bluuebunny/crossref_metadata_2025 huggingface dataset:
The feasibility of an educational and monitoring smartphone application for patients with advanced renal cell carcinoma undergoing combination immunotherapy.
Authors: Roman Souza Gabriel , Paravathaneni Mahati , Ionescu Filip , Gullapalli Keerthi , Raymond Sarah , Jameel Ghazal , Chadha Juskaran , Jain Rohit K. , Trujillo Gillian , Budet DeJesus Amayla M. , Manley Brandon J. , Schneider Amy , Kim Youngchul , Semaan Adele , Jim Heather S.L. , Spiess Philippe E. , Chahoud Jad
Published: January 2024

413

Background: Renal Cell Carcinoma (RCC) is a global public health burden with over 400,000 new cases and over 175,000 deaths annually. Immune checkpoint inhibitors (ICI) in combination with vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKI) has become an integral part of the management of patients with advanced RCC which requires adaptation of healthcare systems to provide information and optimize the management of drug-related adverse events. This study aims to improve the education on therapy-related symptoms and the quality of life of patients with RCC treated with these drugs. Methods: We created a smartphone application (mHealth) that combines educational data, patient-reported outcomes, and peer-to-peer interactions. We aim to assess the feasibility of expansion of this pilot study. We prospectively enrolled stage IV RCC patients (n=20) undergoing treatment with combination ICI and VEGF-TKI. Therapy-related symptom education, knowledge PRO questionnaires, and peer-to-peer support were provided at baseline and at different time points throughout this study duration (Table 1). Time-course data of PROs were visualized using line plots and then compared with paired t-tests. The study's primary endpoint was to assess acceptability and feasibility of mHealth, defined as acceptable if 50% of patients offered participation agree to be enrolled and feasible if 50% of enrolled patients complete the intervention with 70% of these completing at least 50% of survey instruments. Results: Eighty percent of patients were male, 80% were white, 75% had at least some college education, 70% were married, and the mean age of the cohort was 66 years.A total of 22 patients were approached for the study with an acceptance rate of 90%. Sixty percent of patients completed every questionnaire and knowledge assessment at every timepoint of the intervention and 75% of those completed at least 50% of instruments. PROs data showed no significant difference compared to baseline in global health status, functional scales, and symptom scales across the 24 weeks. We noticed an improvement in the patients' knowledge assessment on symptom management after completion of the mHealth knowledge component. Conclusions: Our pilot study was considered acceptable and feasible, showing preliminary evidence of improvement in patient knowledge with mHealth. Our future direction will be to assess, in a larger randomized study, the efficacy of mHealth in improving the quality of life of patients with advanced RCC treated with ICI and VEGF-TKI. Clinical trial information: NCT05579847 . [Table: see text]
Association of radiographic and pathologic outcomes in patients (pts) with advanced renal cell carcinoma (RCC) with and without thrombus receiving preoperative immune checkpoint inhibitor (ICI) regimens and circulating biomarkers.
Authors: Issa Wadih , Gunenc Damla , Zhang Song , Zhou Qinhan , Gerald Thomas , Tachibana Isamu , Bhanvadia Raj Ramnik , Kapur Payal , Woldu Solomon L. , Lotan Yair , Cadeddu Jeffrey A. , Gaston Kris , Qin Qian , Brugarolas James , Hammers Hans J. , Wang Andrew Zhuang , Margulis Vitaly , Zhang Tian
Published: January 2024

415

Background: Primary RCC tumors and associated IVC thrombus have similar histology, however response to ICI is not always concordant. RCC with IVC thrombus is often difficult to manage, and perioperative ICI treatment responses remain largely unstudied. Methods: We conducted a retrospective analysis of pts with advanced RCC receiving preoperative ICI-based regimens at UTSW stratified by the presence of tumor thrombus. The primary objectives were pathologic change in both groups and radiographical response by RECIST 1.1 criteria for tumor and thrombus level change. The secondary objective was to evaluate biomarkers associated with thrombus. Comparisons were performed using a two-sample t-test or aChi-square test. Results: 65 pts were included (median age 64 years), 31 (48%) with baseline thrombus (9 (29%) renal vein thrombus; 6 (19%) level 1 IVC thrombus; 10 (32%) level 2; 2 (7%) level 3; and 4 (13%) level 4). 28 pts (43%) received ICI+ICI, while 20 pts (31%) received ICI+TKI and the rest received ICI monotherapy. 18/31 pts (58%) with thrombus and 20/34 without thrombus (59%) had metastasis at baseline. Pathological Tumor (pT) downstaging occurred in 13 pts with and 11 pts without thrombus; of these, 12 pts had received ICI+TKI and 12 pts ICI+ICI. Radiographic tumor (cT) downstaging occurred in 8/31 pts with thrombus and 7/34 pts without. 12/31 pts experienced thrombus downstaging. 5 pts with thrombus vs 2 pts without had complete tumor necrosis/pCR in the primary and radiographic PR, of whom 4/7 received ICI+TKI. In pts with IVC thrombus, preoperative ICI based regimens reduced median tumor size from 9.1 to 7.7 cm. Among responders in pts with IVC thrombus, ICI+TKI had a trend toward higher tumor shrinkage median (-3.3 vs -1.9 cm, p=0.3) and thrombus downstaging median ( -2 vs -1 levels , p=0.27) than ICI+ICI. Baseline anemia (Hemoglobin (Hgb), 11.1 vs 13.1 g/dL, p=0.002), lower Absolute Lymphocyte Count (ALC) (1.35x10^3 vs 1.55 x10^3 cells/uL, p=0.03), and higher Neutrophil-to-Lymphocyte ratio (NLR) (3.6 vs 3.2, p=0.03) were observed in pts with IVC thrombus. Conclusions: ICI+TKI regimens tend to have tumor downstaging, complete tumor necrosis/pCR in primary tumors, and some IVC thrombus control compared to ICI+ICI regimens. IVC thrombus is associated with lower Hgb and ALC and higher NLR levels. Prospective trials are ongoing to investigate perioperative treatment in pts with IVC thrombus. [Table: see text]
Systemic and surgical treatment in renal cell carcinoma: Does timing matter?
Authors: Seitzer Konstantin Egon , Darr Christopher , Hilser Thomas , Schrader Andres Jan , Huberth Linda , Mausbach Anne , Janssen Martin , Krabbe Laura-Maria , Heitplatz Barbara , Hadaschik Boris A. , Boegemann Martin , Schlack Katrin , Grünwald Viktor
Published: January 2024

417

Background: Today, targeted systemic therapy is standard 1st line treatment of advanced/metastatic renal cell carcinoma (aRCC). Upfront cytoreductive nephrectomy (CN) has been an important treatment option. Recently its role is under debate, especially in combination with the new 1st line treatments. Our study evaluated the current relevance of initial surgical intervention and the role of inductive systemic therapy in aRCC. Methods: We included 33 patients with aRCC from the University Hospitals in Essen and Münster initiating 1st line treatment from 03/18 to 01/23 pre or post surgery. We retrospectively formed two cohorts, either CN followed by systemic therapy (cohort 1; 13 patients) or vice versa (cohort 2; 20 patients). Patients received either Ipilimumab/Nivolumab (Ipi/Nivo) (42.4%) or a checkpoint inhibitor and tyrosine kinase inhibitor (CPI/TKI) combination (57.6%). Progression-free survival (PFS) was estimated with Kaplan-Meier-method from initiation of systemic therapy or CN to progression or death. In Cohort 2, we additionally analyzed the radiologic response of the primary measured by change of the longest diameter. The radiographic response was analysed according to RECIST1.1. Results: Patients’ age ranged from 44 to 80 years with a median of 63 years. Intermediate and poor prognosis occurred in 61.3% and 38.7% of cases. The two cohorts did not differ significantly regarding baseline characteristics. Median PFS was 8 vs. 23 months (p=0.03) in cohort 1 (95% CI 0.9-15.1) compared to cohort 2 (95% CI 18.8-27.2). In cohort 2 the time between start of systemic therapy and surgery was in median 8.5 months (95% CI 3.3-21.1), the primary had a median diameter of 10.7 cm (95% CI 4.5-13.3). Median reduction of the primary was in total 32.2%, 28.9% in the Ipi/Nivo and 34.7% in the CPI/TKI group (p=0.74). In seven patients (35%) response led to modification of the surgical approach, enabling partial instead of radical nephrectomy. Conclusions: The sequence of systemic therapy followed by surgery was associated with a significant PFS benefit. In addition, prior systemic therapy led to a primary reduction and better operability, in some cases even to kidney sparing surgery. Major limitation is the retrospective nature of our analysis and a potential selection bias. However, the sequence of prior systemic therapy followed by surgery in aRCC was associated with notably better outcomes.
Pembrolizumab plus lenvatinib (P+L) versus alternate therapies in first-line (1L) for advanced renal cell carcinoma (aRCC): A network meta-analysis (NMA).
Authors: Yan Kevin , Rane Pratik , Schmidinger Manuela , Peer Avivit , Druyts Eric , Burgents Joseph E. , Sundaram Murali
Published: January 2024

422

Background: Patients with advanced renal cell carcinoma (aRCC) have poor prognosis resulting in significant burden. In the KEYNOTE-581/CLEAR trial, pembrolizumab plus lenvatinib (P+L) as 1L therapy showed statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) versus sunitinib in patients with aRCC. This NMA synthesized evidence from randomized clinical trials (RCTs) to indirectly compare the relative treatment effects of P+L vs alternate therapies in treatment-naïve aRCC. Methods: A systematic literature review was conducted to identify systemic therapies in 1L aRCC. A Bayesian NMA with fixed-effect models was performed to indirectly compare P+L to alternate therapies using sunitinib as the common comparator in 1L aRCC. Hazard ratios (HRs) for OS and PFS were calculated with 95% credible intervals (CrIs). NMAs assuming constant hazard ratios (HRs) and time-varying HRs were performed for OS and PFS. For the proportion of patients experiencing response, a binomial likelihood and logit link were used, and relative effects were expressed as odds ratios (OR). Results: A total of 33 unique RCTs met the inclusion criteria and were included in the analyses. The constant HR analysis resulted in no significant differences in OS between P+L and alternatives in network. Results showed statistically significant higher ORR for P+L compared to nivolumab + ipilimumab (N+I) (OR=3.19; 95% CrI: 2.14, 4.82) and pembrolizumab + axitinib (P+A) (OR=1.84; 95% CrI: 1.21, 2.80). The analysis also favored P+L over nivolumab + cabozantinib (N+C) (OR=1.35; 95% Crl: 0.86, 2.12) and avelumab + axitinib (A+A) (OR=1.46; 95% Crl: 0.96, 2.23), but was not statistically significant. The constant HR analysis showed that P+L resulted in a statistically significant improvement in PFS compared to N+I (HR=0.55; 95% CrI: 0.40, 0.75), A+A (HR=0.68; 95% Crl: 0.49, 0.96) and P+A (HR=0.69; 95% CrI: 0.51, 0.94). The analysis also favored P+L over N+C (HR=0.81; 95% Crl: 0.58, 1.14), but was not statistically significant. Conclusions: NMA indicates P+L has higher ORR and improved PFS compared to other regimens in 1L aRCC. No significant differences in OS were observed between P+L and competing interventions.
Impact of renin-angiotensin system inhibitors on response to PD1/L1 inhibitors in patients with metastatic renal cell carcinoma (mRCC).
Authors: Fortune Kathryn , Ali Soham , Masur Jack , Viscuse Paul Vincent , Devitt Michael Edward , Dreicer Robert , Skelton William Paul
Published: January 2024

424

Background: The renin-angiotensin system (RAS), traditionally associated with blood pressure regulation and fluid balance, also plays a role in tumor development and growth among several cancer types. Renin-angiotensin system inhibitors (RASI), such as angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown in studies of various malignant neoplasms to be associated with improved outcomes. In metastatic urothelial cancer, the use of ACEI and ARBs has been associated with higher rates of tumor regression among patients (pts) receiving immunotherapy (IO) with PD1/L1 inhibitors. One potential mechanistic explanation is RASI-induced downregulation of TGF-beta, for which high expression is a known mechanism of PD1/L1 inhibitor resistance. While the development of novel IO therapies has changed the treatment landscape for mRCC, only one study to date has examined the impact of RAS inhibition in pts with mRCC receiving IO. We hypothesized that concurrent RASI in pts with mRCC receiving IO is associated with increased tumor regression. Methods: We conducted a retrospective analysis of pts with mRCC receiving immunotherapy as a first or second line of treatment from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RASI on tumor regression. The primary endpoint in this study was any regression of tumor on imaging. Results: Data were available for 147 pts with mRCC who received IO as a first- (n=104, 70.7%) or second- (n=43, 29.3%) line treatment. 52 pts (35.4%) received ACEI/ARBs during IO; 42 pts (40.4%) who received IO as first-line treatment were on ACEI/ARBs and 10 patients (23.2%) who received IO as a second-line treatment were on ACEI/ARBs. Analysis showed that pts who received ACEI or ARBs during IO were more likely to have tumor regression compared to pts who were not on concurrent RASI (OR 7.43 [95% CI 2.70-23.53], p=0.0002). This held true regardless if pts received IO as a first-line (OR 6.02 [95% CI 1.84-23.38], p=0.005) or second-line (OR 9.71 [95% CI 1.51-122], p=0.032) treatment. Conclusions: Our hypothesis generating study suggests that in our RCC population the concurrent use of RASI in pts with mRCC receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RASI in combination with IO for mRCC pts. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population.[Table: see text]
Immune-related adverse events (irAEs) and the association with clinical outcomes in advanced genitourinary cancers treated with immunotherapy: A systematic review and meta-analysis.
Authors: Zhang Yaowen , Chen Junru , Sun Guangxi , Zhang Xingming , Zeng Hao
Published: January 2024

431

Background: The approval of several immune checkpoint inhibitors (ICIs) for the treatment of advanced genitourinary cancers has resulted in a significant revolution in the management of urological tumors. This study investigated the profile of the irAEs and evaluated the association between irAEs and clinical outcomes in the patients with advanced genitourinary cancers treated with ICIs. Methods: We conducted a comprehensive search of online databases up to April 2023 to identify eligible studies. We extracted the type, grade, and frequency of irAEs, the hazard ratios(HRs) and corresponding 95% confidence intervals (95%CIs) for overall survival (OS) and progression-free survival (PFS), raw data or the odds ratios (ORs) and corresponding 95% confidence intervals (95%CIs) for objective response rate (ORR) and disease control rate (DCR). RevMan5.3 software was used to calculate pooled results. Results: A total of 21 studies with 4779 patients were included. Of those, 13 studies investigated renal cell carcinoma (RCC), 6 studies investigated urothelial carcinoma (UC), and 2 investigated mixed population with RCC or UC. The pooled overall incidence was 29.0% (95%CI: 28.0%-30.0%) for any-grade irAEs in RCC and UC and 13.0% (95%CI: 11.0%-14.0%) for grade ≥3 irAEs. Furthermore, the HRs for OS and PFS in advanced genitourinary cancer patients with versus without irAEs were 0.45 (95%CI: 0.40-0.51, p < 0.001) and 0.41 (95%CI: 0.31-0.55, p < 0.001), respectively. The ORs for overall ORR and DCR in advanced genitourinary cancer patients with irAEs versus without irAEs were 3.65 (95%CI: 3.03-4.39, p < 0.001) and 4.19 (95%CI: 2.94-5.97, p < 0.001), respectively. In the subgroup analysis, we also observed a positive association between the occurrence of irAEs and improved treatment outcomes in UC and RCC, respectively. Specifically, patients with skin irAEs showed a better OS, patients with skin irAEs and thyroid disfunction were associated with better PFS. Conclusions: Our study provides a comprehensive overview of irAEs in advanced genitourinary cancers treated with immunotherapy. Our findings suggest that the occurrence of irAEs could be a favorable prognostic factor for advanced genitourinary cancer patients treated with ICIs.
Outcomes of patients (pts) with advanced renal cell carcinoma (aRCC) treated with cabozantinib (CABO) after lenvatinib plus pembrolizumab (LEN+PEM).
Authors: Haro-Silerio Jaime Ivan , Johns Andrew , Moussa Mohammad Jad , Wang Mindy , Wang Emily , Kovitz Craig A. , Campbell Matthew T , Jonasch Eric , Shah Amishi Yogesh , Tannir Nizar M.
Published: January 2024

433

Background: LEN+PEM is an approved first-line therapy for aRCC. In the CLEAR study, it produced a 71% objective response rate (ORR), an 18% complete response rate, and improved progression-free survival (PFS) and overall survival (OS) compared to sunitinib. CABO is approved as second and later line therapy for aRCC. We explored the efficacy of CABO in pts with aRCC after treatment with LEN+PEM. Methods: This is a retrospective study of pts with aRCC who received CABO after LEN+PEM at our institution from 12/2019 to 8/2023. Demographics and clinical data were abstracted from the EMR. A blinded radiologist assessed tumor response using RECIST v1.1. We measured PFS, time on therapy (TOT) and OS from start date of CABO. Results: 22 pts were analyzed (Table 1). Median follow up was 7.7 months (mo); 11 pts received LEN+PEM on the HOPE 111 trial (NCT02501096). Among all 22 pts, 11 (50%) had a partial response (PR), 5 (22.7%) had stable disease (SD), and 6 (27.3%) had progressive disease (PD) on LEN+PEM. Median TOT with LEN+PEM was 7.4 mo (range: 1.8-29). 20 pts (90.9%) discontinued LEN+PEM due to PD, 1 pt (4.5%) due to fatigue, and 1 pt (4.5%) due to elevated liver enzymes. 17 pts received CABO right after LEN+PEM; 3 pts received 1 line and 2 pts received 2 lines of therapy before CABO after LEN+PEM. Of 19 pts with evaluable radiographic response on CABO, 1 pt had a PR (ORR 5.3%, PFS 16.1 mo) and 3 pts had SD for ≥6 mo. Median TOT with CABO was 4.3 mo (range: 0.2-18.2); 13 pts (59.1%) took CABO for ≥4 mo, 7 pts (31.8%) took it for ≥6 mo, of which 3pts receivedpalliative radiation andcontinued CABO therapy beyond PD. Median PFS and median OS with CABO were 4.1 mo (range: 1.2-16.1) and 8.1 mo (range: 0.8-22.5), respectively. At time of analysis, 4 pts were still taking CABO (3 SD, 1 not yet evaluated); 15 pts discontinued CABO: 12 for PD, 1 for Grade 3 hand-foot skin reaction, 1 per pt request, and 1 for transition to hospice; 3 pts died during CABO therapy (bowel obstruction [1], COVID-19 [1], cardiac arrest [1]). Adverse events attributed to CABO were consistent with published reports. Conclusions: In this cohort of heavily pretreated pts who received CABO after LEN+PEM, CABO demonstrated a modest clinical benefit in a minority of pts, underscoring the need to develop effective novel therapies for aRCC. [Table: see text]
Single institutional experience of neoadjuvant therapy prior to planned surgical resection for complex or locoregional renal cell carcinoma.
Authors: Puri Dhruv , Yuen Kit , Wang Luke , Meagher Margaret , Afari Jonathan , Nguyen Mimi , Cortes Julian , Mahmood Mirha , Mansour Mariam , Matian Joshua , Javier-Desloges Juan , Derweesh Ithaar
Published: January 2024

439

Background: Cytoreduction via systemic neoadjuvant therapy is an emerging investigational strategy in localized renal cell carcinoma (RCC). We analyzed our single institutional experience with neoadjuvant therapy. Methods: ingle institutional retrospective analysis of patients with T2-T3N0M0 RCC. Patients received confirmatory biopsy for clear cell histology prior to receipt of systemic therapy and underwent radical (RN) or partial nephrectomy (RN). Neoadjuvant therapy consisted of tyrosine kinase inhibitor (TKI) or Immuno-oncology (IO) therapy and/or combination (TKI-IO). Neoadjuvant therapy was given prior to planned partial nephrectomy for complex renal mass with imperative indications for nephron preservation and prior to planned radical nephrectomy in setting of locoregional disease with possible adjacent organ or great vessel involvement where multiorgan system resection was risked. Primary outcome was percentage cytoreduction comparing pre-treatment and post treatment mass size. Secondary outcome included partial response (PR) rate as per RECIST criteria, negative surgical margins, and lack of major 30-day complications (Clavien ≥3). Comparative analysis was conducted for outcomes between groups for overall survival (OS), cancer specific survival (CSS), and progression free survival utilizing Kaplan Meier Analyses (KMA). Results: A total of 50 patients (33 TKI, 17 IO + TKI-IO) were analyzed (median follow up 31.1 months). Overall PR and cytoreduction rates were 18.0% and 4.2%. No differences in tumor size were noted (7.7 vs. 10.4 cm, p= 0.08). There were no differences in % cytoreduction (12.2 vs. 11.8, p=0.13) and % PR (17.8% vs. 30.7%, p=0.73) between the groups. Overall, 18 patients and 30 patients underwent PN and RN, respectively. 30-day major complication rate was 28.0% and 20.5% was PSM rate. KMA revealed 3-year OS, CSS and PFS of 74%, 75%, and 14%. No differences were noted between TKI and IO/IO-combination groups for PFS (16.7% vs. 10.0%, p=0.45), CSS (70.9% vs. 93.3%, p=0.20), and OS (68.3% vs. 93.3%, p=0.06). Conclusions: Neoadjuvant therapy prior to surgery for complex and locoregional disease resulted in cytoreduction and was associated with acceptable safety, surgical quality, and short term oncological outcomes. Further investigation is requisite to delineate role of neoadjuvant therapy in localized RCC.
Serum IgG: A potential biomarker for predicting the efficacy of systemic therapy in metastatic renal cell carcinoma.
Authors: Cui Honglei , Wu Jie , Xie Rui-Yang , Du Gan , Shang Bing-Qing , Dong Xin , Song Yan , Qu Wang , Bai Hongsong , Guan Youyan , Shi Hongzhe , Bi Xin-Gang , Zhou Ai-Ping , Shou Jianzhong
Published: January 2024

442

Background: Immunotherapy-tyrosine kinase inhibitor (IO-TKI) and tyrosine kinase inhibitor (TKI) are the main treatment strategies that have significantly improved outcomes of metastatic renal cell carcinoma (mRCC) patients. However, there are no effective biomarkers available to predict the efficacy of these regimens. We aim to explore the predictive value of serum immunoglobulin G (IgG) in systemic treatment. Methods: The study consisted of 292 mRCC patients who received TKI or IO-TKI therapy. Serum IgG in the pre-treatment baseline, 1 month, and 3 months after systemic treatment were measured using the immunoturbidimetric method. The Wilcox test was used to compare baseline serum IgG levels and paired t-test was utilized to compare serum IgG levels between baseline and 3 months after treatment. Kaplan-Meier curve were used to evaluate the PFS and Cox proportional hazard regression analysis was conducted to identify independent determinant factors for PFS. Results: The baseline level of IgG was not associated with objective response rate (ORR) in the overall patient cohort. However, there was a significant decrease in IgG in patients achieving CR/PR and an increase in patients with SD/PD after 3 months of treatment (p<0.05). In the TKI cohort, the estimated 9-month PFS was significantly higher in the IgG-decrease group versus the IgG-increase group (HR 2.5, 95%CI 1.8-3.4, p<0.001). The results were similar in the IO-TKI cohort. The predictive value of alteration of IgG after 1-month treatment was demonstrated in terms of the estimated 9-month PFS (HR 1.5, 95%CI 1.0-2.3, p=0·048). The ROC curve showed outstanding performance of alteration of serum IgG in predicting PFS. Conclusions: Alteration of serum IgG after systemic treatment is a reliable biomarker to predict the efficacy in mRCC patients. The change of IgG after 1-month treatment could serve as indicator of treatment efficacy and improve individualized drug selection. Further validation is warranted.
Monocyte to lymphocyte ratios and cancer-specific mortality for patients with renal cell carcinoma and inferior vena cava tumor thrombus.
Authors: Sandberg Maxwell , Ritts Rory , Namugosa Mary , Temple Davis , Whitman Wyatt , Costa Claudia Marie , Refugia Justin , Eilender Benjamin , Mehrazin Reza , Zanotti Rafael Ribiero , Garcia Marchiñena Patricio , Zequi Stenio Cassio , Rodriguez Alejandro
Published: January 2024

444

Background: Renal cell carcinoma (RCC) with inferior vena cava (IVC) tumor thrombus carries a poor prognosis and presents complex medical management to urologists. Long-term data examining RCC with IVC tumor thrombus is sparse. Specifically, markers predicting cancer-specific survival are lacking. Recently, immune cell markers in cancer, such as neutrophils, lymphocytes, and monocytes, have come into focus. These cell counts and/or ratios may provide a window into cancer-specific outcomes. The purpose of this study was to examine the use of immune cell ratios in patients with RCC and IVC tumor thrombus to predict survival outcomes through a collaboration project across North and South America. Methods: Patients were included in this study if they had a diagnosis of RCC with IVC tumor thrombus and underwent nephrectomy with IVC thrombectomy for their RCC. Data was reviewed and entered into a multi-institutional/continental database. Complete blood counts taken as close to the date prior to/date of surgery were used to calculate immune cell ratios. Neutrophil to (/) lymphocyte ratios were done by dividing patients’ neutrophil cell count by their lymphocyte count. Monocyte/lymphocyte ratios were calculated in the same manner. Independent samples t-test was used to test for significance in cause of death post-operatively (RCC versus non-RCC cause) based on immune cell ratio. Results: There were 107 patients included in the study with long-term follow-up data (Mean: 2.6 years; Range: 0-16-years). Of all patients, 43/107 died by the end of the study, with 31/43 (72.1%) dying due to RCC and 12/43 (27.9%) from other causes. No difference existed in neutrophil/lymphocyte ratios based on cause of death (p=0.260). Monocyte/lymphocyte ratios were significantly lower in those who died from RCC relative to another cause (p=0.035). Conclusions: Immune cell ratios may have a role in predicting death from RCC. In our study, monocyte/lymphocyte ratios were significantly lower in patients who died from RCC compared to death from other reasons. Our results stem from a multi-continental/institutional study, and thus hold clinical utility as an increased focus is turned towards including diverse populations in research. Urologists may consider monocyte/lymphocyte ratios in the future when managing patients with RCC and an IVC thrombus. [Table: see text]
Significance of CD73/adenosine receptor 2 (A2aR) and immune microenvironmental status in renal cell carcinoma with sarcomatoid changes and rhabdoid features.
Authors: Takamatsu Dai , Eto Masatoshi
Published: January 2024

447

Background: One of the most aggressive forms among the kidney cancer is sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC). There is still no effective treatment, and new therapies are needed. In this study, we focused on CD73 and A2aR, which regulate Treg involved in immune escape, and examined them clinicopathologically. Methods: We reviewed a total 1390 formalin-fixed, paraffin-embedded specimens of surgically resected RCC between 1989 and 2016. We detected 60 cases of RCC with sarcomatoid changes and rhabdoid features. We performed immunohistochemistry of CD73, A2aR, PD-L1, and CD8. We attempted to examine clinicopathological significance of CD73- and A2aR- positive RCC with S/R RCCs. The relationship between clinical and pathological features was evaluated using Wilcoxon’s rank sum and Fisher’s exact tests. A Cox proportional hazards regression model was used for multivariate analysis. Both PFS and OS were analyzed by using the Kaplan-Meier method and compared by the Wilcoxon’s rank test. All statistically signiﬁcances were defined as P<0.05. Results: High-grade components were sarcomatoid changes (31 cases, 51.7%), rhabdoid features (16 cases, 21.7%), and both sarcomatoid and rhabdoid (13 cases, 21.7%). CD73 expression in the high-grade component was observed in 41 cases (68.3%), and A2aR expression was observed in 27 cases (45%). Significant differences among cMstage and high-grade components, sarcomatoid and rhabdoid, are detected in A2aR positive cases, respectively (p=0.0368, 0.0396, 0.0187). The univariate analysis showed a significantly poorer OS for patients whose tumors expressed CD73 and A2aR ( P = 0.0109 and P < .0001). To validate this finding further, a multivariate analysis was performed using the Cox proportional hazards model). The results indicated that A2aR expression ( P = 0.0206) and pTstage ( P = 0.0433) were independent markers for unfavorable prognosis in S/R RCCs. CD73 and A2aR expressions were significantly related to poor PFS ( P = 0.0395, P = 0.0043, respectively). CD73 and A2aR expressions were significantly related to poor OS ( P = 0.0188, P < .0001, respectively). Conclusions: CD73 and A2aR expression correlated with the poorest prognosis group among S/R RCCs, indicating that the use of inhibitors against them in combination with conventional therapies may improve prognosis.
Detection of sarcomatoid renal cell carcinoma using plasma cell-free DNA methylation.
Authors: Semaan Karl , El Zarif Talal , Seo Ji-Heui , Eid Marc , Canniff John , Fortunato Brad , Savignano Hunter , Davidsohn Matthew P. , Lakshminarayanan Gitanjali , Saad Eddy , Saliby Renee Maria , Bakouny Ziad , Matar Sayed , Nuzzo Pier Vitale , Berchuck Jacob E , Signoretti Sabina , Braun David A. , Freedman Matthew , Baca Sylvan , Choueiri Toni K.
Published: January 2024

449

Background: Sarcomatoid differentiation (SD) in renal cell carcinoma (RCC) is associated with poor survival and heightened response to immune checkpoint blockade. Detection of SD can be challenging due to spatial heterogeneity and sampling error. Herein, we introduce a novel tissue–informed epigenomic approach to noninvasively identify sarcomatoid differentiation in patients with RCC from cell-free DNA (cfDNA) using <1mL of plasma. Methods: Methylated immunoprecipitation and high-throughput sequencing (MeDIP-seq) was performed on pathologically reviewed clear cell RCC frozen tissue samples with and without SD (sarcomatoid-RCC and epithelioid-RCC, resp.) collected at the Dana-Farber Cancer Institute. Differentially methylated regions (DMRs) between sarcomatoid and epithelioid subtypes were identified using DESeq2 (false discovery rate of q < 0.01). Then, MeDIP-seq was performed on cell-free DNA (cfMeDIP-seq) from patients with sarc-RCC and epi-RCC. A Sarcomatoid Methylation Score (SMS) was derived for each sample by aggregating the methylated cfDNA signal at tissue-derived sarcomatoid-enriched DMRs (sarc-DMRs), while normalizing to signal at epithelioid-enriched DMRs (epi-DMRs). Scores were compared between the two groups using a Wilcoxon rank-sum test. A classifier was built to distinguish sarc-RCC from epi-RCC based on SMS and its performance was evaluated using the area under the receiver operating characteristic (AUROC) curve. Results: We identified 32,086 DMRs between 9 sarc-RCC and 10 epi-RCC tissue samples at a false discovery rate of q < 0.01, among which We selected 16,083 DMRs that are enriched in sarcomatoid vs. epithelioid. We generated high-quality cfMeDIP-seq profiles from plasma of 46 patients, 13 with sarc-RCC and 33 with epi-RCC. SMS were significantly higher in sarc-RCC vs. epi-RCC plasma samples (p = 6.7×10-8). These scores achieved an AUROC curve of 0.95 for classifying patients with sarc-RCC from patients with epi-RCC. Conclusions: We present the first proof of concept study for the detection of sarcomatoid differentiation in RCC based on tissue-informed assessment of DNA methylation signals in cfDNA using <1mL of plasma. This approach could overcome the challenges of spatial heterogeneity and sampling error that make identification of sarc-RCC difficult. More generally, it establishes a paradigm for identifying histologic subtypes of cancer based on their epigenomic correlates from cfDNA, with possible therapeutic implications in real-time.
Topological heterogeneity of genomic and immunologic effects from combination immunotherapy treatment in the neoadjuvant setting for renal cell carcinoma (RCC).
Authors: Alban Tyler , Singh Salendra , Pavicic Paul G. , Rayman Patricia A. , Bangalore Prerana Parthasarathy , Rupani Amit , Makarov Vladimir , Przybycin Christopher , Ko Jennifer S. , Krishnamurthi Venkatesh , Campbell Steven , Chan Timothy An-thy , Rini Brian I. , Diaz-Montero C. Marcela , Ornstein Moshe Chaim
Published: January 2024

454

Background: We present a multi-regional genomic analysis of tumor from a phase 1b clinical trial of perioperative durvalumab (D) and tremelimumab (T) in patients (pts) with high-risk RCC. Genomic & transcriptomic analyses were performed on nephrectomy samples post neoadjuvant therapy to assess genomic/immunologic impact of combinatorial D+T therapy compared to D alone. Methods: Post-treatment nephrectomy samples were regionally sampled at 4 locations: non-tumor, tumor distant, tumor near, and tumor center. RNA-sequencing was performed on all 4 regions and utilized on a per patient basis to identify regional tumor microenvironment alterations compared to normal kidney. Whole exome sequencing was performed on tumor center. Results: 29 pts enrolled in the trial. 15 were included in the analysis; 5 received neoadjuvant D and 10 received D+T. 60 multi-regional specimens were analyzed; each patient's own normal kidney tissue served as their baseline. There were significant transcriptional differences in D+T compared to D alone (Table). While many of these genes overlapped between treatment arms, the amplitude of differentially expressed genes (i.e., differences between normal and tumor tissue) were greater in the D+T arm, particularly among immune related genes, such as CD8A, CXCL9, CXCL13 and PRAME. Enhanced immune activity was confirmed by immune deconvolution analyses showing broad regional immune infiltration of lymphocytes, including CD8+ T cells, in D+T, which was not detected in D alone. Further comparison of mutational profiles within this cohort showed that D+T treatment resulted in increased clonality compared to D. Conclusions: These data highlight the potential differential genomic/immunologic impact of combination immunotherapy vs single agent across tumor topology. It also demonstrates the utility of pt specific comparisons and a multiregional sampling approach. D+T treatment resulted in enhanced immune activity in RCC tumors and activation of anti-tumor processes above and beyond D alone. This design increases power & biological interpretation of small pt cohorts and allows additional insight into enhanced activation of the immune system with D+T. Summary of transcriptomic comparisons within D & D+T cohorts per region where p <0.05 was used as selection criteria along with positive & negative log fold change. Pathway analysis performed using Hallmarked pathways based on differentially expressed genes, and Celltype deconvolution via ssGSEA (p<0.05). [Table: see text]
Association between β3-adrenergic receptor agonist use and risk of kidney cancer among patients with overactive bladder.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Shin Gwangmo , Ham Won Sik
Published: January 2024

456

Background: New aspects of β3-AR have been recently described with overexpression in cancers. Although post-authorization safety study of mirabegron, the first approved β3-AR agonist for overactive bladder (OAB), found no association between mirabegron use and risk of overall cancer, subgroup analysis revealed that some malignancies were significantly associated with β3-AR agonist use. This study aimed to examine whether cumulative β3-AR agonist use is associated with a higher risk of kidney cancer and demonstrate underlying mechanisms of β3-AR agonist through murine model. Methods: This nationwide population cohort study included newly diagnosed OAB patients who initiated their OAB medications between 2015 and 2020. In pulmonary metastatic orthotopic murine mRCC model, primary tumor weight and number of lung nodules were measured and evaluation of browning of perinephric fat (PF) and tumor immune microenvironment (TIME) was performed and compared between β3-AR agonist and vehicle treatment groups. Results: Among a total of 3,728,929 patients, 7,437 (0.2%) developed kidney cancer after starting OAB medications. There was an increased risk of kidney cancer among β3-AR agonist users (hazard ratio (HR)=1.514, 95% confidence interval (CI) 1.418–1.615) compared to anticholinergic users. The incidence of kidney cancer was also significantly increased with an increase in the cumulative dose of mirabegron (adjusted HR (aHR)=1.221 (1.104-1.351) for 30-180 cDDDs (cumulative defined daily doses), aHR=1.413 (1.281-1.558) for >181 cDDDs) compared to low-dose cDDDs (<30 cDDDs)). The β3-AR agonist treated mice demonstrated significantly higher primary tumor burden and lung metastasis with increased mitosis in cancer cells and browning of PF. Immunofluorescence analysis demonstrated that β3-AR agonist modulate TIME by increasing both myeloid-derived suppressor cells and regulatory T cells. Conclusions: This is the first study to demonstrate the association of kidney cancer and β3-AR agonist both in murine and human studies. By showing that the β3-AR agonist not only increases PF browning but also induces immune tolerance which eventually increases the initiation and progression of kidney cancer, we suggest β3-AR as the potential therapeutic target for novel anti-neoplastic approaches.
Effect of cytoreductive nephrectomy on the efficacy of immunotherapy in metastatic renal cell carcinoma by decreasing IL-6 to modulate tumor-associated macrophage and myeloid-derived suppressor cell.
Authors: Park Jee Soo , Lee Myung Eun , Jang Won Sik , Kim Jongchan , Shin Gwangmo , Ham Won Sik
Published: January 2024

457

Background: Although the contemporary role of cytoreductive nephrectomy (CN) has been significantly downsized, the role of CN in immuno-oncology era still remains. Since the efficacy of immune checkpoint inhibitor (ICI) is limited, the role of CN in combination with ICI from the perspective tumor immune microenvironment (TIME) was evaluated using murine models and hypothesized that interleukin 6 (IL-6) blockade would enhance the efficacy of ICI therapy. Methods: Low- and high-tumor burden pulmonary metastatic orthotopic murine mRCC models have been developed. Antibodies targeting PD-1, CTLA-4, and IL-6 were systemically injected through the peritoneum. Renca implanted kidney was removed in the CN performed group and the timing of CN was differentiated according to the upfront and deferred CN group. The remodeling of the TIME was analyzed by flow cytometry, immunofluorescence analysis, and measurement of cytokines. Results: Upfront CN group demonstrated significantly better survival outcomes compared to deferred CN group in low-tumor burden models, while significantly longer survival was reported in deferred CN group compared to upfront CN group in high-tumor burden models. CN modulate IL-6 levels which act as a negative regulator of myeloid-derived stem cells (MDSCs) and M2 tumor-associated macrophage (TAM). The blockade of IL-6 activated CD8+ T-cell accumulation and led to decreased expression of MDSCs and M2 TAM, which is similar to the effects on TIME by CN combined with ICI therapy. Conclusions: This study is the first animal study to demonstrate the role of CN in combination with ICI. CN decreases the production of the cytokine IL-6, increasing the anti-cancer immunity TIME through modulation of MDSC and M2 TAM. Our study provides a research basis for the significant role of IL-6 in tumor regression and highlights a novel target to improve the efficacy of immunotherapy.
Clinicopathological features and transcriptomic profiles of MED15-TFE3-rearranged renal cell carcinoma: A retrospective study of 14 cases.
Authors: He Sike , Liu Haoyang , Hu Xu , Sun Guangxi , Liu Zhenhua , Shen Pengfei , Zeng Hao
Published: January 2024

462

Background: TFE3-rearranged renal cell carcinoma (TFE3-rRCC) is a rare type of RCCs with various fusion types and heterogeneous clinicopathological features. MED15-TFE3 is a fusion that usually present as an extensive cystic mass with low malignant potential. We sought to summarize the clinicopathological, transcriptomic characteristics and survival outcome in MED15-TFE3-rRCC patients. Methods: All 14 cases were collected retrospectively fromSichuan University West China Hospital from 8/2011 to now. Diagnosis of MED15-TFE3 fusion was confirmed by fluorescence in situ hybridization and RNA sequencing. The clinicopathological features and follow-up data were collected for further analysis. The tumor transcriptomic profiles were analyzed by Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis via R tool. Results: The median age was 43.5 years (range, 22 to 70). Majority of the cases were female (10/14). 8 patients (57.1%) underwent radical nephrectomy, 1 patient received cytoreductive surgery, and 5 patients (35.7%) received partial nephrectomy. At initial diagnosis, most cases (10/14) were localized disease, while 2 patients had regional lymph nodes metastasis, and 1 patient had distant metastasis (bone). For the patients without distant metastasis (n=13), 2 patients developed metastasis (liver, lung, abdominal, in situ) with disease-free survival of 11.4 and 29.0 months. As for the pathological features, 10 (71.4%) of thesamples presentedcystic morphologically, and other 4 (28.6%) were papillary. 10 (71.4%) were in G2 by ISUP score. For metastatic patients, 3 received first-line therapy (1 axitinib, 1 axitinib + sintilimab, 1 sunitinib), 2 received second-line therapy (1 axitinib + sintilimab, 1 axitinib + toripalimab), 1 received third-line therapy (axitinib + toripalimab + everolimus). They are still under follow-up. GSEA analysis illustrated that compared to paraneoplastic tissue, apical surface, bile acid metabolism, KRAS signaling, Xenobiotic Metabolism, and estrogen response were upregulated in tumor. For the patients with distant metastases, the transcriptomic analysis revealed that organelle fission, nuclear division, mitotic nuclear division, and chromosome segregation were significantly upregulated, which may be associated with tumor metastasis. The overall immune cell infiltration was comparable in metastatic patients and non-metastatic patients. However, the expression level of type 17 T helper cell, B cells, plasmacytoid dendritic cell, and activated dendritic cell were significantly different. Conclusions: MED15-TFE3 rRCC mainly present low-grade cystic renal neoplasm with favorable prognosis. For metastatic MED15-TFE3 rRCC, there is no standard therapy. And the transcriptomic evidence may provide insights for future research.
Development of AB-2100, an autologous integrated circuit T (ICT) cell therapy targeting CA9 intended for the treatment of ccRCC.
Authors: Landon Mark , Scarfo Irene , Chew Marvin , Sudhakah Rakesh , Nguyen Michelle , Mohanty Suchismita , Chen Jeremy , Gomez Alma , Attanasio Nickolas , Fearon Amanda , Chan Ivan , Sail Vibhavari , Gardner Thomas , Millare Beatriz , Thomas Vince , Zhou Stanley , Smith Jenessa , Mcdevitt Jennifer , Boroughs Angela , Gray-Rupp Levi
Published: January 2024

472

Background: Relapsed/refractory clear cell renal cell carcinoma (ccRCC) progressing after treatment with CPI and VEGF inhibitor remains an area of unmet need. We have developed AB-2100, an autologous, integrated circuit T (ICT) cell engineered to include three new features: a sequential “AND” logic gate that requires the IO presence of two antigens in the tumor microenvironment (TME) to trigger T cell killing; a shRNA-miR module to enhance resistance to suppressive TME via constitutive knockdown of FAS and TGFBR2; and a constitutive synthetic pathway activator (SPA) that increases STAT3 signaling for enhanced T cell cytotoxicity and expansion. Methods: A previous clinical study of CA9-specific CAR-T cell therapy was limited by on-target, off-tumor toxicity. To overcome this, AB-2100 includes a sequential “AND” logic gate that consists of a priming receptor (PrimeR) targeting PSMA, and a CA9-targeted CAR that is upregulated upon PrimeR engagement with PSMA expressed on the tumor neovasculature. A series of assays were performed to assess the specificity and potency of AB-2100: dual-antigen specificity of the logic gate was assessed in vitro and in vivo against CA9+ and PSMA+CA9+ tumors; vascular priming was modeled by co-culturing AB-2100 cells with PSMA-expressing endothelial cells and CA9+ tumor cells; a FAS cross-linking assay was conducted to assess the impact of FAS knockdown; the enhanced anti-tumor activity conferred by TGFBR2 shRNA and SPA modules were assessed in a 786-O xenograft model; and AB-2100 potency was measured in a subcutaneous renal A498 xenograft. Results: AB-2100 selectively kills tumors that express both CA9 and PSMA, and not tumors that express CA9 alone, as assessed by in vitro cytotoxicity against single or dual antigen expressing tumor cell lines and by a dual flank xenograft model. Furthermore, we confirmed that co-culture with PSMA-expressing endothelial cells was sufficient to upregulate CA9 CAR expression and enable tumor cell killing. Finally, AB-2100 containing both shRNA-miR and SPA modules demonstrated enhanced anti-tumor activity in xenograft RCC models. Conclusions: These data demonstrate that AB-2100 selectively targets tumors co-expressing PSMA and CA9, and can overcome multiple suppressive mechanisms in the TME. These results support the evaluation of AB-2100 in the clinic for the treatment of advanced or metastatic ccRCC.