bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Latino ethnicity on the gut microbiome composition of patients with metastatic renal cell cancer (mRCC).
Authors: Barragán Carrillo Regina , Dizman Nazli , Ebrahimi Hedyeh , Meza Luis A , Bergerot Paulo Gustavo , Dorff Tanya B. , Hsu Joann , Zengin Zeynep Busra , Salgia Nicholas , Chehrazi-Raffle Alex , Tripathi Abhishek , Castro Daniela V. , Mercier Benjamin , Caporaso Gregory , Lee Keehoon , Pal Sumanta Kumar 
Published: June 2024

4521 Background: Latinos with mRCC may have poorer outcomes with frontline immune checkpoint inhibition (ICI) compared to their non-Latino counterparts (Chehrazi-Raffle et alOncologist 2023). Recent studies have shown that the composition of the gut microbiome can impact outcomes with ICI (Routy et alScience 2018). Therefore, we aimed to investigate the differences in gut microbiome composition between Latino and non-Latino patients (pts) with mRCC. Methods: Stool specimens were prospectively collected in treatment-naïve pts with mRCC. We dichotomized pts into Latino vs non-Latino groups. Pts provided a stool sample (OMNIgene Gut) at baseline. Whole metagenome sequencing was performed on stool specimens collected. Taxonomic profiling was conducted using MetaPhlAn 4. ANCOM-BC analysis was used to identify differences in the relative abundance of bacterial species between groups. Alpha-diversity was evaluated using the Shannon diversity index and Evenness analysis, employing the Kruskal-Wallis test. Beta-diversity was assessed using the Bray-Curtis and Jaccard dissimilarity measures. The ratio of Firmicutes/Bacteroidetes (F/B), a measure of gut dysbiosis, was computed at baseline in the two cohorts. Results: Among 59 pts assessed, 27 and 32 were Latino and non-Latino, respectively. Median age of the cohort was 60 (range, 36-90). Most were male (71%), had clear cell RCC (88%) and had intermediate/poor risk disease (79%). ANCOM-BC analysis showed an enrichment of 14 bacterial species and a depletion in 3 species at baseline in the Latino group (p ≤ 0.05). Three Roseburiaspp. were enriched in the Latino pts, namely R. faecis (log-fold change [LFC]: 2.6), R. hominis (LFC: 2.0) and R. inulinivorans (LFC: 1.8). Additionally, Eubacterium rectalewas also enriched in the Latino group (LFC: 2.0). In contrast, in non-Latino pts Methylobacterium spp. was enriched (LFC: 1.3). The F/B ratio was higher in the Latino group as compared to the non-Latino group (1.00 vs 0.92). We did not observe any differences in alpha and beta diversity. A detailed analysis of simultaneously collected dietary logs is ongoing. Conclusions: Our examination of the gut microbiota of pts with mRCC revealed significant differences based on ethnicity at baseline. Specifically, the Latino group exhibited an enhancement of Roseburia spp. and E. rectale, species previously linked to favorable outcomes with ICIs, despite a higher F/B ratio (suggesting a greater degree of dysbiosis). Our findings advocate that clinical trials related to the microbiome should potentially account for baseline differences in ethnicity.
Lenvatinib plus pembrolizumab (L+P) vs sunitinib (S) in advanced renal cell carcinoma (aRCC): Patterns of progression and subsequent therapy in the CLEAR trial.
Authors: Grünwald Viktor , Motzer Robert J. , Keizman Daniel , Bedke Jens , Schmidinger Manuela , Staehler Michael D. , Matveev Vsevolod B. , George Saby , Hutson Thomas E. , Vaishampayan Ulka N. , Merchan Jaime R. , Eto Masatoshi , Rha Sun Young , Waddell Tom , Sabbatini Roberto , Barthelemy Philippe , Burgents Joseph E. , Ren Min , Brown Ian , CHOUEIRI Toni K. 
Published: June 2024

4524 Background: In the primary analysis of the CLEAR trial of patients (pts) with aRCC, L+P significantly improved efficacy vs S (Motzer NEJM 2021). Results were further confirmed at the final prespecified OS analysis (Motzer JCO 2024). Here, we discuss patterns of progression and subsequent therapy in CLEAR. Methods: Treatment-naïve pts (n=1069) who had aRCC with a clear-cell component were randomly assigned (1:1:1) to receive: L 20 mg PO QD + P 200 mg IV Q3W; or L 18 mg + everolimus 5 mg PO QD; or S 50 mg PO QD (4 wks on/2 wks off). Stratification factors were region and MSKCC prognostic risk group. To explore progression pattern within individual organs, time to progression was defined for each organ independently using lesions within each specific organ only, based on Independent Image Review per RECIST v1.1. Medians and quartiles were estimated with Kaplan-Meier (KM) method; 95% CIs were estimated with a generalized Brookmeyer and Crowley method. Hazard ratio (HR) reported is for L+P vs S based on Cox regression model with treatment as factor; HR was stratified by region and MSKCC prognostic groups. The Efron method was used for correction for ties. Results: The HRs (95% CI) of time to progression for L+P vs S across tumors in different organs were: bone, 0.40 (0.25-0.63); CNS, 0.47 (0.19-1.19); kidney, 0.65 (0.37-1.14); liver, 0.52 (0.32-0.84); lung, 0.48 (0.36-0.62); and lymph nodes, 0.63 (0.46-0.85). At overall disease progression, the median sums of diameters of target lesions were lower with L+P vs S (29.8mm vs 42.8mm; Table). In the L+P arm, 181 pts received subsequent anticancer regimens during survival follow-up (43 received axitinib and 101 received cabozantinib). In the S arm, 246 pts received subsequent anticancer regimens (47 received axitinib and 107 received cabozantinib). The median duration of axitinib as the first anticancer regimen (95% CI) after L+P was 23.7 months (5.3-not estimable [NE]), and after S was 12.6 months (6.8-NE). The median duration of cabozantinib as the first anticancer regimen (95% CI) after L+P was 13.2 months (8.2-NE), and after S was 7.1 months (4.1-20.0). Conclusions: Pts in the L+P arm trended to show later progression across tumors in different organs. At overall disease progression, the tumor burden of target lesions was lower with L+P vs S; and pts in the L+P arm stayed on 2L axitinib or cabozantinib longer than pts in the S arm. Together, these results continue to support L+P as a standard-of-care 1L therapy in pts with aRCC. Clinical trial information: NCT02811861 . [Table: see text]
Effect of antibiotic, proton pump inhibitor, H2 blocker, metformin and statin use on outcomes with immune checkpoint inhibitors (ICIs) in patients (pts) with metastatic urothelial carcinoma (mUC) in a real-world setting.
Authors: Hobeika Charbel , Dawsey Scott , Patgunarajah Ubenthira , Lynn David , Pramod Nikhil , Wei Wei , Nair Monica , Maroli Kimberly , Martin Allison , Ornstein Moshe Chaim , Wee Christopher Eing , Gilligan Timothy D. , Nizam Amanda , Bonham Amanda , Mian Omar Y. , Paul G. Jr.  , Diaz-Montero C. Marcela , Gupta Shilpa 
Published: June 2024

4589 Background: Some reports suggest that concomitant medications like metformin (M) and statins (S) may enhance efficacy of ICIs in various solid tumors via immune remodeling. Meanwhile other drugs like antibiotics (Abx), proton-pump inhibitors (PPI), H2 blockers (H2b)—may negatively impact outcomes with ICI by affecting the gut microbiome. We report the effect (Abx), (PPI), (H2b), (M)and (S) in our larger cohort of mUC pts treated with ICI; atezolizumab (A), pembrolizumab (P), and maintenance Avelumab (Av). Methods: In our cohort of 474 pts with mUC treated with >/=2 cycles of ICI with A, P or Av between 2015 and 2023, we retrospectively reviewed the use of (Abx), (PPI), (H2b), (M) and (S) and their timing in relation to ICI start (within 60 or 30 days (d) prior to and after ICI start). Progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method, outcomes compared using log-rank testing and multivariate (MVA) Cox regression analysis. Results: Of 474 pts, 18.99% received A, 56.75% received P and 24.26% received Av. Median follow-up was 15.6 months. Survival data was available for 455 pts. On MVA Cox regression analysis, Abx use within 60 (d) before ICI start was associated with significantly worse OS while Abx use within 60 (d) post ICI start was associated with significantly worse PFS. PPI use was associated with significantly worse OS and PFS when used 60 (d) prior to ICI use. Metformin was associated with significantly worse PFS when used 60 days prior to ICI start and H2b and Sta did not have any effect on survival outcomes in our cohort. (Table) Conclusions: In our large cohort of pts with mUC treated with either A, P or Av, (Abx), (PPI) and (M) use 60 (d) prior to ICI start were associated with worse OS and PFS. These findings have the potential to influence clinical practice, considering a higher threshold for prescribing antibiotics or PPIs in mUC pts planned to start ICI. These findings warrant further validation in prospective trials. [Table: see text]
Association between hemoglobin (Hb) improvement and patient-reported outcomes (PROs) in patients (pts) with myelofibrosis (MF) and anemia: Post hoc pooled analysis of momelotinib (MMB) phase 3 trials.
Authors: Palmer Jeanne M. , Mazerolle Flora , Liu Tom , M'Hari Manal , Regnault Antoine , Zhang Shiyuan , Cardellino Anna , Wang Zhaohui , Strouse Bryan , Sahni Jasmine , LeBlanc Thomas William 
Published: June 2024

6574 Background: Pts with MF experience debilitating symptoms that negatively impact health-related quality of life (HRQOL), a burden compounded in those with anemia. Prior analysis of the phase 3 SIMPLIFY-1 (S1) and SIMPLIFY-2 (S2) trials found that achieving transfusion independence at wk 24 was associated with improved PROs, but the association of anemia severity by Hb level with PROs was inconclusive (Mesa, ASCO 2023, Poster 7066). This new post hoc analysis explored the impact of Hb improvement on PROs in pts with MF and anemia. Methods: The pooled treatment-agnostic analysis set included pts with anemia (baseline [BL] Hb <10 g/dL) from 3 phase 3 trials: S1 (JAK inhibitor [JAKi] naive; MMB vs ruxolitinib), S2 (JAKi experienced; MMB vs best available therapy), and MOMENTUM (JAKi experienced; MMB vs danazol). The EQ-5D-5L was administered, and health state index (UK value set) and visual analog scale (VAS) scores derived, in all 3 trials. Patient Global Impression of Change (PGIC) was administered in S1/S2. Hb improvement was defined as an increase of ≥1, ≥1.5, or ≥2 g/dL from BL at wk 24. Multivariate (MV) analyses included change in EQ-5D-5L scores from BL as the dependent variable, with wk 24 Hb improvement and key BL characteristics as independent variables. Results: Mean age of the anemic subpopulation (N=480) was 68.8 y; 62% were male, 81% were White, and 64% had primary MF.436 pts were evaluable for Hb improvement at wk 24; 298 and 297 were evaluable for EQ-5D-5L index and VAS scores, respectively. Mean improvements from BL in index and VAS scores were greater in pts who achieved Hb improvement at any threshold than in those who did not (Table). 241 pts were evaluable for Hb improvement at wk 24 in S1/S2; 215 were evaluable for PGIC. Hb improvement was associated with a higher percentage of pts with any symptom improvement and lower percentage with symptom worsening based on PGIC (Table). In MV analyses, Hb improvement at any threshold was significantly associated with positive change in EQ-5D-5L VAS scores at wk 24 (mean change estimates of 5.5 to 7.3); similar trends were observed in MV analyses for EQ-5D-5L index scores. Conclusions: In these trial populations, Hb improvement at wk 24 was associated with improved HRQOL and symptoms in pts with MF and anemia. These results highlight the value of treatments with anemia-related benefits in improving the pt experience in MF. Clinical trial information: NCT04173494 ; NCT02101268 ; NCT01969838 . [Table: see text]
Analysis of outcomes in resected early-stage non-small cell lung cancer (NSCLC) with rare targetable driver mutations.
Authors: Ghazali Nadia , Feng Jamie , Hueniken Katrina , Waddell Thomas K. , Yasufuku Kazuhiro , Pierre Andrew , Donahoe Laura , Wakeam Elliot , Cypel Marcelo , Yeung Jonathan , Keshavjee Shaf , De Perrot Marc , Leighl Natasha B. , Liu Geoffrey , Bradbury Penelope Ann , Sacher Adrian G. , Eng Lawson , Stockley Tracy , Tsao Ming Sound , Shepherd Frances A. 
Published: June 2024

8052 Background: As postoperative adjuvant NSCLC treatment has evolved with EGFR and ALK targeted therapies, consideration may be given to treating other NSCLC with targetable mutations. Thus, having baseline outcomes for early-stage NSCLC with these targetable mutations is crucial, given their rarity. This study reports on recurrence-free survival (RFS) and overall survival (OS) in patients with resected NSCLC with treatable rare driver mutations. Methods: A retrospective single centre study identified stage I-III NSCLC patients with rare targetable mutations who underwent curative surgery. Tissue based next-generation sequencing identified mutations in KRAS G12C, EGFR Exon20, ERBB2, ALK, ROS1, BRAFV600E, MET exon14 skipping, RET. Baseline characteristics, adjuvant chemotherapy, mutation subtype, and TP53 co-mutation were correlated with RFS and OS using Cox regression. The KRAS G12C cohort was used as the reference for survival comparisons. Results: Among 201 patients (mean age: 66.4, 63% female) 61% had stage I, 19% stage II, 20% stage III. Predominant histology was adenocarcinoma (95%) and lobectomy (77%) was the most common surgery. Adjuvant chemotherapy was given to 37% (median 4 cycles). Mutations identified included: KRAS G12C (87, 43%), EGFR Exon 20 (27, 13%), ERBB2 (23, 11%), MET (20, 10%), ALK (14, 7%), ROS1 (13, 6%), BRAF (10, 5%) and RET (5, 2%). For all patients, 5-year survival probabilities were 75% stage I, 56% stage II (Hazard ratio [HR]: 2.17, p=0.038), 55% for stage III (HR: 2.38, p=0.015). Stage was also a significant predictor of RFS: stage II (HR: 1.90, p=0.04), stage III (HR: 2.26, p=0.006) vs stage I. TP53 co-mutation was associated with poorer OS (stage-adjusted HR (aHR): 2.50, p=0.004) and RFS (aHR: 1.70, p=0.037). All patients with rare mutations had shorter RFS compared to those with KRAS G12C mutation (Table). The difference for ERBB2 was significant (aHR 2.26, p=0.014), with only 37% of patients relapse free at 5 years. In contrast, except for ERBB2, other mutations were associated with better OS, with fusion mutations having the greatest difference (aHR 0.24, p=0.021). ERBB2 mutation had the highest cumulative incidence of brain metastasis, 29% at 5 years. Conclusions: Despite consistently poorer RFS, our study shows that, with the exception of ERBB2, OS of all other rare mutations was superior to KRAS G12C mutated NSCLC. TP53 co-mutation was demonstrated to be prognostic of poorer outcome. These dichotomous results may be explained by the use of targeted treatments at relapse, and suggest a potential role of targeted agents in the adjuvant setting. [Table: see text]
Prediction of recurrence in stage I EGFR mutation-positive NSCLC: Combination of CT appearance and selected co-occurring gene alterations by machine learning.
Authors: Tateishi Akiko , Horinouchi Hidehito , Takasawa Ken , Kouno Nobuji , Mizuno Takaaki , Okubo Yu , Yoshida Yukihiro , Watanabe Shun-ichi , Miyake Mototaka , Kusumoto Masahiko , Inaba Koji , Igaki Hiroshi , Yatabe Yasushi , Mukai Masami , Tanaka Katsuya , Mihara Naoki , Shiraishi Kouya , Kohno Takashi , Ohe Yuichiro , Hamamoto Ryuji 
Published: June 2024

8053 Background: Predicting the risk of postoperative recurrence is becoming increasingly important in patients (pts) with resectable EGFR mutation positive ( EGFRm) non-small cell lung cancer (NSCLC) after the ADAURA trial. The presence of non-solid ground-grass opacity (GGO) component on computed tomography (CT) images is known to affect the prognosis of stage I lung cancer. Only a few reports investigating the relationship between gene alterations and CT images in stage I EGFRm NSCLC. Methods: We have developed a machine learning-based model to predict recurrence within five years in TNM stage I (UICC 8th) EGFRm NSCLC pts who underwent surgery between 1985 and 2019 using whole exome sequencing in the PRISM project. We evaluated the pts’ characteristics, recurrence-free survival (RFS), the CT appearance (pure GGO and part solid [GGO]), without GGO [pure solid]), and consolidation tumor ratio (CTraio). Then, we analyzed the correlation between the image findings and gene alterations predicting a high risk of recurrence. Results: Among 1351 pts, stage I, EGFRm were 308 (22.8%). The median RFS for stage I EGFR-m pts was 123.2 months (m). In the prediction model, TP53 and RBM10 genes were among the gene alterations that had a high impact on the high-risk recurrence within five years. Among the 302 stage I, EGFRm pts for whom CT images were available, 166 (55.6%) pts had GGO, and 137 (45.4%) pts had pure solid appearance. The median CTratio was 0.87. The median RFS was not reached (NR) for GGO, 86.5m for pure solid (hazard ratio [HR] 2.42 [1.58-3.73], p<0.0001). There was a negative correlation indicating that the larger the CTratio, the shorter the RFS (p<0.0047). The proportion of TP53 mutation (TP53m) was lower in GGO and higher in pure solid (p<0.0001, Table). The median RFS was NR for GGO plus TP53m-negative pts, was 119.7m for GGO plus TP53m-positive pts, 84.8m for pure solid plus TP53m-negative pts, and 98.8m for pure solid plus TP53m-positive pts, respectively. Among pts with 0≦CTratio<0.5 46 (15.2%), with 0.5≦CTratio<1 119 (39.4%), and with CTratio=1 137 (45.4%), the proportion of TP53m increased as the CTratio increased. Conclusions: We found a linear relationship between CTratio and proportion of co-occurring TP53m with EGFRm. Combination of CT appearance (GGO or pure solid) and co-occurring TP53m can predict recurrence in stage I, EGFRm NSCLC. [Table: see text]
A phase II, open-label, combination therapy of durvalumab and ceralasertib in relapsed and refractory small cell lung cancer (SUKSES-N4).
Authors: Lee Se-Hoon , Kim Jiyeon , Park Sehhoon , Mortimer Peter G. , Kim Heejung (Rosa) , Smith Simon , Dean Emma , Kim Yu Jung , Jung Hyun Ae , Sun Jong-Mu , Park Woong-Yang , Ahn Jin Seok , Ahn Myung-Ju , Park Keunchil 
Published: June 2024

8104 Background: In extensive stage small-cell lung cancer (SCLC), the standard first-line treatment is an immune checkpoint inhibitor (ICI) combined with chemotherapy. However, in the relapsed or refractory setting, the benefits of ICI-based combinations are modest, regardless of prior ICI exposure. Ceralasertib, a selective ATR inhibitor, not only enhances DNA damage, inducing apoptosis, but also affects immune and inflammatory pathways. This study assesses the safety and efficacy of combining durvalumab with ceralasertib in SCLC patients. Methods: This open-label, phase II, multi-cohort umbrella trial recruited relapsed and refractory SCLC patients independent of biomarker status. Initially, patients received 1500mg of durvalumab on day 1, followed by 240mg of ceralasertib twice daily from day 15 to 28 of a 28-day cycle (Dose A). An amendment aligned the dosing regimen to other studies to 240mg of ceralasertib twice daily from day 1 to 7, with 1500mg of durvalumab administered on day 8 (Dose B). The primary endpoint was the objective response rate (ORR), with a target enrollment of 40 evaluable patients. Results: Between June 2022 and May 2023, forty-two patients were recruited (Dose A: 27; Dose B: 15). The median age was 67 (range: 43-83), with a predominance of males (n = 36) and smokers (n = 40). ECOG PS scores were 0 (n = 1) or 1 (n = 41), and nearly half (n = 20, 47.6%) had prior ICI exposure. The ORR per RECIST was 9.5%, with a disease control rate of 26.2%, including 4 partial responses (PR) and 7 cases of stable disease (SD). Median progression-free survival (PFS) was 1.64 months (95% CI: 1.61-1.97), and overall survival was 7.16 months (95% CI: 6.07-13.9). The duration of responses was notable, showing PFS of 4.8, 17.0, and 18.3 months in ICI-naïve PR patients and 14.1 months in ICI-exposed patient currently still ongoing on treatment. A sustained clinical benefit of up to 10.7 months was observed in an ICI-naïve patient with SD. Hematologic adverse events (AEs) included thrombocytopenia as grade 4 (n = 9) and grade 3 (n = 3), anemia as grade 3 (n = 3), and neutropenia as grade 4 (n = 3) and grade 3 (n = 1). Other AEs were mostly grades 1 or 2 and manageable. Exploratory biomarker analysis is in progress and will be presented. Conclusions: Ceralasertib and durvalumab combination therapy have demonstrated durable responses in select patients with manageable hematologic toxicity. Biomarker research is ongoing to identify patients most likely to benefit from this treatment strategy. Clinical trial information: NCT04361825 .
Comprehensive molecular characterization of thymic epithelial tumors.
Authors: Kim Chul , Adeyelu Tolulope Tosin , Maniar Rohan , Farrell Alex Patrick , Zaemes Jacob Peter , Solzak Jeffrey Peter , Hancock Bradley Allen , Elliott Andrew , Micaily Ida , Nagasaka Misako , Nieva Jorge J. , Borghaei Hossein , Halmos Balazs , Ma Patrick C. , Radovich Milan , Badve Sunil S , Loehrer Patrick J. 
Published: June 2024

8113 Background: Thymic epithelial tumors (TETs), which include thymomas (T) and thymic carcinomas (TC), are rare, yet they are the most common neoplasms in the anterior mediastinum. TETs can lead to significant morbidity and mortality. To develop more effective therapeutics for TETs, it is necessary to better understand their molecular underpinnings. Herein, we present the findings from an in-depth molecular characterization of TETs. Methods: TETs samples (n = 138; 55 from thymus and 78 from metastatic sites) were profiled using next generation sequencing (NGS) of DNA (592-genes/WES) and RNA (WTS) at Caris Life Sciences (Phoenix, AZ). Prevalence was calculated for pathogenic SNVs/Indels, deficient mismatch repair/microsatellite instability (dMMR/MSI) status assessed by IHC and NGS, PD-L1 expression measured by IHC (SP142; positive: ≥ 2+, ≥ 5%), and high tumor mutational burden (TMB-High) defined as ≥ 10 mut/Mb. The relative expression (transcript per million -TPM) of surface antigens (surfaceome) were evaluated. Pathway enrichment was determined by Gene Set Enrichment Analysis (GSEA). Mann-Whitney U, chi-square, and Fisher exact tests were applied where appropriate. Results: Central pathology review showed that the 138 TET samples were comprised of 34.8% (n = 48) thymic carcinomas (TC) and 65.2% (n = 90) thymomas (T). Thymomas were further stratified into the WHO classification subtypes (n = 10 A, 13 AB, 6 B1, 15 B2, and 46 B3). Median patient age was 60.5 years (range: 17-88). TP53 was the most frequently mutated gene in TETs. GTF2I mutations were found in 8 cases exclusively in thymomas. KIT mutations were identified in B3 and TC. KRAS, HRAS, and PIK3CA mutations were present in < 3% of all TETs patients. Genomic alterations in cell cycle-related genes (n = 19, 13.8%), the DNA repair pathway (n = 11, 8.0%), and chromatin remodeling (n = 27, 19.6%) were also observed in TETs, with these alterations more prevalent in TC compared to T. dMMR/MSI-H was detected in a subset of TETs, specifically B3 thymoma (n = 1) and TC (n = 4), showing a correlation with TMB-H in 80% of these cases. GSEA revealed that the MYC, angiogenesis, and mTORC1 pathways are more enriched in TC than in T. Surfaceome genes ( ERBB2: fold change (FC) = 1.51, ERBB3: FC = 1.45, TROP2: FC = 1.45, NECTIN-4: FC = 1.77 and MESOTHELIN: FC = 5.25) were significantly highly expressed in TC compared to T. Conclusions: Our findings offer insights into the molecular characteristics of TETs and reveal potential therapeutic targets. The relatively high prevalence of dMMR/MSI-H status in TC underscores the potential utility of assessing dMMR/MSI-H in patients with TC. [Table: see text]