bluuebunny/crossref_metadata_2025 huggingface dataset:
Individualized neoantigen vaccine with nivolumab plus cabozantinib for translocation renal cell carcinoma: Single patient investigational new drug.
Authors: Kase Adam McLain , Tan Winston , Copland John A. , Gustafson Michael , Asmann Yan W. , Necela Brian , Knutson Keith L.
Published: February 2025

537

Background:
Translocation renal cell carcinoma (tRCC) is a rare renal cell carcinoma subtype found in about 1-4% of adult patients with RCC and 40% of pediatric RCC cases. Management of advanced tRCC has been guided by clear cell RCC therapy and retrospective reviews which include tRCC cohorts. Novel therapeutic strategies are needed to improve outcomes. This study assessed an individualized neoantigen vaccine with nivolumab plus cabozantinib in a patient with metastatic TFE3-tRCC.
Methods:
Patient was consented (IRB# 20-011945) for a single-patient investigational new drug (IND#27755). In-house neoantigen prediction bioinformatics pipeline (REAL-neo v2.0) was performed to identify and prioritize neoantigen candidates. Patient underwent lymphodepletion with cyclophosphamide followed by vaccine administration on days 1, 4, 8, 11, 20, 40, week 12, and week 20. Patient was also treated with concurrent nivolumab 480 mg every 4 weeks and cabozantinib 40 mg daily. Objective response rate (ORR) and progression-free survival (PFS) were measured.
Results:
Patient was diagnosed with TFE3-tRCC and underwent nephrectomy prior to developing metastatic disease. He was treated with multiple liver surgeries, ablations, and radiation therapy without systemic therapy. This controlled his disease for 7 years before he required systemic therapy with ipilimumab plus nivolumab. After 4 cycles, imaging showed progression and was started on cabozantinib which controlled his disease for 1 year. Patient was consented for the neoantigen vaccine. Cycle 1 was administered in April 2022. Three liver lesions and 1 periportal lymph node were monitored. After 4 months of therapy, imaging showed partial response with 34% decrease in sum of target lesions. In June 2023, partial response was ongoing with a 57.4% decrease. A 2
nd
vaccine series was administered in June 2023 and had stable disease until progression in June 2024 when patient held his cabozantinib for at least 4 weeks. Neoantigen combination therapy achieved a progression-free survival of 26 months and was well tolerated without significant vaccine-related adverse events.
Conclusions:
Individualized neoantigen vaccine plus nivolumab and cabozantinib achieved a durable partial response with prolonged progression-free survival. A randomized clinical trial is warranted to further evaluate the efficacy of this combination therapy.
The influence of body composition on the survival of patients with metastatic clear cell renal carcinoma (mccRCC) treated with nivolumab (nivo) + ipilimumab (ipi).
Authors: Grewal Kabir , Chauhan Pankaj Kumar , Mukhida Sagar S , Tannir Nizar M. , Venkatesh Neha , Shah Amishi Yogesh , Zurita Amado J. , Johns Andrew , Campbell Matthew T. , Goswami Sangeeta , Gao Jianjun , Jonasch Eric , McQuade Jennifer Leigh , Alhalabi Omar , Msaouel Pavlos , Hahn Andrew Warren
Published: February 2025

545

Background:
Over the last decade, immune checkpoint therapy (ICT) has become the cornerstone of first-line treatment for mccRCC. Despite the widespread use, there is heterogeneity in tumor response to ICT, and there is growing interest in how host factors modulate the tumor microenvironment. Recent studies in patients with mccRCC and other malignancies suggest that ICT may be more effective in patients with higher body mass index (BMI). Since BMI is an imperfect surrogate for distinct compartments of adipose tissue and muscle, we investigated the influence of body composition on outcomes with first-line (1L) nivo + ipi in patients with mccRCC.
Methods:
A retrospective analysis was conducted on patients with mccRCC at MD Anderson Cancer Center from June 2015 to Dec 2021 who received nivo + ipi as 1L treatment for advanced or mccRCC. Clinical data including demographics, BMI, and IMDC risk score were collected. Body composition was measured using an AI segmentation tool at the L3 vertebra from a pre-treatment CT scan obtained within 45 days of starting nivo + ipi. Efficacy endpoints of interest were time to treatment discontinuation (TTD), progression-free survival (PFS) and overall survival (OS). We constructed flexible multivariable Cox regression models guided by directed acyclic graphs to flexibly model the association of treatment outcomes with body composition measures as continuous variable, including nonlinear terms as cubic splines, and adjusting for IMDC risk and sarcomatoid dedifferentation as confounders.
Results:
209 patients received 1L nivo + ipi (78.5% male, median age of 61 years, 59.3% and 32.5% IMDC intermediate- and poor-risk). Increasing skeletal muscle mass (SMMi) was associated with inferior PFS (HR 1.52, 95% CI 1.01 - 2.31 for 1-unit increase), whereas BMI and adiposity measures were not associated with PFS. Body composition measures were not significantly associated with OS, yet noteworthy trends were observed for visceral adiposity (VATi, HR 0.69, 95% CI 0.42 - 1.15 for 1-unit increase) and SMMi (HR 1.22, 95% CI 0.72 - 2.07).
Conclusions:
In a large cohort of patients with mccRCC, skeletal muscle mass was surprisingly associated with inferior PFS on 1L nivo + ipi. These results build upon conflicting body composition studies in mccRCC and suggest that future studies should investigate how skeletal muscle influences the tumor microenvironment.
Efficacy of systemic treatments for advanced non-clear cell renal cell carcinoma: A single-arm systematic review and meta-analysis.
Authors: Wei Xinyuan , Shen Yu , Liang Jiayu , Zhao Jinge , Zhang Xingming , Chen Junru , Sun Guangxi , Hu Xu , Shen Pengfei , Zeng Hao , Liu Zhenhua
Published: February 2025

550

Background:
Non-clear cell renal cell carcinoma (nccRCC) represents a genetically and histologically diverse subset of renal cancers, accounting for 15–30% of all renal malignancies. Patients with nccRCC generally face poorer prognoses compared to those with clear cell renal cell carcinoma (ccRCC). While many therapies, such as tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors (ICI), have broadened treatment options for nccRCC, high-quality randomized controlled trials (RCTs) assessing these treatments remain scarce. Consequently, RCT-based reviews provide an incomplete understanding of systemic therapy in nccRCC. In contrast, single-arm trials (SATs), more commonly conducted in nccRCC patients, offer additional insights into therapeutic efficacy. This study aims to synthesize evidence from both RCTs and SATs to comprehensively evaluate the efficacy of systemic treatments for nccRCC.
Methods:
We conducted a systematic review and meta-analysis of SATs and arms of RCTs, retrieving studies from PubMed, MEDLINE, EMBASE, and the Cochrane Library up to October 1, 2024. Primary outcome was objective response rate (ORR), and secondary outcomes were progression-free survival (PFS), and overall survival (OS). A random-effects meta-analysis was employed to pool data, and subgroup analyses were conducted based on treatment regimens.
Results:
Thirty-two studies encompassing 1,958 patients were included in the meta-analysis. The pooled ORR across all treatments and therapy lines for nccRCC was 20% (95% CI 15%–26%). The median PFS and OS were 5.56 months (95% CI 4.03–7.09 months) and 17.25 months (95% CI 12.48–22.01 months), respectively. Among them, the pooled ORR for TKI and ICI monotherapy was 19% (95% CI 10%–30%) and 19% (95% CI 13%–26%), respectively, while the pooled ORR for TKI and ICI combination therapy was 39% (95% CI 28%–51%). For first-line therapy, the ORR was 20% (95% CI 12%–28%). Combination therapies (e.g., TKI+ICI, TKI+mTOR and ICI+ICI) demonstrated a higher pooled ORR of 32% (95% CI 19%–46%), while monotherapies (TKI, mTOR or ICI) had an ORR of 14% (95% CI 8%–21%). In papillary RCC (pRCC), the ORR for first-line therapy was 17% (95% CI 9%–26%). Combination therapies showed an ORR of 31% (95% CI 14%–51%), and single-agent therapies had an ORR of 12% (95% CI 6%–21%).
Conclusions:
This meta-analysis provides evidence supporting the efficacy of existing systemic therapies, particularly combination therapies, in advanced nccRCC. However, the inherent limitations of single-arm analysis necessitate further large-scale, multicenter trials to validate these findings and guide future clinical practice.
Updated results of the Tide-A study evaluating avelumab (Ave) plus intermittent axitinib (Axi) in previously untreated patients with metastatic renal cell carcinoma (mRCC).
Authors: Arduini Daniela , Ciccarese Chiara , Acunzo Alessandro , Perrino Matteo , Maruzzo Marco , Verzoni Elena , Accettura Caterina , Bonomi Lucia , Buttigliero Consuelo , Cremante Malvina , Pipitone Stefania , Scartozzi Mario , Masini Cristina , Mollica Veronica , Primi Francesca , Strusi Alessandro , Buti Sebastiano , Zucali Paolo Andrea , Fantinel Emanuela , Iacovelli Roberto
Published: February 2025

551

Background:
Combinations of therapies with VEGFR-TKI (TKI) and anti-PD1/PDL1 immunotherapy (IO) are considered the standard of care for first line treatment of patients (pts) with mRCC. The Tide-A trial previously reported the feasibility of TKI interruption and immunotherapy maintenance in pts achieving tumor response after TKI+IO combination, achieving its primary endpoint. Here we reported the updated results with a longer follow-up.
Methods:
Pts with surgery for primary tumor, without symptomatic/bulky disease or liver mets, were treated with Ave 800 mg flat dose IV Q2W + Axi 5 mg PO BID for 36 weeks (W). At W36, pts who achieved partial response (PR) interrupted Axi and continued Ave until progression of disease (PD) or unacceptable toxicity. In case of PD while on Ave, Axi was restarted and interrupted again in case of new PR. Pts without PR at W36 continue the combo until PD. Here we reported the updated results for mPFS and mOS in the overall population and in those pts who interrupted Axi. The outcome after Axi reintroduction was also described.
Results:
75 pts were evaluated in the efficacy analysis (40% favorable risk, 60% intermediate/poor risk). At the cutoff data Apr 2024, after a median follow up of 31.7 mos, the mPFS was 27.9 mos (95%CI, 23.0 - 32.8) while the mOS was not reached and the 24-mos OS rate was 85%. The median duration of 1
st
avelumab maintenance was 16 weeks. Among the 29 pts who interrupted Axi at W36, the mPFS and the mOS were not reached; while the 24-mos PFS and OS rates were 68% and 82%, respectively. After Axi interruption 5 pts were ongoing with avelumab without evidence of PD; 1 discontinued Ave for toxicity after 35.8 mos of maintenance; 2 patients continue Ave alone despite the evidence of PD;21 restarted Axi. Among these 21 pts, after the restart of axitinib, the ORR was 50% (10 pts PR; 8 pts SD; 2 pts PD; 1 pt NA), and the mPFS was 17.2 mos (95%CI, 11.9 – 22.5).
Conclusions:
Updated results of the TIDE-A study confirmed the feasibility of TKI interruption and IO maintenance in selected mRCC pts after initial response to first line combination of Ave plus Axi. The progression during maintenance with IO alone did not affect the response to the subsequent TKI reintroduction. This strategy warrants further investigation in a randomized trial. Clinical trial information:
NCT04698213
.
Systemic therapies in renal cell carcinoma with brain metastases: A comparative meta-analysis of immunotherapy and tyrosine kinase inhibitors.
Authors: Jamil Abdur , Qureshi Zaheer , Bardhan Roshmita , Ahmad Mohsin , Selene Insija Ilyas
Published: February 2025

559

Background:
Renal cell carcinoma (RCC) with brain metastases presents a clinical challenge. Management remains unclear, as systemic therapy data are limited and many trials exclude patients with active brain metastases. Current treatment primarily involves CNS-targeted radiation (e.g., stereotactic radiosurgery and whole-brain radiation therapy), while systemic therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are underexplored. This meta-analysis evaluates the efficacy of systemic treatments and whether these patients should continue to be excluded from clinical trials.
Methods:
A systematic search of PubMed, CENTRAL, MEDLINE, and Google Scholar was conducted through October 2024, focusing on studies of mRCC patients with brain metastases treated with ICIs, TKIs, or their combination. ICI therapies included nivolumab, ipilimumab, pembrolizumab, atezolizumab, and avelumab, while TKIs included sorafenib, sunitinib, and cabozantinib. Case reports, ongoing trials, narrative reviews, and meta-analyses were excluded. Primary endpoints were complete response (CR), partial response (PR), objective response rate (ORR), and overall survival (OS). Statistical analyses used fixed/random-effects models based on heterogeneity.
Results:
Nineteen studies involving 947 mRCC patients with brain metastases were included. The pooled analysis showed an ORR for ICIs of 29.9%, with a CR of 3.4% and PR of 28.9%. Brain-specific ORR, CR, and PR for ICIs were 27.5%, 10.8%, and 17.9%. TKIs alone showed a pooled ORR of 11.7%, with a CR of 1.3% and PR of 11.6%. Brain-specific ORR, CR, and PR for TKIs alone were 38.1%, 6.9%, and 29.5%. Only one study reported on ICI-TKI combinations, with an ORR of 0%. Survival analysis showed significantly worse OS for brain metastasis patients treated with ICIs plus TKIs (HR: 2.06, p=0.001) and TKIs alone (HR: 2.51, p=0.02) compared to those without brain metastases.
Conclusions:
ICIs had superior overall response rates compared to TKIs and ICI-TKI combinations in mRCC patients with brain metastases. Brain-specific response rates were similar between ICIs and TKIs. Given the poor prognosis of brain metastasis patients treated with TKIs, further research is needed to determine if they should continue to be excluded from trials. Larger prospective studies are required to confirm these findings and optimize treatment.
Innovative diagnostic approaches: Serum protein markers in renal cell carcinoma.
Authors: Davis Laura Elizabeth , Wang Betty , Maina Eran Ndegwa , Campbell Rebecca , Sindhani Mohit , Wee Christopher Eing , Weight Christopher , Abbosh Phillip , Campbell Steven , Abouassaly Robert , Calaway Adam C. , Barata Pedro C. , Bukavina Laura
Published: February 2025

560

Background:
In the era of precision medicine, we pursue less invasive, more powerful methods for screening, response prediction, and recurrence detection. While liquid biopsy has proven useful in other malignancies, similar diagnostic and prognostic tools for renal cell carcinoma (RCC) remain to be elucidated. We therefore aimed to investigate serum protein expression in patients before their RCC diagnosis vs. non-cancer controls to identify protein-cancer associations likely to have a role in cancer development and progression.
Methods:
Utilizing UK Biobank, we analyzed proteomic data in patients previously diagnosed with RCC (n=2245) vs. patients without RCC at time of serum collection who were later diagnosed (n=1225) vs. a cohort of non-cancer controls (n=44386). We estimated hazard ratios (HRs) and 95% confidence intervals (CI) using Cox proportional regression models. We investigated protein and RCC cancer-risk associations to examine the effects of reverse causality and conducted analyses to generate area under the curve (AUC) values to evaluate diagnostic performance of biomarkers.
Results:
We identified associations between elevated levels of tafa5, klk11, klk8, csdn, and clmp proteins and undiagnosed RCC. Highly expressed proteins in each cohort showed increased HR for cancer association (95% CI), with tafa5 exhibiting the highest HR in the treated group HR 9.7 (95%CI 6.3-12.0;p<0.00). Receiver operating characteristic curve demonstrated strong predictive capabilities: igfbp4 (AUC 0.9127;SN 0.8056;SP 0.8606), tafa5 (AUC 0.9134;SN 0.7500;SP 0.8996), tgfbr2 (AUC 0.9057;SN 0.6667;SP 0.9083), scarb2 (AUC 0.8968;SN 0.7500;SP 0.9197), nectin4 (AUC 0.9269;SN 0.7222;SP 0.9299) in the treated group. These findings indicate that specific proteomic biomarkers may have a significant association with RCC diagnosis, with high AUC values supporting their potential utility in RCC diagnosis and prognosis. Prospective validation in clinical settings is warranted.
Conclusions:
Our study highlights distinct protein elevations between patients presenting with RCC vs. those who were later diagnosed. Although further studies are warranted, the favorable HR, AUC, SN, and SP values for several proteins identified here underscore their potential as biomarkers for RCC diagnosis and prognosis.
PSMA-positive tumor vessels around renal cell carcinoma with high angiogenic potential as therapeutic targets and predictors of tumor recurrence.
Authors: Watanabe Ryuta , Kagimoto Keito , Chosei Mami , Arai Haruna , Sakaue Tomohisa , Kurata Mie , Miura Noriyoshi , Kitazawa Riko , Kikugawa Tadahiko , Higashiyama Shigeki , Saika Takashi
Published: February 2025

561

Background:
The expression of prostate-specific membrane antigen (PSMA) protein increases as prostate cancer advances and metastasizes. Recently, 68Ga-labeled PSMA PET has been used in diagnosing prostate cancer. Our previous studies demonstrated that PSMA-positive vesicles secreted by prostate cancer cells enhance the angiogenic activity of vascular endothelial cells, suggesting a role for PSMA in tumor angiogenesis. In this study, we focus on renal cell carcinoma, examining the relationship between PSMA expression in peritumoral blood vessels and clinical outcomes, particularly tumor recurrence, in surgically excised renal cancer specimens.
Methods:
Immunohistochemical analysis was performed on renal cell carcinoma samples from 45 patients who underwent nephrectomy or partial nephrectomy at our institution between January 2018 and December 2022. The correlation between PSMA expression levels in tumor-associated vessels and the rate of recurrence was evaluated. In addition, PSMA levels in human umbilical vein endothelial cells (HUVECs) treated with conditioned medium (CM) from renal cancer cell lines Caki1 and ACHN were analyzed by Western blotting (WB) and immunofluorescence (IF). Angiogenic activity was measured using a tube formation assay, and RNA sequencing (RNA-seq) was conducted to examine gene expression changes in endothelial cells influenced by vesicles secreted from renal cancer cells. Spatial gene expression analysis was performed to compare differences in gene expression between tumor vessels near and vessels away from the tumor.
Results:
Immunohistochemical staining for PSMA and CD31 revealed that only peritumoral vessels exhibited PSMA positivity. PSMA expression was categorized into three levels: weak (18 cases), moderate (11 cases), and strong (16 cases), with these levels corresponding to different recurrence rates. When the 10,000 g pellet fraction of CM from renal cancer cell lines was applied to HUVECs, they became PSMA-positive, leading to enhanced tube formation. RNA-seq analysis further demonstrated that HUVECs exposed to CM from renal cancer cells showed upregulation of pathways associated with angiogenesis.
Conclusions:
Vesicles secreted by renal cancer cells promote PSMA expression in vascular endothelial cells and boost angiogenic activity. Future research will aim to elucidate the mechanism by which PSMA becomes expressed in normal vascular endothelial cells, with the potential to pave the way for new anti-angiogenic therapies.
The prognostic utility of preoperative β2 microglobulin in patients with renal cell carcinoma.
Authors: Palmateer Gregory , Nicaise Edouard , Goodstein Taylor , Patil Dattatraya H. , Joshi Shreyas , Narayan Vikram M. , Ogan Kenneth , Master Viraj A.
Published: February 2025

565

Background:
β2 microglobulin is a nonglycosylated protein synthesized by all nucleated cells. It has been utilized as a tumor marker in several different malignancies, however, studies examining its role in renal cell carcinoma (RCC) are limited.
Methods:
Using the Emory kidney cancer database, patients with any stage or histology RCC who underwent partial or radical nephrectomy from 2000 to 2022 and had an available β2 microglobulin within 90 days before surgery were included. β2 microglobulin ≥ 2.34 mg/L was considered elevated. Patient and surgical characteristics were recorded. Kaplan-Meier curves and multivariable Cox hazards models were used to assess the association between an elevated β2 microglobulin and overall (OS) and cancer-specific survival (CSS). Subgroup analysis was performed based on renal function (estimated glomerular filtration rate (eGFR) ≤ or > 60 mL/min/1.73m
2
) and metastatic disease status.
Results:
Of 429 patients who met inclusion criteria, 178 (41.5%) had an elevated preoperative β2 microglobulin. After adjusting for confounders, an elevated β2 microglobulin was independently associated with worse CSS (HR 2.08 [95% CI 1.20–3.60]; p = 0.009) and OS (HR 1.58 [95% CI 1.03–2.41]; p = 0.035) compared to a normal β2 microglobulin. On subgroup analysis, however, elevated β2 microglobulin remained significantly associated with worse OS/CSS only in patients with normal renal function and non-metastatic disease (Table).
Conclusions:
A preoperatively elevated β2 microglobulin level is independently associated with worse OS and CSS in patients with RCC undergoing nephrectomy. The utility of β2 microglobulin as a prognostic indicator is most relevant for patients with normal renal function and non-metastatic disease.

Multivariable Cox hazards model for the effect of preoperative β2 microglobulin on cancer-specific and overall survival in patients with renal cell carcinoma according to renal function and metastatic disease status.

Covariants

n(%)
Cancer-specific SurvivalHazard Ratio (95% CI)
p-value
Overall SurvivalHazard Ratio (95% CI)
p-value

β2 microglobulin ≥ 2.34 mg/L
metastatic disease
102 (63)
0.95 (0.51-1.76)
0.872
0.93 (0.56-1.55)
0.779

non-metastatic disease
76 (28.5)
4.55 (1.24-16.77)
0.023
2.99 (1.37-6.54)
0.006

eGFR ≤ 60*
99 (23.1)
1.31 (0.69-2.49)
0.410
1.51 (0.95-2.41)
0.083

eGFR > 60*
79 (18.4)
2.90 (1.54-5.44)
< 0.001
2.00 (1.19-3.36)
0.009

β2 microglobulin < 2.34 mg/L
eGFR ≤ 60*
50 (11.7)
1.24 (0.55-2.78)
0.600
1.39 (0.74-2.60)
0.309

eGFR > 60*
201 (46.9)
Ref

Ref

*Calculated using Chronic Kidney Disease Epidemiology Collaboration 2021 equation. Variables in model include age, sex, race, Body Mass Index (BMI), Charlson Comorbidity Index (CCI) pT stage, Fuhrman grade, presence of IVC thrombus, receipt of systemic therapy, and IMDC risk score (metastatic patients only).
Association between site of metastases and survival stratification of the IMDC classification in metastatic renal cell carcinoma (mRCC).
Authors: Zeppellini Annalisa , Patelli Giorgio , Pedrani Martino , Vaghi Caterina , Romanò Rebecca , Roazzi Laura , Martinelli Francesca , Pierri Silvia , Calvanese Gabriele , Ciarlo Gabriele , Sartore-Bianchi Andrea , Spina Francesco , Siena Salvatore
Published: February 2025

566

Background:
The IMDC risk model is pivotal for prognostic stratification of mRCC, dividing patients into favorable (FAV), intermediate (INT) and poor-risk (POOR) groups with distinct overall survival (OS) estimates. While valuable for treatment decisions in first line, IMDC does not encompass sites of metastasis, potentially missing a significant prognostic factor.
Methods:
We retrospectively included mRCC patients receiving first-line therapy at Niguarda Cancer Center, Milan, Italy from 2008 to 2024. The primary aim was to evaluate if specific metastatic sites could redefine IMDC prognostic stratification. OS was analyzed using Kaplan-Meier estimates. Univariate and multivariate Cox regression analyses were performed including variables in the table.
Results:
164 patients were eligible for analysis. Bone, liver and nodal metastases were independent negative prognostic factors both in univariate and multivariate analyses (HR 2.83, IC95% 1.78-4.49, p<0.001; HR 1.79, IC95% 1.12-2.85, p=0.014; HR 1.92, IC95% 1.28-2.88, p=0.002, respectively). As expected, FAV IMDC and first-line immunotherapy-based combinations (IO-IO or IO-TKI) were positive prognostic factors (both p<0.001). Having at least one bone and/or liver and/or nodal metastasis (B/L/N) was significantly associated with poorer prognosis and could re-stratify INT IMDC patients into two subpopulations with different OS (HR 1.88, p=0.046): B/L/N-positive INT OS rates were not different from POOR (p=0.193) and B/L/N-negative INT OS rates were comparable to FAV (p=0.193).
Conclusions:
B/L/N metastases are independent prognostic factors in mRCC, despite being unaddressed by IMDC. Present findings align with prior research supporting the inclusion of metastatic sites in prognostic scores. IMDC classification could be refined with inclusion of metastatic sites to improve prognostic accuracy.

Patient characteristics.

Age
≥50
147 (90)

Sex
Male
123 (75)

IMDC
FAV
42 (26)

INT
85 (52)

POOR
37 (22)

Site of metastasis
Bone
40 (24)

Liver
31 (19)

Nodal
85 (52)

Oligometastases (<4)

33 (20)

First-line immunotherapy-based combinations

38 (23)

Data are shown as number of patients (N) and, within brackets, percentage (%).
ABCA1 and ABCG1 cholesterol transporters expression on metastatic renal cell carcinoma: Impact on immunotherapy outcomes (CHOMET study).
Authors: Giudice Giulia Claire , Mazzaschi Giulia , Maffezzoli Michele , Acunzo Alessandro , Gnetti Letizia , Silini Enrico Maria , Campanini Nicoletta , Rapacchi Elena , Caruso Giuseppe , Tuttobene Pietro , Buti Sebastiano
Published: February 2025

568

Background:
Although immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, most patients do not achieve benefits, emphasizing the need to understand the mechanisms of resistance. Previous analysis highlighted the association between blood cholesterol levels, passive cholesterol diffusion efflux and oncological outcomes. Here we reported the preliminary data of the CHOMET study, aimed at assessing the cholesterol transporters ABCA1 and ABCG1 expression in ICIs-treated patients with metastatic renal cell carcinoma (mRCC).
Methods:
The present is a monocentric retrospective study on patients with mRCC receiving first-line ICI-based combination. The primary objective was to assess the ABCA1/G1 expression by immunohistochemistry and its impact on overall survival (OS). The secondary objectives included the impact on progression-free survival (PFS) and disease control rate (DCR: complete and partial responses plus stable disease). Survival times were calculated by Kaplan-Meier method and comparisons between groups were performed by log-rank test.
Results:
61 patients were enrolled, clear cell RCC was the most frequent histotype (78.8%). With a median follow-up of 30.4 months (22.1-37.0), median OS was 38.9 months (CI 33.9-NR) and median PFS was 24.4 months (CI 10.1-34.2). For the present analysis, the ABCA1/G1 histological evaluation of tumour samples was available for 43 and 41 patients, respectively. The median expression level was 50% for ABCA1 and 45% for ABCG1. We found a significant correlation between higher ABCA1/G1 staining intensity expression and both shorter median OS and PFS (Table). Similarly they were inversely related to DCR (Table).
Conclusions:
For the first time, we reported a high expression of ABCA1/G1 cholesterol transporter on kidney cancer. An inverse association between staining intensity expression and oncological outcomes in patients receiving ICIs combinations was found.

Oncological outcomes according to ABCA1/G1 staining intensity expression.

IHC
mPFS months (95%CI)
mOSmonths (95%CI)
DCR%

ABCA1 intensity expression

1+
30.1 (25.8-NR)
NR (NR-NR)
88.9

2+
24.4 (9.9-NR)
NR (33.9-NR)
72.7

3+
4.5 (3.20-NR)
12.2 (8.2-NR)
25.0

p
value

0.016

< 0.001

0.013

ABCG1 intensity expression

1+
62.7 (25.6-NR)
NR (NR-NR)
87.5

2+
17.4 (9.9-NR)
NR (NR-NR)
68.2

3+
6.65 (2.9-NR)
12.2 (3.8-NR)
37.5

p value

0.006

0.013

0.101

DCR: disease control rate, IHC: immunohistochemistry, mOS: median overall survival, mPFS: median progression-free survival, NR: not reached.
Identification of potential immune evasion mechanisms in aggressive small renal cell carcinomas through single-cell and bulk RNA sequencing.
Authors: Park Jee Soo , Kim Eun Chae , Song Seol , Kim Jongchan , Jang Won Sik , Hwang Byungjin , Ham Won Sik
Published: February 2025

574

Background:
Small renal cell carcinoma (RCC) is generally nonaggressive but in some cases, small RCCs exhibit distant metastasis. The biology and biomarker of small aggressive RCCs remain unclear, necessitating appropriate evaluation to avoid undertreatment. Previous biomarker studies via genetic profiling of tumor tissues were hindered by RCC heterogeneity. We utilized bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) of blood samples to identify genetic biomarkers and characterize the tumor immune microenvironment in patients with aggressive small RCC.
Methods:
We identified four T1a (≤4 cm) clear cell RCCs (ccRCC) with synchronous distant metastasis as aggressive, and four age-, sex-, and tumor size-matched ccRCC patients without metastasis as non-aggressive, from a prospective cohort (ClinicalTrials.gov Identifier: NCT03694912). Two healthy kidney donors served as controls. Using the 10X Genomics platform, we performed scRNA-seq and bulk analysis on ten peripheral blood mononuclear cell (PBMC) samples. Samples were demultiplexed with Souporcell, and sequencing reads were normalized and analyzed using R/Seurat. Cellular components were identified with marker genes, and bulk analysis included differential gene expression and pathway enrichment.
Results:
The mean tumor size and age of the eight ccRCC patients were 2.5 cm and 63 years, respectively. Among the four aggressive ccRCCs, two had lung metastasis and two had bone metastasis. We analyzed 32,417 cells, identifying 41 subpopulations. Single-cell analysis revealed variations in T and natural killer (NK) cell proportions among aggressive, non-aggressive, and normal groups, with significant differences. The aggressive group showed increased MYOM2, OVCH1-AS1, and HLA-DQA2 expression. Despite an increased proportion of CD4+ cytotoxic T lymphocytes (CTLs) with disease severity, key cytotoxic and immune regulatory genes like GNLY, CD247, CCL4, NKG7, and TGFB1 were decreased, suggesting compromised antitumor function in aggressive states.
Conclusions:
This study offers insights into the molecular and cellular characteristics of aggressive small RCCs via PBMC analysis using single-cell and bulk RNA sequencing. The increased proportion of CD4+ CTLs with decreased expression of critical cytotoxic and immune regulatory genes in aggressive RCCs suggests a mechanism for immune evasion. These findings enhance our understanding of aggressive small RCC biology and highlight potential biomarkers and therapeutic targets for adjuvant treatment. Clinical trial information:
NCT03694912
.
A comprehensive evaluation of gene expression-based signatures for detecting tertiary lymphoid structures (TLS) in metastatic renal cell carcinoma (mRCC).
Authors: Saad Eddy , El Ahmar Nourhan , Simsek Berkay , Jegede Opeyemi , Matar Sayed , Mohanna Razan Assaad , Yekeduz Emre , McDermott David F. , Plimack Elizabeth R. , Sosman Jeffrey A. , Haas Naomi Balzer , Hurwitz Michael E. , Hammers Hans J. , Van Allen Eliezer Mendel , Choueiri Toni K. , Atkins Michael B. , Signoretti Sabina , Braun David A.
Published: February 2025

591

Background:
TLS are organized lymphoid aggregates linked to improved response to immunotherapy in multiple cancers, including mRCC. Traditionally, TLS assessment relies on pathological staining of tumor sections. In this study, we evaluated the performance of TLS gene-expression signatures as an alternative diagnostic tool.
Methods:
Primary tumors from treatment-naïve patients with mRCC in the HCRN GU16-260 trial were analyzed using multiparametric immunofluorescence (IF), staining for CD3, CD20 (TLS), CD21 (mature TLS), and CD8. The counts and densities of total and mature TLS were calculated. Bulk RNA sequencing was performed on the same specimens, and 4 gene signature scores (Meylan, Cabrita, Coppola, and Ng) were estimated using gene set variation analysis (GSVA). Spearman's correlations between signature scores and TLS IF parameters, as well as the area under the receiver operator characteristic (AUROC) curve, were computed.
Results:
Our cohort included 78 patients with matched IF and RNA-seq data. All 4 TLS signatures demonstrated strong predictive performance for detecting the presence (vs. absence) of TLS by IF in each sample (AUROC 0.8 to 0.85). Quantitatively, the 4 TLS signature scores, measured as continuous variables, correlated with IF-based counts and densities of total TLS, and to a lesser extent, mature TLS (Table). In terms of comparative performance, Meylan’s signature showed the highest correlation with IF TLS features, while Ng’s was the least correlated (Table). Furthermore, Meylan’s signature achieved the best predictive ability to stratify high vs. low TLS (AUROC 0.83) and was more specifically correlated with TLS compared to CD8 density (Table).
Conclusions:
Expression-based signatures exhibit robust predictive ability for TLS detection and quantification, similar to previously established CD8 signatures, and represent valid surrogate tools to complement pathological diagnosis.

Spearman’s correlations between IF parameters and TLS signatures.

Parameter
Meylan
Cabrita
Coppola
Ng

Total TLS count

ρ=0.65,
P=
1.1x10
-10

ρ=0.58,
P=
2.9x10
-8

ρ=0.56,
P=
7.1x10
-8

ρ=0.42,
P=
1.4x10
-4

Mature TLS count

ρ=0.51,
P=
2.1x10
-6

ρ=0.41,
P=
1.8x10
-4

ρ=0.34,
P=
2.3x10
-3

ρ=0.39,
P=
5.0x10
-4

Total TLS density

ρ=0.63,
P=
6.1x10
-10

ρ=0.58,
P=
3.4x10
-8

ρ=0.55,
P=
2.2x10
-7

ρ=0.42,
P=
1.4x10
-4

Mature TLS density

ρ=0.49,
P=
5.1x10
-6

ρ=0.39,
P=
3.5x10
-3

ρ=0.32,
P=
4.3x10
-3

ρ=0.38,
P=
6.8x10
-4

CD8 density

ρ=0.42,
P=
3.1x10
-4

ρ=0.62,
P=
2.1x10
-8

ρ=0.67,
P
<2.2x10
-16

ρ=0.35,
P=
2.9x10
-3
Evaluating the combined role of HHLA2 and PD-L1 as biomarkers in first-line nivolumab therapy in advanced clear cell renal cell carcinoma.
Authors: Nabil Laimon Yasmin , El Ahmar Nourhan , Jegede Opeyemi , Baghari Sheshdeh Aseman , Freeman Gordon J. , McDermott David F. , Atkins Michael B. , Signoretti Sabina , Mahoney Kathleen Margaret
Published: February 2025

598

Background:
PD-1 directed immune checkpoint inhibitors are effective in many tumor types, including kidney cancers. HHLA2 is a negative immune checkpoint, generally expressed on PD-L1 negative clear cell renal cell carcinomas (ccRCC) (Bhatt, et al. 2021). Therapeutics targeting either HHLA2 or its inhibitory receptor KIR3DL3 are in Phase I trials and predictive biomarkers are needed to help direct treatment. We previously reported that efficacy of nivolumab correlated with tumor PD-L1 status in patients with kidney cancer treated in the first line setting (GU16- 260; Atkins, et al. 2022). We hypothesize that HHLA2 expression in combination with PD-L1 expression may provide a clinically significant biomarker for resistance to PD-1 blockade in patients with advanced ccRCC.
Methods:
HHLA2 expression in tumor cells (TC) was assessed by immunohistochemistry coupled with image analysis algorithms in 63 pre-treatment primary ccRCC tissues from patients enrolled in the HCRN GU16-260 trial. TC PDL-1 positivity had been previously evaluated in this cohort (Atkins, 2022). TC HHLA2 expression in combination with TC PD-L1 expression was correlated with progression-free survival (PFS) and objective response rate (ORR).
Results:
Consistent with our prior reports, HHLA2 expression did not overlap with PD-L1 expression on tumor cells. TC HHLA2 expression in combination with TC PD-L1 expression identified three groups of patients with different clinical outcomes with regards to ORR (trend test p-value = 0.016) and PFS (trend test p-value = 0.024) (Table). Patients with positive (>0%) TC PD-L1 expression had the best outcomes (ORR=62.5%, median PFS=24.7 months); patients with negative TC PD-L1 expression and low (<61%) TC HHLA2 expression had intermediate outcomes (ORR=38.5%, median PFS=10.6 months) and patients with negative TC PD-L1 expression and high (≥61%) TC HHLA2 expression had the worst outcomes (ORR=12.5%, median PFS=3.5 months).
Conclusions:
Further investigation of the HHLA2/PD-L1 combined biomarker is warranted as it may be helpful in identifying patients that do not respond to anti-PD-1 therapy but could benefit from agents targeting the HHLA2/KIR3DL3 pathway.

HHLA2 and PDL-1 category
Number of patients(63 total)
ORR
PFS (median, months)

TC PD-L1 >0%
16
62.5%
24.7

TC PD-L1 = 0% & TC HHLA2 <61% (low)
39
38.5%
10.6

TC PD-L1 = 0% & TC HHLA2 ≥61% (high)
8
12.5%
3.5

Trend test p-value

0.016

0.024
Risk factors of complications after inguinal lymph node dissection in patients with penile cancer.
Authors: Gao Yilong , Shao Yanxiang , Li Xiang
Published: February 2025

6

Background:
Inguinal lymph node dissection (ILND) is a crucial step in the management of patients with penile cancer, particularly for those with lymph node involvement. However, ILND is associated with a significant risk of postoperative complications, which can impact recovery and long-term outcomes. Identifying the risk factors that contribute to these complications may help in improving patients’ quality of life after ILND and perioperative management.
Methods:
We conducted a retrospective analysis of 192 penile cancer patients who underwent ILND between October 2008 and October 2023 at West China Hospital. 370 surgeries were conducted. Data on patient demographics, tumor characteristics, comorbidities, surgical details, and postoperative outcomes were collected. Complications were classified as minor or major based on the Clavien-Dindo classification. Multivariate logistic regression was performed to identify independent risk factors for each complications. Receiver operating characteristic (ROC) curves were used to analyze the relationship between certain risk factors and postoperative complications and find cut-off points for certain risk factors.
Results:
The overall complication rate was 87.5%, with most patients experiencing minor complications. Common complications included wound infections (35.4%), lymphatic fistula (50%), lymphocele (42.2%) and lower limb edema (28.6%). Except for the common risk factors, such as surgery type (conventional or minimally invasive, Odds Ratio (OR): 0.157, 95% Confidence Interval (CI): [0.036, 0.692],

p

=0.014) for wound infection, we additionally found that the shorter retention time of drainage tube (OR: 0.784, 95% CI: [0.724, 0.850],

p

<0.001) is strongly correlated with subsequent lymphocele, with cut-off points of 6.5 days. And longer retention time of drainage tube (OR: 1.065, 95% CI: [1.031, 1.100],

p

<0.001) is correlated with wound infection, with cut-off points of 10.5 days.
Conclusions:
Our study highlights several modifiable and non-modifiable risk factors associated with each complications following ILND in penile cancer patients. Optimizing perioperative care and conducting minimally invasive surgery when possible may reduce postoperative complication rate. And the duration of drainage tube retention is associated with both lymphocele and wound infection. Further prospective studies are warranted to validate these findings.
Surgical variables and risk factors associated with urinary leak following partial nephrectomy: Insights from a high-risk population.
Authors: Patel Milan , Loebach Lauren , Blachman-Braun Ruben , Millan Braden , Saini Jaskirat , Gurram Sandeep , Linehan W Marston , Ball Mark Wayne
Published: February 2025

604

Background:
Urinary leak (UL) is a common complication following partial nephrectomy (PN). This study aims to identify the risk factors and surgical variables associated with the development of UL following PN in a cohort that includes a significant number of patients with hereditary renal cancer syndromes, multiple tumors, and a history of prior PNs.
Methods:
A retrospective chart review was conducted to identify patients who underwent PN at our institution from January 2006 to December 2023. Clinical, demographic, and surgical characteristics were recorded and analyzed. Statistical analysis was performed with SPSS v.29.0.
Results:
A total of 1173 PNs were analyzed, of which 89 (7.6%) had a UL. Patients had a median age at time of surgery of 50 [Interquartile range (IQR): 38 - 59] years, and 3 [IQR: 1 - 6] tumors removed per procedure. The robotic approach was utilized in 61.6% of cases, and the most common diagnosis was von Hippel-Lindau disease (47.4%). The frequency of UL was 5.1% for first-time PN, 10.4% for second, and 19.6% for third. Multivariable-adjusted analysis demonstrated an increased risk of UL with 3
rd
PN (OR 2.379; p = 0.013), higher intraoperative estimated blood loss (per 100mL: OR 1.016; p = 0.006) and a decreased risk with robotic approach (OR 0.376; p < 0.001). (Table) Overall, 98.9% of UL cases (88 patients) were successfully managed with conservative management (post-op drain and foley), ureteral stent placement, percutaneous drain, or nephrostomy tube.
Conclusions:
In this cohort, UL is associated with the complexity of the surgery (repeat PN and higher EBL). A robotic approach had a lower risk of UL, while all but one UL were effectively managed non-operatively. Future research should investigate intraoperative and postoperative strategies to minimize this complication.

Multivariable-adjusted logistic regression analysis evaluating the association between clinical variables and urinary leak after partial nephrectomy.*

OR
95% CI
p-value

Partial nephrectomy count

1
1

2
1.693
0.973 - 2.944
0.062

3
2.379
1.200 - 4.714
0.013

≥ 4
1.121
0.326 - 3.848
0.856

Surgical approach

Open
1

Laparoscopic
0.324
0.042 - 2.517
0.281

Robotic
0.376
0.225 - 0.631
< 0.001

EBL (per 100 mL)
1.016
1.004 - 1.028
0.006

CI: Confidence interval, EBL: Estimated blood loss, OR: Odds ratio.

*Analysis conducted using variables listed as well as age, gender, kidney laterality, race, ethnicity, presence of solitary kidney, surgical technique, total number of tumors removed, and size of largest tumor removed.
Prospective COTRIMS (Cologne trial of retroperitoneal lymphadectomy in metastatic seminoma) trial: Final results.
Authors: Heidenreich Axel , Pfister David , Paffenholz Pia
Published: February 2025

618

Background:
Radiation or chemotherapy represent the standard treatment in clinical stage IIA/B seminoma. Despite high cure rates both modalities are associated with significant long-term toxicities. The COTRIMS trial evaluated the oncological and functional efficacy of primary retroperitoneal lymphadenectomy (RPLND) without adjuvant chemotherapy in CS IIA/B seminomas.
Methods:
34 patients with CS IIA/B pure semimomas were prospectively recruited. Exclusion criteria were adjuvant chemotherapy following orchiectomy, CS IIC, previous retroperitoneal surgery or radiation, positive tumor markers. All patients underwent nerve sparing RPLND with a unilateral template; no adjuvant chemotherapy was delivered. Follow-up was done according to EAU guidelines. In 22 patients miR371 was evaluated preoperatively and correlated with pathohistology of lymph nodes. The primary endpoint of the study was a relapse-free rate of < 20% at 3 years.
Results:
Median age is 34.2 (21-54) years, mean and median follow-up is 41.5 (4-73) and 33.4 (13-56) months. 22 and 12 pts had CS IIA and CS IIB, resp. Mean OR-time, blood loss and hospitalisation were 131 (105-195) min, < 150ml and 4 (3-9) days. 4 (11.7%) pts experienced Clavien Dindo 3a complication. Antegrade ejaculation was preserved in 88%. A mean of 19 (7-57) lymph nodes were dissected. Mean number of positive lymph nodes was 1.4 (1-2), mean diameter was 2.3 (0.8-4.1) cm. Seminoma was present in 85%, non-malignancy and nonseminoma were found in 8.9% and 5.9%. miR371 was positive in 17/18 pts with metastases und negative in 3/3 with benign lesions. 4 (11.7%) pts relapsed after 4, 6, 9 and 12 months and all were salvaged by chemotherapy.
Conclusions:
RPLND results in high cure rates associated with low frequency of surgery – related complication even after a follow-up of about 3 years. Nearly 90% of patients can be managed without systemic chemotherapy. RPLNSD should be included in the treatment options for CS IIA/B seminomas. miR371 appears to be a valid biomarker to predict presence of lymph node metastases. Clinical trial information:
DRKS00025384
.
Survival outcomes of testicular cancer (TC) in Hispanic men based on analyses from the National Cancer Database (NCDB).
Authors: Yu Eun-mi , Wang Hongkun , Aragon-Ching Jeanny B.
Published: February 2025

622

Background:
The incidence of TC among Hispanic men has been rising, as reported in our analysis of patients in the United States (Yu et al., JCO 2024 42 (4):503). We sought to determine the survival outcomes in Hispanic men based on data obtained from the National Cancer Database (NCDB).
Methods:
We extracted patient-level data from the NCDB and identified the incidence, demographics, treatment patterns, and outcomes in Hispanic men with TC diagnoses (non-seminoma, NS; seminoma, S) from 2004 to 2020.
Results:
There were a total of 89550 patients (pts) in the database. Median age at diagnosis was 37 years and 29 years for S and NS pts, respectively. There were 11005 (12.3%) TC pts designated as Hispanic (H), of whom 5396 and 5609 had S and NS TCs, respectively. In contrast, there were a total number of 74350 non-Hispanic (NH) patients with TC; n = 43629 with S, n = 30721 with NS. The majority of H pts had a Charlson-Deyo score of 0 (94.2%). Less than half of H pts had private insurance (48.8%) compared to three-quarters of NH patients (75.1%). 19.6% of H pts were diagnosed with stage II & III TC (compared to 15.8% in NH pts). Pts were treated at academic/research centers in 6.6% of H pts versus 10.8% in NH pts. For S pts, radiation was utilized in 19.4% of H pts vs 25.8% in NH pts, chemotherapy utilized in 28.3% H pts vs 24.4% in NH pts, whereas chemotherapy for NS pts was utilized in 60.1% in H pts vs 53.4% in NH pts. Overall Survival (OS) was not significantly different in S pts for H pts vs NH pts (Log-rank p = 0.066), but among NS pts, H patients did worse compared to NH pts (Log-rank p < 0.001) although OS differences were seen in pooled analyses of S and NS pts (log-rank p < 0.001).
Conclusions:
Our analysis reports on the treatment patterns and survival of Hispanic men with TC. Survival appears to be worse for Hispanic patients with non-seminoma compared to non-Hispanic patients, but outcomes for seminoma are similar. We also noted slight differences in patterns of treatment receipt for seminoma versus non-seminoma in Hispanic men which may have to do with stage at diagnosis and access to care.