tbuckley/cabot-search huggingface dataset:
Comprehensive molecular characterization of thymic epithelial tumors.
Authors: Chul Kim, Tolulope Tosin Adeyelu, Rohan Maniar, Alex Patrick Farrell, Jacob Peter Zaemes, Jeffrey Peter Solzak, Bradley Allen Hancock, Andrew Elliott, Ida Micaily, Misako Nagasaka, Jorge J. Nieva, Hossein Borghaei, Balazs Halmos, Patrick C. Ma, Milan Radovich, Sunil S Badve, Patrick J. Loehrer
Journal: Journal of Clinical Oncology (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 &lt; 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]
Real-world data based on PD-L1 expression in early-stage NSCLC in an east-Asian patient population: A 10-year follow-up study.
Authors: Ji Hyung Hong, Elaine Yee-Ling Ko, Young Sub Lee, Youngkyu Moon, Seoung Joon Kim, Marc Lecoultre, David Jen-Hao Shih, Victor Ho-Fun Lee, Rina Hui, Sook-Hee Hong, Aya EL Helali
Journal: Journal of Clinical Oncology (2024)

8019 Background: Recent studies on the perioperative treatment of Non-Small Cell Lung Cancer (NSCLC) have often excluded patients with stage IA. To address this issue and bridge the knowledge gap, we aim to investigate the impact of PD-L1 and EGFR status on survival in stage IA NSCLC. Methods: Our study aimed to determine the impact of PD-L1 expression on overall survival (OS) in patients with resectable stage IA-IIIB NSCLC who underwent curative resection between May 2010 and April 2020. We analyzed survival and clinicopathological data and categorized patients based on PD-L1 tumor proportion score (TPS). PD-L1 TPS ≥ 50% were categorized as PD-L1 high and &lt; 50% as PD-L1 negative/low. Our primary objective was to assess the association between PD-L1 expression status and OS in resectable NSCLC patients. We also investigated the relationships between OS, PD-L1 expression, EGFR status, and tumor stage. Results: Among the 386 patients recruited, those with PD-L1 negative/low and high had a 5-year OS of 82% and 63%, respectively ( p = 0.00011). Among patients with stage IA NSCLC, those with PD-L1 negative/low demonstrated the most favorable 5-year OS (96%) compared to the other subgroups (stage IA PD-L1 high 63%, stage IB-IIIB PD-L1 negative/low 67% and stage IB-IIIB PD-L1 high 62%, p &lt; 0.0001). Stage IA EGFR mutant NSCLC showed a significantly better 5-year OS compared to EGFR wildtype (97% versus 84%, p= 0.0028). In comparison, survival in stage IB-IIIB NSCLC was similar regardless of EGFR status (stage IB-IIIB/EGFR mutant 66% vs EGFR wildtype 65%, p= 0.13). Next, we addressed the impact of the co-occurrence of an EGFR mutation and PD-L1 expression on survival in stage IA. In stage IA, the PD-L1 high EGFR mutant and wildtype subgroups demonstrated a 5-year OS of 83% and 56%, respectively, while in the PD-L1 negative/low subgroup, the EGFR mutant and wildtype had a 98% and 93% OS ( p&lt; 0.0001), respectively. Conclusions: Stage IA NSCLC patients with PD-L1 high and EGFR wildtype, surprisingly, were associated with poorer survival outcomes. These findings highlight the urgent need for clinical trials investigating perioperative management strategies in this population.
Implications of EGFR expression in MAPK dependency and adaptive immunity status of <i>EGFR</i>-mutated lung adenocarcinoma.
Authors: Masahiro Torasawa, Tatsuya Yoshida, Kouya Shiraishi, Shigehiro Yagishita, Yuji Uehara, Jun Miyakoshi, Ryoko Inaba Higashiyama, Akifumi Mochizuki, Yuji Matsumoto, Yuki Shinno, Yusuke Okuma, Yasushi Goto, Hidehito Horinouchi, Ryuji Hamamoto, Noboru Yamamoto, Shun-ichi Watanabe, Yasushi Yatabe, Kazuhisa Takahashi, Takashi Kohno, Yuichiro Ohe
Journal: Journal of Clinical Oncology (2024)

8028 Background: EGFR expression (EGFR-exp) varies among patients (pts) with EGFR-mutated (m EGFR) NSCLC. It remains unknown how EGFR-exp status influences tumor and clinical characteristics in m EGFR NSCLC. Methods: Whole-exome and RNA sequencing were performed of pts with resectable early-stage (ES) and advanced-stage (AS) lung adenocarcinoma (LUAD) and EGFRmutations. EGFR-exp was classified into low or high groups based on median transcripts per million. We retrospectively examined the association between EGFR-exp, mutation status, copy number variations, EGFR clonality, and clinical outcomes. Additionally, we assessed EGFR signaling by evaluating the MAPK activation score, derived from the transcript levels of 10 MAPK target genes. Gene set enrichment analysis was used to compare transcriptional profiles, and immune cell (IC) infiltration was estimated through RNA deconvolution. Results: This study involved 450 and 45 pts in the ES and AS cohorts, respectively. In the AS cohort, all pts received osimertinib (Osi) as first-line treatment. The EGFR-exp low group exhibited a lower incidence of TP53 co-mutation and EGFR amplification, more subclonal EGFRmutations, and lower MAPK activation scores than the EGFR-exp high group (Table). Additionally, the EGFR-exp low group had significantly up-regulated adaptive immune responses pathway (q &lt; 0.0001) and increased IC infiltration in the tumor microenvironment (TME) in both cohorts. The EGFR-exp low group in the ES cohort exhibited significantly longer relapse-free survival than the EGFR-exp high group (median, 105.9 vs. 37.1 months; hazard ratio, 0.6; p &lt; 0.0001), and low EGFR-exp was a significant favorable factor for postoperative relapse (odds ratio [OR], 0.6; p = 0.04) in multivariate analysis. In the AS cohort, the EGFR-exp low group had a higher proportion of Osi non-responders than the EGFR-exp high group (34.8% vs 4.5%, respectively; p = 0.02), and low EGFR-exp was a significant risk factor for primary Osi resistance (OR, 29.1; p = 0.04) on multivariate analysis. Conclusions: Pts with low EGFR-exp in m EGFR LUAD demonstrated less activation of MAPK signaling, along with enhanced adaptive immunity and increased IC infiltration in the TME. These pts are less likely to experience postoperative relapse; however, they showed suboptimal benefit with Osi in AS setting. The EGFR-exp status can be valuable in decision making for adjuvant Osi and perioperative immunotherapy in pts with resectable m EGFR LUAD. [Table: see text]
Comprehensive analysis of the value of dynamic changes in ctDNA in SCLC.
Authors: Peronne Joseph, Zhengyi Chen, Abhishek Ajay, Pingfu Fu, Afshin Dowlati
Journal: Journal of Clinical Oncology (2024)

8107 Background: Dynamic changes in circulating tumor DNA (ctDNA) have not been studied in small-cell lung cancer (SCLC). Here, we assessed the changes of ctDNA over time and clinical outcomes. Methods: We performed a 105-gene, hybrid-capture, next-generation sequencing (NGS) liquid biopsy assay that detects SNVs, in/dels, CNVs, and chromosomal rearrangements. Patients had ctDNA assessed at 3 time points: 1) before initiation of front-line therapy; 2) at remission (within 3-6 weeks of 4th cycle of chemotherapy+/- immunotherapy), and 3) at the time of relapse (based on radiographic imaging). Study outcome measures include OS, PFS, DFS (duration of response from completion of 4 th cycle of systemic treatment until relapse), and overall response rate (ORR). Survivor distribution was estimated using Kaplan-Meier methods. Cox model was also used to estimate the effects on OS, PFS and DFS. The effects of predictors on ORR were estimated using logistic regression. The T-test was used to examine the difference in continuous measures between the two groups, and the chi-square test was used to examine the association between two categorical factors. All tests were two-sided, and p-values &lt; 0.05 were considered significant. Results: 62 patients were enrolled. The median follow-up was 12.3 mos. Patients were treated with standard-of-care chemotherapy +/- immunotherapy for 4 cycles. 71% had extensive stage disease. At baseline, 100% of patients had detectable variant alleles in TP53,and 70% had variant RB1. Patients with ES-SCLC had significantly higher maximum (max) Variant Allelic Fraction (VAF) (alteration with highest VAF) compared to LS-SCLC (59.1 vs 27.2%, p = 0.04). Median max VAF at baseline was 52.3%, 0.3% at remission, and 38.4% at relapse, indicating a response to therapy. However, ORR did not correlate with baseline max VAF (p = 0.2). Baseline max VAF (comparing those &lt; or &gt; VAF of 45%) was not associated with OS (19.4 vs 12.2 mos, p = 0.6) but highly impacted PFS (11.2 vs. 6.1 mos, p = 0.02) and DFS (12.1 vs 2.2 mos, p = 0.004). Baseline max VAF was an independent predictor of PFS and DFS. A drop in max VAF from pretreatment to remission (comparing those with a &gt; or &lt; 99% decrease) also did not associate with OS, PFS, or DFS. Patients with RB1 alterations at pretreatment that had residual RB1 alterations at the time of clinical remission had significantly worse PFS (6.3 vs 12.1 mos) and DFS (1 vs 8 mos, p = 0.02). Conclusions: Baseline max VAF ctDNA levels strongly correlate with PFS and DFS (duration of remission from completion of 4 th cycle of treatment) but not OS and ORR. Most strikingly, those with detectable residual RB1 alterations at completion of proscribed chemotherapy have an extremely short DFS of 1 month that justifies early assessment for clinical trials. This approach has led to a near 90% success rate in enrollment on 2 nd line clinical trials or SOC options.
Plasma infrared fingerprinting with machine learning enables single-measurement multi-phenotype health screening
Authors: Tarek Eissa, Cristina Leonardo, Kosmas V. Kepesidis, Frank Fleischmann, Birgit Linkohr, Daniel Meyer, Viola Zoka, Marinus Huber, Liudmila Voronina, Lothar Richter, Annette Peters, Mihaela Žigman
Journal: Cell Reports Medicine (2024)

Infrared spectroscopy is a powerful technique for probing the molecular profiles of complex biofluids, offering a promising avenue for high-throughput in vitro diagnostics. While several studies showcased its potential in detecting health conditions, a large-scale analysis of a naturally heterogeneous potential patient population has not been attempted. Using a population-based cohort, here we analyze 5,184 blood plasma samples from 3,169 individuals using Fourier transform infrared (FTIR) spectroscopy. Applying a multi-task classification to distinguish between dyslipidemia, hypertension, prediabetes, type 2 diabetes, and healthy states, we find that the approach can accurately single out healthy individuals and characterize chronic multimorbid states. We further identify the capacity to forecast the development of metabolic syndrome years in advance of onset. Dataset-independent testing confirms the robustness of infrared signatures against variations in sample handling, storage time, and measurement regimes. This study provides the framework that establishes infrared molecular fingerprinting as an efficient modality for populational health diagnostics.
Survival outcomes and subgroup analyses derived from a phase III randomized trial comparing afatinib to chemotherapy in treatment-naïve non-small cell lung cancer with a sensitizing uncommon epidermal growth factor receptor mutation (ACHILLES/TORG1834).
Authors: Yuki Sato, Satoru Miura, Toshihiro Misumi, Hiroshige Yoshioka, Takaaki Tokito, Tatsuro Fukuhara, Ou Yamaguchi, Toshihide Yokoyama, Shoichi Kuyama, Takayasu Kurata, Terufumi Kato, Hidehito Horinouchi, Yuichi Takiguchi, Yasuhiro Goto, Kentaro Tanaka, Masahide Mori, Satoshi Ikeda, Eiki Ichihara, Hiroshi Tanaka, Hiroaki Okamoto
Journal: Journal of Clinical Oncology (2024)

8588 Background: The ACHILLES/TORG1834 trial is the first randomized phase 3 study, demonstrating the superiority of afatinib to chemotherapy in terms of progression-free survival (PFS) as a primary endpoint in sensitizing uncommon epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) (the hazard ratio [HR] of PFS was 0.422, p=0.0007). This trial was early terminated due to efficacy according to the recommendation by the data and safety monitoring committee. Here we report the overall survival (OS) result, subgroup analysis of PFS, and the response data according to detailed mutation status at the primary analysis. Methods: In this open-label phase III study, treatment-naïve patients (n=109) with sensitizing uncommon EGFR mutant NSCLC were randomized 2:1 to oral afatinib (30 mg or 40 mg daily) or the combination of platinum (cisplatin 75 mg/m 2 or carboplatin AUC 5 or 6) and pemetrexed (500 mg/m 2 ), followed by pemetrexed maintenance therapy every 3 weeks. The primary endpoint was PFS per RECIST 1.1. The secondary endpoints included objective response rate (ORR), time to treatment failure (TTF), and OS. Results: Median follow-up time was 12.5 (range, 0 to 43.5) months. The OS HR of afatinib compared to chemotherapy was 0.989 (95% confidence interval [CI], 0.457 to 2.141; p=0.9772; 29/109 events, 26.6% maturity). Median OS was not reached in either population. All subgroups of PFS did better in the afatinib arm. In the subgroup regarding the starting dose of afatinib, the PFS HR in the 40mg afatinib arm (HR 0.128, 95%CI, 0.050 to 0.327) were favorable compared to that in the 30mg afatinib arm (HR 0.704, 95%CI, 0.352 to 1.406). In this subgroup, there were several differences in the baseline characteristics regarding age and gender. The detail of ORR and PFS according to mutations status was shown in the table. The safety profiles in both arms were consistent compared to previous reports. Conclusions: A consistent PFS benefit of afatinib over platinum-doublet chemotherapy was shown regardless the mutation status in patients with uncommon or compound EGFR mutations. The OS data were immature, and further follow-up will be warranted. Clinical trial information: 031180175. [Table: see text]
Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank
Authors: Frederik H. Lassen, Samvida S. Venkatesh, Nikolas Baya, Barney Hill, Wei Zhou, Alex Bloemendal, Benjamin M. Neale, Benedikt M. Kessler, Nicola Whiffin, Cecilia M. Lindgren, Duncan S. Palmer
Journal: Cell Genomics (2024)

The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF < 0.38%). We identify six recessive gene-trait associations (p < 1.68 × 10
Molecular Expression Assays Improve the Prediction of Local and Invasive Local Recurrence After Breast-Conserving Surgery for Ductal Carcinoma In Situ
Authors: Ezra Hahn, Rinku Sutradhar, Lawrence Paszat, Lena Nguyen, Danielle Rodin, Sharon Nofech-Mozes, Sabina Trebinjac, Katarzyna J. Jerzak, Cindy Fong, Eileen Rakovitch
Journal: Journal of Clinical Oncology (2024)

Ductal carcinoma in situ (DCIS) is routinely treated with adjuvant radiotherapy (RT) after breast-conserving surgery (BCS). The inability to accurately estimate an individual's risk of local recurrence (LR) and invasive LR using clinicopathologic factors (CPF) contributes to the overtreatment of DCIS. We examined the impact of the 12-gene DCIS Score (DS) and the 21-gene Recurrence Score (RS) on the accuracy of predicting LR and invasive LR.
Discovery of highly potent phosphodiesterase-1 inhibitors by a combined-structure free energy perturbation approach
Authors: Zhe Li, Mei-Yan Jiang, Runduo Liu, Quan Wang, Qian Zhou, Yi-You Huang, Yinuo Wu, Chang-Guo Zhan, Hai-Bin Luo
Journal: Acta Pharmaceutica Sinica B (2024)

Accurate receptor/ligand binding free energy calculations can greatly accelerate drug discovery by identifying highly potent ligands. By simulating the change from one compound structure to another, the relative binding free energy (RBFE) change can be calculated based on the theoretically rigorous free energy perturbation (FEP) method. However, existing FEP-RBFE approaches may face convergence challenges due to difficulties in simulating non-physical intermediate states, which can lead to increased computational costs to obtain the converged results. To fundamentally overcome these issues and accelerate drug discovery, a new combined-structure RBFE (CS-FEP) calculation strategy was proposed, which solved the existing issues by constructing a new alchemical pathway, smoothed the alchemical transformation, increased the phase-space overlap between adjacent states, and thus significantly increased the convergence and accelerated the relative binding free energy calculations. This method was extensively tested in a practical drug discovery effort by targeting phosphodiesterase-1 (PDE1). Starting from a PDE1 inhibitor (compound 9, IC50 = 16.8 μmol/L), the CS-FEP guided hit-to-lead optimizations resulted in a promising lead (11b and its mesylate salt formulation 11b-Mesylate, IC50 = 7.0 nmol/L), with ∼2400-fold improved inhibitory activity. Further experimental studies revealed that the lead showed reasonable metabolic stability and significant anti-fibrotic effects in vivo.
Modulating cancer mechanopathology to restore vascular function and enhance immunotherapy
Authors: Fotios Mpekris, Myrofora Panagi, Antonia Charalambous, Chrysovalantis Voutouri, Triantafyllos Stylianopoulos
Journal: Cell Reports Medicine (2024)

Solid tumor pathology, characterized by abnormalities in the tumor microenvironment (TME), challenges therapeutic effectiveness. Mechanical factors, including increased tumor stiffness and accumulation of intratumoral forces, can determine the success of cancer treatments, defining the tumor's "mechanopathology" profile. These abnormalities cause extensive vascular compression, leading to hypoperfusion and hypoxia. Hypoperfusion hinders drug delivery, while hypoxia creates an unfavorable TME, promoting tumor progression through immunosuppression, heightened metastatic potential, drug resistance, and chaotic angiogenesis. Strategies targeting TME mechanopathology, such as vascular and stroma normalization, hold promise in enhancing cancer therapies with some already advancing to the clinic. Normalization can be achieved using anti-angiogenic agents, mechanotherapeutics, immune checkpoint inhibitors, engineered bacterial therapeutics, metronomic nanomedicine, and ultrasound sonopermeation. Here, we review the methods developed to rectify tumor mechanopathology, which have even led to cures in preclinical models, and discuss their bench-to-bedside translation, including the derivation of biomarkers from tumor mechanopathology for personalized therapy.
Using neurocognitive phenotypes to inform interventions for adult survivors of childhood cancer
Authors: Pia Banerjee, Nicholas S Phillips, Wei Liu, Matthew J Ehrhardt, Nickhill Bhakta, Tara M Brinkman, Annalynn M Williams, Yutaka Yasui, Raja B Khan, Deokumar Srivastava, Kirsten K Ness, Leslie L Robison, Melissa M Hudson, Kevin R Krull
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Neurocognitive impairments are sequelae of childhood cancer treatment, however little guidance is given to clinicians on common phenotypes of impairment or modifiable risk factors that could lead to personalized interventions in survivorship. Methods Standardized clinical testing of neurocognitive function was conducted in 2958 (74.1%) eligible survivors, who were at least 5 years postdiagnosis and aged older than 18 years, and 477 community controls. Impairment was examined across 20 measures, and phenotypes were determined by latent class analysis. Multinomial logistic regression was used to estimate risk for phenotype, predicted by cancer diagnosis and treatment exposures, chronic health conditions, and lifestyle, adjusted for sex and age. Associations between phenotypes and social attainment were examined. Results Five neurocognitive phenotypes were identified in survivors (global impairment 3.7%, impaired attention 5.0%, memory impairment 7.2%, processing speed and executive function impairment 9.3%, no impairment 74.8%). Risk of global impairment was associated with severe chronic health condition burden (odds ratio [OR] = 20.17, 95% confidence interval [CI] = 11.41 to 35.63) including cerebrovascular disease (OR = 14.5, 95% CI = 5.47 to 38.44) and cerebrovascular accident (OR = 14.7, 95% CI = 7.50 to 26.40). Modifiable risk factors, such as quitting smoking, reduced risk for global impairment (OR = 0.21, 95% CI = 0.06 to 0.66). Low physical activity increased risk for global impairment (OR = 4.54, 95% CI = 2.86 to 7.21), attention impairment (OR = 2.01, 95% CI = 1.41 to 2.87), processing speed and executive function impairment (OR = 1.90, 95% CI = 1.46 to 2.48), and memory impairment (OR = 2.09, 95% CI = 1.54 to 2.82). Conclusions Results support the clinical utility of neurocognitive phenotyping to develop risk profiles and personalized clinical interventions, such as preventing cerebrovascular disease in anthracycline-treated survivors by preventing hypercholesterolemia, smoking, and sedentary lifestyle, to reduce the risk for global impairment.
Heritability of Body Mass Index Among Familial Generations
Authors: Gabriel Chodick, Maya Simchoni, Britt Wang Jensen, Estela Derazne, Orit Pinhas-Hamiel, Regev Landau, Alon Abramovich, Arnon Afek, Jennifer Lyn Baker, Gilad Twig
Journal: JAMA Network Open (2024)

Studies on the familial effects of body mass index (BMI) status have yielded a wide range of data on its heritability.