Evolution of cell therapy for renal cell carcinoma.

Treatment for renal cell carcinoma (RCC) has improved dramatically over the last decade, shifting from high-dose cytokine therapy in combination with surgical resection of tumors to targeted therapy, immunotherapy, and combination therapies. However, curative treatment, particularly for advanced-stage disease, remains rare. Cell therapy as a "living drug" has achieved hematological malignancy cures with a high response rate, and significant research efforts have been made to facilitate its translation to solid tumors. Herein, we overview the cellular therapies for RCC focusing on allogeneic hematopoietic stem cell transplantation, T cell receptor gene-modified T cells, chimeric antigen receptor (CAR) T cells, CAR natural killer (NK) cells, lymphokine-activated killer (LAK) cells, γδ T cells, and dendritic cell vaccination. We have also included perspectives for using other recent approaches, such as CAR macrophages, dendritic cell-cytokine induced killer cells and regulatory CAR-T cells to shed light on preclinical development of cell therapy and advancing cell therapy into clinic to achieve cures for RCC.

The effect of timing between preoperative embolization and surgery: A retrospective analysis of hypervascular bone metastases.

BACKGROUND AND OBJECTIVES: The optimal timing between preoperative embolization of hypervascular metastatic bone lesions and surgery has yet to be established. Our analysis sought to evaluate embolization timing impacts blood loss, transfusion risk, and operative time in patients with hypervascular primary tumors. METHODS: We identified patients with renal cell (RCC) or thyroid carcinoma undergoing surgery between 1992 and 2023. Patients were segregated into the following cohorts: (1) no embolization preoperatively, (2) surgery <24 h of embolization, and (3) surgery >24 h after embolization. Multivariate logistic regression analyses were performed to assess the effect of embolization timing while controlling for confounding variables. RESULTS: No differences were seen in all evaluated outcomes between immediate and delayed embolization cohorts. No differences in estimated blood loss were seen between the immediate (OR: 0.685, 95% CI: 0.159-2.949; p = 0.611) and delayed (OR: 0.568, 95% CI: 0.093-3.462; p = 0.539) surgery cohorts compared with patients without embolization. Surgery >24 h after embolization was not associated with a higher risk of prolonged operative time (OR: 13.499, 95% CI: 0.832-219.146; p = 0.067). CONCLUSIONS: These findings suggest that surgery may be safely delayed beyond 24 h from embolization without a higher risk of bleeding. In appropriately selected cohorts, embolization may not be needed preoperatively.

Pathology of hereditary renal cell carcinoma syndromes: Tuberous sclerosis complex (TSC).

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomatous tumors involving multiple organs such as the brain, skin, heart, lung and kidney. TSC is caused by inactivating mutations in TSC1/TSC2, which encodes hamartin and tuberin, respectively, and forms a complex that regulates mechanistic target of rapamycin complex 1 (mTORC1), resulting in cell overgrowth and oncogenesis. Since a leading cause of morbidity and mortality in TSC relates to chronic kidney disease and the ability to preserve renal function, this review describes the important pathologic findings in TSC-associated renal neoplasms and their correlating sporadic counterparts. The most common renal tumor in TSC patients are AMLs, followed by a heterogeneous spectrum of renal epithelial tumors, which may provide clues to establishing a diagnosis of TSC.

Integrated analysis identifies microRNA-188-5p as a suppressor of AKT/mTOR pathway in renal cancer.

Many current microRNA (miRNA) expression datasets for renal cell carcinoma (RCC) often show inconsistent analysis results, so a shift to comprehensive analysis of multiple datasets can effectively accelerate molecular screening for precision medicine and translational medicine research. MicroRNA (miR)-188-5p is a clinically noteworthy miRNA whose aberrant expression was previously observed in a variety of cancers, but its role in RCC is unclear. In this study, we undertook a comprehensive analysis of four RCC miRNA expression datasets and validated the results using The Cancer Genome Atlas (TCGA) dataset and a cohort of collected clinical samples. Fifteen miRNAs were identified as potential diagnostic markers by the analysis of four RCC miRNAs datasets. Analysis of the TCGA kidney renal clear cell carcinoma dataset showed significantly shorter survival in RCC patients with reduced miR-188-5p expression levels, and our collection of RCC clinical samples showed low miR-188-5p expression in the tumors. Overexpression of miR-188-5p in Caki-1 and 786-O cells inhibited cell growth, colony formation, invasion, and migration. In contrast, miR-188-5p inhibitors reversed these cell phenotypes. We identified a binding site for miR-188-5p in the 3'-UTR region of myristoylated alanine-rich C-kinase substrate (MARCKS) mRNA and demonstrated an interaction between these two molecules. Quantitative RT-PCR and western blot analysis revealed that miR-188-5p could regulate the AKT/mTOR signaling pathway through MARCKS. Mouse transplantation tumor assay indicated that miR-188-5p reduced the tumorigenicity of RCC in vivo. MicroRNA-188-5p could be a valuable new molecule for RCC diagnosis and prognosis.

Creatinine to Cystatin-C Ratio in Renal Cell Carcinoma: A Clinically Pragmatic Prognostic Factor and Sarcopenia Biomarker.

INTRODUCTION: Low creatinine to cystatin-C ratio (Cr/Cys-C) may be a biomarker for low-muscle mass. Furthermore, low Cr/Cys-C is associated with decreased overall survival (OS), but to date, has not been examined in patients with renal cell carcinoma (RCC). Our objective is to evaluate associations between low Cr/Cys-C ratio and OS and recurrence-free survival (RFS) in patients with RCC treated with nephrectomy. METHODS: We performed a retrospective review of patients with RCC treated with nephrectomy. Patients with end-stage renal disease and less than 1-year follow up were excluded. Cr/Cys-C was dichotomized at the median for the cohort (low vs. high). OS and RFS for patients with high versus low Cr/Cys-C were estimated with the Kaplan-Meier method, and associations with the outcomes of interest were modeled using Cox proportional Hazards models. Associations between Cr/Cys-C and skeletal muscle mass were assessed with correlations and logistic regression. RESULTS: A total of 255 patients were analyzed, with a median age of 64. Median (IQR) Cr/Cys-C was 1 (0.8-1.2). Low Cr/Cys-C was associated with age, female sex, Eastern Cooperative Oncology Group Performance Status ≥1, TNM stage, and tumor size. Kaplan-Meier and Cox regression analysis demonstrated an association between low Cr/Cys-C and decreased OS (HR = 2.97, 95%CI, 1.12-7.90, P =0.029) and RFS (HR = 3.31, 95%CI, 1.26-8.66, P = .015). Furthermore, a low Cr/Cys-C indicated a 2-3 increase in risk of radiographic sarcopenia. CONCLUSIONS: Lower Cr/Cys-C is associated with inferior oncologic outcomes in RCC and, pending validation, may have utility as a serum biomarker for the presence of sarcopenia in patients with RCC treated with nephrectomy.

Imaging Techniques to Determine Degree of Sarcopenia and Systemic Inflammation in Advanced Renal Cell Carcinoma.

PURPOSE OF REVIEW: The purpose of this review is to provide an up-to-date understanding regarding the literature on sarcopenia and inflammation as prognostic factors in the context of renal cell carcinoma (RCC). RECENT FINDINGS: Sarcopenia is increasingly recognized as a prognostic factor in RCC. Emerging literature suggests monitoring quantity of muscle on successive imaging and examining muscle density may be additionally informative. Inflammation has prognostic ability in RCC and is also considered a key contributor to development and progression of both RCC and sarcopenia. Recent studies suggest these two prognostic factors together may provide additional prognostic ability when used in combination. Ongoing developments include quality control regarding sarcopenia research and imaging, improving understanding of muscle loss mechanisms, and enhancing clinical incorporation of sarcopenia via improving imaging analysis practicality (i.e., artificial intelligence) and feasible biomarkers. Sarcopenia and systemic inflammation are complementary prognostic factors for adverse outcomes in patients with RCC. Further study on high-quality sarcopenia assessment standardization and expedited sarcopenia assessment is desired for eventual routine clinical incorporation of these prognostic factors.

Oncologic and perioperative outcomes of laparoscopic versus open radical nephrectomy for the treatment of renal tumor (> 7 cm): a systematic review and pooled analysis of comparative outcomes.

OBJECTIVE: Systematic evaluation of the effectiveness and safety of laparoscopic radical nephrectomy (LRN) for renal tumor (>7 cm). METHODS: The databases PubMed, Scopus, SinoMed, ScienceDirect, and Google Scholar were systematically searched for trials up to November 2022. The pooled results were evaluated by weighted mean difference (WMD), odds ratio (OR), and hazard ratio (HR). RESULTS: This meta-analysis (18 trials) demonstrated that compared to open radical nephrectomy (ORN), LRN had a longer operative time (OT) (WMD=15.99, 95% CI: 6.74 to 25.24, p = 0.0007), lower estimated blood loss (EBL) (WMD = -237.07, 95% CI: -300.02 to -174.12, p < 0.00001), lower transfusion rates (OR = 0.37, 95% CI: 0.24 to 0.55, p < 0.00001), and shorter length of stay (LOS) (WMD = -2.95, 95% CI: -3.86 to -2.03, p < 0.00001). No statistically relevant differences were found in overall survival (OS) (HR = 1.04, 95% CI: 0.81 to 1.35, p = 0.76), cancer-specific survival (CSS) (HR = 1.28, 95% CI: 0.97 to 1.68, p = 0.08), progression-free survival (PFS) (HR = 1.20, 95% CI 0.97 to 1.48, p = 0.1), recurrence-free survival (RFS) (OR = 1.27, 95% CI: 0.89 to 1.81, p = 0.56), local recurrence rate (OR = 0.85, 95% CI: 0.42 to 1.71, p = 0.65), and intraoperative and postoperative complications. CONCLUSION: For patients with renal tumors (> 7 cm), LRN has specific perioperative advantages over ORN (LOS, EBL, and transfusion rates). However, the OT was prolonged in the LRN group. In addition, no differences in complication or oncological outcomes (OS, CSS, PFS, RFS, and local recurrence rate) were reported. TRIAL REGISTRATION: PROSPERO CRD42022367114.

Endoplasmic Reticulum Stress in Renal Cell Carcinoma.

The endoplasmic reticulum is an organelle exerting crucial functions in protein production, metabolism homeostasis and cell signaling. Endoplasmic reticulum stress occurs when cells are damaged and the capacity of this organelle to perform its normal functions is reduced. Subsequently, specific signaling cascades, together forming the so-called unfolded protein response, are activated and deeply impact cell fate. In normal renal cells, these molecular pathways strive to either resolve cell injury or activate cell death, depending on the extent of cell damage. Therefore, the activation of the endoplasmic reticulum stress pathway was suggested as an interesting therapeutic strategy for pathologies such as cancer. However, renal cancer cells are known to hijack these stress mechanisms and exploit them to their advantage in order to promote their survival through rewiring of their metabolism, activation of oxidative stress responses, autophagy, inhibition of apoptosis and senescence. Recent data strongly suggest that a certain threshold of endoplasmic reticulum stress activation needs to be attained in cancer cells in order to shift endoplasmic reticulum stress responses from a pro-survival to a pro-apoptotic outcome. Several endoplasmic reticulum stress pharmacological modulators of interest for therapeutic purposes are already available, but only a handful were tested in the case of renal carcinoma, and their effects in an in vivo setting remain poorly known. This review discusses the relevance of endoplasmic reticulum stress activation or suppression in renal cancer cell progression and the therapeutic potential of targeting this cellular process for this cancer.

Diagnostic Utility of EMA, Vimentin and CD117 Immunohistochemical Markers in Subtyping Renal Cell Carcinoma in a Nigerian Tertiary Hospital: A 10-year Retrospective Study.

BACKGROUND: Renal cell carcinoma is the most lethal urological cancer and contributes significantly to morbidity and mortality due to cancers of the urogenital tract. In routine diagnostic surgical pathology practice of renal tumours, immunohistochemistry is a helpful ancillary technique after routine H & E. The role of renal immunohistochemistry is explored in this study. MATERIALS AND METHODS: The paraffin-embedded tissue blocks of all the confirmed cases of renal cell carcinoma seen at the University College Hospital (UCH), Ibadan, during the 10-year study period of 2007 to 2016 were retrieved, sectioned and immunohistochemistry done using monoclonal antibodies for EMA, Vimentin and CD117 following standard protocols. Frequency statistics and chi-square were applied to data to determine proportions and associations using the Statistical Package for the Social Sciences (SPSS) version 23. RESULTS: A total of 48 cases of renal cell carcinoma were seen within the study period that met the inclusion criteria for the study. The age range of the patients was between 3 to 76 years with an average age of 44.17 years. The male-to-female ratio was 1:1.3. Fuhrman Grade 2 nuclei were predominant (43.75%) while Fuhrman Grade 4 nuclei had the lowest frequency (6.25%). EMAstaining patterns for the different histological patterns of RCC showed no statistically significant difference while Vimentin and CD117 staining patterns showed a statistically significant difference. There was no statistically significant difference observed between the staining patterns of all three markers and the nuclear grades of the cases of RCC. CONCLUSION: This study demonstrated the usefulness of Vimentin and CD117 in differentiating chromophobe variant of renal cell carcinoma from other subtypes while EMA showed variable expression across the various subtypes.

CONTEXTE: Le carcinome à cellules rénales est le cancer urologique le plus mortel et contribue de manière significative à la morbidité et à la mortalité liées aux cancers du tractus urogénital. Dans la pratique courante de la pathologie chirurgicale diagnostique des tumeurs rénales, l'immunohistochimie est une technique auxiliaire utile après la coloration H & E (hématoxyline et éosine). Le rôle de l'immunohistochimie rénale est exploré dans cette étude. MATÉRIEL ET MÉTHODES: Les blocs de tissus inclus en paraffine de tous les cas confirmés de carcinome à cellules rénales observés à l'hôpital universitaire du collège (UCH) d'Ibadan, au cours de la période d'étude de 10 ans de 2007 à 2016, ont été récupérés, sectionnés et soumis à une immunohistochimie en utilisant des anticorps monoclonaux dirigés contre l'EMA, la vimentine et le CD117 suivant des protocoles standard.Des statistiques de fréquence et le test du chi-carré ont été appliqués aux données pour déterminer les proportions et les associations à l'aide du logiciel Statistical Package for the Social Sciences (SPSS) version 23. RÉSULTATS: Au cours de la période d'étude, un total de 48 cas de carcinome à cellules rénales répondant aux critères d'inclusion de l'étude ont été observés. L'âge des patients variait de 3 à 76 ans, avec un âge moyen de 44,17 ans. Le ratio hommes-femmes était de 1:1,3. Les noyaux de grade Fuhrman 2 étaient prédominants (43,75 %), tandis que les noyaux de grade Fuhrman 4 présentaient la fréquence la plus basse (6,25 %). Les schémas de coloration de l'EMA pour les différentes variantes histologiques du RCC n'ont montré aucune différence statistiquement significative, tandis que les schémas de coloration de la vimentine et du CD117 ont montré une différence statistiquement significative. Aucune différence statistiquement significative n'a été observée entre les schémas de coloration des trois marqueurs et les grades nucléaires des cas de RCC. CONCLUSION: Cette étude a démontré l'utilité de la vimentine et du CD117 pour différencier la variante chromophobe du carcinome à cellules rénales des autres sous-types, tandis que l'EMA a montré une expression variable dans les différents sous-types. Mots-clés: Carcinome à cellules rénales (CCR), antigène membranaire épithélial (EMA), vimentine, C-Kit (tyrosine kinase, CD 117), hématoxyline et éosine (H & E).

The landscape of miRNA-related ceRNA networks for marking different renal cell carcinoma subtypes.

We know that different types of cancers usually have different responses to the same treatment. Therefore, it is important to understand the similarities and differences across subtypes of cancers, so as to provide a basis for the individualized treatments. Until now, no comprehensive investigation on competing endogenous RNAs (ceRNAs) has been reported for the three main subtypes of renal cell carcinoma (RCC), so the regulation characteristics of ceRNAs in three subtypes are not well revealed. This paper firstly describes a comparative analysis of ceRNA-ceRNA interaction networks for all the three subtypes of RCC based on differential microRNAs (miRNAs). We comprehensively summarized all miRNA and messenger RNAdata of RCC from 126 matched tumor-normal tissues in The Cancer Genome Atlas, systematically analyzed a total of more than 80 000 ceRNA interactions and highlighted the common and specific properties among them, aiming to identify critical genes to classify them for providing supplementary help in the precise diagnosis of RCC. From three aspects, including common or specific ceRNAs, upregulated or downregulated and classifications across the three subtypes, we highlighted the common and specific properties for the three subtypes and also explored the classification of RCC by combining the specific ceRNAs with differential regulations. Moreover, for the most major subtype of clear cell renal cell carcinoma (KIRC), three critical genes were screened out from KIRC ceRNA network and further demonstrated to be the potential biomarkers of KIRC by performing biological experiments at the transcriptional level.

Cancer Risk and Mortality in Patients With Kidney Disease: A Population-Based Cohort Study.

RATIONALE & OBJECTIVE: Patients with chronic kidney disease (CKD) may be at increased risk for cancer. CKD may also be associated with worse cancer outcomes. This study examined cancer incidence and mortality across the spectrum of CKD. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: All adult Ontario residents with data on estimated glomerular filtration rate (eGFR) or who were receiving maintenance dialysis or had received a kidney transplant (2007-2016). EXPOSURE: Patients were categorized as of the first date they had 2 eGFR assessments or were registered as receiving maintenance dialysis or having received a kidney transplant. eGFR levels were further categorized as ≥60, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2; the latter 4 groups are consistent with KDIGO (Kidney Disease: Improving Global Outcomes) CKD categories G3a, G3b, G4, and G5, respectively. OUTCOMES: Overall and site-specific cancer incidence and mortality. ANALYTICAL APPROACH: Fine and Gray subdistribution hazard models. RESULTS: Among 5,882,388 individuals with eGFR data, 29,809 receiving dialysis, and 4,951 having received a kidney transplant, there were 325,895 cancer diagnoses made during 29,993,847 person-years of follow-up. The cumulative incidence of cancer ranged between 10.8% and 15.3% in patients with kidney disease. Compared with patients with eGFR ≥60 mL/min/1.73 m2, adjusted hazard ratios (AHRs) for a cancer diagnosis among patients with CKD G3a, G3b, G4, and G5 were 1.08 (95% CI, 1.07-1.10), 0.99 (95% CI, 0.97-1.01), 0.85 (95% CI, 0.81-0.88), and 0.81 (95% CI, 0.73-0.90), respectively. The AHRs for patients receiving dialysis and who had received a transplant were 1.01 (95% CI, 0.96-1.07) and 1.25 (95% CI, 1.12-1.39), respectively. Patients with kidney disease had higher proportions of stage 4 cancers at diagnosis. Patients with CKD G3a, G3b, and G4 and transplant recipients had increased risks of cancer-specific mortality (AHRs of 1.27 [95% CI, 1.23-1.32], 1.29 [95% CI, 1.24-1.35], 1.25 [95% CI, 1.18-1.33], and 1.48 [95% CI, 1.18-1.87], respectively). The risks of bladder and kidney cancers and multiple myeloma were particularly increased in CKD, and mortality from these malignancies increased with worsening kidney function. LIMITATIONS: Possible unmeasured confounding and limited ability to infer causal associations. CONCLUSIONS: Cancer incidence in the setting of kidney disease is substantial. Cancer risk was increased in mild to moderate CKD and among transplant recipients, but not in advanced kidney disease. Cancer-related mortality was significantly higher among patients with kidney disease, particularly urologic cancers and myeloma. Strategies to detect and manage these cancers in the CKD population are needed.

Extrarenal renal cell carcinoma arising in the kidney proximity but without an identifiable renal primary - an intriguing dilemma: report of three cases and review of the literature.

AIM: To raise awareness of the existence of extrarenal renal cell carcinoma (RCC). METHODS AND RESULTS: We report three patients with extrarenal RCC found in the renal proximity, but unattached to the kidney. None had a history of RCC or an identifiable primary renal neoplasm at the time of the diagnosis and on follow-up. The patients included two males and one female aged 57, 77, and 63 years, respectively. One carcinoma was found in the perirenal tissue adjacent to the adrenal, one involved the adrenal gland, and one was a retroperitoneal mass found within the lymph nodes. Two extrarenal RCCs represented clear-cell RCCs and one was an unclassifiable RCC. No patient had evidence of metastases at presentation and disease progression during the follow-up. This report adds to the literature on this unusual clinical scenario and further supports the concept of extrarenal RCC, which is not a well-recognized clinical phenomenon. We also reviewed other similar reports documenting the absence of identifiable renal primaries in the setting of either disseminated metastatic disease or isolated distant metastases of presumed renal origin. Similarly, some carcinomas of apparent renal derivation have been also identified during a work-up of metastatic carcinomas of unknown primary. CONCLUSIONS: There should be an awareness of this unusual and intriguing clinical scenario that currently lacks a definitive explanation and standardized therapy strategies. Establishing a correct diagnosis may allow treatment with specific targeted therapies in selected clinical cases.

Clinical potential of PD-1/PD-L1 blockade therapy for renal cell carcinoma (RCC): a rapidly evolving strategy.

Programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) blockade therapy has become a game-changing therapeutic approach revolutionizing the treatment setting of human malignancies, such as renal cell carcinoma (RCC). Despite the remarkable clinical activity of anti-PD-1 or anti-PD-L1 monoclonal antibodies, only a small portion of patients exhibit a positive response to PD-1/PD-L1 blockade therapy, and the primary or acquired resistance might ultimately favor cancer development in patients with clinical responses. In light of this, recent reports have signified that the addition of other therapeutic modalities to PD-1/PD-L1 blockade therapy might improve clinical responses in advanced RCC patients. Until, combination therapy with PD-1/PD-L1 blockade therapy plus cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitor (ipilimumab) or various vascular endothelial growth factor receptors (VEGFRs) inhibitors axitinib, such as axitinib and cabozantinib, has been approved by the United States Food and Drug Administration (FDA) as first-line treatment for metastatic RCC. In the present review, we have focused on the therapeutic benefits of the PD-1/PD-L1 blockade therapy as a single agent or in combination with other conventional or innovative targeted therapies in RCC patients. We also offer a glimpse into the well-determined prognostic factor associated with the clinical response of RCC patients to PD-1/PD-L1 blockade therapy.

Sequential reinforcement active feature learning for gene signature identification in renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the deadliest cancers and mainly consists of three subtypes: kidney clear cell carcinoma (KIRC), kidney papillary cell carcinoma (KIRP), and kidney chromophobe (KICH). Gene signature identification plays an important role in the precise classification of RCC subtypes and personalized treatment. However, most of the existing gene selection methods focus on statically selecting the same informative genes for each subtype, and fail to consider the heterogeneity of patients which causes pattern differences in each subtype. In this work, to explore different informative gene subsets for each subtype, we propose a novel gene selection method, named sequential reinforcement active feature learning (SRAFL), which dynamically acquire the different genes in each sample to identify the different gene signatures for each subtype. The proposed SRAFL method combines the cancer subtype classifier with the reinforcement learning (RL) agent, which sequentially select the active genes in each sample from three mixed RCC subtypes in a cost-sensitive manner. Moreover, the module-based gene filtering is run before gene selection to filter the redundant genes. We mainly evaluate the proposed SRAFL method based on mRNA and long non-coding RNA (lncRNA) expression profiles of RCC datasets from The Cancer Genome Atlas (TCGA). The experimental results demonstrate that the proposed method can automatically identify different gene signatures for different subtypes to accurately classify RCC subtypes. More importantly, we here for the first time show the proposed SRAFL method can consider the heterogeneity of samples to select different gene signatures for different RCC subtypes, which shows more potential for the precision-based RCC care in the future.

RBM10-TFE3 fusions: A FISH-concealed anomaly in adult renal cell carcinomas displaying a variety of morphological and genomic features: Comprehensive study of six novel cases.

The accurate diagnosis of Xp11-translocation renal cell carcinoma (RCC) in adults is challenging. TFE3 (located on chromosome X) fuses with a partner gene generally located on another chromosome. In rare cases TFE3 may fuse with a neighboring gene: RBM10. Because TFE3 false-positive immunostaining is a common pitfall in many laboratories, demonstration of the chromosomal rearrangement is required in order to ascertain the diagnosis. Fluorescence in situ hybridization (FISH)-that has been considered as the gold standard method-reaches its limits for detecting small Xp11 paracentric inversions. We performed a comprehensive clinical, histological and genomic study of six novel cases of RCC with RBM10-TFE3 fusion. Using FISH, TFE3 rearrangement was equivocal in one case and negative in others. RBM10-TFE3 fusion was discovered using targeted RNA sequencing (RNASeq). As all the previously reported cases (mean age: 50), the six patients were adults (mean age: 42), suggesting an epidemiologic difference between RBM10-TFE3 RCC and tumors harboring some other partner genes, such as ASPSCR1 that rather occur in children. Array-comparative genomic hybridization showed several alterations, notably a gain of 17q in four cases with papillary features and loss of 3p in one case with clear cells. Our study demonstrates that, though rare among adult cases of RCC, RBM10-TFE3 fusion is not exceptional and warrants appropriate molecular detection. Notably, it would be worthy to systemically investigate by RNASeq challenging RCC with type-2 papillary features and 17q gain.

Impact of blood transfusion on survival after nephrectomy for localized or locally advanced renal cancer.

OBJECTIVE: Several studies have reported blood transfusion were associated with a decrease of survival after oncological surgery. For kidney cancer, the effect of blood transfusion is still debated. The objective of this study was to determine the effect of blood transfusion after oncological nephrectomy on overall, specific and recurrence-free survival in a retrospective cohort of localized or locally advanced kidney cancer. MATERIAL AND METHODS: We performed a monocentric retrospective analysis of all patients managed by surgery for localized or locally advanced renal cancer between January 2000 and December 2016. We compared overall and specific survival and recurrence-free survival between two groups: patients transfused and not transfused. Demographic, surgical and tumor characteristics were compared. Survival analyses were performed using univariate Cox regression and multivariate Cox proportional regression test. RESULTS: We included 382 patients in this study: 320 (83.8%) were not transfused and 62 (16.2%) were transfused. Transfused patients were significantly older (P=0.001) and had a lower pre-operative hemoglobin level (P=0.008). Operative and oncological characteristics were also different between both groups. In univariate analysis, we showed that blood transfusion was associated with lower overall survival (P<0.001), specific survival (P<0.001), and recurrence-free survival (P<0.001). In multivariate analysis, we found that blood transfusion was not associated with overall survival, or specific survival, but it was associated with lower recurrence-free survival (HR: 1.967, CI95% [1.024-3.780], P=0.042). CONCLUSIONS: Perioperative blood transfusion is an independent risk factor that increases tumor recurrence among patients treated with nephrectomy for renal cancer.

Circular RNAs and their role in renal cell carcinoma: a current perspective.

Circular RNAs (circRNAs) are a new class of long non-coding RNAs, that results from a special type of alternative splicing referred to as back-splicing. They are widely distributed in eukaryotic cells and demonstrate tissue-specific expression patterns in humans. CircRNAs actively participate in various important biological activities like gene transcription, pre-mRNA splicing, translation, sponging miRNA and proteins, etc. With such diverse biological functions, circRNAs not only play a crucial role in normal human physiology, as well as in multiple diseases, including cancer. In this review, we summarized our current understanding of circRNAs and their role in renal cell carcinoma (RCC), the most common cancer of kidneys. Studies have shown that the expression level of several circRNAs are considerably varied in RCC samples and RCC cell lines suggesting the potential role of these circRNAs in RCC progression. Several circRNAs promote RCC development and progression mostly via the miRNA/target gene axis making them ideal candidates for novel anti-cancer therapy. Apart from these, there are a few circRNAs that are significantly downregulated in RCC and overexpression of these circRNAs leads to suppression of RCC growth. Differential expression patterns and novel functions of circRNAs in RCC suggest that circRNAs can be utilized as potential biomarkers and therapeutic targets for RCC therapy. However, our current understanding of the role of circRNA in RCC is still in its infancy and much comprehensive research is needed to achieve clinical translation of circRNAs as biomarkers and therapeutic targets in developing effective treatment options for RCC.

Real-time US/cone-beam CT fusion imaging for percutaneous ablation of small renal tumours: a technical note.

INTRODUCTION: Fusion imaging is gaining attention as an imaging technique to assist minimally invasive tumour ablation. Ultrasound (US) and computed tomography (CT) are the most common imaging modalities to guide thermal ablation of renal tumours, yet cone-beam CT (CBCT) has recently been described to successfully assist percutaneous renal interventions. Our goal was to evaluate primary technical success and correct lesion targeting of US/CBCT fusion imaging to guide the ablation of kidney masses < 2 cm in a small group of patients. MATERIAL AND METHODS: Six renal lesions (maximum diameter 11-17 mm) were treated with RFA in 5 different patients using real-time US/CBCT. Fusion imaging was used to identify and monitor tumour ablation. Demographics, tumour characteristics and mean serum creatinine levels were recorded before and after the procedure. Primary technical success and correct lesion targeting represented the main endpoints of the study. Primary technique efficacy was confirmed at 1-month and 3-month contrast-enhanced CT follow-ups. RESULTS: In all cases, a confident US/CBCT synchronisation was reached and allowed for a correct targeting and a successful percutaneous ablation. Primary technique efficacy was 100%. No recurrence was observed at the follow-up that ranged from 8 to 26 months (mean 16 months). CONCLUSIONS: US/CBCT fusion proved to be a viable method to precisely guide safe and effective percutaneous thermal ablation in patients with small renal tumours, especially when hardly detectable on US. KEY POINTS: • US/CBCT fusion imaging for renal ablation is safe and feasible. • US/CBCT fusion imaging allows for an improved targeting and complete ablation of small RCC with poor US-conspicuity.

Perivascular Neuropilin-1 expression is an independent marker of improved survival in renal cell carcinoma.

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.

Cancer Screening in Patients Undergoing Maintenance Dialysis: Who, What, and When.

Cancer screening guidelines were developed for the general population with the aim of improving health outcomes through early detection. However, these screening recommendations are not generalizable to patients undergoing maintenance dialysis given that their life expectancy is often less than 5 years. In addition, the performance characteristics of screening tests in patients treated by dialysis may not be the same as in the general population, leading to differences in these tests' sensitivity and specificity in detecting cancer. Survival benefits in patients receiving dialysis may also be tempered by increased risks of curative therapies. Given the uncertainties of cancer screening in patients treated by maintenance dialysis, an individualized approach to cancer screening is warranted. This approach should balance the patient's life expectancy and the potential benefits from screening with its potential costs and harm. The special circumstance of renal cell carcinoma in patients treated by dialysis is also discussed.