Primary Renal Cell Carcinoma Research Articles

Collecting duct carcinoma (Bellini Duct Carcinoma) of kidney-An overview

Renal cell carcinoma (RCC) accounts for more than eighty-five percent of primary renal cell carcinomas with male preponderance in 5 to 7 decades. Collecting duct carcinoma (CDC) constitutes for less than 1% of all renal cell carcinomas. Histopathological examination of all types of RCC is almost importance in view of therapeutic and prognostic implications of its varied subtypes. The purpose of this editorial is to highlight the morphology and rarity of collecting duct carcinoma and differentiation of it from papillary renal cell carcinoma.

Long-Term Outcomes of SABR to Primary Renal Cell Carcinoma: A Multicenter Analysis from IROCK (International Radiosurgery Oncology Consortium for Kidney)

<h3>Purpose/Objective(s)</h3> Patients with renal cell carcinoma (RCC) not suitable for surgery have few curative treatment options, particularly as thermal ablation has diminishing efficacy in RCC > 3 cm or adjacent to collecting system. Stereotactic ablative body radiotherapy (SABR) is a novel option limited by lack of long-term outcome data. We hypothesize that SABR represents an effective and safe, nephron-sparing alternative for RCC in the long-term. <h3>Materials/Methods</h3> Individual patient data from 12 institutions from IROCK were pooled. Patients with M1 disease and/or upper tract urothelial carcinoma were excluded. Minimum eligible follow-up was ≥ 2 years. Demographics, treatment, oncologic and renal function outcomes were assessed using descriptive statistics. Kaplan-Meier estimates and univariable and multivariable Cox proportional hazards regression were generated for oncologic outcomes. Local failure was investigator defined using RECIST 1.1. Patterns of failure were described using a cumulative incidence function with death as competing event. Toxicity was described using CTCAE v4.0. <h3>Results</h3> In 190 patients, the median follow-up was 5.0 years (range?). The mean ± SD tumor diameter was 4.2 ± 2.2 cm and 95 patients (50%) had ≥ T1b (≥ 4 cm) primaries. Median age was 74 years (interquartile range [IQR]: 66-82), 73.2% were male and 87.6% had good performance status (ECOG 0-1 or KPS ≥ 70%). In patients for whom operability details were reported, 75.0% were defined as inoperable by the referring urologist, mostly for cardiovascular comorbidities (46.9%). Baseline tumor complexity was moderate (median RENAL [1] score of 7 [IQR: 5-9]), and 56 patients (29.5%) had a solitary kidney. Mean ± SD BED₁₀ delivered was 88.3 ± 24.7 Gy. Mean ± SD baseline estimated glomerular filtration rate (eGFR) was 58.9 ± 22.6 mL/min (mild-to-moderate dysfunction) with 53 patients (28.0%) of the cohort having moderate-to-severe dysfunction (eGFR < 45 mL/min). At 3- and 5-years following SABR, mean ± SD eGFR decreased by -10.8 ± 16.6 mL/min and -13.5 ± 14.9 mL/min, respectively. Nine patients (4.7%) required dialysis. Seventy patients (36.8%) had a grade 1-2 toxicity, and one patient (0.5%) had a grade 4 toxicity (gastrointestinal). Cancer-specific survival (CSS) and progression-free survival (PFS) at 3 years were 95.5% and 72.1%, and at 5 years were 92.0% and 63.6%, respectively. Local, distant and any failure at 5 years were 5.5%, 10.8% and 13.0%. On multivariable analysis, increasing tumor size was associated with inferior CSS (HR per 1 cm increase: 1.41; 95% CI: 1.15-1.71; <i>p</i> < 0.001), PFS (HR: 1.10; 95% CI: 1.01-1.19; <i>p</i>=0.030), and any failure (HR: 1.20; 95% CI: 1.10-1.32; <i>p</i> < 0.001). <h3>Conclusion</h3> At 5-years post-therapy, SABR for primary RCC was associated with excellent local efficacy and good oncological outcomes, with only modest impact on renal function. [1] A. Kutikov & R.G. Uzzo "The RENAL nephrometry score: a comprehensive standardized system for quantitating renal tumor size, location and depth." J. Urol (2009)182(3):844

Location matters: LAG3 levels are lower in renal cell carcinoma metastatic sites compared to primary tumors, and expression at metastatic sites only may have prognostic importance.

While great strides have been made in the treatment of advanced renal cell carcinoma (RCC) with the emergence of immune checkpoint inhibitors (ICIs) and VEGFR-targeting drugs, sizable proportions of patients still do not respond to upfront therapy and long-term responses only occur in a minority of patients. There is therefore a great need for the development of better predictors of response and an increased understanding of mechanisms of resistance to these therapies. Alternative immune checkpoints outside the PD-1/PD-L1 axis, such as LAG3, have been implicated as one mechanism of resistance to ICIs. These checkpoints thus represent attractive therapeutic targets, and indeed the LAG3 inhibitor relatlimab was recently approved for the treatment of metastatic melanoma in combination with anti-PD-1 therapy. LAG3 inhibitors are being evaluated for RCC as well. In this context, a better understanding of LAG3 expression patterns in RCC and how they relate to clinicopathologic features of disease and response to immunotherapy may give insight into mechanisms of resistance to PD-1 inhibitors and aid in the identification of subgroups of patients more likely to benefit from certain drug regimens. In this study, we assessed LAG3 protein levels in leukocytes in normal kidney adjacent to RCC, primary RCC tumors, and matched metastatic tumors, including large numbers of brain metastases. We found that LAG3 protein levels are on average lower at metastatic sites compared to matched primary tumors, and that the difference was more pronounced in patients with high-risk clinical characteristics, including those with larger primary tumor size, grade 4 tumors, IMDC poor-risk disease, and initial presentation with brain metastases. We further saw that the prognostic value of LAG3 levels varies depending on the tissue site queried (i.e., primary tumor versus metastases), and that relatively higher LAG3 levels at metastatic sites may predict a better response to immunotherapy and longer overall survival after the development of metastatic disease. These findings may have important implications for the design of future studies involving LAG3 or other immunotherapies in RCC.

A Rare Case Of Primary Squamous Cell Carcinoma Of Kidney: A Case Report

Adenocarcinomas are the most prevalent kidney neoplasms. Only a few cases of primary squamous cell carcinoma have been reported.It is responsible for 6–15% of all kidney tumors. Majorly found in males as compare to females. This case report is of is of A 65-yearold man with pain on the left side of his abdomen. CT Urography showed the right kidney measuring 11.2 x 4.9 cm and striatednephrogram in initial images with evidence of multiple non enhancing areas with peripheral enhancement, largest measuring 2.2 x 1.2cm. Mild thickening of the renal pelvis is noted. Presence of diffuse tumor ranging from size 15 x 8 x 7 cm occupying almost whole ofthe kidney with unattainable origin was observed. Primary renal squamous cell carcinomas are extremely rare tumours that are rarelysuspected or identified clinically. It is an important factor to consider while making a diagnosis of kidney tumours.

S2542 A Rare Case of Renal Cell Carcinoma Diagnosed on EGD

Introduction: Neoplasms of the duodenum account for a fraction of overall gastrointestinal tumors. Even when a lesion is found in the duodenum, it is more likely to be of secondary neoplastic origin than primary. Here we present a unique case of primary renal cell carcinoma (RCC) diagnosed on EGD. Case Description/Methods: A 55-year-old male with a history of alcohol use disorder presented to the emergency department for lightheadedness, fatigue, and 100-pound unintentional weight loss over 3 months. On exam, the patient was found to be hypotensive, tachycardic, and jaundiced. Laboratory values were pertinent for a Hemoglobin of 4.4 g/dl. After adequate resuscitation, esophagogastroduodenoscopy (EGD) was performed that showed a large partially obstructive, infiltrative, and ulcerated mass with no bleeding in the second part of the duodenum. Histology from the duodenal mass biopsy revealed clear cell carcinoma of renal origin with mucosal ulceration. An abdominal computerized tomography (CT) scan showed a heterogeneous, centrally necrotic right renal mass causing mass effect on the second and third portions of the duodenum, right hemicolon, and hepatic flexure. The scan was also suggestive of duodenal invasion by the mass. Solid pulmonary nodule biopsy was unequivocal for metastasis. The patient was discussed in tumor board and deemed to be a candidate for cytoreductive surgery with partial duodenal resection and systemic immunotherapy if metastasis was confirmed on future biopsies (Figure). Discussion: Duodenal metastasis from RCC is very rare and poses a diagnostic challenge. The most common presentation is with upper gastrointestinal hemorrhage or obstruction, though sometimes it can present with perforation, intussusception, or obstructive jaundice. Duodenal involvement is often from direct infiltration or metastatic spread. Delay in care and large tumor size are the likely reasons for the rare presentation seen in this patient. This case highlights the importance of considering all neoplasms of extraintestinal origin when duodenal lesions are identified endoscopically.Figure 1.: Left: 2nd portion of duodenum. Right: CT Abdomen/Pelvis.

S3238 A Case of Concurrent Cholecystitis and Stauffer Syndrome

Introduction: Stauffer syndrome (SS) is a paraneoplastic syndrome seen in some malignancies, most commonly 4-15% of primary renal cell carcinomas, resulting in nephrogenic hepatic dysfunction. SS commonly results in elevated alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and prothrombin time (PT) as well as decreased albumin in the absence of liver metastasis. The etiology of SS is unknown, although three have been suggested: elevated interleukin-6, elevated colony stimulating factor or, least likely, autoimmune. We describe a case of a woman presenting with right upper quadrant (RUQ) pain who was found to have indirect predominant hyperbilirubinemia and acute cholecystitis and renal mass on ultrasound. Case Description/Methods: An 81-year-old female presented to an outside hospital for RUQ and epigastric pain that worsened after fatty meals. Imaging showed acute cholecystitis as well as a right renal mass. Physical exam at the time was remarkable only for diffuse tenderness to abdominal palpation, most notably in the RUQ. There was no scleral icterus or costovertebral angle tenderness on exam. Labs on presentation can be seen in Table 1. Given the elevated indirect bilirubin, gastroenterology was consulted and suggested Gilbert syndrome (GS) or SS given their concern for renal cell carcinoma (RCC). The next day the patient underwent a laparoscopic cholecystectomy notable for acute gangrenous cholecystitis with cholelithiasis, and had rapid normalization of bilirubin over 48 hours. The patient followed with outpatient urology for renal biopsy, which was positive for clear cell RCC. Follow up imaging revealed scattered pulmonary nodules up to 1.1cm, with concern for metastasis. Surgery was deemed inappropriate and the patient was conservatively managed, given her wishes to prioritize quality of life and not undergo chemotherapy. (Figure) Discussion: This case illustrates an interesting clinical picture where a patient with confirmed cholecystitis also has a new renal mass, with elevated indirect bilirubin and PT, consistent with SS. The diagnosis of SS is made clinically, with hopeful resolution of abnormal lab values upon RCC resection. In this case, surgery was not indicated, hemolysis was ruled out with stable hemoglobin and normal peripheral smear, and the diagnoses of acute cholecystitis and RCC causing SS was made. In addition to hemolysis, GS, and Criggler-Najjar when working up indirect hyperbilirubinemia, it is imperative to include SS on the differential diagnosis.Figure 1.: CT abdomen with right renal mass. Table 1. - Patient labs on presentation and 2 days post-cholecystectomy Lab Admission Post-Op Day 2 Normal WBC Count (103 cells/uL) 17 14 4.1-9.3 Platelet (103/uL) 246 248 130-350 Hemoglobin (g/dL) 10.6 9.8 11-14.7 Albumin (g/dL) 3.3 2.7 3.5-5.2 Total Bilirubin (mg/dL) 2.8 0.9 0.1-1.2 Indirect Bilirubin (mg/dL) 2.4 0-0.9 Alkaline Phosphatase (IU/L) 96 102 30-115 AST (IU/L) 23 20 5-45 ALT (IU/L) 12 16 5-60 Lipase (U/L) 12 11-82 Prothrombin Time (s) 14.3 9.4-12.9 INR 1.2 0.83-1.14 AST = aspartate transaminase, ALT = alanine transaminase.

An unusual metastasis of atypical pulmonary carcinoid to the renal adipose capsule mimicking primary renal cell carcinoma.

An unusual metastasis of atypical pulmonary carcinoid to the renal adipose capsule mimicking primary renal cell carcinoma.

44: Long-Term Outcomes of SABR to Primary Renal Cell Carcinoma: A Multi-Centre Analysis from the International Radiosurgery Oncology Consortium for Kidney (IROCK)

44: Long-Term Outcomes of SABR to Primary Renal Cell Carcinoma: A Multi-Centre Analysis from the International Radiosurgery Oncology Consortium for Kidney (IROCK)

Immune checkpoint receptor VISTA on immune cells is associated with expression of T-cell exhaustion marker TOX and worse prognosis in renal cell carcinoma with venous tumor thrombus

PurposeThe study aimed to determine the expression of VISTA and TOX within venous tumor thrombus and primary clear cell renal cell carcinoma (ccRCC) and to assess their prognostic value.MethodsThe study enrolled 82 patients with ccRCC and coexisting venous tumor thrombus treated radically from 2012 to 2019 in two tertiary centers. Tissue microarrays were prepared and stained with respective antibodies. The expression of markers was assessed separately on tumor cells (TCs) and/or tumor-associated immune cells (TAICs).ResultsTOX expression was positively correlated with the percentage of VISTA-positive TAICs in venous thrombus (p = 0.011), but not in the primary tumor (p = 0.674). High TOX expression was associated with a higher percentage of PD-L1-positive TAICs in both compartments (p = 0.001, p = 0.011, respectively). Positive expression of VISTA on TAICs was associated with PD-L1 expression on TCs (p = 0.005) and TAICs (p = 0.004) in the primary tumor, and only with PD-L1 on TAICs in thrombus (p = 0.006). The presence of VISTA-positive TAICs in venous thrombus was significantly more common in females (p = 0.034), and positively correlated with metastases (p = 0.028), and tumor necrosis (p = 0.013). The cases with VISTA-positive TAICs in venous tumor thrombi had significantly shorter OS than VISTA-negative cases (p = 0.041).ConclusionFor the first time, we demonstrated the expression of VISTA- and TOX-positive TAICs in the venous tumor thrombus. We found the association between immune checkpoint receptors and T cell exhaustion markers in both tumor mass and venous thrombus. Finally, we demonstrated that abundance of VISTA-positive TAICs in venous tumor thrombus correlates with worse outcomes in ccRCC.

Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Cancer: 24-Month Results of the RSR1 Phase 1 Dose Escalation Study

PurposeStereotactic body radiation therapy (SBRT) has become a new therapeutic option for primary renal cell carcinoma. However, treatment doses lack consistency in the literature. The primary objective of this study was to determine the maximum tolerated dose for renal cancer SBRT. Methods and MaterialsThis phase 1 multicentric dose-escalation study assessed 4 dose levels: 8 Gy × 4, 8 Gy × 5, 10 Gy × 4, and 12 Gy × 4. The primary objective of this study was to determine the maximal tolerated dose, defined by the occurrence of dose-limiting toxicity was defined as any acute side effect of grade ≥4 based on the Common Terminology Criteria for Averse Events, version 4.0. ResultsFrom October 2010 to September 2017, 13 patients were enrolled. The median follow-up was 23 months. There was no dose-limiting toxicity in our study, and the highest dose was reached successfully. No acute or late toxic effects above grade 2 were seen. There was no significant alteration of renal function after treatment. At 24 months, 2 patients had partial response and the others had stable disease. ConclusionsAfter 24 months of follow-up, no dose-limiting toxicity was seen at any of the prescribed dose levels in our study. The findings suggest that our last dose level of 48 Gy in 4 12-Gy fractions can be considered safe and can be used in further studies.

Left Renal Failure with Lung Metastasis: A Case Report

Background : Lung metastasis is a lung cancer complication that can harm a person’s lung and lessen their ability to breathe fully on exhalation and inspiration. Adrenal glands, the liver, and the pancreas will all be impacted by metastasis, and in a very small percentage of instances, the kidney will also be affected and its function hampered. Here, we describe a case of primary renal cell carcinoma with left kidney failure due to lung metastasis. Metastasis is the process by which cancer cells move to different body organs from the site where they initially developed through the lymphatic and circulatory systems. The fourth stage of cancer, known as metastasis, is typically when the fatality rate increases the most since it affects the body’s organs’ ability to digest food, make bone and tissue repairs, produce blood, and operate normally. Case presentation : Breathlessness, back pain, severe compensated metabolic acidosis, multiple lung metastases in the lateral lung parenchyma, and multiple metastases in the bilateral lung parenchyma were the main complaints of a 70-year-old man with known lung metastases. These appear to be a cannonball. The atrial blood gases (ABG) showed compensated metabolic acidosis, which led to the patient being intubated as a result of the body’s increased oxygen demand. The patient previously experienced a cerebral vascular stroke (which resulted in left-side paralysis), for which he received treatment eight years ago and was subsequently cured. Know the patient is on treatment injection clindamycin, injection linezolid, injection DEXA, injection pantop, injection emset, injection optineuron, tab urimax, syp. duphalac. Conclusion : it is important to take into consideration lung metastasis with primary renal cell carcinoma to left kidney failure differentiation diagnosis, especially in patients with concomitant conditions as they may lead to life-saving intervention for the patient but typically with the patient fourth stage of metastasis have less chance of survival rate. The fiveyear life expectancy for lung metastasis associated primary renal cell carcinoma is approximately seven percent (7%)

Healthcare costs and resource utilization associated with renal cell carcinoma among older Americans: A longitudinal case-control study using the SEER-Medicare data.

To determine 1-year and 5-year total healthcare costs and healthcare resource (HRU) associated with renal cell carcinoma (RCC) in older Americans, from a healthcare sector perspective. This was a longitudinal, retrospective cohort study using the Surveillance, Epidemiology and End Results-Medicare linked data (2006-2014), which included older (≥66 years) patients with primary RCC and 1:5 matched noncancer controls. Patients/controls were followed from diagnosis (pseudo-diagnosis for controls) until death or up to loss-to-follow-up (censored). Per-patient average 1-year and 5-year cumulative total and incremental total healthcare costs and HRU were reported. A total of 11,228 RCC patients were matched to 56,140 controls. Per-patient cumulative average 1-year (incremental = $38,291 [$36,417-$40,165]; $57,588 vs. $19,297) and 5-year (incremental = $68,004 [$55,123-$80,885]; $183,550 vs. $115,547) total costs (excluding prescription drug costs) were 3 and 1.6 times higher for RCC vs. controls. These estimates were 3.6 and 1.7 times higher for RCC vs. controls when prescription costs were included in total costs. Prescription drug costs accounted for 8.4% (incremental = $3,715) and 18.1% (incremental = $15,375) of the 1-year and 5-year incremental total costs, respectively. RCC patients had greater cumulative number of hospitalizations, emergency department visits and prescriptions in 1- and 5-years, compared to controls. Average first year total cost for a patient with incident diagnosis of RCC is substantially higher than that for controls and it varies depending on the stage at diagnosis. Study findings could help in planning future resource allocation and in determining research and unmet needs in this patient population.

Primary renal small cell carcinoma: A case report

BACKGROUNDSmall cell carcinoma (SCC) is a malignant tumour that is frequently accompanied by extensive metastasis. Primary renal SCC has typical characteristics related to SCC and is extremely rare, with no uniform treatment standard. Clinical treatment is mainly based on the literature. Here we report the diagnosis and treatment of an interesting case of primary renal SCC.CASE SUMMARYWe report a tortuous course of treatment for a 68-year-old man. Four years before diagnosis, the patient developed continuous gross haematuria, during which he underwent several ureteral biopsies, ureteral stricture relief, and urine exfoliated cell examinations; however, SCC was not confirmed. One month before radical resection of the renal pelvic carcinoma, the severe haematuria recurred. Computed tomography revealed transitional cell carcinoma in the right kidney and right upper ureter. A preoperative examination exluded the possibility of a pulmonary origin of the tumour, and primary renal SCC was diagnosed. The postoperative pathology findings were suggestive of SCC. The patient was treated with combined chemotherapy but died of tumour progression at 7 mo postoperative.CONCLUSIONOur patient's disease onset in the context of a succession of regular testing and the fact that it occurred so quickly with perirenal encroachment immediately after diagnosis reveals the cruel and unforgiving side of the disease. Furthermore, patients with poor comprehensive treatment results require new treatment regimens.

Abstract CT106: Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study

Abstract Background: Some patients with primary renal cell carcinoma (RCC) are unable to have surgery for different reasons (functional single kidney with a central, high-complexity RCC, high risk of nephrectomy and dialysis, patients with complex coagulation disorders, etc.). We hypothesize that combination of nivolumab and ipilimumab could eliminate the primary tumor in T1aN0M0 patients ineligible for surgical treatment. Methods: This is a prospective, multicenter, non-randomized phase 2 pilot study. Patients with biopsy-proven clear-cell RCC of ≤4 cm (cT1a), no evidence of any metastases, and unable to have surgery or other nephron-sparing interventions (ablation) or with preference to have no surgery or intervention for any reason received combination of ipilimumab (1 mg/kg intravenously) every 3 weeks for four doses, and nivolumab (240 mg intravenously) every 2 weeks during 16 weeks. The primary endpoint was complete response rate. Simon's two-stage design was used. The null hypothesis that the true complete response rate was 11% and was tested against a one-sided alternative. This design yields a type I error rate of 0.05 and power of 0.9 when the true complete response rate is 60% (alternative hypothesis). The null hypothesis should be rejected if 3 or more responses are observed in 8 patients. Results: Between February 2020 and June 2021, 8 patients were included. Median age was 77.9 years (range 73-89). Patients were Caucasian (100%), predominantly male (75%), 62.5% had centrally located RCC, 25% had ECOG PS 1, and 6 of 8 patients had moderate and severe comorbidities. Median follow-up was 12.7 months (95% CI 5.2-16.5). All patients received immunotherapy during 4 months without grade ≥2 adverse events. No complete responses were observed. Partial responses were found in 2 patients (25%). Median size of the primary tumor at RCC diagnosis and after immunotherapy was 3.11 cm (range 2.2-3.9) and 2.86 cm (range 1.5-4.0), respectively. Any shrinkage of the primary tumor was reported in 4 (50%) patients (change in median sum of diameters -18%). Only one patient had tumor enlargement (+0.5 cm (+13%) after 9 months. SBRT was used in this patient. All other patients are under active surveillance. Next secondary end-point of 3-year progression-free survival will be reported. Conclusions: The activity of immunotherapy against primary tumor was limited in patients with T1aN0M0 RCC ineligible for surgical treatment. Duration of stable disease will be studied with long-term follow-up of these patients. Treatment with nivolumab and ipilimumab was safe in patients with moderate and severe comorbidities. Citation Format: Ilya Tsimafeyeu, Maria Volkova, Rustem Gafanov, Igor Myslevtsev, Andrey Andrianov, Axel Bex. Primary tumor response in T1aN0M0 renal cell carcinoma patients ineligible for surgery and treated with nivolumab and ipilimumab: Results from phase 2 pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT106.

Comprehensive analysis of lower mitochondrial complex I expression is associated with cell metastasis of clear cell renal cell carcinoma.

BackgroundClear cell renal cell carcinoma (ccRCC) is characterized by high metastasis potential. It is of great importance to explore the mechanisms underlying ccRCC metastasis and to enable development of potent therapeutics. The mitochondrial complex I (CI) had been considered to play an important role in the development of cancers, but less known in ccRCC.MethodsWe utilized available public databases of ccRCC, including single-cell RNA sequencing (scRNA-seq) data GSE73121 and The Cancer Genome Atlas-kidney renal clear cell carcinoma (TCGA-KIRC). Principal component analysis (PCA) and t-Distributed Stochastic Neighbor Embedding (tSNE) analysis were evaluated the heterogeneity of metastatic renal cell carcinoma (mRCC) and primary renal cell carcinoma (pRCC). Protein-protein interaction (PPI) network identified critical gene. Gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) performed to explore the potential biologic pathways.ResultsOur study revealed a significant gene expression heterogeneity between pRCC and mRCC. A PPI network based on differentially expressed genes (DEGs) identified electron transport chain (ETC), especially mitochondrial CI, as the key network hub. Further analysis revealed that the role of mitochondrial CI is associated with tumor metastasis and immune responds of ccRCC. Although CI had low frequency mutations in ccRCC, CI expression is associated with the high frequency mutated genes. A prognosis model included 7 CI genes, and these had a significant effect on overall survival (OS). The area under the curve at 1, 3, and 5 years was 0.717, 0.685, and 0.728, respectively. Transcription factor analysis predicted that PPARG possibly is a potential transcription activator of CI genes in ccRCC.ConclusionsOverall, we found that CI expression is associated with ccRCC progress. CI and PPARG may be potential biomarkers for metastatic ccRCC.

Nicotinamide-N-methyltransferase is a promising metabolic drug target for primary and metastatic clear cell renal cell carcinoma.

BackgroundThe metabolic enzyme nicotinamide‐N‐methyltransferase (NNMT) is highly expressed in various cancer entities, suggesting tumour‐promoting functions. We systematically investigated NNMT expression and its metabolic interactions in clear cell renal cell carcinoma (ccRCC), a prominent RCC subtype with metabolic alterations, to elucidate its role as a drug target.MethodsNNMT expression was assessed in primary ccRCC (n = 134), non‐tumour tissue and ccRCC‐derived metastases (n = 145) by microarray analysis and/or immunohistochemistry. Findings were validated in The Cancer Genome Atlas (kidney renal clear cell carcinoma [KIRC], n = 452) and by single‐cell analysis. Expression was correlated with clinicopathological data and survival. Metabolic alterations in NNMT‐depleted cells were assessed by nontargeted/targeted metabolomics and extracellular flux analysis. The NNMT inhibitor (NNMTi) alone and in combination with the inhibitor 2‐deoxy‐D‐glucose for glycolysis and BPTES (bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl‐sulfide) for glutamine metabolism was investigated in RCC cell lines (786‐O, A498) and in two 2D ccRCC‐derived primary cultures and three 3D ccRCC air–liquid interface models.ResultsNNMT protein was overexpressed in primary ccRCC (p = 1.32 × 10–16) and ccRCC‐derived metastases (p = 3.92 × 10–20), irrespective of metastatic location, versus non‐tumour tissue. Single‐cell data showed predominant NNMT expression in ccRCC and not in the tumour microenvironment. High NNMT expression in primary ccRCC correlated with worse survival in independent cohorts (primary RCC—hazard ratio [HR] = 4.3, 95% confidence interval [CI]: 1.5–12.4; KIRC—HR = 3.3, 95% CI: 2.0–5.4). NNMT depletion leads to intracellular glutamine accumulation, with negative effects on mitochondrial function and cell survival, while not affecting glycolysis or glutathione metabolism. At the gene level, NNMT‐depleted cells upregulate glycolysis, oxidative phosphorylation and apoptosis pathways. NNMTi alone or in combination with 2‐deoxy‐D‐glucose and BPTES resulted in inhibition of cell viability in ccRCC cell lines and primary tumour and metastasis‐derived models. In two out of three patient‐derived ccRCC air–liquid interface models, NNMTi treatment induced cytotoxicity.ConclusionsSince efficient glutamine utilisation, which is essential for ccRCC tumours, depends on NNMT, small‐molecule NNMT inhibitors provide a novel therapeutic strategy for ccRCC and act as sensitizers for combination therapies.

PBX1, EMCN and ERG are associated with the sub-clusters and the prognosis of VHL mutant clear cell renal cell carcinoma

The molecular heterogeneity of primary clear cell renal cell carcinoma (ccRCC) has been reported. However, the classifications of Von Hippel–Lindau (VHL) mutant ccRCC are unclear. Here, VHL mutant ccRCC from The Cancer Genome Atlas and E-MTAB-1980 datasets were divided into two sub-clusters through non-negative matrix factorization algorithm. Most VHL mutant ccRCC patients in sub-cluster2 were with pathological T1 stage and VHL mutant ccRCC patients in sub-cluster1 were with decreased overall survival. DNA replication and homologous recombination scores were higher, while, WNT signaling pathway and regulation of autophagy scores were lower in sub-cluster1 VHL mutant ccRCC. Moreover, PBX1 transcriptional scores and mRNA expressions were lower in sub-cluster1 VHL mutant ccRCC patients and were associated with the overall survival of VHL mutant ccRCC. Furthermore, PBX1 associated genes EMCN and ERG were down-regulated in sub-cluster1 VHL mutant ccRCC and overall survival was decreased in EMCN or ERG lowly expressed VHL mutant ccRCC patients. Also, PBX1 and EMCN were down-regulated in ccRCC tissues, compared with normal kidney tissues. At last, we constructed risk models based on PBX1, EMCN and EGR expression features. With the increase of the risk score, the number of death of VHL mutant ccRCC patients was increased.

Circ_0000274 contributes to renal cell carcinoma progression by regulating miR-338-3p/NUCB2 axis and JAK1/STAT3 pathway

BackgroundKidney transplant recipients (KTRs) are at increased risk of developing renal cell carcinoma (RCC). Accumulating evidence has demonstrated that circular RNAs (circRNAs) are essential players in tumor advancement. However, the functions of circ_0000274 in renal cell carcinoma (RCC) are barely explored. MethodsThe primary RCC cell lines 786-O and A498 were used in this study. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was employed for the RNA levels of circ_0000274, microRNA-338-3p (miR-338-3p) and nucleobindin 2 (NUCB2). RNase R assay was conducted to analyze the feature of circ_0000274.Cell Counting Kit-8 (CCK-8) assay, colony formation assay, transwell assay, tube formation assay and flow cytometry analysis were conducted for cell viability, colony formation, metastasis, angiogenesis and apoptosis, respectively. Western blot assay was utilized for protein levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were adopted to analyze the associations of circ_0000274 RNA, miR-338-3p RNA and NUCB2 protein. Murine xenograft model was established to explore the function of circ_0000274 RNA in vivo. Immunohistochemistry (IHC) assay was used to analyze NUCB2 protein level in xenograft tumors. ResultsCompared to normal tissues and cells, circ_0000274 RNA level was elevated in RCC tissues and cells. Knockdown of circ_0000274 RNA suppressed cell viability, colony formation, metastasis and tube formation and promoted apoptosis in RCC cells in vitro. Circ_0000274 RNA sponged miR-338-3p RNA to positively regulate NUCB2 protein in RCC cells. Inhibition of miR-338-3p reversed the impacts of circ_0000274 knockdown on RCC cell malignant behaviors. MiR-338-3p RNA overexpression repressed the malignant phenotypes of RCC cells, while NUCB2 protein elevation could abrogate the effect. Moreover, circ_0000274 RNA knockdown blocked tumorigenesis in vivo. Besides, circ_0000274 RNA knockdown inactivated the JAK1/STAT3 protein signaling pathway. ConclusionCirc_0000274 RNA functioned as an oncogene in RCC development by regulating miR-338-3p RNA/NUCB2 protein axis and activating the JAK1/STAT3 protein signaling pathway.

PD43-08 DEVELOPMENT OF PATIENT-DERIVED KIDNEY CANCER ORGANOID; APPLICATION TO DRUG SCREENING MODELS AND ITS CHALLENGES

You have accessJournal of UrologyCME1 May 2022PD43-08 DEVELOPMENT OF PATIENT-DERIVED KIDNEY CANCER ORGANOID; APPLICATION TO DRUG SCREENING MODELS AND ITS CHALLENGES Akira Kazama, Vladimir Bilim, and Yoshihiko Tomita Akira KazamaAkira Kazama More articles by this author , Vladimir BilimVladimir Bilim More articles by this author , and Yoshihiko TomitaYoshihiko Tomita More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002604.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The selection of effective therapeutic agents is critical to improve the life prognosis of patients with renal cell carcinoma (RCC). In this study, we established 3-dimensional (3D) tumor organoids from freshly resected RCC tumors and tested tyrosine kinase inhibitors (TKIs), targeted therapeutics for metastatic RCC, as a drug testing model for development of potential personalized therapy for RCC patients. METHODS: Surgical tumor specimens were obtained from 20 patients with RCC. 3D tumor organoids were developed ex vivo from freshly resected RCC tumors and their histopathological and molecular characteristics were evaluated using histological staining and whole exome sequencing (WES). Using cell viability assay, we determined the therapeutic efficacy of TKIs in RCC tumor organoids. RESULTS: We found that RCC tumor organoids recapitulate the histological architecture of the primary tumor. Using WES, we identified strong concordance of primary tumors and corresponding tumor organoids at genetic level. We demonstrated that RCC tumor organoids respond differently to targeted therapeutics showing patient-specific sensitivity to the treatment. CONCLUSIONS: Our results identify concordance of genetic aberrations in primary RCC and corresponding tumor organoids, and demonstrate that tumor organoid models allow ex vivo drug testing of tumor samples obtained from RCC patients to predict a potential clinical response to targeted therapeutics. Source of Funding: The present study was supported by a research grant from the Department of Urology, Division of Molecular Oncology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan (grant no. CH29017; August, 2018) © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e704 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Akira Kazama More articles by this author Vladimir Bilim More articles by this author Yoshihiko Tomita More articles by this author Expand All Advertisement PDF DownloadLoading ...

Choroidal Metastasis as First Presenting Sign of Renal Cell Carcinoma without Evidence of Primary Tumour - A Case Report

Renal cell carcinoma (RCC) is a rare malignancy characterized by a variety of clinical features. It represents approximately 3 % of all adult malignancies and ranks 13th in frequency of all carcinomas.[1,2] RCC has been documented to metastasize to every organ in the body although metastasis to the eye and orbit is uncommon. Metastases may present decades after the removal of the primary disease. However, it is uncommon for patients who present with ocular metastasis before primary RCC is identified. We report a rare and unique case of metastatic renal cell carcinoma presenting as a choroidal mass despite no evidence of a primary tumour.&#x0D; We present a case of a 65-year-old Chinese man who had sought treatment for a right-sided painful blind eye for 2 years which progressively worsened over time. His vision was poor since the age of 15 years and he was unsure of the cause. Initially, he was treated for the painful blind eye secondary to glaucoma and went for evisceration. Intraoperatively, we noticed that his vitreous cavity was filled with hard fibrotic mass. Histopathological examination was reported as right eye metastatic renal cell carcinoma with clear cell variant. Further investigation was done and he underwent exenteration in view of right optic nerve bulkiness which was also related to renal cell carcinoma. Interestingly, no tumour marker was positive and computed tomography (CT) thorax, abdomen and pelvis did not reveal any primary tumour. He did not complain of any adverse urinary symptoms and there were no signs and symptoms to suggest a concurrent renal pathology.&#x0D; We report a rare and unique case of metastatic renal cell carcinoma presenting as a choroidal mass as the first presenting sign without evidence of primary tumour. Differential diagnosis of metastases must be considered in patients who present with an ocular mass, despite being asymptomatic of any primary malignancy. This is to ensure that this condition is promptly identified and treatment initiated as soon as possible. By highlighting this case, we seek to bring awareness to this condition and hopefully improve on its current dismal prognosis by early diagnosis.