Cases Of Renal Cell Carcinoma Research Articles

Synchronous Carcinoma Cervix with Renal Cell Carcinoma: An Incidental Finding

Background In India, renal cell carcinoma (RCC) is the most frequent kidney cancer with an increasing tendency, whereas cervical cancer is the second most common disease among women. Synchronicity of RCC with other malignancies is not uncommon, but with the cervical cancer is rare.  Case description A 64-year-old, postmenopausal female, presented with complaint of bleeding per vagina and was diagnosed with carcinoma cervix and later on metastatic work-up also diagnosed with right RCC. After multidisciplinary discussion, patient planned for management for cervix then followed by renal lesion. Patient received radical external beam radiotherapy followed by brachytherapy for carcinoma cervix and underwent nephrectomy for right RCC.  Conclusion Synchronous cases of cervical cancer and renal cell carcinoma are very rare. Advancement in diagnostic protocol makes these kind of cases common and multidisciplinary team decisions are required for their management.

Anaesthetic challenges in a rare case of renal cell carcinoma with inferior vena cava tumor thrombus extension into right atrium under cardiopulmonary bypass with deep hypothermic circulatory arrest

Renal cell carcinoma, an epithelial tumour of the kidney, is the ninth most common cancer worldwide. It is uniquely associated with tumour thrombi extending into the renal vein and inferior vena cava, while rarely extending till the right atrium. This poses challenges in intra-operative and post-operative hemodynamic management as well as perioperative cardio and neuroprotection making it a challenging case from anaesthetic point of view. We report a rare case of Right renal cell carcinoma with thrombus extension into right renal vein, inferior vena cava and right atrium. Right radical nephrectomy with en-bloc tumor-thrombus excision under cardiopulmonary bypass with deep hypothermic circulatory arrest was performed. The case was suspected to have a difficult intraoperative and postoperative course with major hemodynamic instability, neuroprotection, and cardioprotection in mind, and was managed appropriately.

The clinical significance of PRMT8 expression in esophageal squamous cell carcinoma and the influence on prognosis.

e16066 Background: Protein arginine methyltransferase 8 (PRMT8), a member of protein arginine methyltransferases, is an enzyme catalyzing the methylation of arginine residuals of histones and non-histone proteins to serve as one of many critical post-translational modications (PTMs). Esophageal squamous cell carcinoma (ESCC) is the third most common cancer type of the gastrointestinal tract with poor prognosis. Abnormal arginine methylation modifications are closely associated with the development of ESCC and can exert oncogenic effects by regulating a variety of cellular processes. However, the expression of PRMT8 in ESCC and its influence on prognosis is currently unknown. Methods: After passing the application and obtaining the approval of the hospital ethics review committee and obtaining the informed consent of all patients and their families, we collected 46 cases of renal cell carcinoma diagnosed in the Fourth Hospital of Hebei Medical University from 2018 to 2023, and postoperative pathological reports of all patients confirmed to be ESCC. We followed the selected patients and obtained complete data. All the pathological specimens of the selected patients were resectioned and then subjected to immunohistochemical examination to observe the expression differences of PRMT8 in ESCC, and parallel semi-quantitative analysis. Finally, the data of the patients were statistically built. Results: PRMT8 is mainly stained on the plasma membrane of tumor cells. The difference in expression levels between ESCC and normal tissue adjacent to the cancer was statistically significant (P < 0.01). This study found that the patient’s gender, age, tumor side have no correlation with the expression levels of PRMT8 (P > 0.05), while the three indicators of tumor size, TNM stage, and lymph node metastasis are positively correlated with the expression levels of PRMT8 and the difference is statistically significant (P < 0.01). Moreover, the positive staining of PRMT1 in ESCC was significantly correlated with poor prognosis of ESCC patients. Conclusions: The expression of PRMT8 is highly expressed in ESCC and associated with aberrant clinicopathological characteristics and poor prognosis. PRMT8 is a potential target for the stratification and treatment of ESCC.

Renal Cell Carcinoma of Variant Histology: New Biologic Understanding Leads to Therapeutic Advances.

Renal cell carcinoma (RCC) is one of the 10 most commonly diagnosed solid tumors. Most RCCs are histologically defined as clear cell, comprising approximately 75% of diagnoses. However, the remaining RCC cases are composed of a heterogeneous combination of diverse histopathologic subtypes, each with unique pathogeneses and clinical features. Although the therapeutic approach to both localized and metastatic RCCs has dramatically changed, first with the advent of antiangiogenic targeted therapies and more recently with the approval of immune checkpoint inhibitor (ICI)-based combinations, these advances have primarily benefited the clear cell RCC patient population. As such, there remains critical gaps in the optimization of treatment regimens for patients with non-clear cell, or variant, RCC histologies. Herein, we detail recent advances in understanding the biology of RCC with variant histology and how such findings have guided novel clinical studies investigating precision oncology approaches for these rare subtypes. Among the most common variant histology RCCs are papillary RCC, comprising approximately 15%-20% of all diagnoses. Although a histopathologically diverse subset of tumors, papillary RCC is canonically associated with amplification of the MET protooncogene; recently completed and ongoing trials have investigated MET-directed therapies for this patient population. Finally, we discuss the unique biology of RCC with sarcomatoid dedifferentiation and the recent clinical findings detailing its paradoxical sensitivity to ICIs.

Clear cell and non-clear cell renal cell carcinoma in young adults: clinicopathological features, survival outcomes and prognostic factors.

Renal cell carcinoma (RCC) is infrequent among young adults. Few studies reported the outcome of RCC in young adults by pathological subtypes. The purpose of this study was to explore the clinicopathological features, survival outcomes and prognostic factors of young adult patients with clear cell (CCRCC) and non-clear cell renal cell carcinoma (NCCRCC). This study included young adult patients aged 18-40years who were diagnosed as renal cell carcinoma (RCC) between 2012 and 2022 at Peking University Third Hospital. All patients underwent either partial nephrectomy or radical nephrectomy, and some received adjuvant therapy. A comparative analysis was performed to investigate the differences in clinicopathological characteristics between the cohort of CCRCC and NCCRCC. Kaplan-Meier survival analysis was utilized to plot survival curves for young adults with RCC. The univariate and multifactorial prognostic analyses were conducted using the log-rank test and COX proportional hazards model. A total of 300 RCC patients aged 18-40years were performed, of which 201 were diagnosed with CCRCC (67%) and 99 were diagnosed with NCCRCC(33%). The NCCRCC included 29 cases (9.7%) of chromophobe RCC, 28 cases (9.3%) of MiT family translocation RCC, 22 cases (7.3%) of papillary RCC, 11 cases (3.7%) of low malignant potential multifocal cystic RCC, and 6 cases of unclassified RCC (2.0%), 2 cases of mucinous tubule and spindle cell carcinoma (0.7%), and 1 case of FH-deficient RCC (0.3%).The mean age was 33.4±6.1years old. The overall and progression free 5-year survival rate was 99.1 and 95.3%, respectively. The NCCRCC cohort demonstrated a statistically significant decrease in progression-free survival (PFS) rate when compared to the CCRCC cohort (p<0.001). There was no statistically significant difference observed in overall survival (OS) (p=0.069). Pathological stage was a significant independent predictor for OS (p=0.045). Pathological stage and nuclear grade were both independent predictors for PFS (p=0.020; p=0.005). The clinical and pathological features of young adults diagnosed with CCRCC exhibit notable distinctions from those of NCCRCC patients. The survival outcome was significantly influenced by the pathological stage, while both the nuclear grade and pathological stage had a significant impact on tumor progression. This study offered significant contributions to the understanding of the clinicopathological characteristics and prognostic determinants of renal cell carcinoma (RCC) in young adults.

Fumarate hydratase-deficient renal cell carcinoma: an oncology care institutional experience.

Renal cell carcinoma (RCC) accounts for 2% of all cancer cases worldwide, and majority are sporadic. The latest World Health Organization (WHO) classification of renal cell tumors (fifth edition, 2022) has molecularly defined renal tumor entities, which includes fumarate hydratase (FH)-deficient RCC. FH-deficient RCC is an aggressive carcinoma caused by pathogenic alterations in FH gene, seen in 15% of patients with hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) syndrome. These tumors occur more frequently at a younger age and present at an advanced stage, carrying a dismal prognosis. We report a series of 10 cases of FH-deficient RCC. The mean age was 49.8 years, and all cases presented in advanced stages (III and IV). Morphologically, the cases had varied architectural patterns with characteristic eosinophilic macronucleoli and perinucleolar halo. On immunohistochemistry (IHC), all showed diffuse nucleo-cytoplasmic expression of S-(2-succino)-cysteine (2-SC), with loss of FH in seven cases. FH-deficient RCCs are aggressive neoplasms and can be diagnosed using specific IHC markers (FH and 2-SC). These patients should undergo germline testing for FH gene mutation, genetic counseling, and surveillance of family members.

Detection of two synchronous histologically different renal cell carcinoma subtypes in the same kidney:a case report and review of the literature.

Renal cell carcinoma (RCC) is the dominant primary renal malignant neoplasm, encompassing a significant portion of renal tumors. The presence of synchronous yet histologically distinct ipsilateral RCCs, however, is an exceptionally uncommon phenomenon that is rather under-described in the literature regarding etiology, diagnosis, management, and later outcomes during follow-up. We aim to present the 9th case of a combination chromophobe RCC (ChRCC) and clear cell RCC (ccRCC) in literature, according to our knowledge, for a 69-year-old North African, Caucasian female patient who, after complaining of loin pain and hematuria, was found to have two right renal masses with preoperative computed tomography (CT) and underwent right radical nephrectomy. Pathological examination later revealed the two renal masses to be of different histologic subtypes. The coexistence of dissimilar RCC subtypes can contribute to diverse prognostic implications. Further research should focus on enhancing the complex, yet highly crucial, preoperative detection and pathological examination to differentiate multiple renal lesions. Planning optimal operative techniques (radical or partial nephrectomy), selecting suitable adjuvant regimens, and reporting long-term follow-up outcomes of patients in whom synchronous yet different RCC subtypes were detected are of utmost importance.

An epidemiological and clinicopathological study of type 1 vs. type 2 morphological subtypes of papillary renal cell carcinoma– results from a nation-wide study covering 50 years in Iceland

IntroductionPapillary renal cell carcinoma (pRCC) is the second most common histology of renal cell carcinoma (RCC), accounting for 10–15% of cases. Traditionally, pRCC is divided into type 1 and type 2, although this division is currently debated as a prognostic factor of survival. Our aim was to investigate the epidemiology and survival of the pRCC subtypes in a whole nation cohort of patients during a 50-year period.Materials and methodsA Population based retrospective study including consecutive cases of RCC in Iceland from 1971–2020. Comparisons were made between histological classifications of RCC, with emphasis on pRCC subtypes (type 1 vs. 2) for outcome estimation. Changes in RCC incidence were analyzed in 5-year intervals after age standardization. The Kaplan–Meier method and Cox regression were used for outcome analysis.ResultsA total of 1.725 cases were identified, with 74.4%, 2.1% and 9.2% having clear cell (ccRCC), chromophobe (chRCC), and pRCC, respectively. The age standardized incidence (ASI) of pRCC was 1.97/100.000 for males and 0.5/100.000 for females, and the proportion of pRCC increased from 3.7% to 11.5% between the first and last intervals of the study (p < 0.001). Age standardized cancer specific mortality (ASCSM) of pRCC was 0.6/100.000 and 0.19/100.000 for males and females, respectively. The annual average increase in ASI was 3.6% for type 1 pRCC, but the ASI for type 2 pRCC and ASCSM for both subtypes did not change significantly. Male to female ratio was 4.4 for type 1 pRCC and 2.3 for type 2. The average tumor size for type 1 and 2 was 58.8 and 73.7 mm, respectively. Metastasis at diagnosis was found in 8.7% in the type 1 pRCC, compared to 30.0% of patients with type 2 pRCC (p < 0.001). Estimated 5-year cancer-specific survival (CSS) were 94.4%, 80.7%, and 69.3% for chRCC, pRCC and ccRCC, respectively (p < 0.001). For the pRCC subtypes, type 1 was associated with better 5-year CSS than type 2 (86.3% vs. 66.0%, p < 0.001), although this difference was not significant after adjusting for cancer stage and grading.ConclusionspRCC histology was slightly less common in Iceland than in other countries. Males are more than three times more likely to be diagnosed with pRCC, compared to other RCC histologies. The subtype of pRCC was not found to be an independent risk factor for worse survival, and as suggested by the most recent WHO Classification of Urinary Tumors, grade and TNM-stage seem to be the most important factors for estimation of survival for pRCC patients.

Acetylation- and ubiquitination-regulated SFMBT2 acts as a tumor suppressor in clear cell renal cell carcinoma

BackgroundClear cell renal cell carcinoma (RCC) is the most common kidney tumor. The analysis from medical database showed that Scm-like with four MBT domains protein 2 (SFMBT2) was decreased in advanced clear cell RCC cases, and its downregulation was associated with the poor prognosis. This study aims to investigate the role of SFMBT2 in clear cell RCC.MethodsThe expression of SFMBT2 in clear cell RCC specimens were determined by immunohistochemistry staining and western blot. The overexpression and knockdown of SFMBT2 was realized by infection of lentivirus loaded with SFMBT2 coding sequence or silencing fragment in 786-O and 769-P cells, and its effects on proliferation and metastasis were assessed by MTT, colony formation, flow cytometry, wound healing, transwell assay, xenograft and metastasis experiments in nude mice. The interaction of SFMBT2 with histone deacetylase 3 (HDAC3) and seven in absentia homolog 1 (SIAH1) was confirmed by co-immunoprecipitation.ResultsIn our study, SFMBT2 exhibited lower expression in clear cell RCC specimens with advanced stages than those with early stages. Overexpression of SFMBT2 inhibited the growth and metastasis of clear cell RCC cells, 786-O and 769-P, in vitro and in vivo, and its silencing displayed opposites effects. HDAC3 led to deacetylation of SFMBT2, and the HDAC3 inhibitor-induced acetylation prevented SFMBT2 from SIAH1-mediated ubiquitination modification and proteasome degradation. K687 in SFMBT2 protein molecule may be the key site for acetylation and ubiquitination.ConclusionsSFMBT2 exerted an anti-tumor role in clear cell RCC cells, and HDAC3-mediated deacetylation promoted SIAH1-controlled ubiquitination of SFMBT2. SFMBT2 may be considered as a novel clinical diagnostic marker and/or therapeutic target of clear cell RCC, and crosstalk between its post-translational modifications may provide novel insights for agent development.

The effectiveness of the combination of lenvatinib and everolimus in metastatic renal cell carcinoma in patients with resistance to targeted treatment in real clinical practice

Every year, 400,000 new cases of renal cell carcinoma (RCC) and 175,000 deaths are registered worldwide. Currently available advanced treatments for RCC have less toxicity than previously used therapeutic agents, but drug resistance remains a clinically significant problem. Drug resistance occurs as a result of angiogenic transition through activation of pathways that do not depend on VEGF targets of most first-line treatments. Lenvatinib with everolimus can fight resistance to increase both progression-free survival and overall survival in patients with metastatic RCC according to clinical studies.

A pediatric and young adult case of unclassified renal cell carcinoma with medullary phenotype (RCCU-MP): Clinical course and treatment

Renal cell carcinoma (RCC) is the most common kidney tumor in adults. RCC is rare in children, although its incidence increases in the second decade of life. Renal medullary carcinoma (RMC) is a rare and often aggressive RCC subtype characterized by complete loss of SMARCB1/INI1, predominantly diagnosed in patients with sickle cell disease or -trait. Here, we describe a pediatric and a young adult patient with clinicopathological characteristics similar to RMC but without hemoglobinopathies. These tumors are currently classified as “RCC unclassified with medullary phenotype” (RCCU-MP). Both our patients had an infiltrating, rather small kidney tumor with SMARCB1/INI1 deficiency. Remarkably, the aggressiveness and clinical course and treatment differed greatly between these two cases. So far, only nine patients, predominantly adults, have been reported. In a literature overview, most cases were metastatic and progressed or relapsed after varying treatment approaches, with low survival. Whereas the classification of these tumors remains a topic of debate, case reports add to the current knowledge of RMCs without hemoglobinopathies, stressing the importance of sharing experience concerning rare renal neoplasms with often poor outcomes, also concerning younger age categories.

Fumarate Hydratase-Deficient Renal Cell Carcinoma—A Clinicopathological Study of a Series of 11 Cases

Abstract Introduction Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare, molecularly defined renal tumor with aggressive behavior. The diagnosis of these tumors is challenging because of varied morphology and limited access to molecular testing and immunohistochemistry (IHC) for FH and 2-succinocysteine. We aim to elucidate the histomorphology, clinical presentation, and follow-up of this tumor in this first series of cases of FH-deficient RCCs from India. Objectives This article aims to understand and elucidate the clinical presentation, pathologic findings, treatment options, and outcomes of FH-deficient RCC. Materials and Methods Diagnosed cases of FH-deficient RCC between January 2021 and January 2023 including clinical details were retrieved from the electronic medical record database. Histopathological and immunohistochemical slides were reviewed. Results Out of 11 cases of FH-deficient RCC, 36% had been referred with a diagnosis of type 2 papillary RCC. One patient presented with metastatic disease. All had mixed histologic patterns with the predominant pattern being papillary and showed FH loss on IHC. The classically described inclusion like nucleoli was present only focally in most cases. A subset of tumors had low-grade solid-nested morphology and these patients presented at an earlier stage (T2a). Two patients on multikinase inhibitors are alive with disease at 14 months' follow-up. Conclusion FH-deficient RCCs can have varied histologic patterns within the same tumor and show loss of FH expression by IHC. A subset has low grade morphology and tends to have a more indolent course. It is important to have a high index of suspicion for this diagnosis due to its varied histological appearance and aggressive behavior.

Plasma Kidney Injury Molecule-1 for Preoperative Prediction of Renal Cell Carcinoma Versus Benign Renal Masses, and Association With Clinical Outcomes.

Both clear cell and papillary renal cell carcinomas (RCCs) overexpress kidney injury molecule-1 (KIM-1). We investigated whether plasma KIM-1 (pKIM-1) may be a useful risk stratification tool among patients with suspicious renal masses. Prenephrectomy pKIM-1 was measured in two independent cohorts of patients with renal masses. Cohort 1, from the prospective K2 trial, included 162 patients found to have clear cell RCC (cases) and 162 patients with benign renal masses (controls). Cohort 2 included 247 patients with small (cT1a) renal masses from an academic biorepository, of whom 184 had RCC. We assessed the relationship between pKIM-1, surgical pathology, and clinical outcomes. In Cohort 1, pKIM-1 distinguished RCC versus benign masses with area under the receiver operating curve (AUC-ROC, 0.81 [95% CI, 0.76 to 0.86]). In Cohort 2 (cT1a only), pKIM-1 distinguished RCC versus benign masses (AUC-ROC, 0.74 [95% CI, 0.67 to 0.80]) and the addition of pKIM-1 to an established nomogram for predicting malignancy improved the model AUC-ROC (0.65 [95% CI, 0.57 to 0.74] v 0.78 [95% CI, 0.72 to 0.85]). A pKIM-1 cutpoint identified using Cohort 2 demonstrated sensitivity of 92.5% and specificity of 60% for identifying RCC in Cohort 1. In long-term follow-up of RCC cases (Cohort 1), higher prenephrectomy pKIM-1 was associated with worse metastasis-free survival (multivariable MFS hazard ratio [HR] 1.29 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.53) and overall survival (multivariable OS HR 1.31 per unit increase in log pKIM-1, 95% CI, 1.10 to 1.54). In long-term follow-up of Cohort 2, no metastatic events occurred, consistent with the favorable prognosis of resected cT1a RCC. Among patients with renal masses, pKIM-1 is associated with malignant pathology, worse MFS, and risk of death. pKIM-1 may be useful for selecting patients with renal masses for intervention versus surveillance.

Partial Versus Radical Nephrectomy: Comparison of Postoperative Complications and Contribution to Mortality

Background: Partial nephrectomy is the preferred treatment method for certain kidney tumors owing to its nephron-preserving benefit. We aimed to compare the occurrence and importance of complications after radical (RN) or partial (PN) nephrectomy for localized renal cell carcinoma (RCC) and contribution to patient mortality. Methods: All RCC cases were extracted from the National Surgical Quality Improvement Program between 2005 and 2017. All-cause mortality was the primary endpoint that defined a failure to rescue (FTR) after the occurrences of complications. Propensity score matching (PSM) was performed to adjust for confounding variables between the 2 groups. The exclusion criteria included patients on dialysis, those with distant metastases, and those with concurrent procedures. Null hypotheses were rejected when P-values were &lt; .05. Results: The database included 24,830 patients, with 22,015 in the RN group and 2815 in the PN. After PSM, 2226 patients after PN were matched 1:1 to an equal number of patients who underwent RN. Overall, postoperative complications occurred in 20.5% after RN, more frequent than 15.9% after PN (P &lt; .001). While the mortality rates were similar, patients were more likely to experience blood transfusion and reintubation, as well as longer hospital stay after RN, while they were likely to have more infectious complications, including abdominal abscess, and more likely to return to the operating room after PN. In both groups, cardiac and respiratory complications were associated with FTR, leading to mortality. Excessive bleeding (requiring transfusion) was also a significant cause of death after RN but not after PN. Conclusion: When planning PN or RN, patients should be counseled on the risks of their selective procedure and the potential increased mortality risk with certain complications. These risks should be weighed against the benefit of those cancer surgeries.

Collecting duct (Bellini duct) renal cell carcinoma: a clinical case and literature review

A rare subtype of renal cell carcinoma (RCC) is Bellini collecting duct carcinoma, also known as medullary renal carcinoma or distal nephron carcinoma, which accounts for 0.4-2.0% of all RCC cases. This subtype has the poorest prognosis of all RCC subtypes, typically presenting as a low-grade tumor at the pT3 or higher stage. Consequently, many patients have distant metastases at diagnosis and 60% develop metastases following radical treatment. There have been approximately 400 literature-reported cases of Bellini ductal carcinoma to date. We present a case report of a patient with early-stage Bellini duct cancer and a literature review of published reports on this condition.

Associations of Matrix Metalloproteinase-8 Genotypes to Renal Cell Carcinoma in Taiwan.

Renal cell carcinoma (RCC) presents a formidable clinical challenge due to its aggressive behavior and limited therapeutic options. Matrix metalloproteinase-8 (MMP-8) has recently emerged as a potential biomarker and therapeutic target for various cancers. However, the genetic involvement of MMP-8 in RCC has remained largely obscure. This study aimed to elucidate the role of MMP-8 genotypes in RCC susceptibility. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was employed to scrutinize the genotypes of MMP-8 C-799T (rs11225395), Val436Ala (rs34009635), and Lys460Thr (rs35866072) among 118 RCC patients and 590 controls. Furthermore, potential associations between MMP-8 genotypes and age, sex, smoking, alcohol consumption, hypertension, diabetes, and family history status in relation to RCC risk were assessed. No significant disparities in the distribution of MMP-8 rs11225395, rs34009635, and rs35866072 genotypes were observed between the RCC case and control cohorts (p>0.05). Individuals with CT and TT genotypes at MMP-8 rs11225395 exhibited 0.86- and 0.80-fold RCC risks, respectively (OR=0.57-1.31 and 0.42-1.55, p=0.5585 and 0.6228, respectively). Intriguingly, hypertensive individuals carrying the MMP-8 rs11225395 CT or TT genotype demonstrated an elevated risk for RCC compared to those with wild-type CC genotype (p=0.0440). No interactions of MMP-8 genotypes with age, sex, smoking, alcohol consumption, or diabetes status were evident (all p>0.05). No significant association was discerned for MMP-8 rs34009635 or rs35866072 genotypes. MMP-8 genotypes appear to have a modest influence on individual susceptibility to RCC. Hypertensive patients with the CT or TT MMP-8 rs11225395 genotype may have an elevated risk of RCC.

Artificial Intelligence-Based Non-invasive Differentiation of Distinct Histologic Subtypes of Renal Tumors With Multiphasic Multidetector Computed Tomography.

With rising cases of renal cell carcinoma (RCC), precise identification of tumor subtypes is essential, particularly for detecting small, heterogenous lesions often overlooked in traditional histopathological examinations. This study demonstrates the non-invasive use of deep learning for Histopathological differentiation of renal tumors through quadriphasic multidetector computed tomography (MDCT). This prospective longitudinal study includes 50 subjects (32 males, 18 females) with suspected renal tumors. A deep neural network (DNN) is developed to predict RCC subtypes using peak attenuation values measured in Hounsfield Units (HUs) obtained from quadriphasic MDCT scans. The network then generates confidence scores for each of the four primary subtypes of renal tumors, effectively distinguishing between benign oncocytoma and various malignant subtypes. Our neural network accurately distinguishes Renal tumor subtypes, including clear cell, papillary, chromophobe, and benign oncocytoma, with a confidence score of 68% with the network's diagnosis aligning with Histopathological examinations. Our network was also able to accurately classify RCC subtypes on a synthetically generated dataset with 20,000 samples. We developed an artificial intelligence-based RCC subtype classification technique. Our approach is non-invasive and has the potential to transform the methodology in Renal oncology by providing accurate and timely diagnostic information and enhancing clinical decisions.

Clinicopathologic and Molecular Characterization of Xanthomatous Giant Cell Renal Cell Carcinomas: Further Support for a Close Morphologic Spectrum to Eosinophilic Solid and Cystic Renal Cell Carcinomas.

A recent study described a rare subtype of tuberous sclerosis complex ( TSC )-mutated renal cell carcinoma primarily characterized by Xanthomatous giant cell morphology. Only 2 cases in young individuals have been reported so far, making the correct diagnosis challenging from a pathological perspective. It remains unknown whether this tumor represents an independent subtype or belongs to other TSC -mutated tumors. We conducted a clinicopathologic evaluation and immunohistochemical profiling of 5 cases of Xanthomatous Giant Cell Renal Cell Carcinoma (XGC RCC) with confirmed TSC2 mutations through targeted DNA sequencing. In addition, we analyzed transcriptomic profiles using RNA-seq for the following samples: XGC RCC, Low-grade Oncocytic tumors (LOT), High-grade Oncocytic tumors/Eosinophilic Vacuolar Tumors (HOT/EVT), Eosinophilic Solid and Cystic Renal Cell Carcinomas (ESC RCC), Chromophobe cell Renal Cell Carcinomas (ChRCC), Renal Oncocytomas (RO), clear cell Renal Cell Carcinomas (ccRCC), and normal renal tissues. There were 2 female and 3 male patients, aged 22 to 58 years, who underwent radical nephrectomy for tumor removal. The tumor sizes ranged from 4.7 to 9.5cm in diameter. These tumors exhibited ill-defined boundaries, showed an expansive growth pattern, and featured distinctive tumor giant cells with abundant eosinophilic to Xanthomatous cytoplasm and prominent nucleoli. All tumors had low Ki-67 proliferation indices (<1%) and demonstrated immune reactivity for CD10, PAX8, CK20, CathepsinK, and GPNMB. Next-generation sequencing confirmed TSC2 mutations in all cases. RNA sequencing-based clustering indicated a close similarity between the tumor and ESC RCC. One patient (1/5) died of an accident 63 months later, while the remaining patients (4/5) were alive without tumor recurrences or metastases at the time of analysis, with a mean follow-up duration of 43.4 months. Our research supports the concept that Xanthomatous giant cell renal cell carcinoma (XGC RCC) shares clinicopathological and molecular characteristics with ESC RCC and shows a relatively positive prognosis, providing further support for a close morphologic spectrum between the two. We propose considering XGC RCC as a distinct subtype of ESC RCC.

Decreased risk of renal cell carcinoma in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors.

Patients with type 2 diabetes (T2D) are at a higher risk of developing renal cell carcinoma (RCC) than the general population. Invitro and invivo investigations of the effects of sodium glucose cotransporter-2 inhibitors (SGLT2I) have shown a significantly reduced risk of RCC. However, the impact of these drugs on the incidence of RCC in the human population is unclear. This study aimed to examine the association between SGLT2I use and RCC risk in patients with T2D. We undertook a nationwide retrospective cohort study using the Health and Welfare Data Science Center database (2016-2020). The primary outcome was the risk of incident RCC by estimating hazard ratios (HRs) and 95% confidence intervals (CIs). Multiple Cox regression modeling was applied to analyze the association between SGLT2I use and RCC risk in patients with T2D. In a cohort of 241,772 patients with T2D who were using SGLT2Is and 483,544 participants who were not, 220 and 609 RCC cases, respectively, were recorded. The mean follow-up period of the study subjects was 2 years. There was a decreased risk of RCC for SGLT2I users after adjusting for the index year, sex, age, comorbidities, and concurrent medication (adjusted HR 0.68; 95% CI, 0.58-0.81). The sensitivity test for the propensity score 1:1-matched analyses showed similar results (adjusted HR 0.67; 95% CI, 0.55-0.81). The subgroup analysis revealed consistent results for sex, age (<70 years), and comorbidity with chronic kidney disease. The present study indicates that SGLT2I therapy significantly decreases RCC risk in patients with T2D. This finding was also consistent among the sensitivity test and subgroup analysis for those with or without chronic kidney disease/hypertension.

Abstract 3226: PRMT1 is a critical dependency in clear cell renal cell carcinoma with roles in post- transcriptional regulation and DNA damage response

Abstract The majority of sporadic renal cell carcinoma (RCC) cases present as the clear cell subtype (ccRCC) and are associated with the biallelic inactivation of the von Hippel-Lindau (VHL) gene, leading to constitutive activation of the cellular hypoxia response and deleterious alterations to gene expression, metabolism, and growth. Despite the near ubiquity of VHL loss, evidence suggests that it alone is insufficient to drive tumor establishment. Additional loss of function (LOF) mutations in epigenetic regulatory proteins including PBRM1, SETD2 and BAP1 have been identified as tumor drivers. The frequency and penetrance of these mutations in epigenetic regulators implicates a vulnerability in ccRCC that may be exploited to develop new therapies. To explore this vulnerability, the Ailles lab completed a screen of the Structural Genomics Consortium’s (SGC) epiprobe library - a panel of inhibitors targeting an array of epigenetic regulators in patient derived ccRCC models. Among the several promising targets identified, a particularly favorable inhibition profile was noted for MS023, an inhibitor of the type I protein arginine methyltransferase family (PRMT1/3/4/6 and 8). PRMTs transfer methyl groups to nuclear histones and cytoplasmic targets, influencing gene expression, mRNA processing and viability. This growth inhibition was corroborated using an additional type I PRMT compound, GSK3368715. CRISPR-mediated deletion of type I PRMT targets indicated that PRMT1 is the main enzyme responsible for growth inhibition in our ccRCC models. Furthermore, genetic depletion of PRMT1 via shRNA phenocopied pharmacological inhibition and proliferative growth was restored in the presence of MS023 by overexpressing PRMT1. Finally, MS023 treatment of mice bearing ccRCC cell line and patient derived xenografts led to significant inhibition of tumor growth in vivo. Transcriptomic profiling of chemical treatment and PRMT1 genetic depletion demonstrated that PRMT1 inhibition triggers a significant down regulation of genes related to cell cycle progression and DNA damage. ccRCC cells treated with MS023 accumulated significant levels of DNA damage before undergoing cell death, with several DDR-related proteins being down-regulated. Proximity ligation and proteomic analysis (Bio-ID) revealed that PRMT1’s interactors skew heavily towards RNA metabolism regulators and widespread alterations in mRNA processing were noted with MS023 treatment. Evidence continues to mount that PRMT1 is implicated in the biology of cancer, but to our knowledge, no thorough investigations have been performed in the context of ccRCC. Our data suggests that inhibition of PRMT1 inhibits processing of mRNA transcripts, compromises DDR mechanisms, leading to an accumulation of double stranded breaks, cytostasis and cell death. Thus PRMT1 represents a viable therapeutic target in ccRCC. Citation Format: Joseph Walton, Karen Arevalo, Angel SN Ng, Jalna Meens, Christina Karamboulas, Panagiotis Prinos, Brian Raught, Eric Chen, Cheryl Arrowsmith, Laurie Ailles. PRMT1 is a critical dependency in clear cell renal cell carcinoma with roles in post- transcriptional regulation and DNA damage response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3226.