tbuckley/cabot-search huggingface dataset:
Fecal, duodenal, and tumor microbiota composition of esophageal carcinoma patients, a longitudinal prospective cohort
Authors: Tom van den Ende, Nicolien C de Clercq, Mark Davids, Ruben Goedegebuure, Benthe H Doeve, Gati Ebrahimi, Jeroen Buijsen, Ronald Hoekstra, Nadia Haj Mohammad, Maarten F Bijlsma, Max Nieuwdorp, Hanneke W M van Laarhoven
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background The microbiome has been associated with chemotherapy and immune checkpoint inhibitor efficacy. How this pertains to resectable esophageal carcinoma is unknown. Our aim was to identify microbial signatures in resectable esophageal carcinoma associated with response to neoadjuvant chemoradiotherapy with or without an immune checkpoint inhibitor. Methods From 2 prospectively collected esophageal carcinoma cohorts (n = 172 in total) treated with neoadjuvant chemoradiotherapy alone (n = 132) or a combination of neoadjuvant chemoradiotherapy and an immune checkpoint inhibitor (n = 40), fecal samples were available at baseline, during treatment, and presurgery. Additionally, in the immune checkpoint inhibitor–treated patients, tumor and duodenal snap frozen biopsies were collected over time. Fecal, tumor, and duodenal DNA were extracted for 16S ribosomal RNA sequencing. Associations were investigated between microbiome composition pathological complete response and progression-free survival (PFS). Results There was a statistically significant shift in the microbiota profile of the fecal, tumor, and duodenal microbiota over time. In the total cohort, patients with a pathological complete response had a stable fecal alpha diversity, while the diversity of poor responders decreased during treatment (P = .036). Presurgery, lower alpha diversity (&amp;lt;4.12) was related to worse PFS (log-rank P = .025). Baseline tumor biopsies of patients with short PFS had more Fusobacterium. A low baseline duodenal alpha diversity (&amp;lt;3.96) was associated with worse PFS (log-rank P = .012). Conclusions Lower intestinal alpha diversity was associated with worse response and survival of esophageal carcinoma patients. In tumor biopsies, Fusobacterium was more abundant in patients with poor PFS. After further mechanistic validation, these findings may aid in response prediction and the design of novel microbiome modulating treatments for esophageal carcinoma patients.
Dynamic Foxp3–chromatin interaction controls tunable Treg cell function
Authors: Minghong He, Xinying Zong, Beisi Xu, Wenjie Qi, Wenjun Huang, Mohamed Nadhir Djekidel, Yang Zhang, Vishwajeeth R. Pagala, Jun Li, Xiaolei Hao, Clifford Guy, Lu Bai, Richard Cross, Chunliang Li, Junmin Peng, Yongqiang Feng
Journal: The Journal of Experimental Medicine (2024)

Nuclear factor Foxp3 determines regulatory T (Treg) cell fate and function via mechanisms that remain unclear. Here, we investigate the nature of Foxp3-mediated gene regulation in suppressing autoimmunity and antitumor immune response. Contrasting with previous models, we find that Foxp3–chromatin binding is regulated by Treg activation states, tumor microenvironment, and antigen and cytokine stimulations. Proteomics studies uncover dynamic proteins within Foxp3 proximity upon TCR or IL-2 receptor signaling in vitro, reflecting intricate interactions among Foxp3, signal transducers, and chromatin. Pharmacological inhibition and genetic knockdown experiments indicate that NFAT and AP-1 protein Batf are required for enhanced Foxp3–chromatin binding in activated Treg cells and tumor-infiltrating Treg cells to modulate target gene expression. Furthermore, mutations at the Foxp3 DNA-binding domain destabilize the Foxp3–chromatin association. These representative settings delineate context-dependent Foxp3–chromatin interaction, suggesting that Foxp3 associates with chromatin by hijacking DNA-binding proteins resulting from Treg activation or differentiation, which is stabilized by direct Foxp3–DNA binding, to dynamically regulate Treg cell function according to immunological contexts.
Genetically engineered long-acting Esculentin-2CHa(1−30) fusion protein with potential applicability for the treatment of NAFLD
Authors: Jaewoong Lee, Reeju Amatya, Kyung Eun Kim, Young-Hoon Park, Eunmi Hong, Krismala Djayanti, Kyoung Ah Min, Gu Seob Roh, Meong Cheol Shin
Journal: Journal of Controlled Release (2024)
Allosteric regulation of Keap1 by 8β-hydroxy-α-cyclocostunolide for the treatment of acute lung injury
Authors: Juan Zhang, Min Zhang, Qi-Meng Zhu, Xin-Rong Xu, Yan-Li Feng, Sheng Lin, Feng Qiu, Cheng-Peng Sun
Journal: Acta Pharmaceutica Sinica B (2024)

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Endoscopic submucosal dissection and endoscopic mucosal resection for Barrett’s-associated neoplasia: a systematic review and meta-analysis of the published literature
Authors: Dhruvil Radadiya, Madhav Desai, Harsh K Patel, Jena Velji-Ibrahim, Marco Spadaccini, Sachin Srinivasan, Shruti Khurana, Viveksandeep Thoguluva Chandrasekar, Abhilash Perisetti, Alessandro Repici, Cesare Hassan, Prateek Sharma
Journal: Endoscopy (2024)

The role of endoscopic submucosal dissection (ESD) in the treatment of Barrett esophagus-associated neoplasia (BEN) has been evolving. We examined the efficacy and safety of ESD and endoscopic mucosal resection (EMR) for BEN.
Imaging with [89Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial
Authors: Salomon Tendler, Mark P Dunphy, Matthew Agee, Joseph O'Donoghue, Rania G Aly, Noura J Choudhury, Adam Kesner, Assen Kirov, Audrey Mauguen, Marina K Baine, Heiko Schoder, Wolfgang A Weber, Natasha Rekhtman, Serge K Lyashchenko, Lisa Bodei, Michael J Morris, Jason S Lewis, Charles M Rudin, John T Poirier
Journal: The Lancet Oncology (2024)
Behavioural and sleep issues after initiation of elexacaftor–tezacaftor–ivacaftor in preschool-age children with cystic fibrosis
Authors: I Sermet-Gaudelus, Sihem Benaboud, Stéphanie Bui, Tiphaine Bihouée, Sophie Gautier, Mahassen Barboura, Audrey Barzic, Lilia Benhalla, Khadidja Bennour, Katia Bessaci, Antoine Bessou, Thiphaine Bihouee, Anne-Sophie Bonnel, Nesrine Bouleghem, Stéphanie Bui, Frédérique Chedevergne, Harriet Corvol, Laure Cosson, Laure Couderc, Marie-Laure Dalphin, Paola De carli, Eric Deneuville, Pierre Foucaud, Asma Gabsi, Elsa Gachelin, Fatiha Hassani, Veronique Houdouin, Frédéric Huet, Marie Jamin, Kadiatou Kaba, Guillaume Labbe, Jane Languepin, Muriel Laurans, Cathy Lerena, Alexia Letierce, Clotilde Livrozet, Christophe Marguet, Laurent Mely, Rania Messaoudi, Marie Mittaine, Caroline Perisson, Carole Piccini-bailly, Philippe Reix, Natascha Remus, Anna Ronayette, Djouher Sahki, Manuela Scalbert, Isabelle Sermet-Gaudelus, Floriane Socchi, Nathalie Stremler, Aurélie Tatopoulos, Guillaume Thouvenin, Françoise Troussier, Laurence Weiss, Nathalie Wizla
Journal: The Lancet (2024)
Inflammasome activation in patients with Kaposi sarcoma herpesvirus (KSHV)-associated disorders
Authors: Silvia Lucena Lage, Ramya Ramaswami, Joseph Rocco, Adam Rupert, David A Davis, Kathryn Lurain, Maura Manion, Denise Whitby, Robert Yarchoan, Irini Sereti
Journal: Blood (2024)
Optimizing Drug Combinations for T-PLL: Restoring DNA Damage and P53-Mediated Apoptotic Responses
Authors: Jana von Jan, Sanna Timonen, Till Braun, Qu Jiang, Aleksandr Ianevski, Yayi Peng, Kathleen McConnell, Paola Sindaco, Tony Andreas Müller, Sabine Pützer, Hanna Klepzig, Dennis Jungherz, Annika Dechow, Linus Wahnschaffe, Anil K Giri, Matti Kankainen, Heikki Kuusanmäki, Heidi A Neubauer, Richard H Moriggl, Paolo Mazzeo, Nicole Schmidt, Raphael Koch, Michael J Hallek, Amel Chebel, David Armisen, Laurent Genestier, Emmanuel Bachy, Anjali Mishra, Alexandra Schrader, Tero Aittokallio, Satu Mustjoki, Marco Herling
Journal: Blood (2024)
Prognostic factors of relapse in surgically resected small cell neuroendocrine carcinomas of the urothelial tract (SCNEC-URO).
Authors: Mohammad Jad Moussa, Nathaniel R. Wilson, Lianchun Xiao, Georges C. Tabet, Jianjun Gao, Amishi Yogesh Shah, Paul Gettys Corn, Sangeeta Goswami, Pavlos Msaouel, Nizar M. Tannir, Byron H. Lee, Ashish M. Kamat, Mehrad Adibi, Colin P.N. Dinney, Donna E. Hansel, Charles C. Guo, Arlene O. Siefker-Radtke, Matthew T Campbell, Omar Alhalabi
Journal: Journal of Clinical Oncology (2024)

4605 Background: SCNEC-URO are rare aggressive cancers with limited treatments. Although they frequently co-exist (60-70%) with urothelial carcinoma (UC) at diagnosis, most metastatic biopsies of relapsing patients (pts) show pure small cell (SC) morphology. There are major unmet needs to predict relapse after definitive surgery. Methods: Data was extracted from a historical cohort of n=216 pts with surgery for surgically resectable disease (cT1-T4, N0 or N+, M0) at MD Anderson between November 1985 and June 2021. Morphology at resection was defined as: ‘pCR’ (pathological complete response, including no residual carcinoma or carcinoma in situ), ‘Any SCNEC’ (persistence of SC with UC in sample) or ‘Non-SCNEC’ (UC only). Relapse events after surgery were analyzed as time-to-event (TTE) outcome with competing risk non-parametric method. Univariable and multivariable analyses identified prognostic factors of relapse. Results: In TTE analysis, cohort events (n=216) included: n=70 censored (alive and relapse-free), n=92 failure events (with relapse), and n=54 competing events (death without known relapse). n=154 (71.3%) received neoadjuvant chemotherapy, including SCNEC regimens in 125/154 (81.2%) and UC regimens in 16/154 (10.4%). The 5-year cumulative incidence function (CIF) of relapse for all pts was 41.92% [95% CI: 35.2% - 48.5%]. CIF rates were significantly different per morphology at resection (Gray’s test, p&lt;.0001). Pts with pCR had the lowest 5-year CIF rate for relapse (18.5%) [11.1% - 27.4%], while pts with ‘Any SCNEC’ had the highest CIF (69.6%) [58.6% - 78.9%]. Pts with Non-SCNEC had an intermediate CIF risk (31.6%) [17.6% - 46.7%]. Staging at resection also showed different CIF rates (Gray’s test, p&lt;.0001). Pts with pT0N0 had the lowest CIF rate (12.8%) [5.6% - 23.2%], with CIF rates increasing with higher staging: pTisN0 (25%) [11.6% - 41%]; pT1N0 (25%) [5.4% - 51.7%]; pT2 or greater, but N0 (52.4%) [41% - 62.7%]. Pts staged node-positive (pN+) did not have an estimated 5-year CIF as most died within 5 years. In multivariable analysis, clinical staging at diagnosis, pathological staging and cellular morphology at resection were associated with relapse (Table). Conclusions: Besides staging at diagnosis and surgery, morphology at resection is a key predictor of relapse. Persistence of the SC component predicts a higher chance of relapse than its eradication and persistence of the UC component. While adjuvant therapy in UC has made significant progress recently, a tailored adjuvant approach addressing the residual SC component at definitive surgery is needed to improve outcomes and decrease relapse. [Table: see text]
Survival outcome of metastatic pulmonary sarcomatoid carcinoma in immunotherapy era: An NCDB analysis.
Authors: Bolun Liu, Changchuan Jiang, Kristopher Attwood, Stuthi Perimbeti, Hongbin Chen, Lei Deng
Journal: Journal of Clinical Oncology (2024)

8555 Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare subtype of non-small cell lung cancer (NSCLC), with historically poor outcome. Excellent response of metastatic PSC to immunotherapy was previously reported, but its outcome compared with other NSCLCs is unknown in the immunotherapy era. Methods: NCDB was queried for stage IV NSCLC diagnosed from 2016 to 2020. Patients who were treated with chemotherapy only or immunotherapy only in the first course of treatment were included. Log-rank was used for survival analysis and adjusted by cox regression for age, gender, race, academic/integrated center, insurance, and comorbidity. Results: A total of 37,617 patients were identified, including 201 PSCs and 37,416 other NSCLCs. Pleomorphic (54%) was the most common PSC subtype. There was significant interaction between the survival effect of treatment and histology (interaction p = 0.024). When treated with immunotherapy alone, no significant difference was found between PSC and other NSCLCs (median survival 11.4 vs 12.4 months, logrank p = 0.56, HR 1.02, 95% CI 0.81 – 1.30). However, when treated with chemotherapy alone, PSC remained significantly associated with worse survival (median survival 4.5 vs. 8.5 months, logrank p &lt;0.001, HR 0.67, 95% CI 0.54 – 0.83). Among PSC subtypes, spindle/giant cell PSCs were more likely to benefit from immunotherapy alone than pleomorphic PSCs (interaction p = 0.005), when compared with chemotherapy (Spindle/giant cell subtype: HR 0.24, 95% CI 0.14 – 0.42; Pleomorphic subtype: HR 0.60, 95% CI 0.37 – 0.99). Conclusions: Compared with other NSCLCs, PSC may not be associated with worse survival when treated with immunotherapy alone as it was when treated with chemotherapy. Distinct PSC subtypes may respond differently to immunotherapy and warrants further research. [Table: see text]
Comparing treatment modalities for T2N0M0 muscle invasive bladder cancer: A propensity score analysis with the National Cancer Database.
Authors: Alberto Pieretti, Mohamed Mohanna, Saad Sabbagh, Nicolas Muruve, Hong Liang, Christopher Fleming, Christopher Weight, Nima Almassi, Georges-Pascal Haber, Ashish M. Kamat, Rafael Arteta-Bulos, Colin P.N. Dinney
Journal: Journal of Clinical Oncology (2024)

4604 Background: Muscle-invasive Bladder Cancer (MIBC) constitutes 25% of bladder malignancies. Per NCCN guidelines, the primary treatment for stage II (T2N0M0) MIBC is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), RC alone, or bladder preservation chemoradiotherapy (BPCRT). This study aims to compare the overall survival between different treatment modalities with an emphasis on patients considered to be best candidates for BPCRT (No hydronephrosis, extensive or multifocal carcinoma in situ (CIS), and tumor size &lt;6cm, ”low-risk”) versus those who are not (“high-risk”). Methods: We queried 12510 patients from the National Cancer Database from 2004-2020 for stage II T2N0M0 MIBC. Patients were divided in low-risk (&lt; 6 cm and no evidence of CIS) or high-risk MIBC. The propensity score matched (PSM) sample was constructed greedy nearest neighbor matching on the logit of the propensity score using a caliper of width equal to 0.2 of the standard deviation of the logit of the propensity score. We used standardized differences (SD) to evaluate how well the covariates were balanced and a value of &lt; 0.1 was considered negligible. The Cox proportional hazards model was performed to compare the survivorships between the PSM paired samples. All data analyses were conducted using SAS version 9.4. Results: Following PSM and risk factor stratification, we found that median overall survival (OS) was lower with BPRCT compared to RC alone or NAC+RC in both risk groups. In the low-risk group, the median OS of BPRCT compared to NAC+RC was 34 and 76 months, respectively (HR = 1.81, 95%CI = (1.25-2.62), p=0.0017 and there was no statistical significant difference in RC compared to NAC+RC median OS (p=0.3459). In the high-risk group, the median OS of BPRCT compared to NAC+RC was 22 and 68 months, respectively (HR = 2.19, 95%CI = (1.86-2.59), p&lt;0.0001) (Table) and the median OS of RC compared to NAC+RC was 79 and 99 months respectively (HR=1.2, 95%CI = (1.11-1.3), p&lt;0.001 (Table). Conclusions: This nationwide study showed that RC was the optimal treatment for low-risk stage 2 MIBC, with improved OS compared with BPCRT and equivalent OR with NAC+RC, without the added cost or morbidity. For high-risk patients NAC+RC was associated with a significant improvement of OS compared to BPCRT and RC alone.[Table: see text]
Enfortumab vedotin (EV) in non-squamous and squamous non–small cell lung cancer (NSCLC) cohorts of EV-202.
Authors: Kei Muro, Trevor Feinstein, Joaquina Celebre Baranda, Ioana Bonta, Satoru Kitazono, Todd A. Gersten, Leena Gandhi, Toshihiro Kudo, Jason Kaplan, Seema Rao Gorla, Shubin Liu, Michele Wozniak, Anthony Lee, Tejas Patil
Journal: Journal of Clinical Oncology (2024)

8585 Background: EV, a Nectin-4–directed antibody–drug conjugate, is approved for use in urothelial cancer. Nectin-4 is expressed in several solid tumors, including NSCLC. EV monotherapy was evaluated in non-squamous and squamous NSCLC cohorts in EV-202 (NCT04225117). Methods: This open-label, multicohort, phase 2 trial enrolled adults with locally advanced or metastatic solid tumors and ECOG PS 0–1. For NSCLC cohorts, patients (pts) had NSCLC not amenable to curative-intent treatment (tx), 1 platinum-based and ≤2 lines of cytotoxic tx for locally advanced or metastatic NSCLC, and prior PD-1/L1 inhibitor unless contraindicated. Nectin-4 expression was not required for inclusion but was assessed retrospectively. Pts received EV 1.25 mg/kg intravenously on days 1, 8, and 15 of each 28-d cycle until discontinuation. Interim analysis (IA) was conducted for each cohort when 20 pts were response-evaluable. If the cohort-specific minimum number of responders (non-squamous: 3; squamous: 2) was not met, enrollment could be closed. Primary endpoint was confirmed objective response rate (ORR). Secondary endpoints were duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety/tolerability. Antitumor activity was investigator-assessed per RECIST v1.1. Results: The non-squamous cohort met the minimum number of responders at IA and continued enrollment. Of 43 pts in this cohort as of Feb 21, 2022, median age was 67 y (range, 36–82), 51% were male, and 47% had ≥3 prior lines of systemic tx. Histology at diagnosis was adenocarcinoma for 38 (88%) pts. Efficacy and overall tx-related adverse event (TRAE) data are in the table. Common TRAEs in the non-squamous cohort were maculopapular rash and peripheral sensory neuropathy (both n=16, 37%), pruritus (n=15, 35%), and alopecia (n=14, 33%). Grade ≥3 TRAEs in &gt;1 pt were maculopapular rash (n=3, 7%) and decreased neutrophil count (n=2, 5%). Selected TRAEs of special interest were skin reactions (n=24, 56%), peripheral neuropathy (n=16, 37%), and hyperglycemia (n=3, 7%). Only 1 of 20 pts in the squamous cohort had achieved a response at IA; thus, enrollment closed. The table shows data from the primary analysis (Jul 15, 2022; N=23). Conclusions: EV showed antitumor activity in heavily pretreated non-squamous NSCLC and manageable safety consistent with the known safety profile. The IA efficacy threshold was not met in squamous NSCLC. Clinical trial information: NCT04225117 . [Table: see text]
Phase Ib clinical study of first-line treatment with gefitinib in combination with bevacizumab and chemotherapy in advanced non-squamous non-small cell lung cancer with EGFR mutation.
Authors: Yanjuan Xiong, Xiubao Ren, Liang Liu
Journal: Journal of Clinical Oncology (2024)

8554 Background: The safety and efficacy of combination of gefitinib with chemotherapy and bevacizumab in treatment patients with epidermal growth factor receptor (EGFR) mutations are currently unknown. This phase Ib clinical trial was designed to evaluate the safety and preliminary efficacy of a combination therapy consisting of gefitinib, bevacizumab, pemetrexed, and carboplatin in patients with advanced non-squamous non–small cell lung cancer (NSCLC) harboring EGFR mutations. Methods: Eligible patients with EGFR-mutated advanced non-squamous NSCLC were recruited and received gefitinib combination with bevacizumab plus pemetrexed and carboplatin treatment. The primary endpoints were safety and progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), duration of response (DOR), and overall survival (OS). Results: From June 2019 to June 2021, 20 patients were enrolled in this trial. The median follow-up was 33.8 months (95% CI, 31.0-36.6). Grade ≥3 adverse events was 65%, including neutropenia (30%), thrombocytopenia (20%), nausea (20%), skin rash (20%), bleeding (10%), and increased ALT (10%). There was no death related to toxicity occurred. The median PFS was 28 months (95% CI, 20.4-35.6). the ORR was 95% (95% CI, 75.1%-99.9%), the DCR was 100% (95% CI, 83.2%-100%), and the median DOR was 26.4 months (95% CI, 18.9-33.9). The median OS has not been reached. Conclusions: The results of this study demonstrate that the four-drug combination regimen, led by gefitinib, is well-tolerated and effective for patients with EGFR-mutated advanced non-squamous NSCLC.
Identification of prognostic genomic biomarkers in metastatic clear cell renal cell carcinoma (mccRCC): An analysis of the large retrospective real world clinico-genomic data from Flatiron Health (FH)-Foundation Medicine, Inc. (FMI) clinico-genomic database (CGDB).
Authors: Mimma Rizzo, Gaetano Pezzicoli, Camilla Porta, Massimiliano Povero, Lorenzo Pradelli, Emilia Sicari, Valentina Sara Barbiero, Camillo Porta
Journal: Journal of Clinical Oncology (2024)

4553 Background: Despite a number of therapeutic improvements, mccRCC still has a poor prognosis, with limited prognostic predictors for clinical practice. The aim of this study was to evaluate the prognostic value of three clusters of co-occurring genes in mccRCC. Methods: We conducted a retrospective analysis of adult patients with mccRCC who were profiled by performing FMI genomic tests using tissue biopsies or blood samples. Data were from the nationwide (US-based) de-identified FH-FMI CGDB, originating from approximately 280 US cancer clinics (~800 sites of care). Patients diagnosed from January 01, 2011 to June 30, 2022 were followed until death or the last available observation (within December 31, 2022). Overall Survival (OS) was estimated using the Kaplan-Meier methods, while Cox proportional hazard model with risk set adjustment was used to assess the prognostic role of three pre-specified clusters of co-occurring genes; cluster 1 (C1) included VHL, SETD2, PBRM1, KDM5C, MTOR, and NFE2L2, cluster 2 (C2) included TP53, TSC1, and TERT, while cluster 3 (C3) included CDKN2A, CDKN2B, BAP1, NF2, MTAP, and ARID1A. Patients were considered cluster-positive (+) if they exhibited mutations in at least one gene within the cluster, and none in the other clusters. Results: 789 mccRCC patients were included [median age: 61 years, male: 71.1%, white race: 71.2%]. Among the 720 (91.3%) treated patients, 516 (71.7%) and 59 (8.2%) were classified per IMDC score as poor/intermediate and favorable risk, respectively (145 missing). Overall, almost half (45.5%; 359) were profiled after the diagnosis of metastasis (median gap time of 7.9 months) and 29 (3.7%) underwent multiple profile assessments, resulting in a total of 818 specimens analyzed. 332 (42.1%), 27 (3.4%), and 32 (4.1%) patients were C1+, C2+, and C3+, respectively. Median OS was 37 months (95% CI: 34-42). C1+ patients had higher OS compared to C1- (median OS: 50 vs. 30 months; HR: 0.57, p&lt;0.001), while C3+ was associated with worse OS (median OS: 38 vs. 20 months; HR: 1.94, p=0.004). No association was found between C2 and OS (HR: 1.27; p=0.4). C1+ patients were more frequently classified as favorable risk compared to C1- (10.2% C1+ vs. 6.8% C1-, p=0.046) and they had longer duration of first-line (L1) treatment (median DoT: 9 vs. 7 months, p = 0.02). No significant differences between C2+ and C2-, C3+ and C3- patients were observed in L1 duration and IMDC distribution. Conclusions: This large-scale study identified two independent prognostic gene clusters in mccRCC. Further analyses will focus on the validation of the predictive role of these biomarkers with the ultimate aim of helping us develop tailored treatment strategies.