Renal cell carcinoma incidence and mortality in California: a population-based study of sociodemographic patterns and temporal trends from 1988 through 2019.

Renal Cell Carcinoma (RCC) represents about 2% of all cancers in Sweden. While RCC is known for its potential to metastasize to the skeleton, few studies have examined the risk factors for pathological fractures and their impact on survival. The Fuhrman grade and AJCC staging systems are commonly used to assess disease aggressiveness, but their relationship to fracture risk and post-fracture outcomes remains unclear. This study cross-linked data from the Swedish Fracture Register (SFR) and the Swedish Renal Cancer Register (SNR) to identify RCC patients with pathological fractures. Fracture characteristics, cancer staging (Fuhrman, TNM, AJCC), and histological subtypes were analysed. Survival was estimated using the Kaplan-Meier method. One hundred four RCC patients (72 men, 32 women) with pathological fractures were included, with clear cell carcinoma being most common (n=93). Fuhrman grade 3 (n=34) and fractures in the femur (n=44) and humerus (n=37) predominated. Median time from cancer diagnosis to fracture was 11months. Higher Fuhrman grade, TNM, and AJCC stages were significantly associated with shorter time to fracture (p<0.001). The median overall survival was 31months and was related to Fuhrman grade (p=0.013) and AJCC stage (p<0.001). The median survival post-fracture was 8months, with no significant association with cancer grade or stage. Advanced Fuhrman grade and AJCC stage predict faster progression to pathological fractures in RCC. Given the poor prognosis after pathological fractures, early risk stratification and individualized treatment approaches are essential to improve outcomes.

Distinct pathways of disease progression with dual checkpoint blockade versus immunotargeted therapy in metastatic renal cell carcinoma.

Patients with renal cell carcinoma (RCC) in a solitary kidney have limited treatment options. Stereotactic MRI-guided adaptive radiotherapy (SMART) offers a non-invasive alternative that preserves healthy kidney tissue. This study evaluated the clinical outcomes of SMART in patients with renal tumors in a solitary kidney. Oncological outcomes, renal function preservation, and treatment-related toxicity were assessed. All consecutive patients with RCC in a solitary kidney treated with SMART between 2018 and 2024 in a single center were analyzed. Local control was defined as any response or stable disease using RECIST criteria. Kaplan-Meier analysis was used for survival outcomes and paired t-tests assessed renal function changes. Thirty-two patients with a median age of 70years were included. Most patients had WHO status 0-1 (93.8%) and had prior nephrectomy for RCC (78.1%). Median tumor size was 4.2cm, and median pre-treatment eGFR was 45.8ml/min. Seven patients were treated for multiple lesions, in simultaneous or separate sessions. Most patients were treated in a single (22.8%) or five (74.3%) fractions. After a median follow-up of 21.3months, the local control rates at 1 and 2years were 96.2% and 90.1%, respectively. Mean eGFR change was -6.6ml/min, none required dialysis. No grade≥3 toxicity was observed. The overall survival rate at 2years was 80.9%. SMART provides high local control with minimal impact on renal function, offering a non-invasive, kidney-sparing treatment option that also enables repeated treatments within the solitary kidney.

Introduction: Although Renal Angiomyolipoma (AML) is a relatively rare entity, it is the most common benign mesenchymal kidney tumour, made up of varying amounts of thick-walled blood vessels, smooth muscle, and adipose tissue. AML occurs either sporadically or in association with Tuberous Sclerosis Complex (TSC). It is often detected incidentally during imaging, though it can present with flank pain, haematuria, or life-threatening haemorrhage, thereby posing diagnostic and therapeutic challenges. Aim: To analyse the clinicopathological features of surgically resected renal AMLs and evaluate the association between radiological and histopathological findings. Materials and Methods: This was a retrospective, crosssectional study conducted in the Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India, in which the clinicopathological features of surgically resected renal AMLs received between January 2014 and October 2023 were studied. Data retrieval, analysis, and manuscript preparation were carried out between December 2023 and March 2024. Clinicoradiological detailsincluding age, gender, clinical presentation, tumour size, laterality, imaging features (fat-rich or fat-poor), presence of haemorrhage, association with TSC/LAM, and type of surgical procedure were retrieved from the hospital information system of the study Institute. The data were analysed using Statistical Package for the Social Sciences (SPSS), IBM Corp, Armonk, NY), version 26.0. Categorical variables are reported as frequencies and percentages, whereas the mean (standard deviations) or medians with interquartile ranges, as appropriate, were used for continuous variables; the associations between categorical variables were analysed using the Chi-square test, where p-value &lt;0.05 was considered to indicate statistical significance. Results: The study included a total of 31 patients, with a mean age of 48.9±16.8 years, and a mean tumour size of 10.0±6.1 cm, resulting in a female-to-male ratio of 2.4:1. Twenty-seven cases were symptomatic, while four were incidental. The major subtype was classical (24), followed by leiomyoma-like (4), epithelioid (2), and lipoma-like (1). Fat-poor AML patients who underwent surgery for Renal Cell Carcinoma (RCC) on imaging were confirmed via histopathology (epithelioid-1, leiomyomalike-3). Bleeding was observed with tumour size ≥6.0 cm (n=10 cases; p-value=0.012). TSC-associated cases (n=3) were younger (mean age-30.3 years vs sporadic-50.4 years) and had a larger mean tumour size of 16.8 cm (vs sporadic-8.8 cm). One patient had concurrent RCC. Conclusion: TSC-associated cases present at a younger age when compared to sporadic AMLs. Fat-poor AMLs can typically mimic RCC on imaging. Larger tumours are known to cause haemorrhage, particularly TSC-associated, from the rupture of pseudoaneurysms. Immunohistochemistry (IHC) for Human Melanoma Black (HMB) 45 and Smooth Muscle Actin (SMA) was useful in establishing a diagnosis in atypical AMLs.

Network centrality-driven TOPSIS approach for prioritizing cancer therapeutic targets.

Von Hippel-Lindau (VHL) disease is a rare, autosomal dominant, multisystem cancer syndrome. A variety of benign and malignant tumors can develop in VHL, including cranial and spinal hemangioblastomas, retinoblastoma, endolymphatic sac tumor, pheochromocytoma, renal cell carcinoma, pancreatic neuroendocrine tumors, and renal, pancreatic, and genital cysts. Here we present a 57-year-old woman who was diagnosed with VHL and, in the same 68 Ga-DOTATATE PET/CT, exhibits all these components of the syndrome: pheochromocytoma, pancreatic neuroendocrine tumor, pancreatic cysts, renal cysts, liver hemangioma, and hemangioblastoma in the medulla oblongata.

Real-world management and clinical outcomes of first line treatment of advanced renal cell carcinoma in older patients in Canada.

Clear cell renal cell carcinoma (ccRCC) exhibits profound molecular heterogeneity, and reliable biomarkers for predicting clinical outcomes are urgently needed. Proliferating T cells (Tprolif) are central to immune system activation but their related signatures in predicting prognosis and therapeutic effect of ccRCC patients remains unexplored. We developed a Tprolif-related RCC score (TRRS) using an integrative machine learning framework. Transcriptomic data from the CheckMate025 trial formed the discovery cohort. The model was validated across multiple independent cohorts, including IMmotion151, JAVELIN Renal 101, TCGA-KIRC, and West China Hospital (WCH) cohort from our center. Multi-omics analyses, including spatial and single-cell transcriptomics, were employed to investigate the associated biology and identify key mediators. The final TRRS model, built from 7 genes, demonstrated robust performance in stratifying patients for overall survival (OS) and progression-free survival (PFS) in training and all validation sets. TRRS was a powerful predictor of improved outcomes not only for immune checkpoint inhibitor (ICI) monotherapy but also for ICI-based combination therapy and targeted therapies. Biologically, a high TRRS was associated with aggressive tumor hallmarks, a distinct metabolic profile favoring aerobic glycolysis and glutamine metabolism, and an immunosuppressive tumor microenvironment despite high immune cell infiltration based on WCH cohort transcriptome expression profile. Through multi-omics screening, we identified CST3 as a key target, with spatial and single-cell analyses confirming its role in promoting tumor malignancy and enhancing cell-cell communication among microenvironment components. The TRRS is a novel, validated biomarker that effectively predicts prognosis and therapeutic responses in advanced ccRCC. It reflects critical biological features of tumor aggressiveness and immune evasion, with CST3 emerging as a potential central mediator and therapeutic target.

Pathological graph self-supervised learning for clear-cell renal cell carcinoma survival prediction

The Hippo pathway in clear cell renal cell carcinoma (ccRCC): a nexus with the VHL disruption?

Metastatic clear cell renal cell carcinoma (ccRCC) to the thyroid gland is an uncommon but significant presentation, often occurring years after primary tumor resection. We present the case of a 52-year-old female who developed a solitary thyroid metastasis 13 years after undergoing left nephrectomy for ccRCC. Initially presenting with a gradually enlarging neck mass and mild dysphagia, her thyroid nodule exhibited suspicious features on ultrasonography and computed tomography, including hypervascularity. Fine-needle aspiration cytology revealed clear-cell features, prompting a multidisciplinary discussion. Definitive diagnosis was established through right thyroid lobectomy and subsequent immunohistochemical analysis, which confirmed metastatic ccRCC (positive for PAX8, CD10, vimentin; negative for thyroglobulin, TTF-1). This case is unique for its exceptionally long disease-free interval and highlights the diagnostic challenge posed by ccRCC metastases mimicking primary thyroid neoplasms. It underscores the critical importance of a thorough medical history, even for remote malignancies, and the value of comprehensive pathological and immunohistochemical evaluation in guiding accurate diagnosis and management. The patient achieved excellent long-term disease-free survival following surgical resection, reinforcing that aggressive local therapy for solitary thyroid metastases from ccRCC can lead to favorable outcomes and impact future practice by advocating for vigilant, long-term surveillance in ccRCC patients.

Programmed cell death protein 1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1) are key mediators of immune checkpoint blockade therapy in clear cell renal cell carcinoma (RCC). However, immune evasion and primary resistance often limit their efficacy, highlighting the need for improved strategies. Here, we identified dipeptidyl peptidase 9 (DPP9) as a critical regulator of PD-L1 expression in ccRCC. Pharmacological inhibition of DPP9 with 1G244 restores T cell cytotoxicity and enhances checkpoint blockade efficacy. Mechanistically, DPP9 disrupts the BRISC-SHMT2 complex, enhancing BRISC-mediated deubiquitination and stabilization of IFNAR1, which activates the JAK/STAT pathway and drives PD-L1 transcription. 1G244 reverses this process by reducing DPP9 interacting with SHMT2, promoting IFNAR1 ubiquitination and degradation, thereby reducing PD-L1 levels and restoring T cell-mediated cytotoxicity. Moreover, the combination of 1G244 and anti-CTLA-4 therapy further enhanced antitumor immunity, highlighting a potential synergistic therapeutic strategy. Collectively, our findings define a novel DPP9-BRISC-SHMT2 regulatory axis in PD-L1 transcriptional control and identify 1G244 as an alternative combinatorial strategy to enhance the efficacy of cancer immunotherapy.

Predicting aggressiveness of clear cell renal cell carcinoma via mri using artificial intelligence: implications for surgical planning in a retrospective multicenter study.

Abstract Background: In the clear cell renal cell carcinoma (ccRCC) tumor microenvironment (TME), transforming growth factor-β (TGF-β) is a dominant immunosuppressive cytokine that suppresses NK metabolism, proliferation, and cytotoxicity. Rather than blocking TGFβ receptor, we hypothesized that elevated TGFβ in the ccRCC could be harnessed as a trigger to drive local, therapeutic cytokine expression. Methods: We engineered TGFβ-sensing circuits to conditionally express IL-12A3—a collagen-binding IL-12 fusion cytokine, in response to tumor derived TGFβ. The initial forward-strand designs produced TGFβ-inducible 70CAR/IL-12, but with leaky IL-12 expression. However, a bidirectional layout (sensor+IL-12A3 on the reverse, 70CAR on the forward) cut baseline IL-12 expression by ∼87% (43 vs 362 pg/mL, p=0.0019) without affecting CAR expression or NK cell function. To boost efficacy, we added constitutive IL-18 downstream of 70CAR (70CAR-12A3/18), while IL-12 remained TGFβ-regulated. Primary NK cells were transduced and assessed in vitro for activation and cytotoxicity against A498, ACHN, and CD70+ ccRCC PDXs, and in vivo in NSG-IL15 mice bearing A498 tumors. Tumor growth, NK persistence/infiltration/activation, and safety were evaluated, including body weight and day 7 serum cytokines (IL-12, IL-18, IL-1β, IL-2, IL-6, IFNγ, GM-CSF). Results: High transduction efficiency was achieved in NK cells after transduction with constructs 70CAR (45 ∼ 78%, n=8), 70CAR-12A3 (36 ∼ 62%, n=8), 70CAR-18 (41 ∼ 80%, n=8), and 70CAR-12A3/18 (27 ∼ 55% n=8) at MOI=2. 70CAR-12A3/18 NK cells secreted high IL-18 (∼1,800 pg/mL) and TGFβ-inducible IL-12 (21.6 vs 324.2 pg/mL ± TGFβ1; p=0.0013), showed enhanced cytotoxicity against A498, ACHN, and CD70+ ccRCC PDXs, and fully overcame TGFβ-mediated suppression with combined IL-12+IL-18 (either alone was insufficient). In NSG-IL15 mice subcutaneously implanted with A498 tumors, 70CAR-12A3/18 significantly reduced tumor volume (p&amp;lt;0.0001) and extended survival (p&amp;lt;0.0001). It yielded the highest human NK cell percentages among groups in blood at day 14 and, at endpoint, across blood, bone marrow, liver, lung, spleen, and tumor of treated mice. In serum, human IL-12 reached up to 34 pg/mL in 70CAR-12A3/18 or 70CAR-12A3 treated mice, while IL-18 averaged ∼1,300 pg/mL (70CAR-12A3/18) and ∼2,300 pg/mL (70CAR-18). No CRS-related cytokines were significantly elevated. Conclusion: We present a bidirectional TGFβ-sensing circuit that pairs constitutive IL-18 with TGFβ-inducible IL-12 for context-specific cytokine delivery and enhanced CAR NK activity. 70CAR-12A3/18 NK cells reduced tumor burden and extended survival in NSG mice bearing ccRCC xenografts without causing systemic toxicity. This modular TGFβ-sensor is generalizable, offering a blueprint for NK therapies targeting immunosuppressive TMEs in solid and hematologic tumors. Citation Format: Fuguo Liu, Xingyu Deng, Veronica W. Hui, Shikha Gupta, Wenxin Xu, Maily Nguyen, Mubin Tarannum, Andreia Maia, Shaobo Yang, Stephanie Sendker, Alaa K. Ali, John Koreth, Jose A. Cancellas, Jianzhu Chen, Robert Soiffer, Catherine Wu, Jerome Ritz, Toni K. Choueiri, Rizwan Romee. Engineering novel CAR NK cells to overcome TGF-β suppression in renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr A019.

Sterotactic ablative radiotherapy vs. thermal ablation of localized renal cell carcinoma: Is there a preferred second-line management option?

Perivascular epithelioid cell tumor (PEComa) is a rare mesenchymal neoplasm, and primary involvement of the thyroid gland is exceedingly rare. TFE3-rearranged PEComas constitute a distinct molecular subset characterized by epithelioid morphology and strong nuclear TFE3 expression. Cytologic descriptions of PEComa are limited, and to date, only three cytologic cases of TFE3-rearranged PEComa or PEComa-like neoplasm have been reported in the literature, none of which involved the thyroid gland. We report a case of thyroid TFE3-rearranged PEComa-like neoplasm in a 25-year-old woman who presented with a palpable thyroid nodule. Fine-needle aspiration using liquid-based cytology revealed a hypercellular specimen composed predominantly of dispersed and loosely cohesive epithelioid cells with enlarged round to oval nuclei, fine chromatin, and frequent intranuclear pseudoinclusions, resulting in an initial interpretation suspicious for papillary thyroid carcinoma. Histologic examination demonstrated a well-circumscribed epithelioid neoplasm with pseudoalveolar architecture supported by a delicate arborizing vascular network. Immunohistochemical studies showed tumor cell positivity for TFE3, cathepsin K, desmin (patchy), and vimentin, with negativity for epithelial, thyroid-specific, melanocytic, and other smooth muscle markers, as well as PAX8, CD10, MiTF, and PAS/PAS-D stains, arguing against metastatic renal cell carcinoma and alveolar soft part sarcoma. The patient underwent surgical resection and remains disease-free after 7.5 years of follow-up. This case represents the first description of the liquid-based cytologic features of a thyroid TFE3-rearranged PEComa-like neoplasm. Awareness of this rare entity and its cytologic overlap with papillary thyroid carcinoma is essential to avoid diagnostic pitfalls in thyroid fine-needle aspiration.

To identify pretreatment factors associated with developing primary resistance to nivolumab plus ipilimumab therapy in patients with advanced renal cell carcinoma (RCC). We retrospectively reviewed the clinical characteristics, laboratory data, and tumor-related factors in patients with advanced RCC who initiated nivolumab plus ipilimumab as first-line therapy between January 2018 and July 2021. Primary resistance was defined as radiographic or clinical progression within 3months of treatment initiation. Cases with suspected pseudoprogression were excluded. Eighty-nine patients met the inclusion criteria; 23 exhibited primary resistance. Univariate analysis identified the following significant predictive factors: body mass index (P=.006), lymph node metastasis (P=.021), sarcomatoid differentiation (P=.035), solitary metastatic organ (P=.051), liver metastasis (P=.056), and serum lactate dehydrogenase (LDH) (P=.094). Receiver operating characteristic curve analysis determined an LDH cutoff value of 174U/L, which was significantly associated with primary resistance (P=.029). Considering the number of primary resistance cases, multivariable analysis incorporated three candidate variables (lymph node metastasis, sarcomatoid differentiation, and LDH≥174U/L) and identified sarcomatoid differentiation (odds ratio, 4.264; 95% confidence interval (CI), 1.299-14.825; P=.017) and LDH≥174U/L (odds ratio, 3.634; 95% CI, 1.143-13.770; P=.028) as independent predictors of primary resistance. Sarcomatoid differentiation on pretreatment biopsy or elevated serum LDH before treatment initiation may predict primary resistance to nivolumab plus ipilimumab therapy in patients with advanced RCC. Alternative regimens should be considered in such cases, particularly for patients who are likely to experience rapid disease progression or for whom the occurrence of P-res is not clinically acceptable.

Immune checkpoint blockades (ICBs), particularly PD-1 pathway blockades, have significantly improved outcomes in advanced renal cell carcinoma (RCC). However, long-term ICB therapy imposes substantial financial and toxicity burdens. Retrospective data suggest that treatment responses plateau around 24weeks, and some patients maintain disease control even after ICB pause. We initiated a multi-institutional, open-label, randomized controlled trial to confirm the non-inferiority of pausing PD-1 pathway blockade to its continuous administration in patients with advanced clear cell RCC without disease progression. The primary endpoint is overall survival and the secondary endpoint includes time to failure of strategy, progression-free survival, and adverse events. Conducted by the Urologic Oncology Study Group of the Japan Clinical Oncology Group (JCOG), this phase III trial was approved by Certified Review Board in February 2020, with patient enrollment beginning in July 2020. The trial is registered in the Japan Registry for Clinical Trials (JCOG1905; jRCT1031200071).

Abstract GPNMB (Glycoprotein non-metastatic melanoma protein B) is a canonical transcriptional target of MiT/TFE proteins (TFEB/TFE3/MITF), expressed at low levels in normal tissues but upregulated in numerous MiT/TFE-driven tumors such as translocation RCC, alveolar soft part sarcoma and MITF-driven melanoma, where it is associated with poor prognosis. CDX-011 (CR011-MMAE) is an anti-GPNMB ADC, with demonstrated efficacy in pre-clinical models of TFE3-fusion RCC. To further characterize GPNMB functionality and value as a cell-surface therapeutic target in tRCC, we engineered cell lines with genomic deletion of GPNMB via CRSIPR-Cas9 editing. Deletion of GPNMB in PRCC-TFE3 cell lines [UOK120/UOK124] significantly decreased clonogenic growth in 2D, spheroid size and viability and tumor xenograft growth in NSG mice and was associated with a decrease in phosphorylation of mTORC1 substrates [p-P70S6K, p-4EBP1]. We then examined expression of CD44, the primary receptor for GPNMB, and a tumor-associated antigen associated with poor prognosis in many cancers. Expression of CD44 and its ligand SPP1/OPN, was significantly increased in bulk RNA-Seq data from multiple transgenic models of SFPQ-TFE3, PRCC-TFE3 and ASPSCR1-TFE3, in human tRCC cases compared to normal kidney, and in SFPQ-TFE3/ PRCC-TFE3 transgenic kidney tumors and an ASPSCR-TFE3 PDX model, by immunoblotting and IHC, with increased membrane localization. shRNA-mediated depletion of CD44 profoundly and specifically decreased clonogenicity of multiple TFE3-fusion lines, with no effect seen in ccRCC lines. In conclusion, GPNMB regulates the growth of tRCC cells, potentially via an autocrine mechanism involving its receptor CD44, and targeting GPNMB-CD44 signaling may be of therapeutic benefit in tRCC. Citation Format: Kaushal Asrani, Juhyung Woo, Kewen Feng, Thiago Vidotto, Adrianna Amaral, Vikrant Palande, Jayaprakash Mandal, Eddie Imada, Christopher Thoburn, Sangeeta Ray, Huili Li, Yasser Ged, Nirmish Singla, John A. Copland, Laura Schmidt, W. Marston Linehan, Pedram Argani, Tamara Lotan. GPNMB:CD44 signaling drives tumor progression in translocation renal cell carcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Innovations in Kidney Cancer Research: From Molecular Insights to Therapeutic Breakthroughs; 2026 Mar 13-16; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(5_Suppl_2):Abstract nr B014.