bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort.
Authors: Cancel Mathilde , Naffrichoux Jérémie , Poupin Pierre , Pouillot William , Linassier Claude , Rioux-Leclercq Nathalie , De Vries-Brilland Manon , Mourey Loic , Laguerre Brigitte , Oudard Stephane , Gross-Goupil Marine , Gravis Gwenaelle , Rolland Frederic , Moise Laura , Emambux Sheik Muhummud Fardeen , Vassal Cecile , Zanetta Sylvie , Penel Nicolas , Albiges Laurence , Fromont Gaelle 
Published: January 2024

463 Background: Papillary renal cell carcinoma (pRCC) is a rare and aggressive cancer with no specifically established therapeutic strategy in the metastatic setting. Combinations of tyrosine kinase and immune checkpoint inhibitors are a promising option. We aimed to study the immune landscape of metastatic pRCC, and its associations with angiogenesis pathways expressions, to search for potential therapeutic targets. Methods: The expression of immune markers (PD-L1, PD-1, PD-L2, LAG-3) and angiogenic pathways (CAIX, c-MET), was analyzed by immunohistochemistry on 75 metastatic pRCC retrieved from a retrospective multicenter GETUG cohort. Our primary endpoint was to evaluate the prognostic impact on overall survival (OS) of PD-L1 expression in metastatic pRCC. Secondary endpoints were to describe the expression of the other immune markers and of angiogenic pathways and to estimate the associations between the expression of PD-L1 and the expressions of the other markers or angiogenic pathways. Results: In median, patients were 61 years old at metastatic diagnosis. Concerning their first-line metastatic treatment, 67 (89%) had received Sunitinib, and 8 (11%) had received Everolimus. The Karnofsky Performance Score at treatment initiation was ≥ 80 for 62 (83%) patients. Overall, 25.3% of tumors were PD-L1 positive. PD-L2 was more frequently expressed (45.3%), PD-1 and LAG-3 were positive in 17.3% both. Concerning the angiogenic markers, CAIX was expressed in 46.7% of tumors, c-MET in 41.3%. None of these markers were significantly associated with PD-L1 expression. 64% (48/75) expressed at least one immune marker, and 40% (30/75) were “double-positive”, as they expressed both immune and angiogenic markers. In univariate analysis, OS was significantly shorter for patients with PD-L1 positive pRCC (HR=3.3; 95%CI=1.3-8.6; p=0.01). A multivariate analysis confirmed a significant association between PD-L1 expression and shorter survival (HR=5.4; 95%CI=1.4-20.9; p=0.01). Conclusions: These results reinforce clinical data on the expected benefit of immunotherapy in metastatic pRCC treatment, as PD-L1 expression is a factor of poor prognosis in our multicenter cohort.
Glutamine metabolism and VEGF analysis to elucidate and overcome the mechanism of tyrosine kinase inhibitor resistance in renal cell carcinoma.
Authors: Morozumi Kento , Kawasaki Yoshihide , Sato Tomonori , Maekawa Masamitsu , Takasaki Shinnya , Shimada Shuichi , Sakai Takanari , Yamashita Shinichi , Mano Nariyasu , Ito Akihiro 
Published: January 2024

464 Background: Clinical practices have demonstrated improvements in prognosis of patients with advanced renal cell carcinoma (RCC) by combination therapies with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors. However, TKI-resistance is inevitable which hinders further improvement in prognosis. In our previous study, we reported regulating glutamine metabolism could bring about re-sensitivity to Sunitinib (Su) in Su-resistant Renal cell Carcinoma (RCC) cells. However, the mechanism of re-sensitivity and whether it applies to other tyrosine kinase inhibitors (TKIs) has been still unknown. Methods: We established Su and Cabozantinib (Cabo) -resistant cells in 3 RCC cell lines (786-O, Caki-1 and ACHN). We analyzed the activity of glutamine metabolism and VEGF pathway, before and after TKI-resistant、furthermore, conducted antitumor effect in vitro and vivo studies to evaluate re-sensitivity to TKI and relationship between VEGF signaling and regulating glutamine metabolism. Results: In all TKI-resistant cells, the overexpression of glutamine metabolism and VEGF signaling were observed. In vitro and vivo study using Su, the regulating glutaminolysis resulted in 40-74% cell-killing effect in 3 Su-resistant cell lines. Whereas the regulating glutaminolysis also resulted in 35-55% cell-killing effect in 3 Cabo-resistant cell lines. Although the antitumor effect was observed in only 786-O among Su-sensitive cells, it was not observed among Cabo-sensitive cells. Moreover, antitumor effect of regulating glutamine metabolism is more remarkable in vivo. When conducting immunostaining of CD31 to evaluate vascular endothelium, angiogenesis was significantly inhibited by regulating glutamine metabolism.Evaluating VEGF signaling in RT-PCR, VEGFR2 expression and VEGF signaling were downregulated, and PTEN upregulated by suppressing glutamine metabolism. Conclusions: By evaluating glutamate metabolism with VEGF analysis in TKI-resistant RCC cells, we have come to understand a part of the phenomenon of re-sensitivity to TKIs. The inhibition of VEGF signaling and its consequent impact on the tumor microenvironment by regulating glutamine metabolism, are considered to be the mechanisms causing re-sensitivity to TKIs in TKI-resistant cells.We could use TKIs more effectively by regulating glutaminolysis to improve prognosis in advanced RCC patients.
The immune characteristic analysis of BAP1 mutated clear cell renal cell carcinoma.
Authors: Wang Zilin , Liang Jiayu , Zeng Hao 
Published: January 2024

466 Background: Commonly mutated genes in clear cell renal cell carcinoma include VHL, PBRM1, and BAP1. Although the detection rate of BAP1 mutations in RCC is not high, from an evolutionary perspective. BAP1 mutated renal cell carcinoma tends to have clinical features of higher malignancy, faster disease progression, and poor efficacy of classic drug treatments. Therefore, this study uses our center and TCGA database to analyze the correlation between transcriptome, immune cell infiltration, immune checkpoint expression and other characteristics and the efficacy of immune checkpoint inhibitor-based treatment in patients with BAP1 mutated renal cell carcinoma. Methods: 1. The correlation between the expression of immune-related factors CD4, CD8 and immune checkpoints PD-L1, LAG3 and BAP1 RNA and the expression difference between wild and mutant groups were analyzed through the TCGA database. 2. Collect BAP1 mutant and wild-type patients retrospectively, and verify the expression of CD4, CD8, PD-L1 and LAG3 by immunohistochemistry. 3. The enrichment analysis of the signaling pathway was carried out after the intersection of TCGA and the differential genes of the center. 4. To analyze the clinical curative effect difference between BAP1 wild-type and mutant advanced RCC patients receiving target immunotherapy. Results: The TCGA data confirmed that there was no difference in the expression of PD-L1 RNA between the two groups (P=0.5); while there was a significant difference in the expression of LAG-3 RNA, which was higher in the BAP1 mutant type than in the wild type (P=0.023); 24 cases of BAP1 wild-type ccRCC specimens available in the gene detection database of our center were selected, and the results of immunohistochemistry suggested that there were differences in the expression of LAG3 (p=0.009) between the BAP1 wild-type and mutant types, while PD There was no significant difference in the expression of -L1 (p=0.157). The transcriptome data enrichment analysis results of TCGA and our center database showed that BAP1 was closely related to cytokine signaling, cAMP signaling pathway and immune response signals in the tumor immune microenvironment. In terms of clinical efficacy, the PFS time of BAP1 wild-type RCC patients receiving ICI combined with TKI therapy was significantly longer than that of BAP1 mutant patients (median follow-up time: 23.93 months; median PFS: 24.63 vs. 11.73 months, HR: 0.304, 95%CI: 0.070-1.324, p=0.025). Conclusions: This study found that BAP1 and cytokines, cAMP pathway and immune inflammation-related pathways were significantly enriched at the transcriptome level. IHC results suggested that LAG3 was more highly expressed in patients with BAP1 mutation. Clinical treatment analysis found that PD-1 inhibitor-based immune combination therapy is not effective for patients with BAP1 mutations. In summary, LAG3 may be a potential therapeutic target in the future for patients with BAP1-mutated RCC.
Therapeutic targeting of metabolic dysfunction by amino acid restriction and alternate day fasting in renal cell carcinoma models.
Authors: Orsi Sabrina , Rupert Chris , Chang Musea , Colligan Sean , Jawadwala Abbas , Delle Fontane Ilaria , De Nigris Filomena , Pili Roberto 
Published: January 2024

469 Background: The use of immunotherapies and targeted drugs has significantly improved the clinical outcome of kidney cancer patients. However, the inevitable long-term toxicities and development of drug resistance remain a critical challenge for advanced clear cell and non-clear cell renal cell carcinoma (RCC) patients thus highlighting the need for novel therapeutic strategies. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of RCC. As diet has been reported to potentially modulate tumor metabolism, dietary interventions represent an innovative strategy to treat metabolically dysregulated tumors. However, the biological basis of the success of dietary interventions is unknown, representing a critical roadblock in the use of dietary restrictions in patients. In this study, we investigated the role of amino acid (AA) restriction and alternate day fasting in metabolic and energy dynamics in preclinical models of clear cell and translocation RCC with the overall goal of expanding the understanding of metabolism’s role in tumor progression and response to therapies. Methods: Seahorse, immunofluorescence, metabolomics, transcriptomics, genetic silencing, and pharmacological inhibition were utilized to assess the mechanisms underlying nutrient utilization and metabolic dysfunction in RCC. Patient-derived organoids and murine xenograft models were used to demonstrate the impact of dietary interventions and targeted therapies Results: Our data suggests that oxidative-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells but in all the tRCC cells assessed. AA restriction was associated with decreased oxidative phosphorylation in RCC models with baseline elevated mitochondrial function. Similarly, RCC models with a more glycolytic phenotype had decreased glycolytic function and reduced tumor burden in response to fasting conditions. The results from combining dietary interventions and targeted therapies are ongoing and will be presented. Conclusions: Our data suggests that oxidative-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells but in all the tRCC cells assessed. AA restriction was associated with decreased oxidative phosphorylation in RCC models with baseline elevated mitochondrial function. Similarly, RCC models with a more glycolytic phenotype had decreased glycolytic function and reduced tumor burden in response to fasting conditions. The results from combining dietary interventions and targeted therapies are ongoing and will be presented.
Spatial analysis of the tumor immune microenvironment in papillary renal cell carcinoma.
Authors: Hayes Mitch , Sabitov Kirill , Soupir Alex C. , Peak Taylor , Nguyen Jonathan , Moran-Segura Carlos , Saeed-Vafa Daryoush , Lopez-Blanco Neale , Ramos Echevarria Paola , Guske Christopher , Balasi Jodi , Dhillon Jasreman , Kim Youngchul , Mule James J , Fridley Brooke , Manley Brandon J. 
Published: January 2024

471 Background: Spatial analysis of the tumor immune microenvironment (TIME) has yet to be explored in papillary renal cell carcinoma (pRCC). We utilized multiplex immunofluorescence (mIF) and spatial transcriptomics using spatial molecular imaging (SMI) to evaluate TIME properties in pRCC and contrasted these results with clear cell RCC (ccRCC). Methods: Tumor specimens were obtained from localized RCC tumors. mIF was performed on regions of interest (ROIs) selected from matched compartments from tumor, stroma, and tumor/stromal subsets of the interface. Two antibody panels were used for markers against T cells and B cells/macrophages. Marker abundance and clustering differences between pRCC and ccRCC were evaluated across ROIs. Select markers were also explored across pathologic tumor staging in pRCC. The SMI platform used for validation utilized probes against 959 transcripts. Cells were phenotyped using InSituType using the Kidney Cell Atlas as a reference. Cell clustering was quantified by univariate and bivariate Ripley’s K using the spatialTIME package in R. Results: mIF was performed on 1178 ROIs from 16 pRCC tumors and 70 ccRCC tumors. Compared to ccRCC, pRCC immune cell abundance was statistically lower amongst many T cell types and M2-like macrophages (Figure). M1-like macrophages were the only cell line seen at higher levels in interface compartments only. Increased macrophage clustering was observed in pRCC, including doubly positive M2-like macrophages in interface compartments (p=0.001 and 0.007). Higher abundance of CD8+ and FOXP3+ T cells in pRCC was associated with worse clinical stage, but no trend was seen with marker clustering. Four ROIs from 2 pRCC patients underwent SMI validation. On SMI of the tumor compartment, T cells were clustered with other T cells, B cells, and M1 macrophages. Conclusions: Compared to ccRCC, pRCC has fewer T cells and macrophages but more macrophage clustering. Using spatial transcriptomics, we found significant clustering between T cells, macrophages, and B cells in pRCC.
Initial screening efforts for the OPTIC RCC trial.
Authors: Haake Scott Mattox , Beckermann Katy , Chen Yu-Wei , Reddy Anupama , Mar Nataliya , Ornstein Moshe Chaim , Barata Pedro C. , Zhang Tian , Pal Sumanta Kumar , Rathmell W. Kimryn , Rini Brian I. 
Published: January 2024

478 Background: OPTIC RCC (NCT05361720) uses RNA sequencing (seq) of tumor tissue to assign therapy in front-line metastatic clear cell renal cell carcinoma (mccRCC) patients. The operational characteristics of tumor tissue procurement, sequencing, cluster assignment and start of therapy are presented. Methods: Patients diagnosed with mccRCC without prior systemic therapy are eligible for enrollment. RNAseq of primary and/or metastatic tumor tissue is performed by Tempus (Chicago, IL) and data analyzed via an automated cloud-based informatics tool. Results: Twenty-three patients have been screened. Twelve patients (52%) had both primary and metastatic tumors submitted for RNAseq, 4 (17%) had primary only, and 7 (30%) had only metastatic tumor available. Three patients (13%) failed screening because no tumors passed RNAseq quality control (QC). When possible, patients were assigned to clusters based on data from metastatic tumor (15/20, 75%). However, 5/20 (25%) of patients were assigned to clusters based on primary tumor sequencing data because the metastatic tumor was not available or failed QC. Eight patients (40%) were assigned to cluster 1/2, 7 (35%) were assigned to cluster 4/5, and 5 (25%) were assigned to cluster 3/6/7. Primary tumors were more likely to be assigned to cluster 1/2 (12/14, 86%) than metastatic tumors (5/10, 50%) (p<0.01, Fisher’s exact test). Of the 9 pts with both primary and metastatic RNAseq, 5 patients had discordant tumor clusters (primary cluster 1/2 and metastatic cluster 4/5 or 3/6/7); 4 patients with concordant tumor clusters (both cluster 1/2). The mean time from consent to cluster assignment was 32 days (SD +/- 18), though this improved over time. Ten patients have started therapy. Conclusions: Patients with mccRCC can be enrolled on clinical trials that utilize tissue-based RNA sequencing biomarkers. Accrual and analysis correlating cluster assignment with treatment response are ongoing. This trial is funded by the DOD Kidney Cancer Research Program (W81XWH-22-1-1033). Clinical trial information: NCT05361720 .
Safety and efficacy of surgery in renal cell carcinoma with supradiaphragmatic tumor thrombus involving cardiac procedures.
Authors: Nicaise Edouard , Shah Yash , Schmeusser Benjamin , Croll Benjamin , Richter Ellen , Hollon McKenzie , Ogan Kenneth , Daneshmand Mani A. , Maithel Shishir K. , Master Viraj A. 
Published: January 2024

484 Background: Invasion of the IVC is a unique feature of RCC. Tumor extension into the supradiaphragmatic IVC carries high morbidity and mortality attributable to surgical complexity. It is unclear whether safety and efficacy have been shown to warrant cytoreductive surgery for metastatic RCC with concomitant thrombus. We present outcomes of cytoreductive and non-cytoreductive radical nephrectomy (RN) with supradiaphragmatic tumor thrombectomy (TT) involving cardiac surgery. Methods: We reviewed our nephrectomy database for patients with RCC and supradiaphragmatic tumor thrombus. RN with TT was performed by a single team from urology, surgical oncology and cardiothoracic surgery. Rank Sum for numerical and chi-square for categorical variables were used to test for differences between cytoreductive and non-cytoreductive RN. Kaplan Meier curves estimated cancer-specific survival (CSS) and overall survival (OS). Results: From 2006-2023, 43 patients underwent RN with supradiaphragmatic TT. The tableindicates notable clinical and surgical features. No patient participated in a related clinical trial perioperatively. No case required circulatory arrest. One patient required temporary dialysis and later passed from multi-organ failure. 5-year CSS was 12% vs. 78% (p=0.007) and OS was 11% vs. 53% (p=0.044) for cytoreductive and non-cytoreductive surgery respectively. Conclusions: RN with supradiaphragmatic TT is safe with durable treatment response in patients with non-mRCC. Although safety of cytoreductive RN is comparable, further investigation into the role of neoadjuvant therapy is recommended. [Table: see text]
Rethinking the definition of stage IV disease in adrenocortical carcinoma: Assessing the impact of clinical lymph node positive disease.
Authors: Gao Helen , Lichtbroun Benjamin , Chua Kevin J. , Srivastava Arnav , Pfail John , Golombos David , Jang Thomas L. , Ghodoussipour Saum 
Published: January 2024

5 Background: Stage III (pT3N0M0 or pT1-3N1M0) adrenocortical carcinoma (ACC) encompasses both lymph node positive (LN+) and lymph node negative (LN-) disease. However, in other malignancies, prior data demonstrates that LN+ disease portends outcomes similar to metastatic, stage IV disease. We similarly wanted to examine the impact of clinical LN+ disease on oncologic outcomes in ACC. Methods: Patients with clinical stage III and stage IV (M1) disease were identified using the National Cancer Database (NCDB). Stage III patients were stratified as having either LN+ or LN- disease. Kaplan-Meier curves illustrated overall survival of the three groups – stage III LN-, stage III LN+, and stage IV. Further analysis stratified stage III LN+ and stage IV patients by whether or not patients received treatment (systemic therapy, surgery, or both). Results: A total of 917 patients were included in the analysis – 322 stage III LN-, 67 stage III LN+, and 528 stage IV. 3-year OS for patients with stage IV, stage III LN+, and stage III LN – was 15.6% (95% CI, 12.5%-19.4%), 29.4% (95% CI, 19.8%-43.6%), and 48.6% (95% CI, 43.2%-54.6%), respectively. Within the stage III LN+ group 3-year OS was 33.0% (95% CI, 18.5%-58.8%) for those who received treatment and was 27.4% (95% CI, 16.1% - 46.6%) for those who did not. Within the stage IV group 3-year OS was 29.8% (95% CI, 22.7%-39.3%) for those who received treatment and was 10.2% (95% CI, 7.4% - 14.2%) for those who did not. Conclusions: The current staging paradigm of ACC includes LN+ disease as part of the stage III classification. Herein, we see that clinical stage III LN+ disease had a 3-year OS that was more similar to clinical stage IV disease than clinical stage III LN- disease. While the survival curves appear distinct, due to the rarity of the disease and therefore small sample size there was overlapping confidence intervals. In stage IV patients there was a significant difference in OS at 3 years between those who did and did not receive treatment. This same finding was not found in stage III LN + patients.
A novel radiomics-miRNAs integrated model to predict the histopathology of residual retroperitoneal masses in metastatic nonseminomatous germ cell tumors.
Authors: Li Xiangdong , Ding Renjie , Liu Zhuowei 
Published: January 2024

507 Background: Patients with metastatic nonseminomatous germ cell tumours (NSGCTs) are treated with cisplatin-based chemotherapy, followed by postchemotherapy retroperitoneal lymph node dissection (pcRPLND) for patients with residual nodal masses >1 cm. However, 40–50% of patients who undergo pcRPLND are found to have fibrosis/necrotic tissue alone, which may result in overtreatment. Previous prediction models were based on a single method. We hypothesized that a radiomics-based model combined with serum micro-RNAs (miRNAs) including miR371 and miR375 could exhibit better prediction performance in histopathological presence of visible germ cell tumor, teratoma, and fibrosis/necrotic residual retroperitoneal masses. Methods: A retrospective review of 105 patients with 145 residual retroperitoneal masses undergoing pcRPLND for metastatic NSGCTs was performed to develop a prediction model. The dataset was split into separate training cohorts for model construction and validation cohorts for internal validation. On contrast-enhanced axial computed tomography images, 145 corresponding regions-of-interest (ROIs) of residual masses were segmented and 1130 radiomic features per ROI were extracted. After stepwise feature reduction based on reproducibility, variable importance, and correlation analyses, a logistic regression model was established on the selected most important features. Serum miRNA were used to optimize the classifier. The area under receiver operating characteristics curve (AUC), calibration curve, and decision-curve analyses (DCAs) were used to evaluated the prediction model. Results: The trained machine learning model achieved an AUC of 0.772 (95% CI: 0.670-0.875) in the training cohort and 0.764 (95% CI: 0.589-0.938) in the validation cohort. When serum miR371 and miR375 were added to the radiomics signature, the AUC of training cohort was improved to 0.900 (95% CI: 0.826-0.973), and the AUC of validation cohort was improved to 0.939 (95% CI: 0.847-1.000). Nomogram including radiomics score (Radscore) and miRNA was also performed, and the calibration curve analysis and the DCAs confirmed the agreement between prediction and observation and the clinical utility of the radiomics-miRNA prediction model respectively. Conclusions: Radiomics-miRNAs integrated model represents a novel tools for improved prediction of the histopathology of residual retroperitoneal masses in metastatic NSGCTs, aiming at reducing overtreatment. External validation and prospective datasets are needed to further validate this model.