ESMO Real World Data Digit Oncol. 2026 Jan 14;11:100652. doi: 10.1016/j.esmorw.2025.100652. eCollection 2026 Mar.

ABSTRACT

BACKGROUND: Malignant tumors release circulating tumor DNA (ctDNA) into the bloodstream, providing insights into tumor-specific mutations and pathways driving cancer progression. ctDNA testing is currently approved as a type of liquid biopsy to monitor disease burden and detect minimal residual disease (MRD). This study aimed to evaluate the adoption of ctDNA testing in a community oncology practice and assess the overall diagnostic performance of ctDNA and its association with disease progression in stage IV colorectal cancer (CRC), as determined by imaging studies.

PATIENTS AND METHODS: This retrospective study analyzed the medical records of 88 patients with gastrointestinal cancers (80 CRC, 5 gastric, 3 esophageal) who underwent ctDNA molecular testing between January 2020 and April 2022. Electronic medical records from patients aged ≥21 years who had two or more ctDNA tests with concurrent imaging studies or a pathology-confirmed CRC, gastric cancer, or esophageal cancer diagnosis were evaluated.

RESULTS: At baseline, 47 (53.4%) patients had negative and 41 (46.6%) had positive results. Most patients had CRC (90.1%). In stage IV CRC, ctDNA was increasing before radiologic progression in all documented cases (100%), with a median lead time of 2.5 months (range 0.5-15 months). In early-stage CRC (I-III), ctDNA preceded radiologic progression in 40% of cases, with a median lead time of 6 months (range 6-10 months).

CONCLUSIONS: Using real-world data, we report the first-time results of the ctDNA testing adoption in a community oncology setting among patients with gastrointestinal cancers, predominantly CRC. Our findings suggest that integration of ctDNA testing may support disease monitoring in routine clinical practice.

PMID:41930304 | PMC:PMC13040887 | DOI:10.1016/j.esmorw.2025.100652

Eur J Cancer. 2026 Mar 24;239:116699. doi: 10.1016/j.ejca.2026.116699. Online ahead of print.

ABSTRACT

INTRODUCTION: The latest generation of liquid biopsies incorporates multi-omic features, including genomics, methylomics, and fragmentomics. Machine learning (ML) approaches have been proposed to synthesize these complex biological data for the development of diagnostic classifiers. This study aims to evaluate the integration of ML with circulating cell-free DNA (cfDNA) analysis for early cancer detection.

METHODS: Medline, Embase, Cochrane, and Web of Science were searched in July 2025. Eligible studies combined ML and cfDNA features to distinguish cancer patients (stages I-III) from non-cancer controls. Summary diagnostic performance metrics and their 95% confidence intervals (CI) were calculated.

RESULTS: The study included 109 articles permitting analyses for lung (n = 34), liver (n = 29), colorectal (n = 28), pancreatic (n = 16), breast (n = 17), esophageal (n = 12), ovarian (n = 13), gastric (n = 9), head and neck (n = 4), and mixed (n = 27) cancer types. Specificity was consistently high across all tumor types and stages (94%-99%). Sensitivity ranged from 72% to 92% for stage I-III, 44-91% for stage I, 71-98% for stage II and 83-99% for stage III. In the pooled study population, neural networks (90%, 95% CI: 81%-95%), random forest (86%, 95% CI: 77%-92%) and heterogeneous ensemble learning (85%, 95% CI: 79%-89%) demonstrated the highest sensitivity. The stratified analysis by classifier feature revealed 86% (95% CI: 80%-90%) sensitivity for fragmentation and 81% (95% CI: 76%-85%) for methylation, with 92%-96% specificity.

CONCLUSION: ML and cfDNA profiling show potential for early cancer detection, with ensemble methods, neural networks and random forests achieving the best overall performance. Fragmentomic features provide the highest sensitivity.

PMID:41930854 | DOI:10.1016/j.ejca.2026.116699

Eur J Cancer. 2026 Mar 24;239:116699. doi: 10.1016/j.ejca.2026.116699. Online ahead of print.

ABSTRACT

INTRODUCTION: The latest generation of liquid biopsies incorporates multi-omic features, including genomics, methylomics, and fragmentomics. Machine learning (ML) approaches have been proposed to synthesize these complex biological data for the development of diagnostic classifiers. This study aims to evaluate the integration of ML with circulating cell-free DNA (cfDNA) analysis for early cancer detection.

METHODS: Medline, Embase, Cochrane, and Web of Science were searched in July 2025. Eligible studies combined ML and cfDNA features to distinguish cancer patients (stages I-III) from non-cancer controls. Summary diagnostic performance metrics and their 95% confidence intervals (CI) were calculated.

RESULTS: The study included 109 articles permitting analyses for lung (n = 34), liver (n = 29), colorectal (n = 28), pancreatic (n = 16), breast (n = 17), esophageal (n = 12), ovarian (n = 13), gastric (n = 9), head and neck (n = 4), and mixed (n = 27) cancer types. Specificity was consistently high across all tumor types and stages (94%-99%). Sensitivity ranged from 72% to 92% for stage I-III, 44-91% for stage I, 71-98% for stage II and 83-99% for stage III. In the pooled study population, neural networks (90%, 95% CI: 81%-95%), random forest (86%, 95% CI: 77%-92%) and heterogeneous ensemble learning (85%, 95% CI: 79%-89%) demonstrated the highest sensitivity. The stratified analysis by classifier feature revealed 86% (95% CI: 80%-90%) sensitivity for fragmentation and 81% (95% CI: 76%-85%) for methylation, with 92%-96% specificity.

CONCLUSION: ML and cfDNA profiling show potential for early cancer detection, with ensemble methods, neural networks and random forests achieving the best overall performance. Fragmentomic features provide the highest sensitivity.

PMID:41930854 | DOI:10.1016/j.ejca.2026.116699

J Intern Med. 2026 Apr 3. doi: 10.1111/joim.70092. Online ahead of print.

ABSTRACT

Tuberculosis (TB) remains a major global health challenge, with multi-drug antibiotic regimens as the current standard of care. While effective at killing Mycobacterium tuberculosis, these treatments do not resolve persistent inflammation, prevent lung damage, or reverse immune dysregulation that contribute to poor outcomes and disease recurrence. Precision medicine offers a promising alternative but requires deeper insight into disease mechanisms to enable tailored interventions. This comprehensive review introduces the concept of immune endotyping to define the underlying disease mechanisms as tools to decode clinical and immunological heterogeneity in TB. TB displays a wide spectrum of clinical phenotypes, from latent or asymptomatic infection to mild or severe disease with characteristic non-cavitary or cavitary lung pathology. Instead, distinct immune endotypes capture the diverse biological pathways that shape disease progression and treatment response. Similar clinical presentations may arise from different immune dysfunctions, underscoring the need to move beyond broad phenotypic classifications. Advances in multi-omics and computational analyses uncover immune signatures that enable stratification for host-directed therapies (HDTs) targeting hyperinflammation, immunosuppression, coagulopathy or metabolic exhaustion. Integrating clinical, radiological, and immunological data through multimodal profiling is essential for developing personalized interventions. We also explore how endotyping has transformed treatment in other diseases, offering valuable insights for TB. Additionally, we present examples of how putative immune endotypes may be targeted with appropriate HDTs. In summary, this review underscores the potential of immune endotypes to advance precision medicine in TB, moving beyond one-size-fits-all treatment to improve outcomes, especially in severe and drug-resistant cases.

PMID:41930636 | DOI:10.1111/joim.70092

Oncol Res. 2026 Mar 23;34(4):11. doi: 10.32604/or.2026.076176. eCollection 2026.

ABSTRACT

Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8⁺ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability-thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer-spanning glucose, amino acid, and lipid metabolism-and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.

PMID:41930159 | PMC:PMC13040304 | DOI:10.32604/or.2026.076176

Chem Res Toxicol. 2026 Apr 3. doi: 10.1021/acs.chemrestox.5c00440. Online ahead of print.

ABSTRACT

Wildfire smoke exposures are increasingly common, consisting of complex mixtures of gases and particulates known to cause diverse pulmonary health effects. While health outcomes are regularly studied, quantitative links between smoke chemical composition and toxicological outcomes remain poorly defined, limiting interpretation of wildfire smoke health risks. This study explores symbolic regression (SR) as an interpretable artificial intelligence/machine learning method to generate closed-form mathematical models linking chemical exposure to biological responses relevant to wildfire smoke. Prior to application on wildfire-relevant data sets, we benchmarked three Python-based SR packages on simulated data, assessing performance across varying noise levels and operator complexities. Insights from these simulation tests, such as the importance of including necessary operators, were incorporated when applying SR to lab-generated wildland fire exposure-toxicity data. This data set included chemical characterizations of biomass smoke exposures and corresponding pulmonary responses in female CD-1 mice (n = 60). Specifically, we evaluated the ability to predict a lung injury marker using (1) targeted measures of over 80 chemicals measured in smoke (RMSE = 17.57 mg/mL) and (2) lung tissue measures of hundreds of transcripts (RMSE = 15.12 mg/mL). Resulting error metrics were comparable to Random Forest and XGBoost models. To aid model interpretation, we developed directional ensemble contribution scores (DECS), a novel feature importance scoring method that quantifies the direction and magnitude of predictor contributions across top-performing models. Expert toxicologists also contributed to model prioritization, integrating a "biologists-in-the-loop" approach. Results highlighted polycyclic aromatic hydrocarbons as drivers of lung injury and methoxyphenols as suppressors. Transcriptomic analyses highlighted a small set of genes, which have roles in metabolism, cell proliferation, immune regulation, and oncogenic processes, with MYC proto-oncogene (Myc) showing the strongest association. Overall, this study demonstrates SR and associated DECS as practical, interpretable tools for modeling environmental mixtures, such as wildfire smoke, and their toxicological effects.

PMID:41928614 | DOI:10.1021/acs.chemrestox.5c00440

Eur J Cancer. 2026 Mar 24;239:116699. doi: 10.1016/j.ejca.2026.116699. Online ahead of print.

ABSTRACT

INTRODUCTION: The latest generation of liquid biopsies incorporates multi-omic features, including genomics, methylomics, and fragmentomics. Machine learning (ML) approaches have been proposed to synthesize these complex biological data for the development of diagnostic classifiers. This study aims to evaluate the integration of ML with circulating cell-free DNA (cfDNA) analysis for early cancer detection.

METHODS: Medline, Embase, Cochrane, and Web of Science were searched in July 2025. Eligible studies combined ML and cfDNA features to distinguish cancer patients (stages I-III) from non-cancer controls. Summary diagnostic performance metrics and their 95% confidence intervals (CI) were calculated.

RESULTS: The study included 109 articles permitting analyses for lung (n = 34), liver (n = 29), colorectal (n = 28), pancreatic (n = 16), breast (n = 17), esophageal (n = 12), ovarian (n = 13), gastric (n = 9), head and neck (n = 4), and mixed (n = 27) cancer types. Specificity was consistently high across all tumor types and stages (94%-99%). Sensitivity ranged from 72% to 92% for stage I-III, 44-91% for stage I, 71-98% for stage II and 83-99% for stage III. In the pooled study population, neural networks (90%, 95% CI: 81%-95%), random forest (86%, 95% CI: 77%-92%) and heterogeneous ensemble learning (85%, 95% CI: 79%-89%) demonstrated the highest sensitivity. The stratified analysis by classifier feature revealed 86% (95% CI: 80%-90%) sensitivity for fragmentation and 81% (95% CI: 76%-85%) for methylation, with 92%-96% specificity.

CONCLUSION: ML and cfDNA profiling show potential for early cancer detection, with ensemble methods, neural networks and random forests achieving the best overall performance. Fragmentomic features provide the highest sensitivity.

PMID:41930854 | DOI:10.1016/j.ejca.2026.116699

Eur J Cancer. 2026 Mar 24;239:116699. doi: 10.1016/j.ejca.2026.116699. Online ahead of print.

ABSTRACT

INTRODUCTION: The latest generation of liquid biopsies incorporates multi-omic features, including genomics, methylomics, and fragmentomics. Machine learning (ML) approaches have been proposed to synthesize these complex biological data for the development of diagnostic classifiers. This study aims to evaluate the integration of ML with circulating cell-free DNA (cfDNA) analysis for early cancer detection.

METHODS: Medline, Embase, Cochrane, and Web of Science were searched in July 2025. Eligible studies combined ML and cfDNA features to distinguish cancer patients (stages I-III) from non-cancer controls. Summary diagnostic performance metrics and their 95% confidence intervals (CI) were calculated.

RESULTS: The study included 109 articles permitting analyses for lung (n = 34), liver (n = 29), colorectal (n = 28), pancreatic (n = 16), breast (n = 17), esophageal (n = 12), ovarian (n = 13), gastric (n = 9), head and neck (n = 4), and mixed (n = 27) cancer types. Specificity was consistently high across all tumor types and stages (94%-99%). Sensitivity ranged from 72% to 92% for stage I-III, 44-91% for stage I, 71-98% for stage II and 83-99% for stage III. In the pooled study population, neural networks (90%, 95% CI: 81%-95%), random forest (86%, 95% CI: 77%-92%) and heterogeneous ensemble learning (85%, 95% CI: 79%-89%) demonstrated the highest sensitivity. The stratified analysis by classifier feature revealed 86% (95% CI: 80%-90%) sensitivity for fragmentation and 81% (95% CI: 76%-85%) for methylation, with 92%-96% specificity.

CONCLUSION: ML and cfDNA profiling show potential for early cancer detection, with ensemble methods, neural networks and random forests achieving the best overall performance. Fragmentomic features provide the highest sensitivity.

PMID:41930854 | DOI:10.1016/j.ejca.2026.116699

J Intern Med. 2026 Apr 3. doi: 10.1111/joim.70092. Online ahead of print.

ABSTRACT

Tuberculosis (TB) remains a major global health challenge, with multi-drug antibiotic regimens as the current standard of care. While effective at killing Mycobacterium tuberculosis, these treatments do not resolve persistent inflammation, prevent lung damage, or reverse immune dysregulation that contribute to poor outcomes and disease recurrence. Precision medicine offers a promising alternative but requires deeper insight into disease mechanisms to enable tailored interventions. This comprehensive review introduces the concept of immune endotyping to define the underlying disease mechanisms as tools to decode clinical and immunological heterogeneity in TB. TB displays a wide spectrum of clinical phenotypes, from latent or asymptomatic infection to mild or severe disease with characteristic non-cavitary or cavitary lung pathology. Instead, distinct immune endotypes capture the diverse biological pathways that shape disease progression and treatment response. Similar clinical presentations may arise from different immune dysfunctions, underscoring the need to move beyond broad phenotypic classifications. Advances in multi-omics and computational analyses uncover immune signatures that enable stratification for host-directed therapies (HDTs) targeting hyperinflammation, immunosuppression, coagulopathy or metabolic exhaustion. Integrating clinical, radiological, and immunological data through multimodal profiling is essential for developing personalized interventions. We also explore how endotyping has transformed treatment in other diseases, offering valuable insights for TB. Additionally, we present examples of how putative immune endotypes may be targeted with appropriate HDTs. In summary, this review underscores the potential of immune endotypes to advance precision medicine in TB, moving beyond one-size-fits-all treatment to improve outcomes, especially in severe and drug-resistant cases.

PMID:41930636 | DOI:10.1111/joim.70092

Oncol Res. 2026 Mar 23;34(4):11. doi: 10.32604/or.2026.076176. eCollection 2026.

ABSTRACT

Lung cancer remains the leading cause of cancer-related mortality worldwide, primarily driven by metabolic reprogramming and immune evasion mechanisms within tumor cells. To adapt to the nutrient-deprived tumor microenvironment (TME), lung cancer cells undergo profound metabolic reprogramming, characterized by enhanced glycolysis (the Warburg effect), increased glutamine dependency (mediated by GLS1), and accelerated lipid synthesis (involving enzymes such as FASN). These metabolic alterations not only remodel the TME but also dampen antitumor immune responses by promoting immunosuppressive cell populations (e.g., Tregs and M2 macrophages) and inhibiting effector functions of CD8⁺ T cells and natural killer (NK) cells. Critically, a bidirectional crosstalk operates between tumor cell metabolism and the immunosuppressive TME: metabolic reprogramming drives immune suppression through metabolite accumulation, whereas the immunosuppressive TME, in turn, promotes tumor cell adaptability-thus forming a positive feedback loop that reinforces immune evasion and therapy resistance. This review elucidates key molecular pathways governing metabolic reprogramming in lung cancer-spanning glucose, amino acid, and lipid metabolism-and their dynamic crosstalk with immune regulation, including epigenetic modifications and non-coding RNA-mediated mechanisms. Additionally, it evaluates emerging therapeutic strategies targeting the metabolic-immune axis, such as inhibitors of HK2 or GLS1 combined with anti-PD-1/PD-L1 agents, which aim to reverse immunosuppression and improve clinical outcomes. By synthesizing recent advances, this work provides a theoretical framework for precision oncology interventions, highlighting the potential of metabolic immunotherapies and future directions integrating AI and multi-omics data to overcome resistance in lung cancer.

PMID:41930159 | PMC:PMC13040304 | DOI:10.32604/or.2026.076176