Form Of Renal Cell Carcinoma Research Articles

Comparison of 68 Ga-FAPI-04 and 18 F-FDG PET/CT in Fumarate Hydratase-Deficient Renal Cell Carcinoma : A Prospective and Single-Center Study.

Fumarate hydratase-deficient renal cell cancer (FHRCC) is a rare and aggressive form of renal cell carcinoma. The diagnostic value of 68 Ga-FAPI PET/CT for FHRCC remains unexplored. Therefore, we compared the potential value of 68 Ga-FAPI-04 and 18 F-FDG PET/CT in FHRCC. Patients with FHRCC underwent 68 Ga-FAPI-04 and 18 F-FDG PET/CT from May 2022 to December 2023. The SUV max and tumor-to-liver ratio (TLR) of both tracers were compared using the Wilcoxon signed rank test. Eleven patients with 83 lesions were enrolled. The rate of 18 F-FDG PET/CT in detecting lesions was higher than that of 68 Ga-FAPI-04 PET/CT: primary tumors: 75.0% (6/8) versus 50.0% (4/8); lymph nodes: 94.9% (37/39) versus 89.7% (35/39); and bone lesions: 100.0% (21/21) versus 90.5% (19/21). The median SUV max of primary and metastatic lesions on 18 F-FDG PET/CT was comparable to 68 Ga-FAPI-04 PET/CT in semiquantitative analysis (primary lesions: 13.86 vs 16.35, P = 1.000; lymph nodes: 10.04 vs 9.33, P = 0.517; bone lesions: 13.49 vs 9.84, P = 0.107; visceral lesions: 8.54 vs 4.20, P = 0.056). However, the median TLRs of primary and metastatic lesions on 68 Ga-FAPI-04 PET/CT were higher than that of 18 F-FDG PET/CT (primary lesions: 30.44 vs 5.41, P = 0.010; lymph nodes: 17.71 vs 3.95, P = 0.000; bone lesions: 15.94 vs 5.21, P = 0.000; visceral lesions: 9.26 vs 3.44, P = 0.003). 18 F-FDG PET/CT detected more primary and metastatic FHRCC lesions than 68 Ga-FAPI-04 PET/CT. However, the higher TLR in FHRCC on 68 Ga-FAPI-04 PET/CT may indicate therapeutic potential in targeting fibroblast activation protein in FHRCC.

AUY922 improves sensitivity to sunitinib in clear cell renal cell carcinoma based on network pharmacology and in vitro experiments

Clear Cell Renal Cell Carcinoma (ccRCC), the most prevalent form of renal cell carcinoma (RCC), poses a significant threat to human health due to its rising morbidity and mortality rates. Sunitinib, a pivotal targeted drug for the treatment of ccRCC, presents a significant challenge due to the high susceptibility of ccRCC to resistance. HSP90 inhibitor AUY922 has demonstrated anti-tumor activity in a range of cancer types. However, its efficacy in combination with sunitinib for ccRCC treatment has not been evaluated. In this study, we employed bioinformatics, network pharmacology, and in vitro assays to verify that AUY922 inhibits cell viability, proliferation, and migration of ccRCC cell lines 786-O and ACHN, with IC50s of 91.86 μM for 786-O and 115.5 μM for ACHN. The effect of AUY922 enhancing the inhibitory effect of sunitinib on ccRCC was further confirmed. The CCK-8 assay demonstrated that the IC50 of sunitinib was reduced from 15.10 μM to 11.91 μM for 786-O and from 17.65 μM to 13.66 μM for ACHN, after the combined application of AUY922. The EdU assay and wound healing assay indicated that AUY922 augmented the inhibitory impact of sunitinib on the proliferation and migration of ccRCC cells. Western blot and RT-PCR analyses demonstrated that AUY922 increased the sensitivity of ccRCC cells to sunitinib by targeting the HIF-1α/VEGFA/VEGFR pathway. Our study represents the first investigation into the role and mechanism of AUY922 in enhancing the sensitivity of ccRCC to sunitinib. In conclusion, the findings indicate the potential for AUY922 to enhance the therapeutic efficacy of sunitinib and overcome sunitinib resistance in ccRCC.

Qualitative and quantitative assessment of non-clear cell renal cell carcinoma using contrast-enhanced ultrasound

BackgroundNon-clear cell renal cell carcinoma (nccRCC) represents a rare form of renal cell carcinoma (RCC) in the clinic. It is now understood that contrast-enhanced ultrasound (CEUS) exhibits diverse manifestations and can be prone to misdiagnosis. Therefore, summarizing the distinctive features of contrast-enhanced ultrasonography is essential for differentiation from ccRCC.ObjectiveThis study aims to evaluate the diagnostic efficacy of qualitative and quantitative CEUS in diagnosing nccRCC to enhance our understanding of this condition.MethodsWe conducted a retrospective analysis of 21 patients with confirmed nccRCC following surgery and assessed the characteristic conventional ultrasound and CEUS imaging features. The paired Wilcoxon signed-rank sum test was employed to compare differences in CEUS time-intensity curve (TIC) parameters between the lesions and the normal renal cortex.ResultsRoutine ultrasound revealed the following primary characteristics in the 21 nccRCC cases: hypoechoic appearance (10/21, 47.6%), absence of liquefaction (18/21, 66.7%), regular shape (19/21, 90.5%), clear boundaries (21/21, 100%), and absence of calcification (17/21, 81%). Color Doppler flow imaging (CDFI) indicated a low blood flow signal (only 1 case of grade III). Qualitative CEUS analysis demonstrated that nccRCC predominantly exhibited slow progression (76.1%), fast washout (57%), uniformity (61.9%), low enhancement (71.5%), and ring enhancement (61.9%). Quantitative CEUS analysis revealed that parameters such as PE, WiAUC, mTTI, WiR, WiPI, WoAUC, WiWoAUC, and WOR in the lesions were significantly lower than those in the normal renal cortex (Z=-3.980, -3.563, -2.427, -3.389, -3.980, -3.493, -3.528, -2.763, P < 0.001, < 0.001, = 0.015, = 0.001, < 0.001, < 0.001, < 0.001, = 0.006). However, there were no significant differences in RT, TTP, FT, or QOF (all P > 0.05).ConclusionnccRCC exhibits distinctive CEUS characteristics, including slow progression, fast washout, low homogeneity enhancement, and ring enhancement, which can aid in distinguishing nccRCC from ccRCC.

Sustained response to immunotherapy in a renal collecting duct carcinoma: A glimmer of hope for an orphan tumor

Introduction: Renal Collecting Duct Cell Carcinoma (RCDCC) is a distinctive and aggressive form of Renal Cell Carcinoma (RCC). To date, there is no defined therapeutic strategy, and the evidence for Immunotherapy (IT) is very limited. The latest advances in molecular biology are aimed at clarifying therapeutic targets to guide therapeutics in this orphan tumor.

In deep bioinformatic characterization of a novel fumarate hydratase variant FH c.199T > G; (p.Tyr67Asp) in hereditary leiomyomatosis and renal cell carcinoma.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare, autosomal dominant tumor predisposition syndrome characterized by variable development of multiple skin and uterus leiomyomas and aggressive forms of renal cell carcinoma (RCC). Mutations in fumarate hydratase (FH), one of the proteins in homologous recombination repair, precede the development of HLRCC with high penetrance. Considering the risk of early metastasis of RCC, FH has been included in mutation screening panels. The identification of a pathogenic FH variant guides the screening for tumors in the carriers. However, variants of uncertain significance (VUS) are frequent findings, limiting the clinical value of the mutation screening. Here, we describe the associated phenotype and an in-depth, multi-step Bioinformatic evaluation of the germline FH c.199T > G (p.Tyr67 > Asp) variant segregated in an HLRCC family. Evidence for FH c.199T > G; (p.Tyr67Asp) pathogenicity includes the variant segregation with the disease in three affected family members, its absence in populational databases, and the deep evolutionary conservation of the Tyr67 residue. At the protein level, this residue substitution causes the loss of molecular bonds and ionic interactions, affecting molecular dynamics and protein stability. Considering ACMG/AMP criteria, we propose the reclassification of the FH c.199T > G; (p.Tyr67Asp) variant to "likely pathogenic". In addition, the in-depth, in silico approach used here allowed us to understand how and why FH c.199T > G; (p.Tyr67Asp) could cause HLRCC. This could help in clinical management decisions concerning the monitoring of unaffected family members having this variant.

Circulating succinate-modifying metabolites accurately classify and reflect the status of fumarate hydratase-deficient renal cell carcinoma.

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent plasma biomarkers for early diagnosis. These 2 molecules reliably reflected the FH mutation status and tumor mass. We further identified the enzymatic cooperativity by which these biomarkers are produced within the tumor microenvironment. Longitudinal monitoring of patients demonstrated that these circulating biomarkers can be used for reporting on treatment efficacy and identifying recurrent or metastatic tumors.

Abstract 258: Whole genome analysis of hereditary leiomyomatosis and renal cell cancer identifies role of localized hypermutational events

Abstract Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare hereditary condition affecting over 1 in 200,000 people worldwide. Individuals with HLRCC are also at risk of developing an aggressive form of renal cell carcinoma (RCC), as 15-20% of patients develop type 2 papillary RCC associated with poor prognosis. Although RCC risk and cancer penetrance of this condition has been studied, whole genome sequencing of associated tumors has yet to be examined, and the landscape of structural variants of HLRCC is largely unknown. We have therefore performed whole genome sequencing of tumor/normal pairs of HLRCC patients to study the tumor molecular architecture in this form of RCC. Through germline variant and somatic mutation calling, we have identified specific somatic mutational drivers, including those at the structural variant level for the first time in HLRCC. We have also quantified both chromothripsis and kataegis in these tumors, identifying the specific role of localized hypermutational events. Similarly, using tumour subclonal reconstruction techniques, we have inferred the clonality of HLRCC-associated RCC tumors and elucidate the relative timing of key oncogenic events and mutational processes. We also compare each of these mutational features to their equivalents in other RCC tumour subtypes. These studies shed key light on the specific mutational processes and drivers of this rare hereditary malignancy and on its lethality. Citation Format: Selina Wu, Paul C. Boutros. Whole genome analysis of hereditary leiomyomatosis and renal cell cancer identifies role of localized hypermutational events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 258.

Role of ultra-high b-value DWI in the imaging of hereditary leiomyomatosis and renal cell carcinoma (HLRCC).

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is associated with an aggressive form of renal cell carcinoma with high risk of metastasis, even in small primary tumors with unequivocal imaging findings. In this study, we compare the performance of ultra-high b-value diffusion-weighted imaging (DWI) sequence (b = 2000s/mm2) to standard DWI (b = 800s/mm2) sequence in identifying malignant lesions in patients with HLRCC. Twenty-eight patients (n = 18 HLRCC patients with 22 lesions, n = 10 controls) were independently evaluated by three abdominal radiologists with different levels of experience using four combinations of MRI sequences in two separate sessions (session 1: DWI with b-800, session 2: DWI with b-2000). T1 precontrast, T2-weighted (T2WI), and apparent diffusion coefficient (ADC) sequences were similar in both sessions. Each identified lesion was subjectively assessed using a six-point cancer likelihood score based on individual sequences and overall impression. The ability to distinguish benign versus malignant renal lesions improved with the use of b-2000 for more experienced radiologists (Reader 1 AUC: Session 1-0.649 and Session 2-0.938, p = 0.017; Reader 2 AUC: Session 1-0.781 and Session 2-0.921, p = 0.157); whereas no improvement was observed for the less experienced reader (AUC: Session 1-0.541 and Session 2-0.607, p = 0.699). The inclusion of ultra-high b-value DWI sequence improved the ability of classification of renal lesions in patients with HLRCC for experienced radiologists. Consideration should be given toward incorporation of DWI with b-2000s/mm2 into existing renal MRI protocols.

Radiofrequency ablation in Von-Hippel-Lindau disease with bilateral renal cell carcinoma: a case report

&lt;p class="abstract"&gt;Von Hippel-Lindau (VHL) disease is a familial form of renal cell carcinoma which manifests as bilateral renal cell carcinoma. Radiofrequency ablation is a minimally invasive technique helps in treating renal cell carcinoma with renal function preservation. We reported a case of 29 years old male with bilateral renal cell carcinoma. We treated him with left radical nephrectomy and right side multifocal RCC with Radio frequency ablation. Radiofrequency ablation definitely have a role as alternative treatment modality to nephron sparing surgical procedure for small (&amp;lt;4 cm) localised RCC. Further studies are needed to assess its long-term efficacy.&lt;/p&gt;&lt;p&gt; &lt;/p&gt;

Cabozantinib in the treatment of patients with advanced renal cell carcinoma

In recent years, the standards of drug therapy for advanced kidney cancer have undergone significant changes associated with the appearance of the effective immune checkpoint inhibitors, as well as the high affinity second-generation multi-kinase inhibitors. One of the new tyrosine kinase inhibitors associated with the proven antitumor activity and safety in patients with advanced forms of renal cell carcinoma (RCC) is cabozantinib. The standards of drug therapy for advanced renal cancer have significantly changed in recent years with the emergence of effective anti-tumor immune response checkpoint inhibitors and high-affinity second-generation multikinase inhibitors. One of the novel tyrosine kinase inhibitors with proven antitumor activity and safety in patients with advanced renal cell cancer (RCC) is cabozantinib. In the first-line therapy for advanced renal cancer, the combination of cabozantinib with nivolumab became the regimen of choice in patients of all risk groups, according to International Metastatic RCC Database Consortium (IMDC), regardless of the presence of a sarcomatoid component in the tumor based on the results of the randomized phase III CheckMate 9ER clinical trial (n=651), which demonstrated a significant benefit of immune targeted therapy compared to sunitinib in terms of overall survival (OS; median 37.7 and 34.3 months, respectively), progression-free survival (PFS; median 16.6 and 8.3 months, respectively) and objective response rate (ORR; 55.7 and 28.4%, respectively). Cabozantinib monotherapy in the first-line therapy of advanced renal cancer in patients in the intermediate-risk and poor-risk groups is an alternative regimen reserved for patients with contraindications to anti-tumor immune response checkpoint inhibitors. This recommendation is based on the results of the open-label phase II RCT, CABOSUN (n=157), which showed a significant increase in PFS in the cabozantinib group compared to sunitinib (8.6 month vs 5.3 months, respectively). Also, cabozantinib is the drug of choice in papillary RCC due to the proven advantage in terms of PFS over sunitinib (9.0 and 5.6 months, respectively) demonstrated in the SWOG 1500 phase II RCT (n=152). Cabozantinib remains the drug of choice for second-line therapy of RCC resistant to anti-angiogenic therapy, based on the results of the phase III METEOR RCT, in which the drug showed a compelling advantage over everolimus for PFS (7.4 and 3.8 months, respectively) and OS (21.4 and 16.5 months, respectively). The article presents a detailed analysis of these studies.

MP42-18 MANAGEMENT OF HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER (HLRCC)-ASSOCIATED RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Localized: Surgical Therapy III (MP42)1 Sep 2021MP42-18 MANAGEMENT OF HEREDITARY LEIOMYOMATOSIS AND RENAL CELL CANCER (HLRCC)-ASSOCIATED RENAL CELL CARCINOMA Alexis Rompre-Brodeur, Jeunice Owens-Walton, Sandeep Gurram, Patrick T Gomella, Bradley R Webster, Beth Ryan, Deborah Nielson, Christopher J Ricketts, Jeffrey W Nix, Gennady Bratslavsky, Adam R Metwalli, Rabindra Gautam, Ashkan Malayeri, Maria J Merino, Peter A Pinto, Ramaprasad Srinivasan, Mark W Ball, and W Marston Linehan Alexis Rompre-BrodeurAlexis Rompre-Brodeur More articles by this author , Jeunice Owens-WaltonJeunice Owens-Walton More articles by this author , Sandeep GurramSandeep Gurram More articles by this author , Patrick T GomellaPatrick T Gomella More articles by this author , Bradley R WebsterBradley R Webster More articles by this author , Beth RyanBeth Ryan More articles by this author , Deborah NielsonDeborah Nielson More articles by this author , Christopher J RickettsChristopher J Ricketts More articles by this author , Jeffrey W NixJeffrey W Nix More articles by this author , Gennady BratslavskyGennady Bratslavsky More articles by this author , Adam R MetwalliAdam R Metwalli More articles by this author , Rabindra GautamRabindra Gautam More articles by this author , Ashkan MalayeriAshkan Malayeri More articles by this author , Maria J MerinoMaria J Merino More articles by this author , Peter A PintoPeter A Pinto More articles by this author , Ramaprasad SrinivasanRamaprasad Srinivasan More articles by this author , Mark W BallMark W Ball More articles by this author , and W Marston LinehanW Marston Linehan More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002063.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) is a hereditary condition in which affected individuals are at risk for the development of renal cysts, renal tumors and renal cysts with mixed cystic/solid tumors. The renal tumors can be an aggressive, early onset form of renal cell carcinoma (RCC) which has a propensity to metastasize when the primary tumors are small. We report our clinical experience in management of patients who presented with known or suspected HLRCC-associated RCC. METHODS: Patients with HLRCC-associated renal tumors who had surgical management at our institution between 1989 and 2021 were reviewed. Survival time to endpoint was estimated with a Kaplan-Meier method. RESULTS: Sixty-four patients underwent 90 renal surgeries for HLRCC-associated renal tumor. The median age at first renal surgery was 42.9 years (range 18-78 years) and median follow-up period was 58 months. All tested patients (61/64) had documented fumarate hydratase germline pathogenic variation. Two patients (3%) were in their teens, nine (14%) in their twenty’s and three (5%) had their first tumor in their seventies. Twenty-nine patients (45%) had multifocal disease, fifteen (23%) had bilateral disease. Four patients (6%) presented de novo with bilateral multifocal disease, at a median age of 34 years old. Nine patients (14%) subsequently developed additional new renal tumors without disease progression with a median renal tumor free interval of 213 months (95% CI 147-NR). The renal tumors, which were predominantly type 2 papillary renal cell carcinoma, have a propensity to metastasize even when as small as 0.5cm. As the tumors are often infiltrative into the normal renal parenchyma and through the renal capsule, we performed most with open surgical procedures with wide surgical margins. CONCLUSIONS: HLRCC-associated kidney cancers are clinically aggressive and can be early onset, bilateral and multifocal. We recommend lifelong annual MRI imaging starting at age 8 and we do not recommend active surveillance when even a small tumor is identified. When surgery is indicated, we recommend an open procedure with wide margins and intraoperative ultrasound to search for multifocal disease. Source of Funding: NA © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e779-e779 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexis Rompre-Brodeur More articles by this author Jeunice Owens-Walton More articles by this author Sandeep Gurram More articles by this author Patrick T Gomella More articles by this author Bradley R Webster More articles by this author Beth Ryan More articles by this author Deborah Nielson More articles by this author Christopher J Ricketts More articles by this author Jeffrey W Nix More articles by this author Gennady Bratslavsky More articles by this author Adam R Metwalli More articles by this author Rabindra Gautam More articles by this author Ashkan Malayeri More articles by this author Maria J Merino More articles by this author Peter A Pinto More articles by this author Ramaprasad Srinivasan More articles by this author Mark W Ball More articles by this author W Marston Linehan More articles by this author Expand All Advertisement Loading ...

EARLY AND LATE POSTOPERATIVE COMPLICATIONS IN PATIENTS WITH LOCALIZED AND LOCALLY ADVANCED RENAL CELL CARCINOMA

Background: Modern Russian statistics show that the percentage of renal cell carcinoma (RCC) among all oncological diseases has increased and amounted to almost 5% in 2019. The main method of treating RCC is radical nephrectomy in localized RCC, which is supplemented by the removal of regional lymph nodes in locally advanced RCC. Aim: To evaluate early and late postoperative complications in patients with localized and locally advanced renal cell carcinoma. Methods: We’ve analyzed the results of surgical treatment and postoperative complications in 378 patients with clinically proven localized and locally developed RCC. Results: The total number of complications after surgical treatment of patients with localized and locally advanced RCC was 24 (6.3%) patients. Moreover, in the treatment of the localized form of RCC, postoperative complications are 3 times less common than in the locally advanced form of RCC (p &lt;0.05). The most common complication after surgical treatment of RCC was bleeding which we observed in 11(2.9%) patients. Conclusion: After surgical treatment of RCC, the proportion of complications is not high, but they can have unpleasant consequences. In the late postoperative period the most common complication bleeding is followed by lymphorrhea and urinary tract infections.

Glomeruli Sparing Pattern of Unclassified Renal Cell Carcinoma: A Rare Neoplasm

Unclassified renal cell carcinoma (URCC), an aggressive form of renal cell carcinoma (RCC), represents 0.7– 5 .7% of renal tumours. Glomerular sparing in renal neoplasms (GS) is defined as a unique growth pattern in which tumour cells overrun intact glomeruli.&#x0D; An elderly woman presented with symptoms of left flank pain for three months along with fullness in the abdomen. On clinical and radiological examination, a renal mass was revealed and operated upon. A diagnosis of URCC with a glomerular sparing pattern was made on histopathological examination. The pathological details of this rare neoplasm are presented in this article.

Patients with sarcomatoid renal cell carcinoma – re-defining the first-line of treatment: A meta-analysis of randomised clinical trials with immune checkpoint inhibitors

BackgroundSarcomatoid renal cell carcinoma (sRCC) represents a rare form of renal cell carcinoma marked by an aggressive biology, poor prognosis and little benefit from anti-angiogenic targeted therapy. More promising results come from the recent therapeutic strategy based on immune checkpoint inhibitor (ICI) combinations. Materials and methodsFor this meta-analysis, we searched MEDLINE/PubMed, the Cochrane Library and American Society of Medical Oncology (ASCO) Meeting abstracts for phase II or III randomised clinical trials. Data extraction was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis statement. The hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) with the relative 95% confidence intervals were extracted from studies. Summary HRs were calculated using random- or fixed-effects models, depending on the heterogeneity of the included studies. ResultsFour studies were selected for final analysis, including 467 patients (226 treated in with ICI combinations and 241 received sunitinib in the control arms). ICI-based combinations were associated with an improved PFS and OS compared with sunitinib, with a reduction of more than 40% of progression (HR = 0.56; p < 0.0001) and mortality (HR = 0.56; p = 0.001) risk. Moreover, ICI-based combinations are associated with a objective response rate (ORR) of more than 50% (versus 20% with sunitinib), corresponding to a doubled risk of achieving an ORR compared with controls (relative risk [RR] = 2.15; p < 0.00001). Finally, immunotherapy significantly increased the possibility to obtain complete responses (RR = 8.15, p = 0.0002) with an incidence of 11%. ConclusionOur data support the efficacy of ICI-based combinations for sRCC therapy, redefining the first-line treatment.

Clinicopathological Findings on 28 Cases with XP11.2 Renal Cell Carcinoma

Xp11.2 translocation carcinoma is a distinct subtype of renal cell carcinoma characterized by translocations involving the TFE3 gene. Our study included the morphological, immunohistochemical and clinicopathological examination of 28 Xp11.2 RCCs. The immunophenotype has been assessed by using CA9, CK7, CD10, AMACR, MelanA, HMB45, Cathepsin K and TFE3 immunostainings. The diagnosis was confirmed by TFE3 break-apart FISH in 25 cases. The ages of 13 male and 15 female patients, without underlying renal disease or having undergone chemotherapy ranged from 8 to 72. The mean size of the tumors was 78.5 mm. Forty-three percent of patients were diagnosed in the pT3/pT4 stage with distant metastasis in 6 cases. Histological appearance was branching-papillary composed of clear cells with voluminous cytoplasm in 13 and variable in 15 cases, including one tumor with anaplastic carcinoma and another with rhabdoid morphology. Three tumors were labeled with CA9, while CK7 was negative in all cases. Diffuse CD10 reaction was observed in 17 tumors and diffuse AMACR positivity was described in 14 tumors. The expression of melanocytic markers and Cathepsin K were seen only in 7 and 6 cases, respectively. TFE3 immunohistochemistry displayed a positive reaction in 26/28 samples. TFE3 rearrangement was detected in all the analyzed cases (25/25), including one with the loss of the entire labeled break-point region. The follow-up time ranged from 2 to 300 months, with 7 cancer-related deaths. In summary, Xp11.2 carcinoma is an uncommon form of renal cell carcinoma with a variable histomorphology and rather aggressive clinical course.

Potential Impact of Sickle Hemoglobin Concentration on Survival Among Patients with Renal Medullary Carcinoma and Sickle Cell Trait

Background: Renal medullary carcinoma (RMC) is a rare, aggressive form of renal cell carcinoma almost exclusively (&gt;90%) diagnosed in individuals with sickle cell trait (SCT), and 2/3 of those affected are male. Based on population-surveillance data, only 246 patients were diagnosed with RMC between 2005-2014 (Carden etal. J Sickle Cell Disease and Hemoglobinopathies, 2018) and many patients have metastatic disease at diagnosis (Msaeoul et al., Clin Genitourin Cancer, 2019). Median overall survival (OS) in patients with metastatic RMC (mRMC) at diagnosis is less than 12 months and predictors of survival are largely unknown, although case reports suggest novel chemotherapeutic strategies are important (Carden et al., Ped Blood Cancer, 2017&amp;2018). The role SCT plays in RMC pathobiology, however, is largely unknown, as many patients do not have a complete hemoglobin subtype profile completed at diagnosis. Studies evaluating sickle hemoglobin concentrations (%HbS) in relation to survival for patients with RMC are needed, as SCT is associated with renal dysfunction and researchers have hypothesized that HbS polymerization within red cells traversing the kidney disrupts blood perfusion, which leads to kidney injury and an increased possibility for cancer formation (Msaeoul et al, Clin Cancer Res, 2018). Patients with %HbS≤36%, such as patients with SCT and concomitant alpha-globin gene deletion(s) might be protected against HbS polymerization and renal concentrating defects (Gupta etal., J Clin Invest, 1991). We hypothesize that lower %HbS is associated with higher survival. In this preliminary multi-institutional study, we retrospectively reviewed available charts from patients diagnosed with mRMC and SCT to evaluate for an association between %HbS and OS. Methods: We found nine patients (3 adults, 6 children) who were diagnosed with mRMC and SCT at our various institutions between 2002-2017 who had survival data. Eight patients had %HbS levels by hemoglobin quantification at diagnosis. In a post-hoc analysis, patients were separated into two groups (%HbS&gt;36% and %HbS≤36%), levels similar to that found in patients with alpha-globin gene deletions described by Gupta et al. Fit-curves were determined for OS vs. %HbS. Three-year OS was determined using Kaplan-Meier analysis and the log-rank method. P&lt;0.05 was considered statistically significant. Results: Clinical characteristics of patients are shown in Table 1. Average age (standard deviation) at diagnosis was 15.2 years (4.9) and most patients were male (87.5%). Six patients had %HbS &gt;36% and 2 patients had %HbS ≤36%. Median OS was 17.8 months. Using fit-function testing, analysis of survival vs. %HbS yielded an exponential relationship (R2=0.69), suggesting higher survival when %HbS≤36% (p=0.05). OS of the two patients with %HbS≤36% was greater than those with %HbS&gt;36%, though results were not statistically significant (p = 0.09). Conclusion: While there are limitations to this small, retrospective analysis, these data suggest that lower intracellular red cell %HbS concentrations could be protective in patients with mRMC and SCT. Chemotherapy and other treatment regimens may also play a role in survival and need to be studied. Further investigation is needed to determine the role SCT plays in RMC pathobiology and to determine if %HbS concentrations, as well as alpha-thalassemia deletion(s), may be protective in patients with RMC. Disclosures Carden: GBT: Honoraria; NIH: Research Funding.

Key miRNAs and target genes played roles in the development of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (CCRCC) is the most aggressive form of renal cell carcinoma (RCC). This study was aimed to identify the differentially expressed miRNAs and target genes in CCRCC. The miRNA and mRNA next-generation sequencing data were downloaded from The Cancer Genome Atlas (TCGA) dataset. Differential expression analysis was performed, followed by correlation analysis of miRNA-mRNA. Functional enrichment and survival analysis was also performed. Seven hundred and eighty-seven patients with CCRCC from TCGA data portal were included in this study. A total of 52 differentially expressed miRNAs were identified in CCRCC. Then 2361 differentially expressed genes (DEGs) were identified. Prediction analysis and correlation analysis revealed that 89 miRNA-mRNA pairs were not only predicted by algorithms but also had a significant inverse relationship. Several differentially expressed miRNAs such as hsa-mir-501 and their target genes including AK1, SLC25A15 and PCDHGC3 had a significant prognostic value for CCRCC patients. Alterations of differentially expressed miRNAs and target genes may be involved in the development of CCRCC and can be considered as the prognostic markers for CCRCC.

Characterization and Evaluation of Sunitinib and Janus Kinase Inhibitors in a Renal Cell Carcinoma Cell Line, Caki‐2

Kidney cancer is one of the leading cancers detected in middle‐aged men and women. The clear‐cell form of renal cell carcinoma (RCC) is the deadliest form of urogenital cancer; 5‐year prognosis once metastasis has occurred is only 5%. The main challenge of RCC diagnosis is that most symptoms of kidney cancer only appear after it has advanced to metastasis, the most common subtype being clear cell renal carcinoma (ccRCC). At this point, the cancer may have already gained resistance to current treatments. One intracellular signaling pathway, the Janus kinase 2 and signal transducers and activator of transcription 1 and 3 (JAK2/STAT1&amp;3) pathway, has already been implicated in multiple other cancers and is involved in perpetuating many hallmarks of cancer including evasion of apoptosis, angiogenesis, tissue invasion, and metastasis. Microtubule associated protein 7 (MAP7) is a protein involved in tubulin and microtubule stability. High MAP7 expression has been correlated with poor prognosis in colon cancer. Additionally, MAP7 has been shown to be involved in chemo resistance via a STAT1 mechanism. Therefore, we hypothesized that increased MAP7 expression via increased JAK/STAT signaling is a cause of increased chemo resistance and cell proliferation in RCC. Therefore, inhibition of this pathway should increase efficacy of current chemotherapies. Available drugs demonstrate different molecular and physical reactions in RCC cells such as those that effect the cancer promoting unregulated JAK/STAT pathway. MTT analysis of the commercial ccRCC cell line, Caki‐2, with a current chemotherapy drug, sunitinib, shows increased cell viability prior to reaching its EC50 value at 24, 48, and 72 hours of 30 uM, 16.5 uM, and 12 uM, respectively, suggesting therapy resistant mechanisms are taking place. When the known JAK inhibitor Zerumbone was evaluated in Caki‐2 via MTT analysis, EC50 values were 175 uM, 32 uM, and 15 uM at 24, 48, and 72 hours, respectively, with increased cell viability observed only in the 24 hour assay. When these two drugs are used in combination with Caki‐2, MTT data suggests resistance to sunitinib and zerumbone exists in Caki‐2 and co‐treatment aided the ability to decrease cell viability by sunitinib, but not Zerumbone. Based on these results, more studies must be completed to determine whether the inhibition of JAK would be a viable and effective option in treatment of RCC. However, preliminary evaluation of Zerumbone in combination with sunitinib has not proven to be effective.Support or Funding InformationOakland University Center For Biomedical Research, Zafarna Grant, Oakland University Honors CollegeThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A phase 2 study of cabozantinib as first-line treatment in collecting ducts renal cell carcinoma: The BONSAI trial.

TPS709 Background: Collecting ducts carcinoma (CDC) is a rare and aggressive form of renal cell carcinoma, characterized by extremely poor prognosis and resistance to agents effective in other forms of RCC. We hypothesized that cabozantinib, an inhibitor of multiple kinases including VEGFR 2, MET and AXL, may be superior in terms of efficacy to other angiogenesis inhibitors in the treatment of CDC due to its high-spectrum of activity against multiple and non-redundant oncogenic pathways. Methods: The BONSAI study is a prospective, single-centre, single-arm phase II trial evaluating cabozantinib in patients with untreated locally advanced or metastatic CDC. Cabozantinib will be administered at the dose of 60 mg orally once daily until the evidence of disease progression (PD) evaluated by RECIST 1.1 or unacceptable toxicity. Primary objective is the evaluation of objective response rate (ORR). Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety profile of cabozantinib. Exploratory objectives include the evaluation of genetic and immunological landscape of CDC and its correlation with response to treatment. Overall, 23 patients will be enrolled into the study based on a Simon’s two-stage optimal design. In order to reject an ORR equal to 15% with a one-sided alpha error of 10% and to detect an ORR equal to 35% with a power of 80%, 9 patients will be enrolled in the first stage. If at least 2 responses will be observed in the first stage, 14 additional patients will be included in the second stage. If at least 6 responses will be observed at the second stage the activity of cabozantinib will be proved. First patient enrollment is scheduled in November 2017.

The role of biological oncomarkers in the differential diagnosis of complex kidney cysts

The renal cell carcinoma (RCC) ranks first place in mortality among urogenital tumors, and the incidence is third after prostate and bladder cancer. The cystic form of renal cell carcinoma is 5–7%, and according to recent data – even 10% of all kidney tumors. The early diagnosis of RCC allows for effective treatment, which significantly increases survival.Early and accurate diagnosis helps to avoid inadequate treatment, provides a favorable prognosis for progression of the disease and allows for more effective therapy. Most of the renal tumors, including cystic, are diagnosed accidentally during an examination for other reasons. Small tumors are usually asymptomatic, which leads to late diagnosis, and consequently, to the low effectiveness of treatment.Thus, the need for the use of sensitive biomarkers for early diagnosis of RCC and monitoring of its progression is clearly followed. Nowadays, many attempts have been made by scientists to identify a new informative kidney tumor biomarker that could be used for early diagnosis and disease progression, as well as prognostic capabilities. This overview summarizes the latest advances in the discovery of these biomarkers and their clinical value.