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Background: Synchronous occurrence of prostate cancer (PCa) and renal cell carcinoma (RCC) is uncommon. RCC has a higher tendency to metastasize to the adrenal glands, renal hilar, and retroperitoneal lymph nodes compared to PCa. To date, there are no documented cases existing where metastatic tumors in these regions, observed in patients concurrently with PCa and RCC, have originated from the PCa rather than the RCC. Case presentation: In this case report, we described a 67-year-old male presented with dysuria for two months and left lower extremity edema for three days. Percutaneous biopsies revealed synchronous primary RCC and PCa. However, the origin of the metastatic tumors, especially those involving the adrenal glands, renal hilum, and retroperitoneal regions, remained undetermined. Subsequent surgical procedures identified that the metastatic lesions originated from the PCa, while the RCC was localized. Ultimately, the patient with metastatic hormone-sensitive prostate cancer (mHSPC) received combination therapy with rezvilutamide and goserelin, which resulted in a satisfactory treatment response. Conclusion: In patients with concurrent PCa and RCC, metastatic lesions in the adrenal glands, renal hilar, and retroperitoneal lymph nodes may also originate from the PCa. Accurate identification of the primary tumor and proper staging are critical for the appropriate management of patients with multiple primary malignancies with concurrent metastases. [ABSTRACT FROM AUTHOR]

Renal cell carcinoma (RCC) is the most common primary renal malignancy. Prevalence of RCC in developed countries has slowly increased. Although partial or total nephrectomy has been the first-line treatment for early-stage RCC, improved or similar safety and treatment outcomes with locoregional therapies have challenged this paradigm. In this review, we explore locoregional techniques for early-stage RCC, including radiofrequency ablation, cryoablation, and microwave ablation with a focus on procedural technique, patient selection, and safety/treatment outcomes. Furthermore, we discuss future advances and novel techniques, including radiomics, combination therapy, high-intensity focused ultrasound, and catheter-directed techniques. [ABSTRACT FROM AUTHOR]

Giant cell glioblastoma often exhibits genome instability and is frequently associated with mutations in genes involved in DNA repair pathways including TP53 and DNA mismatch repair genes. Several germline mutations have been identified in giant cell glioblastoma, including mutations of MSH1 and MSH2, TP53, and POLE. We have documented a case of a germline mutation in CHEK2, another gene crucial to DNA repair, in a patient with giant cell glioblastoma. The CHEK2 mutation was inherited from the patient's father, who had a history of gastric cancer and renal cell carcinoma. In addition to the germline CHEK2 mutation, the giant cell glioblastoma exhibited a genome-wide loss of heterozygosity, a characteristic observed in a subset of giant cell glioblastomas. Additional mutations detected in the tumor included TP53, PTEN, and a PTPRZ1-MET fusion. This represents the first reported case of a CHEK2 germline mutation in giant cell glioblastoma, further supporting the significance of impaired DNA repair mechanisms in the development of this disease. [ABSTRACT FROM AUTHOR]

As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxiainducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHLdeficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis. [ABSTRACT FROM AUTHOR]

The mTOR inhibitor everolimus has been approved as a sequential or second‐line therapy for renal cell carcinoma (RCC). However, the development of drug resistance limits its clinical applications. This study aims to address the challenge of everolimus resistance and provide new insights into the treatment of advanced RCC. Here, the cytotoxicity of the DNA methyltransferase 1 (DNMT1) inhibitor SGI‐1027 in inducing cell vacuolation and methuosis is discovered and demonstrated for the first time. Additionally, SGI‐1027 exerts synergistic effects with everolimus, as their combination suppresses the growth, migration, and invasion of renal cancer cells. Mechanistically, apoptosis and GSDME‐dependent pyroptosis triggered by lysosomal membrane permeability (LMP) are observed. The upregulation of GSDME expression and increased lysosomal activity in renal cancer cells provide a therapeutic window for the combination of these two drugs to treat renal cancer. The combination treatment exhibits effective anti‐tumor activity and is well tolerated in a subcutaneous tumor model. Overall, this study validates and reveals the specific cytotoxicity property of SGI‐1027 and its potent synergistic effect with everolimus, offering new insights into advanced RCC therapy and everolimus‐resistance overcoming. [ABSTRACT FROM AUTHOR]

Background: The main objective is to discuss why treatment of non-prostate cancers with [177Lu]Lu-PSMA-radioligand achieved only low tumor dose in most published cases, despite high uptake on PSMA PET. We use a patient with renal cell carcinoma as an illustrative example. Furthermore, we discuss how the problem with early washout and low tumor dose might be overcome by using a radionuclide with shorter half-life, matching the target binding residence time. Case presentation: [68Ga]Ga-PSMA-11 PET/CT of a 56-year old man with metastatic renal cell carcinoma showed high lesion uptake. One dose of 6.9 GBq [177Lu]Lu-PSMA-I&T was administrated. Post-therapy dosimetry was performed with SPECT/CT and whole-body planar imaging after 5, 24 and 48 h. Doses to target lesions were only 0.2–0.5 Gy. No treatment effect was achieved. Conclusion: Rapid tumor washout of [177Lu]Lu-PSMA-I&T and low tumor dose despite high uptake of [68Ga]Ga-PSMA-11 are most likely caused by localization of PSMA-receptors on neovasculature rather than on the tumor cells, and unlike in prostate cancer cells, the PSMA-RL / PSMA-receptor complex is not internalized. To overcome the problem with early washout, the use of a radionuclide with shorter half-life matching the target binding residence time will be needed. [ABSTRACT FROM AUTHOR]

Background: Malignant cells exhibit reduced period circadian regulator 3 (PER3) expression. However, the underlying mechanisms of variations in PER3 expression in cancers and the specific function of PER3 in tumor progression remain poorly understood. Results: We explored multiple public databases, conducted bioinformatics analyses, and performed in vitro and in vivo experiments for validation. We found PER3 expression was decreased in most types of cancers, and PER3 downregulation was associated with a poor prognosis in 8 types of cancer. PER3 promoter methylation levels were increased in 11 types of cancer. Promoter hypermethylation (CpG islands [CGIs] cg12258811 and cg14204433) correlated with decreased PER3 expression in six cancers (breast invasive carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma [KIRP], lung adenocarcinoma [LUAD], and uterine corpus endometrial carcinoma). CGI cg12258811 hypermethylation was associated with reduced survival time and advanced cancer stages. Moreover, the bisulfite pyrosequencing assay confirmed CGI cg12258811 hypermethylation and its negative correlation with PER3 expression. In vitro and in vivo experiments demonstrated that PER3 inhibited KIRP and LUAD progression. Decitabine enhanced PER3 expression and inhibited KIRP cell functions by reducing promoter (cg12258811) methylation level. Conclusions: Our findings advanced the mechanistic understanding of variations in PER3 expression in cancers and confirmed the tumor-associated function of PER3 hypermethylation and downregulation. [ABSTRACT FROM AUTHOR]

Background: Malignant cells exhibit reduced period circadian regulator 3 (PER3) expression. However, the underlying mechanisms of variations in PER3 expression in cancers and the specific function of PER3 in tumor progression remain poorly understood. Results: We explored multiple public databases, conducted bioinformatics analyses, and performed in vitro and in vivo experiments for validation. We found PER3 expression was decreased in most types of cancers, and PER3 downregulation was associated with a poor prognosis in 8 types of cancer. PER3 promoter methylation levels were increased in 11 types of cancer. Promoter hypermethylation (CpG islands [CGIs] cg12258811 and cg14204433) correlated with decreased PER3 expression in six cancers (breast invasive carcinoma, colon adenocarcinoma, head and neck squamous cell carcinoma, kidney renal papillary cell carcinoma [KIRP], lung adenocarcinoma [LUAD], and uterine corpus endometrial carcinoma). CGI cg12258811 hypermethylation was associated with reduced survival time and advanced cancer stages. Moreover, the bisulfite pyrosequencing assay confirmed CGI cg12258811 hypermethylation and its negative correlation with PER3 expression. In vitro and in vivo experiments demonstrated that PER3 inhibited KIRP and LUAD progression. Decitabine enhanced PER3 expression and inhibited KIRP cell functions by reducing promoter (cg12258811) methylation level. Conclusions: Our findings advanced the mechanistic understanding of variations in PER3 expression in cancers and confirmed the tumor-associated function of PER3 hypermethylation and downregulation. [ABSTRACT FROM AUTHOR]

Background: Growing evidence shows that ultra-processed food consumption is associated with the risk of cancer. However, prospective evidence is limited on renal cell carcinoma (RCC) incidence and mortality. In this study, we aimed to examine the association of ultra-processed food consumption and RCC incidence and mortality in a large cohort of US adults. Methods: A population-based cohort of 101,688 participants were included from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Ultra-processed food items were confirmed by using the NOVA food classification system. The consumption of ultra-processed food was expressed as a percentage of total food intake (g/day). Prospective associations were calculated using Cox regression. Restricted cubic spline regression was used to assess nonlinearity. Subgroup analyses were performed to investigate the potential effect modifiers on the incidence and mortality of RCC. Results: A total of 410 participants developed RCC during a total of 899,731 person-years of follow-up (median 9.41 years) and 230 RCC deaths during 1,533,930 person-years of follow-up (median 16.85 years). In the fully adjusted model, participants in the highest compared with the lowest quintiles of ultra-processed food consumption had a higher risk of RCC (HR quartile 4 vs 1:1.42; 95% CI: 1.06–1.91; Ptrend = 0.004) and mortality (HR quartile 4 vs. quartile 1: 1.64; 95% CI: 1.10–2.43; Ptrend = 0.027). Linear dose–response associations with RCC incidence and mortality were observed for ultra-processed food consumption (all Pnonlinearity > 0.05). The reliability of these results was supported by sensitivity and subgroup analyses. Conclusion: In conclusion, higher consumption of ultra-processed food is associated with an increased risk of RCC incidence and mortality. Limiting ultra-processed food consumption might be a primary prevention method of RCC. [ABSTRACT FROM AUTHOR]

Aims: Decreased oestrogen receptor (ER) expression is a marker of poor prognosis in endometrial carcinomas (EC) of no specific molecular profile (NSMP), but the optimal cut‐off to separate high‐risk 'low ER' versus low‐risk 'high ER' expression has not been defined. Here we characterised the distribution of ER staining in a cohort of ECs. Methods and results: Biopsy specimens from 120 cases of NSMP EC were stained for ER and assigned an Allred score. In 66 additional cases ER staining of matched biopsy and hysterectomy were compared. Twelve of 120 tumours had an Allred score of 0–3, including three endometrioid carcinomas (EEA) (one G1, two G3), four clear cell carcinomas (CCC), two mesonephric‐like adenocarcinoma (MLA) and one each of: gastric‐type adenocarcinoma, carcinosarcoma and endometrial carcinoma NOS. Three had Allred scores of 4–5: two MLA and one high‐grade carcinoma with yolk sac differentiation. Five had Allred scores of 6: four EEA (one G1, one G2, two G3) and one mixed clear cell and endometrioid carcinoma. The remaining 100 tumours with Allred scores ≥ 7 were all EEA (66 G1, 28 G2, five G3 and one grade unknown). Comparing the biopsy versus hysterectomy ER staining (n = 66), the results were within a single Allred score point, except two cases with strong diffuse expression in the biopsy (Allred 8) and moderate expression in the hysterectomy (Allred 5). Conclusions: Most NSMP ECs (> 80%) show high ER expression (Allred score ≥ 7). All non‐endometrioid carcinomas and a few endometrioid carcinomas had lower ER expression (Allred score ≤ 6) or were completely negative. [ABSTRACT FROM AUTHOR]

Aims: Traditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two‐antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two‐antibody approach. Methods and Results: We performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two‐antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two‐antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used. Conclusion: In general, the application of a two‐antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs. [ABSTRACT FROM AUTHOR]

As the main type of renal cell carcinoma (RCC), clear cell RCC (ccRCC) is often associated with the deletion or mutation of the von Hippel Lindau (VHL) gene, enhancement of glucose and lipid metabolism, and heterogeneity of the tumor microenvironment. VHL alterations in RCC cells lead to the activation of hypoxiainducible factors and their downstream target vascular endothelial growth factor, and to the reprogramming of multiple cell death pathways and metabolic weakness, including ferroptosis, which are associated with targeted therapy or immunotherapy. The changes in biological metabolites (e.g., iron and lipids) support ferroptosis as a potential therapeutic strategy for RCC, while iron metabolism and ferroptosis regulation have been examined as anti-RCC agents in numerous studies, and various ferroptosis-related molecules have been shown to be related to the metastasis and prognosis of ccRCC. For example, glutathione peroxidase 4 and glutaminase inhibitors can inhibit pyrimidine synthesis and increase reactive oxygen species levels in VHLdeficient RCC cells. In addition, the release of damage-associated molecular patterns by tumor cells undergoing ferroptosis also mediates antitumor immunity, and immune therapy can synergize with targeted therapy or radiotherapy through ferroptosis. However, Inducing ferroptosis not only suppresses cancer, but also promotes cancer development due to its potential negative effects on anti-cancer immunity. Therefore, ferroptosis and various tumor microenviroment-related molecules may co-occur during the development and treatment of RCC, and further understanding of the interactions, core targets, and related drugs of ferroptosis may provide new combination drug strategies for RCC treatment. Here we summarize the key genes and compounds on ferroptosis and RCC in order to envision future treatment strategies and to provide sufficient information for overcoming RCC resistance through ferroptosis. [ABSTRACT FROM AUTHOR]

This study aims to broaden the morphological scope of SDH-deficient renal cell carcinoma and to assist clinicians and pathologists in better understanding this entity to prevent misdiagnosis. This study used immunohistochemistry staining and the first-generation sequencing Sanger method for gene detection. It retrospectively analysed the clinical pathology, molecular characteristics, biological behaviour, and treatment information of one case of SDH-deficient renal cell carcinoma. The patient was a 57-year-old female with right back pain for more than 20 days and had no personal or family history of kidney tumours. In addition, the tumour cells had clear boundaries in morphology, and residual normal renal tubules could be seen around them. There were also ossification and adipose tissue around the tumour centre. The tumour cells were arranged in a glandular tubular and cord-like manner. Vacuolar and eosinophilic inclusion bodies could be observed in the cytoplasm. The nucleus was regular, the chromatin distribution was fine, and there were no obvious nucleoli. They were low-grade nuclei. In addition, no atypical mitosis or necrosis could been found. Furthermore, immunohistochemistry staining showed SDHB-negative and keratin 20 -positive tumour. Meanwhile, the first-generation sequencing also pointed out the presence of SDHB gene mutations in the tumour. After 12 months of follow-up, there was no evidence of disease recurrence in the patient. SDH-deficient renal cell carcinoma is a rare tumour associated with SDH gene germline mutations, and suspected cases should undergo SDHB immunohistochemistry staining. Most SDH-deficient renal cell carcinomas have a good prognosis, but undifferentiated cases require long-term follow-up. [ABSTRACT FROM AUTHOR]

Background: One key focus of partial nephrectomy is preserving renal function. Segmental renal artery occlusion with microdissection at the renal hilum confines ischemia, effectively reducing warm ischemic injury. Ultrasound-Guided Renal Artery Balloon Catheter Occluded Hybrid Partial Nephrectomy (UBo-HPN) can achieve branch occlusion without the need for dissecting the renal hilum. Objective: To investigate the feasibility and safety of UBo-HPN of branch renal artery occlusion in the treatment of localized renal tumors. Subject and methods: A prospective single-arm analysis involving 20 patients with renal localized tumors underwent robot assisted UBo-HPN with branch renal artery occlusion from August 2021 to July 2023, with an average follow-up of 12 months. Results: All patient was successfully operated on without conversion to conventional arterial clamping or radical nephrectomy. One case (5%) of minor complication occurred in the whole cohort, which was bruising around the puncture site. The mean total operative time was 95.8 min, with a mean operative time of 21.25 min for vascular intervention. The mean warm ischemia time was 20.35 min, and the median estimated blood loss was 50 ml. The median eGFR preservation percentage at postoperative 48 h, 30 days, and the latest follow-up were 87.52%, 91.47%, and 92.2%, respectively. After a median follow-up of 10.2 (2.3–19.2) months, no patients had radiological tumor recurrence or died from tumor-related causes. Conclusions: UBo-HPN with renal artery branch occlusion emerges as an efficient alternative to partial nephrectomy (PN), which achieved branch artery occlusion without dissecting the renal hilum. Long-term follow-up is expected for functional outcomes. [ABSTRACT FROM AUTHOR]

Background: Lipid droplets (LD) in renal clear cell carcinoma (ccRCC)play a crucial role in lipid metabolism and immune response modulation. The purpose of this study was to create a LD-related signature to predict prognosis and guide the immunotherapy and targeted therapy in ccRCC patients. Methods: We conducted a comprehensive analysis using transcriptional profiles and clinical data obtained from The Cancer Genome Atlas (TCGA). LD-related genes were identified from existing literature and the GeneCards database, and differentially expressed genes were determined. Sequentially, we conducted Cox regression analysis and Lasso regression analysis, to establish a prognostic risk model. The performance of the risk model was evaluated using Kaplan–Meier (KM) analysis and time-dependent receiver operating characteristic (ROC) analysis. Additionally, gene set enrichment analysis (GSEA), ESTIMATE, CIBERSORT, and immunophenoscore (IPS) algorithm were used to assess the tumor microenvironment (TME) and treatment response. Results: We constructed a risk signature with four LD-related genes in the TCGA dataset, which could be an independent prognostic factor in ccRCC patients. Then, patients were classified into two risk groups and exhibited notable differences in overall survival (OS), progression-free survival (PFS), and TME characteristics. Furthermore, we developed a comprehensive nomogram based on clinical features, which demonstrated good prognostic predictive value. According to the results of GSEA analysis, immune-related pathways were found to be significantly enriched in the high-risk group. Additionally, the high-risk group displayed high levels of immune cell infiltration, TMB and IPS scores, indicating better efficacy of immune checkpoint inhibitors (ICIs). Finally, high-risk demonstrated reduced IC50 values compared to the low-risk counterpart for specific targeted and chemotherapeutic drugs, suggesting that the patients receiving these targeted drugs in high-risk group had better treatment outcomes. Conclusions: Our findings suggested that the LD-related gene signature could potentially predict the prognosis of ccRCC patients. Additionally, it showed promise for predicting responses to immunotherapy and targeted therapy in ccRCC patients. These insights might potentially have guided the clinical management of these patients, but further validation and broader data analysis are needed to confirm these preliminary observations. [ABSTRACT FROM AUTHOR]

CRISPR is revolutionizing the ability to do somatic gene editing in mice for the purpose of creating new cancer models. Inactivation of the VHL tumor suppressor gene is the signature initiating event in the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). Such tumors are usually driven by the excessive HIF2 activity that arises when the VHL gene product, pVHL, is defective. Given the pressing need for a robust immunocompetent mouse model of human ccRCC, we directly injected adenovirus-associated viruses (AAVs) encoding sgRNAs against VHL and other known/suspected ccRCC tumor suppressor genes into the kidneys of C57BL/6 mice under conditions where Cas9 was under the control of one of two different kidney-specific promoters (Cdh16 or Pax8) to induce kidney tumors. An AAV targeting Vhl, Pbrm1, Keap1, and Tsc1 reproducibly caused macroscopic ccRCCs that partially resembled human ccRCC tumors with respect to transcriptome and cell of origin and responded to a ccRCC standard-of-care agent, axitinib. Unfortunately, these tumors, like those produced by earlier genetically engineered mouse ccRCCs, are HIF2 independent. [ABSTRACT FROM AUTHOR]

Objectives: Under the classification of multicategory survival outcomes of cancer patients, it is crucial to identify biomarkers that affect specific outcome categories. The classification of multicategory survival outcomes from transcriptomic data has been thoroughly investigated in computational biology. Nevertheless, several challenges must be addressed, including the ultra-high-dimensional feature space, feature contamination, and data imbalance, all of which contribute to the instability of the diagnostic model. Furthermore, although most methods achieve accurate predicted performance for binary classification with high-dimensional transcriptomic data, their extension to multi-class classification is not straightforward. Methods: We employ the One-versus-One strategy to transform multi-class classification into multiple binary classification, and utilize the overlapping group screening procedure with binary logistic regression to include pathway information for identifying important genes and gene-gene interactions for multicategory survival outcomes. Results: A series of simulation studies are conducted to compare the classification accuracy of our proposed approach with some existing machine learning methods. In practical data applications, we utilize the random oversampling procedure to tackle class imbalance issues. We then apply the proposed method to analyze transcriptomic data from various cancers in The Cancer Genome Atlas, such as kidney renal papillary cell carcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma. Our aim is to establish an accurate microarray-based multicategory cancer diagnosis model. The numerical results illustrate that the new proposal effectively enhances cancer diagnosis compared to approaches that neglect pathway information. Conclusions: We showcase the effectiveness of the proposed method in terms of class prediction accuracy through evaluations on simulated synthetic datasets as well as real dataset applications. We also identified the cancer-related gene-gene interaction biomarkers and reported the corresponding network structure. According to the identified major genes and gene-gene interactions, we can predict for each patient the probabilities that he/she belongs to each of the survival outcome classes. [ABSTRACT FROM AUTHOR]

While renal cell carcinoma (RCC) is often linked to smoking, obesity, and hypertension, hereditary forms also account for about 3% of RCC cases. Notably, NCCN guidelines identify 7 major hereditary syndromes associated with an increased RCC risk. Inherited mutations in DNA repair genes, such as ATM, BRCA, and TP53, significantly increase the risk of various cancers. Biallelic pathogenic mutations in ATM cause Ataxia-Telangiectasia (A-T) syndrome, while heterozygous germline pathogenic ATM mutations, present in about 1% of the population, also elevate cancer risk. RCC has not traditionally been associated with germline pathogenic ATM mutations, only limited retrospective analyses have identified such mutations. This case report presents a 68-year-old woman with a germline pathogenic ATM mutation (c.8786+1 G>A) who developed high-risk clear cell RCC followed by an acquired somatic VHL mutation in RCC and a 3-cm serous cystadenoma, illustrating the double-hit phenomenon. Her brother, who shares the same germline pathogenic mutation, was diagnosed with pancreatic cancer and prostate cancer. This case highlights the potential use for enhanced screening protocols for RCC in patients who have germline pathogenic ATM mutations and the importance of research in targeted treatments for tumors driven by dual genetic mechanisms. Increased awareness and vigilant screening for RCC are crucial in managing hereditary cancer syndromes effectively. [ABSTRACT FROM AUTHOR]

Background: The presence of collateral vessels (CVs) on contrast-enhanced computed tomography is a poor prognostic factor in renal cell carcinoma (RCC), but its value in small RCC (sRCC; < 4 cm) remains unknown. In this study, we investigated whether presence of CVs is a predictor of high potential for metastasis in sRCC. Methods: We retrospectively reviewed clinical and imaging data of patients with pathologically confirmed sRCC evaluated at our institution between 2011 and 2021. All sRCCs were pathologically diagnosed by biopsy, metastasectomy, partial nephrectomy, or radical nephrectomy. CVs were defined as blood vessels of any diameter connecting the tumor with the surrounding perirenal tissues on contrast-enhanced computed tomography. The rate of metastasis-free survival (MFS), defined as the time from pathological diagnosis to confirmed metastasis, was compared among patients without CVs, those with one CV, and those with two or more CVs. Results: Of 141 patients, 4 (2.8%) had metastatic sRCC at initial diagnosis. In the 137 patients with nonmetastatic sRCC, the diagnosis was pathologically confirmed following radical surgery. The median follow-up period from pathological diagnosis was 73.9 months, and the overall 5-year MFS was 93.5%. The 5-year MFS was significantly poorer in patients with two or more CVs than in those with one CV (63.8% vs. 96.3%; p = 0.0003) and those without CVs (63.8% vs. 100%; p < 0.0001). Conclusions: sRCCs with two or more CVs might have high potential for metastasis. Conversely, sRCCs without CVs might not be aggressive and be suitable for active surveillance. [ABSTRACT FROM AUTHOR]

Objective: Axitinib is a tyrosine kinase inhibitor characterized by a strong affinity for Vascular Endothelial Growth Factor Receptors (VEGFRs). It was approved in 2012 by Food and Drug Administration and European Medicines Agency as a second line treatment for advanced renal cell carcinoma and is currently under evaluation in clinical trial for the treatment of other cancers. Glioblastoma IDH‐wild type (GBM) is a highly malignant brain tumor characterized by diffusely infiltrative growth pattern and by a prominent neo‐angiogenesis. In GBM, axitinib has demonstrated a limited effectiveness as a monotherapy, while it was recently shown to significantly improve its efficacy in combination treatments. In preclinical models, axitinib has been reported to trigger cellular senescence both in tumor as well as in normal cells, through a mechanism involving intracellular reactive oxygen species (ROS) accumulation and activation of Ataxia Telangiectasia Mutated kinase (ATM). Limiting axitinib‐dependent ROS increase by antioxidants prevents senescence specifically in normal cells, without affecting tumor cells. Methods: We used brain tumor xenografts obtained by engrafting Glioma Stem Cells (GSCs) into the brain of immunocompromised mice, to investigate the hypothesis that the antioxidant molecule N‐Acetyl‐L‐Cysteine (NAC) might be used to reduce senescence‐associated adverse effects of axitinib treatment without altering its anti‐tumor activity. Results: We demonstrate that the use of the antioxidant molecule N‐Acetyl‐Cysteine (NAC) in combination with axitinib stabilizes tumor microvessels in GBM tumor orthotopic xenografts, eventually resulting in vessel normalization, and protects liver vasculature from axitinib‐dependent toxicity. Conclusion: Overall, we found that NAC co‐treatment allows vessel normalization in brain tumor vessels and exerts a protective effect on liver vasculature, therefore minimizing axitinib‐dependent toxicity. [ABSTRACT FROM AUTHOR]

Simple Summary: The characterization of molecular alterations is continuously gaining relevance in pathology as it can contribute to explaining tumors' pathogenesis and address specific targeted therapies. As for the kidney, in recent years, much scientific research has been focused on the MiTF family genes, particularly on the TFE3 gene. In this setting, while initially just accustomed to a subtype of renal cell carcinoma, currently classified as TFE3-rearranged renal cell carcinoma, TFE3 fusions have been identified in a few mesenchymal neoplasms of the kidney viewed as PEComas. In this work, we gather the available data regarding the key clinical and pathological features of these TFE3-rearranged renal epithelial and mesenchymal neoplasms. We seek to propose a comprehensive solution regarding their pathogenesis and sort out their classification conundrum. Background: Identical translocations involving the TFE3 gene and various partners have been found in both renal and soft tissue tumors, like alveolar soft part sarcoma (ASPSCR1), ossifying fibromyxoid tumor (PHF1), epithelioid hemangioendothelioma, and the clear cell stromal tumor of the lung (YAP1). Methods: Herein, we review in detail the clinicopathologic and molecular data of TFE3-rearranged renal tumors and propose our perspective, which may shed light on this emerging conundrum. Results: Among the kidney tumors carrying TFE3 translocations, most are morphologically heterogeneous carcinomas labeling for the tubular marker PAX8. The others are mesenchymal neoplasms known as PEComas, characterized by epithelioid cells co-expressing smooth muscle actin, cathepsin-K, melanogenesis markers, and sometimes melanin pigment deposition. Over the past 30 years, numerous TFE3 fusion partners have been identified, with ASPL/ASPSCR1, PRCC, SFPQ/PSF, and NONO being the most frequent. Conclusions: It is not well understood why similar gene fusions can give rise to renal tumors with different morpho-immunophenotypes, which may contribute to the recent disagreement regarding their classification. However, as these two entities, respectively, epithelial and mesenchymal in nature, are widely recognized by the pathology community and their clinicopathologic features well established, we overall believe it is still better to retain the names TFE3-rearranged renal cell carcinoma and TFE3-rearranged PEComa. [ABSTRACT FROM AUTHOR]

Simple Summary: Stereotactic body radiotherapy (SBRT) is a treatment technique that delivers higher doses of conformal radiation precisely to specific targets. SBRT is utilized for the treatment of the more common cancers such as lung, liver and prostate malignancies, both in the early stage and the oligometastatic setting. The aim of this review is to highlight the current role of SBRT for renal cell carcinoma (RCC), a disease which was previously thought to be radioresistant, particularly to conventionally fractionated radiotherapy. There is now an increasing body of literature encompassing published phase II trials, reviews and meta-analyses demonstrating the effectiveness of SBRT in both early-stage RCC (as an alternative to patients who are not surgical candidates) and within the context of metastasis-directed therapy (MDT) for patients with oligometastatic and oligoprogressive RCC. Ongoing randomized trials are also exploring the role of SBRT as a cytoreductive treatment in metastatic RCC. Renal cell carcinoma (RCC) has been increasing in incidence by around 1.5% per year for several years. However, the mortality rate has been decreasing by 1.6% per year, and this can be attributed to stage migration and improvements in treatment. One treatment modality that has emerged in recent years is stereotactic body radiotherapy (SBRT), which is an advanced radiotherapy technique that allows the delivery of high-dose radiation to the tumor while minimizing doses to the organs at risk. SBRT has developed a role in the treatment of early-stage, oligometastatic and oligoprogressive RCC. In localized disease, phase II trials and meta-analyses have shown that SBRT provides a very high probability of long-term local control with a low risk of severe late toxicity. In oligometastatic (OMD) RCC, the same level of evidence has similarly shown good local control and minimal toxicity. SBRT could also delay the necessity to start or switch systemic treatments. Medical societies have started to incorporate SBRT in their guidelines in the treatment of localized disease and OMD. A possible future role of SBRT involves cytoreduction. It is theorized that SBRT can lower tumor burden and enhance immune-related response, but it cannot be recommended until the results of the phase II trials are published. [ABSTRACT FROM AUTHOR]

Simple Summary: 3-Monochloropropanediol esters (3-MCPDEs) are process contaminants generated during food processing. Although there is no clinical evidence directly linking them to adverse health effects, concerns have been raised regarding their potential to cause renal damage and cancer. To investigate this, we analyzed the concentrations of 3-MCPDEs in kidney tissues from 68 individuals, categorized into two groups: those with kidney cancer and those without. The levels of 3-MCPDEs were quantified using a validated analytical method, with the analyst blinded to the sample origins to ensure objectivity. The results indicated that 3-MCPDE concentrations were significantly higher in the kidneys of patients with kidney cancer compared to those without cancer. However, no significant correlation was found between 3-MCPDE levels and tumor size or stage. These findings suggest that 3-MCPDEs can accumulate in human kidneys and that their levels are elevated in cancerous tissues. Background: 3-Monochloro-propanediol esters (3-MCPDEs), commonly found in refined edible oils and related products, have generated concerns due to their nephrotoxicity and carcinogenicity, yet clinical evidence remains limited. Objectives: In this study, we aimed to assess, for the first time, the accumulation of 3-MCPDEs in human kidney tissues, focusing on 68 participants, some with and others without renal cell carcinoma (RCC). Methods: An analytical method for 3-MCPDE determination in kidney tissues underwent partial validation to ensure its suitability for sample analysis. The analyst was blind to the sample groups. Results: Results revealed significantly higher 3-MCPDE levels in RCC patients compared to non-RCC counterparts (0.22 vs. 0.01 µg/g) (p < 0.01). Moreover, no significant correlation was found between 3-MCPDE levels and tumor stage or size in the RCC group. Conclusions: Accumulation of 3-MCPDEs in humans, with significantly higher levels was observed in kidney tumor specimens compared to non-patients. These findings suggest minimizing the intake of 3-MCPD and its esters in diets in order to reduce potential negative health impacts. [ABSTRACT FROM AUTHOR]

Simple Summary: Renal cancer is the eighth most frequent cancer in Europe, and its prevalence is increasing. Surgery is the treatment of choice for localised renal cell carcinoma requiring interventional management, but less invasive treatment methods are emerging. Stereotactic body radiotherapy (SBRT) utilises precise delivery of high doses of radiation to ablate the primary cancer. In our systematic review and meta-analysis, we pooled data from available prospective trials, including 13 studies involving 308 patients. The results of the meta-analysis show that SBRT for localised renal cell carcinoma is highly effective in controlling local diseases and has low complication rates. In the second year, 97% of patients were free from local recurrence. Only 3% experienced severe adverse events, which included abdominal pain and fatigue. SBRT presents a valuable treatment for patients who require treatment but cannot undergo surgery; however, it has not been yet confirmed to be equieffective to surgery as trials directly comparing these methods are missing. Context: Surgery is the gold standard for the local treatment of primary renal cell carcinoma (RCC), but alternatives are emerging. We conducted a systematic review and meta-analysis to assess the results of prospective studies using definitive stereotactic body radiotherapy (SBRT) to treat primary localised RCC. Evidence acquisition: This review was prospectively registered in PROSPERO (CRD42023447274). We searched PubMed, Embase, Scopus, and Google Scholar for reports of prospective studies published since 2003, describing the outcomes of SBRT for localised RCC. Meta-analyses were performed for local control (LC), overall survival (OS), and rates of adverse events (AEs) using generalised linear mixed models (GLMMs). Outcomes were presented as rates with corresponding 95% confidence intervals (95% CIs). Risk-of-bias was assessed using the ROBINS-I tool. Evidence synthesis: Of the 2983 records, 13 prospective studies (n = 308) were included in the meta-analysis. The median diameter of the irradiated tumours ranged between 1.9 and 5.5 cm in individual studies. Grade ≥ 3 AEs were reported in 15 patients, and their estimated rate was 0.03 (95%CI: 0.01–0.11; n = 291). One- and two-year LC rates were 0.98 (95%CI: 0.95–0.99; n = 293) and 0.97 (95%CI: 0.93–0.99; n = 253), while one- and two-year OS rates were 0.95 (95%CI: 0.88–0.98; n = 294) and 0.86 (95%CI: 0.77–0.91; n = 224). There was no statistically significant heterogeneity, and the estimations were consistent after excluding studies at a high risk of bias in a sensitivity analysis. Major limitations include a relatively short follow-up, inhomogeneous reporting of renal function deterioration, and a lack of prospective comparative evidence. Conclusions: The short-term results suggest that SBRT is a valuable treatment method for selected inoperable patients (or those who refuse surgery) with localised RCC associated with low rates of high-grade AEs and excellent LC. However, until the long-term data from randomised controlled trials are available, surgical management remains a standard of care in operable patients. [ABSTRACT FROM AUTHOR]

Axitinib (AXTN) is an oral tyrosine kinase inhibitor for the treatment of early to advanced renal cell carcinoma. In this work, solvates of AXTN were prepared in five solvents and subjected to desolvation treatment. The crystal form A of AXTN can form solvates in acetonitrile, DMF, acetic acid, acetic acid + water, and methanol. Different ratios of AXTN and acetic acid will form different products (solvate or directly crystallized into another crystal form (form IV)). The characterization results of thermal analyses confirmed the types of the five solvates. The obtained solvates were desolvated using methods of solid-phase desolvation (heating, exposure to solvent steam, microwave) and solvent-mediated phase transformation (SMPT). The desolvated solids were characterized by PXRD, TGA, DSC, FT-IR, and SEM, and it was ultimately inferred that a new crystal form (form Z) of AXTN could be formed after desolvation. In addition, the solvates obtained in this work experienced mutual transformation via SMPT, which depends on the type of solvents or mixed solvents. The phase transformations of different solid forms were summarized. This study is instructive for exploring solvates and polymorphs of AXTN and understanding phase transitions under different environments. [ABSTRACT FROM AUTHOR]

Laminin, fibronectin, and collagen IV are pivotal extracellular matrix (ECM) components. The ECM environment governs the fundamental properties of tumors, including proliferation, vascularization, and invasion. Given the critical role of cell-matrix adhesion in malignant tumor progression, we hypothesize that the concentrations of these proteins may be altered in the plasma of patients with clear cell renal cell carcinoma (ccRCC). This study aimed to evaluate the serum, urine, and tissue levels of laminin-5, collagen IV, and fibronectin among a control group and ccRCC patients, with the latter divided into stages T1–T2 and T3–T4 according to the TNM classification. We included 60 patients with histopathologically confirmed ccRCC and 26 patients diagnosed with chronic cystitis or benign prostatic hyperplasia (BPH). Collagen IV, laminin-5, and fibronectin were detected using Surface Plasmon Resonance Imaging biosensors. Significant differences were observed between the control group and ccRCC patients, as well as between the T1–T2 and T3–T4 subgroups. Levels were generally higher in plasma and tissue for fibronectin and collagen IV in ccRCC patients and lower for laminin. The ROC (Receiver operating characteristic) analysis yielded satisfactory results for differentiating between ccRCC patients and controls (AUC 0.84–0.93), with statistical significance for both fibronectin and laminin in plasma and urine. Analysis between the T1–T2 and T3–T4 groups revealed interesting findings for all examined substances in plasma (AUC 0.8–0.95). The results suggest a positive correlation between fibronectin and collagen levels and ccRCC staging, while laminin shows a negative correlation, implying a potential protective role. The relationship between plasma and urine concentrations of these biomarkers may be instrumental for tumor detection and staging, thereby streamlining therapeutic decision-making. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia is characterized by a loss of muscle mass and function and is often associated with frailty, a syndrome linked to physical disability and shortened survival in various patient populations, including cancer patients. Low serum alanine aminotransferase (ALT) values, serving as a biomarker for sarcopenia, were previously associated with frailty and shortened survival in several cancers. In the current study, we aimed to test the association between low ALT and shorter survival in renal cell carcinoma (RCC) patients and survivors. Methods: This was a retrospective analysis of RCC patients and survivors, both in- and outpatients. We defined patients with sarcopenia as those presenting with ALT < 17 IU/L. Results: We identified records of 3012 RCC patients. The cohort included 1830 patients (mean age 65.6 ± 13.3 years, 68% were men) of whom only 179 underwent surgical treatment. Out of the eligible cohort, 811 patients (44.3%) had ALT < 17 IU/L, with a mean ALT value of patients within the low-ALT group of 11.79 IU/L, while the mean value in the higher ALT level group was 24.44 IU/L (p < 0.001). Patients in the low-ALT group were older (67.9 vs. 63.7 years; p < 0.001) and had lower BMIs (26.6 vs. 28; p < 0.001). In addition, patients with low ALT had lower hemoglobin values (12.14 vs. 12.91 g/dL; p < 0.001), higher serum creatinine (1.49 vs. 1.14; p < 0.001) and higher platelet to lymphocyte ratios (178 vs. 156; p < 0.001). In a univariate analysis, low ALT levels were associated with a 72% increase in mortality (95% CI 1.46–2.02, p < 0.001). In a multivariate model controlled for age, gender, hemoglobin, platelets, LDH, neutrophil to lymphocyte ratios and platelet to lymphocyte ratios, low ALT levels were still associated with a 27% increase in mortality (HR = 1.27, 95% CI 1.08–1.51; p = 0.005). Conclusion. Low ALT values, associated with sarcopenia and frailty, are also associated with shortened survival in RCC patients, and survivors and could potentially be applied for optimizing individual treatment decisions. [ABSTRACT FROM AUTHOR]

Objectives: Cytoreductive nephrectomy for metastatic renal cell carcinoma (mRCC) is a standard of care. Partial nephrectomy (PN) in the setting of metastatic disease is an uncommon occurrence, and we aimed to characterize its utilization in a modern cohort. Methods: The National Cancer Database was reviewed for patients with mRCC from 2010 to 2017. Patients with cTanyNanyM1 who underwent cytoreductive surgery in the form of PN or radical nephrectomy (RN) were compiled. Our primary outcome was survival outcome for patients who underwent PN compared to RN. Secondary outcomes included 30-day readmission, length of stay, and survival outcomes. Results obtained: A total of 13,896 patients with mRCC who underwent cytoreductive surgery were identified. In total, 13,242 underwent RN and 654 underwent PN. The RN population was more likely to have cN positive disease, while the PN population was more likely to have cT1 disease. Length of stay, readmission and 30-day mortality were not significantly different between PN and RN, but overall mortality and 90-day mortality favored PN (p < 0.001). Cox regression for death showed PN with improved overall survival (HR 0.782, p < 0.001). Logistic regression for predictors of cytoreductive PN revealed cT1 and cN0 as significant factors. Overall survival, as seen on KM analysis, identified that PN exhibited improved 2-year (67.1% vs. 52.0%) and 5-year (40.7% vs. 29.2%) overall survival relative to RN (p < 0.001). Conclusions: PN is an infrequent treatment with mRCC and its utilization is stable from 2010 to 2017. Overall survival is significantly better for those undergoing PN, likely due to their favorable oncologic disease characteristics. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICI) have become the cornerstone of treatment in renal cell carcinoma (RCC), for both metastatic disease and in an adjuvant setting. However, an adaptive resistance from cancer cells may arise during ICI treatment, therefore many studies are focusing on additional immune checkpoint inhibitor pathways. Promising targets of immunotherapeutic agents under investigation include T cell immunoglobulin and ITIM domain (TIGIT), immunoglobulin-like transcript 4 (ILT4), lymphocyte activation gene-3 (LAG-3), vaccines, T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and chimeric antigen receptor (CAR) T cells. In this review of the literature, we recollect the current knowledge of the novel treatment strategies in the field of immunotherapy that are being investigated in RCC and analyze their mechanism of action, their activity and the clinical studies that are currently underway. [ABSTRACT FROM AUTHOR]

To our knowledge, this is the first report of percutaneous endoscopic intragastric surgery (PEIGS) for gastric metastases from other organs. A 70‐year‐old male with a history of renal cell carcinoma (RCC) was referred to our department for the treatment of gastric metastasis of RCC. Partial gastrectomy was performed using single‐incision PEIGS. Two years after the surgery, a follow‐up esophagogastroduodenoscopy revealed a tumor located on the middle greater curvature of the stomach. The diagnosis was metastatic renal cell carcinoma, prompting a similar surgery. No recurrence was observed after the second surgery. PEIGS is a minimally invasive option for the treatment of metastatic gastric tumors. [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: Integrated immune checkpoint inhibitors (ICIs) plus tyrosine kinase inhibitors (TKIs) are now the recommended first-line therapy to manage renal cell carcinoma (mRCC). Proteasome 26S subunit non-ATPase 2 (PSMD2) overexpression in tumors has been correlated with tumor progression. Currently, mRCC lacks an established biomarker for the combination of ICI+TKI. Methods: This study involved RNA sequencing of RCC patients from two cohorts treated with ICI+TKI (ZS-MRCC and JAVELIN-Renal-101). We utilized immunohistochemistry alongside flow cytometry, aiming at assessing immune cell infiltration and functionality in high-risk localized RCC samples. Response and progression-free survival (PFS) were evaluated relying upon RECIST criteria. Results: PSMD2 was significantly overexpressed in advanced RCC and among non-responders to ICI+TKI therapy. Overexpressed PSMD2 was correlated with poor PFS in the ZS-MRCC and JAVELIN-101 cohorts. Multivariate Cox analysis validated PSMD2 as an independent PFS predictor. PSMD2 overexpression was related to a reduction in CD8+ T cells, especially GZMB+ CD8+ T cells, besides an increase in PD1+ CD4+ T cells. Additionally, tumors with high PSMD2 levels showed enhanced T cell exhaustion levels and a higher regulatory T cell presence. A Machine Learning (ML) model based on PSMD2 expression and other screened factors was subsequently developed to predict the effectiveness of ICI+TKI. Conclusions: Elevated PSMD2 expression is linked to resistance and decreased PFS in mRCC patients undergoing ICI+TKI therapy. High PSMD2 levels are also associated with impaired function and increased exhaustion of tumor-infiltrating lymphocytes. An ML model incorporating PSMD2 expression could potentially identify patients who may have a higher likelihood of benefiting from ICI+TKI. [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]

Background: To define the incidence and independent predictive factors of intraoperative adverse events (IOAEs) after minimally invasive radical nephrectomy and thrombectomy (RNAT) and to determine the impact of intraoperative adverse events on oncological outcomes. Patients and methods: A total of 294 patients underwent minimally invasive RNAT from January 2010 to December 2023 in our center were included. IOAEs are defined as any deviation from the normal surgical procedure during the operation course. Multivariate logistic regression analysis was performed to identify the independent predictive factors of IOAEs. The Kaplan–Meier curves was used to compare overall survival and cancer-specific survival between patients with IOAEs or not. Results: Seventy-four IOAEs occurred in 57 of 294 patients (19.4%) and the most frequent IOAEs were conversion to open surgery (42/74, 56.7%), followed by excessive hemorrhage (20/74, 27.0%). In multivariate logistic analysis, side (OR 0.0929; 95%Cl 0.0367–0.2160; p < 0.001), operation approach (OR 0.1762; 95%Cl 0.06828–0.4109; p < 0.001), and Mayo grade (OR 6.321; 95%Cl 3.846–11.13; p < 0.001) were independent predictive predictors of IOAEs during minimally invasive RNAT. IOAEs (OR 2.713; 95%Cl 1.242–5.897; p = 0.012) was an independent risk factor of the occurrence of postoperative complications. Between the patients with IOAEs or not, neither overall survival (OS) nor cancer-specific survival (CSS) showed statistical differences. Patients with postoperative complications show shorter OS and CSS. Conclusion: We found that the independent predictive factors of minimally invasive RNAT were side, operation approach and Mayo grade, and it is a risk factor of the occurrence of postoperative complications. In addition, the occurrence of IOAEs had no effect on long-term oncological outcomes. [ABSTRACT FROM AUTHOR]

Introduction: Nuclear envelope spectrin repeat protein (Nesprin) 1 encoded by SYNE1, crucially regulates the morphology and functions of the cell. Mutations in the SYNE1 gene are associated with various diseases; however, their significance in renal cell carcinoma (RCC) remains unknown. In this study, we have investigated the association of SYNE1/Nesprin1 with the progression and prognosis of clear cell RCC (ccRCC). Methods: In silico analyses of publicly available datasets of patients with RCC were performed. Based on the cohort data, Nesprin1 expression in nephrectomized tissue samples acquired from patients with ccRCC was analyzed using immunohistochemical staining. The invasion, migration, and proliferation of the SYNE1-knockdown human RCC cell lines were analyzed in vitro; moreover, RNA sequencing and gene set enrichment analysis were conducted to study the molecular mechanism underlying the association of SYNE1/Nesprin1 with prognosis of RCC. Results: Patients with RCC-associated SYNE1 gene mutations exhibited significantly worse overall and progression-free survivals. Patients with Nesprin1-negative ccRCC tumors exhibit significantly poorer overall, cancer-specific, and recurrence-free survival rates than those recorded in the Nesprin1-positive group. SYNE1 knockdown enhanced the invasion and migration of RCC cells; however, it did not influence the proliferation of cells. RNA sequencing and gene set enrichment analysis revealed that SYNE1 knockdown significantly altered the expression of genes associated with oxidative phosphorylation. Consistently, patients with RCC exhibiting low SYNE1 expression, who were treated with the vascular endothelial growth factor receptor inhibitor sunitinib, had worse progression-free survival. Conclusions: The results indicate that the expression of SYNE1/Nesprin1 and SYNE1 mutations in patients with RCC are closely linked to their prognosis and responsiveness to sunitinib treatment. [ABSTRACT FROM AUTHOR]

Elucidating the molecular dependencies behind the cancer-type specificity of driver mutations may reveal new therapeutic opportunities. We hypothesized that developmental programs would impact the transduction of oncogenic signaling activated by a driver mutation and shape its cancer-type specificity. Therefore, we designed a computational analysis framework by combining single-cell gene expression profiles during fetal organ development, latent factor discovery, and information theory-based differential network analysis to systematically identify transcription factors that selectively respond to driver mutations under the influence of organ-specific developmental programs. After applying this approach to VHL mutations, which are highly specific to clear cell renal cell carcinoma (ccRCC), we revealed important regulators downstream of VHL mutations in ccRCC and used their activities to cluster patients with ccRCC into three subtypes. This classification revealed a more significant difference in prognosis than the previous mRNA profile-based method and was validated in an independent cohort. Moreover, we found that EP300, a key epigenetic factor maintaining the regulatory network of the subtype with the worst prognosis, can be targeted by a small inhibitor, suggesting a potential treatment option for a subset of patients with ccRCC. This work demonstrated an intimate relationship between organ development and oncogenesis from the perspective of systems biology, and the method can be generalized to study the influence of other biological processes on cancer driver mutations. [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: This study aimed to develop and validate a computed tomography—based nomogram assessing visceral and subcutaneous adiposity for predicting outcomes in localized clear cell renal cell carcinoma (ccRCC). Methods: A cohort of 364 patients with pathologically confirmed ccRCC participated in this retrospective study, with 254 patients assigned to the training set and 110 to the validation set (a 7:3 distribution ratio). The adipose score (AS) was generated using the least absolute shrinkage and selection operator Cox regression. Subsequently, a nomogram was constructed by integrating the clinical independent predictor with the AS to predict disease-free survival (DFS) in localized ccRCC after surgery. The performance of the nomogram was compared with the University of California, Los Angeles, Integrated Staging System (UISS), and the Stage, Size, Grade, and Necrosis (SSIGN) score. Results: In both the training and validation cohorts, the nomogram exhibited superior discrimination compared to SSIGN and UISS (C-index: 0.897 vs. 0.781 vs. 0.776 in the training cohort, and 0.752 vs. 0.596 vs. 0.686 in the validation cohort; 5 year AUC: 0.907 vs. 0.805 vs. 0.820 in the training cohort, and 0.832 vs. 0.577 vs. 0.726 in the validation cohort). Decision curve analysis (DCA) revealed a superior net benefit across a wider range of threshold probabilities for predicting 5 year DFS compared to UISS and SSIGN scores. Conclusions: The developed prognostic nomogram demonstrated high accuracy and overall superior performance compared to existing prognostic models. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate radiomics features' reproducibility using inter-package/inter-observer measurement analysis in renal masses (RMs) based on MRI and to employ machine learning (ML) models for RM characterization. Methods: 32 Patients (23M/9F; age 61.8 ± 10.6 years) with RMs (25 renal cell carcinomas (RCC)/7 benign masses; mean size, 3.43 ± 1.73 cm) undergoing resection were prospectively recruited. All patients underwent 1.5 T MRI with T2-weighted (T2-WI), diffusion-weighted (DWI)/apparent diffusion coefficient (ADC), and pre-/post-contrast-enhanced T1-weighted imaging (T1-WI). RMs were manually segmented using volume of interest (VOI) on T2-WI, DWI/ADC, and T1-WI pre-/post-contrast imaging (1-min, 3-min post-injection) by two independent observers using two radiomics software packages for inter-package and inter-observer assessments of shape/histogram/texture features common to both packages (104 features; n = 26 patients). Intra-class correlation coefficients (ICCs) were calculated to assess inter-observer and inter-package reproducibility of radiomics measurements [good (ICC ≥ 0.8)/moderate (ICC = 0.5–0.8)/poor (ICC < 0.5)]. ML models were employed using reproducible features (between observers and packages, ICC > 0.8) to distinguish RCC from benign RM. Results: Inter-package comparisons demonstrated that radiomics features from T1-WI-post-contrast had the highest proportion of good/moderate ICCs (54.8–58.6% for T1-WI-1 min), while most features extracted from T2-WI, T1-WI-pre-contrast, and ADC exhibited poor ICCs. Inter-observer comparisons found that radiomics measurements from T1-WI pre/post-contrast and T2-WI had the greatest proportion of features with good/moderate ICCs (95.3–99.1% T1-WI-post-contrast 1-min), while ADC measurements yielded mostly poor ICCs. ML models generated an AUC of 0.71 [95% confidence interval = 0.67–0.75] for diagnosis of RCC vs. benign RM. Conclusion: Radiomics features extracted from T1-WI-post-contrast demonstrated greater inter-package and inter-observer reproducibility compared to ADC, with fair accuracy for distinguishing RCC from benign RM. Clinical relevance: Knowledge of reproducibility of MRI radiomics features obtained on renal masses will aid in future study design and may enhance the diagnostic utility of radiomics models for renal mass characterization. [ABSTRACT FROM AUTHOR]

Aims: Decreased oestrogen receptor (ER) expression is a marker of poor prognosis in endometrial carcinomas (EC) of no specific molecular profile (NSMP), but the optimal cut‐off to separate high‐risk 'low ER' versus low‐risk 'high ER' expression has not been defined. Here we characterised the distribution of ER staining in a cohort of ECs. Methods and results: Biopsy specimens from 120 cases of NSMP EC were stained for ER and assigned an Allred score. In 66 additional cases ER staining of matched biopsy and hysterectomy were compared. Twelve of 120 tumours had an Allred score of 0–3, including three endometrioid carcinomas (EEA) (one G1, two G3), four clear cell carcinomas (CCC), two mesonephric‐like adenocarcinoma (MLA) and one each of: gastric‐type adenocarcinoma, carcinosarcoma and endometrial carcinoma NOS. Three had Allred scores of 4–5: two MLA and one high‐grade carcinoma with yolk sac differentiation. Five had Allred scores of 6: four EEA (one G1, one G2, two G3) and one mixed clear cell and endometrioid carcinoma. The remaining 100 tumours with Allred scores ≥ 7 were all EEA (66 G1, 28 G2, five G3 and one grade unknown). Comparing the biopsy versus hysterectomy ER staining (n = 66), the results were within a single Allred score point, except two cases with strong diffuse expression in the biopsy (Allred 8) and moderate expression in the hysterectomy (Allred 5). Conclusions: Most NSMP ECs (> 80%) show high ER expression (Allred score ≥ 7). All non‐endometrioid carcinomas and a few endometrioid carcinomas had lower ER expression (Allred score ≤ 6) or were completely negative. [ABSTRACT FROM AUTHOR]

Aims: Traditionally, mismatch repair (MMR) status is determined by a panel of four antibodies (MLH1, PMS2, MSH2, MSH6). If all proteins are retained, cases are MMR proficient (pMMR), while loss of one or more proteins is indicative of MMR deficiency (dMMR). This approach has been challenged in favour of a two‐antibody approach, using PMS2 and MSH6 as a first screening. Their retainment is deemed sufficient to declare cases pMMR. In this study we aim to verify the validity of the two‐antibody approach. Methods and Results: We performed a nationwide study in colorectal cancer (CRC) and endometrial cancer (EC) diagnosed between 2016 and 2023, including 47,657 patients to evaluate the two‐antibody approach. In 0.17% and 0.4% of cases of CRC and EC, respectively, dMMR cases would be missed with the two‐antibody approach. Subgroup analyses pointed towards slightly increased miss rates in younger patients (under the age of 50 years) in both groups and identified special subtypes (signet ring cell carcinoma, medullary carcinoma, and mucinous carcinoma in CRC and clear cell carcinoma in EC) with increased miss rates. For these specific subgroups, a low threshold should be used for further testing. In case of ambiguous or heterogeneous staining patterns, four antibodies should be used. Conclusion: In general, the application of a two‐antibody MMR testing strategy does not lead to considerable failure of dMMR identification and saves costs. [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]

Renal cell carcinoma with fibromyomatous stroma, recognized as a provisional entity in the current 2022 World Health Organization classification of renal neoplasms, is rare. Recent evidence suggests recurrent alterations in the mTOR pathway, supporting its recognition as a distinct entity. Herein, we report 2 renal cell carcinomas with fibromyomatous stroma with MTOR mutations occurring in 62- and 72-year-old women and review the literature to support its recognition as a distinct entity, focusing on the characteristic morphology, immunohistochemical staining patterns as well as genetic alterations. [ABSTRACT FROM AUTHOR]

Purpose: Immune checkpoint inhibitors have revolutionized the treatment of renal cell carcinoma (RCC), but many patients do not respond to therapy and the majority develop resistant disease over time. Thus, there is increasing need for alternative immunomodulating agents. The co-inhibitory molecule T-cell immunoglobulin and ITIM domain (TIGIT) may play a role in resistance to approved immune checkpoint inhibitors and is being investigated as a potential therapeutic target. The purpose of this study was to quantify TIGIT positivity in tumor-infiltrating T cells in RCC. Methods: We employed tissue microarrays containing specimens from primary RCC tumors, adjacent normal renal tissue, and RCC metastases to quantify TIGIT within tumor-infiltrating CD3+ T cells using quantitative immunofluorescent analysis. We also compared these results to TIGIT+ CD3+ levels in four other tumor types (melanoma, non-small cell lung, cervical, and head and neck cancers). Results: We did not observe significant differences in TIGIT positivity between primary RCC tumors and patient-matched metastatic samples. We found that the degree of TIGIT positivity in RCC is comparable to that in lung cancer but lower than that in melanoma, cervical, and head and neck cancers. Correlation analysis comparing TIGIT positivity to previously published, patient-matched spatial proteomic data by our group revealed a negative association between TIGIT and the checkpoint proteins PD-1 and LAG3. Conclusion: Our findings support careful evaluation of TIGIT expression on T cells in primary or metastatic RCC specimens for patients who may be treated with TIGIT-targeting antibodies, as increased TIGIT positivity might be associated with a greater likelihood of response to therapy. [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]

Purpose: Indeterminate renal masses are increasingly incidentally found on cross-sectional imaging. 99mTc-sestamibi single-photon emission computed tomography/computed tomography (SPECT/CT) scans can be used to identify oncocytomas and oncocytic renal neoplasms, including a subset of chromophobe renal cell carcinomas (chRCCs), which are viewed as false-positive. Procedure: Patients imaged with renal sestamibi scans between 2014 and 2023 were reviewed. Those patients with solitary tumors that were originally classified as chRCC were included in the analysis. Imaging with SPECT/CT from the liver dome down had been carried out 75 min after the administration of 925 MBq of 99mTc-sestamibi. All available H&E and immunostained slides were re-reviewed and classified according to WHO 2022 criteria. Confirmatory immunohistochemical stains were performed in tumors considered morphologically suspicious for non-chRCC entities. Result: A total of 18 patients with solitary tumors were included in the final analysis. 13/18 (72.2%) tumors in this cohort remained classified as chRCC, with 4/18 (22.2%) being eosinophilic-variant chRCC. The reclassified tumors (5/18 [27.8%]) included 2/18 (11.1%) low-grade oncocytic tumor (LOT), 1/18 (5.5%) eosinophilic vacuolated tumor (EVT), and 2/18 (11.1%) unclassified low-grade oncocytic neoplasms. As such, only 2/9 (22.2%) qualitatively "hot" tumors were chRCC other than eosinophilic-variant and only 1/9 (11.1%) "cold" tumors was a histology other than chRCC. Conclusion: Based on current histopathologic classification methods, it is likely that the "false-positive" rate of uptake on renal sestamibi scans with chRCC has been over-stated. Further study is warranted to better refine the optimal utility of renal sestamibi scans for non-invasive risk stratification of indeterminate renal masses. [ABSTRACT FROM AUTHOR]