Stemness related lncRNAs signature for the prognosis and tumor immune microenvironment of ccRCC patients.

Long non-coding RNAs (lncRNAs) and cancer stem cells (CSCs) are crucial for the growth, migration, recurrence, and medication resistance of tumors. However, the impact of lncRNAs related to stemness on the outcome and tumor immune microenvironment (TIME) in clear cell renal cell carcinoma (ccRCC) is still unclear. In this study, we aimed to predict the outcome and TIME of ccRCC by constructing a stem related lncRNAs (SRlncRNAs) signature. We firstly downloaded ccRCC patients' clinical data and RNA sequencing data from UCSC and TCGA databases, and abtained the differentially expressed lncRNAs highly correlated with stem index in ccRCC through gene expression differential analysis and Pearson correlation analysis. Then, we selected suitable SRlncRNAs for constructing a prognostic signature of ccRCC patients by LASSO Cox regression. Further, we used nomogram and Kaplan Meier curves to evaluate the SRlncRNA signature for the prognose in ccRCC. At last, we used ssGSEA and GSVA to evaluate the correlation between the SRlncRNAs signature and TIME in ccRCC. Finally, We obtained a signtaure based on six SRlncRNAs, which are correlated with TIME and can effectively predict the ccRCC patients' prognosis. The SRlncRNAs signature may be a noval prognostic indicator in ccRCC.

Stage IV renal cell carcinoma achieves pathologic complete response after two ipilimumab plus nivolumab courses despite severe immune-related adverse events: a case report.

BACKGROUND: Ipilimumab (Ipi) plus nivolumab (Nivo) is the recommended first-line treatment for renal cell carcinoma (RCC). This report describes a case where pancreatic metastases disappeared after only two courses of Ipi + Nivo therapy. The primary tumor was cured by surgery, and a pathological Complete Response (pCR) was observed despite multiple serious immune-related Adverse Events (irAEs). CASE PRESENTATION: A 54-year-old woman with RCC and pancreatic metastasis at stage IV, diagnosed with intermediate risk according to the International Metastatic RCC Database Consortium classification, underwent initiation of Ipi + Nivo therapy. On day 26, she developed hyperthyroidism accompanied by tachycardia, leading to the commencement of metoprolol tartrate treatment. Following the resolution of tachycardia, a second course of Ipi + Nivo therapy was administered on day 50. By day 70, the patient exhibited Grade 3 hepatic dysfunction, followed by the onset of hypothyroidism on day 75, necessitating treatment with steroids and levothyroxine. After positive treatment, a Grade 3 skin disorder emerged on day 87 while tapering steroids, prompting treatment with methylprednisolone (mPSL) pulse therapy. The skin disorder responded to steroids, allowing for tapering. However, on day 113, a recurrence of Grade 3 skin disorder occurred, necessitating another mPSL pulse. The patient responded well to treatment, exhibiting improvement in her condition. On day 131, she presented at the hospital with complaints of respiratory distress, prompting a Computed Tomography (CT) scan that revealed interstitial pneumonia. By day 272, subsequent CT imaging showed the disappearance of pancreatic metastasis and shrinkage of the primary tumor. On day 294, she underwent a laparoscopic left nephrectomy. Pathological analysis confirmed a pCR in the primary tumor, indicating successful eradication of RCC through surgical intervention. CONCLUSIONS: This case report presents a scenario where multiple severe irAEs appeared in a patient, yet metastases disappeared after only two courses of Ipi + Nivo therapy. The patient was ultimately cured by surgery and achieved a pCR. This case highlights that despite the occurrence of severe irAEs during RCC treatment with Ipi + Nivo therapy, they can be managed appropriately to maximize the therapeutic effects of checkpoint inhibitors.

Improved Survival in Contemporary Community-Based Patients With Metastatic Clear-Cell Renal Cell Carcinoma Undergoing Active Treatment.

BACKGROUND: We hypothesized that the evolving treatment paradigms recommended based on phase III trials may have translated into improved overall survival (OS) in contemporary community-based patients with clear-cell metastatic renal cell carcinoma (ccmRCC) undergoing active treatment. PATIENTS AND METHODS: Within the SEER database, contemporary (2017-2020) and historical (2010-2016) patients with ccmRCC treated with either systemic therapy (ST), cytoreductive nephrectomy (CN), or both (ST+CN) were identified. Univariable and multivariable Cox-regression models were used. RESULTS: Overall, 993 (32%) contemporary versus 2,106 (68%) historical patients with ccmRCC were identified. Median OS was 41 months in contemporary versus 25 months in historical patients (Δ=16 months; P<.001). In multivariable Cox-regression analyses, contemporary membership was independently associated with lower overall mortality (hazard ratio [HR], 0.7; 95% CI, 0.6-0.8; P<.001). In patients treated with ST alone, median OS was 17 months in contemporary versus 10 months in historical patients (Δ=7 months; P<.001; multivariable HR, 0.7; P=.005). In patients treated with CN alone, median OS was not reached in contemporary versus 33 months in historical patients (Δ=not available; P<.001; multivariable HR, 0.7; P<.001). In patients treated with ST+CN, median OS was 38 months in contemporary versus 26 months in historical patients (Δ=12 months; P<.001; multivariable HR, 0.7; P=.003). CONCLUSIONS: Contemporary community-based patients with ccmRCC receiving active treatment clearly exhibited better survival than their historical counterparts, when examined as one group, as well as when examined as separate subgroups according to treatment type. Treatment advancements of phase III trials seem to be applied appropriately outside of centers of excellence.

Effect of Perioperative Blood Transfusion on Prognosis after Radical Resection in Patients with Non-Metastatic Renal Cell Carcinoma: A Retrospective Analysis.

OBJECTIVE: Advancements in medical science have improved non-metastatic renal cell carcinoma (NM-RCC) treatment strategies, but long-term survival is influenced by various factors, including perioperative blood transfusion. This study aims to analyse prognostic factors in patients with NM-RCC after radical nephrectomy. METHODS: From January 2018 to December 2021, a total of 132 patients with NM-RCC after radical nephrectomy were studied. According to 2-year follow-up data, the patients were categorised into case (with poor outcomes, including pneumothorax, renal issues, recurrence or death) and control groups. Data on demographics, clinical characteristics and perioperative blood transfusion were collected, and key prognostic factors were identified through logistic regression. RESULTS: A total of 32 patients with poor prognosis were included in the case group, accounting for 24.24% (32/132), and 100 patients without poor prognosis were included in the control group, accounting for 75.76% (100/132). Tumour stage, tumour size and perioperative blood transfusion were all risk factors for the prognosis of patients, and odds ratio (OR) >1. The above indicators had high predictive value for the prognosis of patients after surgery. CONCLUSIONS: The prognostic factors of patients with NM-RCC after radical nephrectomy include tumour stage, tumour size and perioperative blood transfusion, and each factor had predictive value.

Development of a CT-assessed adiposity nomogram for predicting outcome in localized ccRCC.

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.

A new perspective: deciphering the aberrance and clinical implication of disulfidptosis signatures in clear cell renal cell carcinoma.

Recent research has discovered disulfidptosis as a form of programmed cell death characterized by disulfide stress. However, its significance in clear cell renal cell carcinoma (ccRCC) remains unclear. To investigate this, data from The Cancer Genome Atlas were collected and used to identify ccRCC subgroups. Unsupervised clustering was employed to determine ccRCC heterogeneity. The mutation landscape and immune microenvironment of the subgroups were analyzed. The Disulfidptosis-Related Score was calculated using the LASSO-penalized Cox regression algorithm. The E-MATB-1980 cohort was used to validate the signature. The role of SLC7A11 in ccRCC metastasis was explored using western blotting and Transwell assays. Disulfidptosis-related genes are commonly downregulated in cancers and are linked to hypermethylation and copy number variation. The study revealed that ccRCC is divided into two sub-clusters: the disulfidptosis-desert sub-cluster, which is associated with a poor prognosis, a higher mutation frequency, and an immunosuppressive microenvironment. A 14-gene prognostic model was developed using differentially expressed genes and was validated in the E-MATB-1980 cohort. The low-risk group demonstrated longer overall and disease-free survival and responded better to targeted immunotherapy. Results from in vitro experiments identified SLC7A11 as a key participant in ccRCC metastasis.

Evaluation of PET/CT imaging with [89Zr]Zr-DFO-girentuximab: a phase 1 clinical study in Japanese patients with renal cell carcinoma (Zirdac-JP).

BACKGROUND: PET/CT imaging with Zirconium-89 labeled [89Zr]Zr-DFO-girentuximab, which targets tumor antigen CAIX, may aid in the differentiation and characterization of clear cell renal cell carcinomas (RCC) and other renal and extrarenal lesions, and has been studied in European and American cohorts. We report results from a phase I study that evaluated the safety profile, biodistribution, and dosimetry of [89Zr]Zr-DFO-girentuximab in Japanese patients with suspected RCC. METHODS: Eligible adult patients received 37 MBq (± 10%; 10 mg mass dose) of intravenous [89Zr]Zr-DFO-girentuximab. Safety and tolerability profile was assessed based on adverse events, concomitant medications, physical examination, vital signs, hematology, serum chemistry, urinalysis, human anti-chimeric antibody measurement, and 12-lead electrocardiograms at predefined intervals. Biodistribution and normal organ and tumor dosimetry were evaluated with PET/CT images acquired at 0.5, 4, 24, 72 h and Day 5 ± 2 d after administration. RESULTS: [89Zr]Zr-DFO-girentuximab was administered in six patients as per protocol. No treatment-emergent adverse events were reported. Dosimetry analysis showed that radioactivity was widely distributed in the body, and that the absorbed dose in healthy organs was highest in the liver (mean ± standard deviation) (1.365 ± 0.245 mGy/MBq), kidney (1.126 ± 0.190 mGy/MBq), heart wall (1.096 ± 0.232 mGy/MBq), and spleen (1.072 ± 0.466 mGy/MBq). The mean effective dose, adjusted by the radioactive dose administered, was 0.470 mSv/MBq. The radiation dose was highly accumulated in the targeted tumor, while any abnormal accumulation in other organs was not reported. CONCLUSIONS: This study demonstrates that [89Zr]Zr-DFO-girentuximab administered to Japanese patients with suspected RCC has a favorable safety profile and is well tolerated and has a similar dosimetry profile to previously studied populations.

Multifaceted Imaging of Renal Lesions With an Emphasis on Cross-Sectional Imaging.

Introduction Renal lesions are common findings encountered in cross-sectional imaging. Ultrasonography (USG), computed tomography (CT), and magnetic resonance imaging (MRI) are available modalities for evaluating renal lesions. The Bosniak classification system aids in classifying a renal lesion into a particular category based on various imaging characteristics on contrast-enhanced CT (CECT).  Materials and methods The CT report archives were searched for the keyword 'Bosniak' lesions, and six illustrative cases were selected to be included in the review. Results Six cases under Bosniak categories I to IV were included in the review. Operative follow-ups were added in cases where patients underwent surgery. Discussion We have reviewed the imaging features of various renal lesions with cross-sectional modalities, namely CT and MRI, with special emphasis on the Bosniak classification system, including its amendments. Conclusion The Bosniak system is widely used to classify and characterize renal lesions. The authors have presented a scoping review of the features of renal lesions and the Bosniak system.

Demographic Characteristics and Treatment Outcomes of Advanced Renal Cell Carcinoma With Clear Cell Histology: A Single-Center Experience From India.

Background Treatment of metastatic renal cell cancer (mRCC) has revolutionized with the introduction of anti-VEGF tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs). There is limited data in the literature on the outcomes of Indian patients treated with TKI. Here, we report the outcome of mRCC treated with first-line TKI in a resource-poor setting. Material and methods This is a single-center retrospective study of clear cell mRCC treated with first-line TKI from June 2012 to December 2022. Demographic characteristics and treatment details, including outcome data, were captured from electronic medical records. Patients who received at least one week of therapy were eligible for survival analysis. Results A total of 345 patients with metastatic clear cell histology were analyzed, with a median age of 61 years (range: 20-84 years). One hundred and eighty patients (52%) underwent nephrectomy before systemic therapy. The majority received pazopanib (257 patients, 75%), followed by sunitinib (36 patients, 10%) and cabozantinib (21 patients, 6%); 145 (45%) patients required dose interruption, and 143 (43%) required dose modification of TKI for adverse events. After a median follow-up of 44 months, the median progression-free survival (PFS) was 20.3 months (95% CI: 17.8-24.8), and the median overall survival (OS) was 22.7 months (95% CI: 18.8-28.3). In the poor-risk International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) group, no prior nephrectomy emerged as an independent poor-risk factor for both PFS and OS in multivariate analysis. Conclusion This is the largest single-center cohort of clear cell mRCC from Asia. Median PFS was 20.3 months with predominantly TKI monotherapy. In the poor-risk IMDC group, no prior nephrectomy emerged as an independent poor-risk factor for both PFS and OS.

Prognostic value of tumor-stroma ratio in clear cell renal cell carcinoma after surgery.

Background: Clear cell renal cell carcinoma (ccRCC) is one of the most common urological tumors, and its incidence is increasing year by year. Tumor stroma ratio (TSR) can reflect the amount of stromal component around tumor cells, and can independently predict the prognosis of tumor. This study aims to evaluate the prognostic value of TSR in ccRCC patients. Methods: From January 2010 to December 2015, clinical and histopathological data of patients with ccRCC patients who underwent surgical operation were collected. Using TSR (50%) as the cut-off value, the patients were divided into low-TSR group (<50%) and high-TSR group (≥50%). The clinicopathological characteristics and survival status of patients were compared between the two groups. Univariate and multivariate analyses were used to identify the prognostic factors for overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS). Results: The mean age of 569 patients was 56.84±12.76 years old. There were 401 males and 168 females. According to the TSR, patients were divided into low-TSR group (n=333, 58.5%) and high-TSR group (n=236, 41.5%). The median follow-up time was 67.0 months (interquartile range, 33.0-72.0 months). The 5-year OS, CSS and MFS were 91.2%, 94.6% and 91.0%, respectively. The 5-year OS, CSS and MFS were 84.2%,89.7% and 82.7% in the high-TSR group and 96.1%, 98.0% and 96.0% in the low-TSR group (P<0.05). Multivariate analysis showed that age >60 years [hazard ratio (HR) =2.455, 95% confidence interval (CI): 1.292-4.668, P=0.006), tumor grade (HR =6.580, 95% CI: 3.276-13.216, P<0.001) and TSR (HR =2.611, 95% CI: 1.265-5.387, P=0.009) were independent prognostic factors for OS. Multivariate analysis showed that tumor stage (HR =3.213, 95% CI: 1.437-7.184, P=0.004), tumor grade (HR =6.102, 95% CI: 2.664-13.976, P<0.001) and TSR (HR =2.653, 95% CI: 1.063-6.621, P=0.03) were independent prognostic factors for CSS. Multivariate analysis showed that tumor stage (HR =4.805, 95% CI: 2.677-8.624, P<0.001), tumor grade (HR =6.423, 95% CI: 3.432-12.020, P<0.001), hemorrhage (HR =0.514, 95% CI: 0.265-0.996, P=0.049) and TSR (HR =2.370, 95% CI: 1.264-4.443, P=0.007) were independent prognostic factors for MFS. Conclusions: TSR is a new independent prognostic risk factor for ccRCC patients. The assessment of TSR is simple and cost-effective, and it is a useful supplement added to the pathological evaluation system.

Comparison of the monoexponential and biexponential models of diffusion-weighted magnetic imaging in grading clear-cell renal cell carcinoma: a case-control study.

Background: An accurate and noninvasive method to determine the preoperative clear-cell renal cell carcinoma (ccRCC) pathological grade is of great significance for surgical program selection and prognosis assessment. Previous studies have shown that diffusion-weighted imaging (DWI) has moderate value in grading ccRCC. But DWI cannot reflect the diffusion of tissue accurately because it is calculated using a monoexponential model. Intravoxel incoherent motion (IVIM) is the biexponential model of DWI. Only a few studies have examined the value of IVIM in grading ccRCC yet with inconsistent results. This study aimed to compare the value of DWI and IVIM in grading ccRCC. Methods: In this study, 96 patients with pathologically confirmed ccRCC were evaluated by DWI and IVIM on a 3-T scanner. According to the World Health Organization/International Society of Urological Pathology (WHO/ISUP) classification system, these patients were divided into two groups: low-grade (grade I and II) and high-grade (grade III and IV) ccRCC. The apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudodiffusion coefficient (D*), and perfusion fraction of pseudodiffusion (f) values were calculated. The Mann-Whitney test, receiver-operating characteristic (ROC) analysis, and the Delong test were used for statistical evaluations. Results: (I) According to the WHO/ISUP nuclear grading system, 96 patients were divided into low-grade (grade I and II, 45 patients) and high-grade (grade III and IV, 51 patients) groups. (II) Compared with patients of low-grade ccRCC, the ADC and D values of those with high-grade ccRCC decreased while the D* and f values increased (P<0.05). (III) The cutoff value of the ADC, D, D*, and f in distinguishing low-grade from high-grade ccRCC was 1.50×10-3 mm2/s, 1.12×10-3 mm2/s, and 33.19×10-3 mm2/s, 0.31, respectively; the area under the curve (AUC) for the ADC, D, D*, and f values was 0.871, 0.942, 0.621, and 0.894, respectively, with the AUC of the D value being the highest; the sensitivity for the ADC, D, D*, and f values was 94.12%, 92.16%, 47.06%, and 92.16%, respectively; and the specificity for the ADC, D, D*, and f values was 66.67%, 91.11%, 77.78%, and 73.33%, respectively. (IV) Based on the Delong test, AUCD was significantly higher than AUCADC (P=0.02) and AUCD* (P<0.001), but there was no significant difference between AUCD and AUC f (P=0.18). Conclusions: Compared with the monoexponential model DWI, the biexponential model IVIM was more accurate in grading ccRCC.

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

ALK-rearranged renal cell carcinoma: a multi-institutional study of nine cases with expanding the morphologic and molecular genetic spectrum.

ALK-rearranged renal cell carcinoma (ALK-RCC) is very rare, molecularly defined RCC subtype in the recently published 5th edition World Health Organization classification of tumors. In this study, we describe 9 ALK-RCCs from a clinicopathologic, immunohistochemical, and molecular genetic aspect, supporting and extending upon the observations by previous studies regarding this rare subgroup of RCC. There were six male and three female patients with ages ranging from 14 to 59 years (mean, 34.4 years). None of the patients had sickle cell trait. The diagnosis was based on radical or partial nephrectomy specimen for eight patients and on biopsy specimen for one. Tumor size ranged from 2.5 to 7.2 cm (mean, 2.8 cm). Follow-up was available for 6/9 patients (6 to 36 months); five had no tumor recurrence or metastasis and one developed lung metastasis at 24 months. The patient was subsequently treated with resection of the metastatic tumor followed by crizotinib targeted therapy, and he was alive without tumor 12 months later. Histologically, the tumors showed a mixed growth of multiple patterns, including papillary, solid, tubular, tubulocystic, cribriform, and corded, often set in a mucinous background. The neoplastic cells had predominantly eosinophilic cytoplasm. Focally, clear cytoplasm with polarized nuclei and subnuclear vacuoles (n=1), and pale foamy cytoplasm (n=1) were observed on the tumor cells. The biopsied tumor showed solid growth of elongated tubules merging with bland spindle cells. Other common and uncommon features included: psammomatous microcalcifications (n=5), rhabdoid cells (n=4), prominent intracytoplasmic vacuoles (n=4), prominent chronic inflammatory infiltrate (n=3), signet ring-cell morphology (n=2), and pleomorphic cells (n=2). By immunohistochemistry, all 9 tumors were diffusely positive for ALK(5A4) and 4/8 tested cases showed reactivity for TFE3 protein. By fluorescence in-situ hybridization analysis, ALK rearrangement was identified in all the 9 tumors; none of the tested tumors harbored TFE3 rearrangement (0/4) or gains of chromosomes 7 and 17 (0/3). ALK fusion partners were identified by RNA-sequencing in all 8 cases analyzed, including EML4 (n=2), STRN (n=1), TPM3 (n=1), KIF5B (n=1), HOOK1 (n=1), SLIT1(n=1), and TPM1(3'UTR) (n=1). Our study further expands the morphologic and molecular genetic spectrum of ALK-RCC.

Biomimetic Nano-regulator that Induces Cuproptosis and Lactate-Depletion Mediated ROS Storm for Metalloimmunotherapy of Clear Cell Renal Cell Carcinoma.

Herein, we designed a ccRCC targeting nanodrug to enhance chemodynamic therapy (CDT) as well as activate cuproptosis and tumor immunotherapy via ccRCC cell membrane modifying CuO@Gd2O3 yolk-like particles (CGYL) loaded with lactate oxidase (LOx) (mCGYL-LOx). Benefiting from the homologous targeting effect of Renca cell membranes, the mCGYS-LOx could be effectively internalized by Renca cells, opened the "gate", and then released LOx and copper ions. LOx could catalyze excessive lactate in Renca cells into H2O2, following that the produced H2O2 was further converted by copper ions to the highly toxic ·OH, contributing to tumor CDT. Meanwhile, the excessive copper ions effectively triggered tumor cuproptosis. These synergistic effects induced the release of damage associated molecular patterns and activated immunogenic cell death, leading to DC maturation and infiltration of immune effector cells. Moreover, LOx-mediated lactate consumption downregulated the expression of PD-L1, crippling tumor immune escape. In addition, the mCGYL-LOx improved T1-weighted MRI signal, allowing for accurate diagnosis of ccRCC. This study demonstrated that the mCGYL-LOx had great potential for improving therapy of ccRCC via the synergistic actions of CDT and cuproptosis as well as immunotherapy. This article is protected by copyright. All rights reserved.

The prognostic role of perirenal fat tissue in non-metastatic renal cell carcinoma.

PURPOSE: The aim of this study was to evaluate the impact of perirenal fat volume and perirenal fat density on prognosis in surgically treated non-metastatic renal cell carcinomas (RCC). METHODS AND MATERIALS: All consecutive patients who underwent partial or total nephrectomy surgery between March 2019 and December 2021 were assessed. Measurements of perirenal fat volume and perirenal fat density were performed on computed tomography (CT) images. The relationship between progression and perirenal fat parameters was evaluated using ROC analysis, Cox regression analysis, and Kaplan-Meier analysis. RESULTS: In the study population comprising 118 patients diagnosed with RCC (74.6% male, mean age of 59.1 ± 11.8 years), the median follow-up duration was 43 months (interquartile range: 33-51 months). Perirenal fat volume (AUC: 0.669, 95% CI 0.538-0.799, p = 0.011) and perirenal fat density (AUC: 0.680, 95% CI 0.558-0.803, p = 0.007) demonstrated acceptable discrimination performance in predicting progression. There was a significant association between high perirenal fat volume and high perirenal fat density with poor progression-free survival (HR: 1.007, 95% CI 1.003-1.011, p = 0.001 vs. HR: 1.084, 95% CI 1.033-1.137, p = 0.001; respectively). CONCLUSION: High perirenal fat volume and high perirenal fat density are independent predictors for poor progression-free survival. Perirenal fat parameters, easily obtainable from preoperative CT images, may serve as potential tools in predicting the prognosis of non-metastatic RCC.

Format-tuning of in vivo-launched bispecific T cell engager enhances efficacy against renal cell carcinoma.

BACKGROUND: Advanced clear cell renal cell carcinoma (ccRCC) is a prevalent kidney cancer for which long-term survival rates are abysmal, though immunotherapies are showing potential. Not yet clinically vetted are bispecific T cell engagers (BTEs) that activate T cell-mediated cancer killing through intercellular synapsing. Multiple BTE formats exist, however, with limited cross-characterizations to help optimize new drug design. Here, we developed BTEs to treat ccRCC by targeting carbonic anhydrase 9 (CA9) while characterizing the persistent BTE (PBTE) format and comparing it to a new format, the persistent multivalent T cell engager (PMTE). These antibody therapies against ccRCC are developed as both recombinant and synthetic DNA (synDNA) medicines. METHODS: Antibody formatting effects on binding kinetics were assessed by flow cytometry and intercellular synaptic strength assays while potency was tested using T-cell activation and cytotoxicity assays. Mouse models were used to study antibody plasma and tumor pharmacokinetics, as well as antitumor efficacy as both recombinant and synDNA medicines. Specifically, three models using ccRCC cell line xenografts and human donor T cells in immunodeficient mice were used to support this study. RESULTS: Compared with a first-generation BTE, we show that the PBTE reduced avidity, intercellular synaptic strength, cytotoxic potency by as much as 33-fold, and ultimately efficacy against ccRCC tumors in vivo. However, compared with the PBTE, we demonstrate that the PMTE improved cell avidity, restored intercellular synapses, augmented cytotoxic potency by 40-fold, improved tumor distribution pharmacokinetics by 2-fold, and recovered synDNA efficacy in mouse tumor models by 20-fold. All the while, the PMTE displayed a desirable half-life of 4 days in mice compared with the conventional BTE's 2 hours. CONCLUSIONS: With impressive efficacy, the CA9-targeted PMTE is a promising new therapy for advanced ccRCC, which can be effectively delivered through synDNA. The highly potent PMTE format itself is a promising new tool for future applications in the multispecific antibody space.

Practical management of renal cell carcinoma: integrating current approaches with advances in bone metastasis treatment.

Renal cell carcinoma (RCC) is a common type of tumor that can develop in the kidney. It is responsible for around one-third of all cases of neoplasms. RCC manifests itself in a variety of distinct subtypes. The most frequent of which is clear cell RCC, followed by papillary and chromophobe RCC. RCC has the potential for metastasis to a variety of organs; nevertheless, bone metastases are one of the most common and potentially fatal complications. These bone metastases are characterized by osteolytic lesions that can result in pathological fractures, hypercalcemia, and other complications, which can ultimately lead to a deterioration in quality of life and an increase morbidity. While nephrectomy remains a foundational treatment for RCC, emerging evidence suggests that targeted therapies, including tyrosine kinase inhibitors and T cell checkpoint inhibitors, may offer effective alternatives, potentially obviating the need for adjuvant nephrectomy in certain cases of metastatic RCC Bone metastases continue to be a difficult complication of RCC, which is why more research is required to enhance patient outcome.