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Abstract Background Circulating tumor cells (CTCs) are pivotal in tumor metastasis across cancers, yet their specific role in renal cancer remains unclear. Methods This study investigated C–C motif chemokine ligand 5 (CCL5)'s tumorigenic impact on renal cancer cells and CTCs using bioinformatics, in vivo, and in vitro experiments. It also assessed renal cancer patients' CTCs prognostic value through Lasso regression and Kaplan–Meier survival curves. Results Bioinformatics analysis revealed differential genes focusing on cellular adhesion and migration between CTCs and tumor cells. CCL5 exhibited high expression in various CTCs, correlating with poor prognosis in renal cancer. In 786-O-CTCs, CCL5 enhanced malignancy, while in renal cell carcinoma cell line CAKI-2 and 786-O, it promoted epithelial-mesenchymal transition (EMT) via smad2/3, influencing cellular characteristics. The nude mouse model suggested CCL5 increased CTCs and intensified EMT, enhancing lung metastasis. Clinical results shown varying prognostic values for different EMT-typed CTCs, with mesenchymal CTCs having the highest value. Conclusions In summary, CCL5 promoted EMT in renal cancer cells and CTCs through smad2/3, enhancing the malignant phenotype and facilitating lung metastasis. Mesenchymal-type CTC-related factors can construct a risk model for renal cancer patients, allowing personalized treatment based on metastatic risk prediction.

Abstract A macroscopic perspective is indispensable for understanding the intricate relationship between deubiquitinases and tumorigenesis. Proteomics has been proposed as a viable approach for elucidating the complex role of deubiquitylation in cellular progression. Instead of studying the function of a single ubiquitinase, research on a deubiquitinase family with similar catalytic core(s) may provide a new perspective for the pathological understanding of cancer. The Ubiquitin C-terminal hydrolase L (UCHL) family consists of four members: UCHL1, UCHL3, UCHL5, and BRAC1 associated protein-1 (BAP1), and they have been implicated in tumorigenesis and metastasis. Some members are considered hallmarks of intracranial lesions, colon cancer, chromatin remodeling, and histone stability. The present study uncovered an unknown correlation between the UCHL family and renal cancer. We discovered that UCHLs exhibit diverse regulatory effects in renal cancer, establishing connections between the renal cancer and truncated gene mutations, mitochondrial energetic metastasis, immune cell infiltration, and chromosomal stability of UCHLs family. Notably, we found that the increase of UCHL5 expression in renal cancer cells decreases the antigen processing and presentation of RCC tumor-infiltrating B cells. Further research identified that the expression of UCHL5 in RCC tumors is correlated with transport proteins, which led us to find that the abundance of UCHL5 in the blood of late-stage renal cell cancer patients is upregulated from 18 ng/L to 500 ng/L. Therefore, we propose that the abundance of UCHL5 in patients' blood can be a possible indicator of poor prognosis for renal cell cancer.

Abstract Background Understanding sex‐specific factors contributing to advanced‐stage diagnosis can guide interventions to reduce sex inequality in patients with urological cancers. Method We used linked primary care and cancer registry data to examine associations between symptoms and advanced‐stage in 1151 bladder cancer and 440 renal cancer patients diagnosed between January 2012 and December 2015 in England. We performed logistic regression, adjusting for sex, age, deprivation and routes to diagnosis, including interaction terms between symptoms and sex and symptoms and age. Results Female sex (OR vs. men 1.89 [1.28–2.79]; p = 0.001) and patients presenting with urinary tract infections (OR 2.22 [1.34–3.69]) and abdominal symptoms (OR 2.19 [1.30–3.70]) were associated with increased odds of advanced‐stage bladder cancer (vs. haematuria, p = 0.016 for both). Women with haematuria and men with abdominal symptoms (compared with the opposite sex with the same presenting symptom) were more likely to have advanced‐stage bladder cancer. Neither sex nor symptom associations were observed for renal cancer. Conclusion Non‐haematuria symptoms are associated with higher risk of advanced‐stage bladder cancer. Greater risk of advanced‐stage bladder cancer in women may reflect biological differences in haematuria onset and sex differences during diagnostic process. Identifying higher risk women with haematuria may reduce sex inequalities in bladder cancer outcomes.

Introduction Secondary eosinophilia due to solid tumors is a rare case. This is the first study to report secondary eosinophilia due to renal cancer in a patient on dialysis. Case presentation A 70‐year‐old man, on long‐term hemodialysis was incidentally detected with right renal cancer, and workup performed revealed eosinophilia. Allergic symptoms caused by hemodialysis were initially considered; however, treatment did not lead to any improvement in eosinophilia. Therefore, nephrectomy for renal cancer was performed. The resolution of symptoms and eosinophilia after surgery suggested renal cancer as the cause of eosinophilia. Conclusion As demonstrated in this patient with dialysis‐related renal cancer, eosinophilia associated with solid tumors may be addressed by treating the tumor.

Abstract Backgrounds A growing number of expression quantitative trait loci (eQTLs) have been found to be linked with tumorigenesis. In this article, we employed integrated Mendelian randomization (MR) analyses to identify novel susceptibility genes in renal cancer (RC) and reveal their potential mechanisms. Methods Two-sample MR analyses were performed to infer causal relationships between eQTLs, metabolites, and RC risks through the “TwoSampleMR” R package. Sensitivity analyses, such as heterogeneity, pleiotropy, and leave-one-out analysis, were used to assess the stability of our outcomes. Summary-data-based MR (SMR) analyses were used to verify the causal relationships among cis-eQTLs and RC risks via the SMR 1.3.1 software. Results Our results provided the first evidence for AFF3 eQTL elevating RC risks, suggesting its oncogenic roles (IVW method; odds ratio (OR) = 1.0005; 95% confidence interval (CI) = 1.0001–1.0010; P = 0.0285; heterogeneity = 0.9588; pleiotropy = 0.8397). Further SMR analysis validated the causal relationships among AFF3 cis-eQTLs and RC risks (P

Abstract Background Renal neuroendocrine neoplasms (R‐NEN) are exceptionally rare tumours characterized by high mortality rates. Objective The objective of this study is to analyse prognostic factors and treatment impact on overall survival in patients with R‐NEN. Design, setting and participants We identified all patients with R‐NEN in the National Cancer Database (NCDB) from 2004 to 2019 and identified prognostic factors for improved survival. Results and limitations Of 542 R‐NEN cases, 166 (31%) were neuroendocrine tumour grade 1 (NET‐G1), 14 (3%) were neuroendocrine tumour grade 2 (NET‐G2), 169 (31%) were neuroendocrine carcinoma (NEC‐NOS), 18 (3%) were large cell neuroendocrine carcinoma (LC‐NEC) and 175 (32%) were small cell neuroendocrine carcinoma (SC‐NEC). Median overall survival for all patients in the study was 44.88 months (SE, 4.265; 95% CI, 27.57–62.19). Median overall survival was 7.89 months (SE 0.67; 95% CI, 6.58–9.20) for patients without surgical intervention and 136.61 months (SE 16.44; 95% CI, 104.38–168.84, p

Abstract Background Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation. Experimental design We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization. Results EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy. Conclusion Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.

To investigate the impact of Jolkinolide B (JB) on renal cell carcinoma (RCC), we treated RCC cell lines with various concentrations of JB (0, 5, 25, 50 and 100 μM) for 24 hours and assessed cell viability using the cell counting kit-8 (CCK-8) analysis. Then, we examined JB’s effects on proliferation, migration, apoptosis, reactive oxygen species (ROS) accumulation, and endoplasmic reticulum (ER) stress through 5-ethynyl-2′-deoxyuridine (EdU) incorporation, transwell migration assays, flow cytometry, ROS level determination, and western blot assays. Furthermore, we investigated the potential mechanism using western blot. Our results showed that JB dose-dependently reduced cell viability in both 786-O and Caki1 cells. Additionally, JB at concentrations of 5, 25 and 50 μM decreased the number of EdU-positive and migrating cells in both cell lines. Additionally, these concentrations of JB increased apoptosis rates, relative protein expressions of cleaved caspase-3 and cleaved caspase-9, ROS levels, and relative protein expressions of C/EBP-homologous protein (CHOP) and activated transcription factor 4 (ATF4) in both 786-O and Caki1 cells. Mechanistically, treatment with all three concentrations of JB significantly downregulated phosphorylated p38 (p-p38)/p38, phosphorylated protein kinase B (p-AKT)/AKT and phosphorylated phosphatidylinositol-3-kinase (p-PI3K)/PI3K in a dose-dependent manner. In summary, JB inhibited proliferation and migration while promoting apoptosis, ROS accumulation, and ER stress in RCC cells, potentially through the inactivation of mitogen-activated protein kinase (MAPK) and AKT signaling pathways.

Abstract Background Kidney cancer has become known as a metabolic disease. However, there is limited evidence linking metabolic syndrome (MetS) with kidney cancer risk. This study aimed to investigate the association between MetS and its components and the risk of kidney cancer. Methods UK Biobank data was used in this study. MetS was defined as having three or more metabolic abnormalities, while pre-MetS was defined as the presence of one or two metabolic abnormalities. Hazard ratios (HRs) and 95% confidence intervals (CIs) for kidney cancer risk by MetS category were calculated using multivariable Cox proportional hazards models. Subgroup analyses were conducted for age, sex, BMI, smoking status and drinking status. The joint effects of MetS and genetic factors on kidney cancer risk were also analyzed. Results This study included 355,678 participants without cancer at recruitment. During a median follow-up of 11 years, 1203 participants developed kidney cancer. Compared to the metabolically healthy group, participants with pre-MetS (HR= 1.36, 95% CI: 1.06-1.74) or MetS (HR= 1. 70, 95% CI: 1.30-2.23) had a significantly greater risk of kidney cancer. This risk increased with the increasing number of MetS components (P for trend < 0.001). The combination of hypertension, dyslipidemia and central obesity contributed to the highest risk of kidney cancer (HR= 3.03, 95% CI: 1.91-4.80). Compared with participants with non-MetS and low genetic risk, those with MetS and high genetic risk had the highest risk of kidney cancer (HR= 1. 74, 95% CI: 1.41-2.14). Conclusions Both pre-MetS and MetS status were positively associated with kidney cancer risk. The risk associated with kidney cancer varied by combinations of MetS components. These findings may offer novel perspectives on the aetiology of kidney cancer and assist in designing primary prevention strategies.

Abstract Introduction Papillary renal cell carcinoma (pRCC) is the second most common histology of renal cell carcinoma (RCC), accounting for 10–15% of cases. Traditionally, pRCC is divided into type 1 and type 2, although this division is currently debated as a prognostic factor of survival. Our aim was to investigate the epidemiology and survival of the pRCC subtypes in a whole nation cohort of patients during a 50-year period. Materials and methods A Population based retrospective study including consecutive cases of RCC in Iceland from 1971–2020. Comparisons were made between histological classifications of RCC, with emphasis on pRCC subtypes (type 1 vs. 2) for outcome estimation. Changes in RCC incidence were analyzed in 5-year intervals after age standardization. The Kaplan–Meier method and Cox regression were used for outcome analysis. Results A total of 1.725 cases were identified, with 74.4%, 2.1% and 9.2% having clear cell (ccRCC), chromophobe (chRCC), and pRCC, respectively. The age standardized incidence (ASI) of pRCC was 1.97/100.000 for males and 0.5/100.000 for females, and the proportion of pRCC increased from 3.7% to 11.5% between the first and last intervals of the study (p

Abstract To assess epidemiology, clinical presentation, treatment and overall survival of adult patients with renal sarcomas, the 2004–2016 SEER and NCDB databases were queried for adult patients diagnosed with renal sarcoma, calculating average annual age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) as well as overall survival (OS). In n = 1279 included renal sarcoma patients, AAIR remained constant over the study period (average 0.53 cases/1million; AAPC = 0.7, p = 0.6). Leiomyosarcoma (AAIR 0.14 cases/1 million) and malignant rhabdoid tumors (0.06 cases/1 million) were most common. Sarcoma histiotypes demonstrated considerable heterogeneity regarding demographic and cancer-related variables. Patients presented with advanced local extent (T3 33.3%; T4 14.2%) or distant metastases (29.1%) and commonly underwent surgical resection (81.6%). Longer OS was independently associated with younger age, female sex, lower comorbidity index, low T stage, negative surgical margins, absence of tumor necrosis or distant metastases and leiomyosarcoma histiotype (multivariable p

Background and objective: Data regarding open conversion (OC) during minimally invasive surgery (MIS) for renal tumors are reported from big databases, without precise description of the reason and management of OC. The objective of this study was to describe the rate, reasons, and perioperative outcomes of OC in a cohort of patients who underwent MIS for renal tumor initially. The secondary objective was to find the factors associated with OC. Methods: Between 2008 and 2022, of the 8566 patients included in the UroCCR project prospective database (NCT03293563), who underwent laparoscopic or robot-assisted minimally invasive partial (MIPN) or radical (MIRN) nephrectomy, 163 experienced OC. Each center was contacted to enlighten the context of OC: “emergency OC” implied an immediate life-threatening situation not reasonably manageable with MIS, otherwise “elective OC”. To evaluate the predictive factors of OC, a 2:1 paired cohort on the UroCCR database was used. Key findings and limitations: The incidence rate of OC was 1.9% for all cases of MIS, 2.9% for MIRN, and 1.4% for MIPN. OC procedures were mostly elective (82.2%). The main reason for OC was a failure to progress due to anatomical difficulties (42.9%). Five patients (3.1%) died within 90 d after surgery. Increased body mass index (BMI; odds ratio [OR]: 1.05, 95% confidence interval [CI]: 1.01–1.09, p = 0.009) and cT stage (OR: 2.22, 95% CI: 1.24–4.25, p = 0.008) were independent predictive factors of OC. Conclusions and clinical implications: In MIS for renal tumors, OC was a rare event (1.9%), caused by various situations, leading to impaired perioperative outcomes. Emergency OC occurred once every 300 procedures. Increased BMI and cT stage were independent predictive factors of OC. Patient summary: The incidence rate of open conversion (OC) in minimally invasive surgery for renal tumors is low. Only 20% of OC procedures occur in case of emergency, and others are caused by various situations. Increased body mass index and cT stage were independent predictive factors of OC.

Ureteral metastasis of prostate cancer is extremely rare, with less than 50 cases at present. Kidney cancer with prostate cancer is also rare, and ureteral metastasis with prostate cancer is difficult to diagnose. Especially if there are no symptoms of hematuria, the ureteral mass should be clearly understood. Although there is no error in the diagnosis and treatment process in this case, there are still many points worth considering, such as whether unilateral nephroperectomy should be performed if there is no kidney cancerHere, we report a case of renal cancer complicated with prostate cancer and ureteral metastasis.

Abstract Renal cancer is a highlyheterogeneous malignancy characterized by rising global incidence and mortalityrates. The complex interplay and dysregulation of multiple signaling pathways,including von Hippel–Lindau (VHL)/hypoxia‐inducible factor (HIF), phosphoinositide 3‐kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR), Hippo–yes‐associated protein (YAP), Wnt/ß‐catenin, cyclic adenosine monophosphate (cAMP), and hepatocyte growth factor (HGF)/c‐Met, contribute to theinitiation and progression of renal cancer. Although surgical resection is thestandard treatment for localized renal cancer, recurrence and metastasiscontinue to pose significant challenges. Advanced renal cancer is associatedwith a poor prognosis, and current therapies, such as targeted agents andimmunotherapies, have limitations. This review presents a comprehensiveoverview of the molecular mechanisms underlying aberrant signaling pathways inrenal cancer, emphasizing their intricate crosstalk and synergisticinteractions. We discuss recent advancements in targeted therapies, includingtyrosine kinase inhibitors, and immunotherapies, such as checkpoint inhibitors.Moreover, we underscore the importance of multiomics approaches and networkanalysis in elucidating the complex regulatory networks governing renal cancerpathogenesis. By integrating cutting‐edge research and clinical insights, this review contributesto the development of innovative diagnostic and therapeutic strategies, whichhave the potential to improve risk stratification, precision medicine, andultimately, patient outcomes in renal cancer.

Based on a retrospective hospital-based analysis, this study examines the results of retroperitoneal laparoscopic radical nephrectomy for patients with T1-T2 renal cell carcinoma (RCC) from January 2019 to December 2023. Of the 73 patients, 4.1% had TNM stage II tumors and 95.8% had TNM stage I tumors (53.4% T1a and 42.4% T1b). In terms of frequency, clear cell RCC accounted for 84.9%, with papillary RCC coming in at 9.6% and chromophobe RCC at 4.1%. Following surgery, four patients experienced fevers, one needed a blood transfusion, two had infections, and one had emergency surgery. Lumbar masses and hematuria were absent in all patients. Subsequent metastatic lesions and abnormalities of the renal fossa were not observed on follow-up ultrasounds. 4.1% of the deaths after 25.9 months were due to the disease, and 1.4% were caused by accidents. At one, two, three, and four years, the cumulative survival rates were 100%, 97.2%, and 92.8%, respectively. 48.1 months was the mean postoperative survival period. For RCC stages T1-2, retroperitoneal laparoscopic radical nephrectomy offers significant benefits and comparable results to open surgery.

Renal cancer is one of the most common malignancies of the urinary system, and the number of deaths continues to increase. The standardized management of the diagnosis and treatment of renal cancer is challenging due to the great differences in the diagnosis and treatment of renal cancer in different regions. The Renal Cancer Expert Committee of the National Cancer Quality Control Center (NCQCC) identified a lack of authoritative quality control standards as an opportunity to utilize its multidisciplinary membership to improve the standardized diagnosis and treatment of renal cancer. The Renal Cancer Expert Committee of the NCQCC aims to promote quality control and national standardization, uniformity, and normalization of renal cancer diagnosis and treatment, which ultimately improved the survival rate and quality of life of renal cancer patients. A panel of experts with renal cancer surgery, renal cancer medicine, medical imaging, pathology and radiotherapy were drawn together and determined the quality control standards for the standardized diagnosis and treatment of renal cancer. The Indices includes 20 items that cover all key areas in the diagnosis and treatment of renal cancer, such as standard diagnosis, surgery treatment, systemic treatment, and prognostic evaluation.

Abstract Background Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. Methods This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). Discussion Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. Trial registration ClinicalTrials.gov: NCT06059014.

Abstract Background Urinary tract cancers including bladder, kidney, ureter, and pelvis are a common malignancy worldwide with high mortality ratio. Aimed to investigate the prevalence of these cancers, we conducted this study. Methods In this study, all the information related to ICD10 codes, gender, age and province of residence of individuals were obtained from the data of Iran’s cancer registry by the Ministry of Health, Medicine and Medical Education and demographic evidence for each sub-country from the reports of Statistics Center of Iran (SCI). Also, the data of two Iranian national survey studies CASPIAN-III, IV, and V (information related to the care and prevention of non-communicable diseases (NCD) in childhood and adolescence) and STEPs (including information on NCD in adults over 18 years old) were used. The data was analyzed using Poisson regression with mixed effects to estimate the incidence of cancers. Results Bladder and kidney neoplasm are the most common cancers of the urinary system in Iran. The prevalence of bladder cancer has increased from 5.82 to 11.50 per 100,000 individuals. The increasing trend is growing faster in men compared with women. The incidence of kidney neoplasm has increased over the years (2.03 in 2005 vs. 7.02 in 2020 per 100,000). Having a higher incidence ratio compared with bladder cancer, kidney cancer is responsible for 35.06% of all urinary cancers in 2020 compared with 23.71% in 2005. Both neoplasms of the ureter and renal pelvis were recorded rarely and with lower incidence in both sexes during this period. Conclusion Considering the increasing trend in the incidence of urinary neoplasms in Iran during these years, the advantage of focusing on the risk of urinary cancers is highlighted. Therefore, investigating the prevalence and incidence of urinary cancers to plan and manage these cancers will result in prevention and reduction of the disease burden on the Iranian society. Future studies in this field can help in the prevention and well-timed diagnosis of these cancers.

ABSTRACTAlthough immune-based therapies have revolutionized the management of cancer, novel approaches are urgently needed to improve their outcome. We investigated the role of endogenous steroids in the resistance to cancer immunotherapy, as these have strong immunomodulatory functions. Using a publicly available database, we found that the intratumoral expression of 11 beta-hydroxysteroid dehydrogenase type 1 (HSD11B1), which regenerates inactive glucocorticoids into active glucocorticoids, was associated with poor clinical outcome and correlated with immunosuppressive gene signatures in patients with renal cell carcinoma (RCC). HSD11B1 was mainly expressed in tumor-infiltrating immune myeloid cells as seen by immunohistochemistry in RCC patient samples. Using peripheral blood mononuclear cells from healthy donors or immune cells isolated from the tumor of RCC patients, we showed that the pharmacological inhibition of HSD11B1 improved the response to the immune checkpoint inhibitor anti-PD-1. In a subcutaneous mouse model of renal cancer, the combination of an HSD11B1 inhibitor with anti-PD-1 treatment increased the proportion of tumor-infiltrating dendritic cells. In an intrarenal mouse tumor model, HSD11B1 inhibition increased the survival of mice treated with anti-PD-1. In addition, inhibition of HSD11B1 sensitized renal tumors in mice to immunotherapy with resiquimod, a Toll-like receptor 7 agonist. Mechanistically, we demonstrated that HSD11B1 inhibition combined with resiquimod increased T cell-mediated cytotoxicity to tumor cells by stimulating the antigen-presenting capacity of dendritic cells. In conclusion, these results support the use of HSD11B1 inhibitors to improve the outcome of immunotherapy in renal cancer and highlight the role of the endogenous glucocorticoid metabolism in the efficacy of immunotherapy.

Introduction: Renal squamous cell carcinoma (SCC) is a neoplasm with an extremely rare occurrence compared to other renal malignancies. The classic presentation includes a palpable mass and flank pain; however, the presentation is seldom non-specific. Our study describes the significance of programmed death ligand-1 (PD-L1) expression in renal cancer and its association with clinical outcomes, alongside available treatment options. Case description: An 80-year-old female with a history of hypertension and cerebral aneurysm presented with right flank pain and blood in urine and was diagnosed with pyelonephritis and left renal mass/phlegmon. A biopsy revealed SCC of the kidney with metastasis to the lung and aortocaval lymph node. Positron emission tomography (PET) scan confirmed malignancy in the kidney and lung. Treatment with pemrolizumab and carboplatin plus paclitaxel was initiated but poorly tolerated as the haemoglobin dropped rapidly. Conclusion: SCC poses a diagnostic challenge due to its rarity and non-specific symptoms, often leading to advanced stage diagnosis. PD-L1 expression is pivotal in assessing tumour aggressiveness and prognosis. PD-L1 inhibitors offer promise, but their efficacy in renal SCC warrants further investigation. Radical nephrectomy and systemic chemotherapy show potential in advanced cases, necessitating vigilant management of treatment-related side effects. This case emphasises the need for ongoing research to refine therapeutic approaches and enhance outcomes in renal SCC patients.

Cancer is one of the top 10 fatal diseases worldwide, among which advanced metastatic carcinoma has the highest mortality rate. Sunitinib and immune checkpoint blockers are commonly used to treat metastatic renal carcinoma with limited efficacy. Therefore, there is an urgent need to develop novel targeted therapies for metastatic renal cancer. In this study, we designed an antibody fusion protein, 57103, that simultaneously targeted the cluster of differentiation 24 (CD24), interleukin 4 receptor (IL-4R), and integrin receptors αvβ3 and α5β1. In vitro assays showed that 57103 significantly suppressed the proliferation, migration, invasion, colony formation, and adhesion abilities of renal cancer cells, resulting in a comprehensive and significant antitumor effect. Furthermore, 57103 inhibited angiogenesis, promoted THP1-derived M0-type macrophage phagocytosis, and enhanced the antibody-dependent cellular cytotoxicity of peripheral blood mononuclear and NK92MI-CD16a cells. In vivo experiments revealed significant inhibition of tumor growth in ACHN cell xenograft nude mice and an MC38-hCD24 tumor-bearing mouse model. Immunohistochemical analysis showed that 57103 decreased the proliferation and induced the apoptosis of renal cancer cells, while inhibiting angiogenesis. The MC38-hPDL1 and MC38-hCD24-hPDL1 tumor-bearing mouse models further offer the possibility of combining 57103 with the PDL1 antagonist atezolizumab. In conclusion, 57103 is a potential candidate drug for the treatment of metastatic renal carcinoma or PDL1-overexpressing cancer.

Metabolic reprogramming is a cellular process in which cells modify their metabolic patterns to meet energy requirements, promote proliferation, and enhance resistance to external stressors. This process also introduces new functionalities to the cells. The ‘Warburg effect’ is a well-studied example of metabolic reprogramming observed during tumorigenesis. Recent studies have shown that kidney cells undergo various forms of metabolic reprogramming following injury. Moreover, metabolic reprogramming plays a crucial role in the progression, prognosis, and treatment of kidney cancer. This review offers a comprehensive examination of renal cancer, metabolic reprogramming, and its implications in kidney cancer. It also discusses recent advancements in the diagnosis and treatment of renal cancer.

The standard of care for non-metastatic renal cancer is surgical resection followed by adjuvant therapy for those at high risk for recurrences. However, for older patients, surgery may not be an option due to the high risk of complications which may result in death. In the past renal cancer was considered to be radio-resistant, and required a higher dose of radiation leading to excessive complications secondary to damage of the normal organs surrounding the cancer. Advances in radiotherapy technique such as stereotactic body radiotherapy (SBRT) has led to the delivery of a tumoricidal dose of radiation with minimal damage to the normal tissue. Excellent local control and survival have been reported for selective patients with small tumors following SBRT. However, for patients with poor prognostic factors such as large tumor size and aggressive histology, there was a higher rate of loco-regional recurrences and distant metastases. Those tumors frequently carry program death ligand 1 (PD-L1) which makes them an ideal target for immunotherapy with check point inhibitors (CPI). Given the synergy between radiotherapy and immunotherapy, we propose an algorithm combining CPI and SBRT for older patients with non-metastatic renal cancer who are not candidates for surgical resection or decline nephrectomy.

In recent decades, substantial advancements in epigenetics have unveiled a profound understanding of its mechanisms in tumorigenesis and have offered promising strategies for epigenetic therapy in cancer patients. In our study, through bioinformatics analysis, we discovered a significant downregulation and hypermethylation of FOXI2 in clear cell renal cell carcinoma (ccRCC), while the expression in chromophobe cell carcinoma (chRCC) exhibited the opposite trend. Moreover, we established a strong correlation between FOXI2 expression levels and the prognosis of ccRCC. Gene enrichment analysis and cell function experiments unequivocally demonstrate that FOXI2 possesses the capability to induce cell cycle arrest and inhibit cell proliferation.Our research findings demonstrate that the expression of FOXI2 in ccRCC is under the regulation of promoter hypermethylation. Furthermore, in vitro experiments have conclusively shown that the overexpression of FOXI2 induces cell cycle arrest and inhibits cell proliferation.

Abstract Background Defects and deficiency of AT-rich interactive domain-containing protein 1A (ARID1A) encoded by a tumor suppressor gene ARID1A have recently been suggested to get involved in angiogenesis, a crucial process in carcinogenesis. However, molecular mechanisms of ARID1A deficiency to induce angiogenesis in kidney cancer remain underinvestigated. Methods We performed large-scale identification of ARID1A protein interactors in renal tubular epithelial cells (RTECs) using immunoprecipitation (IP) followed by nanoLC-ESI-LTQ-Orbitrap tandem mass spectrometry (MS/MS). Their roles in angiogenesis were investigated using various assays. Results A total of 74 ARID1A-interacting proteins were identified. Protein–protein interactions analysis revealed that these identified proteins interacted directly or indirectly with ARID1A. Among them, the direct interaction between ARID1A and β-actin was validated by IP and reciprocal IP followed by Western blotting. Small interfering RNA (siRNA) was used for single and double knockdowns of ARID1A and ACTB. Semi-quantitative RT-PCR demonstrated that deficiency of ARID1A, but not ACTB, significantly affected expression of angiogenesis-related genes in RTECs (VEGF and FGF2 were increased, whereas PDGF and EGF were decreased). However, the knockdowns did not affect TGFB1 and FGF1 levels. The quantitative mRNA expression data of VEGF and TGFB1 were consistent with the secreted levels of their protein products as measured by ELISA. Only secreted products derived from ARID1A-deficient RTECs significantly increased endothelial cells (ECs) migration and tube formation. Some of the other carcinogenic features could also be confirmed in the ARID1A-deficient RTECs, including increased cell migration and chemoresistance. Double knockdowns of both ARID1A and ACTB did not enhance the effects of single ARID1A knockdown in all assays. Conclusions We report herein a large dataset of the ARID1A-interacting proteins in RTECs using an IP-MS/MS approach and confirm the direct interaction between ARID1A and β-actin. However, the role of ARID1A deficiency in angiogenesis is independent of β-actin.

Abstract Background Patient survival in advanced/metastatic melanoma, non‐small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) has improved with immune checkpoint inhibitors (ICI). Biomarkers' role in prognosis and treatment has been limited by conflicting trial results. Methods This retrospective, observational study analyzed baseline demographic, clinical, laboratory, and treatment data versus outcomes of The US Oncology Network adult outpatients. Patients with advanced/metastatic melanoma, NSCLC, or RCC treated between January 1, 2015 and November 30, 2020 were given ICI monotherapy or combination therapy with ipilimumab, pembrolizumab, nivolumab, or atezolizumab. Treatment outcomes (overall survival [OS], time to treatment discontinuation, time to next treatment) were followed longitudinally until May 31, 2021, last patient record, or date of death. Baseline blood cell counts, including absolute monocyte count (AMC), absolute lymphocyte count (ALC), monocyte‐to‐lymphocyte ratio (MLR), absolute neutrophil count (ANC), and eosinophil count, were subdivided into quintiles for univariate and multivariable Cox regression analyses. Results Data from 18,186 patients with advanced/metastatic melanoma (n = 3314), NSCLC (n = 12,416), and RCC (n = 2456) were analyzed. Better OS correlated with increased baseline serum albumin concentration, increased eosinophil and lymphocyte counts, and Western United States physician practice location. Decreased OS correlated with increased AMC, MLR, ANC, age, and worse Eastern Cooperative Oncology Group performance status. Conclusions To our knowledge, this study is the largest to date to associate baseline survival indicators and outcomes in outpatients with advanced/metastatic melanoma, NSCLC, or RCC and receiving ICIs. Results may inform disease‐specific prognostic models and help providers identify patients most likely to benefit from ICI therapy.

Objective: To evaluate the predictive validity of IRIS™ (Intuitive Surgical®, Sunnyvale, CA, USA) as a planning tool for robot-assisted partial nephrectomy (RAPN) by assessing the degree of overlap with intraoperative execution. Methods: Thirty-one patients scheduled for RAPN by four experienced urologists were enrolled in a prospective study. Prior to surgery, urologists reviewed the IRIS™ three-dimensional model on an iphone Operating System (iOS) app and completed a questionnaire outlining their surgical plan including surgical approach, and ischemia technique as well as confidence in executing this plan. Postoperatively, questionnaires assessing the procedural approach, clinical utility, efficiency, and effectiveness of IRIS™ were completed. The degree of overlap between the preoperative and intraoperative questionnaires and between the planned approach and actual execution of the procedure was analyzed. Questionnaires were answered on a 5-point Likert scale and scores of 4 or greater were considered positive. Results: Mean age was 65.1 years with a mean tumor size of 27.7 mm (interquartile range 17.5–44.0 mm). Hilar tumors consisted of 32.3%; 48.4% of patients had R.E.N.A.L. nephrometry scores of 7–9. On preoperative questionnaires, the surgeons reported that in 67.7% cases they were confident that they can perform the procedure successfully, and on intraoperative questionnaires, the surgeons reported that in 96.8% cases IRIS™ helped achieve good spatial sensation of the anatomy. There was a high degree of overlap between preoperative and intraoperative questionnaires for the surgical approach, interpreting anatomical details and clinical utility. When comparing plans for selective or off-clamp, the preoperative plan was executed in 90.0% of cases intraoperatively. Conclusion: A high degree of overlap between the preoperative surgical approach and intraoperative RAPN execution was found using IRIS™. This is the first study to evaluate the predictive accuracy of IRIS™ during RAPN by comparing preoperative plan and intraoperative execution.

Background: Acute kidney injury (AKI) after robot-assisted partial nephrectomy (RAPN) is a robust surrogate for chronic kidney disease. The objective of this study was to evaluate the association of ischemia type and duration during RAPN with postoperative AKI. Materials and methods: We reviewed all patients who underwent RAPN at our institution since 2011. The ischemia types were warm ischemia (WI), selective artery clamping (SAC), and zero ischemia (ZI). AKI was defined according to the Risk Injury Failure Loss End-Stage (RIFLE) criteria. We calculated ischemia time thresholds for WI and SAC using the Youden and Liu indices. Logistic regression and decision curve analyses were assessed to examine the association with AKI. Results: Overall, 154 patients met the inclusion criteria. Among all RAPNs, 90 (58.4%), 43 (28.0%), and 21 (13.6%) were performed with WI, SAC, and ZI, respectively. Thirty-three (21.4%) patients experienced postoperative AKI. We extrapolated ischemia time thresholds of 17 min for WI and 29 min for SAC associated with the occurrence of postoperative AKI. Multivariable logistic regression analyses revealed that WIT ≤ 17 min (odds ratio [OR] 0.1, p < 0.001), SAC ≤ 29 min (OR 0.12, p = 0.002), and ZI (OR 0.1, p = 0.035) significantly reduced the risk of postoperative AKI. Conclusions: Our results confirm the commonly accepted 20 min threshold for WI time, suggest less than 30 min ischemia time when using SAC, and support a ZI approach if safely performable to reduce the risk of postoperative AKI. Selecting an appropriate ischemia type for patients undergoing RAPN can improve short- and long-term functional kidney outcomes.

Abstract Background There is little prospective evidence exists about whether adherence to a diabetes risk reduction diet (DRRD) is related to a significant reduction in renal cancer risk. We sought to clarify whether adherence to DRRD was associated with a reduced risk of renal cancer in a US population. Methods A population-based cohort of 101,755 American adults was identified from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. A DRRD score was calculated to assess adherence to this dietary pattern, where increased scores indicated greater adherence. The relationship between DRRD score and risk of renal cancer was assessed based on the hazard ratios (HRs) and 95% confidence intervals (CIs), which were both calculated using Cox regression. Non-linear association was determined through restricted cubic spline regression. Potential effect modifiers were identified through subgroup analyses. Results Over a mean follow-up of 8.8 years, 446 renal cancers were detected. In this analysis, the fully adjusted model depicted a notable 29% reduction in the risk of renal cancer among individuals in the highest quartile of DRRD score in comparison with the lowest quartile individuals (HRQ4 vs. Q1: 0.71; 95% CI = 0.54, 0.94; P trend = 0.008). This association remained consistent across a series of sensitivity analyses. A non-linear inverse dose–response association between renal cancer risk with DRRD score was observed (P nonlinearity = 0.026). Subgroup analyses showed that this favorable link was more prominent in participants with low Healthy Eating Index-2015 (P interaction = 0.015). Regarding the individual components of DRRD, a decrease in the risk of renal cancer was linked to increased intake of cereal fiber and whole fruit, and lower sugar-sweetened beverage consumption (all P trend

Cancers of the urinary system account for 13.1% of new cancer cases and 7.9% of cancer-related deaths. Of them, renal cancer, bladder cancer, and prostate cancer are most prevalent and pose a substantial threat to human health and the quality of life. Prostate cancer is the most common malignant tumor in the male urinary system. It is the second most common type of malignant tumor in men, with lung cancer surpassing its incidence and mortality. Bladder cancer has one of the highest incidences and is sex-related, with men reporting a significantly higher incidence than women. Tumor development in the urinary system is associated with factors, such as smoking, obesity, high blood pressure, diet, occupational exposure, and genetics. The treatment strategies primarily involve surgery, radiation therapy, and chemotherapy. Cholesterol metabolism is a crucial physiological process associated with developing and progressing urinary system tumors. High cholesterol levels are closely associated with tumor occurrence, invasion, and metastasis. This warrants thoroughly investigating the role of cholesterol metabolism in urinary system tumors and identifying novel treatment methods for the prevention, early diagnosis, targeted treatment, and drug resistance of urinary system tumors.

Recent advancements in understanding clear cell renal cell carcinoma (ccRCC) have underscored the critical role of the BAP1 gene in its pathogenesis and prognosis. While the von Hippel–Lindau (VHL) mutation has been extensively studied, emerging evidence suggests that mutations in BAP1 and other genes significantly impact patient outcomes. Radiogenomics with and without texture analysis based on CT imaging holds promise in predicting BAP1 mutation status and overall survival outcomes. However, prospective studies with larger cohorts and standardized imaging protocols are needed to validate these findings and translate them into clinical practice effectively, paving the way for personalized treatment strategies in ccRCC. This review aims to summarize the current knowledge on the role of BAP1 mutation in ccRCC pathogenesis and prognosis, as well as the potential of radiogenomics in predicting mutation status and clinical outcomes.

Background: The pivotal role of phospholipase A2 group VII (PLA2G7) has been identified in specific human cancers, such as prostate cancer, diffuse large B cell lymphoma, and melanoma. Given PLA2G7's significant involvement in established tumors, exploring its role in other cancers is highly relevant. Methods: In this study, we acquired and analyzed data from The Cancer Genome Atlas database, the UCSC XENA website, and other online platforms including Gene Set Cancer Analysis, cBioPortal, Tumor Immune Estimation Resource, and TISIDB to investigate PLA2G7's role in human cancers, including renal cancer. Furthermore, in vitro experiments, including immunofluorescence, western blotting, and CCK-8 assays, were conducted to elucidate PLA2G7's role in renal cancer. Finally, the relationship between PLA2G7 and various drug sensitivity was explored. Results: Our findings demonstrate that PLA2G7 is highly expressed and may serve as a valuable candidate biomarker in pan-cancer. PLA2G7 exhibits distinct alteration frequencies across human cancers and is correlated with tumor mutation burden, tumor microenvironment, DNA stemness score, RNA stemness score, tumorigenesis, tumor immunity, and microsatellite instability in pan-cancer. Immunofluorescence and western blotting revealed a relative high level of PLA2G7 protein in renal cancer cell lines (ACHN and 786-O), predominantly localized in the cytoplasm. Treatment with a PLA2G7 gene inhibitor (darapladib) significantly decreased the viability of ACHN and 786-O cell lines. Additionally, we observed an association between PLA2G7 mRNA levels and various drug sensitivity. Conclusions: Our study suggests that PLA2G7 has the potential to serve as a valuable biomarker and therapeutic target for cancer, particularly in the context of renal cancer.

This report delineates the clinical progression of a renal oncocytoma in a 38-year-old female, initially asymptomatic, over a three-year follow-up period following her treatment for papillary thyroid cancer. The timeline of this case is as follows: In 2016, the patient was treated with total thyroidectomy and I131 for thyroid cancer. During an annual follow-up, an incidental renal mass was detected via FDG PET/CT, initially characterized as a benign, non-FDG-avid renal oncocytoma. Over two years, this lesion demonstrated a remarkable increase in FDG uptake and a slight growth in size, coupled with new I131 uptake in subsequent scans. These findings led to a reassessment of the diagnosis, initially suggesting a potential small renal cell carcinoma (RCC). Histopathological analysis eventually confirmed the diagnosis of oncocytoma. This case is notable for the tumor’s unusual metabolic evolution and the challenges it posed in differential diagnosis.

Collecting duct carcinoma is an exceptionally rare and aggressive form of renal cell carcinoma (RCC), representing between 0.4 and 1.8% of RCC cases. The most commonly affected demographic are young African-American males. Here, we present a rare case of collecting duct RCC in a 22 year-old Caucasian female with final pathological staging of pT1aN1 who underwent robot-assisted right radical nephrectomy, with peri-hilar and para-aortic lymph node dissection. Given her node-positivity, adjunctive treatment is discussed.

A 65-year-old male patient presented a large mass of the left kidney and a concomitant saccular abdominal aortic aneurysm (AAA) of the infrarenal aorta. Due to the particular vascularization of the right kidney in order to allow an endovascular Aneurysm Repair (EVAR), a hybrid staged repair was planned. Through a median laparotomy, a left radical nephrectomy and an ilio-renal bypass were performed, thus creating the anatomical feasibility for subsequent EVAR. Two days later the AAA was excluded by positioning of an abdominal straight stent graft. This original surgical strategy showed to be effective and reduced invasiveness of traditional approach.

Abstract Background Hispanics and American Indians (AI) have high kidney cancer incidence and mortality rates in Arizona. This study assessed: (1) whether racial and ethnic minority patients and patients from neighborhoods with high social vulnerability index (SVI) experience a longer time to surgery after clinical diagnosis, and (2) whether time to surgery, race and ethnicity, and SVI are associated with upstaging to pT3/pT4, disease‐free survival (DFS), and overall survival (OS). Methods Arizona Cancer Registry (2009–2018) kidney and renal pelvis cases (n = 4592) were analyzed using logistic regression models to assess longer time to surgery and upstaging. Cox‐regression hazard models were used to test DFS and OS. Results Hispanic and AI patients with T1 tumors had a longer time to surgery than non‐Hispanic White patients (median time of 56, 55, and 45 days, respectively). Living in neighborhoods with high (≥75) overall SVI increased odds of a longer time to surgery for cT1a (OR 1.54, 95% CI: 1.02–2.31) and cT2 (OR 2.32, 95% CI: 1.13–4.73). Race and ethnicity were not associated with time to surgery. Among cT1a patients, a longer time to surgery increased odds of upstaging to pT3/pT4 (OR 1.95, 95% CI: 0.99–3.84). A longer time to surgery was associated with PFS (HR 1.52, 95% CI: 1.17–1.99) and OS (HR 1.63, 95% CI: 1.26–2.11). Among patients with cT2 tumor, living in high SVI neighborhoods was associated with worse OS (HR 1.66, 95% CI: 1.07–2.57). Conclusions High social vulnerability was associated with increased time to surgery and poor survival after surgery.

MCL1 is a member of the BCL2 family of apoptosis regulators, which play a critical role in promoting cancer survival and drug resistance. We previously described PRT1419, a potent, MCL1 inhibitor with anti-tumor efficacy in various solid and hematologic malignancies. To identify novel biomarkers that predict sensitivity to MCL1 inhibition, we conducted a gene essentiality analysis using gene dependency data generated from CRISPR/Cas9 cell viability screens. We observed that clear cell renal cancer (ccRCC) cell lines with damaging PBRM1 mutations displayed a strong dependency on MCL1. PBRM1 (BAF180), is a chromatin-targeting subunit of mammalian pBAF complexes. PBRM1 is frequently altered in various cancers particularly ccRCC with ~40% of tumors harboring damaging PBRM1 alterations. We observed potent inhibition of tumor growth and induction of apoptosis by PRT1419 in various preclinical models of PBRM1-mutant ccRCC but not PBRM1-WT. Depletion of PBRM1 in PBRM1-WT ccRCC cell lines induced sensitivity to PRT1419. Mechanistically, PBRM1 depletion coincided with increased expression of pro-apoptotic factors, priming cells for caspase-mediated apoptosis following MCL1 inhibition. Increased MCL1 activity has been described as a resistance mechanism to Sunitinib and Everolimus, two approved agents for ccRCC. PRT1419 synergized with both agents to potently inhibit tumor growth in PBRM1-loss ccRCC. PRT2527, a potent CDK9 inhibitor which depletes MCL1, was similarly efficacious in monotherapy and in combination with Sunitinib in PBRM1-loss cells. Taken together, these findings suggest PBRM1 loss is associated with MCL1i sensitivity in ccRCC and provide rationale for the evaluation of PRT1419 and PRT2527 for the treatment for PBRM1-deficient ccRCC.

In clear cell renal cell carcinoma (ccRCC), dysregulated lipid metabolism plays a pivotal role in tumor initiation and progression. This study delves into the unexplored landscape of Dysregulated Aldehyde Dehydrogenase 3 Family Member A2 (ALDH3A2) in ccRCC. Using a combination of ''fatty acid metabolism'' dataset analysis and differentially expressed genes (DEGs) derived from Gene Expression Omnibus (GEO) database, potential metabolic regulators in ccRCC were identified. Subsequent investigations utilizing public databases, clinical samples, and in vitro experiments revealed that ALDH3A2 was down-regulated in ccRCC, mediated by miR-1182, highlighting its role as an independent prognostic factor for patient survival. Functionally, ALDH3A2 exhibited tumor-suppressive properties, impacting ccRCC cell phenotypes and influencing epithelial-mesenchymal transition. Mechanistically, silencing ALDH3A2 promoted lipid accumulation in ccRCC cells by activating the PI3K-AKT pathway, thereby promoting tumor progression. These findings shed light on the critical role of the miR-1182/ALDH3A2 axis in ccRCC tumorigenesis, emphasizing the potential for targeting lipid metabolism as a promising anti-cancer strategy.

IntroductionImmune checkpoint blockade (ICB) improved clinical outcomes in renal and bladder cancer patients, but the response rates remain limited especially in metastatic disease. While STAT3 transcription factor is well-known master regulator of tumor immune evasion, little is known about the role of STAT3 in the resistance of renal or bladder cancers to immunotherapy.MethodsTo better understand immune alterations associated with ICB resistance, we assessed blood biomarkers in renal cancer patients classified as responders or non-responders to first line nivolumab/ipilimumab immunotherapy.ResultsWe observed that non-responders showed elevated levels of proinflammatory mediators, such as IL-1RA, IL-6, IL-8 and to lesser extent IL-10, which are associated with STAT3 activation and tumor immunosuppression. In addition, we found STAT3 activation primarily in circulating myeloid immune cells such as tolerogenic MDSCs. To assess whether STAT3 inhibition within these cell subsets can promote antitumor immune responses and/or enhance sensitivity to ICB in vivo, we used an original antisense oligonucleotide (ASO) strategy for myeloid-cell selective STAT3 knockdown (CpG-STAT3ASO). Our results in syngeneic models of renal and bladder cancers in mice demonstrated potent antitumor activity of CpG-STAT3ASO alone in contrast to PD1 blockade alone in both models. The CpG-STAT3ASO/anti-PD1 combination improved therapeutic efficacy especially against bladder tumors. Therapeutic efficacy correlated with activation of dendritic cells (DCs) and M1 macrophages in the tumor microenvironment, reduced percentages of regulatory T cells (Tregs) and the expansion of CD8 T cells in both tumor models.Discussion/ConclusionOur study underscores the potential of using myeloid-cell targeted CpG-STAT3 inhibitors for genitourinary cancer therapy to disrupt tolerogenic signaling, restore immune cell activity and sensitivity to immune checkpoint inhibitors and/or T cell-based immunotherapies.

Abstract Purpose To evaluate three partial nephrectomies (PN) procedures: open (OPN), standard laparoscopy (LPN), and robot-assisted laparoscopy (RAPN), for the risk of initial complications and rehospitalization for two years after the surgery. Materials and methods From the French national hospital database (PMSI-MCO), every hospitalization in French hospitals for renal tumor PN in 2016–2017 were extracted. Complications were documented from the initial hospitalization and any rehospitalization over two years. Chi-square and ANOVA tests compared the frequency of complications and length of initial hospitalization between the three surgical procedures. Relative risks (RR) and 95% confidence intervals were computed. Results The 9119 initial hospitalizations included 4035 OPN, 1709 LPN, and 1900 RAPN; 1475 were excluded as the laparoscopic procedure performed was not determined. The average length of hospitalization was 8.1, 6.2, and 4.5 days for OPN, LPN, and RAPN, respectively. Compared to OPN, there were fewer complications at the time of initial hospitalization for the mini-invasive procedures: 29% for OPN vs. 20% for LPN (0.70 [0.63;0.78]) and 12% for RAPN (RR=0.43, 95%CI [0.38;0.49]). For RAPN compared to LPN, there were fewer haemorrhages (RR=0.55 [0.43;0.72]), anemia (0.69 {0.48;0.98]), and sepsis (0.51 [0.36;0.71]); during follow up, there were fewer urinary tract infections (0.64 [0.45;0.91]) but more infectious lung diseases (1.69 [1.03;2.76]). Over the two-year postoperative period, RAPN was associated with fewer acute renal failures (RR=0.73 [0.55;0.98]), renal abscesses (0.41 [0.23;0.74]), parietal complications (0.69 [0.52;0.92]) and urinary tract infections (0.54 [0.40;0.73]) than for OPN. Conclusions Conservative renal surgery is associated with postoperative morbidity related to the surgical procedure fashion. Mini-invasive procedures, especially robot-assisted surgery, had fewer complications and shorter hospital lengths of stay

Introduction: In estimated glomerular filtration rate equations (eGFR), the race multiplier (RM) yields greater eGFR values and may assign less severe chronic kidney disease (CKD) stages to black individuals. When deciding on appropriateness for partial nephrectomy (PN), patients with CKD are often considered a relative or absolute indication. We hypothesize that the eGFR RM may have ramifications for patients being counseled for radical nephrectomy (RN) versus PN to manage their renal tumor. Methods: We utilized prospective and retrospective, IRB-approved single-center databases to select patients who underwent PN or RN between 2016 and 2022. Demographics, preoperative risk factors, preoperative eGFR, and surgical management were collected. Descriptive statistics and two-tailed difference of proportion tests compared the percentage of patients with CKD who underwent nephrectomy. Results: This cohort included 1137 patients who underwent RN or PN, including 74 (6.5%) Black patients and 93.5% (n = 1063) non-Black patients. There was no statistically significant difference between the eGFR of Black and non-Black individuals using the Modification of Diet in Renal Disease equation (P = 0.24) or Chronic Kidney Disease Epidemiology Collaboration 2009 (CKD-EPI 2009) (P = 0.45); however, there was statistically significant difference in eGFR between sample populations when using CKD-EPI 2021 (P = 0.0055). Of the Black patient cohort, 16.2% of patients reclassified to a worse CKD class using CKD-EPI 2021, including 9.5% of Black patients reclassified to CKD3a or worse, and 14.6% of all patients (Black and non-Black) reclassified to a different CKD class under the CKD-EPI 2021 equation. Conclusions: There are quantitative differences in the evaluation of eGFR when utilizing different equations that may impact clinical considerations and health equity outcomes for nephrectomy across racial groups.

Sunitinib has greatly improved the survival of clear cell renal cell carcinoma (ccRCC) patients in recent years. However, 20–30% of treated patients do not respond. To identify miRNAs and genes associated with a response, comparisons were made between biopsies from responder and non-responder ccRCC patients. Using integrated transcriptomic analyses, we identified 37 miRNAs and 60 respective target genes, which were significantly associated with the NF-kappa B, PI3K-Akt and MAPK pathways. We validated expression of the miRNAs (miR-223, miR-155, miR-200b, miR-130b) and target genes (FLT1, PRDM1 and SAV1) in 35 ccRCC patients. High levels of miR-223 and low levels of FLT1, SAV1 and PRDM1 were associated with worse overall survival (OS), and combined miR-223 + SAV1 levels distinguished responders from non-responders (AUC = 0.92). Using immunohistochemical staining of 170 ccRCC patients, VEGFR1 (FLT1) expression was associated with treatment response, histological grade and RECIST (Response Evaluation Criteria in Solid Tumors) score, whereas SAV1 and BLIMP1 (PRDM1) were associated with metachronous metastatic disease. Using in situ hybridisation (ISH) to detect miR-155 we observed higher tumoural cell expression in non-responders, and non-tumoural cell expression with increased histological grade. In summary, our preliminary analysis using integrated miRNA-target gene analyses identified several novel biomarkers in ccRCC patients that surely warrant further investigation.

(1) Background: Renal-cell carcinoma (RCC) incidence has been steadily rising, with obesity identified as a potential risk factor. However, the relationship between obesity and RCC prognosis remains unclear. This systematic review aims to investigate the impact of different adipose tissue measurements on RCC behavior and prognosis. (2) Methods: A search of MEDLINE databases identified 20 eligible studies focusing on various fat measurements, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), perirenal adipose tissue (PRAT), and the Mayo adhesive probability (MAP) score. (3) Results: The review revealed conflicting findings regarding the association between adipose tissue measurements and RCC outcomes. While some studies suggested a protective role of certain fat deposits, particularly VAT, against disease progression and mortality, others reported contradictory results across different adipose metrics and RCC subtypes. (4) Conclusions: Methodological variations and limitations, such as retrospective designs and sample size constraints, pose challenges to standardization and generalizability. Further research is needed to understand these associations better and establish standardized approaches for adiposity assessment in RCC patients, which could inform clinical practice and therapeutic decision-making.

Off-clamp partial nephrectomy represents one of the latest developments in nephron-sparing surgery, with the goal of preserving renal function and reducing ischemia time. The aim of this study was to evaluate and compare the functional, oncologic, and perioperative outcomes between off-clamp robot-assisted partial nephrectomy (off-C RAPN) and off-clamp open partial nephrectomy (off-C OPN) through a propensity score-matched (PSM) analysis. A 1:1 PSM analysis was used to balance variables potentially affecting postoperative outcomes. To report surgical quality, 1 year trifecta was used. Univariable Cox regression analysis was performed to identify predictors of trifecta achievement. The Kaplan–Meier method was used to compare cancer-specific survival (CSS), overall survival (OS), disease-free survival (DFS), and metastasis-free survival (MFS) probabilities between groups. Overall, 542 patients were included. After PSM analysis, two homogeneous cohorts of 147 patients were obtained. The off-C RAPN cohort experienced shorter length of stay (LoS) (3.4 days vs. 5.4 days; p < 0.001), increased likelihoods of achieving 1 year trifecta (89.8% vs. 80.3%; p = 0.03), lower postoperative Clavien–Dindo ≤ 2 complications (1.3% vs. 18.3%, p < 0.001), and lower postoperative transfusion rates (3.4% vs. 12.2%, p = 0.008). At univariable analysis, the surgical approach (off-C RAPN vs. off-C OPN, OR 2.22, 95% CI 1.09–4.46, p = 0.02) was the only predictor of 1 year trifecta achievement. At Kaplan–Meier analysis, no differences were observed between the two groups in terms of OS (log-rank p = 0.451), CSS (log-rank p = 0.476), DFS (log-rank p = 0.678), and MFS (log-rank p = 0.226). Comparing RAPN and OPN in a purely off-clamp scenario, the minimally invasive approach proved to be a feasible and safe surgical approach, with a significantly lower LoS and minor rate of postoperative complications and transfusions as a result of improved surgical quality expressed by higher 1 year trifecta achievement.

Renal cancer (RC) can spread to different organs, metastatic damage of the pancreas is quite rare. But, in contrast of primary and other metastatic malignant tumors, pancreatic RC metastases can be resectable in 80 % of cases with nearly 90 % 5-year survival rate. Pancreatic oncologic surgery includes 3 different types of resection: distal pancreatic resection, pancreatoduodenal resection and total duodenopancreatectomy. The last type is the most extensive procedure, incorporates except of total removal of the pancreatic gland, total excision of duodenum and, in some cases, partial gastrectomy. In surgery of pancreatic tumors using of total duodenopancreatectomy is relatively rare (6,7-12,3 %). And in spite of low mortality (5-6,25 %) in recent years, whole removal of the gland inevitably leads to severe metabolic changes such as complete exocrine insufficiency and unstable insulin-depended diabetes mellitus which need lifetime medical correction. Gastrointestinal bleeding from pancreatic metastases of RC as a disease complication occurs quite rare and appears due to invasion of cancer tissue located in the pancreatic head to duodenal mucosa and then ulcerated. There are few single observations or little series (2-4 cases) described in literature. Pancreatoduodenal resection in such cases is the main type of surgical intervention. Now we present a case of successful urgent total duodenopancreatectomy, performed for recurrent profuse gastrointestinal bleeding from pancreatic head metastasis of RC invaded duodenum after previously radical nephrectomy. During the operation several cancer nodes in the pancreatic body and tail were found that defined the total gland removal. Postoperative period proceeded uneventfully and the patient was discharged on 15th day. Uniqueness of this case is that emergency total duodenopancreatectomy was successfully done for profuse gastrointestinal bleeding as the only possible chance for cure. We have not found similar reports in the available literature.

Abstract Background Sunitinib is a multi‐target tyrosine kinase inhibitor (TKI) that inhibits VEGF receptor 1, 2, 3 (VEGFRs), platelet‐derived growth factor receptor (PDGFR), colony‐stimulating factor receptor (CSFR), and the stem cell factor receptor c‐KIT. Temsirolimus inhibits mammalian target of rapamycin (mTOR) through binding to intracellular protein FKBP‐12. Both agents are approved for the treatment of metastatic renal cell carcinoma (mRCC), have different anticancer mechanisms, and non‐overlapping toxicities. These attributes form the scientific rationale for sequential combination of these agents. The primary objective of the study was to investigate the efficacy of alternating sunitinib and temsirolimus therapy on progression‐free survival (PFS) in mRCC. Methods We undertook a phase II, multi‐center, single cohort, open‐label study in patients with mRCC. Patients were treated with alternating dosing of 4 weeks of sunitinib 50 mg PO daily, followed by 2 weeks rest, then 4 weeks of temsirolimus 25 mg IV weekly, followed by 2 weeks rest (12 weeks total per cycle). The primary endpoint was PFS. Secondary endpoints included clinical response rate and characterization of the toxicity profile of this combination therapy. Results Nineteen patients were enrolled into the study. The median observed PFS (n = 13 evaluable for PFS) was 8.8 months (95% CI 6.8–25.2 months). Best responses achieved were five partial response, nine stable disease, and three disease progression according to RECIST 1.1 guidelines (two non‐evaluable). The most commonly observed toxicities were fatigue, platelet count decrease, creatinine increased, diarrhea, oral mucositis, edema, anemia, rash, hypophosphatemia, dysgeusia, and palmar‐plantar erythrodysesthesia syndrome. Conclusion Alternating sunitinib and temsirolimus did not improve the PFS in patients with mRCC.

Abstract Background Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined. Methods Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes. Results Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of $$\gamma$$ γ H2AX foci, a marker of double-stranded breaks, in PBMCs from eoRCC patients versus PBMCs from matched cancer-free controls. Knockdown of candidate variant genes in Caki RCC cells increased $$\gamma$$ γ H2AX foci. Immortalized patient-derived B cell lines bearing the candidate variants in DNA polymerase genes (POLD1, POLH, POLE, POLK) had DNA replication defects compared to control cells. Renal tumors carrying these DNA polymerase variants were microsatellite stable but had a high mutational burden. Direct biochemical analysis of the variant Pol δ and Pol η polymerases revealed defective enzymatic activities. Conclusions Together, these results suggest that constitutional defects in DNA repair underlie a subset of eoRCC cases. Screening patient lymphocytes to identify these defects may provide insight into mechanisms of carcinogenesis in a subset of genetically undefined eoRCCs. Evaluation of DNA repair defects may also provide insight into the cancer initiation mechanisms for subsets of eoRCCs and lay the foundation for targeting DNA repair vulnerabilities in eoRCC.

Abstract 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.