bluuebunny/crossref_metadata_2025 huggingface dataset:
Pembrolizumab plus lenvatinib vs nivolumab plus cabozantinib in patients with metastatic renal cell carcinoma: A matching adjusted indirect comparison (MAIC).
Authors: Rane Pratik , Walton Laura , Schmidinger Manuela , Peer Avivit , Mt-Isa Shahrul , Burgents Joseph E. , Sundaram Murali
Published: January 2024

399

Background: Nivolumab plus Cabozantinib (nivo/cabo) and Pembrolizumab plus Lenvatinib (pem/len) have been approved and available for patients in first-line metastatic renal cell carcinoma (RCC). There is no direct evidence of the relative efficacy between pem/len and nivo/cabo from head-to-head clinical trials. Therefore, we conducted MAIC to better inform clinical decision-making on treatment choices. Methods: Individual patient data in the intention to treat (ITT) population from KEYNOTE-581 (pem/len vs. sunitinib; 50.1 months median follow-up) were compared to published aggregated data in the same population from CheckMate-9ER (nivo/cabo vs. sunitinib; 44 months median follow-up). Efficacy outcomes compared were overall survival (OS), progression free survival (PFS), objective response rate (ORR) and complete response (CR). Effect modifiers identified included liver/bone metastasis, sarcomatoid features and IMDC risk category. Using a MAIC, KEYNOTE-581 data were reweighted to match the effect modifiers distribution of CheckMate-9ER participants. Then, matching-adjusted hazard ratios (HR) for OS and PFS, and risk difference (RD) for ORR and CR of pem/len vs. sunitinib were calculated using the reweighted KEYNOTE-581 data. Bucher method was subsequently applied to indirectly compare pem/len to nivo/cabo on these outcomes. Two-sided p-values were calculated. Results: MAIC analyses show that, while OS were comparable between treatments (HR: 1.06 [95% CI:0.77,1.48]; p=0.7072), PFS (HR: 0.75 [95% CI:0.56,0.99]; p=0.0457) and ORR (RD: 11.29 [95% CI:1.10,21.49]; p=0.030) showed a statistically significant result in favor of pem/len when compared to nivo/cabo. The CR rate among pem/len users was higher compared to nivo/cabo but was not statistically significant (RD: 5.75 [95% CI:-0.64,12.15]; p=0.078). Conclusions: In first-line metastatic RCC patients, the MAIC shows a statistically significant result in favor of Pembrolizumab plus Lenvatinib in PFS and ORR, and comparable CR and OS benefit.
Kidney cancer metastases to breast and other genitourinary (GU) organs: A pooled analysis.
Authors: Taboada Phillip , Lee Matthew , Smith Parker , Wang Jue
Published: January 2024

401

Background: As the number of kidney cancer survivors increases, the appearance of second malignancies and unusual metastatic patterns is increasing. We performed a pooled analysis to assess the clinicopathologic findings, treatment, and outcomes of cases involving breast and GU organs. Methods: Pooled analysis of published case reports and case series of renal cell carcinoma (RCC) metastasis to breast and genitourinary (GU) organs, including four cases from our institution. Parameters were compared between GU organ cohorts using a one-way ANOVA test and subgroup analysis. Results: 127 patients with GU metastasis of RCC were analyzed. The overall mean age was 61.2 years (Range: 14-92). GU organs with reported metastasis included 24 to testis (18.9%), 18 to penis (14.2%), 18 to breast (14.2%), 17 to vagina (13.4%), 17 to bladder (13.4%), 14 to ovary (11%), 7 to prostate (5.5%), and 6 to urethra (4.7%). Median Fuhrman grade was 2.5 overall, with penis metastases (n=4) having a median grade of 4. 95 of 111 (86%) cases reported patients with GU metastasis that had a prior nephrectomy for RCC. Patients with breast metastasis (n=16) had a significantly longer time between nephrectomy and metastatic diagnosis (90.1±63.1 months) than penile (12.7±16.1 months, n=6, p<0.01), bladder (28.7±26.6 months, n=15, p<0.01), or vaginal cohorts (6.7±5.2 months, n=3, p<0.05). Co-metastasis to extra-GU sites were most prevalent in penile metastasis (47.4%, n=9). The primary treatments for metastases were excisional surgery (79%), immunotherapy (18%), radiotherapy (14%), and tyrosine kinase inhibitors (13%). The breast cohort (n=10) reported a 90% survival rate at final follow-up, while the vaginal (n=8) and penile (n=12) cohorts reported survival rates of 50%. The urethra cohort (n=2) had a median survival time of 53 months, while the breast cohort (n=10) had a median survival time of 6 months. Conclusions: While kidney cancer's metastasis to other GU organs is relatively uncommon, it presents unique diagnostic and therapeutic challenges. Recognizing these patterns and understanding the biology behind such spread can offer insights into RCC's behavior and drive more effective treatments. [Table: see text]
Real world data on treatment of chromophobe renal cell carcinoma.
Authors: Battle Dena , Griffith Meghan , Msaouel Pavlos , Voss Martin H , Staehler Michael D.
Published: January 2024

409

Background: Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma (RCC), accounting for 5%–7% of all RCCs. ChRCCs are generally viewed to have a favorable clinical outcome compared to clear cell RCC, yet up to 10% of patients with ChRCC will develop metastases. To date, there are no genomic biomarkers that predict post-surgical metastatic recurrence, and no standard of care exists for treating metastatic chRCC. We sought to better understand real world patient experiences in this underrepresented and understudied patient population. Methods: The survey was developed by the Kidney Cancer Research Alliance (KCCure) and was broadcast between 07/2022 and 09/2022 to patients via website, mailing lists and social media platforms. Those who agreed to participate were surveyed for demographics (age, gender, race, income, country) and clinical characteristics (date of the diagnosis, disease stage, treatment history). Out of 1,062 participants 121 patients self-identified with chRCC, 34 patients had metastatic disease, and 23 patients had received systemic therapy. Results: The majority of patients were from the United States (75%), median age was 49.7 years (range 19-74), 70 percent of patients identified as female, and 30 percent of patients identified as male. Stage distribution at initial diagnosis was stage 1 in 37.3%, 27.3% were stage 2 and stage 3 respectively, 8.3% were metastatic at diagnosis. 14% of patients reported having sarcomatoid dedifferentiation. 20 percent of patients (24) experienced recurrent metastatic disease after a median duration of 3.3 years (range 1-6). Of the 23 patients who received treatment, first line therapy consisted of TKI monotherapy (9), combination IO and TKI (7), combination IO/IO (4), mTOR mono-therapy (1), other therapies (2). Second and later line therapies were combination IO/IO (3), IO and TKI (9), Lenvatinib and everolimus (7), TKI monotherapy (5), mTOR monotherapy (5) and other therapies (5). Median duration of therapy was 43 months (range 2-196). The most used TKIs were cabozantinib and lenvatinib. In the metastatic setting, 4 patients reported being treated as part of a clinical trial, 9 patients reported that no one had ever talked to them about participating in a clinical trial. 6 patients said that no trials were being held at their treating center. Conclusions: Patients reported higher rates of recurrence than what is usually reported in ChRCC, however this could reflect sample bias as patients with more aggressive disease may be more likely to engage with patient communities. No standardized treatment for metastatic disease could be identified. Overall treatment duration was comparable to clear cell carcinoma. Very few patients had access to clinical trials. ChRCC-specific clinical trials and tailored treatment regimens are urgently needed.
Final results of a phase I trial of HERV-E TCR transduced T cells for the treatment of HLA-A*11 patients with metastatic clear cell renal cell carcinoma (mccRCC).
Authors: Nadal Rosa , Barisic Stefan , Scurti Gina M. , Cherkasova Elena , Chen Long , Wood Kristen , Highfill Steven L. , Wells Brian , Aue Georg , Shalabi Reem , Hughes Thomas E. , Tian Xin , Xu Yifei , Malayeri Ashkan A. , Reger Robert N. , Nishimura Michael I. , Childs Richard W.
Published: January 2024

435

Background: Human endogenous retrovirus type E (HERV-E) is specifically expressed in ccRCC providing a safe target for T cell-based therapies. We investigated T cells transduced with a TCR targeting HERV-E (HERV-E T cells) for the treatment of mccRCC. Methods: This first-in-human study assessed the safety & efficacy of escalating doses of HERV-E T cells and manufacturing/clinical endpoints correlative analysis. HLA-A*11+ mccRCC patients (pts) were treated with a conditioning regimen, infusion of HERV-E T cells & IL-2. (NCT03354390). Results: Nineteen of185 pts tested were found to express HLA-A*11. 17 HLA-A*11 + pts enrolled on the study: 3 pts on each DL1-3 & 6 pts on DL4. 2 pts did not receive HERV-E T cells given disease progression during manufacturing period. Median age was 57 years. 86% received ≥ 3 prior systemic treatment (range 1-8). The manufacturing failure rate after first apheresis was 12% (n=2); both met target dose after second apheresis and repeat in vitro expansion. All HERV-E T cell products met release criteria for infusion including INF-γ production in response to HERV-E/HLA-A11-expressing tumor cells. Median HERV-E vector copy number (VCN) was 1.9. No dose-limiting toxicities (DLT), off-target toxicities or treatment-related deaths occurred. Pt#17 is on DLT monitoring period. 7 pts completed the planned 14 doses of IL-2 and all received at least 8 doses. Reasons for IL-2 discontinuation: hemodynamic (57%), cardiovascular (28%), pulmonary (28%), renal (14%) criteria & pts decision (14%). The best response was partial response in 7% & stable disease at least 8 weeks in 29% pts. HERV-E mRNA expression was detected in 5 primary & 9 metastatic specimens. HERV-E T cells were measurable in circulation post-dosing, with peak concentrations in the peripheral blood mononuclear compartment on day(D)+7. [DL1: 0.3 %, DL2: 1.2%, DL3: 0.5%, DL4: 12.3%]. Median HERV-E T cell VCN showed no correlation with HERV-E T cells peak concentration on D+4 & D+7. Conclusions: Proof of concept that HERV-T cells can induce tumor regression without evidence of causing off-target toxicities has been established by this trial. Infused HERV-E T cells were detectable transiently in vivo and induce effector cytokine production. Our initial results support the further development of HERV-E-directed therapies that focus on methods to improve in vivo persistence of TCR engineered T-cells and to target HERV-E antigens expressed on more commonly expressed HLA alleles.[Table: see text]
Breaking boundaries: Exploring extended pembrolizumab in first-line treatment of renal cell carcinoma with axitinib-pembrolizumab combination.
Authors: Aydogdu Can , Paffenholz Pia , Stelmach Ramona , Schlack Katrin , Roghmann Florian , Handke Analena , Mandal Subhajit , Schnabel Marco , Merseburger Axel , Ivanyi Philipp , Zschaebitz Stefanie , Darr Christopher , Grünwald Viktor , Stief Christian G. , Casuscelli Jozefina
Published: January 2024

436

Background: The standard first-line treatment for metastatic renal cancer (mRCC) combines immune checkpoint- (ICI) and tyrosine kinase inhibitors (TKI). While TKI therapy continues until disease progression, ICI treatment is typically stopped after 24 months or 35 cycles, aligning with approval study criteria. However, in real-world practice, the decision to discontinue ICI therapy upon achieving a positive response can be distressing for both patients and healthcare providers; thus ICIs are not stopped. We conducted an initial analysis of prolonged pembrolizumab (Pem) use in axitinib-pembrolizumab (Axi-Pem) combination therapy to evaluate its effects and toxicity. Methods: We retrospectively analyzed data from mRCC patients treated with first-line Axi-Pem in 10 German tertiary care centers between 2019 and 2023. After completing 35 cycles or 24 months of Pem, patients were offered continued ICI therapy if positive response was assessed. We calculated objective response rate (ORR) and progression-free survival (PFS) from the treatment start to achievement of 36 therapy months. Adverse events (irAEs) were reported following CTCAE 5.0 criteria. Results: Out of 72 patients, 27 met strict eligibility criteria from the Keynote-426 study (NCT02853331), with a response at 24 months and continuous Pem therapy. Patients had a median age of 65.7 years (range: 34-84), and IMDC risk was favorable/intermediate/poor in 22.2%/55.5%/18.5%. Median follow-up was 33.2 months (range: 25.3-48.4). At the 36-mos landmark, median PFS was not reached (PFS 64.7%), ORR was 63.6%, with complete response, partial response, and stable disease observed in 9.1%(1)/54.5%(6)/9.1%(1) of cases, respectively. Permanent Pem discontinuation occurred due to progressive disease in two cases and complete response in one case. Another case led to Pem discontinuation due to immune-related toxicity. Conclusions: In our selected real-world patient cohort seeking prolonged ICI therapy, responders who received continuous Pem beyond 24 months achieve sustained efficacy in first-line treatment. Furthermore, the incidence of irAEs does not increase with prolonged exposure to ICI therapy. Additional results beyond the 36-month landmark are urgently needed to further support the clinical necessity and feasibility of ongoing ICI treatment in light of its impact on the overall financial burden of cancer care.
Lenvatinib plus everolimus (LenEve) in patients with pre-treated advanced renal cell carcinoma (mRCC): Real world evidence (Relevance).
Authors: Ivanyi Philipp , Eggers Hendik , Stelmach Ramona , Boegemann Martin , Strauß Arne , Thomas Christian , Landmesser Johannes , Kramer Mario W , Zschaebitz Stefanie
Published: January 2024

437

Background: The therapeutic armamentarium in mRCC underwent a rapid change during the recent past. LenEve, proved to be effective as subsequent treatment in mRCC in clinical trials.Here, we evaluate efficacy and safety in mRCC patients in a real-world setting. Methods: mRCC patients who started LenEve treatment between 08/2016 and 12/2021 at 6 tertiary German centers were retrospectively analyzed. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR), were evaluated per local investigator. Subgroup analyses by risk scores, previous therapies and initial dosing were performed. Results: Eighty-one patients were assessed: Median age was 61 years (range 42-80), 81.5% were males, ECOG score was 0 to 1 in 80.2%. Synchronous metastases were found in 39.5% of patients. The median number of treatment lines prior to LenEve was 3. Median treatment duration with LenEve was 6.1 months (range 0.2-29.2). The ORR, DCR, median OS and PFS was 28.4%, 61.7%, 11.3 months (95% CI 8.7-13.9) and 6.5 months (95% CI 5.4-7.6), respectively. Across patients with 0-2 compared to ≥3 previous therapeutic lines median PFS, OS and ORR were similar, as well as for patients with or without previous immunotherapy. Safety was manageable, with 6.2% of patients discontinuing treatment due to treatment related adverse events. Conclusions: High efficacy in second- and later-line in a heavily pre-treated real-world cohort of mRCC patients was demonstrated by LenEve, regardless of treatment line, IMDC risk group, initial dosing or previous treatment with immunotherapy.
Upfront (uCN) vs. deferred (dCN) cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (mRCC): A systematic review and individual patient data (IPD) meta-analysis of 3323 patients.
Authors: Esagian Stepan M. , Karam Jose A. , Msaouel Pavlos , Makrakis Dimitrios
Published: January 2024

440

Background: Despite the well-established role of CN in the management of mRCC, the optimal timing of CN in regard to systemic therapy remains unclear. Methods: We systematically searched the MEDLINE, EMBASE, and Web of Science databases until August 26th, 2023, for studies comparing uCN and dCN and reconstructed overall survival (OS) IPD from their published Kaplan-Meier survival curves. We then performed one-stage and two-stage meta-analyses of OS, using parametric and non-parametric effect estimates. Landmark analyses using 6-month and 12-month cutoffs were used to account for immortal time bias. We also performed subgroup analyses according to MSKCC/IMDC risk and systemic therapy type. The risk of bias was assessed using the ROBINS-I and RoB2 tools. Results: We identified twelve studies (ten retrospective cohort and two randomized controlled trials) eligible for inclusion. Only two out of ten retrospective studies adjusted for immortal time bias and none of them appropriately adjusted for all predetermined confounding factors. A total of 3323 (2610 uCN and 713 dCN) patients were included in our analysis. Baseline characteristics, including age, gender, histology, IMDC/MSKCC risk score, and location of metastases were comparable between the two groups; the dCN group had more patients with ≥2 metastases (65.4% vs. 47.6%). Deferred CN was associated with superior OS in the one stage (HR: 0.75, 95% CI 0.67–0.84), 6-month landmark (HR: 0.74, 95% CI 0.65–0.84), 12-month landmark (HR: 0.78, 95% CI 0.68–0.91) and two-stage (HR: 0.69, 95% CI 0.58–0.84) meta-analyses. Similarly, dCN was associated with superior OS in the TKI-treated (HR: 0.61, 95% CI 0.51–0.74), ICI-treated (HR: 0.67, 95% CI 0.46–0.97), and intermediate IMDC/MSKCC risk (HR: 0.73, 95% CI: 0.55–0.97) subgroups. Conclusions: Deferred CN for the treatment of mRCC is associated with superior overall survival compared to uCN. Randomized studies are warranted to validate or refute these findings. Further studies to establish predictive models are needed to optimize selection of mRCC patients most likely to benefit from dCN. [Table: see text]
Response evaluation criteria in PSMA PET/CT (RECIP 1.0) in metastatic castration-resistant prostate cancer.
Authors: Gafita Andrei , Djaileb Loic , Rauscher Isabel , Fendler Wolfgang P. , Hadaschik Boris A. , Rowe Steven P. , Herrmann Ken , Calais Jeremie , Rettig Matthew , Eiber Matthias , Weber Manuel , Benz Matthias R. , Farolfi Andrea
Published: January 2024

45

Background: Response Evaluation Criteria in Prostate-Specific Membrane Antigen (PSMA) PET/CT (RECIP 1.0) initially integrated software-based quantitative assessment of PSMA-positive total tumor volume (PSMA-VOL). Clinical implementation of such software is not expected soon, limiting the use of RECIP in practice. This study aimed to assess the agreement of RECIP determined using tumor segmentation software (quantitative RECIP) with RECIP determined by qualitative reads by nuclear medicine physicians (visual RECIP) for response evaluation in metastatic castration-resistant prostate cancer. Methods: This multicenter retrospective study at three academic centers included patients who received lutetium-177 (177Lu) PSMA treatment between December 2014 and July 2019. PSMA PET/CT images at baseline and 12 weeks were assessed qualitatively by five nuclear medicine physicians for changes in PSMA-VOL and for new lesions. Quantitative changes in PSMA-VOL were also measured using tumor segmentation software. The status of new lesions was combined with qualitative changes in PSMA-VOL to determine visual RECIP and with quantitative changes in PSMA-VOL to determine quantitative RECIP. The primary outcomes were the agreement between visual and quantitative RECIP and the interreader reliability of visual RECIP according to the Fleiss κ. The secondary outcome was the association of visual RECIP with overall survival according to Cox regression. Results: A total of 124 patients (median age, 73 years [IQR, 67–76 years]) were included. Forty (32%) and 84 (68%) patients had quantitative RECIP progressive disease (PD) and non-PD, respectively. Agreement between visual versus quantitative RECIP was excellent (κ=0.89; 118 of 124 patients [95%]). Agreement among readers in classifying visual RECIP PD versus non-PD was excellent (κ=0.81; 103 of 124 patients [83%]). RECIP-PD was associated with significantly shorter overall survival compared with RECIP-nonPD (hazard ratio, 2.6 [95%CI: 1.7, 3.8]; P <.001). Conclusions: Qualitatively assessed RECIP demonstrated excellent agreement with quantitative RECIP and excellent interreader reliability, and can be readily implemented in clinical practice for response evaluation in patients with metastatic castration-resistant prostate cancer undergoing 177Lu-PSMA therapy and possible other systemic therapies.
Association of microbial metabolism of tryptophan with resistance to immune checkpoint (ICB) therapy in renal cell cancer (RCC).
Authors: Bari Shahla , Manley Brandon J. , Muzaffar Jameel , Sarfraz Humaira , Armstrong Andrew J. , Tannir Nizar M. , George Daniel J. , Conejo-Garcia Jose
Published: January 2024

452

Background: Metastatic RCC has a poor prognosis. Despite improvement in treatment outcomes with ICB and targeted therapy, many patients fail to respond to first line therapy and durable responses remain elusive. The tryptophan metabolite kynurenine, an agonist of the immunosuppressive aryl hydrocarbon receptor (AhR), is associated with resistance to ICB. However, IDO (Indole 2,3 dioxygenase) blockers which inhibit tryptophan metabolism to kynurenine failed to show benefit in clinical trials, suggesting the presence of alternate AhR activation. We hypothesize that microbial metabolism of tryptophan to indole metabolites may be associated with AhR activation and ICB resistance. Methods: We prospectively collected paired stool and blood samples of treatment naïve metastatic RCC patients, treated with ICB +/- Tyrosine kinase inhibitors (TKI) at treatment initiation and at time of first response assessment (12+/-3 weeks). We evaluated stool metagenomics and untargeted stool and plasma metabolomics among responders (R) and non-responders (NR). We focused on kynurenine/tryptophan and indoles/tryptophan ratio to evaluate differential host and microbial metabolism of tryptophan. A responder was classified as progression free survival (PFS) greater than 6 months. We also performed global metabolomics on tumor and plasma of germ-free (GF) & specific pathogen free (SPF) mice to identify microbial & host metabolites. Results: Among 120 patients accrued, baseline paired samples were analyzed from 99 patients, 39 were treated with combination ICB, while 60 patients were treated with ICB + TKI. Median follow up was 15 months. 65% of patients had PFS > 6 months. Using unpaired t test comparing baseline relative abundance of metabolites between R vs NR - plasma Kynurenine/tryptophan ratio was significantly higher in NR vs R, at baseline and at 3 months (baseline-0.042 vs 0.01, p=0.01, 3 months-0.058 vs 0.02, p=0.02). Microbial metabolites of Tryptophan -Indole pyruvic acid (IPA), Indole carboxylic acid (IcA), and Indole acetaldehyde (IAAld) were differentially associated with ICB resistance and was significantly higher in NR (IcA: 8.0 vs 5.2, p=0.03; IPA: 82.4 vs 64.9, p=0.01; IAAld: 78.7 vs 64.6, p=0.03). We also noted differential enrichment of microbial KEGG enzymes associated with IPA, IAAld and IcA production in the stool of NR patients compared to R. Microbial origin of these metablites was confirmed by its absence in tumor of GF mice. Conclusions: This is first study in metastatic RCC which shows the association of indoles (microbial metabolites of tryptophan) with resistance to ICB. These indoles are known to be potent AhR agonists and are associated with immunosuppression suggesting that microbial metabolism of tryptophan may represent a novel pathway for ICB resistance in RCC patients.
Endogenous retrovirus expression and its impact on tumor-infiltrating immune cells in papillary renal cell carcinoma.
Authors: Vento Joseph , Brewer Jared , Reddy Anupama , De Cubas Aguirre , Beckermann Katy , Rini Brian I. , Rathmell W. Kimryn , Haake Scott Mattox
Published: January 2024

453

Background: Endogenous retroviruses (ERVs) represent 5-8% of the human genome, and their expression in cancer cells correlates with response to immunotherapy in clear cell renal cell carcinoma (ccRCC). Whether this association also exists in papillary renal cell carcinoma (PRCC) is unknown. Studying ERV expression in PRCC and its impact on the tumor microenvironment (TME) may help elucidate its role in PRCC response to immunotherapy. Methods: We quantified ERV expression on human PRCC tissue samples using real-time quantitative PCR (RT-qPCR). ERV4700 was selected due its correlation with response to immunotherapy when expressed in ccRCC. In addition, we stained matched human FFPE tissue with 31 antibodies using multiplex immunohistochemistry (mxIHC) to investigate the TME. Using mxIHC protein expression levels, we generated a probabilistic cell classification algorithm to quantify immune cells. We investigated associations between ERV expression data, clinicopathologic variables, and immune cell proportions in the tumor samples using linear regression. Results: We performed ERV expression and mxIHC analysis on 104 PRCC nephrectomy samples from 1997-2016. After quality control, 78 unique patient tumor samples had results from both pipelines. Median patient age was 65 (IQR 56-71), 74.4% were male, and Fuhrman grade was 1 in 3.9%, 2 in 5.9%, 3 in 50.0%, and 4 in 9.0% of patients. Over a median follow-up of 3.03 years (IQR 0.61-6.99 years), 11.5% had recurrence after definitive local therapy, and 7.7% had an RCC-related death. Increased ERV expression correlated with increasing Fuhrman grade (r = 0.057, p <0.001), but not with disease recurrence or RCC-related death. Increased ERV expression was also associated with an increased TME proportion of cytotoxic T cells, memory T cells, and CD20+ B cells, and with a decreased TME proportion of macrophages (see Table 1). Conclusions: Higher expression of ERV4700 correlates with increased proportions of cytotoxic T cells in the TME of PRCC samples. Given its association with immunotherapy response in ccRCC, further studies are warranted to study ERV expression as a prognostic and predictive biomarker in PRCC. [Table: see text]
Tumor characteristics associated with detectable circulating tumor DNA preoperatively in patients with renal masses suspicious for RCC.
Authors: Ben-David Reuben , Alerasool Parissa , Kalola Hitasha , Tillu Neeraja , Tsao Kai , Galsky Matt D. , Attalla Kyrollis , Sfakianos John P. , Wiklund Peter , Waingankar Nikhil , Mehrazin Reza
Published: January 2024

461

Background: Understanding the specific tumor characteristics associated with detectable ctDNA in the blood of patients with renal cell carcinoma (RCC) is critical to informing future studies seeking to establish the clinical utility of such testing. We characterized pathological and clinical characteristics associated with ctDNA detected preoperatively in patients with renal masses suspicious of RCC. Methods: Using our single institution prospectively maintained database, we identified consecutive patients who underwent partial or radical nephrectomy for non-metastatic suspected RCC (stages cT1b-cT3) during 2022-2023. Included were patients who had undergone tumor-informed ctDNA testing using the commercial Signatera assay (Natera). Baseline characteristics, pathology results, imaging study results, and oncological treatment and follow-up data were collected from the electronic medical records. ctDNA results were collected through the Natera portal. Study findings were reported using descriptive statistics. A p-value of <0.05 was considered statistically significant. R programming language version 4.3 was used for all statistical analyses. Results: A total of 54 patients with a median age of 63 years (IQR 51-71) were included in the study. Twenty-one (39%) were women. The median follow-up time was 4 months (range: 1-21 months). Among the 54 patients, 27 (50%) had detectable ctDNA pre-operatively Post-operative results were available for 33 patients, and 3 (9%) had detectable tDNA (of those 2 had Inferior vena cava involvement). The first patient developed metastatic disease. The two other patients are receiving adjuvant immunotherapy. Analysis of 50 patients with solely malignant RCC revealed that patients with detectable versus undetectable ctDNA were older 67 vs. 54 years (p=0.03), had a higher pathological stage (p= 0.002), larger tumors (7.2 vs. 4.7 cm, p = 0.004), and higher pathological grade (grade 3-4 vs. grade 1-2; p=0.035) (Table 1). All the patients with renal vein or inferior vena cava involvement had detectable ctDNA (n=8). Conclusions: In our cohort, preoperative ctDNA was detectable in 50% of patients with suspected clinically localized RCC. Detectable ctDNA preoperatively correlated with clinically relevant features. The ability of preoperative ctDNA to predict recurrence and survival in patients with clinically localized RCC warrants further evaluation. [Table: see text]
Diversity among editorial boards of genitourinary oncology journals.
Authors: Arter Zhaohui , Mar Nataliya , Rezazadeh Arash , Benjamin David Joseph
Published: January 2024

481

Background: Several studies have evaluated the ethnic and gender diversity among editorial boards of academic journals in science and medicine, and revealed disparities among representation of historically underrepresented groups. However, the diversity among editorial boards in the field of genitourinary oncology remains unclear. Methods: Using the master journal list from Clarivate, we identified academic journals with a dedicated or primary focus in genitourinary cancers. We then identified the list of editorial board members on each journal’s website. We evaluated economic diversity based off each editor’s country of origin, and classified countries as high income based off World Bank listing for the 2024 fiscal year. We confirmed gender from each editor’s self-reported gender on his or her academic profile. Results: We identified 7 journals with a focus in genitourinary cancers. Among these journals, a total of 485 editor positions were identified, with 397 men (81.86%) and 80 women (16.49%). The gender of 8 individuals (1.65%) could not be confirmed. 28 editors (5.77%) were from countries not identified as high-income countries per World Bank criteria. Conclusions: There are disparities in country of origin among editors of genitourinary oncology journals, with a small proportion of editors originating from countries classified as middle- or low-income. [Table: see text]
Using automated machine learning to detect kidney anomalies.
Authors: Rawal Rushil , Heard John , Castaneda Peris , Davood Joshua , Ahdoot Michael
Published: January 2024

483

Background: Artificial Intelligence (AI) in Urology has been used for many conditions including benign prostatic hyperplasia (BPH), urological oncology, and kidney transplant. Many computer models use algorithms that may be intricate for urologists to implement, but automated machine learning (AML) can be used to create simple models. Here we expand the use of AI and AML in image detection of kidney tumors, stones, and unremarkable kidney from computed tomography (CT) using Google Vertex AI, a machine learning platform that allows for the building, training, and deployment of models. Methods: Google Vertex AI machine learning system was trained to perform image detection. CT Kidney images were taken from publicly available data from Kaggle, an online database and machine learning platform. Images are from multiple hospitals in Dhaka, Bangladesh. 300 CT Kidney Images were uploaded on Google Vertex AI: 100 tumors, 100 stone, and 100 normal. 240 images were used to train the model, 30 for validation, and a final 30 images for assessing the accuracy of predictions after the training phase. To comprehensively evaluate our model, CT kidney images from the Cedars Sinai Medical Center were employed for further testing. All training images lacked annotations and were solely classified as normal, stone, or tumor. Results: True positivity rate for image detection during model training was 100% for tumors, stones, and normal CTs. We further tested accuracy using Cedars Sinai patient images, using 10 tumors, 10 stones, and 5 normal. The accuracy of the AI prediction was 80%, 70%, and 100%, respectively. Conclusions: Artificial Intelligence can be useful in interpreting urological imaging even in a minimally trained system. A model such as ours may allow for rapid identification and labeling of renal masses, kidney stones, and normal studies with moderate fidelity. Further training of this model may increase accuracy.
Survival and fracture risk with radium-223 therapy in metastatic castrate-resistant prostate cancer (mCRPC): A real-world analysis.
Authors: Zhang Hanbo , Graham Jeffrey , Czaykowski Piotr , Gingerich Joel Roger , Bybel Bohdan , Dawe David E
Published: January 2024

50

Background: Radium-223 is a life-prolonging radionuclide therapy for men with bone-predominant metastatic castrate-resistant prostate cancer (mCRPC). It accumulates at sites of high bone turnover with emerging evidence suggesting use of radium-223 increases risk of pathologic fractures. Bone-protective agents (BPAs) reduce skeletal-related events including pathologic fractures in men with mCRPC. We evaluated real-world outcomes of patients treated with radium-223, including the effect of BPA use on pathologic fracture risk. Methods: This was a single institution retrospective cohort study that included patients with mCRPC treated with radium-223 in Manitoba, Canada from 2014 to 2021. Outcomes of interest included incidence of pathologic fracture, pain response, alkaline phosphatase (ALP) response, and overall survival. Kaplan-Meier method was used for time to event outcomes and multivariable Cox regression models were used to adjust for covariates. Results: We identified 92 patients who received radium-223 for mCRPC (Table). Thirty patients (33%) completed 6 cycles of radium-223. Documented pain relief occurred in 39% of patients. For those with elevated ALP at baseline (n = 46), 57% had at least 30% reduction in total ALP. PSA reduction occurred in 29% with 11% having at least 30% reduction in PSA. Median overall survival (OS) was 9.4 months (95% CI 5.8 to 15.9). Of those who did not receive concurrent BPA, 26% developed a pathologic fracture, compared to 3% who received concurrent BPA during a median follow up of 8.1 months. BPA use was associated with significant delay in time to pathologic fracture (median not reached vs. 15.9 months; HR = 0.20, 95% CI: 0.05 – 0.76, p < 0.05) after adjusting for number of bone metastases and corticosteroid use. Conclusions: In this real-world study, concurrent BPA use was associated with significant reduction in risk of pathologic fractures in mCRPC patients receiving radium-223. BPA administration should be considered for patients receiving radium-223. [Table: see text]
North American patterns of care in clinical stage I testicular cancer from SWOG S1823.
Authors: Morin Coulombe Antoine , Colby Sarah , King Jennifer , Neuhouser Marian L. , Arun Banu , Daneshmand Siamak , Harzstark Andrea , Arnold Kathryn B. , Nichols Craig R. , Nappi Lucia
Published: January 2024

509

Background: SWOG/CCTG S1823/GCC-001 is a non-interventional translational prospective cohort investigation with a primary endpoint of defining pre-treatment operational characteristics of the liquid germ cell cancer biomarker microRNA 371a-3p in predicting the presence of active germ cell malignancy. Opened in June 2020, 813 of the projected 956 patients have been registered with anticipated completion of accrual in early 2024. While analysis of the final endpoint awaits complete accrual and sufficient follow-up, S1823 creates a rich template of baseline clinical information and real-world treatment. Herein, we report baseline patterns of care in modern day real-world care delivery for Clinical Stage I (CSI) germ cell tumors across academic and community practices in North America. Methods: Data is obtained from case report forms and source documents for 547 S1823 enrollees with CSI seminoma or nonseminoma. Aggregate baseline clinical data unrelated to the primary endpoint are described to understand baseline clinical characteristics and management recommendations for CSI germ cell tumors. Results: Clinical characteristics and management recommendations for CSI are described in the table. The leading contributor to date is the Kaiser Permanente NCI NCORP followed by Canadian Institutions which together make up 38% of accruals from top level institutions. The majority of these largely young males were overweight or obese (67%). S1823 did not stipulate management which was at the discretion of local institutions/investigators. Active surveillance is the dominant strategy in both CSI seminoma and nonseminoma (85% overall). In CSI seminoma, adjuvant treatment with radiation is very rare (1/547) and adjuvant treatment with single agent carboplatin (1 or 2 cycles) is uncommon (4%). In CSI nonseminoma, adjuvant retroperitoneal lymph node dissection is also uncommon (3%) as is adjuvant chemotherapy with BEP X 1 or 2 (6%). Conclusions: In this large prospective multi-institutional observational cohort, surveillance appears to be the predominant management strategy for CSI germ cell tumors with very limited use of adjuvant chemotherapy or RPLND and virtual elimination of recommendation for radiation therapy for seminoma. Clinical trial information: NCT04435756 .[Table: see text]
Safety of pegfilgrastim in patients with metastatic germ-cell tumor receiving combination chemotherapy containing bleomycin.
Authors: King Jennifer , Hassoun Rebecca , Althouse Sandra K. , Schneck Stephanie , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil
Published: January 2024

513

Background: There are conflicting reports on the impact of growth factor support in combination with bleomycin on the development of bleomycin associated lung toxicity in various malignancies. In addition, theories remain surrounding the possibility of worsened hematologic toxicity when receiving pegfilgrastim too close to the time of subsequent chemotherapy that is given in consecutive weeks. Here, we aim to evaluate the safety of the use of pegfilgrastim in patients with germ-cell tumor (GCT) undergoing combination chemotherapy containing bleomycin. Methods: The prospectively maintained Indiana University testicular cancer database was queried for patients with metastatic GCT treated between 2010-2023 at Indiana University with chemotherapy containing bleomycin. Safety in patients who received at least one dose of pegfilgrastim were compared to patients who did not receive any doses. Bleomycin lung toxicity was per the discretion of treating physician. Comparison between groups was done using Chi-square tests for categorical variables or Wilcoxon test for continuous variables. Results: 196 patients met eligibility. Median age at diagnosis was 26.7 (range, 20.2-50). Primary site was testis in 95.4%, retroperitoneum in 2.6%, and mediastinum in 2%. 79% of patients included had nonseminomatous germ-cell tumor (NSGCT). IGCCCG risk was good in 146, intermediate in 19, and poor in 31 patients. First-line chemo was BEPX3 in 71% of patients, BEPX3 with EPX1 in 9% of pts, BEPX4 in 10% of patients, and other in 10% of patients. There were 49 patients (25%) who received at least one dose of pegfilgrastim with chemotherapy. There was no statistically significant difference in the type of chemotherapy received, metastatic sites of disease at time of diagnosis, or IGCCCG risk in patients who received pegfilgrastim vs. those who did not. The median number of pegfilgrastim doses received was 2. The median number of doses of bleomycin received was 9 for both patients who received pegfilgrastim and those who did not. In those who received pegfilgrastim, 4 patients developed bleomycin lung toxicity vs. 13 patients who did not receive pegfilgrastim (p=1.000). Of these 17 pts, 9 were diagnosed on symptoms and exam alone, 2 by imaging with symptoms, 2 by imaging without symptoms, 3 on PFTs ordered because of symptoms, and 1 on PFTs alone without symptoms. 3 patients required steroids. There were no fatalities related to pulmonary toxicity. Median nadir ANC in those who received pegfilgrastim was 3350 vs. 800 in those who did not (p<0.0001). Conclusions: The administration of pegfilgrastim with combination chemotherapy containing bleomycin for metastatic GCT did not increase the risk for bleomycin associated lung toxicity. Hematologic toxicity, demonstrated by nadir ANC, was worse in pts who did not receive pegfilgrastim.
Single-stage retrocrural and retroperitoneal lymph node dissection for metastatic germ cell tumor: The University of Southern California experience.
Authors: Ghoreifi Alireza , Alsyouf Muhannad , Djaladat Hooman , Schuckman Anne K. , Daneshmand Siamak
Published: January 2024

515

Background: Resection of retrocrural disease in patients with metastatic germ cell tumors is a surgical challenge, especially in the post-chemotherapy setting. Herein, we present our experience with single-stage retrocrural metastasectomy and retroperitoneal lymph node dissection (RPLND). Methods: Using our IRB-approved testicular cancer database we identified patients who underwent one-stage retrocrural and retroperitoneal mass resection between September 1997 and December 2022. Clinical characteristics, surgical approach, peri-operative complications, and oncological outcomes of these patients were reviewed. Results: Among 400 patients who underwent RPLND for testicular cancer over the study interval, concurrent retrocrural resection was performed in 23 cases. Demographics and clinical features of the patients are shown in the table. All surgeries were performed in the post-chemotherapy setting, except one who underwent primary RPLND for seminoma. Surgical approach has evolved over time, including thoracoabdominal (TA) in 6 (all before 2010) and midline transabdominal (MA) in 17, including 3 midline extraperitoneal. There were 9 (39%) patients who required adjunctive procedures. Histology of retrocrural masses revealed viable tumor in 2 (embryonal carcinoma and seminoma), teratoma in 18 (including one with malignant transformation), and necrosis/fibrosis in 3. Pathologic concordance rate between retrocrural and retroperitoneal pathology was 83%. Median length of hospital stay was 5 days (9 vs. 3.5 for TA and MA, respectively). The 90-day complication rate was 43% (Clavien 3=17%), with a lower rate in patients undergoing MA vs. TA incisions (35% vs. 67%). With a median (IQR) follow-up of 24 (6-90) months, only one patient had retrocrural recurrence requiring re-resection, and no mortality was reported. Conclusions: The midline transabdominal is an effective approach for the concurrent retrocrural and retroperitoneal lymph node dissection in select patients with metastatic germ cell tumors. It is associated with a lower perioperative complication rate compared to the traditional thoracoabdominal approach.[Table: see text]
Defining molecular features associated with microsatellite instability and response to immune checkpoint blockade in urothelial carcinoma.
Authors: Alam Syed Muneeb , Teo Min Yuen , Woo Jun , Sarfaty Michal , Funt Samuel A , Aggen David H , Lee Chung-Han , Carlo Marie Isabel , Gandhi Jatin , Ratna Neha , Regazzi Ashley M. , Donoghue Mark , Bajorin Dean F. , Coleman Jonathan , Rosenberg Jonathan E. , Al-Ahmadie Hikmat A. , Solit David B. , Iyer Gopa
Published: January 2024

536

Background: Microsatellite instability (MSI) and deficient mismatch repair (dMMR) are associated with sensitivity to immune checkpoint blockade (ICB) in urothelial carcinoma (UC). MSI status may only partially explain this sensitivity, and the molecular features that distinguish MSI-high (MSI-H) UC are not well described. Methods: Retrospective review of UC patients having undergone targeted exome sequencing of up to 505 genes was performed. Using the previously validated MSIsensor score, we identified MSI-H (score ≥10) and MSI stable (MSS) (score <3) UC tumors. Tumor mutational burden (TMB) was quantified. Gene alterations enriched in MSI-H UC were evaluated using the false discovery method with q<0.05 considered statistically significant. Mutational process signatures (MPS) were characterized using COSMIC v3.3. Survival analysis was performed using the Kaplan-Meier method with Cox proportional-hazards to determine progression-free (PFS) and overall survival (OS) based on molecular features. Results: Targeted exome sequencing data were available for 3,811 UC specimens representing 2,608 patients, of which 471 carried a diagnosis of upper tract UC. Of the total, 60 (1.6%) MSI-H tumors from 55 (2.1%) patients were identified. Germline testing (n=52) revealed dMMR mutations in 24 cases (46.2%) with MSH2 (59.6%) being most common. Median MSIsensor score was 19.8 (IQR 15.5, 27) and median TMB was 52.7 mut/Mb (IQR 39.7, 63.2). Notable gene alterations enriched in MSI-H tumors are summarized in Table 1. Dominant MPS in MSI-H UC included dMMR (85.0%), APOBEC (8.3%), and Aging (6.7%). MSI-H tumors clustered with dMMR mutational signatures SBS6 and SBS44. A total of 21 MSI-H and 160 MSS patients having received ICB for metastatic disease were identified for survival analysis. Median follow-up was 18.4 months (IQR 6.6, 58.5). MSI-H UC demonstrated superior PFS (HR 0.34, 95% CI 0.22-0.55) and OS (HR 0.48, 95% CI 0.28-0.80) following ICB. There was no association between TMB or MPS and survival following ICB in MSI-H UC. In MSS UC, TMB ≥10 mut/mB was associated with improved PFS (HR 0.56, 95% CI 0.40-0.79) and OS (HR 0.71, 95% CI 0.50-1.0). Conclusions: Targeted sequencing reveals distinct genomic features of MSI-H UC. The findings from this relatively large clinical cohort of MSI-H UC patients affirm previous associations between MSI status, TMB, and response to ICB in metastatic UC. [Table: see text]