tbuckley/cabot-search huggingface dataset:
Role of <i>RAS/BRAF</i> and <i>PIK3CA</i> mutations in tissue and plasma for prognostic assessment in metastatic colorectal cancer (mCRC).
Authors: Eduardo Terán-Brage, Yolanda Lopez-Mateos, María Mar Abad Hernández, Jose Maria Sayagues-Manzano, Aline Rodrigues Francoso, Pablo Díaz-Sánchez, Emilio Fonseca-Sánchez, Rosario Vidal-Tocino
Journal: Journal of Clinical Oncology (2025)

281 Background: Mutations in RAS/BRAF ( RAS/BRAFm ) and PIK3CA ( PIK3CAm ) genes have been described as mechanisms of resistance to anti-EGFR agents in mCRC. However, the utility of liquid biopsy in their baseline detection remains unknown. We aim to analyse oncological outcomes according to RAS/BRAF and PIK3CA mutational status in tissue &amp; plasma in mCRC. Methods: We conducted aretrospective study in patients (pts) with mCRC from 2017 to 2024. RAS/BRAF and PIK3CA mutational status assessment was performed at baseline using Idylla (Biocartis) and Cobas PIK3CA kits, respectively. Cox models were used to analyse overall survival (OS) in RAS/BRAFm and PIK3CAm vs wild-type (WT) population. Results: We analysed 404 paired samples (tissue &amp; plasma) from 202p with mCRC. RAS/BRAFm was described in 45% (91p) in tissue and in 43.6% (88p) in plasma. PIK3CA was tested in 84p, with PIK3CAm detection in 19% (16p) in tissue and 11.9% (10p) in plasma. Liver involvement was more frequent in RAS/BRAFm vs WT (80.6% vs 63.9%; p=0.02), and in PIK3CAm vs WT population (94.4% vs 63.6%; p=0.01). Concordance study (tissue &amp; plasma) for RAS/BRAF and PIK3CA are presented (Table). Subjects with concordant results had worse OS in RAS/BRAFm (18.1m vs 51.1m, HR=2.60; p&lt;0.001) regardless of liver involvement, and showed the same trend in PIK3CAm (22.6m vs 28.1m, p=0.81). Patients with discordant results and plasma RAS/BRAFm or plasma PIK3CAm showed worse OS (23.7 m vs 51.1m; p = 0.006 and 16.4 m vs 42.5 m; p=0.18, respectively) and a lower disease control rate with anti-EGFR therapy (p = 0.04 and p=0.42, respectively). PIK3CAm were evenly distributed in RAS/BRAF WT vs mutated tumors (50% vs 51.5%; p=0.92) and had no independent prognostic impact in OS after stratifying by RAS/BRAF mutational status; RAS/BRAF WT (p=0,93) and RAS/BRAFm (p=0,91). Conclusions: Baseline determination of RAS/BRAFm and PIK3CAm by liquid biopsy in mCRC provide valuable prognostic and predictive information, extending its utility beyond tissue-based analysis. Correlation study of RAS/BRAF and PIK3CA mutational status in tissue and plasma in mCRC. RAS/BRAF tissue PIK3CA tissue RAS/BRAF Plasma Mutated n (%) WT n (%) Total n (%) PIK3CA Plasma Mutated n (%) WT n (%) Total n (%) Mutated n (%) 72 (80) 15 (13.4) 87 (43.1) Mutated n (%) 7 (43.8) 2 (2.9) 9 (10.7) WT n (%) 18 (20) 97 (86.6) 115 (56.9) WT n (%) 9 (56.2) 66 (97.1) 75 (89.3) Total n (%) 90 (100) 112 (100) 202 (100) Total n (%) 16 (100) 68 (100) 84 (100) Positive agreement: 72/90: 80% Positive agreement: 7/16: 43.8% Negative agreement: 97/112: 86.6% Negative agreement: 66/68: 97.1% Overall agreement: 169/202: 83.6% Overall agreement: 73/84: 86.9% KI*: 0.67 KI: 0.49 KI: Kappa Index.
A multimodal deep learning approach for the prognostic stratification of patients with colorectal cancer (CRC).
Authors: Nuha Shaker, Noor Shaker, Aatur D. Singhi
Journal: Journal of Clinical Oncology (2025)

287 Background: Traditional prognostic systems like the AJCC TNM staging for colorectal cancer (CRC) often fall short in predicting long-term patient outcomes. These systems often rely on limited pathologic features, leading to generalized approaches to treatment despite diverse tumor heterogeneity, such as the complex interaction between the tumor-host microenvironment. There is therefore a pressing need for more accurate, scalable tools to enhance decision-making and predict outcomes for patients with CRC. Methods: Tumor sections from 191 CRC patients were comprehensively stained for CD8 to examine CD8-positive tumor-infiltrating lymphocytes (TILs). To account for tumor heterogeneity, multiple areas of the tumor were evaluated to include intertumoral and peritumoral areas. Slides were digitized and quantitatively analyzed using a cloud-based platform (SpatialX Diagnostics, Inc. USA). Additionally, clinicopathologic features including patient demographics, 8th edition AJCC staging, lymphovascular invasion (LVI), perineural invasion (PNI), mismatch repair (MMR) protein status, tumor location, presence/development of distant metastases, and patient follow-up were collected. Merging CD8 AI findings with clinicopathologic features, a complete data set was available for 175 patients. Cases were randomly assigned into 70% training and 30% validation. In the training set, unsupervised artificial intelligence (AI) models integrated clinicopathologic data and CD8-positive TIL counts using vision transformer models. The final model combined spatially resolved pathologic features with clinical variables to statistically predict overall survival (OS) and distant metastasis risk (DMR). Results: In the validation cohort, the model stratified patients into two groups based on a deep learning-derived risk score, with statistically significant differences between low-risk and high-risk groups for OS (p&lt;0.02) and DMR prediction (p&lt;0.0001), For OS prediction, the model selected tumor site, PNI, MMR status, epithelial and stromal CD8-positive TILs, and 5 deep vision features as the top 10 clinically significant features. For DMR prediction, the age, T- and N-stage, PNI, and 6 deep vision-derived features as key predictors. Conclusions: As captured by vision transformers, the distribution and spatial arrangement of CD8-positive TILs are critical factors in patient stratification for OS and DMR. AI-driven models like the one herein offer the potential for more personalized management strategies, advancing CRC management and improving patient outcomes beyond traditional prognostic staging systems and parameters.
BTN1A1 expression in colon cancer: Implications for immunotherapy and patient stratification.
Authors: Stephen S. Yoo, Bong-Ki Hong, Chunai Wu, Seung Hoon Lee, Youngseung Kim, Soohyeon Lee, Hyunjin Jung
Journal: Journal of Clinical Oncology (2025)

249 Background: Butyrophilin 1A1 (BTN1A1) is a promising immune checkpoint protein offering a novel option for immunotherapy. We discovered that BTN1A1 and PD-L1 expression are mutually exclusive through the JAK/STAT pathway in various tumors. Recently, Nelmastobart, an antibody targeting BTN1A1, successfully completed a Phase 1 clinical trial at three sites in the United States and two in the Republic of Korea, spanning 98 weeks. This abstract focuses on the results from the Phase 1 trial in patients with colorectal cancer (CRC), emphasizing biomarker diagnostics and therapeutics derived from translational research. Methods: We conducted a first-in-human, multicenter, open-label Phase I clinical trial to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of hSTC810 monotherapy in CRC patients. Extensive analyses of BTN1A1 expression were performed using patient specimens through immunohistochemistry and multi-immunofluorescence techniques to identify critical biomarkers and accurately assess nelmastobart's anticancer activity. We then analyzed progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety alongside translational research findings using patient tissue samples. Results: A total of 47 patients were enrolled in the study. The median PFS across all cohorts was 1.9 months, while the median Kaplan-Meier estimate for OS was 12.8 months. Among the 16 CRC patients enrolled, tissue samples were obtained and analyzed using IHC in 12 patients and OPAL staining in 7 patients. The objective response rate (ORR) for CRC was 2.3%. The median progression-free survival (PFS) and overall survival (OS) were 3.6 months and 11 months, respectively. Notably, PFS, OS, and ORR strongly correlated with BTN1A1 expression levels in CRC patients. High levels of BTN1A1 expression in colorectal tumor tissues correlated with clinical outcomes, identifying BTN1A1 as a potential biomarker for predicting patient responses to targeted therapies. The mutual exclusivity of BTN1A1 and PD-L1 expression suggests that BTN1A1 could serve as a diagnostic marker to identify patients who may be unresponsive to PD-1/PD-L1 blockade therapy and might benefit from BTN1A1 blockade therapy. Conclusions: This Phase 1 clinical trial demonstrated that antibody-mediated BTN1A1 blockade effectively suppresses tumor growth in patients with BTN1A1-positive CRC. These findings suggest that BTN1A1-targeted therapies could provide a viable treatment option for patients with colon cancers that are refractory or resistant to anti-PD-1/PD-L1 therapies. Clinical trial information: NCT05231746 .
Multi-target stool-DNA test for colorectal cancer screening and effects on health and economic outcomes compared to blood-based tests: Influence of adherence.
Authors: Vahab Vahdat, Derek W. Ebner, Michael Dore, A. Mark Fendrick, Chris Estes, John B. Kisiel, Paul J. Limburg
Journal: Journal of Clinical Oncology (2025)

88 Background: There are an estimated 60 million individuals in the US who are not up-to-date with average-risk colorectal cancer (CRC) screening, as screening rates and adherence have remained stubbornly below the national target of 80%. Efforts are ongoing to improve CRC screening performance and participation, including the development of new blood-based tests. Despite high expectations for these tests, performance remains lower than other guideline-recommended strategies, particularly with respect to advanced precancerous lesion (APL) sensitivity. We conducted a simulation study of estimated clinical and economical outcomes for CRC screening with a blood-based test (at perfect adherence) compared to the multi-target stool-DNA (mt-sDNA) test (at published adherence rates). Methods: Utilizing CRC-AIM, a calibrated and validated microsimulation model, CRC screening outcomes were calculated for 1 million average-risk individuals screened between ages 45-75 years with triennial blood-based versus mt-sDNA testing. CRC and APL sensitivity and specificity inputs were derived from two large clinical validation studies for these screening modalities: ECLIPSE (NCT04136002) and DeeP-C (NCT01397747), respectively. To demonstrate the maximum benefits and burdens of blood-based screening, adherence to initial screening and follow-up colonoscopy after a positive blood test was modeled at 100%, while real-world adherence estimates of 65.6% were used for the mt-sDNA test. Outcomes of interest included life years-gained (LYG) and CRC cases missed by the blood-based test compared to the stool-based test, additional treatment costs imposed by theblood-based test, and additional CRC-related deaths per 1 million screened. Results: Compared to triennial screening with mt-sDNA at real-world adherence, blood-based screening at perfect adherence resulted in a higher number of incident (n=18,464) and fatal (n=6,483) CRC cases that would been avoided with the mt-sDNA test. Over a lifetime, screening with blood-based tests required 1,276,310 more tests (21% more) and 52,942 additional follow-up colonoscopies (7% more) compared to mt-sDNA screening. This increased testing burden did not generate additional benefits and instead reduced life-years gained by 67,645 per 1 million screened, resulting in an additional $1.6 billion in treatment costs compared to the mt-sDNA strategy. Conclusions: Data from this CRC-AIM modeling study show that even with perfect adherence, blood-based screening yields inferior clinical and economic benefits compared to mt-sDNA screening, due to suboptimal APL detection with the former test.
Histopathology of the small airways: Similarities and differences between ageing and COPD
Authors: Andrew Higham, Sophie Booth, Josiah Dungwa, Dave Singh
Journal: Pulmonology (2024)

Age-related lung function decline is associated with small airway closure and gas trapping. The mechanisms which cause these changes are not fully understood. It has been suggested that COPD is caused by accelerated ageing. We have investigated pathological changes in the small airways during ageing, and evaluated whether the same or different processes exist in COPD. Histopathology and immunohistochemistry were used to examine small airway remodelling in healthy ageing, and then compare to age matched COPD patients. Ageing was associated with reduced alveolar attachment numbers (rho= -0.4 p = 0.049), increased epithelial area (rho = 0.5 p = 0.01), greater luminal narrowing due to epithelial expansion (rho = 0.5 p = 0.04) and increased alveolar septal neutrophils (rho = 0.6 p = 0.005). Compared to age matched controls, COPD small airways had 31% less alveolar attachments per airway (p = 0.02) and significantly more alveoalr septal neutrophils (p = 0.0007). Increased airway wall thickness was a feature of COPD but was not related to ageing in non-smokers. Alveolar attachment loss, accompanied by alveolar septum neutrophilic inflammation, and increased luminal narrowing due to epithelial expansion are major features of small airway remodelling during ageing. These features can explain the increased small airway narrowing and closure during ageing. Alveolar attachment loss is accelerated in COPD, likely due to increased neutrophilic inflammation.
Assessment of the underreporting of rhinitis in patients with asthma: A MASK-air® real-world study
Authors: Bernardo Sousa-Pinto, Gilles Louis, Rafael José Vieira, Ana Margarida Pereira, Bilun Gemicioglu, Maciej Kupczyk, Violeta Kvedariene, Renaud Louis, Oliver Pfaar, João A. Fonseca, Torsten Zuberbier, Jean Bousquet
Journal: Pulmonology (2024)

Rhinitis is a common comorbidity in patients with asthma. However, the frequency of underreported rhinitis in asthma is not known. In this study, we aimed to assess the characteristics of patients with self-reported asthma and no self-reported rhinitis, as well as the extent of the underreporting of rhinitis. We performed a cross-sectional study of all MASK-airⓇ users (2015-2022, 27 countries), comparing reported symptoms and medication use in patients with (i) self-reported asthma without rhinitis ("asthma alone"), (ii) self-reported rhinitis+asthma and (iii) self-reported rhinitis without asthma ("rhinitis alone"). In patients reporting asthma alone and providing MASK-airⓇ data in at least three different months, a cluster analysis was performed to potentially identify groups of patients underreporting rhinitis and/or undertreated for rhinitis. We assessed 35,251 users (529,751 days): 671 (1.9%) reporting asthma alone 25,882 (73.4%) reporting rhinitis alone and 8698 (24.7%) reporting rhinitis+asthma. Overall, 27% of the patients reporting asthma alone were treated with rhinitis medications. Patients reporting asthma alone displayed a lower frequency of days under rhinitis medication and less severe nasal symptoms than those reporting rhinitis+asthma. Among patients reporting asthma alone, three clusters of patients were identified: (A; 22.2%) severe rhinitis symptoms and low frequency of rhinitis medication use, (B, 41.0%) moderate rhinitis symptoms and high frequency of rhinitis medication use (41.0%), and (C, 36.8%) mild or no rhinitis symptoms and almost no rhinitis medication use. This study suggests that, among patients with self-reported asthma, the underreporting or undertreatment of rhinitis may be common.
Physiological effects of nasal high flow therapy during exercise in patients with chronic obstructive pulmonary disease: A crossover randomised controlled trial
Authors: Tristan Bonnevie, Francis-Edouard Gravier, Pauline Smondack, Emeline Fresnel, Isabelle Rivals, Helena Brunel, Yann Combret, Clément Médrinal, Guillaume Prieur, Fairuz Boujibar, Thomas Similowski, Jean-François Muir, Antoine Cuvelier, Maxime Patout
Journal: Pulmonology (2024)

Nasal high flow (NHF) has been proposed to sustain high intensity exercise in people with COPD, but we have a poor understanding of its physiological effects in this clinical setting. What is the effect of NHF during exercise on dynamic respiratory muscle function and activation, cardiorespiratory parameters, endurance capacity, dyspnoea and leg fatigue as compared to control intervention. Randomized single-blind crossover trial including COPD patients. Two constant workload exercise testing were performed at 75% of peak power with NHF (30L/min, 34°C) or with control intervention. Pressure time product of the transdiaphragmatic pressure (PTPdi/min) and other physiological measurements were continuously monitored. Dyspnoea and lower limb fatigue were assessed using the 10-Borg scale. 14 patients with severe obstruction (median FEV1: 40 (IQR 28 to 52) %) were included. Their median age was 70 (IQR 57 to 72) years. At isotime, NHF had little to no effect on PTPdi/min (MD -15cmH2O.s/min, 95% CI -62 to 33) but increased tidal volume (MD 77mL, 95% CI 21 to 133). NHF also improved endurance capacity (MD 20s, 95% CI 2 to 40) and dyspnoea at isotime (MD -1.1, 95% CI -2.1 to -0.1). NHF had no or uncertain effect on other outcomes. NHF has little to no effect on dynamic respiratory muscle function and activation but improves Vt. It leads to a trivially small increase in endurance capacity but a worthwhile improvement in dyspnoea. NHF may be beneficial for individuals experiencing critical inspiratory constraints and significant dyspnoea.
Risk assessment of persistent incidental pulmonary subsolid nodules to guide appropriate surveillance interval and endpoints
Authors: Mengwen Liu, Meng Li, Hao Feng, Xu Jiang, Rongshou Zheng, Xue Zhang, Jianwei Li, Xin Liang, Li Zhang
Journal: Pulmonology (2024)

Guidelines for the follow-up of pulmonary subsolid nodule (SSN) vary in terms of frequency and criteria for discontinuation. We aimed to evaluate the growth risk of SSNs and define appropriate follow-up intervals and endpoints. The immediate risk (IR) and cumulative risk (CR) of SSN growth were assessed using the Kaplan-Meier method according to nodule consistency and size. Follow-up plans were proposed based on optimal growth risk threshold of 5%. 892 SSNs, comprising 833 pure ground-glass nodules (pGGNs) and 59 part-solid nodules (PSNs) were included. For pGGNs ≤ 6.6 mm, the CR exceeded 5% at every 3-year interval in the first 9 years. For pGGNs measuring 6.6-8.8 mm and >8.8 mm, the IR remained above 5% for the first 2-7 years, and the 2-year CR for pGGNs measuring 6.6-8.8 mm in the 8th and 9th years achieved 6.66%. For PSNs, the IR peaked in the 4th year (44%) and then declined. Therefore, triennial follow-up for 9 years is recommended for pGGNs ≤ 6.6 mm, annual follow-up for 7 years followed by biennial follow-up for 2 years for pGGNs measuring 6.6-8.8 mm, annual follow-up for 7 years for pGGNs > 8.8 mm, and continuous annual follow-up until nodule growth for PSNs.
Increased plasma interleukin-1β is associated with accelerated lung function decline in non-smokers
Authors: Xinru Ran, Haiqing Li, Zihui Wang, Fan Wu, Zhishan Deng, Qiaorui Zhou, Cuiqiong Dai, Jieqi Peng, Lifei Lu, Kunning Zhou, Pixin Ran, Yumin Zhou
Journal: Pulmonology (2024)

Interleukin-1β is one of the major cytokines involved in the initiation and persistence of airway inflammation in chronic obstructive pulmonary disease (COPD). However, the association between plasma interleukin-1β and lung function decline remains unclear. We aimed to explore the association between plasma interleukin-1β and lung function decline. This longitudinal evaluation of data from the Early COPD study analysed the association between the plasma interleukin-1β concentration, lung function decline, and COPD exacerbation. Overall, 1,328 participants were included in the baseline analysis, and 1,135 (85%) completed the 1-year follow-up. Increased plasma interleukin-1β was associated with accelerated lung function decline in non-smokers (forced expiratory volume in 1 s: per unit natural log-transformed increase, adjusted unstandardised β [95% confidence interval] 101.46 [16.73-186.18] mL/year, p=0.019; forced vital capacity: per unit natural log-transformed increase, adjusted unstandardised β [95% confidence interval] 146.20 [93.65-198.75] mL/year, p<0.001), but not in smokers. In non-smokers, participants with an interleukin-1β concentration in the top 30% (>5.02 pg/mL) had more respiratory symptoms, more severe emphysema and air trapping, and higher levels of inflammation-related biomarkers. In this study, a subgroup with increased plasma interleukin-1β was identified among non-smokers, and increased plasma interleukin-1β was associated with lung function accelerated decline.
The clinical meaning of the UIP pattern in fibrotic hypersensitivity pneumonitis on cryobiopsy: A multicentre retrospective study
Authors: Simone Petrarulo, Claudia Ravaglia, Sissel Kronborg White, Line Bille Madsen, Frederik Lex, Alessandra Dubini, Elisabetta Fabbri, Elisabeth Bendstrup, Paolo Spagnolo, Sara Piciucchi, Venerino Poletti
Journal: Pulmonology (2024)

Fibrotic hypersensitivity pneumonitis (f-HP) is an interstitial lung disease in which various antigens in susceptible individuals may play a pathogenetic role. This study evaluates the role of transbronchial lung cryobiopsy (TBLC) and bronchoalveolar lavage (BAL) in identifying a UIP-like pattern and its association with fibrosis progression. We conducted a multicentre retrospective cohort study of patients diagnosed with f-HP who underwent BAL and TBLC between 2011 and 2023. A UIP-like pattern was defined by the presence of (A) patchy fibrosis and fibroblastic foci or (B) honeycombing ± (A). We investigated BAL's role in predicting UIP-like patterns within a clinical-radiological-serological framework, examining disease progression in these patients using spirometry and mortality data. A total of 195 patients were enrolled, 59 (30%) of whom exhibited a UIP-like pattern. These patients showed greater lung function decline, lower BAL lymphocytosis (14.4% vs. 37.4%, p < 0.001), higher nintedanib prescription (35% vs. 14%, p < 0.001), and higher 10-year mortality (HR 2.8, 95% CI 1.3-5.8, p = 0.004). f-HP patients with a UIP-like pattern exhibit worse clinical outcomes and higher mortality. In cases of low BAL lymphocytosis with a high pre-test clinical suspicion of f-HP, lung biopsy may not be necessary as it increases the likelihood of identifying a UIP-like pattern.