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Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients’ nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression.

Up to 20% of renal masses ≤4 cm is found to be benign at the time of surgical excision, raising concern for overtreatment. However, the risk of malignancy is currently unable to be accurately predicted prior to surgery using imaging alone. The objective of this study is to propose a machine learning (ML) framework for pre-operative renal tumor classification using readily available clinical and CT imaging data. We tested both traditional ML methods (i.e., XGBoost, random forest (RF)) and deep learning (DL) methods (i.e., multilayer perceptron (MLP), 3D convolutional neural network (3DCNN)) to build the classification model. We discovered that the combination of clinical and radiomics features produced the best results (i.e., AUC [95% CI] of 0.719 [0.712–0.726], a precision [95% CI] of 0.976 [0.975–0.978], a recall [95% CI] of 0.683 [0.675–0.691], and a specificity [95% CI] of 0.827 [0.817–0.837]). Our analysis revealed that employing ML models with CT scans and clinical data holds promise for classifying the risk of renal malignancy. Future work should focus on externally validating the proposed model and features to better support clinical decision-making in renal cancer diagnosis.

Background Three-dimensional (3D) models improve the comprehension of renal anatomy. Objective To evaluate the impact of novel 3D-derived parameters, to predict surgical outcomes after robot-assisted partial nephrectomy (RAPN). Design, setting, and participants Sixty-nine patients with cT1-T2 renal mass scheduled for RAPN were included. Three-dimensional virtual modeling was achieved from computed tomography. The following volumetric and morphological 3D parameters were calculated: VT (volume of the tumor); VT/VK (ratio between tumor volume and kidney volume); CSA3D (ie, contact surface area); UCS3D (contact to the urinary collecting system); Tumor-Artery3D: tumor’s blood supply by tertiary segmental arteries (score = 1), secondary segmental artery (score = 2), or primary segmental/main renal artery (scoren = 3); ST (tumor’s sphericity); ConvT (tumor’s convexity); and Endophyticity3D (ratio between the CSA3D and the global tumor surface). Intervention RAPN with a 3D model. Outcome measurements and statistical analysis Three-dimensional parameters were compared between patients with and without complications. Univariate logistic regression was used to predict overall complications and type of clamping; linear regression was used to predict operative time, warm ischemia time, and estimated blood loss. Results and limitations Overall, 11 (15%) individuals experienced overall complications (7.2% had Clavien ≥3 complications). Patients with urinary collecting system (UCS) involvement at 3D model (UCS3D = 2), tumor with blood supply by primary or secondary segmentary arteries (Tumor-Artery3D = 1 and 2), and high Endophyticity3D values had significantly higher rates of overall complications (all p ≤ 0.03). At univariate analysis, UCS3D, Tumor-Artery3D, and Endophyticity3D are significantly associated with overall complications; CSA3D and Endophyticity3D were associated with warm ischemia time; and CSA3D was associated with selective clamping (all p ≤ 0.03). Sample size and the lack of interobserver variability are the main limits. Conclusions Three-dimensional modeling provides novel volumetric and morphological parameters to predict surgical outcomes after RAPN. Patient summary Novel morphological and volumetric parameters can be derived from a three-dimensional model to describe surgical complexity of renal mass and to predict surgical outcomes after robot-assisted partial nephrectomy.

Background Urogenital cancers are common, accounting for approximately 20% of cancer incidence globally. Cancers belonging to the same organ system often present with similar symptoms, making initial management challenging. In this study, 511 cases of cancer were recorded after the date of consultation among 61,802 randomly selected patients presenting in primary care in six European countries: a subgroup analysis of urogenital cancers was carried out in order to study variation in symptom presentation. Methods Initial data capture was by completion of standardised forms containing closed questions about symptoms recorded during the consultation. The general practitioner (GP) provided follow-up data after diagnosis, based on medical record data made after the consultation. GPs also provided free text comments about the diagnostic procedure for individual patients. Results The most common symptoms were mainly associated with one or two specific types of cancer: ‘Macroscopic haematuria’ with bladder or renal cancer (combined sensitivity 28.3%), ‘Increased urinary frequency’ with bladder (sensitivity 13.3%) or prostatic (sensitivity 32.1%) cancer, or to uterine body (sensitivity 14.3%) cancer, ‘Unexpected genital bleeding’ with uterine cancer (cervix, sensitivity 20.0%, uterine body, sensitivity 71.4%). ‘Distended abdomen, bloating’ had sensitivity 62.5% (based on eight cases of ovarian cancer). In ovarian cancer, increased abdominal circumference and a palpable tumour also were important diagnostic elements. Specificity for ‘Macroscopic haematuria’ was 99.8% (99.7–99.8). PPV > 3% was noted for ‘Macroscopic haematuria’ and bladder or renal cancer combined, for bladder cancer in male patients. In males aged 55–74, PPV = 7.1% for ‘Macroscopic haematuria’ and bladder cancer. Abdominal pain was an infrequent symptom in urogenital cancers. Conclusions Most types of urogenital cancer present with rather specific symptoms. If the GP considers ovarian cancer, increased abdominal circumference should be actively determined. Several cases were clarified through the GP’s clinical examination, or laboratory investigations.

Multiple primary cancers in a single patient are uncommon. The prevalence of multiple primary neoplasms ranges from 0.73% to 11.7%. The simultaneous diagnosis of primary renal and gastric malignancies is even rarer. Only 45 cases of synchronous multiple primary cancers of the stomach and kidney had been reported in the literature up until 2020. We present a case report of a 67-year-old female patient with synchronous renal cell carcinoma and gastric adenocarcinoma. Our case has two specificities: The first is the female gender since most of the case reports concern male patients and the second is the bilateral renal involvement. &nbsp

Clear cell renal cell carcinoma (ccRCC) is a hypervascular tumor that is characterized by bi-allelic inactivation of the VHL tumor suppressor gene and mTOR signalling pathway hyperactivation. The pro-angiogenic factor PDGFB, a transcriptional target of super enhancer-driven KLF6, can activate the mTORC1 signalling pathway in ccRCC. However, the detailed mechanisms of PDGFB-mediated mTORC1 activation in ccRCC have remained elusive. Here, we investigated whether ccRCC cells are able to secrete PDGFB into the extracellular milieu and stimulate mTORC1 signalling activity. We found that ccRCC cells secreted PDGFB extracellularly, and by utilizing KLF6- and PDGFB-engineered ccRCC cells, we showed that the level of PDGFB secretion was positively correlated with the expression of intracellular KLF6 and PDGFB. Moreover, the reintroduction of either KLF6 or PDGFB was able to sustain mTORC1 signalling activity in KLF6-targeted ccRCC cells. We further demonstrated that conditioned media of PDGFB-overexpressing ccRCC cells was able to re-activate mTORC1 activity in KLF6-targeted cells. In conclusion, cancer cell-derived PDGFB can mediate mTORC1 signalling pathway activation in ccRCC, further consolidating the link between the KLF6-PDGFB axis and the mTORC1 signalling pathway activity in ccRCC.

C-X-C Motif Chemokine Receptor 4 (CXCR4) is part of the human chemokine system and involved in progression and metastasis in renal cell carcinoma (RCC). However, the role of CXCR4 protein expression in RCC remains controversial. In particular, data regarding the subcellular distribution of CXCR4 in RCC and RCC metastasis as well as CXCR4 expression in renal tumors of variant histology are limited. The aim of the present study was the evaluation of the differential CXCR4 expression in RCC primary tumor and metastatic tissue as well as in variant renal histologies. In addition, the prognostic capacity of CXCR4 expression in organ-confined clear cell RCC (ccRCC) was evaluated. Three independent renal tumor cohorts (primary ccRCC cohort n1 = 64; cohort of various histological entities n2 = 146; metastatic RCC tissue cohort n3 = 92) were evaluated using tissue microarrays (TMA). After immunohistochemical staining for CXCR4, nuclear and cytoplasmic expression patterns were evaluated. CXCR4 expression was correlated with validated pathologic prognosticators, clinical data, and overall and cancer-specific survival. Positive cytoplasmic staining was observed in 98% of the benign and 38.9% of the malignant samples. Nuclear staining was positive for 94.1% of the benign samples and 83% of the malignant samples. The median cytoplasmic expression score was found to be higher in benign tissue than in ccRCC (130.00 vs. 0.00); median nuclear expression score analysis indicated the opposite (56.0 vs. 71.0). Within malignant subtypes, the highest expression score was seen in papillary renal cell carcinomas (cytoplasmic: 117.50, nuclear: 41.50). Within benign renal tumors, high cytoplasmic and nuclear CXCR4 expression scores were seen for oncocytomas (cytoplasmic: 100.00, nuclear: 31.00). Expression scores in RCC metastasis ranked between benign renal tissue and ccRCC in cytoplasmic and nuclear expression. Cytoplasmic CXCR4 expression was identified as a prognostic factor for OS and CSS (p = 0.042; p = 0.019). Multivariate analysis including clinicopathological parameters did not reveal an independent prognostic character of CXCR4 expression. CXCR4 expression differs significantly within benign lesions and renal neoplasms. Cytoplasmic and nuclear expression of CXCR4 could be detected across all RCC subtypes. The prognostic value of CXCR4 in ccRCC was confirmed in univariate analysis.

Sulfur-containing amino acids methionine (Met), cysteine (Cys) and taurine (Tau) are common dietary constituents with important cellular roles. Met restriction is already known to exert in vivo anticancer activity. However, since Met is a precursor of Cys and Cys produces Tau, the role of Cys and Tau in the anticancer activity of Met-restricted diets is poorly understood. In this work, we screened the in vivo anticancer activity of several Met-deficient artificial diets supplemented with Cys, Tau or both. Diet B1 (6% casein, 2.5% leucine, 0.2% Cys and 1% lipids) and diet B2B (6% casein, 5% glutamine, 2.5% leucine, 0.2% Tau and 1% lipids) showed the highest activity and were selected for further studies. Both diets induced marked anticancer activity in two animal models of metastatic colon cancer, which were established by injecting CT26.WT murine colon cancer cells in the tail vein or peritoneum of immunocompetent BALB/cAnNRj mice. Diets B1 and B2B also increased survival of mice with disseminated ovarian cancer (intraperitoneal ID8 Tp53−/− cells in C57BL/6JRj mice) and renal cell carcinoma (intraperitoneal Renca cells in BALB/cAnNRj mice). The high activity of diet B1 in mice with metastatic colon cancer may be useful in colon cancer therapy. Junta de Andalucía 2017/CTS-657, 2019/CTS-657, 2021/CTS657 Universidad de Sevilla VIPPIT2019-I.5, VIPPIT-2020-I.5, VIPPIT-2021-I.5, VIPPIT-2020-II.3

To compare outcomes of sutureless (SL) vs. renorrhaphy (RR) off-clamp robotic partial nephrectomy (ocRPN), we retrospectively analyzed procedures performed at our center, from January 2017 to April 2021, for cT1-2N0M0 renal masses. All the patients with a minimum follow-up < 1 month were excluded from the analysis. The trifecta rate defined surgical quality. Any worsening from chronic kidney disease (CKD) I-II to ≧ IIIa (from IIIa to ≧ IIIb, and from IIIb to ≧ IV) was considered as significant stage migration (sCKDsm). A 1:1 propensity score-matched (PSM) analysis minimized baseline imbalances between SL and RR cohorts in terms of age, gender, ASA score, baseline estimated glomerular filtration rate (eGFR), tumor size, and RENAL score. Logistic regression analyses identified predictors of trifecta achievement. Kaplan–Meier (KM) analysis assessed the impact of RR on significant chronic kidney disease sCKDsm-free survival (SMFS), while Cox regression analyses identified its predictors. Overall, 531 patients were included, with a median tumor size of 3.5 cm (IQR: 2.7–5); 70 (13%) presented with a cT2 mass. An SL approach was pursued in 180 cases, but 10 needed conversion to RR. After PSM analysis, patients receiving SL showed a higher trifecta rate (94% vs. 84%; p = 0.007). SMFS probabilities were comparable at KM analysis (log-rank = 0.69). Age (OR: 0.97; 95%CI: 0.95–0.99; p = 0.01), a RENAL score ≧ 10 (OR: 0.29; 95%CI: 0.15–0.57; p < 0.001), and RR (OR: 0.34; 95%CI: 0.17–0.67; p = 0.002) were independent predictors of trifecta achievement. Age (OR: 1.04; 95%CI: 1.003–1.07; p = 0.03) and baseline eGFR (OR: 0.99; 95%CI: 0.97–0.99; p = 0.05) independently predicted sCKDsm. Compared to RR, our experience seems to show that the SL approach significantly increased the probabilities of achieving the trifecta in the observed group of cases.

Background RAPN training usually takes place in-vivo and methods vary across countries/ institutions. No common system exists to objectively assess trainee capacity to perform RAPN at predetermined performance levels prior to in-vivo practice. The identification of objective performance metrics for RAPN training is a crucial starting point to improve training and surgical outcomes. Objective The authors sought to examine the reliability, construct and discriminative validity of objective intraoperative performance metrics which best characterize optimal and suboptimal performance of a reference approach for training novice RAPN surgeons. Design, setting, and participants: Seven Novice and 9 Experienced RAPN surgeons videorecorded one or two independently performed RAPN procedures in the human. The videos were anonymized and two experienced urology surgeons were trained to reliably score RAPN performance, using previously developed metrics. The assessors were blinded to the performing surgeon, hospital and surgeon group. They independently scored surgeon RAPN performance. Novice and Experienced group performance scores were compared for procedure steps completed and errors made. Each group was divided at the median for Total Errors score, and subgroup scores (i.e., Novice HiErrs and LoErrs, Experienced HiErrs and LoErrs) were compared. Results The mean inter-rater reliability (IRR) for scoring was 0.95 (range 0.84–1). Compared with Novices, Experienced RAPN surgeons made 69% fewer procedural Total Errors. This difference was accentuated when LoErr Expert RAPN surgeon’s performance was compared with the HiErrs Novice RAPN surgeon’s performance with an observed 170% fewer Total Errors. GEARS showed poor reliability (Mean IRR = 0.44; range 0.0–0.8), for scoring RAPN surgical performance. Conclusions The RAPN procedure metrics reliably distinguish Novice and Experienced surgeon performances. They further differentiated performance levels within a group with similar experience. Reliable and valid metrics will underpin quality-assured novice RAPN surgical training.

Background: Progress in the diagnosis and treatment of clear cell renal cell carcinoma (ccRCC) has significantly prolonged patient survival. However, ccRCC displays an extreme heterogenous characteristic and metastatic tendency, which limit the benefit of targeted or immune therapy. Thus, identifying novel biomarkers and therapeutic targets for ccRCC is of great importance. Method: Pan cancer datasets, including the expression profile, DNA methylation, copy number variation, and single nucleic variation, were introduced to decode the aberrance of copper death regulators (CDRs). Then, FDX1 was systematically analyzed in ccRCC to evaluate its impact on clinical characteristics, prognosis, biological function, immune infiltration, and therapy response. Finally, in vivo experiments were utilized to decipher FDX1 in ccRCC malignancy and its role in tumor immunity. Result: Copper death regulators were identified at the pancancer level, especially in ccRCC. FDX1 played a protective role in ccRCC, and its expression level was significantly decreased in tumor tissues, which might be regulated via CNV events. At the molecular mechanism level, FDX1 positively regulated fatty acid metabolism and oxidative phosphorylation. In addition, FDX1 overexpression restrained ccRCC cell line malignancy and enhanced tumor immunity by increasing the secretion levels of IL2 and TNFγ. Conclusions: Our research illustrated the role of FDX1 in ccRCC patients’ clinical outcomes and its impact on tumor immunity, which could be treated as a promising target for ccRCC patients.

Background and Objectives: A significant role was played by costimulatory molecules in renal cancer. However, the lncRNAs regulating costimulatory molecules have not been fully investigated. Materials and Methods: Data from the next-sequence file and clinical data were downloaded from the Cancer Genome Atlas (TCGA) database. All analyses were conducted using the R and GraphPad Prism software. Results: A total of 1736 costimulatory molecule-related lncRNAs were determined under the threshold of |Cor| > 0.5 and p-value < 0.001. Furthermore, a prognosis prediction signature consisting of five lncRNAs: LINC00941, AC016773.1, AL162171.1, HOTAIRM1, and AL109741.1 was established with great prediction ability. By combining risk score and clinical parameters, a nomogram plot was constructed for better clinical practice. A biological enrichment analysis indicated that E2F targets, coagulation, IL6/JAK/STAT3 signaling, G2/M checkpoint, and allograft rejection pathways were activated in high-risk patients. Furthermore, a higher infiltration level of resting CD4+ T cell, M2 macrophage, and resting mast cells, while a lower CD8+ T cell infiltration was observed in high-risk patients. It is worthy of note that, low-risk patients might respond better to PD-1 checkpoint therapy. A correlation analysis of LINC00941 revealed that it was positively correlated with Th2 cells, Th1 cells, macrophages, and Treg cells, but negatively correlated with Th17 cells. A pathway enrichment analysis indicated that the pathways of the inflammatory response, G2M checkpoint, and IL6/JAK/STAT3 signaling were significantly activated in patients with high LINC00941 expression. In vitro experiments indicated that LINC00941 can enhance the malignant biological behaviors of renal cancer cells. Conclusions: Our study established a costimulatory molecule-related lncRNAs-based prognosis model with a great prediction prognosis. In addition, LINC00941 could enhance the malignant biological behaviors of renal cancer cells.

Background: Nephron-sparing surgery represents the gold standard treatment for organ-confined renal tumors. We present 15-years of outcomes after off-clamp laparoscopic partial nephrectomy (ocLPN). Methods: a retrospective analysis was performed on patients who underwent ocLPN between May 2001 and December 2005. Baseline demographic, clinical, pathologic, surgical, functional and survival data were collected. The Kaplan–Meier method evaluated group-specific oncologic outcomes at 5, 10 and 15 years and the log rank test assessed differences between groups. The same analysis investigated the probabilities of developing a significant renal function impairment (sRFI) and achieving ROMeS. Cox analyses identified predictors of this latter tricomposite outcome. Results: We included 63 patients whose median tumor size was 3 cm (IQR:2–4). At 15 years, the chances of developing local recurrence, metachronous renal cancers or distant metastases were 2 ± 2%, 23 ± 6% and 17 ± 5%, respectively. Consequently, disease-free, cancer-specific and overall-survival probabilities were 68 ± 6%, 90 ± 4% and 72 ± 6%. MCRSS and UCISS well predicted oncologic outcomes. Overall, nine (14%) patients experienced an sRFI and 33 (52%) achieved ROMeS. Age (HR: 1.046; p = 0.033) and malignant histology (low-risk cancers HR: 3.233, p = 0.048) (intermediate/high risk cancers HR: 5.721, p = 0.023) were independent predictors of ROMeS non-achievement. Conclusions: At 15 years from ocLPN, most of patients will experience both excellent functional and oncologic outcomes.

Renal cell carcinoma (RCC) is the seventh most common cancer in men and the ninth most common cancer in women worldwide. There is plenty of evidence about the role of the immune system in surveillance against tumors. Thanks to a better understanding of immunosurveillance mechanisms, immunotherapy has been introduced as a promising cancer treatment in recent years. Renal cell carcinoma (RCC) has long been thought chemoresistant but highly immunogenic. Considering that up to 30% of the patients present metastatic disease at diagnosis, and around 20–30% of patients undergoing surgery will suffer recurrence, we need to identify novel therapeutic targets. The introduction of immune checkpoint inhibitors (ICIs) in the clinical management of RCC has revolutionized the therapeutic approach against this tumor. Several clinical trials have shown that therapy with ICIs in combination or ICIs and the tyrosine kinase inhibitor has a very good response rate. In this review article we summarize the mechanisms of immunity modulation and immune checkpoints in RCC and discuss the potential therapeutic strategies in renal cancer treatment.

Objective:Partial nephrectomy is the gold standard treatment in small renal tumours. During partialnephrectomy, the renal artery is clamped which creates transient ischemia. This can damage nephronsand may affect kidney function immediately postoperatively and on long-term.Objective:In the present study, we investigated the effect of ischemia time during partial nephrec-tomy with regards to affection of renal function immediately post-operatively and 1-year post-surgery.Materials and method: A retrospective cohort study including 124 patients who underwent partialnephrectomy at a single regional hospital in the period from 2018 to 2020 was conducted.Results: We divided patients into subgroups based on the ischemia time: [0–8], [9–13] and [14–29]minutes. The mean value for kidney function was an eGFR (mL/min) of 73.9 before and 66.8 at a 12-month post-surgery. We found no significant correlation between ischemia time and renal function.Noticeably, none of the patients had ischemia time greater than 30 min.Conclusion:In this cohort, the duration of ischemia time was not associated with differences in renalaffection neither on short term nor long term parameters if the ischemia time was kept below 30min Objective: Partial nephrectomy is the gold standard treatment in small renal tumours. During partial nephrectomy, the renal artery is clamped which creates transient ischemia. This can damage nephrons and may affect kidney function immediately postoperatively and on long-term. In the present study, we investigated the effect of ischemia time during partial nephrectomy with regards to affection of renal function immediately post-operatively and 1-year post-surgery. Materials and method: A retrospective cohort study including 124 patients who underwent partial nephrectomy at a single regional hospital in the period from 2018 to 2020 was conducted. Results: We divided patients into subgroups based on the ischemia time: [0–8], [9–13] and [14–29] minutes. The mean value for kidney function was an eGFR (mL/min) of 73.9 before and 66.8 at a 12-month post-surgery. We found no significant correlation between ischemia time and renal function. Noticeably, none of the patients had ischemia time greater than 30 min. Conclusion: In this cohort, the duration of ischemia time was not associated with differences in renal affection neither on short term nor long term parameters if the ischemia time was kept below 30 min.

Background: We aimed to assess whether clear cell renal cell carcinoma (ccRCC) can be differentiated from renal oncocytoma (RO) on a contrast-enhanced ultrasound (CEUS). Methods: Between January 2021 and October 2022, we retrospectively queried and analyzed our prospectively maintained dataset. Renal mass features were scrutinized with conventional ultrasound imaging (CUS) and CEUS. All lesions were confirmed by histopathologic diagnoses after nephron-sparing surgery (NSS). A multivariable analysis was performed to identify the potential predictors of ccRCC. The area under the curve (AUC) was depicted in order to assess the diagnostic accuracy of the multivariable model. Results: A total of 126 renal masses, including 103 (81.7%) ccRCC and 23 (18.3%) RO, matched our inclusion criteria. Among these two groups, we found significant differences in terms of enhancement (homogeneous vs. heterogeneous) (p < 0.001), wash-in (fast vs. synchronous/slow) (p = 0.004), wash-out (fast vs. synchronous/slow) (p = 0.001), and rim-like enhancement (p < 0.001). On the multivariate logistic regression, heterogeneous enhancement (OR: 19.37; p =

The Global Alliance for Genomics and Health (GA4GH) is a standards-setting organization that is developing a suite of coordinated standards for genomics. The GA4GH Phenopacket Schema is a standard for sharing disease and phenotype information that characterizes an individual person or biosample. The Phenopacket Schema is flexible and can represent clinical data for any kind of human disease including rare disease, complex disease, and cancer. It also allows consortia or databases to apply additional constraints to ensure uniform data collection for specific goals. We present phenopacket-tools, an open-source Java library and command-line application for construction, conversion, and validation of phenopackets. Phenopacket-tools simplifies construction of phenopackets by providing concise builders, programmatic shortcuts, and predefined building blocks (ontology classes) for concepts such as anatomical organs, age of onset, biospecimen type, and clinical modifiers. Phenopacket-tools can be used to validate the syntax and semantics of phenopackets as well as to assess adherence to additional user-defined requirements. The documentation includes examples showing how to use the Java library and the command-line tool to create and validate phenopackets. We demonstrate how to create, convert, and validate phenopackets using the library or the command-line application. Source code, API documentation, comprehensive user guide and a tutorial can be found at https://github.com/phenopackets/phenopacket-tools. The library can be installed from the public Maven Central artifact repository and the application is available as a standalone archive. The phenopacket-tools library helps developers implement and standardize the collection and exchange of phenotypic and other clinical data for use in phenotype-driven genomic diagnostics, translational research, and precision medicine applications.

Purpose To systematically review studies focused on screening programs for renal cell carcinoma (RCC) and provide an exhaustive overview on their clinical impact, potential benefits, and harms. Methods A systematic review of the recent English-language literature was conducted according to the European Association of Urology guidelines and the PRISMA statement recommendations (PROSPERO ID: CRD42021283136) using the MEDLINE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases. Risk-of-bias assessment was performed according to the QUality In Prognosis Studies (QUIPS) tool. Results Overall, nine studies and one clinical trials were included. Eight studies reported results from RCC screening programs involving a total of 159 136 patients and four studies reported screening cost-analysis. The prevalence of RCC ranged between 0.02 and 0.22% and it was associated with the socio-demographic characteristics of the subjects; selection of the target population decreased, overall, the screening cost per diagnosis. Conclusions Despite an increasing interest in RCC screening programs from patients and clinicians there is a relative lack of studies reporting the efficacy, cost-effectiveness, and the optimal modality for RCC screening. Targeting high-risk individuals and/or combining detection of RCC with other health checks represent pragmatic options to improve the cost-effectiveness and reduce the potential harms of RCC screening.

In this contribution, we performed cytotoxicity screening of 51 extracts from 17 plant species, representing 14 families growing in Turkey. Cytotoxic activities of the dichloromethane, ethyl acetate, and methanol extracts of the plants were investigated against the renal (A498 and U031) cancer cell lines. 28 extracts exhibited more than 50% growth inhibition at a 25 ug/mL concentration on both renal cancer A498 and UO31 cell lines. The extracts showed higher activity against UO31 cells than A498 cells. The dichloromethane extract of the aerial parts of Scabiosa columbaria ssp. columbaria showed the highest cytotoxic activity with 64% inhibition at a 25 ug/mL concentration on the renal cancer UO31 cell line. The methanol extract of the aerial parts of Epilobium minutiflorum showed the highest cytotoxic activity with 63% inhibition at a 25 ug/mL concentration on the renal cancer A498 cell line.

Tumor DNA vaccine as an effective therapeutic approach can induce systemic immunity against malignant tumors, but its therapeutic effect is still not satisfactory in advanced renal cancer. Herein, a novel DNA vaccine containing dual antigens of fibrinogen-like protein 1 (FGL1) and carbonic anhydrase IX (CAIX) was developed and intramuscularly delivered by PLGA/PEI nanoparticles for renal cancer therapy. Compared with PLGA/PEI-pCAIX immunization, PLGA/PEI-pFGL1/pCAIX co-immunization significantly inhibited the subcutaneous tumor growth and promoted the differentiation and maturation of CD11c+ DCs and CD11c+CD11b+ DCs subset. Likewise, the increased capabilities of CD8 T cell proliferation, CTL responses, and multi-functional CD8+ T cell immune responses were observed in PLGA/PEI-pFGL1/pCAIX vaccine group. Interestingly, depletion of CD8+ T cells by using CD8 mAb resulted in a loss of anti-tumor function of PLGA/PEI-pFGL1/pCAIX vaccine, suggesting that the anti-tumor activity of the vaccine was dependent on CD8+ T cell immune responses. Furthermore, PLGA/PEI-pFGL1/pCAIX co-immunization also suppressed the lung metastasis of tumor mice by enhancing the multi-functional CD8+ T cell responses. Therefore, these results indicate that PLGA/PEI-pFGL1/pCAIX vaccine could provide an effective protective effect for renal cancer by enhanced DC-mediated multi-functional CD8+ T cell immune responses. This vaccine strategy offers a potential approach for solid or metastatic tumor treatment., Graphical abstract, Here, Chai et al. investigate the therapy effect of dual-targeting vaccine of FGL1/CAIX in renal cancer. They found that the vaccine could induce DC-mediated multi-functional CD8 T cell immunity to suppress tumor growth and metastasis. This vaccine strategy offers a potential approach for cancer care.

Background Despite efforts aimed at preserving renal function, the functional decline after robot-assisted partial nephrectomy (RAPN) is not negligible. To address the risk of intraparenchymal vessel injuries during renorrhaphy, with consequent loss of functional renal parenchyma, we introduced a new surgical technique for RAPN. Objective To compare perioperative patient outcomes between selective-suturing or sutureless RAPN (suRAPN) and standard RAPN (stRAPN). Design, setting, and participants Ninety-two consecutive patients undergoing RAPN for a renal mass performed by a high-volume surgeon at a European tertiary center were included. Propensity-score matching was used to account for baseline differences between suRAPN and stRAPN patients. Intervention RAPN using a selective-suturing or sutureless technique versus standard RAPN. Outcome measurements and statistical analysis Perioperative outcomes included operative time, blood loss, length of stay, and intraoperative and 30-d postoperative complications. We also evaluated trifecta achievement (warm ischemia time ≤25 min, negative surgical margins, and no perioperative complications) and the incidence of postoperative acute kidney injury (AKI). We applied χ2 tests, t tests, and Kruskal-Wallis tests to assess differences in perioperative outcomes between suRAPN and stRAPN. Results and limitations Overall, 29 patients (31%) were treated with suRAPN. Only one suRAPN patient experienced intraoperative complications (p = 0.9). Two suRAPN patients (6.9%) and four stRAPN patients (13.8%) experienced 30-d postoperative complications (p = 0.3). Operative time (110 vs 150 min; p Conclusions A selective-suturing or sutureless technique in RAPN is feasible and safe. Moreover, suRAPN is a lower-impact surgical procedure. We obtained promising results for trifecta and functional outcomes, but prospective randomized trials are needed to validate the impact of selective suturing or a sutureless technique on long-term functional outcomes. Patient summary We assessed a new technique in robotic surgery to remove part of the kidney because of kidney cancer. Our new technique involves selective suturing or no suturing of the area from where the tumor is removed. We found that the rate of complications did not increase and the operating time and length of hospital stay were shorter using this new technique.

Virus-related cancers in humans are widely recognized, but in the case of renal cancer, the link with the world of viruses is not clearly established in humans, despite being known in animal biology. In the present review, we aimed to explore the literature on renal cell carcinoma (RCC) for a possible role of viruses in human RCC tumorigenesis and immune homeostasis, hypothesizing the contribution of viruses to the immunogenicity of this tumor. A scientific literature search was conducted using the PubMed, Web of Science, and Google Scholar databases with the keywords “virus” or “viruses” or “viral infection” matched with (“AND”) “renal cell carcinoma” or “kidney cancer” or “renal cancer” or “renal carcinoma” or “renal tumor” or “RCC”. The retrieved findings evidenced two main aspects testifying to the relationship between RCC and viruses: The presence of viruses within the tumor, especially in non-clear cell RCC cases, and RCC occurrence in cases with pre-existing chronic viral infections. Some retrieved translational and clinical data suggest the possible contribution of viruses, particularly Epstein-Barr virus, to the marked immunogenicity of sarcomatoid RCC. In addition, it was revealed the possible role of endogenous retrovirus reactivation in RCC oncogenesis, introducing new fascinating hypotheses about this tumor’s immunogenicity and likeliness of response to immune checkpoint inhibitors.

In Japan, the robot-assisted partial nephrectomy (RAPN) started to be covered by health insurance since 2016, and it is replacing conventional open partial nephrectomy (OPN). RAPN is a minimally invasive surgery, and the spreading of RAPN in partial nephrectomy (PN) performed annually is expected to reduce the number of blood transfusions in Japan. The number of PN surgery in Japan was calculated using the Japanese NDB open data in 2018. We extracted articles comparing the transfusion rates of RAPN and OPN from 2017 to 2021 using PubMed, Web of Science, and Ichu-shi, and integrated the ratios of transfusion rates by meta-analysis. We estimated the reduction in the annual transfusion cases in PN due to the widespread use of RAPN. The total number of renal cancer surgeries in 2018 was 21,298, of which 3,876 (18.2%) were RAPN and 4,384 (20.6%) were OPN. For the comparison of transfusion implementation rate between RAPN and OPN, 871 articles were screened and 27 articles were included. The pooled ratio in transfusion rate of RAPN compared with OPN was 0.49 [0.46, 0.52]; the introduction of RAPN was estimated to have reduced the annual number of transfusions in PN by 9.1% compared with that of unintroduced RAPN. This study showed quantitatively evaluated the impact of the introduction of RAPN on the decrease in the annual number of transfusions in Japan. This method has the potential to evaluate the impact of robot-assisted surgery on the use of blood products for transfusion. Supplementary Information The online version contains supplementary material available at 10.1007/s11701-021-01365-7.

Highlights • We performed a validity test of the Renal Graded Prognostic Assessment. • Therefore, we developed a new grading index. These results were validated using another dataset including 397 renal cancer patients with BMs. • This new grading system was clearly useful for predicting post-SRS outcomes of BM patients with renal cancer., Background and purpose The Renal Graded Prognostic Assessment (GPA) is relatively new and has not been sufficiently validated using a different dataset. We thus developed a new grading index, the Renal Brain Metastasis Score (Renal-BMS). Materials and methods Using our dataset including 262 renal cancer patients with brain metastases (BMs) undergoing stereotactic radiosurgery (SRS) (test series), we validity tested the Renal-GPA. Next, we applied clinical factor-survival analysis to the test series and thereby developed the Renal-BMS. This system was then validated using another series of 352 patients independently undergoing SRS at nine gamma knife facilities in Japan (verification series). Results Using the test series, with the Renal-GPA, 95% confidence intervals (CIs) of the post-SRS median survival times (MSTs) overlapped between pairs of neighboring subgroups. Among various pre-SRS clinical factors of the test series, six were highly associated with overall survival. Therefore, we assigned scores for six factors, i.e., “KPS ≥ 80%/

In response to the COVID-19 pandemic, the European Association of Urology (EAU) Guidelines Office Rapid Reaction Group (GORRG) defined priority groups to guide the prioritization of surgery for nonmetastatic renal cell carcinoma (RCC). In this study we explored the diversity and predictors of histopathological findings across the EAU GORRG priority groups using a large database of 1734 consecutive patients undergoing elective surgery for nonmetastatic renal masses between 2017 and 2020 at a referral institution. Overall, 940 (54.2%), 358 (20.6%), and 436 (25.2%) patients were classified as low-, intermediate-, and high-priority, respectively. The low-, intermediate-, and high-risk groups significantly differed regarding all primary histopathological outcomes: benign histology (21.6% vs 15.9% vs 6.4%; p

Sigma‐2 receptor/TMEM97 is overexpressed in many tumours, and sigma‐2 receptor ligands are under investigation for cancer therapy. We intended to evaluate the effect of PB28 on renal cancer in proliferation, migration and invasion in vitro and in vivo. Invasive renal cancer cell lines treated with PB28 (or sigma‐2 receptor antagonist 1) were subjected to cell proliferation, migration and invasion assays. The therapeutic effect of PB28 was performed on nude mice. Western blot for proteins in the PI3K‐AKT‐mTOR signalling pathway was conducted. A CCK‐8 assay was used to examine the effect of the combination of PB28 and cisplatin on renal cancer cells. Significant inhibitory effects were observed on proliferation, migration and invasion of 786‐O and ACHN cells after culturing with PB28. But, the outcomes of sigma‐2 receptor antagonist 1 presented the opposite tendency. PB28 significantly inhibited the proliferative and invasive ability of OS‐RC‐2 cells in vivo. Treatment resulted in decreased phosphorylation of constituents of the PI3K‐AKT‐mTOR pathway. The combination of PB28 and cisplatin showed enhanced efficacy in the inhibition of renal cancer cell proliferation. Taken together, PB28 inhibited the tumorigenic behaviours of renal cancer cells by regulating the PI3K‐AKT‐mTOR signalling pathway and was expected to be a sensitizer of cisplatin.

After nephron-sparing surgery (NSS), postsurgical fatty tumor could be mistakenly reported as angiomyolipoma during radiologic imaging of some patients. In the present paper, we studied the postsurgical fatty tumor detected after NSS but not covered before in the literature. In addi-tion, we also evaluated whether the postsurgical fatty tumor was related to the surgical technique employed. Patients admitted to the urology department of our university hospital from 2014 to 2019 and operated with open NSS were evaluated retrospectively. We detected those 156 patients were operated with NSS. Nine patients with angiomyolipoma as primary pathology and four patients with surgical border positivity were excluded from the study. The patients were divided into two groups based on the repair of tumor extraction region. In Group 1, fatty tissue was used for repair, and Group 2 is the primary repair group. In all, 143 patients (Group 1 = 79, and Group 2 = 64) were included in the study. No demographic and radiologic differences, such as number of patients, age, gender, positioning of tumor, mass localization, tumor diameter, and RENAL nephrometry scoring system, were detected between the two groups. Postsurgical fatty tumors were detected in 28 patients in Group 1 and in two patients in Group 2 (P < 0.001). In patients with negative surgical margins after partial nephrectomy, lesions that were radiologically detected mimicking as angiomyolipoma were defined as “postsurgical fatty tumor.” This mass containing adipose tissue only nei-ther depicted vascularization and enhancement nor increase in size for at least 1 year. We assumed that these lesions must be followed as benign lesions not requiring additional treatment.

Renal tumors account for 2 to 3 % of all malignant tumors in adults. Of all patients with renal cell carcinoma, 30 to 40 % have advanced forms of the disease. In the literature, the term "giant renal tumor" is used for tumors larger than 20 cm. In this article, we report a case of surgical treatment for a giant malignant kidney tumor.Patient N., female, 54 years old, referred to an outpatient clinic with complaints of a change in the shape of the abdomen on the left with a palpable large tumor, abdominal pain, shortness of breath, weakness, constipation, episodes of blood in the urine and increased blood pressure. Body mass index 30.2 kg/m2. Ultrasound examination revealed a large tumor in the left retroperitoneal space. Laboratory testing of blood, urine was performed, findings were unremarkable. According to the data of magnetic resonance imaging, the left kidney was transformed into a large cystic solid formation, measuring 30.5 х 17.5 х 17.0 cm, heterogeneously accumulating a contrast agent with a solid component. Patient was admitted to the urology department for surgical treatment. We performed radical nephrectomy on the left with thoracolumbar laparotomy access on the left with resection of the 10th rib, resecting the renal tumor with the adrenal gland, total weight of the complex was 10.7 kg. The histological structure was determined as poorly differentiated renal carcinoma with invasion of the perinephric tissue. In the adrenal gland, fields of fresh erythrocytes with an admixture of tumor tissue were noted. Examined lymph node tissue was completely replaced by tumor cells. Postoperative period was characterized by episodes of dynamic intestinal obstruction. The patient was discharged from the department in a satisfactory condition on the 13th day after the operation, but died 1.5 months after discharge, the cause of death has not been established, as no autopsy was performed. Thus, the size of the tumor is not a contraindication to surgical treatment, which improves the survival rate of patients with malignant renal tumors.

Organoid models have gained importance in recent years in determining the toxic effects of drugs in cancer studies. Organoid designs with the same standardized size and cellular structures are desired for drug tests. The field of microfluidics offers numerous advantages to enable well-controlled and contamination-free biomedical research. In this study, simple and low-cost microfluidic devices were designed and fabricated to develop an organoid model for drug testing for renal cancers. Caki human renal cancer cells and mesenchymal stem cells isolated from human umbilical cord were placed into alginate hydrogels. The microfluidic system was implemented to form size-controllable organoids within alginate hydrogels. Alginate capsules of uniform sizes formed in the microfluidic system were kept in cell culture for 21 days, and their organoid development was studied with calcein staining. Cisplatin was used as a standard chemotherapeutic, and organoid sphere structures were examined as a function of time with an MTT assay. HIF-1α, CXCR4 and CXCL-12 chemokine protein, and CXCR4 and CXCL-12 gene levels were tested in organoids and cisplatin responses. In conclusion, it was found that the standard renal cancer organoids made on a lab-on-a-chip system can be used to measure drug effects and tumor microenvironment responses.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney cancer, of which the incidence is increasing worldwide with a high mortality rate. Bioactive peptides are considered a significant class of natural medicines. We applied mass spectrometry-based peptidomic analysis to explore the peptide profile of human renal clear cell carcinoma and adjacent normal tissues. A total of 18,031 peptides were identified, of which 105 unique peptides were differentially expressed (44 were up-regulated and 61 were down-regulated in ccRCC tissues). Through bioinformatic analysis, we finally selected one peptide derived from the HSPB1 protein (amino acids 12–35 of the N-terminal region of HSPB1). Next, we fused this peptide to the HIV-Tat, generated a novel peptide named Tat-hspb1, and found that Tat-hspb1 inhibited ccRCC cells’ viability while being less cytotoxic to normal epithelial cells. Furthermore, Tat-hspb1 induced apoptosis and inhibited the proliferation and migration of ccRCC cells. Furthermore, we demonstrated that Tat-hspb1 was predominantly localized in lysosomes after entering the ccRCC cell and induced lysosomal membrane permeabilization (LMP) and the release of cathepsin D from lysosomes. Taken together, Tat-hspb1 has the potential to serve as a new anticancer drug candidate.

Mass spectrometry imaging (MSI) is an emerging technology that is capable of mapping various biomolecules within their native spatial context, and performing spatial multiomics on formalin-fixed paraffin-embedded (FFPE) tissues may further increase the molecular characterization of pathological states. Here we present a novel workflow which enables the sequential MSI of lipids, N-glycans, and tryptic peptides on a single FFPE tissue section and highlight the enhanced molecular characterization that is offered by combining the multiple spatial omics data sets. In murine brain and clear cell renal cell carcinoma (ccRCC) tissue, the three molecular levels provided complementary information and characterized different histological regions. Moreover, when the spatial omics data was integrated, the different histopathological regions of the ccRCC tissue could be better discriminated with respect to the imaging data set of any single omics class. Taken together, these promising findings demonstrate the capability to more comprehensively map the molecular complexity within pathological tissue.

PYCARD is a protein engaged in inflammation, pyroptosis, and apoptosis. However, the function of PYCARD in human cancers remains unclear. The objective of our study was to explore PYCARD expression and prognostic value in human cancers. Public databases were used to assess PYCARD expression and prognostic value. The TISIDB database was used to explore the associations between PYCARD expression and different immune subtypes. The correlations between PYCARD expression and ICP genes, MMR genes, MSI, and TMB were also investigated. The immunotherapy response was assessed using the TIDE database. Single-cell RNA databases evaluated the PYCARD expression of immune cells. External datasets and immunohistochemical staining were conducted to validate PYCARD expression and prognostic value. The results showed that PYCARD expression varied in several cancers and was associated with prognosis, immune-related genes, published biomarkers, and immunotherapy response. Of note, PYCARD expression was upregulated in renal cancers with high diagnostic ability. Upregulation of PYCARD was correlated with worse prognosis in KIRC and external validation cohorts. In conclusion, PYCARD demonstrated strong correlations with prognosis, immune response, and disease progression in pan-cancer analysis. In ccRCC, PYCARD might serve as a biomarker for diagnosis and therapeutic target-boosting immunotherapy response.

Background In clear cell renal cell carcinoma, 80% of cases have biallelic inactivation of the VHL gene, leading to constitutive activation of both HIF1α and HIF2α. As HIF2α is the driver of the disease promoting tumour growth and metastasis, drugs targeting HIF2α have been developed. However, resistance is common, therefore new therapies are needed. Methods We assessed the effect of the HIF2α antagonist PT2385 in several steps of tumour development and performed RNAseq to identify genes differentially expressed upon treatment. A drug screening was used to identify drugs with antiproliferative effects on VHL-mutated HIF2α-expressing cells and could increase effectiveness of PT2385. Results PT2385 did not reduce cell proliferation or clonogenicity but, in contrast to the genetic silencing of HIF2α, it reduced in vitro cell invasion. Many HIF-inducible genes were down-regulated upon PT2385 treatment, whereas some genes involved in cell migration or extracellular matrix were up-regulated. HIF2α was associated with resistance to statins, addition to PT2385 did not increase the sensitivity. Conclusions: this study shows key differences between inhibiting a target versus knockdown, which are potentially targetable.

© The Author(s)., [Background]: Treatment of renal cancer has significantly improved with the arrival to the clinic of kinase inhibitors and immunotherapies. However, the disease is still incurable in advanced stages. The fact that several approved inhibitors for kidney cancer target receptor tyrosine kinases (RTKs) suggests that these proteins play a critical role in the pathophysiology of the disease. Based on these precedents, we decided to explore whether RTKs other than those targeted by approved drugs, contribute to the development of kidney cancer., [Methods]: The activation status of 49 RTKs in 44 paired samples of normal and tumor kidney tissue was explored using antibody arrays, with validation by western blotting. Genetic and pharmacologic approaches were followed to study the biological implications of targeting the epidermal growth factor receptor (EGFR) and its ligand Transforming Growth Factor-α (TGFα)., [Results]: Activation of the EGFR was found in a substantial number of tumors. Moreover, kidney tumors expressed elevated levels of TGFα. Down-regulation of EGFR or TGFα using RNAi or their pharmacological targeting with blocking antibodies resulted in inhibition of the proliferation of in vitro cellular models of renal cancer. Importantly, differences in the molecular forms of TGFα expressed by tumors and normal tissues were found. In fact, tumor TGFα was membrane anchored, while that expressed by normal kidney tissue was proteolytically processed., [Conclusions]: The EGFR-TGFα axis plays a relevant role in the pathophysiology of kidney cancer. This study unveils a distinctive feature in renal cell carcinomas, which is the presence of membrane-anchored TGFα. That characteristic could be exploited therapeutically to act on tumors expressing transmembrane TGFα, for example, with antibody drug conjugates that could recognize the extracellular region of that protein., AP: Ministry of Economy and Competitiveness of Spain (BFU2015–71371-R), the Instituto de Salud Carlos III through CIBERONC, Junta de Castilla y León (CSI146P20), the Scientific Foundation of the Spanish Association Against Cancer (AECC), ALMOM, ACMUMA and the CRIS Cancer Foundation. JCM is funded by the Instituto de Salud Carlos III through a Miguel Servet program (CP12/03073 and CPII17/00015) and receives research support from the same institution (PI18/00796). LGS is recipient of a predoctoral contract (BES-2016-077748). IRP is recipient of a predoctoral contract (CSI030–18). SGA is recipient of a predoctoral contract from the MINECO (BES-2013-065223). Work carried out in our laboratory receives support from the European Community through the Regional Development Funding Program (FEDER).

We aimed to develop a sandwich ELISA to detect prostate-specific membrane antigen (PSMA) on small extracellular vesicles (EVs) using T-cell immunoglobulin domain and mucin domain-containing protein 4 (Tim4) as a capture molecule for EVs and to evaluate its diagnostic potential in urologic malignancies. First, we optimized the conditions for sandwich ELISA measuring the PSMA level on EVs captured from serum by Tim4 and found that the use of highly-purified EVs released from Tim4 that had captured EVs in serum reduced the background. Second, we confirmed its validity by studying mouse xenograft model for prostate cancer (PC). Lastly, we measured PSMA-EVs in serum of patients with urologic malignancies. The PSMA-EV levels were significantly higher in metastatic PC and castration-resistant PC (CRPC) patients than in therapy-naïve PC patients. In renal cell carcinoma (RCC) patients, PSMA-EVs were elevated in those with metastasis compared with those without metastasis, which may reflect the development of the neovasculature positive for PSMA in tumors. In conclusion, we developed a sandwich ELISA for detection of PSMA-EVs using highly-purified EVs isolated from serum by Tim4. Our results suggest that PSMA-EVs may be useful to diagnose and monitor not only PC but also RCC and possibly other hypervascular solid tumors.

DNA hypermethylation is frequently observed in clear cell renal cell carcinoma (ccRCC) and correlates with poor clinical outcomes. However, the detailed function of DNA hypermethylation in ccRCC has not been fully uncovered. Here, we show the role of DNA methylation in ccRCC progression through the identification of a target(s) of DNA methyltransferases (DNMT). Our preclinical model of ccRCC using the serial orthotopic inoculation model showed the upregulation of DNMT3B in advanced ccRCC. Pretreatment of advanced ccRCC cells with 5‐aza‐deoxycytidine, a DNMT inhibitor, attenuated the formation of primary tumors through the induction of apoptosis. DNA methylated sites were analyzed genome‐wide using methylation array in reference to RNA‐sequencing data. The gene encoding ubiquinol cytochrome c reductase hinge protein (UQCRH), one of the components of mitochondrial complex III, was extracted as a methylation target in advanced ccRCC. Immunohistochemical analysis revealed that the expression of UQCRH in human ccRCC tissues was lower than normal adjacent tissues. Silencing of UQCRH attenuated the cytochrome c release in response to apoptotic stimuli and resulted in enhancement of primary tumor formation in vivo, implying the tumor‐suppressive role of UQCRH. Moreover, 5‐aza‐deoxycytidine enhanced the therapeutic efficiency of mammalian target of rapamycin inhibitor everolimus in vivo. These findings suggested that the DNMT3B‐induced methylation of UQCRH may contribute to renal cancer progression and implicated clinical significance of DNMT inhibitor as a therapeutic option for ccRCC., DNMT3B‐induced methylation of ubiquinol cytochrome c reductase hinge protein (UQCRH) contributes to renal cancer progression. Decreased expression of UQCRH inhibits cyt c release from mitochondria, which may be important for anti‐apoptotic phenotype of renal cancer cells. Inhibitors of DNA methyltransferases may enhance the therapeutic efficacy of anticancer drugs.

Objectives To assess imaging features of primary renal sarcomas in order to better discriminate them from non-sarcoma renal tumors. Methods Adult patients diagnosed with renal sarcomas from 1995 to 2018 were included from 11 European tertiary referral centers (Germany, Belgium, Turkey). Renal sarcomas were 1:4 compared to patients with non-sarcoma renal tumors. CT/MRI findings were assessed using 21 predefined imaging features. A random forest model was trained to predict “renal sarcoma vs. non-sarcoma renal tumors” based on demographics and imaging features. Results n = 34 renal sarcomas were included and compared to n = 136 non-sarcoma renal tumors. Renal sarcomas manifested in younger patients (median 55 vs. 67 years, p < 0.01) and were more complex (high RENAL score complexity 79.4% vs. 25.7%, p < 0.01). Renal sarcomas were larger (median diameter 108 vs. 43 mm, p < 0.01) with irregular shape and ill-defined margins, and more frequently demonstrated invasion of the renal vein or inferior vena cava, tumor necrosis, direct invasion of adjacent organs, and contact to renal artery or vein, compared to non-sarcoma renal tumors (p < 0.05, each). The random forest algorithm yielded a median AUC = 93.8% to predict renal sarcoma histology, with sensitivity, specificity, and positive predictive value of 90.4%, 76.5%, and 93.9%, respectively. Tumor diameter and RENAL score were the most relevant imaging features for renal sarcoma identification. Conclusion Renal sarcomas are rare tumors commonly manifesting as large masses in young patients. A random forest model using demographics and imaging features shows good diagnostic accuracy for discrimination of renal sarcomas from non-sarcoma renal tumors, which might aid in clinical decision-making. Key Points • Renal sarcomas commonly manifest in younger patients as large, complex renal masses. • Compared to non-sarcoma renal tumors, renal sarcomas more frequently demonstrated invasion of the renal vein or inferior vena cava, tumor necrosis, direct invasion of adjacent organs, and contact to renal artery or vein. • Using demographics and standardized imaging features, a random forest showed excellent diagnostic performance for discrimination of sarcoma vs. non-sarcoma renal tumors (AUC = 93.8%, sensitivity = 90.4%, specificity = 76.5%, and PPV = 93.9%).

Wei Xi,1,&ast; Qinxuan Tan,2,&ast; Yingyong Hou,3,&ast; Xiaoyi Hu,1 Hang Wang,1 Li Liu,1 Yu Xia,1 Qi Bai,1 Jiajun Wang,1 Jianjun Zhou,2 Jianming Guo1 1Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 2Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China; 3Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianming GuoDepartment of Urology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail guo.jianming@zs-hospital.sh.cnJianjun ZhouDepartment of Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, People’s Republic of ChinaEmail zhou.jianjun@zs-hospital.sh.cnObjective: Pseudocapsule (PS) of tumor-parenchyma interface (TPI) can be detected by MDCT (ctPS) in renal cell carcinoma (RCC) with exceptions. We aim to study the prognostic implications and histological reflections of no detection of ctPS in RCC.Patients and Methods: A total of 210 RCC patients who had MDCT examination and received nephrectomy in our institution were included in the analysis. Absence or presence of ctPS was recognized, and its associations with overall survival (OS) and progression-free survival (PFS), pathological PS (pPS) and vasculature were studied.Results: A total of 172 (81.9%) patients were recognized to have a ctPS and 38 (18.1%) had no detection of it. They had comparable histology, stage, grade, and necrosis. Patients without a ctPS had significantly shortened overall survival (OS, p = 0.001) and progression-free survival (PFS, p < 0.001), the significance of which persisted in multivariable analysis (OS, HR 3.104, p = 0.003; PFS, HR 3.313, p = 0.001). Nearly all tumors (34/38, 89.4%) without a ctPS actually had a pPS being detected and incompleteness of pPS was also irrelevant (p = 0.739). Compared with ctPS presence, those without a ctPS had significantly thinned pPS (0.36 vs 0.43 mm, p = 0.005). In clear-cell histology, those without a ctPS also contained increased vascular density and cross-sectional area of vessels with long diameter ≥ 200 um in the pPS layer (p = 0.005 and 0.011) and increased vascular density in the 500 um layer outside pPS (p = 0.017).Conclusion: Absence of ctPS on MDCT significantly increases the risk of adverse clinical outcome in RCC. It is the reflection of a thinner pPS and enriched vasculature of TPI rather than absence of pPS itself.Keywords: renal cancer, pseudocapsule, MDCT, prognosis, histological reflection

Metallothioneins (MTs), a family of low-weight cysteine-rich proteins, play key roles in tumor biology, such as proliferation, differentiation, apoptosis, and drug resistance. Clinical studies have demonstrated that deregulation of MTs in various types of solid cancers. However, a comprehensive overview of MT1 isoforms expression and clinical relevance in clear cell renal cell cancer (ccRCC) is lacking. The present study explored mRNA expression levels and prognostic values of MT1 isoforms in ccRCC tissues using The Cancer Genome Atlas (TCGA), Gene Expression Profiling and Interactive Analysis (GEPIA) and Oncomine database. The study observed that mRNA expression levels of six members of MT1 isoforms decreased in renal cancer tumor tissues compared with normal tissues. We further found that high-expression of MT1G, MT1H, MT1F and MT1X was related with poor overall survival time in ccRCC patients and high-expression of MT1G, MT1F and MT1X were inversely associated with disease-free survival time in ccRCC patients. Based on the correlation analysis, MT1G was identified to be co-expressed with MT1H and MT1F in ccRCC tissues. These findings suggested that MT1 isoforms mRNA may serve as diagnostic and prognostic markers for ccRCC.

The incidence of renal cell carcinoma (RCC) and small renal masses (SRMs), defined as 0.90). MethylBoostER predicted consistent classification of multi-region samples from the same patient in 90% of individuals, suggesting ITH does not limit model applicability in a biopsy setting. Subsequently, I undertook a systematic evaluation of methylation heterogeneity in ccRCC, exploring associations with clinical/prognostic parameters and highlighting implications for biomarker selection. I evaluated multi-region tissue samples (N=135) from ccRCC patients (N=18) and assessed heterogeneity between patients, within a patient and within a sample. Inter-patient heterogeneity dominated over intra-tumoural heterogeneity. My analysis represents the first evaluation of epipolymorphism, a measure of methylation heterogeneity within a sample, in ccRCC. Significant differential epipolymorphism was noted in ccRCC versus normal kidney at the promoter region of genes known to be implicated in kidney cancer and this finding was externally validated in an independent cohort (N=71). Although changes in epipolymorphism are believed to be a stochastic process, my results suggest that disordered methylation may accumulate in functionally relevant loci which are known to contribute to ccRCC tumorigenesis. Circulating tumour DNA (ctDNA) represents a promising target for non-invasive liquid biopsy in both diagnostic and prognostic applications. Mutational analyses of ctDNA have produced disappointing detection rates in ccRCC, possibly hampered by low ctDNA levels and high mutational ITH. I therefore performed targeted methylation analysis of ctDNA using a novel method- Nimbus (Non-destructive Integration of Methylation to Boost Underlying Signals). Targeted analysis of hypomethylated regions in plasma ctDNA distinguished ccRCC from cancer-free controls with an AUC of 0.96 and produced superior detection rates compared to mutational analysis (93% vs 50%). My results suggest that tumour signal may be enriched in post-biopsy fluid (proximal sample) compared to plasma (distal sample), a strategy that could be useful in patients with SRMs to complement the current diagnostic pathway and overcome low concentrations of plasma ctDNA. In summary, I comprehensively characterise DNA methylation in tissue and liquid samples derived from patients with renal tumours. In the future, DNA methylation analysis of renal tumour biopsy tissue and/or liquid biopsy samples could enable improved diagnosis of patients with SRMs as well as facilitating prognostic stratification., Cancer Research UK PhD studentship; The Evelyn Trust Research Grant.

Renal cancer is the most lethal urological cancer and characterized by high metastasis rate at initial diagnosis and drug resistance to current chemotherapeutics. Betulinic acid is a pentacyclic triterpene with broad biological activity that occurs naturally in variety of plants. Even though the anti-cancer efficacy of betulinic acid have been reported by many studies, the information about the pathways and the molecules which are affected by betulinic acid in renal cancer are limited. Epithelial-mesenchymal transition (EMT) is considered as the initial step of metastasis and contributes to drug resistance of cancer cells. Depending on the role of EMT in cancer progression and drug resistance, targeting EMT may represent an effective strategy in this context. Therefore, we aimed to investigate the anti-metastatic effects of betulinic acid on renal cell carcinoma cells by evaluating two EMT markers, SNAIL-1, and SDC-2. Following the treatment of betulinic acid at determined doses by WST-1 cytotoxicity assay in our previous study, SDC-2 expression level was decreased in both cell lines. Additionally, in correlation with this result, we also found a reduction in SDC-2 and SNAIL-1 protein levels which are measured by ELISA. Furthermore, the migration and invasion capacities were suppressed by betulinic acid treatment in metastatic renal adenocarcinoma ACHN cells. Taken together, our findings indicate that betulinic acid may constitute a potential treatment approach for renal cancer with further investigations. Istanbul University--TSA-2019-35150 WOS:000841289400014 2-s2.0-85136093961 PMID: 35972672

BACKGROUND: Mycotoxins have been suggested to contribute to a spectrum of adverse health effects in humans, including at low concentrations. The recognition of these food contaminants being carcinogenic, as co-occurring rather than as singularly present, has emerged from recent research. The aim of this study was to assess the potential associations of single and multiple mycotoxin exposures with renal cell carcinoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.METHODS: Food questionnaire data from the EPIC cohort were matched to mycotoxin food occurrence data compiled by the European Food Safety Authority (EFSA) from European Member States to assess long-term dietary mycotoxin exposures, and to associate these with the risk of renal cell carcinoma (RCC, n = 911 cases) in 450,112 EPIC participants. Potential confounding factors were taken into account. Analyses were conducted using Cox's proportional hazards regression models to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs) with mycotoxin exposures expressed as µg/kg body weight/day.RESULTS: Demographic characteristics differed between the RCC cases and non-cases for body mass index, age, alcohol intake at recruitment, and other dietary factors. In addition, the mycotoxin exposure distributions showed that a large proportion of the EPIC population was exposed to some of the main mycotoxins present in European foods such as deoxynivalenol (DON) and derivatives, fumonisins, Fusarium toxins, Alternaria toxins, and total mycotoxins. Nevertheless, no statistically significant associations were observed between the studied mycotoxins and mycotoxin groups, and the risk of RCC development.CONCLUSIONS: These results show an absence of statistically significant associations between long-term dietary mycotoxin exposures and RCC risk. However, these results need to be validated in other cohorts and preferably using repeated dietary exposure measurements. In addition, more occurrence data of, e.g., citrinin and fumonisins in different food commodities and countries in the EFSA database are a prerequisite to establish a greater degree of certainty.

Objective: Although laparoscopic partial nephrectomy (LPN) is minimally invasive, it is also a technically challenging procedure. Currently, open partial nephrectomy (OPN) remains the only alternative in many centers for T1 kidney tumors. We reported our initial experience of LPN compared to OPN regarding clinical, oncological findings and renal functions .Material and Methods: Between 2004-2013, 81 patients who underwent OPN (n=55) or LPN (n=26) for clinically T1 renal tumors were included. Perioperative and postoperative data were compared, retrospectively. Follow-up times for OPN and LPN groups were 72.9± 41.1 and 47.6± 32.4 months, respectively (p, Amaç: Laparoskopik parsiyel nefrektomi (LPN) minimal invaziv olmasına rağmen teknik olarak zor bir prosedürdür. Günümüzde halen birçok merkezde, T1 evre böbrek tümöründe açık parsiyel nefrektomi (APN) tek seçenek olarak sunulmaktadır. Biz bu çalışmamızda LPN’deki erken dönem tücrebelerimizi klinik, onkolojik bulgular ve böbrek fonksiyonları açısından açık yöntemle karşılaştırarak sunmayı hedefledik.Gereç ve Yöntemler: 2004-2013 yılları arasında klinik T1 evre böbrek tümörü nedeniyle APN (n = 55) veya LPN (n = 26) uygulanan 81 hasta çalışmaya dahil edildi. Perioperatif ve postoperatif veriler retrospektif olarak karşılaştırıldı. APN ve LPN grupları için takip süreleri sırasıyla 72.9 ± 41.1 ve 47.6 ± 32.4 aydı (p

Intratumoral heterogeneity, including in clear cell renal cell carcinoma, is a potential cause of drug resistance and metastatic cancer progression. We specified the heterogeneous population marked by endoglin (also known as CD105) in a preclinical model of clear cell renal cell carcinoma progression. Highly malignant derivatives of human clear cell renal cell carcinoma OS‐RC‐2 cells were established as OS5Ks by serial orthotopic inoculation in our previous study. Expression of both ENG (encoding endoglin) mRNA and protein were heterogeneously upregulated in OS5Ks, and the endoglin‐positive (ENG+) population exhibited growth dependency on endoglin in anchorage‐independent cultures. Despite the function of endoglin as a type III receptor, transforming growth factor β and bone morphogenetic protein‐9 signaling were unlikely to contribute to the proliferative phenotype. Although endoglin has been proposed as a marker for renal cancer‐initiating cells, the OS5K‐3 ENG+ population did not enrich other reported cancer‐initiating cell markers or differentiate into the ENG– population. Mouse tumor inoculation models revealed that the tumor‐forming capabilities of OS5K‐3 ENG+ and ENG– cells in vivo were highly dependent on the microenvironment, with the renal microenvironment most preferable to ENG+ cells. In conclusion, the renal microenvironment, rather than the hypothesized ENG+ cell‐centered hierarchy, maintains cellular heterogeneity in clear cell renal cell carcinoma. Therefore, the effect of the microenvironment should be considered when evaluating the proliferative capability of renal cancer cells in the experimental settings., The impact of endoglin expression in renal tumorigenesis and metastasis was examined. We developed an orthotopic tumor model to identify the heterogeneous population marked by endoglin in renal cancer cells. The results showed that the renal microenvironment, rather than the hypothesized endoglin‐positive cell‐centered hierarchy, maintains cellular heterogeneity in renal cancer.

We report a case of Birt-Hogg-Dube syndrome (BHDS), a rare hereditary syndrome, the main visible sign of which is the development of multiple skin fibrofolliculomas. In our case, there was a manifestation of BHDS consisting in the absence of fibrofolliculomas and presence of other characteristic features of this syndrome: lung cysts and renal cancer. The 26-year-old woman was admitted to a clinic for diagnosis and treatment of a neoplasm of the left kidney and had a history of renal cell cancer (RCC) of the right kidney and spontaneous pneumothorax. Multiple tumors of the left kidney and lung cysts were observed upon clinical and laboratory testing. Tumors of the left kidney were resected and diagnosed by a pathologist as chromophobe RCC. Sequencing of FLCN exons 4–14 from blood DNA revealed the heterozygous germline nonsense mutation c.1429C>T (p.R477*), confirming the diagnosis of BHDS. Several somatic variants were detected by tumor DNA sequencing using the Comprehensive Cancer Panel and Ion S5 platform. Medical-genetic counseling was conducted, and follow-up management was outlined. To our knowledge, this case report is the first comprehensive clinical and genetic examination of a patient with BHDS in Russia. The p.R477* mutation has been described by other authors in patients with fibrofolliculomas and lung cysts, but not in those with RCC, while RCC was the first manifestation of BHDS in our case. The case report may help geneticists, oncologists, and other specialists to better understand the clinical and genetic heterogeneity of BHDS in various populations.

Renal cell carcinoma (RCC) is the deadliest primary genitourinary malignancy typically associated with asymptomatic initial presentation and poorly predictable survival. Next to established risk factors, tumor microenvironment may alter metastatic capacity and immune landscape. Due to their high concentrations, sulfoglycolipids (sulfatides) were among the first well-described antigens in RCC that are associated with worse prognosis. As sulfatide detection in routine diagnostics is not possible, we aimed to test the prognostic value of its protein counterpart, sulfatide-producing enzyme Gal3ST1. We performed retrospective long-term follow up analysis of Gal3ST1 expression as prognostic risk factor in a representative RCC patient cohort. We observed differentially regulated Gal3ST1 expression in all RCC types, being significantly more associated with clear cell RCC than to chromophobe RCC (p = 0.001). Surprisingly, in contrast to published observations from in vitro models, we could not confirm an association between Gal3ST1 expression and a malignant clinical behaviour of the RCC. In our cohort, Gal3ST1 did not significantly influence progression-free survival (Hazard Ratio (HR): 1.7 95% CI (0.6–4.9), p = 0.327). Particularly after adjusting for histology, T-stage, N-status and M-status at baseline, we observed no independent prognostic effect (HR = 1.0 95% CI (0.3–3.3), p = 0.96). The analysis of Gal3ST1 mRNA expression in a TCGA dataset supported the results of our cohort. Thus, Gal3ST1 might help to differentiate between chromophobe RCC and other frequent RCC entities but—despite previously published data from cell culture models—does not qualify as a prognostic marker for RCC. Further investigation of regulatory mechanisms of sulfatide metabolism in human RCC microenvironment is necessary to understand the role of this quantitatively prominent glycosphingolipid in RCC progression.

Renal Cell Carcinoma (RCC) is the most common form of kidney cancer, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. There are limited curable treatments available for metastatic ccRCC because this disease is unresponsive to conventional targeted systemic pharmacotherapy. Exosomes (Exo) are small extracellular vesicles (EVs) secreted from cancer cells with marked roles in tumoral signaling and pharmacological resistance. Ketoconazole (KTZ) is an FDA approved anti-fungal medication which has been shown to suppress exosome biogenesis and secretion, yet its role in ccRCC has not been identified. A time-course, dose-dependent analysis revealed that KTZ selectively decreased secreted Exo in tumoral cell lines. Augmented Exo secretion was further evident by decreased expression of Exo biogenesis (Alix and nSMase) and secretion (Rab27a) markers. Interestingly, KTZ-mediated inhibition of Exo biogenesis was coupled with inhibition of ERK1/2 activation. Next, selective inhibitors were employed and showed ERK signaling had a direct role in mediating KTZ’s inhibition of exosomes. In sunitinib resistant 786-O cells lines, the addition of KTZ potentiates the efficacy of sunitinib by causing Exo inhibition, decreased tumor proliferation, and diminished clonogenic ability of RCC cells. Our findings suggest that KTZ should be explored as an adjunct to current RCC therapies.

Background and Objectives: To assess efficacy and safety of Percutaneous Cryoablation (PCA) of small renal masses (SRMs) using Trifecta outcomes in a large cohort of patients who were not eligible for surgery. Materials and methods: All PCAs performed in four different centers between September 2009 and September 2019 were retrospectively evaluated. Patients were divided in two different groups depending on masses dimensional criteria: Group-A: diameter ≤ 25 mm and Group-B: diameter > 25 mm. Complications rates were reported and classified according to the Clavien–Dindo system. The estimate glomerular filtration rate (eGFR) was calculated before PCA and during follow-up schedule. Every patient received a Contrast Enhanced Ultrasound (CEUS) evaluation on the first postoperative day. Radiological follow-up was taken at 3, 6, and 12 months for the first year, then yearly. Radiological recurrence was defined as a contrast enhancement persistence and was reported in the study. Finally, Trifecta outcome, which included complications, RFS, and preservation of eGFR class, was calculated for every procedure at a median follow-up of 32 months. Results: The median age of the patients was 74 years. Group-A included 200 procedures while Group-B included 140. Seventy-eight patients were eligible for Trifecta evaluation. Trifecta was achieved in 69.6% of procedures in Group-A, 40.6% in Group-B (p = 0.02). We observed an increased rate of complication in Group-B (13.0% vs. 28.6; p < 0.001). However, 97.5% were

Oksidatif stres, renal kanser için önemli parametrelerden birisidir. Antioksidan sistem renal kanser oluşumunda devreye girerek oksidatif strese karşı koyar. Endojen antioksidanlar olarak tanımlanan GR ve GPx, böbreklerin antioksidan sistemindeki önemli enzimlerdir. Renal kanserdeki önemli parametrelerden biri olan CA-IX, bir pH pompası olarak görev yaparak tümör mikroçevresinin asidifikasyonuna sebep olur ve karsinogenezde rol oynar. Çalışmamızın temel amacı, bir karbonik anhidraz enzim inhibitörü olan AZA’nın glutatyon mekanizması üzerine olan etkisinin renal kanserde incelenmesidir. Deneysel çalışmalarda öncelikle renal kanser hücre hattı olan CAKI-2 çoğaltılarak WST-1 sitotoksisite testi ile AZA’nın uygun dozu 48. saatte 8.65 µM olarak bulunmuştur. AZA’nın CAKI-2 hücrelerinde CA-IX enzimi üzerine olan etkisi belirlenmek için ELISA testi yapılmıştır. CAKI-2 hücrelerine AZA uygulandıktan sonra GR ve GPx üzerine olan etkisini belirlemek için “Glutathione Reductase Assay Kit” ve “Glutathione Peroxidase Assay Kit” kullanılarak Epoch™ Microplate Spectrophotometer cihazında 340 nm’de ölçüm yapılmıştır. AZA uygulaması sonrası GR ve GPx enzim aktivitelerinde artış görülmüştür (p≤0.05). Çalışmanın sonucu olarak AZA inhibisyonunun, renal kanserde glutatyon mekanizmasının devreye girmesi için önemli bir ajan olabileceği söylenebilir. Renal kanserde hem CA-IX enziminin önemli bir terapötik biyobelirteç olması hem de glutatyon mekanizmasının bu kanser türündeki öneminden dolayı çalışmamız literatüre önemli bir katkı sağlamaktadır. Bu çalışmanın devamı niteliğinde olması planlanan diğer endojen antioksidan enzim aktivitelerinin renal kanserde araştırılması yeni terapötik yaklaşımların geliştirilmesini sağlayacaktır. Oxidative stress is one of the important parameters for renal cancer. The antioxidant system plays a prominent role and resists oxidative stress in the development of renal cancer. The endogenous antioxidants GPx and GR, are defined as crucial enzymes in the antioxidant system of the kidneys. The main purpose of this study is to determine the effect of AZA, a carbonic anhydrase classical enzyme inhibitor in the renal cancer cell line CAKI-2 to evaluate the GPx and GR enzyme activities. The optimal dose of AZA was found to be 8.65 µM at the 48th hour by WST-1 cytotoxicity test. ELISA test was performed to determine the effect of AZA on CA-IX enzyme in CAKI-2 cells. All measurements were performed at 340 nm by Epoch™ Microplate Spectrophotometer using “Glutathione Reductase Assay Kit” and “Glutathione Peroxidase Activity Assay Kit”. After AZA application, an increase was observed in GR and GPx enzyme activities (p≤0.05). As a consequence, AZA may be an important therapeutic agent for the glutathione mechanism related to renal cancer. Our study makes a valuable contribution to the literature due to the importance of the CA-IX enzyme related to renal cancer. The investigation of other endogenous antioxidant enzymes in renal cancer may be designed for further prospective studies.

Oksidatif stres, renal kanser için önemli parametrelerden birisidir. Antioksidan sistem renal kanser oluşumunda devreye girerek oksidatif strese karşı koyar. Endojen antioksidanlar olarak tanımlanan GR ve GPx, böbreklerin antioksidan sistemindeki önemli enzimlerdir. Renal kanserdeki önemli parametrelerden biri olan CA-IX, bir pH pompası olarak görev yaparak tümör mikroçevresinin asidifikasyonuna sebep olur ve karsinogenezde rol oynar. Çalışmamızın temel amacı, bir karbonik anhidraz enzim inhibitörü olan AZA’nın glutatyon mekanizması üzerine olan etkisinin renal kanserde incelenmesidir. Deneysel çalışmalarda öncelikle renal kanser hücre hattı olan CAKI-2 çoğaltılarak WST-1 sitotoksisite testi ile AZA’nın uygun dozu 48. saatte 8.65 μM olarak bulunmuştur. AZA’nın CAKI-2 hücrelerinde CA-IX enzimi üzerine olan etkisi belirlenmek için ELISA testi yapılmıştır. CAKI-2 hücrelerine AZA uygulandıktan sonra GR ve GPx üzerine olan etkisini belirlemek için “Glutathione Reductase Assay Kit” ve “Glutathione Peroxidase Assay Kit” kullanılarak Epoch™ Microplate Spectrophotometer cihazında 340 nm’de ölçüm yapılmıştır. AZA uygulaması sonrası GR ve GPx enzim aktivitelerinde artış görülmüştür (p≤0.05). Çalışmanın sonucu olarak AZA inhibisyonunun, renal kanserde glutatyon mekanizmasının devreye girmesi için önemli bir ajan olabileceği söylenebilir. Renal kanserde hem CA-IX enziminin önemli bir terapötik biyobelirteç olması hem de glutatyon mekanizmasının bu kanser türündeki öneminden dolayı çalışmamız literatüre önemli bir katkı sağlamaktadır. Bu çalışmanın devamı niteliğinde olması planlanan diğer endojen antioksidan enzim aktivitelerinin renal kanserde araştırılması yeni terapötik yaklaşımların geliştirilmesini sağlayacaktır., Oxidative stress is one of the important parameters for renal cancer. The antioxidant system plays a prominent role and resists oxidative stress in the development of renal cancer. The endogenous antioxidants GPx and GR, are defined as crucial enzymes in the antioxidant system of the kidneys. The main purpose of this study is to determine the effect of AZA, a carbonic anhydrase classical enzyme inhibitor in the renal cancer cell line CAKI-2 to evaluate the GPx and GR enzyme activities. The optimal dose of AZA was found to be 8.65 μM at the 48th hour by WST-1 cytotoxicity test. ELISA test was performed to determine the effect of AZA on CA-IX enzyme in CAKI-2 cells. All measurements were performed at 340 nm by Epoch™ Microplate Spectrophotometer using “Glutathione Reductase Assay Kit” and “Glutathione Peroxidase Activity Assay Kit”. After AZA application, an increase was observed in GR and GPx enzyme activities (p≤0.05). As a consequence, AZA may be an important therapeutic agent for the glutathione mechanism related to renal cancer. Our study makes a valuable contribution to the literature due to the importance of the CA-IX enzyme related to renal cancer. The investigation of other endogenous antioxidant enzymes in renal cancer may be designed for further prospective studies.