tbuckley/cabot-search huggingface dataset:
Lenvatinib's efficacy in heavily pre-treated metastatic renal cell carcinoma: Insights from a European multicenter study.
Authors: Javier Gavira, Edouard Auclin, Macarena Rey-Cárdenas, Pritha Roy, Jose C. Tapia, Paula Nay, Armelle Vinceneux, Simon Nannini, Adela Randis, Delphine Borchiellini, Guillermo de Velasco, Philippe Barthelemy, Sylvie Negrier, Stephane Oudard, Ricky Dylan Frazer, Ronan Flippot, Laurence Albiges
Journal: Journal of Clinical Oncology (2025)

510 Background: Lenvatinib-based therapy has shown efficacy in the frontline treatment of metastatic renal cell carcinoma (mRCC). However, there is uncertainty about the role of Lenvatinib (LEN) in subsequent lines of treatment, particularly after immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI). This study aimed to describe the real-world clinical outcomes of patients (pts) with mRCC treated with LEN-based therapies beyond first-line treatment. Methods: Retrospective multicenter study including all pts with mRCC treated with LEN-based therapies beyond first-line at seven European centers from October 2020 to August 2024. Data on patient characteristics, treatments, and outcomes were collected. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Secondary endpoints included disease control rate (DCR), overall survival (OS), and safety. This study was approved by a centralized institutional review board (Gustave Roussy). Results: A total of 115 pts were included, 80% males, with a median age of 60.0 years. Of them, 80.9% had clear-cell subtype. Lenvatinib was mainly used after a median of 3 previous lines of treatment (range 2-8), either alone (41.7%) or in combination with everolimus (35.7%), pembrolizumab (PEM) (20.0%), or investigational agents (2.6%). Most of the pts had previously received ICI (88.7%) or TKI (96.5%), including cabozantinib (89.6%). The ORR was 28.2% and DCR was 65.5%. With a median follow-up time of 13.5 months (mo), the median PFS was 6.0 mo (95% CI 4.3-8.4 mo). Previous Cabozantinib (HR 4.3, p=0.02), bone metastases (HR 2.1, p=0.002) and the intermediate (HR 3.4, p=0.009) or poor IMDC risk (HR 7.7, p&lt;0.001) significantly impacted PFS in the multivariate analysis. Median OS was 10.1 mo (95% CI 6.9-12.4 mo). Multivariate Cox models identified poor IMDC risk (HR 7.4, p&lt;0.001) and bone metastases (HR 2.3, p=0.002) as negative independent prognostic factors for OS. On the contrary, LEN-PEM treatment (HR 0.3, p=0.017) had a positive impact on OS. Up to 38.3% of the pts started LEN with a dose adjustment (&lt;18mg per day). On treatment, dose modifications were required in 33.9% of pts, with 9.6% discontinuing due to toxicities. Conclusions: In our cohort, LEN demonstrated meaningful clinical activity in heavily pretreated mRCC pts. The safety profile was manageable. These findings provide evidence to support its utilization in pretreated pts with mRCC.
Body composition and immunotherapy outcomes in patients with advanced urothelial carcinoma.
Authors: Sojin Kim, Shinkyo Yoon, Inkeun Park, Jae Lyun Lee, Hyehyun Jeong, Yousun Ko, Kyung Won Kim, Sun Young Kim
Journal: Journal of Clinical Oncology (2025)

762 Background: Abnormalities in body composition, including sarcopenia and myosteatosis, have been identified as prognostic factors in patients (pts) receiving cytotoxic chemotherapy. However, data regarding the impact of these factors in patients undergoing immune checkpoint inhibitors (ICI) therapy, particularly in those with advanced urothelial carcinoma (aUC), remain limited. This study aimed to evaluate the prognostic significance of body compositions obtained from abdomen-pelvis computed tomography (APCT) in pts with aUC. Methods: This retrospective study included pts with aUC who received ICI (atezolizumab or pembrolizumab) between Jan 2019 and Dec 2022 at Asan Medical Center, Seoul, Korea. Body composition was evaluated using selected axial images at the L3 lumbar vertebrae level from APCT, through an artificial intelligence-driven imaging analysis platform. T-score ≤-2 (-2 SD from the mean reference value in Korean population) was used as cutoff points for sarcopenia and myosteatosis. Visceral obesity (VO) was defined as visceral fat area ≥ 100cm 2 and subcutaneous obesity (SFO) as subcutaneous fat area / height 2 ≥ 50cm 2 /m 2 in males and 42cm 2 /m 2 in females. The associations between body composition parameters with overall survival (OS) and progression-free survival (PFS) were analyzed. Results: A total of 212 pts were included. Median age was 68 (range, 31-86) and 53 pts (25%) were females. ICIs were primarily administered as second-line treatment following failure to platinum-based treatment (N=207, 98%), with 5 pts (2%) receiving ICI as first-line treatment in a metastatic setting. Atezolizumab was given to 174 pts (82%) and pembrolizumab to 38 pts (18%). The prevalence of sarcopenia prior to treatment was 22% (45/212), while myosteatosis was observed in 52% of pts (110/212). VO and SFO were present in 62% and 43% of pts, respectively, with 37% classified as overweight (body mass index (BMI) ≥25kg/m 2 ). Myosteatosis at baseline was associated with an increased risk of mortality (HR 1.58, 95% CI: 1.11–2.23), while sarcopenia, VO, SFO, and BMI did not show significant associations with OS. PFS was not affected by any body composition parameters. Multivariate Cox regression analysis demonstrated that liver metastasis (HR 2.78, 95% CI: 1.94–4.00), hemoglobin (HR 0.52, 95% CI 0.35-0.77), and myosteatosis (HR 1.57, 95% CI 1.12-2.19) were independently associated with OS after adjusting for age and sex. Conclusions: In pts with aUC treated with ICI, myosteatosis showed poorer OS, while sarcopenia, VO, SFO, and BMI did not demonstrate a significant impact. Myosteatosis was significantly associated with OS after adjusting for other clinical factors, which suggests a possibility of a novel prognostic marker in pts with aUC receiving ICI.
Association between baseline and changes in hemoglobin levels and treatment response and prognosis in metastatic renal cell carcinoma: A Mexican retrospective study.
Authors: Saul Campos Gomez, Sandra Vargas Melendez, Arturo Gonzalez Santana
Journal: Journal of Clinical Oncology (2025)

518 Background: Clinical markers of response and outcome in metastatic renal cell carcinoma (mRCC) are lacking. Low hemoglobin (Hb) is associated with poor outcomes in the IMDC risk score. Hb levels also appear to be associated with mRCC response to VEGFI monotherapy, although this relationship is nuclear. This study evaluates the role of Hb increases as a predictive biomarker of clinical response and outcomes. Methods: Patients with advanced RCC treated with VEGF receptor tyrosine kinase inhibitors (TKIs) as a first-line therapy were identified. Hemoglobin levels were retrieved at baseline and then at monthly intervals for 6 months. Absolute and percentage increases over baseline were evaluated as predictors of objective response rate, progression free survival. Patients were categorized as responders (CR+PR) or nonresponders (SD+PD) using cross-sectional imaging at week 12. The Kaplan-Meier method was used to estimate PFS for patients who had an increase vs. decrease from baseline Hb, and the log-rank test used to assess survival differences between the groups. The Cox proportional hazards model was used for univariate and multivariate regression analysis to determine the significance of individual variables on PFS. Results: Among the 47 eligible patients, elevations in hemoglobin were observed in 64%. The median age at start of treatment was 59 years. Changes in hemoglobin at time of response were associated with objective response rate. Landmark analysis at 1 month showed that increases in hemoglobin were associated with longer PFS (mPFS 15 vs. 50 months; P = .004) Responders had a significantly higher Hb level than nonresponders at 1rs month P= 0.004. An increase in Hb was a significant independent predictor of progression-free survival (HR 0.47, P= .039). Conclusions: In this retrospective clinical study, we demonstrate that Hb levels are a valuable clinical marker of outcomes in patients receiving first-line therapy for mRCC in our population. These findings are readily applicable to routine clinical practice and may help clinicians deliver more personalized care.
Validation of PAM50 for predicting progression in active surveillance: Results from the Miami MAST prospective clinical trial.
Authors: David J Lee, Brandon A. Mahal, Sanoj Punnen
Journal: Journal of Clinical Oncology (2025)

238 Background: Active surveillance (AS) has emerged as an increasingly common management strategy for men with low- to favorable intermediate-risk prostate cancer. Although rates of prostate cancer mortality and metastasis remain low, some men experience cancer progression that necessitates treatment. Tools that improve the prediction of progression can enable more risk-adapted and timely treatment. We evaluated a PAM50 molecular classification profile for predicting cancer progression in men undergoing AS for prostate cancer. Methods: A total of 205 men enrolled in the Miami MAST trial who underwent a follow-up protocol involving serial multiparametric MRI and biopsies, including MRI-targeted and systematic biopsies. The highest-grade cores from each targeted and systematic biopsy were sent to Veracyte for genomic profiling. Patients were categorized into three groups based on the PAM50 genomic profile from the Decipher GRID. Time to progression, mutation analysis, and other prognostic signatures available on the Decipher GRID were compared across the three PAM50 classifier groups. Statistical analysis was performed using ANOVA and the rank-sum test, with significance defined as p&lt;0.05. Results: Among the 205 patients enrolled in the trial, 128 had successful genomic profiling for baseline PAM50 classification. 46 were classified as Luminal A, 26 as Luminal B, and 56 as Basal subtypes. The Luminal B subtype demonstrated the highest risk of progression (77%), while the Basal subtype showed the lowest risk (45%) (p=0.011). Median time to progression was shorter in the Luminal B subtype (1.7 years) compared to the Luminal A and Basal subtypes (2.9 years each) (p=0.005). Decipher scores were lowest in the Luminal A group, followed by the Basal group, and highest in the Luminal B group (p=0.0015). Intra-patient variability based on subtyping of different cores within the same biopsy was observed in 37.1% of cases. Transcriptome analysis revealed distinct enrichment profiles for each PAM50 subtype, and mutation pattern analysis highlighted differences in mutation associations, with Luminal B showing a stronger association with SPOP and PTEN mutations. Conclusions: PAM50 shows promise as a molecular classification tool for predicting the risk of progression in prostate cancer. Given its stronger association with SPOP and PTEN mutations, as well as associations with higher progression risk, shorter progression times, and higher Decipher scores, the Luminal B subtype indicates a poorer prognosis compared to the Luminal A and Basal subtypes. This is the first study to validate PAM50 for predicting cancer progression in a prospective cohort of men undergoing active surveillance for prostate cancer. Clinical trial information: NCT02242773 . Progression rates among different PAM50 subtypes. PAM50 Group Non-progressor (%) Progressor (%) P VALUE BASAL 31 (55) 25 (45) 0.011 LUMINAL A 26 (57) 20 (43) LUMINAL B 6 (23) 20 (77)
Temporal trends and socioeconomic determinants of cytoreductive nephrectomy (CN) utilization for metastatic renal cell carcinoma (mRCC) in the United States (US).
Authors: Stepan M. Esagian, Pavlos Msaouel, Jose A. Karam, Benjamin Gartrell, Dimitrios Makrakis
Journal: Journal of Clinical Oncology (2025)

447 Background: The evolving treatment landscape in mRCC since the advent of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) has rendered the role of CN unclear. We sought to quantify CN utilization in the US over the past two decades and assess factors that affect equitable access to CN. Methods: We performed an analysis of the National Inpatient Sample database, using ICD-9 and ICD-10 diagnostic and procedure codes to identify mRCC patients undergoing CN from 2006 to 2021. We calculated annual CN utilization rates, stratified by demographic and socioeconomic factors. We then performed univariable and directed acyclic graph-guided multivariable logistic regression analyses to determine the effect of demographic, socioeconomic, and clinical factors on CN utilization rates. Results: There has been a significant decrease in CN utilization in 2021 compared to 2006 (8.7% vs. 15.8%; OR 0.51, 95% CI 0.42-0.61), consistent across all demographic and socioeconomic groups. Factors associated with decreased CN utilization include Black race (OR 0.70, 95% CI 0.64-0.76), Hispanic race (OR 0.87, 95% CI 0.80-0.95), female gender (OR 0.94, 95% CI 0.90-0.98), being a Medicare (aOR 0.69, 95% CI 0.64-0.73) or Medicaid beneficiary (aOR 0.59, 95% CI 0.54-0.64), lowest income quartile (aOR 0.84, 95% CI 0.78-0.90), Southern US location (aOR 0.83, 95% CI, 0.74-0.93), and treatment in small-sized (aOR 0.57, 95% CI 0.51-0.63) or rural hospitals (aOR 0.33, 95% CI 0.27-0.40). CN utilization has significantly decreased during the ICI era compared to the TKI era (OR 0.69, 95% CI 0.64-0.75). Conclusions: CN utilization has steadily declined across the US over the past two decades, reflecting the uncertainty surrounding its role in mRCC management as new systemic therapies emerge. Access to CN is marked by significant demographic and socioeconomic disparities. Defining the evolving role of CN in the current mRCC treatment era and addressing these disparities is crucial to optimize patient outcomes. Characteristic Univariable analysis(OR [95% CI]) p -value Multivariable analysis(aOR [95% CI]) p -value Black race (ref. White) 0.70 (0.64-0.76) &lt;0.001 - - Hispanic race (ref. White) 0.87 (0.80-0.95) 0.001 - - Female gender (ref. male) 0.94 (0.90-0.98) 0.008 - - 1 st quartile income (ref. 4 th quartile) 0.79 (0.73-0.85) &lt;0.001 0.84 (0.78-0.90) &lt;0.001 Medicare (ref. private insurance) 0.55 (0.53-0.58) &lt;0.001 0.69 (0.64-0.73) &lt;0.001 Medicaid (ref. private insurance) 0.58 (0.54-0.63) &lt;0.001 0.59 (0.54-0.64) &lt;0.001 Southern US (ref. Northeastern US) 0.82 (0.73-0.92) 0.001 0.83 (0.74-0.93) 0.002 Small hospital (ref. large hospital) 0.56 (0.50-0.62) &lt;0.001 0.57 (0.51-0.63) &lt;0.001 Rural hospital (ref. urban teaching hospital) 0.32 (0.27-0.38) &lt;0.001 0.33 (0.27-0.40) &lt;0.001
Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome
Authors: Usua Oyarbide, Valentino Bezzerri, Morgan Staton, Christian Boni, Arish Shah, Marco Cipolli, Eliezer Calo, Seth J. Corey
Journal: Journal of Clinical Investigation (2025)

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency, and bony abnormalities with an increased risk of myeloid neoplasia. Almost all cases of SDS result from biallelic mutations in SBDS. SBDS interacts with EFL1 to displace EIF6 from the 60S ribosomal subunit. Released EIF6 permits the assembly of ribosomal large and small subunits in the cytoplasm. Decreased EIF6 levels due to haploinsufficiency or missense mutations which lead to decreased protein expression may provide a somatic genetic rescue and anti-leukemic effects. We observed accumulation of EIF6 protein in sbds knockout (KO) zebrafish models, confirmed in patient-derived tissues, and correlated with changes in ribosome proteins and TP53 pathways. The mechanism of action for this adaptive response is unknown. To address this, we generated an eif6 zebrafish KO line which do not survive past 10 days post fertilization. We also created two mutants with low Eif6 expression, 5-25% of the wildtype levels, that can survive until adulthood. We bred them with sbds-null strains and analyzed their phenotype and biochemical properties. Low Eif6 levels reduced Tp53 pathway activation but did not rescue neutropenia in Sbds-deficient zebrafish. Further studies elucidating the interplay between SBDS, EIF6, TP53, and cellular stress responses offer promising insights into SDS pathogenesis, somatic genetic rescue, and therapeutic strategies.
Aberrant ERK signaling in astrocytes impairs learning and memory in RASopathy-associated BRAF mutant mouse models
Authors: Minkyung Kang, Jihye Choi, Jeongho Han, Toshiyuki Araki, Soo-Whee Kim, Hyun-Hee Ryu, Min-Gyun Kim, Seoyeon Kim, Hanbyul Jang, Sun Yong Kim, Kyoung-Doo Hwang, Soobin Kim, Myeongjong Yoo, Jaegeon Lee, Kitae Kim, Pojeong Park, Ja Eun Choi, Dae Hee Han, Yujin Kim, Jeongyeon Kim, Sunghoe Chang, Bong-Kiun Kaang, Jung Min Ko, Keun-Ah Cheon, Joon-Yong An, Sang Jeong Kim, Hyungju Park, Benjamin G. Neel, Chul Hoon Kim, Yong-Seok Lee
Journal: Journal of Clinical Investigation (2025)

RAS/MAPK pathway mutations often induce RASopathies with overlapping features, such as craniofacial dysmorphology, cardiovascular defects, dermatologic abnormalities, and intellectual disabilities. Although BRAF gene mutations are associated with cardio-facio-cutaneous (CFC) syndrome and Noonan syndrome, it remains unclear how these mutations impair cognition. Here, we investigated the underlying neural mechanisms using several mouse models harboring a gain-of-function BRAF mutation (K499E) discovered in RASopathy patients. We found expressing BRAF K499E (KE) in neural stem cells under the control of a Nestin-Cre promoter (Nestin;BRAFKE/+) induced hippocampal memory deficits, but expressing it in excitatory or inhibitory neurons did not. BRAF KE expression in neural stem cells led to aberrant reactive astrogliosis, increased astrocytic Ca2+ fluctuations, and reduced hippocampal long-term depression (LTD) in mice. Consistently, 3D human cortical spheroids expressing BRAF KE also showed reactive astrogliosis. Astrocyte-specific AAV-BRAF KE delivery induced memory deficits, reactive astrogliosis, and increased astrocytic Ca2+ fluctuations. Notably, reducing ERK activity in astrocytes rescued the memory deficits and altered astrocytic Ca2+ activity of Nestin;BRAFKE/+ mice. Furthermore, reducing astrocyte Ca2+ activity rescued the spatial memory impairments of BRAF KE-expressing mice. Our results demonstrate that ERK hyperactivity contributes to astrocyte dysfunction associated with Ca2+ dysregulation, leading to the memory deficits of BRAF-associated RASopathies.
Super-enhancer-driven EFNA1 fuels tumor progression in cervical cancer via the FOSL2-Src/AKT/STAT3 axis
Authors: Shu-Qiang Liu, Xi-Xi Cheng, Shuai He, Tao Xia, Yi-Qi Li, Wan Peng, Ya-Qing Zhou, Zi-Hao Xu, Mi-Si He, Yang Liu, Pan-Pan Wei, Song-Hua Yuan, Chang Liu, Shu-Lan Sun, Dong-Ling Zou, Min Zheng, Chun-Yan Lan, Chun-Ling Luo, Jin-Xin Bei
Journal: Journal of Clinical Investigation (2025)

Super-enhancers (SEs) are expansive cis-regulatory elements known for amplifying oncogene expression across various cancers. However, their role in cervical cancer (CC), a remarkable global malignancy affecting women, remains underexplored. Here we applied integrated epigenomic and transcriptomic profiling to delineate the distinct SE landscape in CC by analyzing paired tumor and normal tissues. Our study identifies a tumor-specific SE at the EFNA1 locus that drives EFNA1 expression in CC. Mechanically, the EFNA1 SE region contains consensus sequences for the transcription factor FOSL2, whose knockdown markedly suppressed luciferase activity and diminished H3K27ac enrichment within the SE region. Functional analyses further underlined EFNA1's oncogenic role in CC, linking its overexpression to poor patient outcomes. EFNA1 knockdown strikingly reduced CC cell proliferation, migration, and tumor growth. Moreover, EFNA1 cis-interacted with its receptor EphA2, leading to decreased EphA2 tyrosine phosphorylation and subsequent activation of the Src/AKT/STAT3 forward signaling pathway. Inhibition of this pathway with specific inhibitors substantially attenuated the tumorigenic capacity of EFNA1-overexpressing CC cells in both in vitro and in vivo models. Collectively, our study unveils the critical role of SEs in promoting tumor progression through the FOSL2-EFNA1-EphA2-Src/AKT/STAT3 axis, providing new prognostic and therapeutic avenues for CC patients.
Asparagine drives immune evasion in bladder cancer via RIG-I stability and type I IFN signaling
Authors: Wenjie Wei, Hongzhao Li, Shuo Tian, Chi Zhang, Junxiao Liu, Wen Tao, Tianwei Cai, Yuhao Dong, Chuang Wang, Dingyi Lu, Yakun Ai, Wanlin Zhang, Hanfeng Wang, Kan Liu, Yang Fan, Yu Gao, Qingbo Huang, Xin Ma, Baojun Wang, Xu Zhang, Yan Huang
Journal: Journal of Clinical Investigation (2025)

Tumor cells often employ many ways to restrain type I interferon signaling to evade immune surveillance. However, whether cellular amino acid metabolism regulate this process remains unclear and its effects on antitumor immunity are relatively unexplored. Here, we find that asparagine inhibits IFN-I signaling and promotes immune escape in bladder cancer. Depletion of asparagine synthetase (ASNS) strongly limits in vivo tumor growth in a CD8+ T cell-dependent manner and boosts immunotherapy efficacy. Moreover, clinically approved ASNase synergizes with anti-PD-1 therapy in suppressing tumor growth. Mechanistically, asparagine can directly bind to RIG-I and facilitate CBL-mediated RIG-I degradation, thereby suppressing IFN signaling and antitumor immune responses. Clinically, tumors with higher ASNS expression show decreased responsiveness to ICIs therapy. Together, our findings uncover asparagine as a natural metabolite to modulate RIG-I-mediated IFN-I signaling, providing the basis for developing the combinatorial use of ASNase and anti-PD-1 for bladder cancer.
CDK1-mediated phosphorylation of USP37 regulates SND1 stability and promotes oncogenesis in colorectal cancer
Authors: Liang Wu, Can Cheng, Ning Zhao, Liang Zhu, Heng Li, Jingwen Liu, Yang Wu, Xi Chen, Hanhui Yao, Lianxin Liu
Journal: Acta Pharmaceutica Sinica B (2025)