bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between molecular changes and perioperative immunotherapy in patients with advanced clear cell renal cell carcinoma undergoing cytoreductive nephrectomy.
Authors: Issa Wadih , Kaur Navneet , DeVilbiss Andrew , Yu Ze , Zhou Qinhan , Gunenc Damla , Xing Chao , Wang Andrew Zhuang , Zhang Tian
Published: February 2025

573

Background:
Immunotherapy (IO) combinations are standard first-line treatments for advanced clear cell renal cell carcinoma (ccRCC). However, identifying patients who will respond to IO remains a challenge, complicating treatment selection. Previous studies on biomarkers for IO response or resistance often used unmatched biopsies, limiting insights into therapy-induced changes due to patient heterogeneity. This study aims to evaluate transcriptomic changes in matched pre- and post-IO patient samples to detect treatment-induced gene and pathway alterations.
Methods:
A retrospective analysis was performed on patients with advanced ccRCC receiving IO-based therapies who underwent cytoreductive nephrectomy (Nx) at UT Southwestern/Simmons Comprehensive Cancer Center (SCCC). Patient-level data were extracted from an IRB-approved registry, and samples were collected from the SCCC biorepository. The primary endpoint was to identify IO-induced transcriptomic changes using paired pre- and post-treatment tissue sections. Regions of interest (ROIs) were selected based on pan-cytokeratin (PanCK) expression using the GeoMx Digital Spatial Profiler (DSP, NanoString). Whole-transcriptome analysis was performed, and data were analyzed using a two-sample t-test.
Results:
We identified 58 patients with advanced ccRCC who received perioperative IO regimens and deferred Nx. Of these, 7 patients had paired pre- and post-treatment samples sequenced (3 received ipilimumab/nivolumab, 3 nivolumab, and 1 pembrolizumab/axitinib). Individual analysis of each matched pair revealed an average of 92 DE genes (log fold-change >1.3, p<0.01). Gene set enrichment analysis (GSEA) showed differential enrichment in pathways such as immune response (interleukin signaling, JAK/STAT signaling, innate immune system activation), translational machinery, MHC-mediated tumor antigen presentation, axon guidance, and cell death pathways. Notably, a key post-IO downregulated pathway was GPCR signaling, which is implicated in tumor growth and metastasis. Taken in aggregate, bulk analysis revealed only 9 differentially expressed (DE) genes in PanCK+ tumor regions, and GSEA did not identify commonly enriched pathways.
Conclusions:
While bulk analysis detected few changes, individual pair analysis highlighted significant transcriptomic shifts in RCC tumors post-IO. These RCC tumors upregulated gene expression in several immune pathways, including interleukin, JAK/STAT, and innate immune pathways. This study underscores the importance of matched samples to capture patient-specific changes after IO combinations.
Association between vascular patterns of clear cell renal cell carcinoma and immune cell infiltration and therapeutic response.
Authors: Toma Marieta , Kempchen Tim , Li Yangping , Baschun Katharina , Hörst Fabian , Kehl Melina , Klümper Niklas , Ellinger Joerg , Ritter Manuel , Erdmann Kati , Hartmann Arndt , Kristiansen Glen , Pinetz Thomas , Grünwald Viktor , Effland Alexander , Hölzel Michael
Published: February 2025

575

Background:
Clear cell renal cell carcinoma (ccRCC) is a highly vascularized tumor with histological heterogenous appearance. We explored whether vascular pattern (VP) are predictive to response of therapy.
Methods:
We defined three categories of VP in the publicly available TCGA cohort: high-branching (HB), low-branching (LB) and sinusoid. VP-based gene signatures were generated by integrating the transcriptomes of matched ccRCC samples. We developed a learning-based (AI) algorithm for the classification of VP based on CD31 immunohistochemistry and analyzed histology specimens from patients treated with tyrosine kinase inhibitors +/- immunotherapy (TKI) (University Clinic Dresden, retrospective cohort n=38, and NivoSwitch trial NCT:
NCT03013946
, n=38 respectively) as well as the publicly available transcriptome datasets from two phase III clinical trials (JAVELIN Renal 101; IMmotion 151). Multiplex immunofluorescence (CODEX) was used for spatial mapping. Outcome measures employed KM-plots and log-rank analyses.
Results:
We identified a trajectory from a HB to LB vascular phenotype, paralleled by a decline in the expression of proximal tubule cell lineage traits. Applying the VP gene signatures to the transcriptome datasets from JR101 and IM151 we found that the progression-free survival (PFS) benefit from adding immunotherapy to anti-angiogenic therapy (IMmotion151: Bevacizumab; JAVELIN Renal 101: Axitinib) was limited to low-branching ccRCC (IM151: HR (95% CI): 0.64 (0.51-0.80), JR101: HR (95% CI): 0.45 (0.33-0.61, both p < 0.001), respectively) and linked to an immune cell infiltrated microenvironment. Patients with a HB ccRCC demonstrated prolonged PFS in the Dresden TKI cohort (p = 0.026) and in the NivoSwitch trial (p = 0.01). CODEX analysis using the SPACEc pipeline revealed profound differences in cellular neighborhoods, characterized by dense immune cell infiltration of ccRCC with LB compared to HB vascular patterns. Using 30 ccRCC patient-derived organoid in air-liquid interface (ALI) cultures, we confirmed the association between LB pattern and higher T cell infiltration, resulting in reduced viability of LB ccRCC organoids under immune-stimulating conditions.
Conclusions:
Vascular pattern can reliably predict therapy response in advanced ccRCC. Tumors with high branching phenotype respond better to anti-angiogenic TKI therapy. Low branching pattern was associated with improved response to immunotherapy.
FGD1
splice variants as predictors of brain and bone metastatic organotropism in clear cell renal cell carcinoma.
Authors: Miller Justin , Obermayer Alyssa N , Hayes Mitchell T. , Elias Roy , Singla Nirmish , Churchman Michelle L. , Grass George Daniel , Tarhini Ahmad A. , Ramos Echevarria Paola , Soupir Alex C. , Kim Youngchul , Singer Eric A. , Kern Sean , Zakharia Yousef , Viscuse Paul Vincent , Hensley Patrick J. , Shaw Timothy I , Manley Brandon J.
Published: February 2025

577

Background:
Approximately 30% of patients with ccRCC present with metastatic disease (stage IV) and close to half of patients with stage III disease will recur during follow-up surveillance. Two of the most common and morbid sites of metastatic development are brain and bone metastasis. Existing treatment guidelines do not recommend routine brain or bone directed imaging during either initial staging or surveillance in the absence of clinical signs or symptoms. A group of recurrently altered aberrant splice variants in primary ccRCC tumors associated with metastatic progression have previously been identified. Our study aims to investigate metastatic organotropism of the
FGD1
-splice variant (
FGD1
-SV) to refine risk stratification and therapeutic decision-making as cabozantinib is drug with activity at these disease sites.
Methods:
This study leveraged the ORIEN AVATAR network, a data-sharing alliance of 18 NCI-designated cancer centers, to evaluate the presence of
FGD1
-SV in a cohort of 1,001 clear cell renal cell carcinoma (ccRCC) patients using bulk RNA-sequencing (RNA-seq). Samples with three or more
FGD1
-SV reads were classified as positive. Clinical and survival data were collected, and Kaplan-Meier curves were generated. Odds ratios (ORs) evaluated the presence of
FGD1
-SV on brain and bone metastases, while hazard ratios (HRs) assessed association with cabozantinib response. Of 1,037 RNA-seq samples, 84 were metastatic tumor specimens. The relationship between
FGD1
-SV positivity and metastasis to common sites was assessed with Fisher's exact test.
Results:
Brain and bone metastases demonstrated the highest
FGD1
-SV positivity (50% and 44%, respectively). A grouped comparison of brain and bone metastases versus all other common metastatic sites (adrenal, lymph node, pancreas, lung, and liver) revealed significant enrichment of
FGD1
-SV in these metastases (OR 5.33, 95% CI [1.64 - 18.42], p=0.002).
FGD1
-SV positivity in primary tumors was associated with greater risk of recurrence after surgical resection (p=0.0029). Furthermore,
FGD1
-SV positive tumors were associated with poor survival when not treated with cabozantinib (HR 2.04, 95% CI [1.20 - 3.45], p=0.01).
Conclusions:
FGD1
-SV positivity is significantly associated with brain and bone metastatic organotropism in ccRCC. Our findings warrant prospective studies to validate these results and investigate the integration of
FGD1
-SV into clinical decision-making, potentially guiding surveillance and therapeutic approaches in high-risk and metastatic patients.
Optimizing clear cell renal cell carcinoma tumor-infiltrating lymphocytes under controlled hypoxic conditions.
Authors: Chahoud Jad , Potez Marine , Guske Christopher , Miller Justin , Ali Johannes , Carter Michael , Khambati Fatema , Johnson Jeffrey S , Fazili Adnan Nazir , Gullapalli Keerthi , Sexton Wade J. , Zemp Logan , Manley Brandon J. , Roman Souza Gabriel , Beatty Matthew , Spiess Philippe E. , Pilon-Thomas Shari
Published: February 2025

581

Background:
Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) represents a promising approach for advanced solid tumor treatment. Historically, the success of TIL therapy in clear cell renal cell carcinoma (ccRCC) has been limited by difficulty expanding cytotoxic functional TILs. Hypoxic conditions in the ccRCC tumor microenvironment have been associated with mixed tumor characteristics, including metabolic dysregulation and tumor progression. Given the significant role of hypoxia in ccRCC progression, we investigated TIL expansion under controlled hypoxic conditions and its impact on TIL cytotoxic functions.
Methods:
Fragments or tumor digests from 41 ccRCC patients were cultured with high-dose (6000IU/mL) IL-2 for four weeks. TIL expansion success was defined as at least one fragment expanding to a minimum of 2 wells. Primary TIL underwent rapid expansion protocol (REP) at 20% (normoxic) or 5% (hypoxic) O
2
levels. Cells were rested in post-REP media for 3–4 days in their respective conditions (20% or 5% O
2
) and subsequently collected for downstream analysis. Reactivity to autologous tumor, expression of activation/co-inhibitory markers, and memory phenotype were analyzed with flow cytometry and co-culture assays.
Results:
TILs were successfully grown in 87.8% of samples (36/41). TILs secreted IFNγ in response to autologous tumors in 88.6% (31/35) of the samples. Both TIL expansion and reactivity occurred independently of tumor stage or grade. TIL REP under hypoxic conditions (5% O2) was successful, and these conditions salvaged more CD8+ TILs compared to normoxic conditions (p=0.0382). Hypoxic REP TILs showed increased IFNγ, TNFα, and Granzyme B release in response to autologous tumor compared to normoxic conditions. Additionally, hypoxic REP TILs expressed higher LAG3 and TIM3 markers (p<0.05), with significantly increased proportions of tissue-resident memory-like (TRM) CD8+ T-cells (CD69+CD103+) compared to normoxic conditions (18.2% CD69+CD103+ versus 2.6%, respectively, p<0.0001). These features have been associated with clinical responders TILs in melanoma.
Conclusions:
This study demonstrates the feasibility of expanding tumor-reactive TILs from ccRCC despite tumors harboring exhausted CD8+ T-cells. Exposing TILs to hypoxic conditions enhanced effector functions and promoted the acquisition of a TRM T-cell phenotype. These findings suggest that ccRCC TIL expansion under controlled hypoxia is feasible and could confer improvement to the clinical efficacy of TIL therapy for ccRCC.
Development of an ex-vivo platform to model immunotherapy in kidney cancer.
Authors: Gulati Shuchi , Chang Wen-Hsin , Lim Aedric K , Parikh Mamta , Mitsiades Nicholas , Dall'era Marc , Chandrasekar Thenappan , Hsiao Philip , Lara Primo N , Chen Ching-Hsien
Published: February 2025

592

Background:
The treatment landscape for metastatic clear cell renal cell carcinoma (mccRCC) has evolved, with immune checkpoint inhibitor (ICIs) combinations contributing to improved survival. However, many patients remain unresponsive, highlighting the need for alternative strategies. While preclinical models have been instrumental in drug development, their translation to human applications often encounters challenges related to reproducibility. This emphasizes the urgent requirement for accurate, immunocompetent models of ccRCC that reflect human disease, identify effective immunotherapy regimens, and support reliable drug development. This study presents the development and characterization of a precision cut tissue slices (PCTS) model for primary ccRCC, capturing patient-specific heterogeneity.
Methods:
Twelve patients undergoing nephrectomy for primary ccRCC were consented. PCTS were obtained and co-cultured with autologous peripheral blood mononuclear cells (PBMCs) (5x10^5 co-cultured with one PCTS) and treated for six days. Treatment groups included: i) cabozantinib (cabo) alone, ii) cabo with cemiplimab (cemi, a PD-1 inhibitor), iii) cemi with fianlimab (fin, a LAG-3 inhibitor), and iv) the triplet regimen of cabo, cemi, and fin. The co-cultured PCTS were analyzed using H&E staining and a Live-Dead stain to assess cell viability. Following co-culture, PBMCs were imaged and cytospun for histological analysis and characterized using multiplex immunofluorescence (MxIF).
Results:
Viability assessment of co-cultured PCTS indicated a significantly higher proportion of dead cells in the triplet-treated group (cabo+cemi+fin) compared with either doublet strategy. Additionally, the number of viable PBMCs, assessed six days post-co-culture, was also highest in the triplet group. Ongoing MxIF analysis aims to characterize the PBMCs further.
Conclusions:
This study characterizes an organotypic, patient-derived model based on the culture of tumor slices from primary renal cancers, where we have optimized for extended viability of PCTS in ex vivo culture. The drug treatment experiments conducted on the slices demonstrate the potential of PCTS as a preclinical tool for screening effective therapies for primary ccRCC, including immunotherapeutic approaches, which has been challenging in previous animal models. Our findings suggest that the triplet regimen (cabo+cemi+fin) may offer greater efficacy compared to the cabo+cemi or cemi+fin. Based on these results, an early-phase clinical trial to investigate the triplet in ccRCC patients is under development.
Correlates of immunotherapy response in metastatic clear cell renal cell carcinoma from circulating cell-free epigenomes.
Authors: El Hajj Chehade Razane , Semaan Karl , Zhang Ze , Phillips Noa , Grisham Lexi , Prather Rebecca , Beckermann Katy , Vaishampayan Ulka N. , Haas Naomi Balzer , Hammers Hans J. , McDermott David F. , Wood Lauren Michelle , Solley Travis , Rini Brian I. , Jonasch Eric , Choueiri Toni K. , Freedman Matthew , Haake Scott Mattox , Baca Sylvan C. , Berchuck Jacob E
Published: February 2025

593

Background:
Immune checkpoint inhibitors (ICIs) are a mainstay of treatment for metastatic clear cell renal cell carcinoma (mccRCC). With a growing number of treatment options for mccRCC, biomarkers are needed to guide treatment selection by predicting benefit from ICIs. Cell-free DNA (cfDNA)-based assays that measure tumor DNA in plasma are promising biomarkers for treatment response in several cancers, but their role in RCC remains unclear. Here, we tested whether epigenomic profiling of cell-free DNA can identify or predict radiographic responses to immunotherapy in mccRCC.
Methods:
Plasma samples were obtained from 180 patients (400 total samples collected, up to 4 samples per patient) with mccRCC enrolled in the DOD-funded Kidney Cancer Research Consortium ctDNA study (NCT04883827). Patients received an immune checkpoint inhibitor and were categorized as non-responders or responders based on CT scan results obtained at 3- or 6-months following treatment initiation. Cell-free chromatin immunoprecipitation sequencing (cfChIP-seq) was performed on patient plasma to profile H3K4me3, a histone modification associated with active gene promoters. DNA methylation was profiled with cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq). H3K4me3 signal at the promoters of ccRCC-associated genes variation between pre-treatment and on-treatment timepoints was assessed for non-responders and responders. We calculated changes in H3K4me3 signal for on- and pre-treatment plasma draws. We then compared these changes between non-responders and responders using the Wilcoxon sum-rank test. The immune cell types contributing to cfDNA were inferred from cfMeDIP-seq data.
Results:
Comparing pre- and on-treatment timepoints drawn between 1-5 months after starting therapy, cfDNA promoter H3K4me3 at RCC-associated genes was concordant with radiographic response in 10 of 11 patients (91%), with signal increasing from pre- to on-treatment samples in 6 of 7 non-responders (86%) and decreasing in 4 of 4 responders (100%). The median change in H3K4me3 differed significantly for non-responders and responders (p = 0.02). Analysis of cfDNA methylation profiles identified a higher proportion of memory CD8 T cell-derived cfDNA in non-responders compared to responders in pre-treatment samples (p = 0.003)
Conclusions:
This pilot study suggests that epigenomic profiling of cfDNA may identify pre-treatment and on-treatment biomarkers of ICI response. Profiling of larger cohorts is underway to test the generalizability of these findings.
Concordance between clinical and pathologic staging of T2a–b and T3a renal cell carcinoma.
Authors: Goodstein Taylor , Goradia Rajvi R. , Srivastava Arnav , Sood Akshay , Dason Shawn , Master Viraj A. , Singer Eric A.
Published: February 2025

600

Background:
Among patients with renal cell carcinoma (RCC), 5–23% of those with cT1 and smaller cT2 tumors may be upstaged to pT3a disease after surgery. The pathologic restaging rate of larger or clinically more invasive tumors is understudied and has implications for perioperative systemic therapy clinical trial enrollment. We examined rates of pathologic restaging for cT2a-b and cT3a RCC after surgery.
Methods:
Using the National Cancer Database, we identified adult patients with cT2a, cT2b, and cT3a RCC undergoing partial or radical nephrectomy. We compared pathologic restaging rates between the clinical stage groups using a Chi-square test. Subgroup analysis of restaging rates was performed for histology (clear cell vs non–clear cell), clinical nodal status (cN1 vs cN0), and clinical metastatic status (cM1 vs cM0). Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for the overall cohort and subgroups. Multivariable logistic regression was performed to assess predictors of pT3a upstaging among patients with cT2a and cT2b tumors.
Results:
We identified 31,912 patients who met inclusion criteria (13,840 cT2a, 8,079 cT2b, and 9,993 cT3a). he overall rate of restaging was 47.4% for cT2a disease (10.7% downstaged and 36.7% upstaged) for a sensitivity and specificity of 89% and 72%, respectively. The overall rate of restaging was 52.5% for cT2b disease (10.6% downstaged and 41.9% upstaged), for a sensitivity and specificity of 85% and 96%, respectively. The overall rate of restaging was 9.5% for cT3a disease (5.1% downstaged and 4.4% upstaged), for a sensitivity and specificity of 55% and 94%, respectively (p < 0.001). The positive predictive value was 52.5%, 47.5%, and 90.6%, and the negative predictive value was 95%, 97%, and 67% for cT2a, cT2b, and cT3a disease, respectively. On multivariable analysis, among patients with cT2 tumors, the presence of clinically node-positive (OR 2.8 [95% CI 2.43–3.17]) metastatic (OR 2.4 [95% CI 2.18–2.65]) or cT2b disease (OR 1.18 [95% CI 1.10–1.26]) was associated with pathologic upstaging (p < 0.001).
Conclusions:
Restaging is common for patients with cT2a and cT2b tumors, but the specificity of cT3a staging is high. These findings suggests that opportunities exist to improve the accuracy of clinical staging for cT2 tumors, which will have implications for future adjuvant/perioperative RCC clinical trials.
Impact of upstaging from cT2a–b to pT3a on overall survival (OS) among patients with renal cell carcinoma.
Authors: Goodstein Taylor , Goradia Rajvi R. , Srivastava Arnav , Sood Akshay , Dason Shawn , Master Viraj A. , Singer Eric A.
Published: February 2025

601

Background:
Identifying patients with renal cell carcinoma (RCC) who may benefit from adjuvant systemic therapy has proven difficult. Approximately 40% of patients with cT2a-b tumors will be upstaged to pT3a disease following surgery. These patients, given their large tumor size, may represent a higher risk cohort compared to patients with concordant T3a staging. We assessed OS among cT2a-b patients who were upstaged to pT3a compared to their cT3a counterparts with concordant pathologic staging.
Methods:
Using the National Cancer Database, we identified N0M0 adult patients with cT2a, cT2b, and cT3a RCC who underwent partial or radical nephrectomy and had pT3a disease on final pathology. We categorized patients into three groups: (1) cT2a to pT3a, (2) cT2b to pT3a, and (3) cT3a to pT3a. We compared OS between the groups using Kaplan Meier estimates and multivariable analysis using Cox proportional hazards models. Subgroup analysis of overall survival was performed for histology (clear cell vs non–clear cell).
Results:
11,241 patients met inclusion criteria (3,067 cT2a, 1,893 cT2b, and 6,281 cT3a). Median pathological tumor size was 8.0, 11.2, and 7.5 cm for cT2a, cT2b and cT3a tumors, respectively. Mean 5-year OS was 37% for both cT2a and cT2b disease upstaged to pT3a and 48% for cT3a disease with concordant pathological staging (log rank p < 0.0001). This finding persisted on multivariable analysis (cT3a HR 0.81 [0.77–0.85], p < 0.001).
Conclusions:
Patients who were pathologically upstaged from cT2 to pT3a disease had worse OS compared to patients with concordant staging, a finding likely related to differences in median tumor size. Our findings imply that it is reasonable to include well-selected cT2 tumors in the next iteration of perioperative trials. However, those designing and conducting clinical trials must power their studies to adjust for heterogeneity in pathologic restaging.
Presurgical treatment for inferior vena cava tumor thrombus in patients with renal cell carcinoma: A scoping review.
Authors: Baralo Bohdan , Dziarnowski Natasha , McIntire Cody , Daniels Peter , Puglisi Morgan , Lee Hyun , Melson John W. , Paul Asit KR
Published: February 2025

602

Background:
To date, there is no evidence-based standard of care for the management of patients with tumor-related thrombus (TT) in the inferior vena cava (IVC) associated with renal cell carcinoma (RCC).The aim of our study is to analyze published papers on presurgical treatment and their effect on reducing the TT length, level and deintensification of surgical approach.
Methods:
MEDLINE, Embase, and Cochrane Central were systematically searched using PRISM-Scr checklist for studies evaluating presurgical therapies intended to decrease the TT length, and level in RCC patients as well as surgical outcome. Patient were reviewed to have the following outcomes: clinically significant (>20%) reduction in TT length, reduction in TT level by Mayo classification and deintensification of planned surgical intervention.
Results:
After comprehensive review of 1175 studies by PRISMA-Scr protocol, 21 studies fulfilled prespecified criteria that included 1 phase II clinical trial, 3 case series and 16 retrospective cohort studies. Among 216 patients reviewed, 178 (82.4%) had clear cell RCC, 106 (49.07%) had stage T3b and 53 (24.53%) had nodal involvement. Presurgical regimes included Thyrosine Kinase Inhibitors (TKI) (81%), TKI-Immune check point inhibitor (ICI) combination (6%), ICI monotherapy (3%), Stereotactic radiation (4%) and others (6%). Significant decrease in length in TT was reported in 40.29%, 42.86% and 84.62% of patients treated with TKI, ICI and TKI-ICI combination, respectively. Levels of TT were decreased in 30.32%, 46.15% and 14.29% patients treated with TKI, ICI and TKI-ICI combination, respectively. Among the patients reported to have less invasive surgical approach following presurgical treatment (n=34), 29.41% avoided cardiac bypass.
Conclusions:
Published studies have reported benefits of presurgical treatment in reducing length and level of TT as well as improving surgical outcome. However, significant heterogeneity exists and prospective studies are required to draw a meaningful conclusion.
Assessing racial disparities in testicular cancer survival: Evidence from a nationwide cohort.
Authors: Morgan Kylie Margaret , Riviere Paul , Pandit Kshitij Margaret , Nelson Tyler , Sabater Minarim Daniel , Meagher Margaret , Puri Dhruv , Yodkhunnatham Nuphat Margaret , Millard Frederick E. , McKay Rana R. , Rose Brent S , Bagrodia Aditya
Published: February 2025

621

Background:
Testicular cancer is one of the most common and curable malignancies in young men, with a 5 year survival rate of 95%. Limited research has explored long-term survival outcomes among Black men, given rarity of disease among this demographic. Our study aims to assess potential racial differences in overall survival (OS) and cancer-specific mortality (CSM) among testicular cancer patients using a large, equal access nationwide Veterans Affairs (VA) database, focusing on self-identified Black and White race.
Methods:
This retrospective study analyzed Black and White testicular cancer patients from the VA database utilizing Veterans Informatics and Computing Infrastructure (VINCI). Self-identified race was obtained from the VA Cancer Registry, with OS and CSM as the primary outcomes. CSM was identified using the National Death Index (NDI). NDI data is available through 12/31/2020, after which date all patients with continued follow-up were censored. Cox proportional hazard models were applied to examine the associations of race on OS and CSM, adjusting for relevant clinical factors such as cancer staging, Charlson Comorbidity Index (CCI), and receipt of adjuvant chemotherapy or radiation. All time to event analyses were done from time of testicular cancer diagnosis to outcome of interest.
Results:
We compared 1799 White patients to 118 Black patients. A total of 431 (22.49%) patients died, of whom 405 were White and 26 were Black. There was no statistically significant difference in survival at 10 years between Black and White individuals (80.4% vs 81.6%, p = 0.68). The multivariable cox-regression analysis showed no statistically significant difference between Black and White men. Of the 431 deaths, 72 were identified as CSM (71 White, 1 Black). There was no significant difference in 10-year cumulative incidence of CSM in Black and White individuals (0% vs 4.1%, p=0.12). Similarly, no significant differences were found for CSM between Black and White men in the multivariable analysis.
Conclusions:
Our study found no significant racial disparities in OS or CSM between Black and White testicular cancer patients in the VA healthcare system. As the VA represents an equal access to care setting, these findings may not be generalizable to the broader U.S. population, where disparities in care are more notable. Conversely, access to care may overcome known sociodemographic disparities that drive worse clinical outcomes. The analysis is limited by the small number of patients experiencing the event of interest. Future research should be conducted to validate the association between self-identified race and survival outcomes in more diverse healthcare settings.
Regional and racial disparities in testicular cancer-related mortality among HIV/AIDS adults in the United States and Texas: A 21-year retrospective study (1999-2020).
Authors: Naz Sidra , Naz Hira , Ali Kashif , Hanif Muhammad , Jaiswal Vikash , Patel Nirmit
Published: February 2025

624

Background:
Men with HIV/AIDS have a significantly higher risk of developing germ cell tumors (GCT), with a notable increase in the incidence of testicular cancer (TC). We aim to study the annual trends and sociodemographic factors in testicular cancer-related mortality in individuals with HIV/AIDS in the United States and its state of Texas from 1999 to 2020 to analyze public health initiatives and to identify areas requiring targeted intervention and prevention strategies.
Methods:
Mortality trends in TC among HIV/AIDS adults aged ≥25 years were analyzed using CDC WONDER database, identifying through ICD-10 codes C62.9 “Testicular neoplasms” and B20 “HIV/AIDS”. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs, with 95% confidence intervals, were determined using joint point regression analysis across various demographic (sex, race/ethnicity, age) and geographic (state, urban-rural, regional) subgroups.
Results:
Between 1999 and 2020, 89721 documented deaths were attributed to TC due to HIV. The overall AAMR for TC-related mortality in HIV/AIDS adults increased in the US from an adjusted rate (AR) 0.8 in 1999 to (2.9) in 2004 (APC: 4.17%; 95% CI: -2.76% to 38.8%), then it decreased to 1.5 in 2020 (APC: -5.01%; 95% CI: -15.5% to -3.94%). In Texas, AAMR for TC in immunocompromised adults increased from AR 1.5 in 1999 to 3.5 in 2001 (APC: 42.3%; 95% CI: 10.5% to 74.8%), after which it decreased to 1.9 in 2020 (APC: -0.03%; 95% CI: -1.47% to 1.89%). The AAMR in U.S. men increased from 1.4 in 1999 to 4.1 in 2001 (APC: 27.6%; 95%CI: -1.34% to 59.1%) and then decreased to 2.4 in 2020 (APC: -3.99%; 95% CI: -6.09% to -3.27%). The non-Hispanic (NH) Black or African American (AA) (4.9) population has the greatest AAMR, followed by the NH American Indian or Alaska Native (1.9) and the Hispanic or Latino population with AAMR (1.7). The lower-risk population was NH White with AAMR (0.9) and NH Asian or Pacific Islander (0.4). AAMR also varied by region (South: 1.9; Northeast: 1.5; West: 1.3; Midwest: 1) and metropolitan areas had higher AAMR (large central metropolitan: 2.3; large fringe areas: 1.4) than non-metropolitan areas (small metro: 1.1; micropolitan: 1.1; non-core areas: 1.2). The states in the upper 90th percentile of AAMRs were New York, Maryland, South Carolina, Georgia, Florida, Mississippi, Louisiana, and New Jersey exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile i.e Idaho, Wyoming, Utah, Wisconsin, Minnesota and North Dakota.
Conclusions:
Mortality rates from testicular cancer among HIV/AIDS adults have declined in the United States and Texas over the past two decades. However, NH Black or AA, NH American Indian or Alaska Native, Hispanic or Latino men are at more risk than NH White and NH Asian or Pacific Islander.
Validation of new prognostic factors for relapse in patients with clinical stage I seminoma.
Authors: Nestler Tim , Strauch Angelina , Schoch Justine , Schmelz Hans
Published: February 2025

625

Background:
Patients with clinical stage I (cSI) seminomatous testicular germ cell tumors (GCT) have a relapse risk of 5 - 30% under surveillance after orchiectomy, depending on tumor size and rete testis infiltration. Recently, two studies introduced new prognostic risk models to improve clinical decision-making: the Danish Testicular Cancer database (DaTeCa) and an Individual Patient Data Analysis by the European Association of Urology (EAU) Testicular Cancer Guidelines Panel and Guidelines Office. This study aimed to validate these new prognostic risk models in an independent cohort of cSI seminoma patients.
Methods:
We included patients with unilateral cSI seminoma (retroperitoneal lymph nodes <10 mm in short-axis diameter), normalized serum tumor markers post-orchiectomy (β-human chorionic gonadotropin (β-hCG) and lactate dehydrogenase (LDH)), and no adjuvant therapy. All patients had at least 12 months of follow-up. Cox regression analysis was applied to evaluate the proposed prognostic factors and relapse probabilities were estimated using the Kaplan-Meier method.
Results:
Among 139 patients, 25 (18%) relapsed within a median follow-up of 37 months (CI 47.9–63.1). In multivariate analysis, only rete testis infiltration was confirmed as an independent predictor of relapse (p=0.039). The other prognostic factors of DaTeCa (lymphovascular invasion, elevated pre-orchiectomy β-hCG and LDH) and EAU (tumor size and lymphovascular invasion) could not be confirmed. The 5-year relapse risk according to DaTeCa risk groups was consistent with our cohort (no risk factors: 4% vs. 6%; all four risk factors: 67% vs. 62%). Similarly, the EAU classification showed comparable 5-year relapse risks for low (13% vs. 8%) and intermediate (22% vs. 20%) groups. However, the high-risk group showed a greater discrepancy (67% vs. 44%), although our study included only a limited number of high-risk patients (n=6, 4.3%).
Conclusions:
The risk classification models from DaTeCa and EAU demonstrated good overall reproducibility in our cohort. These models may aid in identifying seminoma patients at high-risk for relapse who might be candidates for adjuvant therapy. However, the proposed prognostic factors were mainly not independently confirmed in the multivariate analysis in our study cohort.
Patient characteristics and overall survival with lutetium (Lu
177
) vipivotide tetraxetan (
177
Lu-PSMA-617): A real-world analysis of early adopters.
Authors: George Daniel J. , Shore Neal D. , Nguyen Jennifer , Patel Jeetvan , Sawhney Amrita , Kang Barinder , Chen Chi-Chang , Gorritz Magdaliz , Wei Xiao X.
Published: February 2025

63

Background:
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Lu-PSMA-617, a prostate-specific membrane antigen (PSMA)-targeting radioligand therapy for metastatic castration-resistant prostate cancer (mCRPC), received FDA approval in March 2022 for the treatment of adult patients with PSMA-positive mCRPC who have received both an androgen receptor pathway inhibitor (ARPI) and a taxane-based chemotherapy. Outside of clinical trials, limited real-world evidence evaluating the effectiveness of
177
Lu-PSMA-617 has been reported. The aim of the current study was to evaluate patient characteristics and overall survival (OS) among patients diagnosed with mCRPC who were treated with
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Lu-PSMA-617 within a large-scale real-world cohort.
Methods:
This retrospective, observational study used the IQVIA PharMetrics Plus claims data from July 1, 2013 to December 31, 2023, and linked social determinants of health data as well as mortality data to obtain month and year of death. Adult men with mCRPC who had received
177
Lu-PSMA-617 were included (first receipt of
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Lu-PSMA-617 = index date). Patient demographics and characteristics were evaluated descriptively; patient demographics were reported on the index date and clinical characteristics were evaluated over the 12 months prior to index date. OS was measured from the start of the first
177
Lu-PSMA-617 treatment until death or end of available follow-up, and assessed using Kaplan–Meier analysis.
Results:
A total of 643 patients were included in the analysis; median age was 69 years. Treatment for the majority of patients (490/643 [76.2%]) was managed by oncologists (169 [26.3%] of which had specialty in radiation oncology). White patients (292 [72.8%]) made up the largest part of the patient population followed by Black (37 [9.2%]), Hispanic (23 [5.7%]), and Asian (8 [2.0%]). Most patients had multiple comorbidities with either one (226/643 [35.1%]) or two (224/643 [34.8%]) sites of metastasis. Most patients experienced bone metastases (581/643 [90.4%]); 284/643 (44.2%) also experienced visceral metastases of which the liver was the most common site (78/643 [12.1%]). The median OS from start of
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Lu-PSMA-617 therapy was 15.3 months (95% confidence interval [CI]: 14.6–16.3); a total of 137/643 (21.3%) patients died. OS was analyzed in different patient subgroups and no major differences were observed by metastatic site, number of metastatic sites, race, or age.
Conclusions:
To our knowledge, this is the first large-scale study reporting OS with
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Lu-PSMA-617 in clinical practice. OS observed with
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Lu-PSMA-617 in this study (median: 15.3 months) was consistent with results from the VISION Phase III clinical trial (median: 15.3 months; NCT03511664). Furthermore,
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Lu-PSMA-617 demonstrated similar survival across different patient subgroups.
Stage II embryonal predominant NSGCT: Minimizing treatment burden.
Authors: Zeng Jiping , Thakker Parth , Masterson Timothy A. , Salous Tareq , King Jennifer , Adra Nabil , Einhorn Lawrence H. , Cary Clint
Published: February 2025

634

Background:
Embryonal carcinoma predominance (ECP) in the orchiectomy specimen is linked to a higher risk of retroperitoneal and systemic relapse. Both chemotherapy and primary retroperitoneal lymph node dissection (RPLND) are recommended options for stage II disease, but the approach that minimizes treatment burden remains unclear.
Methods:
We queried the Indiana University Testicular Cancer Database to identify patients with non-seminomatous germ cell tumors (NSGCT) and ECP >50% in the orchiectomy specimen, stage II with retroperitoneal adenopathy <5 cm, and normal serum tumor markers. Patients with malignant transformation (n=3) or bilateral cancer (n=3) or receiving 1-2 cycles of BEP after orchiectomy were excluded (n=14). Treatment courses and outcomes were compared.
Results:
Between 2005 and 2022, 142 patients met the criteria. Of 67 patients who underwent primary RPLND, 62 had active EC in final pathology. Adjuvant chemotherapy (2 cycles of EP or BEP) was given to 5 patients. After a median follow-up of 37.7 months, 10 recurred, with a recurrence-free survival (RFS) of 85.1%. Following induction chemotherapy for documented recurrence, 9 patients were disease-free, with 1 disease-related death. Disease-free survival (DFS) was 98.5%. There were no in-field recurrences in the primary RPLND group. Of the 75 patients who received chemotherapy, 25 required post-chemotherapy (PC) RPLND, which revealed either teratoma or necrosis, and no active cancer was found. One recurred and needed re-do RPLND. Five patients who achieved complete remission after chemotherapy recurred, requiring second-line and high-dose chemotherapy. The RFS was 92%, with a median follow-up of 34.1 months. DFS was 97.3%. Univariate analysis showed pre-orchiectomy AFP >100 ng/mL (OR 7.6, 95% CI 1.6–54.9) and teratoma >5% in the orchiectomy specimen (OR 4.1, 95% CI 1.3–13.2) were associated with the need for PC-RPLND, but no parameters were predictive in multivariate analysis.
Conclusions:
Primary RPLND achieved complete remission as a single treatment modality in 85% of patients, compared to 67% for chemotherapy. Primary RPLND may reduce treatment burden in early-stage II ECP NSGCT in well-selected patients.
Management of relapsed primary retroperitoneal (RP) germ-cell tumor (GCT) after front-line chemotherapy.
Authors: Lewis Kirsten , Hassoun Rebecca , Althouse Sandra K. , Salous Tareq , Hanna Nasser H. , Einhorn Lawrence H. , Adra Nabil , King Jennifer
Published: February 2025

637

Background:
Primary RP GCT represents a rare subset of extragonadal GCTs. While front-line therapy remains similar to gonadal GCT, there is limited data on management of relapsed disease for these patients (pts). Here, we describe management and outcomes of pts with relapsed primary RP GCT.
Methods:
The prospectively maintained Indiana University testicular cancer database was queried for patients with primary RP GCT who relapsed after first-line therapy between 1990-2024. Kaplan-Meier method was used to analyze progression free survival (PFS) and overall survival (OS). Survival outcomes based on type of second-line chemotherapy was compared using the log rank test.
Results:
53 pts were included in the analysis. Median age at diagnosis was 33.7yrs (17.4-67.9). Primary tumor pathology was non-seminoma in 75.5% and seminoma in 24.5%. Predominant histology was seminoma (30.2%), mixed (26.4%), choriocarcinoma (17.0%), yolk sac tumor (13.2%), embryonal (9.4%), teratoma (3.8%). Other metastasis sites included pulmonary (56.6%), liver (35.9%), posterior mediastinum (15.1%), pelvic lymph nodes (13.2%), brain (13.2%), bone (9.4%). IGCCCG risk was good in 30.2%, intermediate in 15.1%, and poor in 54.7%. First-line chemo was BEPx4 (54.6%), VIPx4 (11.3%), BEP x3 (7.5%), EPx4 (7.6%), BEPx2 + HDCTx2 (2.0%), and other (17.0%). All 53 pts had progression of disease after first-line chemo. 44 received salvage chemotherapy, 5 received RPLND, 2 other salvage surgery, 1 radiation, and 2 received no salvage therapy. Salvage chemo was HDCT for 69.8% vs. standard salvage chemo for 30.2%. For pts treated with HDCT, 83% completed 2 cycles. 46.7% of those treated with HDCT progressed afterward. Of pts who had salvage RPLND, 3 were found to have teratoma and 2 had active GCT. 2 pts had other salvage surgery; 1 had thoracotomy with GCT and 1 had craniotomy with GCT. At time of last follow-up, 28.3% of all pts were alive with NED, 11.3% were alive with disease, 13.2% were lost to follow-up, and 47.2% had died of disease. The table lists PFS and OS by salvage chemo type.
Conclusions:
Patients with relapsed primary RP GCT seem to have worse outcomes compared with historical results from relapsed gonadal GCT. A subset of patients with relapsed primary RP GCT are curable with salvage therapy.

Survival outcomes by salvage chemotherapy received.

HDCT N=30
Standard dose chemo N= 14
p-value

2-yr PFS
47.7% (95% 28.7-64.5)
31.8% (95% 7.7-59.9)
p=0.18

2yr OS
53.8% (95% 34.0-70.0)
68.6 (95% 30.5-88.7)
p=0.84
Immune checkpoint inhibitors in patients with testicular cancer: A systematic review.
Authors: Salazar-Mejía Carlos Eduardo , Guadarrama-Rendon Estefanía , Guerra-Garza Andrea Sarahi , Salazar-Salazar Karina Alicia , de la Cruz-de la Cruz Carlos , Alvarado-Ruiz Sofia Alejandra , Quiroz-Huerta Ramiro , Alvarez-Villalobos Neri Alejandro , Vidal-Gutiérrez Oscar , Villarreal-Gonzalez Rosalaura
Published: February 2025

638

Background:
Germ cell tumors (GCT) are chemosensitive neoplasms with high cure rates, even in the metastatic setting. However, a small group of these patients will present tumors refractory to chemotherapy, with a dismal prognosis and very few effective management options. Although immune checkpoint inhibitors (ICIs) are approved for use in chemotherapy-refractory GCT for those tumors with a high microsatellite instability (MSI-H/dMMR) or high tumor mutational burden (TMB-H), the evidence supporting this indication is scarce.
Methods:
Original research studies, conducted on patients with GCT refractory to chemotherapy treated with ICI up to December 2023 were included. Comprehensive search strategies of 5 databases and MeSH keywords were used to locate eligible literature. Study characteristics, participant demographics, and oncological outcomes were recorded.
Results:
A total of 13 studies (n = 106) were identified for inclusion; 5 of which corresponded to single-patient case reports, one was identified as a retrospective cohort, 6 were phase II RCTs and we included a recent abstract from the preliminary results of a phase II RCT. Most of the studies evaluated did not request biomarkers as inclusion criteria. The median overall response rate across all patients included was 3.4% (range, 0-57), versus 0% (range 0-6) in those reported in retrospective cohort and phase II studies. Progressive disease as best clinical response was reported in most patients, with 75% (range, 0-82.9) in the overall population and 82% (range, 75 -83) in patients from retrospective cohort and phase II trials. Some of the most durable clinical responses documented in this systematic review corresponded to TMB-H or MSI-H/dMMR tumors.
Conclusions:
Analysis from retrospective cohorts and clinical trials evaluating ICIs for the treatment of chemotherapy-refractory GCT documented a limited activity of these drugs as a single intervention in patients not selected by biomarkers, with a tendency to better results described in those with TMB-H or MSI-H/dMMR tumors. Future prospective study designs should attempt to select patients by biomarkers to shed light on the determination of clinical and molecular factors that can predict response to ICIs in this scenario.
The prognostic value of LDH in patients with good risk metastatic seminoma treated with single agent carboplatin AUC10.
Authors: Abdul Aziz Nasreen , Ng Kenrick , Ganguli Sushila , Rajan Prabhakar , Sharma Anand , Shamash Jonathan
Published: February 2025

644

Background:
Raised lactate dehydrogenase (LDH) is a surrogate marker for disease burden and an independent adverse prognostic factor for IGCCCG good risk metastatic seminoma patients treated with cisplatin and etoposide-based chemotherapy (Beyer et al, 2021). Patients with a pre-treatment LDH greater than 2.5x the upper limit of normal (ULN), despite still categorized as good risk disease, have a poorer 3-year progression free survival (PFS) of 80% with this combination treatment. Carboplatin Area Under the Curve (AUC) 10 monotherapy is an alternative to cisplatin and etoposide-based chemotherapy, with comparable effectiveness and a better side effect profile. However, the prognostic value of LDH and specific outcomes of patients with raised LDH in patients treated with carboplatin AUC10 has not been evaluated.
Methods:
A retrospective analysis of outcomes of good risk metastatic seminoma patients treated with carboplatin AUC10 from January 2000 to January 2021 at two supra-regional cancer centres was conducted. Data were extracted using electronic health records. The variables collected included primary tumor location, stage, tumor markers, relapse date, post-relapse treatment and cause of death.
Results:
245 patients were identified with a median follow up period of 5.9 years. The primary site of the tumor was most commonly the testes (n=229, 93.5%). 76 (31%) presented with stage 2a, 81 (33%) with stage 2b and 43 (16%) with stage 2c. 14 patients (6%) experienced a relapse, with 11 patients received bleomycin, etoposide and cisplatin as salvage treatment. 24 patients (10%) had LDH levels >2.5 ULN. The 3-year PFS rate for patients with LDH >2.5 ULN was 79.2% versus 95% in LDH <2.5 ULN (p=0.0004). This was comparable to the 80% reported in the high LDH group by Beyer et al.
Conclusions:
Our results confirm the validity of raised LDH as an adverse prognostic factor in good risk metastatic seminoma patients treated with carboplatin AUC10, with similar PFS outcomes compared to etoposide-cisplatin based chemotherapy described in Beyer et al. Elevated LDH does not appear to be a contraindication to the use of carboplatin AUC10 monotherapy in this patient population and represents a less toxic alternative to etoposide-cisplatin based chemotherapy.