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Purpose: This study investigates the rare occurrence of tumor-to-tumor metastasis in Pituitary Neuroendocrine Tumors (PitNETs), also known as pituitary adenomas, aiming to enhance understanding of its diagnostic and therapeutic challenges. We report two cases from our institution of tumor-to-tumor metastasis involving PitNETs, followed by a systematic literature review. Methods: We conducted a comprehensive literature review using PubMed and Google Scholar databases. This review provides insights into patient demographics, clinical presentations, primary tumor origin, management approaches and outcomes. Results: We identified 38 documented cases of tumor-to-tumor metastasis involving the pituitary gland in the literature. This revealed a diverse range of primary tumor origins, with lung, breast, and renal carcinomas being the most prevalent. Clinical presentations varied, with visual disturbances emerging as the most frequently reported symptom. Surgical interventions predominantly resulted in subtotal resection. Kaplan–Meier survival analysis demonstrated that endoscopic endonasal approaches (EEA) are associated with longer median survival times compared to other surgical methods. Conclusion: Tumor-to-tumor metastasis to PitNETs must be considered in differential diagnoses of sellar masses. Prompt and accurate diagnosis, coupled with a multidisciplinary treatment strategy, is essential. Our study contributes to the scarce literature on such metastases, providing a foundation for further understanding of this complex pathological entity. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) comprises the majority, approximately 70–80%, of renal cancer cases and often remains asymptomatic until incidentally detected during unrelated abdominal imaging or at advanced stages. Currently, standardized screening tests for renal cancer are lacking, which presents challenges in disease management and improving patient outcomes. This study aimed to identify ccRCC-specific volatile organic compounds (VOCs) in the urine of ccRCC-positive patients and develop a urinary VOC-based diagnostic model. Methods: This study involved 233 pretreatment ccRCC patients and 43 healthy individuals. VOC analysis utilized stir-bar sorptive extraction coupled with thermal desorption gas chromatography/mass spectrometry (SBSE-TD-GC/MS). A ccRCC diagnostic model was established via logistic regression, trained on 163 ccRCC cases versus 31 controls, and validated with 70 ccRCC cases versus 12 controls, resulting in a ccRCC diagnostic model involving 24 VOC markers. Results: The findings demonstrated promising diagnostic efficacy, with an Area Under the Curve (AUC) of 0.94, 86% sensitivity, and 92% specificity. Conclusions: This study highlights the feasibility of using urine as a reliable biospecimen for identifying VOC biomarkers in ccRCC. While further validation in larger cohorts is necessary, this study's capability to differentiate between ccRCC and control groups, despite sample size limitations, holds significant promise. [ABSTRACT FROM AUTHOR]

Background: Cancer stem-like cells (CSCs), a distinct subset recognized for their stem cell-like abilities, are intimately linked to the resistance to radiotherapy, metastatic behaviors, and self-renewal capacities in tumors. Despite their relevance, the definitive traits and importance of CSCs in the realm of oncology are still not fully comprehended, particularly in the context of clear cell renal cell carcinoma (ccRCC). A comprehensive understanding of these CSCs' properties in relation to stemness, and their impact on the efficacy of treatment and resistance to medication, is of paramount importance. Methods: In a meticulous research effort, we have identified new molecular categories designated as CRCS1 and CRCS2 through the application of an unsupervised clustering algorithm. The analysis of these subtypes included a comprehensive examination of the tumor immune environment, patterns of metabolic activity, progression of the disease, and its response to immunotherapy. In addition, we have delved into understanding these subtypes' distinctive clinical presentations, the landscape of their genomic alterations, and the likelihood of their response to various pharmacological interventions. Proceeding from these insights, prognostic models were developed that could potentially forecast the outcomes for patients with ccRCC, as well as inform strategies for the surveillance of recurrence after treatment and the handling of drug-resistant scenarios. Results: Compared with CRCS1, CRCS2 patients had a lower clinical stage/grading and a better prognosis. The CRCS2 subtype was in a hypoxic state and was characterized by suppression and exclusion of immune function, which was sensitive to gefitinib, erlotinib, and saracatinib. The constructed prognostic risk model performed well in both training and validation cohorts, helping to identify patients who may benefit from specific treatments or who are at risk of recurrence and drug resistance. A novel therapeutic target, SAA2, regulating neutrophil and fibroblast infiltration, and, thus promoting ccRCC progression, was identified. Conclusions: Our findings highlight the key role of CSCs in shaping the ccRCC tumor microenvironment, crucial for therapy research and clinical guidance. Recognizing tumor stemness helps to predict treatment efficacy, recurrence, and drug resistance, informing treatment strategies and enhancing ccRCC patient outcomes. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer. It advances quickly and often metastasizes, making the prognosis for patients challenging. This study used weighted gene co-expression network analysis (WGCNA) to study gene expression data of different stages of ccRCC obtained in the GEO database. The analysis identified three significant highly preserved gene modules across the datasets: GSE53757, GSE22541, GSE66272, and GSE73731. Functional annotation and pathway enrichment analysis using DAVID revealed inflammatory pathways (e.g., NF-kB, Hippo, and HIF-1 pathways) that may drive ccRCC development and progression. The study also introduced the involvement of viral infections associated with the disease in the metabolic reprogramming of ccRCC. A drug repurposing analysis was also conducted to identify potential drug candidates for ccRCC using the upregulated and downregulated hub genes. The top candidates are ziprasidone (dopamine and serotonin receptor antagonist) and fentiazac (cyclooxygenase inhibitor). Other drug candidates were also obtained, such as phosphodiesterase/DNA methyltransferase/ATM kinase inhibitors, acetylcholine antagonists, and NAD precursors. Overall, the study's findings suggest that identifying several genes and signaling pathways related to ccRCC may uncover new targets, biomarkers, and even drugs that can be repurposed, which can help develop new and effective treatments for the disease. [ABSTRACT FROM AUTHOR]

In recent years, kidney cancer has shown an increased worldwide incidence of more than 400 000 novel cases annually. Although more than half of patients are diagnosed at a localised stage, this disease presents a high-risk of relapse after surgery. Thus, there is a need for adjuvant therapy post-resection to reduce cancer recurrence and prolong disease-free and overall survival. Thorough investigation of adjuvant drugs for renal cell carcinoma (RCC) has shown little promise in the last fifty years, with no recorded overall survival benefits. This was the case until pembrolizumab, an immune checkpoint inhibitor, was introduced into the adjuvant RCC space through the KEYNOTE-564 trial. The adjuvant administration of this novel anti-PD-1 drug demonstrated a significant overall survival benefit which has led to an update in the current treatment guidelines of RCC. This substantial change in the standard of care also caused an investigation of possible treatment combinations and an adoption of innovative predictive biomarkers. In this review, we will present the evolution of past adjuvant ICI trials for the treatment of RCC, the implications of pembrolizumab's overall survival benefits and a discussion of future directions concerning new RCC drug trials and liquid biopsy-based biomarkers. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) accounts for roughly 85% of all malignant kidney cancer. Therapeutic options for RCC have expanded rapidly over the past decade. Targeted therapy and immunotherapy have ushered in a new era of the treatment of RCC, which has facilitated the outcomes of RCC. However, the related adverse effects and drug resistance remain an urgent issue. Natural compounds are optional strategies to reduce mobility. Natural compounds are favored by clinicians and researchers due to their good tolerance and low economic burden. Many studies have explored the anti‐RCC activity of natural products and revealed relevant mechanisms. In this article, the chemoprevention and therapeutic potential of natural compounds is reviewed and the mechanisms regarding natural compounds are explored. [ABSTRACT FROM AUTHOR]

Background Despite complete resection, 20%-50% of patients with localized renal cell carcinoma (RCC) experience recurrence within 5 years. Accurate assessment of prognosis in high-risk patients would aid in improving outcomes. Here we evaluate the use of circulating tumor DNA (ctDNA) in RCC using banked samples and clinical data from a single institution. Methods The cohort consisted of 45 RCC patients (≥pT1b) who underwent complete resection. The presence of ctDNA in plasma was determined using a personalized, tumor-informed ctDNA assay (Signatera RUO, Natera, Inc.). Relationships with outcomes and other relevant clinical variables were assessed. The median follow-up was 62 months. Results Plasma ctDNA was detected in 18 out of 36 patients (50%) pre-operatively and was associated with increased tumor size (mean 9.3 cm vs. 7.0 cm, P  < .05) and high Fuhrman grade (60% grades III-IV vs 27% grade II, P  = .07). The presence of ctDNA, either pre-operatively or at any time post-operatively, was associated with inferior relapse-free survival (HR = 2.70, P  = .046; HR = 3.23, P  = .003, respectively). Among patients who were ctDNA positive at any time point, the sensitivity of relapse prediction was 84% with a PPV of 90%. Of note, ctDNA positivity at a post-surgical time point revealed a PPV of 100% and NPV of 64%. The lack of ctDNA detection at both time points yielded an NPV of 80%. Conclusions Detection of plasma ctDNA using a personalized assay is prognostic of recurrence in patients with resected RCC. Herein, we describe a successful approach for its application and identify potential limitations to be addressed in future studies. [ABSTRACT FROM AUTHOR]

Background Even though cytoreductive nephrectomy (CN) was once the standard of care for patients with advanced renal cell carcinoma (RCC), its role in treatment has not been well analyzed or defined in the era of immunotherapy (IO). Materials and Methods This study analyzed pathological outcomes in patients with advanced or metastatic RCC who received IO prior to CN. This was a multi-institutional, retrospective study of patients with advanced or metastatic RCC. Patients were required to receive IO monotherapy or combination therapy prior to radical or partial CN. The primary endpoint assessed surgical pathologic outcomes, including American Joint Committee on Cancer (AJCC) staging and frequency of downstaging, at the time of surgery. Pathologic outcomes were correlated to clinical variables using a Wald-chi squared test from Cox regression in a multi-variable analysis. Secondary outcomes included objective response rate (ORR) defined by response evaluation criteria in solid tumors (RECIST) version 1.1 and progression-free survival (PFS), which were estimated using the Kaplan-Meier method with reported 95% CIs. Results Fifty-two patients from 9 sites were included. Most patients were male (65%), 81% had clear cell histology, 11% had sarcomatoid differentiation. Overall, 44% of patients experienced pathologic downstaging, and 13% had a complete pathologic response. The ORR immediately prior to nephrectomy was stable disease in 29% of patients, partial response in 63%, progressive disease in 4%, and 4% unknown. Median follow-up for the entire cohort was 25.3 months and median PFS was 3.5 years (95% CI, 2.1-4.9). Conclusions IO-based interventions prior to CN in patients with advanced or metastatic RCC demonstrates efficacy, with a small fraction of patients showing a complete response. Additional prospective studies are warranted to investigate the role of CN in the modern IO-era. [ABSTRACT FROM AUTHOR]

Purpose: Metabolite‐specific balanced SSFP (MS‐bSSFP) sequences are increasingly used in hyperpolarized [1‐13C]Pyruvate (HP 13C) MRI studies as they improve SNR by refocusing the magnetization each TR. Currently, pharmacokinetic models used to fit conversion rate constants, kPL and kPB, and rate constant maps do not account for differences in the signal evolution of MS‐bSSFP acquisitions. Methods: In this work, a flexible MS‐bSSFP model was built that can be used to fit conversion rate constants for these experiments. The model was validated in vivo using paired animal (healthy rat kidneys n = 8, transgenic adenocarcinoma of the mouse prostate n = 3) and human renal cell carcinoma (n = 3) datasets. Gradient echo (GRE) acquisitions were used with a previous GRE model to compare to the results of the proposed GRE‐bSSFP model. Results: Within simulations, the proposed GRE‐bSSFP model fits the simulated data well, whereas a GRE model shows bias because of model mismatch. For the in vivo datasets, the estimated conversion rate constants using the proposed GRE‐bSSFP model are consistent with a previous GRE model. Jointly fitting the lactate T2 with kPL resulted in less precise kPL estimates. Conclusion: The proposed GRE‐bSSFP model provides a method to estimate conversion rate constants, kPL and kPB, for MS‐bSSFP HP 13C experiments. This model may also be modified and used for other applications, for example, estimating rate constants with other hyperpolarized reagents or multi‐echo bSSFP. [ABSTRACT FROM AUTHOR]

Purpose: Dialysis patients are at an increased risk of developing renal cell carcinoma (RCC); however, differentiating between RCC and benign cysts can sometimes be difficult using modalities, such as computed tomography (CT) and ultrasonography. 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET)/CT efficiently detects malignant tumors; however, physiological accumulation of FDG in the kidney limits its efficacy in detecting renal tumors. However, in patients with severely impaired renal function, the renal accumulation of FDG is decreased, possibly improving the detection of renal malignancies in this patient population. This study evaluated the usefulness of FDG-PET/CT as a screening tool for detecting RCC in patients with end-stage renal disease. Materials and methods: This prospective study recruited 150 participants from 2012 to 2016 who were on dialysis or underwent renal transplantation and were on dialysis until transplantation. FDG-PET/CT was performed to screen for RCC. Three radiologists independently evaluated the images. No protocol was defined for the additional management of positive examinations, leaving decisions to the discretion of each participant. Negative examinations were observed until the end of 2019. Results: In total, 150 participants (mean age, 58 ± 13 years; 105 men) underwent FDG-PET/CT. Twenty patients (13.4%) were diagnosed as positive. Fifteen patients underwent additional examinations and/or procedures, and RCC was found in seven patients. Of the four patients who underwent surgical resection, the pathological results were clear cell RCC in one, papillary RCC in one, and acquired cystic disease-associated RCC in two. Two participants were diagnosed with RCC on bone biopsy, and one was diagnosed on dynamic CT but opted for observation. The sensitivity, specificity, and negative predictive value were 100%, 93.9%, and 100%, respectively. Conclusion: FDG-PET/CT was useful for detecting RCC in patients with end-stage renal disease. Our findings show the potential use of FDG-PET/CT as a screening tool for RCC in this patient population. [ABSTRACT FROM AUTHOR]

Context: The MEIS proteins, originally described as the "helper groups" of HOX proteins, are now becoming recognized as significant and incredibly diverse controllers of cellular behavior. The MEIS agents can incorporate a variety of epigenetic modulators into chromatin to aid in embryonic growth or tissue homeostasis by adult stem cells. The MEIS gene's expression, binding, stability, post-translational protein modification, and controlled intracellular availability are all fully regulated, and they all react to external stimuli. Objectives: We explored the diverse roles of MEIS proteins in cellular behavior and epigenetic regulation and investigated the potential of MEIS proteins as diagnostic and therapeutic biomarkers in cancers. Results: The MEIS proteins can be diagnostic and therapeutic biomarkers for cancer. The MEIS-PBX heterotrimeric is involved in neurogenesis processes, and the formation of the MEIS2 heterodimer with PAX6 and DLX2 can proliferate periplomerular dopaminergic neurons in the olfactory bulb. The estrogen receptor in breast cancer upregulates MEIS1 and FOXP3. The estrogen receptor pathway's cancer-related genes can express themselves more strongly when MEIS1-FOXP3 interacts with a positive feedback mechanism. Because MEIS1 expression is decreased in clear renal cell carcinoma (ccRCC) cell lines, MEIS1 may function as a tumor suppressor in the development of ccRCC. Conclusions: MEIS1 is recognized as one of the main contributors to the development of leukemias. The MEIS proteins influence the c-MYC signaling pathway, cell proliferation, and invasion of PC by contributing to its development. [ABSTRACT FROM AUTHOR]

Xp11.2 translocation renal cell carcinomas (tRCC) are a rare and highly malignant type of renal cancer, lacking efficient diagnostic indicators and therapeutic targets. Through the analysis of public databases and our cohort, we identified NMRK2 as a potential diagnostic marker for distinguishing Xp11.2 tRCC from kidney renal clear cell carcinoma (KIRC) and kidney renal papillary cell carcinoma (KIRP) due to its specific upregulation in Xp11.2 tRCC tissues. Mechanistically, we discovered that TFE3 fusion protein binds to the promoter of the NMRK2 gene, leading to its upregulation. Importantly, we established RNA‐ and protein‐based diagnostic methods for identifying Xp11.2 tRCC based on NMRK2 expression levels, and the diagnostic performance of our methods was comparable to a dual‐color break‐apart fluorescence in situ hybridization assay. Moreover, we successfully identified fresh Xp11.2 tRCC tissues after surgical excision using our diagnostic methods and established an immortalized Xp11.2 tRCC cell line for further research purposes. Functional studies revealed that NMRK2 promotes the progression of Xp11.2 tRCC by upregulating the NAD+/NADH ratio, and supplementation with β‐nicotinamide mononucleotide (NMN) or nicotinamide riboside chloride (NR), effectively rescued the phenotypes induced by the knockdown of NMRK2 in Xp11.2 tRCC. Taken together, these data introduce a new diagnostic indicator capable of accurately distinguishing Xp11.2 tRCC and highlight the possibility of developing novel targeted therapeutics. © 2024 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Clear cell ovarian carcinoma (CCOC) is an aggressive malignancy affecting younger women. Despite ovarian cancer subtypes having diverse molecular and clinical characteristics, the mainstay of treatment for advanced stage disease remains cytotoxic chemotherapy. Late stage CCOC is resistant to conventional chemotherapy, which means a suboptimal outcome for patients affected. Despite detailed genomic, epigenomic, transcriptomic, and proteomic characterisation, subtype‐specific treatment for CCOC has shown little progress. The unique glycogen accumulation defining CCOC suggests altered metabolic pathway activity and dependency. This study presents the first metabolomic landscape of ovarian cancer subtypes, including 42 CCOC, 20 high‐grade serous and 21 endometrioid ovarian carcinomas, together comprising the three most common ovarian carcinoma subtypes. We describe a distinct metabolomic landscape of CCOC compared with other ovarian cancer subtypes, including alterations in energy utilisation and cysteine metabolism. In addition, we identify CCOC‐specific alterations in metabolic pathways including serine biosynthesis and ROS‐associated pathways that could serve as potential therapeutic targets. Our study provides the first in‐depth study into the metabolome of ovarian cancers and a rich resource to support ongoing research efforts to identify subtype‐specific therapeutic targets that could improve the dismal outcome for patients with this devastating malignancy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

ABSTRACT Uveal melanoma (UM) is a rare yet aggressive eye cancer causing over 50% mortality from metastasis. Familial UM, amounting to 1%–6% of patients in Finland and the United States, mostly lack identified genetic cause, while 8% show associations with other cancer syndromes. We searched novel genetic associations for predisposition to UM, additional to already studied BAP1 and MBD4, by using targeted amplicon sequencing of 19 genes associated with UM, BAP1, or renal cell carcinoma in 270 consecutively enrolled Finnish patients with UM. Key UM drivers GNAQ, GNA11, CYSLTR2, PLCB4, EIF1AX, and SF3B1 lacked pathogenic germline variants. One patient carried the pathogenic BRCA1 variant c.3626del p.(Leu1209*), and one harbored a novel truncating MET variant c.252C > G p.(Tyr84*), classified as likely pathogenic. FLCN and BRCA2, previously identified with pathogenic variants in patients with UM, did not have such variants in our cohort. Two patients were heterozygous for a pathogenic recessive BLM variant c.2824‐2A > T. None of the carriers of identified variants had familial UM. We identified BRCA1 and MET as genes with pathogenic germline variants in Finnish UM patients, each with a frequency of 0.4% (95% confidence interval, 0–2). [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is the most prevalent subtype of kidney cancer. Although there is increasing evidence linking ccRCC to genetic alterations, the exact molecular mechanism behind this relationship is not yet completely known to the researchers. Though drug therapies are the best choice after the metastasis, unfortunately, the majority of the patients progressively develop resistance against the therapeutic drugs after receiving it for almost 2 years. In this case, multi-targeted different variants of therapeutic drugs are essential for effective treatment against ccRCC. To understand molecular mechanisms of ccRCC development and progression, and explore multi-targeted different variants of therapeutic drugs, it is essential to identify ccRCC-causing key genes (KGs). In order to obtain ccRCC-causing KGs, at first, we detected 133 common differentially expressed genes (cDEGs) between ccRCC and control samples based on nine (9) microarray gene-expression datasets with NCBI accession IDs GSE16441, GSE53757, GSE66270, GSE66272, GSE16449, GSE76351, GSE66271, GSE71963, and GSE36895. Then, we filtered these cDEGs through survival analysis with the independent TCGA and GTEx database and obtained 54 scDEGs having significant prognostic power. Next, we used protein-protein interaction (PPI) network analysis with the reduced set of 54 scDEGs to identify ccRCC-causing top-ranked eight KGs (PLG, ENO2, ALDOB, UMOD, ALDH6A1, SLC12A3, SLC12A1, SERPINA5). The pan-cancer analysis with KGs based on TCGA database showed the significant association with different subtypes of kidney cancers including ccRCC. The gene regulatory network (GRN) analysis revealed some crucial transcriptional and post-transcriptional regulators of KGs. The scDEGs-set enrichment analysis significantly identified some crucial ccRCC-causing molecular functions, biological processes, cellular components, and pathways that are linked to the KGs. The results of DNA methylation study indicated the hypomethylation and hyper-methylation of KGs, which may lead the development of ccRCC. The immune infiltrating cell types (CD8+ T and CD4+ T cell, B cell, neutrophil, dendritic cell and macrophage) analysis with KGs indicated their significant association in ccRCC, where KGs are positively correlated with CD4+ T cells, but negatively correlated with the majority of other immune cells, which is supported by the literature review also. Then we detected 10 repurposable drug molecules (Irinotecan, Imatinib, Telaglenastat, Olaparib, RG-4733, Sorafenib, Sitravatinib, Cabozantinib, Abemaciclib, and Dovitinib.) by molecular docking with KGs-mediated receptor proteins. Their ADME/T analysis and cross-validation with the independent receptors, also supported their potent against ccRCC. Therefore, these outputs might be useful inputs/resources to the wet-lab researchers and clinicians for considering an effective treatment strategy against ccRCC. [ABSTRACT FROM AUTHOR]

Function of HECTD2 in renal cell carcinoma malignant progression is undefined. Molecular mechanism behind anti-cancer effects of veratric acid (VA) from traditional Chinese medicine (TCM) is underexplored. The Cancer Genome Atlas was leveraged to study HECTD2 expression in renal cell carcinoma and its relationship with histological grading. Kaplan–Meier survival analysis was performed. HECTD2 expression was detected in cancer cells and tissues via qRT-PCR and immunohistochemistry. GPX4 and SLC7A11 expression in tumor samples with high or low HECTD2 expression was examined by immunohistochemistry, cell viability by CCK8, cell proliferation by colony formation assay, lipid ROS and mitochondrial superoxide levels by flow cytometry, Fe2+ and MDA content by assay kits, and GPX4 and SLC7A11 proteins by western blot. SeeSAR software screened TCM small molecule compounds with highest affinity to HECTD2, confirmed with cellular thermal shift assay. VA IC50 was measured by CCK8. Xenograft model was developed and treated with VA. Tumor size and weight were monitored, with immunohistochemistry to detect HECTD2 expression in tumors and assess ferroptosis-related markers. HECTD2 was overexpressed in tumor tissues and cells, which positively correlated with histological grading. HECTD2 depletion inhibited cell vitality and proliferation, raised intracellular lipid ROS, mitochondrial superoxide, Fe2+, and MDA. HECTD2 was a target with highest VA affinity. In vitro and vivo experiments concurred that VA treatment hindered malignancy of renal cell carcinoma and enhanced its susceptibility to ferroptosis. HECTD2 supports ferroptosis resistance in renal cell carcinoma, but VA, through its targeting of HECTD2, initiates ferroptosis, showcasing its anti-cancer efficacy. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC), a prevalent malignant tumor, exhibits resistance to chemotherapy, necessitating advanced therapeutic approaches. Sonocatalytic therapy has emerged as a promising non‐invasive treatment for solid tumors due to its ability to penetrate deep tissue. Herein, the development of single atomic Au‐doped 2D TiO2 nanosheets are presented with oxygen vacancies (Au‐SA/Def‐TiO2, ASDT) for sonocatalytic treatment of ccRCC. Surface defects on TiO2 nanosheets effectively stabilize Au single atomic sites via the Ti‐Au‐Ti structure, enhancing catalytic properties and facilitating reactive oxygen species (ROS) generation by reducing energy barriers and improving electron (e−) and hole (h+) separation. Additionally, ASDT exhibits peroxidase‐like activities, further augmenting ROS production, leading to significant inhibition of tumor growth in subcutaneous and orthotopic ccRCC models under ultrasound irradiation. This study underscores the efficacy of defect engineering for stabilizing single atoms to boost ROS production and achieve effective tumor eradication by the enhanced sonocatalytic effect. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the prognostic value of the geriatric nutritional risk index (GNRI) in patients with non-metastatic clear cell renal cell carcinoma (ccRCC) who underwent nephrectomy. Methods: Patients with non-metastatic ccRCC who underwent nephrectomy between 2013 and 2021 were analyzed retrospectively. The GNRI was calculated within one week before surgery. The optimal cut-off value of GNRI was determined using X-tile software, and the patients were divided into a low GNRI group and a high GNRI group. The Kaplan-Meier method was used to compare the overall survival (OS), cancer-specific survival (CSS) and recurrence-free survival (RFS) between the two groups. Univariate and multivariate Cox proportional hazard models were used to determine prognostic factors. In addition, propensity score matching (PSM) was performed with a matching ratio of 1:3 to minimize the influence of confounding factors. Variables entered into the PSM model were as follows: sex, age, history of hypertension, history of diabetes, smoking history, BMI, tumor sidedness, pT stage, Fuhrman grade, surgical method, surgical approach, and tumor size. Results: A total of 645 patients were included in the final analysis, with a median follow-up period of 37 months (range: 1-112 months). The optimal cut-off value of GNRI was 98, based on which patients were divided into two groups: a low GNRI group (≤ 98) and a high GNRI group (> 98). Kaplan-Meier analysis showed that OS (P < 0.001), CSS (P < 0.001) and RFS (P < 0.001) in the low GNRI group were significantly worse than those in the high GNRI group. Univariate and multivariate Cox analysis showed that GNRI was an independent prognostic factor of OS, CSS and RFS. Even after PSM, OS (P < 0.05), CSS (P < 0.05) and RFS (P < 0.05) in the low GNRI group were still worse than those in the high GNRI group. In addition, we observed that a low GNRI was associated with poor clinical outcomes in elderly subgroup (> 65) and young subgroup (≤ 65), as well as in patients with early (pT1-T2) and low-grade (Fuhrman I-II) ccRCC. Conclusion: As a simple and practical tool for nutrition screening, the preoperative GNRI can be used as an independent prognostic indicator for postoperative patients with non-metastatic ccRCC. However, larger prospective studies are necessary to validate these findings. [ABSTRACT FROM AUTHOR]

Notably, clear cell renal cell carcinoma (ccRCC) is characterized by a distinct metabolic tumor phenotype that involves the reprogramming of multiple metabolic pathways. Although there is increasing evidence linking FUCA1 to malignancies, its specific role and downstream signaling pathways in ccRCC remain poorly understood. Here we found that FUCA1 expression was significantly downregulated in ccRCC tissues, which also predicts poor prognosis of ccRCCpatients. Moreover, enhancing FUCA1 expression resulted in reduced invasion and migration of ccRCC cells, further indicating its protective role. CHIP-qPCR and luciferase assays showed that CTCF was an upstream transcription factor of FUCA1 and could reverse the effects caused by FUCA1 inactivation. The change in FUCA1 led to changes in the results of various autophagy-related proteins and the mRFP-GFP-LC3 dual fluorescence system, indicating that it may play a role in the fusion stage of autophagy. Protein-protein interaction analysis revealed that FUCA2 exhibited the closest interaction with FUCA1 and strongly predicted the prognosis of ccRCC patients. Additionally, serum AFU encoded by FUCA2 could serve as a valuable predictor for survival in ccRCC patients. FUCA1 suppresses invasion and migration of ccRCC cells, with its activity being modulated by CTCF. FUCA1 regulates the autophagy process in ccRCC cells by influencing the fusion between autophagosomes and lysosomes. FUCA2 shares similarities with FUCA1, and elevated serum AFU levels along with increased expression of FUCA2 are indicative of a favorable prognosis in ccRCC. [ABSTRACT FROM AUTHOR]

N6-methyladenosine (m6A) is a prevalent mRNA modification known for its implications in various cancer types, yet its role in chromophobe renal cell carcinoma (chRCC) remains largely unexplored. In this study, we performed m6A-SEAL-seq and RNA-seq analyses on tissues from three chRCC subjects, aiming to uncover m6A alterations in chRCC. Our findings revealed reduced expression levels of four m6A regulators in chRCC tissues and highlighted differences in m6A levels compared to normal tissues. Furthermore, we identified specific genes and cancer-related pathways affected by these differences, including notable candidates like NOTCH1 and FGFR1, implicated in chRCC development. Additionally, we developed a predictive model based on the expression level of m6A associated genes, demonstrating promising prognostic capabilities for patient survival prediction. Overall, our study provides valuable insights into the role of m6A in chRCC and its potential as a prognostic indicator. [ABSTRACT FROM AUTHOR]

Objectives: To develop radiomics models based on multi-sequence MRI from two centers for the preoperative prediction of the WHO/ISUP grade of Clear Cell Renal Cell Carcinoma (ccRCC). Methods: This retrospective study included 334 ccRCC patients from two centers. Significant clinical factors were identified through univariate and multivariate analyses. MRI sequences included Dynamic contrast-enhanced MRI, axial fat-suppressed T2-weighted imaging, diffusion-weighted imaging, and in-phase/out-of-phase images. Feature selection methods and logistic regression (LR) were used to construct clinical and radiomics models, and a combined model was developed using the Rad-score and significant clinical factors. Additionally, seven classifiers were used to construct the combined model and different folds LR was used to construct the combined model to evaluate its performance. Models were evaluated using receiver operating characteristic (ROC) curves, area under the curve (AUC), and decision curve analysis (DCA). The Delong test compared ROC performance, with p < 0.050 considered significant. Results: Multivariate analysis identified intra-tumoral vessels as an independent predictor of high-grade ccRCC. In the external validation set, the radiomics model (AUC = 0.834) outperformed the clinical model (AUC = 0.762), with the combined model achieving the highest AUC (0.855) and significantly outperforming the clinical model (p = 0.003). DCA showed that the combined model had a higher net benefit within the 0.04–0.54 risk threshold range than clinical model. Additionally, the combined model constructed using logistic regression has a higher priority compared to other classifiers. Additionally, 10-fold cross-validation with LR for the combined model showed consistent AUC values (0.849–0.856) across different folds. Conclusion: The radiomics models based on multi-sequence MRI might be a noninvasive and effective tool, demonstrating good efficacy in preoperatively predicting the WHO/ISUP grade of ccRCC. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs. Methods: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed. Results: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1–36.8) and 63.8% (95% CI, 48.0–75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS. Conclusion: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases. [ABSTRACT FROM AUTHOR]

Purpose: The management of renal cell carcinoma (RCC) relies on clinical and histopathological features for treatment decisions. Recently, radiomics, which involves the extraction and analysis of quantitative imaging features, has shown promise in improving RCC management. This review evaluates the current application and limitations of radiomics for predicting treatment and oncological outcomes in RCC. Methods: A systematic search was conducted in Medline, EMBASE, and Web of Science databases or studies that used radiomics to predict response to treatment and survival outcomes in patients with RCC. The study quality was assessed using the Radiomics Quality Score (RQS) tools. Results: The systematic review identified a total of 27 studies, examining 6,119 patients. The most used imaging modality was contrast-enhanced abdominal CT. The reviewed studies extracted between 19 and 3376 radiomics features, including Histogram, Texture, Filter, or transformation method. Radiomics-based risk stratification models provided valuable insights into treatment response and oncological outcomes. All developed signatures demonstrated at least modest accuracy (AUC range: 0.55–0.99). The studies included in this analysis reported heterogeneous results regarding radiomics methods. The range of Radiomics Quality Score (RQS) was from − 5 to 20, with a mean RQS total of 9.15 ± 7.95. Conclusion: Radiomics has emerged as a promising tool in the management of RCC. It offers the potential for improved risk stratification and response assessment. However, future trials must demonstrate the generalizability of findings to prospective cohorts before progressing towards clinical translation. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to analyze the expression patterns of immune cells in renal cancer patients, including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), CD3 + /CD4 + T cells, CD3 + / CD8 + T cells, and CD3- CD16 + CD56 + cells. In addition, this study will explore the correlation between these immune markers and the progression of renal cell carcinoma and evaluate their potential application in predicting the therapeutic effect of renal cell carcinoma. Methods: In this study, 80 renal cancer patients who received treatment in our hospital from October 2022 to December 2023 were selected as the research object and 50 healthy people who underwent a physical examination at the same time were selected as the control group. All participants had a 3 ml venous blood sample taken in the morning on an empty stomach. All patients with renal cell carcinoma have been confirmed by histopathological diagnosis. Clinicopathological data including age, gender, BMI, clinical stage, tumor size and pathological type were collected.MDSC, Treg, CD3 + /CD4 + T cells, CD3 + /CD8 + T cells, the ratio of CD3 + /CD4 + T cells/CD3 + /CD8 + T cell and the expression level of CD3-CD16 + CD56 + cells were detected by flow cytometry. Results: Through the detection of flow cytometry, we observed that there was no significant difference in gender, age, BMI and other baseline characteristics between renal cancer patients and healthy controls, and the P value was greater than 0.05. However, in the analysis of peripheral blood immune cell subsets, including CD3 + /CD4 + , CD3 + /CD8 + , CD3 + /CD4 + /CD3 + /CD8 + ratio, NK cells, regulatory T cells (T-reg), polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and mononuclear myeloid-derived suppressor cells (M-MDSC) were significantly different between renal cell carcinoma group and normal control group (P < 0.05). Specifically, the expression levels of CD3 + /CD4 + and CD3 + /CD8 + cells in renal cancer patients were lower than those in normal subjects, while the expression levels of T-reg, PMN-MDSC and M-MDSC were relatively high. (2) In the flow cytometry analysis, the expression level of immune cell subsets in the peripheral blood of renal cancer patients was detected.The results showed that there was no significant correlation between the expression of CD3 + /CD4 + , CD3 + /CD8 + , CD3 + /CD4 + /CD3 + /CD8 + ratio, NK cells, T-reg cells, PMN-MDSC and M-MDSC and the sex, age, BMI and pathological type of the patients. These differences were not statistically significant (P > 0.05).At the same time, CD3 + /CD8 + T cells, the ratio of CD3 + /CD4 + /CD3 + /CD8 + and the expression level of NK cells were not significantly correlated with tumor size and clinical stage (P > 0.05). However, the expression levels of CD3 + /CD4 + cells, M-MDSC, PMN-MDSC, and T-reg cells were statistically significantly different with tumor size and clinical stage (P < 0.05).There was a significant difference between these indexes and lymph node metastasis (P < 0.05). (3) The results of Logistic regression analysis showed that the low expression of CD3 + /CD4 + lymphocytes and the high expression of T-reg, PMN-MDSC and M-MDSC in peripheral blood may be related to the clinical stage of renal cell carcinoma. Conclusion: (1) Compared with healthy individuals, patients with renal cell carcinoma showed a significant decrease in CD3 + /CD4 + T cells, CD3 + /CD8 + T cells and CD3-CD16 + CD56 + cells, while the CD4 + /CD8 + ratio increased. In addition, the number of PMN-MDSC, M-MDSC and T-reg cells was significantly increased compared with the normal population, indicating that the immune system function of patients was impaired. (2) The expression levels of CD3 + /CD4 + , PMN-MDSC, M-MDSC and T-reg were different in tumor size and clinical stage. Specifically, the expression levels of PMN-MDSC, M-MDSC, and T-reg increased correspondingly with the increase in tumor diameter and the progression of the clinical stage. [ABSTRACT FROM AUTHOR]

Tumour immunity is highly important for the occurrence and development of tumours, and many cancers are resistant to ferroptosis. This study aims to explore the relationship between ferroptosis-related genes (FRGs) and the immunological characteristics of kidney renal clear cell carcinoma (KIRC). We obtained RNA-seq profiles and clinical data of KIRC patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases and identified CD44 and GLRX5 as the key FRGs involved in KIRC immune infiltration through Spearman's correlation analysis. Based on the expression of CD44 and GLRX5, the consensus clustering algorithm was used to classify the TCGA-KIRC samples into two clusters. A nomogram was constructed to evaluate the prognosis of KIRC patients. ESTIMATE, CIBERSORT, and single-sample gene set enrichment analysis (ssGSEA) were performed to evaluate immune infiltration between the two clusters. A weighted gene co-expression network analysis (WGCNA) was used to identify the most relevant genes to the clusters and immunity. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed. The external dataset GSE53757 was used to validate the immunological features between the two clusters. Cluster 2 patients had more active immune infiltration and might be more sensitive to immunotherapy; Cluster 2 patients also had a worse prognosis and might be at a more advanced stage of KIRC. We identified key ferroptosis-related genes and subgroups involved in the immune infiltration of KIRC, which is highly important for exploring the molecular mechanisms and treatments of KIRC. [ABSTRACT FROM AUTHOR]

Background: Metastasis, the leading cause of renal cell carcinoma (RCC) mortality, involves cancer cells resisting anoikis and invading. Until now, the role of the matrix metalloproteinase (MMP)-related enzyme, A disintegrin and metalloprotease with thrombospondin motifs 1 (ADAMTS1), in RCC anoikis regulation remains unclear. Methods: The clinical significance of ADAMTS1 and its associated molecules in patients with RCC was investigated using data from the Gene Expression Omnibus (GEO) and TCGA datasets. Human phosphoreceptor tyrosine kinase (RTK) array, luciferase reporter assays, immunoprecipitation (IP) assays, western blotting, and real-time reverse-transcription quantitative polymerase chain reaction (RT–qPCR) were used to elucidate the underlying mechanisms of ADAMTS1. Functional assays, including anoikis resistance assays, invasion assays, and a Zebrafish xenotransplantation model, were conducted to assess the roles of ADAMTS1 in conferring resistance to anoikis in RCC. Results: This study found elevated ADAMTS1 transcripts in RCC tissues that were correlated with a poor prognosis. ADAMTS1 manipulation significantly affected cell anoikis through the mitochondrial pathway in RCC cells. Human receptor tyrosine kinase (RTK) array screening identified that epidermal growth factor receptor (EGFR) activation was responsible for ADAMTS1-induced anoikis resistance and invasion. Further investigations revealed that enzymatically active ADAMTS1-induced versican V1 (VCAN V1) proteolysis led to EGFR transactivation, which in turn, through positive feedback, regulated ADAMTS1. Additionally, ADAMTS1 can form a complex with p53 to influence EGFR signaling. In vivo, VCAN or EGFR knockdown reversed ADAMTS1-induced prometastatic characteristics of RCC. A clinical analysis revealed a positive correlation between ADAMTS1 and VCAN or the EGFR and patients with RCC with high ADAMTS1 and VCAN expression had the worst prognoses. Conclusions: Our results collectively uncover a novel cyclic axis involving ADAMTS1–VCAN–EGFR, which significantly contributes to RCC invasion and resistance to anoikis, thus presenting a promising therapeutic target for RCC metastasis. [ABSTRACT FROM AUTHOR]

Renal Cell Carcinoma (RCC) is the most common malignant tumor (85%) of kidney cancer and has a complex histological pattern and nuclear structure. The manual diagnosis of kidney cancer or any other cancer from histopathology image depends on the knowledge and experience of pathologists, and the pathologist's experience influences the results. According to studies, the kind of histology in kidney cancer is related to the prognosis and course of treatment. Since the kind of histology, molecular profile, and stage of the disease all affect how the disease is treated, there is an essential need to develop an automated system that can precisely analyze the histopathological images of the disease. This work demonstrates how a deep learning framework can be used to predict and classify associated grades of RCC from provided haematoxylin and eosin (H &E) images. The proposed model focuses on two important tasks- First to capture and extract associated features from the H &E images of five different grades. Second, to classify the new set of unseen H &E images into five separate grades using the obtained features. The proposed architecture has been tested and experimented on two independent datasets containing H &E stained histopathology images. The proposed architecture has been examined using the following performance metrics namely precision, recall, F1 - score, accuracy, Floating-point operations (FLOPs), and the total number of parameters. The obtained results show that the proposed architecture attains better results over seven state-of-the-art deep learning architectures on two different H &E stained histopathology image datasets. [ABSTRACT FROM AUTHOR]

Importance: Renal cell carcinoma (RCC) is a common malignancy, with an estimated 434 840 incident cases worldwide in 2022. In the US, it is the sixth most common cancer among males and ninth among females. Observations: Clear cell RCC is the most common histologic subtype (75%-80% of cases) and is characterized by inactivation of the von Hippel Lindau (VHL) tumor suppressor gene. Many patients (37%-61%) are diagnosed with RCC incidentally on an abdominal imaging study such as ultrasound or computed tomographic scan, and 70% of patients have stage I RCC at diagnosis. Although its incidence has increased approximately 1% per year from 2015 through 2019, the mortality rate of RCC has declined about 2% per year in the US from 2016 through 2020. Patients with a solid renal mass or complex cystic renal mass should be referred to urology. Treatment options for RCC confined to the kidney include surgical resection with partial or radical nephrectomy, ablative techniques (eg, cryoablation, radiofrequency ablation, radiation), or active surveillance for some patients (especially those with renal masses <2 cm). For patients with renal masses less than 4 cm in size (48% of patients), partial nephrectomy can result in a 5-year cancer-specific survival of more than 94%. For advanced or metastatic RCC, combinations of immune checkpoint inhibitors or the combination of immune checkpoint inhibitors with tyrosine kinase inhibitors are associated with tumor response of 42% to 71%, with a median overall survival of 46 to 56 months. Conclusions and Relevance: RCC is a common malignancy that is often diagnosed incidentally on an abdominal imaging study. Seventy percent of patients are diagnosed with stage I RCC and 11% of patients with stage IV. First-line treatments for early-stage RCC are partial or radical nephrectomy, which can result in 5-year cancer-specific survival of more than 94%, ablative techniques, or active surveillance. New treatment options for patients with metastatic RCC include immune checkpoint inhibitors and tyrosine kinase inhibitors. This review summarizes the epidemiology, clinical presentation, pathophysiology, and management of renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Drug resistance after long‐term use of Tyrosine kinase inhibitors (TKIs) has become an obstacle for prolonging the survival time of patients with clear cell renal cell carcinoma (ccRCC). Here, genome‐wide CRISPR‐based screening to reveal that HDAC8 is involved in decreasing the sensitivity of ccRCC cells to sunitinib is applied. Mechanically, HDAC8 deacetylated ETS1 at the K245 site to promote the interaction between ETS1 and HIF‐2α and enhance the transcriptional activity of the ETS1/HIF‐2α complex. However, the antitumor effect of inhibiting HDAC8 on sensitized TKI is not very satisfactory. Subsequently, inhibition of HDAC8 increased the expression of NEK1, and up‐regulated NEK1 phosphorylated ETS1 at the T241 site to promote the interaction between ETS1 and HIF‐2α by impeded acetylation at ETS1‐K245 site is showed. Moreover, TKI treatment increased the expression of HDAC8 by inhibiting STAT3 phosphorylation in ccRCC cells is also found. These 2 findings highlight a potential mechanism of acquired resistance to TKIs and HDAC8 inhibitors in ccRCC. Finally, HDAC8‐in‐PROTACs to optimize the effects of HDAC8 inhibitors through degrading HDAC8 and overcoming the resistance of ccRCC to TKIs are synthesized. Collectively, the results revealed HDAC8 as a potential therapeutic candidate for resistance to ccRCC‐targeted therapies. [ABSTRACT FROM AUTHOR]

Introduction: Renal cell carcinoma (RCC) represents cancer originating from the renal epithelium and accounts for > 90% of cancers in the kidney. Prostatespecific membrane antigen (PSMA) is overexpressed in tumor-associated neovascular endothelial cells of many solid tumors, including metastatic RCC. Although studied in several small clinical studies, PSMA-based imaging and therapy have not been pursued rigorously in preclinical RCC. This study aimed to evaluate the preclinical performance of PSMA-based radiotheranostic agents in a relevant murine model. Methods: A PSMA-overexpressing murine cell line, PSMA+ RENCA, was developed by lentiviral transduction. PSMA-based theranostic agents, 68Ga-L1/177Lu-L1/225Ac-L1, were synthesized in high radiochemical yield and purity following our reported methods. Immunocompetent BALB/c mice were used for flank and orthotopic tumor inoculation. 68Ga-L1 was evaluated in small animal PET/CT imaging in flank and PET/MR imaging in orthotopic models. Cell viability studies were conducted for 177Lu-L1 and 225Ac-L1. Proof-of-concept treatment studies were performed using 225Ac-L1 (0, 37 kBq, 2 kBq × 37 kBq, 1 week apart) using PSMA+ RENCA in the flank model. Results: Cellular uptake of 68Ga-L1, 177Lu-L1, and 225Ac-L1 confirmed the specificity of the agents to PSMA+ RENCA cells rather than to RENCA (wt) cells, which are low in PSMA expression. The uptake in PSMA+ RENCA cells at 1 h for 68Ga-L1 (49.0% incubated dose [ID] ± 3.6%ID/million cells), 177Lu-L1 (22.1% ID ± 0.5%ID)/million cells), and 225Ac-L1 (4.1% ± 0.2% ID)/million cells), respectively, were higher than the RENCA (wt) cells (~ 1%ID-2%ID/million cells). PET/CT images displayed > 7-fold higher accumulation of 68Ga-L1 in PSMA+ RENCA compared to RENCA (wt) in flank implantation at 1 h. A twofold higher accumulation of 68Ga-L1 was observed in orthotopic tumors than in normal kidneys during 1-3 h postinjection. High lung uptake was observed with 68Ga-L1 PET/MR imaging 3 weeks after orthotopic implantation of PSMA+ RENCA due to spontaneous lung metastases. The imaging data were further confirmed by immunohistochemical characterization. 225Ac-L1 (0-37 kBq) displayed a dose-dependent reduction of cell proliferation in the PSMA+ RENCA cells after 48 h incubation; ~ 40% reduction in the cells with treated 37 kBq compared to vehicle (p < 0.001); however, no effect was observed with 177Lu-L1 (0-3700 kBq) up to 144 h postinoculation, suggesting lower efficacy of β-particle-emitting radiations in cellular studies compared to a-particle-emitting 225Ac-L1. Animals treated with 225Ac-L1 at 1 week posttumor inoculation in flank models displayed significant tumor growth delay (p < 0.03) and longer median survival of 21 days and 24 days for the treatment groups 37 kBq and 2 kBq × 37 kBq, respectively, compared to the vehicle group (12 days). Conclusion: The results suggest that a theranostic strategy targeting PSMA, employing PET and α-emitting radiopharmaceuticals, enabled tumor growth control and enhanced survival in a relevant immunocompetent murine model of RCC. These studies provide the rationale for clinical studies of PSMA-targeted theranostic agents in patients with RCC. [ABSTRACT FROM AUTHOR]

Automatic segmentation of renal tumours during renal cell carcinoma surgery can help doctors accurately locate the tumour region, protect the tissues and organs around the kidneys, enhance surgical efficiency, and reduce the possibility of leakage and misdiagnosis. However, since general polyp endoscopic image segmentation models have many problems when facing the task of renal tumour segmentation, there needs to be more research on the segmentation of endoscopic images of renal tumours. This paper proposes a multi‐scale dynamic segmentation kernel network for endoscopic image segmentation of kidney tumours. First, a spatial receptive field module is proposed to augment the feature information and improve the performance of the whole network. Second, an enhanced cross‐attention module is offered to attenuate the effect of a high‐similarity segmentation background. Finally, a multi‐scale dynamic segmentation kernel module is introduced to gradually refine the segmentation results from small to large sizes to obtain more accurate tumour boundaries. Extensive experiments on the established kidney tumour endoscopic dataset and publicly available endoscopic datasets show that this method exhibits enhanced performance and generalization capabilities compared to existing techniques. On this renal tumour dataset, MDSK‐Net achieved excellent results of 94.1% and 90.1% on mDice and mIoU. [ABSTRACT FROM AUTHOR]

Background: Clear cell renal cell carcinoma (ccRCC) poses substantial treatment challenges, especially in advanced stages where the efficacy of immune checkpoint blockade (ICB) therapy varies significantly. Elevated expression of the oncogene TUBA1C has been correlated with poor prognosis in various cancers, however, its role in ccRCC is unclear, especially concerning ICB resistance. Methods: Single-cell analysis was used to examine gene expression variations in malignant cells post-ICB therapy. This included investigating TUBA1C expression across different ICB response groups and its relationship with CD274. A general module of action was identified through pan-cancer and pan-tissue analysis. TUBA1C expression and its association with clinical characteristics and prognosis was further validated. Multiple algorithms were employed to explore immune cell infiltration levels, and the DepMap database was utilized to assess gene dependency and mutation status in kidney cancer cell lines. The in silico knockout of TUBA1C was performed using deep learning model, complemented by immunohistochemical assays, clinical cohort and functional assays validations. Results: TUBA1C expression is elevated in malignant cells following ICB therapy and is correlated with ICB resistance in ccRCC. High TUBA1C expression activates PI3K/AKT pathway and is associated with increased infiltration of regulatory T cells and myeloid-derived suppressor cells, which contributes to an immunosuppressive microenvironment in ccRCC. Patients with high TUBA1C expression exhibit a greater tumor mutation burden and increased genetic variation, which causes a worse prognosis. Additionally, TUBA1C dependency and its effects were evident in kidney cancer cell lines, where mutations conferred resistance to anti-PD-L1 therapy. In silico knockout analyses indicated that treatment targeting TUBA1C shifted malignant cells to a state responsive to ICB therapy. Immunohistochemistry, RT-qPCR and clinical cohort validation further confirmed that TUBA1C expression was upregulated and contributed to poorer outcome in ccRCC. Finaly, wound healing and CCK-8 assays demonstrated the potent oncogenic function of TUBA1C. Conclusions: TUBA1C is a pivotal regulator in ccRCC, affecting both disease progression and the effectiveness of ICB therapy by fostering an immunosuppressive microenvironment mediated by the PI3K/AKT pathway. Additionally, TUBA1C holds promise, both as a prognostic biomarker and a therapeutic target, for enhancing responsiveness to ICB. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma is a urological malignancy with a high metastatic rate, while targeted therapy for renal cell carcinoma still has much room for improvement. Some cutting-edge researches have focused on exosome in cancer treatment and there are some breakthroughs in breast cancer, lung cancer, and pancreatic cancer. Up to now, exosome in renal cell carcinoma progression and implications for targeted therapy has been under research by scientists. In this review, we have summarized the structure, formation, uptake, functions, and detection of exosomes, classified the mechanisms of exosomes that cause renal cell carcinoma progression, and listed the promising utilization of exosomes in targeted therapy for renal cell carcinoma. In all, based on the mechanisms of exosomes causing renal cell carcinoma progression and borrowing the successful experience from renal cell carcinoma models and other cancers, exosomes will possibly be a promising target for therapy in renal cell carcinoma in the foreseeable future. [ABSTRACT FROM AUTHOR]

In addition to the ubiquitous loss of the VHL gene in clear cell renal cell carcinoma (ccRCC), co-deletions of chromatin-regulating genes are common drivers of tumorigenesis, suggesting potential vulnerability to epigenetic manipulation. A library of chemical probes targeting a spectrum of epigenetic regulators is screened using a panel of ccRCC models. MS023, a type I protein arginine methyltransferase (PRMT) inhibitor, is identified as an antitumorigenic agent. Individual knockdowns indicate PRMT1 as the specific critical dependency for cancer growth. Further analyses demonstrate impairments to cell cycle and DNA damage repair pathways upon MS023 treatment or PRMT1 knockdown. PRMT1-specific proteomics reveals an interactome rich in RNA binding proteins and further investigation indicates significant widespread disruptions in mRNA metabolism with both MS023 treatment and PRMT1 knockdown, resulting in R-loop accumulation and DNA damage over time. Our data supports PRMT1 as a target in ccRCC and informs a mechanism-based strategy for translational development. Here, the authors show that PRMT1 targeting inhibits clear cell renal cell carcinoma cells through perturbation of RNA metabolism and down-regulation of DNA repair pathways, resulting in the accumulation of unresolved R-loops and DNA damage. [ABSTRACT FROM AUTHOR]

Background: Ailanthone (Ail) extracted from medicinal plants has played an anticancer role in multiple cancers, while there is no research about Ail in renal cell carcinoma (RCC). Methods: In the present study, we performed CCK-8 and flow cytometry to assess the effect of Ail on cell viability, apoptosis and cycle. We also performed tandem mass tags (TMT)-labeled quantitative proteomic technology and bioinformatic analysis to identify the functional pathway and proteins of Ail in RCC. Results: The results showed Ail could inhibit cell viability and induce cell apoptosis. Proteomic profiling identified 1732 differentially expressed proteins in cells treated with Ail, compared to the negative control group. Gene ontology function annotation and Gene Set Enrichment Analysis (GSEA) were performed to identified the involved biological processes, molecular function and pathway. Results of GSEA proved the enrichment of Deps in EZH2 targets. The comparison between Deps and EZH2 co-expressed genes revealed 44 overlapped genes and we identified 4 hub genes (CDC20, CEP55, TOP2A, and UBE2C) associated with RCC progression. The molecular docking study revealed a moderate to tight binding potential of Ail and EZH2, and western blotting showed EZH2 was suppressed after cells treated with Ail. Conclusion: Altogether, we identified the anticancer role of Ail in RCC, including inhibition of cell proliferation and induction of apoptosis. The results also screened the key proteins mediate the function of Ail, which have laid a theoretical foundation for elucidating the applications of Ail in clinical research. [ABSTRACT FROM AUTHOR]

Introduction: Imaging in renal cell carcinoma (RCC) is a constantly evolving landscape. The incidence of RCC has been rising over the years with the improvement in image quality and sensitivity in imaging modalities resulting in "incidentalomas" being detected. We aim to explore the latest advances in imaging for RCC. Methods: A literature search was conducted using Medline and Google Scholar, up to May 2024. For each subsection of the manuscript, a separate search was performed using a combination of the following key terms "renal cell carcinoma", "renal mass", "ultrasound", "computed tomography", "magnetic resonance imaging", "18F-Fluorodeoxyglucose PET/CT", "prostate-specific membrane antigen PET/CT", "technetium-99m sestamibi SPECT/CT", "carbonic anhydrase IX", "girentuximab", and "radiomics". Studies that were not in English were excluded. The reference lists of selected manuscripts were checked manually for eligible articles. Results: The main imaging modalities for RCC currently are ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). Contrast-enhanced US (CEUS) has emerged as an alternative to CT or MRI for the characterisation of renal masses. Furthermore, there has been significant research in molecular imaging in recent years, including FDG PET, PSMA PET/CT, 99mTc-Sestamibi, and anti-carbonic anhydrase IX monoclonal antibodies/peptides. Radiomics and the use of AI in radiology is a growing area of interest. Conclusions: There will be significant change in the field of imaging in RCC as molecular imaging becomes increasingly popular, which reflects a shift in management to a more conservative approach, especially for small renal masses (SRMs). There is the hope that the improvement in imaging will result in less unnecessary invasive surgeries or biopsies being performed for benign or indolent renal lesions. [ABSTRACT FROM AUTHOR]

Angiomyolipoma (AML) are the most common benign solid renal mass. Differentiation from malignant tumours is essential. Imaging features in ultrasound may overlap between malignant lesions, especially between renal cell carcinoma (RCC) and AML. So far, sectional imaging has been necessary for reliable differentiation. The aim of this study is to evaluate the use of the ultrasound-guided attenuation parameter (UGAP), a recently established tool for assessing hepatic steatosis, in the differentiation of AMLs from other renal masses. Therefore, 27 patients with unknown solid renal masses were examined by ultrasound including UGAP. The attenuation was assessed qualitatively by attenuation map and quantitatively in comparison to the surrounding renal tissue. UGAP was applicable in 26/27 patients. Findings were compared with CT/MRI as the current imaging standard. A total of 18 AML and 9 other renal tumours were found. The diagnostic performance of B-Mode (hyperechogenic lesion) ultrasound was 77.8% in identifying AML. The diagnostic performance of the attenuation map showed a diagnostic performance of 92.6%, whereby UGAP measurements were successful in 76.9% of cases. Quantitatively, we found a significant difference (p < 0.034) in mean measured attenuation between AML (0.764 ± 0.162 dB/cm/MHz) vs. other renal tumours (0.658 ± 0.155 dB/cm/MHz). The best performance was found by a combined parameter of a hyperechogenic lesion with a positive attenuation map with an accuracy of 95.0%. In conclusion, UGAP may represent a possibility for differentiating solid renal lesions more accurately by ultrasound, especially classic hyperechoic AMLs from other renal lesions. Further studies are needed to increase the diagnostic reliability further. [ABSTRACT FROM AUTHOR]

Simple Summary: In this retrospective study, we compared the survival outcomes of first-line ICI regimens versus single-agent TKIs in patients with mRCC from two centres in Saudi Arabia. The patients receiving ICI regimens exhibited improved progression-free survival (PFS) and overall survival (OS) compared to those treated with TKIs. The choice of first-line therapy significantly improves the survival outcomes, underscoring the importance of personalized treatment approaches in managing mRCC. The findings emphasize the significance of baseline patient characteristics in tailoring treatment strategies for mRCC. This research contributes valuable insights into optimizing treatment strategies for mRCC, aiming to enhance patient outcomes in clinical practice. Background: Metastatic renal cell carcinoma (mRCC) represents a challenging condition characterised by poor prognosis and limited response to chemoradiotherapy. In this retrospective study, we compared the survival outcomes of first-line ICI regimens versus single-agent TKIs in patients with mRCC from two centres in Saudi Arabia. Methods: This study included 84 patients diagnosed with clear cell mRCC between January 2016 and December 2023. Patients were grouped based on treatment regimens. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan–Meier curves and Cox proportional hazards regression. Results: The median first-line PFS was 9.7 months (95% CI: 5.3–14.1) for the overall cohort, with no significant difference between the single-agent tyrosine kinase inhibitor (TKI) group (9.4 months; 95% CI: 6.4–12.4), combination ICI group (9.0 months; 95% CI: 0.0–24.9), and single-agent ICI group (21.2 months; 95% CI: 2.6–39.8; p = 0.591). The median OS for the overall cohort was 42.0 months (95% CI: 14.9–69.2), with the single-agent TKI group having a median OS of 33.3 months (95% CI: 0.0–71.7), the combination ICI group, 42.0 months (95% CI: 0.06–84.0), and the single-agent ICI group, 23.0 months (95% CI: 19.2–26.7; p = 0.73). In comparison, the ICI-based combination therapy group exhibited a higher ORR of 41.0% (95% CI: 26.3–57.8%), while the single-agent ICI group had an ORR of 20.0% (95% CI: 3.5–55.8%). Cox regression identified liver metastasis as a significant independent predictor of PFS (HR = 1.8, p = 0.043), while a lower Karnofsky Performance Status was a significant independent predictor of OS (HR = 3.5, p < 0.001). Conclusions: In real-world practice from Saudi Arabia, first-line, single-agent ICI therapy offers promising anti-tumour activity and non-inferior survival outcomes compared to standard ICI-based combinations and single-agent TKIs. [ABSTRACT FROM AUTHOR]

Simple Summary: This research aims to explore how specific imaging features on computed tomography (CT) scans, related to lipid metabolism, can be linked to a protein called adipose differentiation-related protein (ADFP) in clear cell renal cell carcinoma. This study suggests that tumors with higher lipid content, which can be seen as lower values on a CT scan, are associated with lower-grade, less aggressive cancers that express ADFP. This finding is significant because it could lead to non-invasive methods for evaluating tumor characteristics, potentially helping better understand the nature of the cancer and tailor treatment plans without needing invasive procedures. This study aimed to investigate the association between metabolic lipid computed tomography (CT) features and adipose differentiation-related protein (ADFP) expression in clear cell renal cell carcinoma (ccRCC), providing insights into non-invasive methods for assessing ADFP expression and tumor characteristics. This study utilized data from The Cancer Genome Atlas and the Cancer Imaging Archive to analyze genetic alterations and imaging characteristics in ccRCC patients. Tumoral Hounsfield units (HU) analysis and quantification of abdominal adipose tissue compartments were performed using CT images. Statistical analyses were conducted to compare tumoral HU values according to ADFP gene expression and World Health Organization/International Society of Urological Pathology (WHO/ISUP) tumor grade, as well as to explore correlations between tumoral HU values and adipose tissue quantification. Among the 174 identified patients, those with ADFP gene expression showed significantly lower minimum tumoral HU values in low-grade cancers compared to high-grade cancers. Similarly, patients with low-grade cancers expressing ADFP exhibited lower minimum tumoral HU values compared to those without ADFP expression. Negative correlations were observed between minimum tumoral HU values and visceral adipose tissue, subcutaneous adipose tissue, and total adipose tissue in both ccRCC patients with and without ADFP expression. This study reveals a significant association between metabolic lipid CT features and ADFP expression in ccRCC patients. Lower minimum tumoral HU values, suggestive of higher intracellular lipid accumulation, were observed in tumors with low WHO/ISUP grade and ADFP expression. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment options for patients with advanced renal cancer are limited, as one of the main methods, chemotherapy, is prone to drug resistance in the course of treatment. There have been numerous studies confirming that ferroptosis is involved in the development of renal cancer and drug resistance during treatment. In this review, we provide new insights into the resistance of classical chemotherapy drugs sorafenib and sunitinib in renal cancer and explore the mechanism of different types of ferroptosis-related drugs to treat renal cancer, such as herb extract medicine, ferroptosis inducers, natural compounds, nanomaterials, etc. We have also conducted an in-depth discussion on the application of ferroptosis-related drugs in the clinical treatment of renal cancer. Renal cancer is a common and serious malignant tumor of the urinary system. While surgery effectively treats early-stage renal cancer, advanced cases pose a significant challenge due to poor treatment outcomes and chemotherapy resistance. Therefore, there is an urgent need to develop alternative therapeutic strategies. Ferroptosis is a newly defined form of programmed cell death characterized by the accumulation of iron-dependent lipid peroxides, which plays a critical role in tumor progression and drug resistance. Recent studies have shown that ferroptosis is involved in the occurrence and development of renal cancer, and ferroptosis-related genes can induce cell apoptosis and can be used as potential biomarkers for early diagnosis of renal cancer and participate in drug resistance of renal cancer chemotherapy. With the continuous improvement of the mechanism of ferroptosis, drugs targeting ferroptosis for the treatment of renal cancer are emerging in an endless stream. Based on the theoretical basis of the occurrence of ferroptosis, this paper reviewed drug-induced ferroptosis in renal cancer cells from the aspects of herbal medicine, natural compounds, drug resistance mechanisms, and nanomaterials, and delves into the clinical application potential of ferroptosis-related drugs in the treatment of renal cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic ablative radiation (SAbR) is a focused, high-dose radiation technique used to treat cancers that have spread to the adrenal glands. One of the feared consequences of this therapy is causing adrenal insufficiency in patients, which is a lack of adrenal function; however, the rates and severity at which this occurs in patients are still poorly studied. We studied patients with 66 treated adrenal glands using SAbR, which demonstrated that this technique was effective at controlling cancer sites with a control rate of 75% at 1 year. The risk of patients developing adrenal insufficiency in the entire cohort was significant at 14%, with a median time of 4.3 months. There was a higher risk in patients who had both adrenal glands treated with SAbR, or who had received a prior surgical removal of their other adrenal gland prior to SAbR therapy, with 44% of these patients developing adrenal insufficiency. Background: Adrenal metastases are often treated with stereotactic ablative radiation (SAbR). We aimed to assess the incidence, timing, and factors associated with the development of primary adrenal insufficiency (PAI) following SAbR. Methods: A retrospective cohort study comprised 66 consecutive patients (73% men, median age 61 years) who underwent SAbR for adrenal metastasis. Results: The series encompassed metastases from renal cell carcinoma (41%), lung tumors (38%), colorectal adenocarcinoma (9%), melanoma (5%), and others (7%). Median follow-up was 17 months from SAbR. Nine (14%) patients developed PAI at a median of 4.3 months (range, 0.7–20.2). The incidence of PAI was 44% in patients with prior adrenalectomy receiving unilateral SAbR, 44% with bilateral SAbR, 2% with unaffected contralateral gland, and 0% with bilateral metastases treated with unilateral SAbR. PAI was associated with prior adrenalectomy (odds ratio [OR] 32) and bilateral SAbR (OR 8.2), but not age, sex, metastasis size, or biological effective dose. Post-SAbR 6-month and 1-year local control rates were 82% and 75%, respectively. Conclusions: Patients undergoing SAbR for adrenal metastasis are at high risk of developing PAI. PAI is associated with bilateral SAbR and contralateral adrenalectomy. PAI is unlikely with a remaining unaffected adrenal gland or in the setting of bilateral adrenal metastases with unilateral SAbR. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the sixth most common cancer in men and is often asymptomatic, leading to incidental detection in advanced disease stages that are associated with aggressive histology and poorer outcomes. Various cancer biomarkers are found in urine samples from patients with RCC. In this study, we propose to investigate the use of Attenuated Total Reflection-Fourier Transform Infrared Spectroscopy (ATR-FTIR) on dried urine samples for distinguishing RCC. We analyzed dried urine samples from 49 patients with RCC, confirmed by histopathology, and 39 healthy donors using ATR-FTIR spectroscopy. The vibrational bands of the dried urine were identified by comparing them with spectra from dried artificial urine, individual urine components, and dried artificial urine spiked with urine components. Urea dominated all spectra, but smaller intensity peaks, corresponding to creatinine, phosphate, and uric acid, were also identified. Statistically significant differences between the FTIR spectra of the two groups were obtained only for creatinine, with lower intensities for RCC cases. The discrimination of RCC was performed through Principal Component Analysis combined with Linear Discriminant Analysis (PCA–LDA) and Support Vector Machine (SVM). Using PCA–LDA, we achieved a higher discrimination accuracy (82%) (using only six Principal Components to avoid overfitting), as compared to SVM (76%). Our results demonstrate the potential of urine ATR-FTIR combined with machine learning techniques for RCC discrimination. However, further studies, especially of other urological diseases, must validate this approach. [ABSTRACT FROM AUTHOR]

Background: The population diagnosed with renal cell carcinoma, especially in Asia, represents 36.6% of global cases, with the incidence rate of renal cell carcinoma in Korea steadily increasing annually. However, treatment options for renal cell carcinoma are diverse, depending on clinical stage and histologic characteristics. Hence, this study aims to develop a machine learning based clinical decision-support system that recommends personalized treatment tailored to the individual health condition of each patient. Results: We reviewed the real-world medical data of 1,867 participants diagnosed with renal cell carcinoma between November 2008 and June 2021 at the Pusan National University Yangsan Hospital in South Korea. Data were manually divided into a follow-up group where the patients did not undergo surgery or chemotherapy (Surveillance), a group where the patients underwent surgery (Surgery), and a group where the patients received chemotherapy before or after surgery (Chemotherapy). Feature selection was conducted to identify the significant clinical factors influencing renal cell carcinoma treatment decisions from 2,058 features. These features included subsets of 20, 50, 75, 100, and 150, as well as the complete set and an additional 50 expert-selected features. We applied representative machine learning algorithms, namely Decision Tree, Random Forest, and Gradient Boosting Machine (GBM). We analyzed the performance of three applied machine learning algorithms, among which the GBM algorithm achieved an accuracy score of 95% (95% CI, 92–98%) for the 100 and 150 feature sets. The GBM algorithm using 100 and 150 features achieved better performance than the algorithm using features selected by clinical experts (93%, 95% CI 89–97%). Conclusions: We developed a preliminary personalized treatment decision-support system (TDSS) called "RCC-Supporter" by applying machine learning (ML) algorithms to determine personalized treatment for the various clinical situations of RCC patients. Our results demonstrate the feasibility of using machine learning-based clinical decision support systems for treatment decisions in real clinical settings. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma with clear cells (ccRCC) is the most frequent kind; it accounts for almost 70% of all kidney cancers. A primary objective of current research was to find genes that may be used in ccRCC gene therapy to understand better the molecular pathways underlying the disease. Based on PubMed microarray searches and meta-analyses, we compared overall survival and recurrence-free survival rates in ccRCC patients with those in healthy samples. The technique was followed by a KEGG pathway and Gene Ontology (GO) function analyses, both performed in conjunction with the approach. Tumor immune estimate and multi-gene biomarkers validation for clinical outcomes were performed at the molecular and clinical cohort levels. Our analysis included fourteen GEO datasets based on inclusion and exclusion criteria. A meta-analysis procedure, network construction using PPIs, and four significant gene identification standard algorithms indicated that 11 genes had the most important differences. Ten genes were upregulated, and one was downregulated in the study. In order to analyze RFS and OS survival rates, 11 genes expressed in the GEPIA2 database were examined. Nearly nine of eleven significant genes have been found to beinvolved in tumor immunity. Furthermore, it was found that mRNA expression levels of these genes were significantly correlated with experimental literature studies on ccRCCs, which explained these findings. This study identified eleven gene panels associated with ccRCC growth and metastasis, as well as their immune system infiltration. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusion Immune checkpoint inhibitors, such as nivolumab, combined with small molecule antiangiogenic receptor tyrosine kinase inhibitors (TKIs), present a promising strategy for future immunotherapy. However, combination therapy can lead to specific adverse drug reactions (ADRs) in various clinical settings. Current research on the ADRs associated with combination therapy is limited. Our study aims to assess the safety of combination therapy.We extracted ADR reports on combination therapy from the Food and Drug Administration (FDA) Adverse Event Reporting System database, covering the period from the first quarter of 2012 to the third quarter of 2023, and conducted a large‐scale retrospective study. We evaluated ADR risk signals using the reporting odds ratio (ROR) and calculated the Ro/e ratio to compare the differences in the risk of fatal ADRs among various tumour types.We comprehensively reported the occurrence of ADRs in pan‐cancer patients undergoing combination therapy. The combination therapy significantly increased the risk of sensitive skin (ROR: 231.43, 95% CI: 55.01–973.72, P < .05), metastatic renal cell carcinoma (ROR: 220.71, 95% CI: 28.99–1695.41, P < .05) and renal cell carcinoma (ROR: 188.22, 95% CI: 44.24–800.85, P < .05). We also compared the differences in ADRs resulting from different small molecule drug combinations, as well as the differences in ADRs among patients with different types of tumours under combination therapy. Furthermore, we analysed the characteristics of patients prone to experiencing fatal ADRs.These results can help enhance understanding of the ADRs commonly associated with combination therapy and assist oncologists in formulating screening protocols. [ABSTRACT FROM AUTHOR]

Background: Renal cell carcinoma is the most fatal form of renal tumors, representing about ninety percent of all renal cancers. There are different variations in prognosis among various histological types of RCC. In recent years, there has been a greater emphasis on differentiating between RCC subtypes. Evaluation of different subtypes of renal cell carcinoma using intravoxel incoherent motion (IVIM) diffusion-weighted MRI is the aim of this study. Results: Clear cell renal cell carcinoma (CCRCCs) showed highest f and D values, followed by chromophobe renal cell carcinoma (ChRCCs), while papillary renal cell carcinoma (PRCCs) had the lowest values. CCRCCs had significantly different D and f values compared to non-clear types (PRCC and ChRCC) (P < 0.05). The D* values of CCRCC were the highest, PCRCC had intermediate values, while ChRCCs had the lowest values (P < 0.05). The D* values of ChRCCs demonstrated significant difference when compared to both CCRCCs and PRCCs (P < 0.05). The cutoff points of D, D* and f parameters for distinguishing CCRCCs from non-clear cell types (ChRCCs and PRCC) were 0.835, 0.0355 and 0.335, respectively, yielding specificities of 97.2%, 83.3% and 76.5% and sensitivities of 100%, 57.5% and 72.7%, respectively. Conclusion: Intravoxel incoherent motion (IVIM) can be utilized to distinguish renal cell carcinoma subtypes. [ABSTRACT FROM AUTHOR]

Introduction: Pretreatment hemoglobin and neutrophil levels were previously reported to be important indicators for predicting the effectiveness of ipilimumab plus nivolumab (IPI + NIVO) therapy for renal cell carcinoma (RCC). Therefore, we aimed to validate this in a large external cohort. Methods: In total, 172 patients with RCC who underwent IPI + NIVO treatment at a multicenter setting were divided into three groups according to their pretreatment hemoglobin and neutrophil levels (group 1: non-anemia; group 2: anemia and low-neutrophil; and group 3: anemia and high-neutrophil). Results: Group 1 showed better survival than groups 2 and 3 (overall survival: 52.3 vs. 21.4 vs. 9.4 months, respectively; progression-free survival: 12.1 vs. 7.0 vs. 3.4 months, respectively). Discussion: In this large cohort, we validated our earlier observation that hemoglobin and neutrophil levels can be reliable predictors of the effectiveness of IPI + NIVO in advanced RCC. Thus, our approach may aid in selecting the optimal first-line therapy for RCC. [ABSTRACT FROM AUTHOR]

Aims Methods and results Conclusions BRCA1‐associaed protein‐1 (BAP1) inactivated tumours (BIMT) are rare melanocytic tumours that may be mistaken for Spitz tumours or melanoma. They occur sporadically or in association with the BAP1 tumour predisposition syndrome (BAP1–TPDS), which may be complicated by uveal or cutaneous melanoma, mesothelioma, basal cell carcinoma and renal cell carcinoma. The aim of this study was to characterise the clinicopathological features and the immunohistochemical expression pattern of preferentially expressed antigen in melanoma (PRAME) of BIMT in a large patient cohort.Ethical approval was obtained, haematoxylin and eosin‐stained slides were reviewed, PRAME immunohistochemistry was performed and clinical follow‐up was obtained from patient records. Sixty‐five BIMT from 38 patients (F:M = 4.4:1) were identified. BIMT were typically located on the trunk and head and neck (median size = 0.5 cm). Seven patients with BAP1–TPDS (range = 16–66 years, median = 25) had multiple BIMT (median = 5), while sporadic BIMT were solitary (median patient age = 39 years). One of seven patients with BAP1–TPDS developed additional malignancies (mesothelioma and cutaneous spindle cell melanoma) and died of complications of mesothelioma. All other patients are alive without recurrence of BIMT (median follow‐up = 42 months). BIMT presented as intradermal, nodular aggregates of epithelioid melanocytes with low mitotic activity and moderate to severe cytological atypia in 63% of cases. A background conventional naevus was present in 64%. PRAME immunohistochemistry showed negative or weakly patchy positive staining in all BIMT.BIMT are more common in a sporadic setting and behave indolently, despite worrying cytological atypia. PRAME immunohistochemistry is a reassuring tool in distinguishing BIMT from melanoma. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is a substantial pathology of the urinary system with a growing prevalence rate. However, current clinical methods have limitations for managing RCC due to the heterogeneity manifestations of the disease. Metabolic analyses are regarded as a preferred noninvasive approach in clinics, which can substantially benefit the characterization of RCC. This study constructs a nanoparticle‐enhanced laser desorption ionization mass spectrometry (NELDI MS) to analyze metabolic fingerprints of renal tumors (n = 456) and healthy controls (n = 200). The classification models yielded the areas under curves (AUC) of 0.938 (95% confidence interval (CI), 0.884–0.967) for distinguishing renal tumors from healthy controls, 0.850 for differentiating malignant from benign tumors (95% CI, 0.821–0.915), and 0.925–0.932 for classifying subtypes of RCC (95% CI, 0.821–0.915). For the early stage of RCC subtypes, the averaged diagnostic sensitivity of 90.5% and specificity of 91.3% in the test set is achieved. Metabolic biomarkers are identified as the potential indicator for subtype diagnosis (p < 0.05). To validate the prognostic performance, a predictive model for RCC participants and achieve the prediction of disease (p = 0.003) is constructed. The study provides a promising prospect for applying metabolic analytical tools for RCC characterization. [ABSTRACT FROM AUTHOR]

Background. As cancer survivorship continues to improve, the perioperative morbidity and mortality following surgical treatment of metastatic bone disease become an increasingly important consideration. The objective of this study is to identify risk factors for early postoperative complications and mortality following extremity prophylactic fixation and pathologic fracture stabilization. Methods. A single‐centre retrospective review of 185 patients (226 total surgeries) who underwent prophylactic fixation or pathologic fracture stabilization for extremity metastatic bone disease between 2005 and 2020 was performed. Skull, spine, pelvic, and revision surgeries along with diagnosis of primary bone neoplasm were excluded. Univariate, multivariate, and subgroup analyses were performed to identify predictors and independent risk factors for 30‐day postoperative morbidity and mortality. Results. Primary cancers included lung (n = 41), breast (n = 36), multiple myeloma (n = 35), prostate (n = 16), lymphoma (n = 11), renal cell carcinoma (n = 10), and other (n = 36). The 30‐day postoperative complication and mortality rates were 32.30% (n = 73) and 17.26% (n = 39), respectively. The most common complications were pulmonary‐related, cardiac events, surgical site infection, sepsis, and thromboembolism. Pathologic fracture, presence of extra‐skeletal metastases, longer surgical duration, and blood transfusion requirements were associated with 30‐day postoperative complications overall. A past medical history for cardiac disease was also associated with systemic but not local surgical complications. Pathologic fracture, presence of extra‐skeletal metastases, lung cancer, blood transfusion requirements, and increasing pack‐year smoking history were predictors for 30‐day mortality. In the multivariate analysis, pathologic fracture (p = 0.016) and presence of extra‐skeletal metastases (p = 0.029) were independent predictors of complications. For mortality, pathologic fracture (p = 0.014), presence of extra‐skeletal metastases (p = 0.0085), and increased blood transfusion requirements (p = 0.048) were independent risk factors. Conclusions. The findings of this study provide additional guidance for perioperative risk assessment and patient counselling. Additionally, improving clinical assessment tools to identify and quantify patients at risk of pathologic fractures becomes increasingly important given the significant morbidity and mortality associated with pathologic fracture treatment. [ABSTRACT FROM AUTHOR]