RCC-infiltrating T and NK cells showed reduced DNAM-1 expression (Figure 1B and Supplementary Figure S1C-D). The frequency of intratumoral DNAM-1+ NK and T cells negatively correlated with PVR expression levels in RCC tumors (Figure 1C and Supplementary Figure S1E-F). Collectively, these results suggest that PVRhigh tumors may evade the immune system by downregulating DNAM-1 on NK and T cells, thereby impacting the prognosis of RCC patients. To investigate if PVR expression by tumor cells influences DNAM-1 expression, peripheral blood mononuclear cells (PBMC) were cultured with RCC cell lines expressing different levels of PVR but at comparable expression of Nectin-2 (Supplementary Figure S2A). Upon co-culture, both the frequency of DNAM-1+ NK and T cells and the expression of DNAM-1 were significantly decreased. Notably, co-culture with Caki-1 cells expressing the highest level of PVR resulted in the strongest down-regulation of DNAM-1 (Supplementary Figure S2B). To confirm that reduced DNAM-1 expression on NK cells depends on PVR expression by tumor cells, PVR was knocked out (KO) with clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) in Caki-1 cells prior to co-culture with PBMC. Importantly, KO of PVR did not affect the expression of Nectin-2 and major histocompatibility complex (MHC) class I (Supplementary Figure S3A). Although DNAM-1 expression was significantly reduced in both T and NK cells upon culture with wild-type (WT) Caki-1 cells, a stronger reduction in DNAM-1 expression was observed in NK cells (Supplementary Figure S3B). In addition, purified NK cells showed significant downregulation of DNAM-1 after culture with WT but not PVR-KO Caki-1 cells (Figure 1D). Exposure to Caki-1 cell culture supernatant did not influence the expression of DNAM-1 in NK cells suggesting that the reduced expression of DNAM-1 might indeed depend on cell contact (data not shown). Similarly, Chauvin et al. [5] demonstrated that membrane-bound but not soluble PVR reduced DNAM-1 on NK cells. The expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) but not CD96 was also reduced upon culture with WT Caki-1 cells, though the effect was not as profound as for DNAM-1 (6.5-fold decrease for DNAM-1; 1.35-fold decrease for TIGIT) (Figure 1D and Supplementary Figure S3C-D). The expression of other NK cell receptors, including CD57, killer cell immunoglobulin-like receptors (KIRs), natural killer group 2 member A (NKG2A), NKG2C NKG2D and the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46, did not differ between cultures with WT or PVR-KO Caki-1 cells (Supplementary Figure S3C). In comparing the phenotype of DNAM-1+ and DNAM-1− NK cells upon co-culture with WT Caki-1 cells, DNAM-1− NK cells express lower levels of KIRs (KIR3DL1/KIR2DL2/ KIR2DL3), NKG2A, and CD96 (Supplementary Figure S4). In contrast, the expression of KIR2DL1/S1, NKG2C, NKG2D, NKp30, NKp44, NKp46, CD57, and TIGIT did not differ between DNAM-1+and DNAM-1− NK cells. Importantly, the reduced DNAM-1 expression upon exposure to WT but not PVR-KO Caki-1 cells significantly reduced NK cell-mediated cytotoxicity (Figure 1E and Supplementary Figure S5A). These findings demonstrate that RCC tumors downregulate DNAM-1 expression via PVR ligation and attenuate NK activity in vitro. A recent study showed that ligation of PVR results in the degradation of internalized DNAM-1 mediated by the E3 ubiquitin ligase Casitas B-Lineage Lymphoma Proto-Oncogene B (Cbl-b) in CD8+ T cells [2]. Analysis of the single-cell RNA sequencing dataset from peripheral blood and RCC tumors (Figure 1F) revealed that tumor-infiltrating NK cells (clusters 1 and 3) featured genes that are related to the ubiquitin processes, and peripheral blood NK cells (cluster 2) featured genes that are related to cytotoxicity (Figure 1G). Of note, CBLB was preferentially expressed in tumor-infiltrating NK cells compared with peripheral blood NK cells (Figure 1H), implying Cbl-b-mediated DNAM-1 degradation in NK cells in RCC tumors. The anticoagulant warfarin has been proposed to exert anti-metastatic activity by modulating the growth arrest-specific protein 6 (Gas6)/ Tyro3, Axl, and Mer (TAM)/Cbl-b pathway in NK cells [6]. Consistent with this study, we found that warfarin inhibited PVR-mediated downregulation of DNAM-1 in NK cells cultured with WT Caki-1 cells (Figure 1I), suggesting that DNAM-1 downregulation might be due to ubiquitin-mediated proteolysis. Since CBLB knockout or knockdown has been shown to increase NK cell cytotoxicity against tumor cells, targeting CBLB may be a potential way to enhance NK cell antitumor activities [7, 8]. Various cell populations within the tumor microenvironment can negatively impact NK cell activity. For instance, cancer-associated fibroblasts express PVR, which may influence the expression of DNAM-1 on NK cells [9]. Myeloid-derived suppressor cells (MDSC) display an array of immunosuppressive properties and have been shown to negatively affect overall survival in RCC patients [8]. Furthermore, MDSC can downregulate the expression of NKG2D on NK cells [10]. Herein, we found that the frequency of polymorphonuclear (PMN) MDSC negatively correlated with DNAM-1+ CD56dim NK cells but not total NK cells (Supplementary Figure S5B). In addition, the frequency of DNAM-1+ CD56dim NK cells negatively correlated with the frequency of Lin−CD11b+ myeloid cells, CD11b+ myeloid cells expressing cyclooxygenase-2 (COX-2+), arginase-1 (Arg-1+), and the expression level of inducible nitric oxide (iNOS) on CD11b+ myeloid cells (Supplementary Figure S5C). Collectively, these results suggest additional suppressive factors imposed by RCC are likely responsible for DNAM-1 downregulation in NK cells. The importance of DNAM-1 in T and NK cell cytotoxicity and tumor surveillance is well-established [1]. However, the high expression of DNAM-1 ligands in tumor cells may also represent an immune escape mechanism. Here, we show that DNAM-1 is downregulated in T but more profound in NK cells upon contact with PVR−positive tumors, resulting in attenuated NK-mediated killing of tumor cells. In support of this finding, analysis of TCGA data revealed that higher PVR expression is associated with a worse prognosis. In conclusion, the downregulation of DNAM-1 on NK cells via ligation of PVR provides a novel mechanism for escaping NK-mediated surveillance by RCC tumors. Designing research studies: Le Tong, Veronika Kremer, Shi Yong Neo, Ulrika Harmenberg, Eugenia Colón, Ann-Helén Scherman Plogell, Lisa Lei Liu, and Andreas Lundqvist. Conducting experiments: Le Tong, Veronika Kremer, Shi Yong Neo, Arnika Kathleen Wagner, Ziqing Chen, Ying Yang, and Christina Seitz. Acquiring data: Le Tong and Veronika Kremer. Analyzing data: Le Tong, Veronika Kremer, Shi Yong Neo, Yaxuan Liu, Yi Chen, Ziqing Chen, Christina Seitz, Nicholas Patrick Tobin, Maarten Alexander Ligtenberg, Xinsong Chen, and Felix Haglund. Providing reagents and materials: Evren Alici, Xinsong Chen, Barbara Seliger, Ulrika Harmenberg, Eugenia Colón, and Ann-Helén Scherman Plogell. Writing the manuscript: Le Tong, Veronika Kremer, Shi Yong Neo, Lisa Lei Liu, and Andreas Lundqvist. We thank Anna Malmerfelt, Department of Oncology-Pathology, Karolinska Institutet, for technical histological support. We thank Drs. Björn Önfelt and Valentina Carannante, Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, for intellectual input. No competing interests are related to this work. This work was supported by grants from The Swedish Cancer Society (#CAN 2018/451 and #21 1524 Pj), The Cancer Research Funds of Radiumhemmet (#161192, #181183, and #211253), The Swedish Society for Medical Research (P17-0134), and The Swedish Society of Medicine (SLS-960960). Not applicable The study was approved by the Regional Ethical Review Board in Stockholm (Ethical approval #2013-570-31). All patients provided informed consent. The data that support the findings of this study are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

Immune checkpoint inhibitors (ICIs) are associated with a wide range of immune-related adverse events. As oncological indications for ICIs widen, their rare side effects become increasingly visible in clinical practice and impact therapy decisions.Here, we report a rare case of early-onset, mild cytokine release syndrome (CRS) in a patient who received ICIs for a metastasized renal cell carcinoma, which led to treatment discontinuation.We further provide a systematic review of the literature of CRS and related life-threatening side effects of ICI treatment, such as hemophagocytic lymphohistiocytosis (HLH). We searched Medline, Embase and the Web of Science Core Collection from inception to October 2021 for reports on CRS, cytokine storm, macrophage activation syndrome, HLH, and related hyperinflammatory disorders in patients with solid cancers receiving ICIs. We found n=1866 articles, which were assessed for eligibility independently by two examiners. Of those, n=49 articles reporting on n=189 individuals were eligible for review. We found that the median time from last infusion to the occurrence of CRS/HLH was approximately nine days, while the onset of symptoms varied from immediately after infusion to one month after treatment. Most patients were treated with either corticosteroids or the anti-interleukin 6 (IL-6) antibody tocilizumab, and although the majority of patients recovered, a few cases were fatal. Concomitant IL-6 and ICI treatment were reported as beneficial for both the antitumoral effect and for limiting side effects. Data from international pharmacovigilance databases underscored that ICI-related CRS and HLH are rare events, but we identified significant differences in reported frequencies, which might suggest substantial under-reporting.The results from this first systematic review of CRS/HLH due to ICI therapy highlight that life-threatening systemic inflammatory complications of ICIs are rare and might be associated with fatal outcome in approximately 10% of patients. Limited data support the use of IL-6 inhibitors in combination with ICIs to augment the antitumoral effect and reduce hyperinflammation.

Abstract Objective To examine the association between surgical waiting times (SWTs) and all-cause mortality (ACM) in non-metastatic patients with RCC, in relation to tumour stage. Patients and methods This nation-wide population-based cohort study included 9,918 M0 RCC patients registered in the National Swedish Kidney Cancer Register, between 2009 and 2021, followed-up for ACM until 9 December 2021, and having measured SWTs. The associations between primarily SWTs from date of radiological diagnosis to date of surgery (WRS) and secondarily SWTs from date of radiological diagnosis to date of treatment decision (WRT) and date of treatment decision to date of surgery (WTS), in relation to ACM, were analysed using Cox regression analysis, adjusted for clinical and demographic characteristics, stratified and unstratified according to T-stage. Results During a mean follow-up time of 5 years (49,873 person-years), 23% (n = 2291) of the patients died. The adjusted hazard ratio (AHR) for WRS (months) for all patients was 1.03 (95% confidence interval [CI] = 1.02–1.04; p < 0.001). When subdividing WRS on T-stage, the AHRs were 1.03 (95% CI = 1.01–1.04; p < 0.001) and 1.05 (95% CI = 1.02–1.08; p = 0.003) for stages T1 and T3, respectively, while non-significant for T2 (p = 0.079) and T4 (p = 0.807). Similar results were obtained for WRT and WTS. Conclusions Prolonged SWTs significantly increased the risk of early overall death among patients with RCC. The increased risk of early death from any cause show the importance of shortening SWTs in clinical work of patients with this malignant disease.

Background: T1a renal cell carcinoma (RCC) is typically considered a curable disease, irrespective of the choice of local treatment modality. Objective: To identify factors associated with the risk of local and distant recurrence, and overall survival (OS) in patients with primary nonmetastatic clinical T1a RCC. Design, setting, and participants: A population-based nationwide register study of all 1935 patients with cT1a RCC, diagnosed during 2005–2012, identified through The National Swedish Kidney Cancer Register, was conducted. Outcome measurements and statistical analysis: Outcome variables were recurrence (local or distant) and OS. Possible explanatory variables included tumor size, RCC type, T stage, surgical technique, age, and gender. Associations with disease recurrence and OS were evaluated by multivariable regression and Cox multivariate analyses, respectively. Results and limitations: Among 1935 patients, 938 were treated with radical nephrectomy, 738 with partial nephrectomy, and 169 with ablative treatments, while 90 patients had no surgery. Seventy-eight (4%) patients were upstaged to pT3. Local or metastatic recurrences occurred in 145 (7.5%) patients, significantly more often after ablation (17.8%). The risk of recurrence was associated with tumor size, upstaging, and ablation. Larger tumor size, disease recurrence, and older age adversely affected OS, whereas partial nephrectomy and chromophobe RCC (chRCC) were associated with improved survival. Limitations include register design and a lack of comorbidity or performance status data. Conclusions: Upstaging and recurrence occurred, respectively, in 4.0% and 7.5% of patients with nonmetastatic RCCs ≤4 cm. Tumor size upstaging and ablation were associated with the risk for recurrence, while tumor size and recurrence were associated with decreased OS. Patients with chRCC and partial nephrectomy had prolonged OS in a real-world setting. Patient summary: We studied factors that may influence the risk of disease recurrence and overall survival, in a large nationwide patient cohort having nonmetastatic renal cell carcinoma ≤4 cm. Tumor size, tumor type, and treatment were associated with the risk of recurrence and overall death. Partial nephrectomy prolonged overall survival.

Renal cell carcinoma (RCC) is the most common type of kidney cancer and has the highest mortality rate among genitourinary cancers. Despite the advances in molecular targeted therapies to treat RCC, the inevitable emergence of resistance has delineated the need to uncover biomarkers to prospectively identify patient response to treatment and more accurately predict patient prognosis. Fringe is a fucose specific β1, 3N-acetylglucosaminyltransferase that modifies the Notch receptors. Given the link between its function and aberrant Notch activation in RCC, Fringe may be implicated in this disease. The Fringe homologs comprise of Lunatic fringe (LFng), Manic fringe (MFng) and Radical fringe (RFng). MFng has been reported to play a role in cancer. MFng is also essential in the development of B cells. However, the expression profile and clinical significance of MFng, and its association with B cells in RCC are unknown. CD20 is a clinically employed biomarker for B cells. This pilot study aimed to determine if MFng protein expression can be utilized as a prospective biomarker for therapeutics and prognosis in RCC, as well as to determine its association with CD20+ B cells. Analysis of publicly available MFng gene expression datasets on The Cancer Genome Atlas Netlwork (TCGA) identified MFng gene expression to be up-regulated in Kidney Clear Cell Renal Carcinoma (KIRC) patients. However there was no significant association between the patient survival probability and the level of MFng expression in this cohort. Immunohistochemistry performed on a tissue microarray containing cores from 64 patients revealed an elevated MFng protein expression in the epithelial and stromal tissues of RCC compared to the normal kidney, suggesting a possible role in tumorigenesis. Our study describes for the first time to our knowledge, the protein expression of MFng in the nuclear compartment of normal kidney and RCC, implicating a prospective involvement in gene transcription. At the cellular level, cytoplasmic MFng was also abundant in the normal kidney and RCC. However, MFng protein expression in the malignant epithelial and stromal tissue of RCC had no positive correlation with the patients' overall survival, progression-free survival and time to metastasis, as well as the gender, age, tumor stage and RCC subtype, indicating that MFng may not be an appropriate prognostic marker. The association between CD20+ B cells and epithelial MFng was found to approach borderline insignificance. Nonetheless, these preliminary findings may provide valuable information on the suitability of MFng as a potential therapeutic molecular marker for RCC, thus warrants further investigation using a larger cohort.

Renal cell carcinoma (RCC) treatment has improved in the last decade with the introduction of drugs targeting tumor angiogenesis. However, the 5-year survival of metastatic disease is still only 10-15%. Here, we explored the prognostic significance of compartment-specific expression of Neuropilin 1 (NRP1), a co-receptor for vascular endothelial growth factor (VEGF). NRP1 expression was analyzed in RCC tumor vessels, in perivascular tumor cells, and generally in the tumor cell compartment. Moreover, complex formation between NRP1 and the main VEGF receptor, VEGFR2, was determined. Two RCC tissue microarrays were used; a discovery cohort consisting of 64 patients and a validation cohort of 314 patients. VEGFR2/NRP1 complex formation in cis (on the same cell) and trans (between cells) configurations was determined by in situ proximity ligation assay (PLA), and NRP1 protein expression in three compartments (endothelial cells, perivascular tumor cells, and general tumor cell expression) was determined by immunofluorescent staining. Expression of NRP1 in perivascular tumor cells was explored as a marker for RCC survival in the two RCC cohorts. Results were further validated using a publicly available gene expression dataset of clear cell RCC (ccRCC). We found that VEGFR2/NRP1 trans complexes were detected in 75% of the patient samples. The presence of trans VEGFR2/NRP1 complexes or perivascular NRP1 expression was associated with a reduced tumor vessel density and size. When exploring NRP1 as a biomarker for RCC prognosis, perivascular NRP1 and general tumor cell NRP1 protein expression correlated with improved survival in the two independent cohorts, and significant results were obtained also at the mRNA level using the publicly available ccRCC gene expression dataset. Only perivascular NRP1 expression remained significant in multivariable analysis. Our work shows that perivascular NRP1 expression is an independent marker of improved survival in RCC patients, and reduces tumor vascularization by forming complexes in trans with VEGFR2 in the tumor endothelium. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Background Recently, the CARMENA and SURTIME studies, suggested that upfront cytoreductive nephrectomy (CN) should be abandoned for patients with intermediate and high-risk metastatic renal cell carcinoma (mRCC). However, CN remains an indication in low-risk and when immediate systemic treatment is not required. The aim was to evaluate the long-term overall survival (OS) in patients with primary mRCC, based on the first line treatment. Methods There were 1483 patients with primary mRCC in the National Kidney Cancer Registry from 2005 to 2013. Data on primary treatment, TNM stage, RCC type, tumor size, patient age and sex were extracted. Survival time was calculated from time of diagnosis to time of death or until July 2019. Mann-Whitney U and Chi-square tests, the Kaplan-Meyer method and Cox regression analyses were used. Results Patients primary treated with CN had a significantly longer OS (p < .001) than patients primary treated with systemic therapy or palliation. In a Cox regression multivariate analysis, the hazard ratio for CN compared with no CN was 1.600, 95%Ci (1.492 - 1.691),p < .001. Also occurrence of lymph node metastases, T-stage, patients age and year of diagnosis, remained as independent predictors of OS. Conclusion Patients primary treated with CN survived significantly longer than patients primary treated with systemic therapy or palliation, in all age groups. CN was an important first-line treatment option in mRCC patients.

Introduction The effects of single-fraction gamma knife radiosurgery (sf-GKRS) on patients with renal cell carcinoma (RCC) brain metastases (BM) in the era of targeted agents (TA) and immune checkpoint inhibitors (ICI) are insufficiently studied. Methods and materials Clear cell metastatic RCC patients treated with sf-GKRS due to BM in 2005-2014 at three European centres were retrospectively analysed (n= 43). Median follow-up was 56 months. Ninety-five percent had prior nephrectomy, 53% synchronous metastasis and 86% extracranial disease at first sf-GKRS. Karnofsky performance status (KPS) ranged from 60 to 100%. Outcome measures were overall survival (OS), local control (LC) and adverse radiation effects (ARE). Results One hundred and ninety-four targets were irradiated. The median number of targets at first sf-GKRS was two. The median prescription dose was 22.0 Gy. Thirty-seven percent had repeated sf-GKRS. Eighty-eight percent received TA. LC rates at 12 and 18 months were 97% and 90%. Median OS from the first sf-GKRS was 15.7 months. Low serum albumin (HR for death 5.3), corticosteroid use pre-sf-GKRS (HR for death 5.8) and KPS < 80 (HR for death 9.1) were independently associated with worse OS. No further prognostic information was gleaned from MSKCC risk group, synchronous metastasis, age, number of BM or extracranial metastases. Other prognostic scores for BM radiosurgery, including DS-GPA, renal-GPA, LLV-SIR and CITV-SIR, again, did not add further prognostic value. ARE were seldom symptomatic and were associated with tumour volume, 10-Gy volume and pre-treatment perifocal oedema. ARE were less common among patients treated with TA within 1 month of sf-GKRS. Conclusions We identified albumin, corticosteroid use and KPS as independent prognostic factors for sf-GKRS of clear cell RCC BM. Studies focusing on the prognostic significance of albumin in sf-GKRS are rare. Further studies with a larger number of patients are warranted to confirm the above analytical outcome. Also, in keeping with previous studies, our data showed optimal rates of local tumour control and limited toxicity post radiosurgery, rendering GKRS the tool of choice in the management of RCC BM.

Background:The long-term benefits of local therapy in metastatic renal cell carcinoma (mRCC) have been widely documented. In this context, single fraction gamma knife radiosurgery (SF-GKRS) is routinely used in the management of brain metastases. However, SF-GKRS is not always feasible due to volumetric and regional constraints. We intend to illustrate how a dose-volume adaptive hypofractionated GKRS technique based on two concurrent dose prescriptions termed rapid rescue radiosurgery (RRR) can be utilized in this particular scenario.Case Description:A 56-year-old man presented with left-sided hemiparesis; the imaging showed a 13.1 cc brain metastasis in the right central sulcus (Met 1). Further investigation confirmed the histology to be a metastatic clear cell RCC. Met 1 was treated with upfront RRR. Follow-up magnetic resonance imaging (MRI) at 10 months showed further volume regression of Met 1; however, concurrently, a new 17.3 cc lesion was reported in the boundaries of the left frontotemporal region (Met 2) as well as a small metastasis (<1 cc) in the left temporal lobe (Met 3). Met 2 and Met 3 underwent RRR and SF-GKRS, respectively.Results:Gradual and sustained tumor ablation of Met 1 and Met 2 was demonstrated on a 20 months long follow- up. The patient succumbed to extracranial disease 21 months after the treatment of Met 1 without evidence of neurological impairment post-RRR.Conclusion:Despite poor prognosis and precluding clinical factors (failing systemic treatment, eloquent location, and radioresistant histology), RRR provided optimal tumor ablation and salvage of neurofunction with limited toxicity throughout follow-up.

Introduction: In 2005, the National Swedish Kidney Cancer Register (NSKCR) was set up to collect data on newly diagnosed patients with renal cell carcinoma (RCC). In 2015, the NSKCR was linked to a number of national healthcare and demographic registers to construct the Renal Cell Cancer Database Sweden (RCCBaSe). The aim was to facilitate research on trends in incidence, effects of treatment and survival, with detailed data on tumour characteristics, treatment, pharmaceutical prescriptions, socioeconomic factors and comorbidity.Material and methods: All patients registered in the NSKCR between 2005 and 2014 were included. For each case, ten controls and first-degree relatives for cases and controls were identified. The RCCBaSe was created linking all cases, controls and first-degree relatives to a number of national registers with information on co-morbidity, socioeconomic factors and pharmaceutical prescriptions.Results: Between 2005 and 2014, a total of 9,416 patients with RCC were reported to the NSKCR. 94,159 controls and a total cohort of 575,007 individuals including cases, controls and first-degree relatives were identified. Linkage to the Swedish cancer register resulted in 106,772 matches. When linked to the National patient register, 432,677 out-patient and 471,359 in-patient matches were generated. When linked to the Swedish renal registry 1,778 matches were generated. Linkage to the Prescribed drug register resulted in 448,084 matches and linkage to the The Longitudinal integration database for health insurance and labour market studies database resulted in 450,017 matches.Conclusion: By linking the NSKCR to several Swedish national databases, a unique database for RCC research has been created.

Background: Metastatic papillary renal cell carcinoma (mPRCC) is understudied. The disease is often aggressive and specific treatment options are lacking.Patients and methods: mPRCC patients (n=86) referred to three academic centres in Sweden and Germany in the years 2005-2015 were retrospectively identified from medical records. Statistical analyses included Kaplan-Meier curves and calculation of Cox proportional hazards, generating hazard ratios with 95% confidence intervals. The aim of the study was to evaluate overall survival (OS) of mPRCC patients treated outside of clinical trials in the era of targeted agents (TA) and to identify clinically useful prognostic factors.Results: Median OS of all mPRCC patients was 11.2 months. TA were used in 77% of the patients and associated with younger age and better Eastern Cooperative Oncology Group performance status (PS). Brain metastases were common (28%). Patients with synchronous or metachronous metastases had similar OS. Variables independently associated with risk of death included age 60 years, worse PS and 3 metastatic sites. The MSKCC criteria did not provide additional prognostic information. A subgroup analysis of TA-treated patients revealed an association of lymph node metastasis with risk of death in addition to the other prognostic factors.Conclusion: OS in mPRCC remained short in the era of targeted agents. Age, PS, and number of metastatic sites provided independent prognostic information.

OBJECTIVE:To explore cost-effectiveness of targeted therapies (TTs) in the treatment of metastatic renal cell carcinoma (mRCC) in a real-world context using a nationwide population-based approach.METHODS:Data on patients diagnosed with mRCC between 2002 and 2012 were extracted from Swedish national health data registers. To facilitate comparisons of patients diagnosed before and after TT introduction to the market, three cohorts were derived: pre-TT introduction (preTT), patients diagnosed 2002-2005; early TT introduction (TTi), patients diagnosed 2006-2008; and late TT introduction (TTii), which was limited to patients diagnosed 2009-2010 to ensure availability of total health care resource utilization (HCRU) data. Patients were followed until end of 2012. The value of TTs across cohorts was estimated using mean HCRU costs per life-year (LY) gained. Data on HCRU were obtained through national health registers for dispensed medication and inpatient and outpatient care, and the associated costs were estimated using the Lin method to account for censoring. LYs gained were defined as the difference in mean survival over the study period.RESULTS:The preTT, TTi, and TTii cohorts consisted of 1,366, 1,158, and 806 patients, respectively. Mean survival in years from mRCC diagnosis was 1.45 in the preTT cohort, 1.62 in the TTi cohort, and 1.83 in the TTii cohort. The respective mean total HCRU cost per patient over the study period was US$16,894, US$29,922, and US$30,037. The cost per LY gained per cohort was US$78,656 for TTi vs preTT, US$34,132 for TTii vs preTT, and US$523 for TTii vs TTi.CONCLUSION:Given common willingness-to-pay per LY gained thresholds, this study in a real-world population suggests the use of TTs in the Swedish mRCC population is increasingly cost-effective over time.

Background The role of B-lymphocytes in solid tumours is unclear. Tumour biology studies have implied both anti- and pro-tumoural effects and prognostic studies have mainly linked B-cells to increased survival. This study aimed to analyse the clinical relevance of B-lymphocytes in renal cell cancer (RCC), where information on the prognostic impact is lacking. Methods Following immunohistochemistry (IHC) stainings with a CD20 antibody, density of CD20+ B-cells was quantified in an RCC discovery- and validation cohort. Associations of B-cell infiltration, determined by CD20 expression or a B-cell gene-signature, and survival was also analysed in 14 publicly available gene expression datasets of cancer, including the kidney clear cell carcinoma (KIRC) dataset. Results IHC analyses of the discovery cohort identified a previously unrecognised subgroup of RCC patients with high infiltration of CD20+ B-cells. The B-cell-high subgroup displayed significantly shorter survival according to uni- and multi-variable analyses. The association between poor prognosis and high density of CD20+ B-cells was confirmed in the validation cohort. Analyses of the KIRC gene expression dataset using the B-cell signature confirmed findings from IHC analyses. Analyses of other gene expression datasets, representing 13 different tumour types, indicated that the poor survival-association of B-cells occurred selectively in RCC. Conclusion This exploratory study identifies a previously unrecognised poor-prognosis subset of RCC with high density of CD20-defined B-cells.

Background and purpose Investigate effects of stereotactic radiotherapy (SRT) or surgical metastasectomy (SM) on overall survival (OS) in metastatic renal cell carcinoma (mRCC) in the era of targeted agents (TA). Material and methods mRCC patients (n = 117) treated with SRT (n = 57), SM (n = 30) or both modalities sequentially (n = 30) at two oncological centres in Sweden in 2005–2014 were retrospectively included. Median follow-up (mFU) was 63 months. Results A majority had clear cell histology, 1–3 metastases, and ECOG performance status of 0 or 1. Two thirds had intermediate or poor risk and 44% synchronous metastases. 65% received TA. SRT patients were more likely to have adverse risk profiles. Median OS was 51 months without significant differences between SRT and SM. ECOG 1 vs 0 (HR 2.9; CI 1.6–5.2; p < 0.001), intracranial targets (HR 1.8; CI 1.1–3.2; p = 0.03) and watchful waiting >18 months prior to treatment (HR 0.3; CI 0.2–0.6; p = 0.001) were independently associated with OS. 15% of curatively treated patients (n = 60) were relapse-free with mFU of 87 months. Conclusions OS after SRT was comparable to SM and longer than expected considering patients with adverse risk profiles were common. Fit patients with non-brain metastases treated after an initial period of watchful waiting had the best prognosis.

Background: Response patterns to nivolumab differ from those seen with other approved targeted therapies.Objective: To investigate the efficacy of nivolumab in previously treated patients with advanced renal cell carcinoma who were treated beyond (Response Evaluation Criteria In Solid Tumors) RECIST progression.Design, setting, and participants: This was a subgroup analysis of patients treated with nivolumab in the phase 3 CheckMate 025 study. Patients continuing to tolerate therapy and exhibiting investigator-assessed clinical benefit were eligible to be treated beyond RECIST progression (TBP) and received therapy for >= 4 wk after first progression; patients not treated beyond RECIST progression (NTBP) received 0 wk to <4 wk of therapy after progression.Interventions: Nivolumab 3 mg/kg intravenously every 2 wk.Results and limitations: Of 406 nivolumab-treated patients, 316 (78%) progressed by RECIST criteria. Of those who progressed, 48% were TBP, 52% were NTBP. Before being TBP, objective response rate (95% confidence interval) was 20% (14-28) and 14% (9-21) in patients TBP and NTBP, respectively. Differences in clinical characteristics assessed at first progression between patients TBP versus NTBP included better Karnofsky performance status, less deterioration in Karnofsky performance status, shorter time to response, lower incidence of new bone lesions, and improved quality of life. Postprogression, 13% of all patients TBP (20/153) had >= 30% tumor burden reduction including patients with preprogression and postprogression tumor measurements (n = 142) and complete/partial response (28%, 8/29), stable disease (6%, 3/47), and progressive disease (14%, 9/66) as their best response before being TBP. Incidence of treatment-related adverse events in patients TBP was lower after (59%) versus before (71%) progression. Limitations included potential bias from the nonrandomized nature of the analysis.Conclusions: A subset of patients with advanced renal cell carcinoma and RECIST progression experienced tumor reduction postprogression with nivolumab, and had an acceptable safety profile. Clinical judgment remains essential when switching therapy. ClinicalTrials.gov Identifier: NCT01668784.Patient summary: A subset of patients with advanced renal cell carcinoma and disease progression may continue to benefit from nivolumab treatment beyond progression as evidenced by tumor reduction postprogression and an acceptable safety profile. (C) 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Regulatory T cells (Treg) suppress anti-tumor immune responses and their infiltration in the tumor microenvironment is associated with inferior prognosis in cancer patients. Thus, in order to enhance anti-tumor immune responses, selective depletion of Treg is highly desired. We found that treatment with zoledronic acid (ZA) resulted in a selective decrease in the frequency of Treg that was associated with a significant increase in proliferation of T cells and natural killer (NK) cells in peripheral blood of patients with metastatic cancer. In vitro, genome-wide transcriptomic analysis revealed alterations in calcium signaling pathways in Treg following treatment with ZA. Furthermore, co-localization of the nuclear factor of activated T cells (NFAT) and forkhead box P3 (FOXP3) was significantly reduced in Treg upon ZA-treatment. Consequently, reduced expression levels of CD25, STAT5 and TGFβ were observed. Functionally, ZA-treated Treg had reduced capacity to suppress T and NK cell proliferation and anti-tumor responses compared with untreated Treg in vitro. Treatment with ZA to selectively inhibit essential signaling pathways in Treg resulting in reduced capacity to suppress effector T and NK cell responses represents a novel approach to inhibit Treg activity in patients with cancer.