PubMed

(tuberculosis[Title/Abstract]) OR (lung cancer[Title/Abstract])

Filters applied: from 2025/4/1 - 2025/4/30

1. Lancet Respir Med. 2025 Apr;13(4):348-363. doi: 10.1016/S2213-2600(24)00428-4.

Epub 2025 Feb 3.

Estimated worldwide variation and trends in incidence of lung cancer by histological subtype in 2022 and over time: a population-based study.

Luo G(1), Zhang Y(2), Rumgay H(1), Morgan E(1), Langselius O(1), Vignat J(1)

BACKGROUND: Lung cancer is the most common cancer worldwide, yet the current epidemiological profile of lung-cancer incidence by histological subtype is only partly understood. We aimed to assess geographical variation in incidence of lung cancer by subtype worldwide in 2022, geographical variation in adenocarcinoma incidence attributable to ambient particulate matter (PM) pollution worldwide in 2022, temporal trends in lung-cancer incidence by subtype from 1988 to 2017 in 19 countries, and generational changes.

METHODS: For this population-based study, we used data from the Global Cancer Observatory (GLOBOCAN) 2022, Cancer Incidence in Five Continents Volumes VII-XII, and members of the African Cancer Registry Network. To obtain national estimates of lung cancer in 2022 for the four main histological subtypes (ie, adenocarcinoma, squamous cell carcinoma [SCC], small-cell carcinoma, and large-cell carcinoma) by year, sex, and age group, we combined national estimates with representative, subsite-specific incidence proportions of lung cancer on the basis of recorded incidence data compiled in Cancer Incidence in Five Continents Volume XII and from members of the African Cancer Registry Network. We calculated country-specific, sex-specific, and age-specific proportions of and sex-specific and age-specific incidence rates per 100 000 people for all four histological subtypes. To account for differences in age composition between populations by country, we calculated age-standardised incidence rates (ASRs) per 100 000 people for lung cancer by subtype and sex at national and regional levels. We also quantified the burden of adenocarcinoma incidence attributable to ambient PM pollution for 179 countries in 2022. We conducted joinpoint regression and age-period-cohort analysis to assess temporal trends in ASRs in 19 countries by sex.

FINDINGS: In 2022, we estimated that there were 1 572 045 new cases of lung cancer worldwide among male individuals, of which 717 211 (45·6%) were adenocarcinoma, 461 171 (29·4%) were SCC, 180 063 (11·5%) were small-cell carcinoma, and 101 861 (6·5%) were large-cell carcinoma. In 2022, we estimated that there were 908 630 new cases of lung cancer worldwide among female individuals, of which 541 971 (59·7%) were adenocarcinoma, 155 598 (17·1%) were SCC, 87 902 (9·7%) were small-cell carcinoma, and 59 271 (6·5%) were large-cell carcinoma. Among male individuals, the highest ASRs were in east Asia for adenocarcinoma (27·12 [95% CI 27·04-27·21] per 100 000 people), east Europe for SCC (21·70 [21·51-21·89] per 100 000 people) and small-cell carcinoma (9·85 [9·72-9·98] per 100 000 people), and north Africa for large-cell carcinoma (4·33 [4·20-4·45] per 100 000 people). Among female individuals, the highest ASRs were in east Asia for adenocarcinoma (19·04 [18·97-19·11] per 100 000 people), north America for SCC (5·28 [5·21-5·35] per 100 000 people) and small-cell carcinoma (4·28 [4·21-4·35] per 100 000 people), and north Europe for large-cell carcinoma (2·87 [2·78-2·96] per 100 000 people). We estimated that 114 486 adenocarcinoma cases among male individuals and 80 378 adenocarcinoma cases among female individuals were attributable to ambient PM pollution worldwide in 2022, with ASRs of 2·35 (95% CI 2·33-2·36) per 100 000 male individuals and 1·46 (1·45-1·47) per 100 000 female individuals. Temporal trends in lung-cancer incidence by subtype and sex during 1988-2017 varied considerably across the 19 countries.

INTERPRETATION: Estimated geographical and temporal distribution of lung-cancer incidence varied across the four main subtypes worldwide. Our study highlights the need for future studies that identify possible causal factors that contribute to the changing risk patterns of lung cancer.

PMID: 39914442

2. Mol Cancer. 2025 Apr 9;24(1):111. doi: 10.1186/s12943-025-02287-w.

Single-cell and spatial transcriptomic analyses revealing tumor microenvironment remodeling after neoadjuvant chemoimmunotherapy in non-small cell lung cancer.

Cui X(#)(1), Liu S(#)(2), Song H(3), Xu J(4), Sun Y(5)

Non-small cell lung cancer (NSCLC) represents the most common pathological type of lung cancer, and the combination of neoadjuvant immunotherapy with chemotherapy has emerged as the first-line treatment for NSCLC. Nevertheless, the efficacy of this therapeutic approach remains variable. The present study aims to examine the impact of chemoimmunotherapy in NSCLC patients, with a view to identifying key molecules, critical cell subpopulations, communication patterns and spatial distributions that potentially correlate with therapeutic sensitivity. A total of 16 lung cancer tissue samples were collected from a cohort of 12 NSCLC patients and subjected to single-cell RNA and spatial transcriptome sequencing. Our data demonstrated that the distribution of CD4 + Treg T cells and mCAFs indicated an immunosuppressive tumor microenvironment, while the accumulation of CD4 + Th17 T cells and iCAFs could act as a positive marker for the sensitivity to chemoimmunotherapy. Furthermore, a significant high level of SELENOP-macrophages was observed in tissues from positive responders, and a strong co-localization between SELENOP-macrophages and antigen-presenting cancer associated fibroblasts (CAFs) in the tumor boundaries was identified, indicating the cooperative roles of these two cell types in response to combined therapy. Moreover, SELENOP-macrophages were observed to be accumulated in tertiary lymphoid structures, which further suggested its critical role in recruiting lymphocytes. Furthermore, analysis of cell-cell communication, based on spatial transcriptomics, suggests that the interactions between SELENOP-macrophages, apCAFs, CD4 + and CD8 + T cells were significantly enhanced in responders. In addition, SELENOP-macrophages recruited CD4 + Naïve, Helper and CD8 + Naïve T cells through pathways such as the cholesterol, interleukin, chemokine and HLA when responding to combined therapy. The present study further unveils the dynamic spatial and transcriptional changes in the tumor microenvironment of non-small cell lung cancer in response

to combination therapy.

PMID: 40205583 [Indexed for MEDLINE]

3. Lancet Public Health. 2025 Apr;10(4): e343-e346. doi:10.1016/S2468-2667(25)00014-3. Epub 2025 Feb 25.

Confronting the growing epidemic of silicosis and tuberculosis among small-scale miners.

Howlett P(1), Said B(2), Mwanga E(2), Mbuya A(2), Nota M(3), Kon OM(4)

An estimated 49·5 million small-scale miners worldwide are exposed to high concentrations of silica during their work. The substantial morbidity and mortality of silicosis and tuberculosis among workers exposed to such intensities have been documented. This Viewpoint raises concern at the failure to respond to a growing epidemic of lung disease (predominantly silicosis and tuberculosis) among small-scale miners. The Viewpoint is framed around four arguments: outlining the huge burden of lung disease among SSMs; critically examining these figures in the context of high silica exposures; illustrating the failure to support research; and examining historical, socioeconomic, and political factors influencing the epidemic. We then outline a strategy for response. An urgent and coordinated response is needed to address the devastating health effects of silicosis and tuberculosis in small-scale miners and their preventable workplace causes.

PMID: 40020695 [Indexed for MEDLINE]

4. Lancet Microbe. 2025 Apr 11:101094. doi: 10.1016/j.lanmic.2025.101094. Online ahead of print.

Integrating genomic and spatial analyses to describe tuberculosis transmission: a scoping review.

Lan Y(1), Rancu I(2), Chitwood MH(2), Sobkowiak B(2), Nyhan K(3), Lin HH(4)

Tuberculosis remains a leading cause of infection-related mortality, and efforts to reduce its incidence have been hindered by an incomplete understanding of local Mycobacterium tuberculosis transmission dynamics. Advances in pathogen sequencing and spatial analysis have created new opportunities to map M tuberculosis transmission patterns more precisely. In this scoping review, we searched for studies combining pathogen genetics and location data to analyse the spatial patterns of M tuberculosis transmission and identified 142 studies published between 1994 and 2024. Secular changes in genetic methods were observed, with genome sequencing approaches largely replacing lower-resolution genotyping methods since 2020. The included studies addressed four primary research questions: how are tuberculosis cases and M tuberculosis transmission clusters geographically distributed; do spatially concentrated M tuberculosis clusters exist, and where are these areas located; when spatial concentration occurs, what host, pathogen, or environmental factors contribute to these patterns; and do identifiable relationships exist between the spatial proximity of tuberculosis cases and the genetic similarity of the M tuberculosis isolates infecting these individuals? Collectively, in this Review, we examined the available study data, evaluated the analytical requirements for addressing these questions, and discussed opportunities and challenges for future research. We found that the integration of spatial and genomic data can inform a detailed understanding of local M tuberculosis transmission patterns, but improved study designs and new analytical methods to address gaps in sampling completeness and to integrate additional movement data are needed to fully realise the potential of these tools.

PMID: 40228509

5. J Thorac Oncol. 2025 Apr;20(4):425-436. doi: 10.1016/j.jtho.2024.12.016. Epub 2024 Dec 19.

Prospective Evaluation of Lung Cancer Screening Eligibility Criteria and Lung Cancer Detection in the Yorkshire Lung Screening Trial.

INTRODUCTION: Low-dose computed tomography screening for lung cancer reduces lung cancer mortality, but there is a lack of international consensus regarding the optimal eligibility criteria for screening. The Yorkshire Lung Screening Trial was designed to evaluate lung cancer screening (LCS) implementation, and a primary objective was prospective evaluation of three predefined eligibility criteria.

METHODS: Individuals who had ever smoked, aged 55 to 80 years, who responded to written invitation, underwent telephone risk assessment and if eligible by at least one criterion (PLCOM2012 ≥ 1.51%, LLPv2 ≥ 5%, USPSTF2013) were offered biennial low-dose computed tomography screening.

RESULTS: Of 44,957 individuals invited, 22,814 responded and underwent eligibility assessment, of whom a total of 7826 were eligible according to any of the three LCS criteria. Comparing PLCOM2012 ≥ 1.51%, LLPv2 ≥ 5%, and USPSTF2013, the proportions of responders eligible for screening were 28.0%, 20.5%, and 18.9%, respectively (p < 0.0001 for each comparison), and the proportion of all cancers detected 91.1%, 77.0%, and 62.8%, respectively (p ≤ 0.0002 for each comparison). When risk thresholds were selected to result in equivalent numbers of people eligible for screening, cancer detection proportions were higher for PLCOM2012 (74.5%) and LLPv2 (71.3%) than USPSTF2013 (62.8%) (p = 0.0002 and p = 0.032, respectively), but there was no significant difference between the two risk models. Reducing the LLPv2 risk threshold from 5% to 2.5% (as currently used in the English LCS program) and reducing the pack-year requirement for the USPSTF2021 versus the USPSTF2013 criteria increased the numbers eligible for screening, but subsequent cancer yield was not measured in this study.

CONCLUSION: The PLCOM2012 ≥ 1.51% criteria identified more people eligible for screening in Yorkshire Lung Screening Trial and resulted in more screen-detected lung cancers than LLPv2 ≥ 5% or USPSTF2013. When compared in equivalent populations, there was no significant difference between risk models in terms of lung cancer detection and each appeared more efficient at screening population selection than USPSTF2013.

PMID: 39709114 [Indexed for MEDLINE]

6. Lancet Public Health. 2025 Apr;10(4): e285-e294. doi: 10.1016/S2468-2667(24)00325-6.

Changes in incarceration and tuberculosis notifications from prisons during the COVID-19 pandemic in Europe and the Americas: a time-series analysis of national surveillance data.

Zheng A(1), Faust L(2), Harries AD(3), Avedillo P(4), Akodu M(5), Galvan M(5)

BACKGROUND: The COVID-19 pandemic disrupted tuberculosis control programmes globally; whether or not this disproportionately affected people who were incarcerated is unknown. We aimed to evaluate changes in incarceration and tuberculosis notifications in prisons in Europe and the Americas during the COVID-19 pandemic.

METHODS: Data from WHO Pan American Health Organization (PAHO) and WHO Europe were used to conduct a joint hierarchical Bayesian negative binomial time-series. This approach accounted for world region, country-specific temporal trends, and country-specific autocorrelated random effects to simultaneously model and predict both annual prison population (ie, the offset) and prison tuberculosis cases (ie, the primary outcome). Results were used to calculate percentage differences between predicted and observed annual tuberculosis notifications and prison populations during the COVID-19 pandemic years (2020-22).

FINDINGS: In total, 22 of 39 countries from PAHO and 25 of 53 countries from WHO Europe were included (representing 4·9 million people incarcerated annually), contributing 520 country-years of follow-up. Observed tuberculosis notifications in prisons were lower than predicted in 2020 (-26·2% [95% credible interval -66·3 to 7·8), 2021 (-46·4% [-108·8 to 3·9]), and 2022 (-48·9 [-124·4 to 10·3]). These decreasing trends were consistent across Europe and the Americas, but larger decreases were seen in low-burden settings in 2020 (-54·8% [-112·4 to -4·8]) and 2021 (-68·4% [-156·6 to -2·9]), high-burden settings in 2021 (-89·4% [-190·3 to -10·4]), and Central and North America in 2021 (-100·3% [-239·0 to -6·3]). Observed incarceration levels were similar to predicted levels (<10% difference overall) during all COVID-19 pandemic years.

INTERPRETATION: Tuberculosis notifications in prisons from 47 countries in Europe and the Americas were lower than expected (at times >50% lower) during COVID-19 pandemic years, despite consistent incarceration levels. Reasons for this change in tuberculosis notifications might be multifactorial and include missed diagnoses and implementation of COVID-19 pandemic measures, reducing transmission. Greater prioritisation of people who are incarcerated is needed to ensure appropriate access to care in the face of future pandemics.

PMID: 40175010 [Indexed for MEDLINE]

7. Adv Mater. 2025 Apr;37(17): e2415818. doi: 10.1002/adma.202415818. Epub 2025 Mar 17.

Translational Selenium Nanoparticles Promotes Clinical Non-small-cell Lung Cancer Chemotherapy via Activating Selenoprotein-driven Immune Manipulation.

Yu Y(1), Xie B(1), Wang J(2), Luo W(2), Yang M(1), Xiong Z(1), Huang G(1), Yang J(1)

Reconstructing the tumor immune microenvironment is an effective strategy to enhance therapeutic efficacy limited by immunosuppression in non-small-cell lung cancer (NSCLC). In this study, it is found that selenium (Se) depletion and immune dysfunction are present in patients with advanced NSCLC compared with healthy volunteers. Surprisingly, Se deficiency resulted in decreased immunity and accelerated rapid tumor growth in the mice model, which further reveals that the correlation between micronutrient Se and lung cancer progression. This pioneering work achieves 500-L scale production of Se nanoparticles (SeNPs) at GMP level and utilizes it to reveal how and why the trace element Se can enhance clinical immune-mediated treatment efficacy against NSCLC. The results found that translational SeNPs can promote the proliferation of NK cells and enhance its cytotoxicity against cancer cells by activating mTOR signaling pathway driven by GPXs to regulate the secretion of cytokines to achieve an antitumor response. Moreover, a clinical study of an Investigator-initiated Trial shows that translational SeNPs supplementation in combination with bevacizumab/cisplatin/pemetrexed exhibits enhanced therapeutic efficacy with an objective response rate of 83.3% and a disease control rate of 100%, through potentiating selenoprotein-driven antitumor immunity. Taken together, this study, for the first time, highlights the translational SeNPs-enhanced therapeutic efficacy against clinical advanced NSCLC.

PMID: 40095246 [Indexed for MEDLINE]

8. Signal Transduct Target Ther. 2025 Apr 18;10(1):124. doi: 10.1038/s41392-025-02206-x.

RNase1-driven ALK-activation is an oncogenic driver and therapeutic target in non-small cell lung cancer.

Zha Z(#)(1), Liu C(#)(2), Yan M(#)(3), Chen C(#)(1), Yu C(1), Chen Y(1), Zhou C(4)(5)

Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, and colony formation. Additionally, RDAA facilitates tumor formation in fibroblast models, further underscoring its oncogenic potential in vivo. Importantly, RDAA lung cancer cells exhibit marked sensitivity to FDA-approved ALK inhibitors. Tumor growth suppression and survival were substantially improved in both RDAA-positive NSCLC cell line-derived and patient-derived xenograft tumor models treated with ALK inhibitors. Monoclonal antibodies against RNase1 and phosphorylated-ALK were used to analyze two different human NSCLC tissue cohorts by immunohistochemical staining identified 10.4% (5/48) and 8.5% (100/1173) patients who were RDAA positive, respectively. Notably, among the nine RDAA-positive NSCLC patients who accepted ALK inhibitor treatment, five achieved objective response including two who experienced complete response (CR). Together, the current study identifies RDAA as an oncogenic driver and proposes an effective targeted therapy strategy for non-mutated NSCLC patients.

PMID: 40246819 [Indexed for MEDLINE]

9. J Thorac Oncol. 2025 Apr;20(4):437-450. doi: 10.1016/j.jtho.2024.12.011. Epub 2024 Dec 16.

LIBELULE: A Randomized Phase III Study to Evaluate the Clinical Relevance of Early Liquid Biopsy in Patients With Suspicious Metastatic Lung Cancer.

Swalduz A(1), Schiffler C(2), Curcio H(3), Ambasager B(4), Le Moel G(5)

OBJECTIVES: Genomic profiling is a major component for first-line treatment decisions in patients with NSCLC and the timeliness of biomarker testing is essential to improve time to treatment initiation (TTI) or avoid inappropriate treatment.

METHODS: The phase III LIquid Biopsy for the Early detection of LUng cancer Lesion trial (NCT03721120) included patients with radiological suspicion of advanced lung cancer. They were randomized (1:1), the control arm receiving diagnostic procedures according to each center's practice, and the liquid biopsy arm with additional testing performed at the first visit using the InVisionFirst-Lung assay. Treatment initiation and type were defined according to the European Society for Medical Oncology guidelines. Primary endpoint was the time from randomization to initiation of appropriate treatment on the basis of informative genomic and pathological results in the intention-to-treat population.

RESULTS: A total of 319 patients were enrolled (liquid biopsy [LB]: 161; control: 158). The median age was 68 years, 28.8% were non-smokers, 18.1% had a performance status of 2 or higher, and 56.7% had adenocarcinoma. In the LB arm, 81% of patients had circulating tumor DNA findings. The mean TTI was not significantly reduced (LB: 29.0 d; control 34 d (p = 0.26)). Sensitivity analyses found a shorter TTI in patients from the LB arm who received systemic treatment (LB: 29.1 d; control: 38.9 d, p = 0.01), in patients with advanced non-squamous NSCLC (LB: 29.5 d; control: 40.3 d, p = 0.01), and in patients with first-line targetable alterations (LB: 21d; control 37.4 d) (p = 0.004). Time to contributory genomic results was significantly reduced (LB: 17.9 d; control: 25.6 d, p < 0.001).

CONCLUSION: Early liquid biopsy testing did not significantly shorten the TTI in unselected patients referred for suspected advanced lung cancer. Nevertheless, it could reduce the TTI in patients eligible for systemic treatment, particularly for those with actionable alterations.

PMID: 39694415 [Indexed for MEDLINE]

10. Lancet Glob Health. 2025 Apr 15: S2214-109X(25)00046-4. doi: 10.1016/S2214-109X(25)00046-4. Online ahead of print.

Live-attenuated Mycobacterium tuberculosis vaccine, MTBVAC, in adults with or without M tuberculosis sensitisation: a single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial.

Luabeya AKK(1), Rozot V(1), Imbratta C(1), Ratangee F(1), Shenje J(1), Tameris M(1)

BACKGROUND: An effective adult vaccine is needed to control tuberculosis. We evaluated the safety and immunogenicity of a live-attenuated Mycobacterium tuberculosis vaccine (MTBVAC).

METHODS: This single-centre, phase 1b-2a, double-blind, dose-escalation, randomised controlled trial (NCT02933281) enrolled South African adults previously vaccinated with BCG, who were HIV negative and aged 18-50 years, with or without M tuberculosis sensitisation assessed by QuantiFERON-tuberculosis Gold-Plus assay (QFT). Participants were recruited from the local community and randomly allocated (2:1) to receive MTBVAC (5 × 103, 5 × 104, 5 × 105, or 5 × 106 colony-forming unit [CFU] doses) or BCG revaccination (5 × 105 CFU dose). The primary outcomes were the occurrence of systemic solicited adverse events within 7 days and unsolicited adverse events within 28 days after vaccination, the occurrence of solicited and unsolicited injection-site reactions within 84 days after vaccination, and the occurrence of serious adverse events (SAEs) until the end of study, 365 days after vaccination. Data were analysed per modified intention to treat. The trial is now complete and closed.

FINDINGS: Between Jan 15, 2019, and Sept 7, 2020, 485 participants provided consent and were screened. 144 participants were enrolled and 143 (99%) were vaccinated. BCG was administrated to 47 (33%) of 143 and MTBVAC to 96 (67%) of 143. 12 participants with QFT-negative results and 12 with QFT-positive results were randomly allocated to receive each dose of MTBVAC and 24 participants with QFT-negative results and 24 with QFT-positive results were randomly allocated to receive BCG revaccination. Injection-site pain, discharge, erythema, and swelling increased with MTBVAC dose level. MTBVAC 5 × 105 CFU recipients reported a similar proportion of related adverse events (23 [96%] of 24) as BCG recipients (45 [96%] of 47). MTBVAC recipients who were QFT positive reported more injection-site reactions (46 [96%] of 48; 95% CI 85·7-99·5) than MTBVAC recipients who were QFT negative (32 [67%] of 48; 51·6-79·6). No vaccine-related SAEs were reported. All doses of MTBVAC were immunogenic; vaccine-induced antigen-specific CD4 T-cell responses peaked 28 days after vaccination. The MTBVAC 5 × 105 and 5 × 106 CFU doses induced T-helper-cell-1 cytokine-expressing CD4 T-cell responses that exceeded BCG-induced responses in participants who were QFT negative and QFT positive.

INTERPRETATION: MTBVAC at the 5 × 105 dose showed similar safety and reactogenicity and greater immunogenicity when compared to BCG. These results suggest that the 5 × 105 dose of MTBVAC could be selected for a subsequent efficacy evaluation.

PMID: 40250461

11. Cancer Cell. 2025 Apr 17:S1535-6108(25)00128-X. doi: 10.1016/j.ccell.2025.03.027. Online ahead of print.

Circular RMST cooperates with lineage-driving transcription factors to govern neuroendocrine transdifferentiation.

Teng M(1), Guo J(2), Xu X(3), Ci X(3), Mo Y(4), Kohen Y(1), Ni Z(3), Chen S(3)

Circular RNA (circRNA) is a class of noncoding RNA with regulatory potentials. Its role in the transdifferentiation of prostate and lung adenocarcinoma into neuroendocrine prostate cancer (NEPC) and small cell lung cancer (SCLC) remains unexplored. Here, we identified circRMST as an exceptionally abundant circRNA predominantly expressed in NEPC and SCLC, with strong conservation between humans and mice. Functional studies using shRNA, siRNA, CRISPR-Cas13, and Cas9 consistently demonstrate that circRMST is essential for tumor growth and the expression of ASCL1, a master regulator of neuroendocrine fate. Genetic knockout of Rmst in NEPC genetic engineered mouse models prevents neuroendocrine transdifferentiation, maintaining tumors in an adenocarcinoma state. Mechanistically, circRMST physically interacts with lineage transcription factors NKX2-1 and SOX2. Loss of circRMST induces NKX2-1 protein degradation through autophagy-lysosomal pathway and alters the genomic binding of SOX2, collectively leading to the loss of ASCL1 transcription.

PMID: 40250444

12. Nat Cancer. 2025 Apr 30. doi: 10.1038/s43018-025-00945-y. Online ahead of print.

An organoid library unveils subtype-specific IGF-1 dependency via a YAP-AP1 axis in human small cell lung cancer.

Fukushima T(#)(1), Togasaki K(#)(2)(3)(4), Hamamoto J(1), Emoto K(5)

Small cell lung cancer (SCLC) is a devastating disease with limited therapeutic advancements. Although SCLC has recently been classified into four molecular subtypes, subtype-specific therapies are still lacking. Here, we established 40 patient-derived SCLC organoid lines with predominant TP53 and RB1 alterations and rare targetable genetic lesions. Transcriptome profiling divided the SCLC organoids into neuroendocrine (NE)-type SCLC and non-NE-type SCLC, with the latter characterized by YAP1 or POU2F3 expression. NE-type SCLC organoids grew independent of alveolar niche factors, whereas non-NE-type SCLC organoids relied on insulin-like growth factor (IGF)-1-driven YAP1 and AP1 activation. Therapeutic targeting of IGF-1, YAP1 and AP1 effectively suppressed the growth of non-NE-type organoids. Co-knockout of TP53 and RB1 in human alveolar cells altered their lineage toward the airway epithelium-like fate and conferred IGF-1 dependency, validating the subtype-phenotype connection. Our SCLC organoid library represents a valuable resource for developing biology-based therapies and has the potential to reshape the drug discovery landscape.

PMID: 40307487

13. Sci Transl Med. 2025 Apr 9;17(793): eadp6411. doi: 10.1126/scitranslmed.adp6411.Epub 2025 Apr 9.

Rapid tuberculosis diagnosis from respiratory or blood samples by a low cost, portable lab-in-tube assay.

Youngquist BM(1)(2), Saliba J(1)(2), Kim Y(1)(2), Cutro TJ(3), Lyon CJ(1)(2)

Rapid portable assays are needed to improve diagnosis, treatment, and reduce transmission of tuberculosis (TB), but current tests are not suitable for patients in resource-limited settings with high TB burden. Here we report a low complexity, lab-in-tube system that is read by an integrated handheld device that detects Mycobacterium tuberculosis (Mtb) DNA in blood and respiratory samples from a variety of clinical settings. This microprocessor-controlled device uses an LCD user interface to control assay performance, automate assay analysis, and provide results in a simple readout. This point-of-care single-tube assay uses a DNA enrichment membrane and a low-cost cellulose disc containing lyophilized recombinase polymerase amplification and CRISPR-Cas12a reagents to attain single-nucleotide specificity and high sensitivity within 1 hour of sample application, without a conventional DNA isolation procedure. Assay results obtained with serum cell-free DNA isolated from a cohort of children aged 1 to 16 years detected pulmonary and extrapulmonary TB with high sensitivity versus culture and GeneXpert MTB/RIF results (81% versus 55% and 68%) and good specificity (94%), meeting the World Health Organization target product profile criteria for new nonsputum TB diagnostics. Changes in assay results for serum isolated during treatment were also highly predictive of clinical response. Results obtained with noninvasive sputum and saliva specimens from adults with bacteriologically confirmed pulmonary TB were also comparable to those reported for reference methods. This rapid and inexpensive lab-in-tube assay approach thus represents one means to address the need for point-of-care TB diagnostics useable in low-resource settings.

PMID: 40203083 [Indexed for MEDLINE]

14. Am J Respir Crit Care Med. 2025 Apr;211(4):600-609. doi: 10.1164/rccm.202408-1661OC.

Effect of Long-Term Fine Particulate Matter Exposure on Lung Cancer Incidence and Mortality in Chinese Nonsmokers.

Zhu M(1)(2)(3), Han Y(4), Mou Y(1), Meng X(5)(6)(7), Ji C(1), Zhu X(1), Yu C(4)(8)(9)

Comment in

    Am J Respir Crit Care Med. 2025 Apr;211(4):548-549. doi: 10.1164/rccm.202501-0061ED.

Rationale: The association between fine particulate matter (particulate matter ⩽2.5 μm in aerodynamic diameter, PM2.5) and lung cancer incidence in nonsmokers (LCINS) remains inconsistent. Objectives: To investigate the association between long-term PM2.5 exposure and LCINS in a Chinese population and to assess the modifying effect of genetic factors. Methods: Time-dependent Cox proportional hazard models were used to evaluate the hazard ratios (HRs) and 95% confidence intervals (CIs) of PM2.5 with LCINS risk and LCINS-related mortality. The polygenic risk score was constructed to further explore the interactions between genetic risk and PM2.5 exposure. In addition, the population attributable fraction of PM2.5 to lung cancer risk and mortality was calculated. Measurements and Main Results: The results demonstrated significant associations between PM2.5 exposure and LCINS incidence (HR, 1.10 per 10 μg/m3; 95% CI, 1.04-1.17 per 10 μg/m3) and mortality (HR, 1.17 per 10 μg/m3; 95% CI, 1.08-1.27 per 10 μg/m3). Compared with the lowest-risk group, individuals exposed to the high PM2.5 concentration (⩾50.9 μg/m3) and high genetic risk (top 30%) exhibited the

highest LCINS incidence (HR, 2.01; 95% CI, 1.39-2.87) and mortality (HR, 2.30; 95% CI, 1.38-3.82). A significant additive interaction between PM2.5 and genetic risk on LCINS incidence was observed. Approximately 33.6% of LCINS cases and 48.5% of LCINS-related deaths in China could be prevented if PM2.5 concentrations were reduced to meet World Health Organization guidelines. Conclusions: Long-term exposure to outdoor PM2.5 increases LCINS risk and LCINS-related mortality, especially in populations with high genetic risk. Strengthening air pollution control measures in China has the potential to significantly reduce the burden of LCINS.

PMID: 39918842 [Indexed for MEDLINE]

15. Lancet. 2025 Apr 5;405(10485):1155-1166. doi: 10.1016/S0140-6736(24)02847-2. Epub 2025 Mar 11.

Effect of digital adherence technologies on treatment outcomes in people with drug-susceptible tuberculosis: four pragmatic, cluster-randomised trials.

Jerene D(1), van Kalmthout K(2), Levy J(2), Alacapa J(3), Deyanova N(4), Dube T(5)

BACKGROUND: The impact of digital adherence technologies on tuberculosis treatment outcomes remains poorly understood. We investigated whether smart pillboxes and medication labels can reduce poor treatment outcomes in patients with tuberculosis.

METHODS: We did independent pragmatic, cluster-randomised trials in the Philippines, South Africa, Tanzania, and Ukraine. 110 clusters were randomly assigned (1:1) to standard of care versus intervention arms, which were further randomly assigned (1:1; except in Ukraine) to a smart pillbox or medication labels. We enrolled adult patients receiving treatment for drug-susceptible tuberculosis. The pillbox gave an audio-visual reminder to take medication, and when the box was opened, a signal was transmitted to the adherence platform. Those in the labels arm received medications with label attached, showing a code, which they messaged when a dose was taken; otherwise, a reminder was sent. The primary outcome was a composite poor end of treatment outcome, defined as having documented treatment failure, loss to follow-up (treatment interruption for ≥2 consecutive months), switched to a multidrug-resistant regimen more than 28 days after treatment start, or death. The trials are complete and registered with ISRCTN, 17706019.

FINDINGS: Between June 21, 2021, and July 8, 2022, we enrolled 25 606 individuals (12 626 on standard of care and 12 980 on intervention) across 220 clusters in the four trials, of whom 23 483 (91·7%; 11 313 on standard of care and 12 170 on intervention) were included in the intention-to-treat population. 8208 (35·0%) of 23 483 individuals were female. 9717 (85·9%) of 11 313 individuals in the standard of care arm and 10 540 (86·6%) of 12 170 individuals in the intervention arm were analysed for the primary outcome. The risk of the primary outcome did not differ by intervention arm for all countries (Philippines adjusted odds ratio 1·13, 95% CI 0·72-1·78, p=0·59; Tanzania 1·49, 0·99-2·23; p=0·056; South Africa 1·19, 0·88-1·60; p=0·25; Ukraine adjusted risk ratio 1·15, 95% CI 0·83-1·59; p=0·38). Two incidents of social harm were reported due to inadvertent disclosure of treatment status in the pillbox arm, resulting in withdrawal of the participants.

INTERPRETATION: Digital adherence technologies did not reduce poor treatment outcomes in the four countries investigated. The use of digital adherence technologies should be based on careful review of additional data on economic evaluation, patient and stakeholder preferences, and the effect on other important patient outcomes beyond programmatic treatment outcomes.

PMID: 40086457 [Indexed for MEDLINE]

16. Lancet Infect Dis. 2025 Apr;25(4):435-444. doi: 10.1016/S1473-3099(24)00601-7. Epub 2024 Nov 26.

Safety, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both in adults with pulmonary tuberculosis: a randomised, active-controlled, open-label trial.

Dawson R(1), Diacon AH(2), De Jager V(2), Narunsky K(3), Moodley VM(4)

BACKGROUND: Quabodepistat (formerly OPC-167832) showed potent activity in preclinical studies and in the first stage of an early bactericidal activity study in adults with smear-positive, drug-susceptible pulmonary tuberculosis. Stage 2 of this study was designed to evaluate the safety, tolerability, pharmacokinetics, and early bactericidal activity of quabodepistat in combination with delamanid, bedaquiline, or both versus rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy for 14 days.

METHODS: Stage 2 of this open-label, active-controlled, randomised, parallel-group study was conducted at two research sites in South Africa in adults (aged 18-64 years) with drug-susceptible pulmonary tuberculosis. Eligible participants had a BMI of 16-32 kg/m2 and the ability to produce an adequate volume of sputum (≥10 mL overnight) and were excluded if they had drug-resistant tuberculosis or previous treatment for Mycobacterium tuberculosis within the past 3 years. Participants were centrally randomly assigned via interactive web response technology system, with no stratification, into four treatment groups in a ratio of 14:14:14:4 (quabodepistat 30 mg plus delamanid 300 mg, quabodepistat 30 mg plus bedaquiline 400 mg, or quabodepistat 30 mg plus delamanid 300 mg plus bedaquiline 400 mg orally once daily for 14 days, or rifampicin, isoniazid, ethambutol, and pyrazinamide combination therapy [control] according to local standard of care for 20 days). The primary outcomes were safety and tolerability during and after 14 days of treatment in all participants who received any study medication and pharmacokinetics at day 1 and day 14 in participants in the quabodepistat groups with adequate data for deriving pharmacokinetics parameters. The main secondary outcome was bactericidal activity from baseline to day 14 in all eligible participants who were quantitatively culture-positive at baseline. The study was not powered for formal statistical hypothesis testing; therefore, data were summarised by treatment group with descriptive statistics. This study is registered with ClinicalTrials.gov (NCT03678688) and is closed to new participants.

FINDINGS: 98 participants were screened for entry into stage 2 of the trial between Feb 1, 2021, and Jan 27, 2022, of whom 46 were randomly assigned (14 to each quabodepistat group, 4 to the control group) and 44 received at least one dose of study medication (one patient excluded from the quabodepistat plus delamanid and quabodepistat plus bedaquiline groups). 32 (73%) of 44 participants had at least one treatment-emergent adverse event. Most events (30/32 [94%]) were mild or moderate; the most common treatment-emergent adverse events (≥2 participants; not related to study drugs) were headache (4/44 [9%]), dizziness (3/44 [7%]), abdominal pain (2/44 [5%]), pruritus (2/44 [5%]), and nausea (2/44 [5%]). Two serious adverse events were reported in two participants in the quabodepistat and bedaquiline cohort (anal abscess [n=1], pneumothorax [n=1]); both were deemed not related to study drug. Quabodepistat exposure was minimally affected by coadministration of delamanid or bedaquiline, with lower exposure in the quabodepistat and bedaquiline cohorts (maximum plasma concentration for quabodepistat plus delamanid 208 ng/mL [SD 61; n=11]; quabodepistat plus bedaquiline 175 ng/mL [31; n=10]; quabodepistat plus delamanid plus bedaquiline 183 ng/mL [52; n=11]). Maximum quabodepistat concentrations were achieved approximately 3 h after administration in all combinations. Mean elimination half-life was shorter in combinations with bedaquiline than without bedaquiline (12·3-14·5 h vs 15·2 h). Mean changes from baseline to day 14 of sputum log10 colony-forming units per mL were -2·73 (SD 1·51) for quabodepistat plus delamanid plus bedaquiline (n=12) and -2·71 (SD 0·92) for control (n=19); mean change was -2·17 (SD 1·83) in the quabodepistat plus delamanid cohort (n=11) and -1·97 (SD 1·29) in the quabodepistat plus bedaquiline cohort (n=11).

INTERPRETATION: In this 14-day trial, quabodepistat plus delamanid plus bedaquiline, a novel three-drug combination, appeared to be safe, well tolerated, and provided robust early bactericidal activity in adults with drug-susceptible pulmonary tuberculosis. Further evaluation is warranted.

PMID: 39612928 [Indexed for MEDLINE]

17. J Clin Oncol. 2025 Apr 20;43(12):1453-1462. doi: 10.1200/JCO-24-02239. Epub 2025 Jan 8.

Neoadjuvant Nivolumab Plus Ipilimumab Versus Chemotherapy in Resectable Lung Cancer.

Awad MM(1), Forde PM(2), Girard N(3), Spicer J(4), Wang C(5), Lu S(6)

PURPOSE: Neoadjuvant immune checkpoint blockade with nivolumab plus ipilimumab improves overall survival (OS) in non-small cell lung cancer (NSCLC); however, randomized data for resectable lung cancer are limited. We report results from the exploratory concurrently randomized nivolumab plus ipilimumab and chemotherapy arms of the international phase III CheckMate 816 trial.

METHODS: Adults with stage IB-IIIA (American Joint Committee on Cancer seventh edition) resectable NSCLC received three cycles of nivolumab once every 2 weeks plus one cycle of ipilimumab or three cycles of chemotherapy (on day 1 or days 1 and 8 of each 3-week cycle) followed by surgery. Analyses included event-free survival (EFS), OS, pathologic response, surgical outcomes, biomarker analyses, and safety.

RESULTS: A total of 221 patients were concurrently randomly assigned to nivolumab plus ipilimumab (n = 113) or chemotherapy (n = 108). At a median follow-up of 49.2 months, the median EFS was 54.8 months (95% CI, 24.4 to not reached [NR]) with nivolumab plus ipilimumab versus 20.9 months (95% CI, 14.2 to NR) with chemotherapy (HR, 0.77 [95% CI, 0.51 to 1.15]); 3-year EFS rates were 56% versus 44%. Higher rates of EFS events were initially seen, with later benefit favoring nivolumab plus ipilimumab; 3-year OS rates were 73% versus 61% (HR, 0.73 [95% CI, 0.47 to 1.14]); pathologic complete response rates were 20.4% versus 4.6%, respectively. In the respective arms, 83 (74%) and 82 patients (76%) underwent definitive surgery. Grade 3-4 treatment-related adverse events occurred in 14% and 36% of patients, respectively.

CONCLUSION: Neoadjuvant nivolumab plus ipilimumab showed potential long-term clinical benefit versus chemotherapy, despite early crossing of EFS curves in the preoperative phase and a lower rate of high-grade toxicity.

PMID: 39778121 [Indexed for MEDLINE]

18. Nat Med. 2025 Apr;31(4):1351-1363. doi: 10.1038/s41591-025-03530-z. Epub 2025 Feb 27.

Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases.

Tagore S(#)(1)(2)(3), Caprio L(#)(1)(3)(4), Amin AD(#)(1)(3)(4), Bestak K(#)(5)

Brain metastases frequently develop in patients with non-small cell lung cancer (NSCLC) and are a common cause of cancer-related deaths, yet our understanding of the underlying human biology is limited. Here we performed multimodal single-nucleus RNA and T cell receptor, single-cell spatial and whole-genome sequencing of brain metastases and primary tumors of patients with treatment-naive NSCLC. Chromosomal instability (CIN) is a distinguishing genomic feature of brain metastases compared with primary tumors, which we validated through integrated analysis of molecular profiling and clinical data in 4,869 independent patients, and a new cohort of 12,275 patients with NSCLC. Unbiased analyses revealed transcriptional neural-like programs that strongly enriched in cancer cells from brain metastases, including a recurring, CINhigh cell subpopulation that preexists in primary tumors but strongly enriched in brain metastases, which was also recovered in matched single-cell spatial transcriptomics. Using multiplexed immunofluorescence in an independent cohort of treatment-naive pairs of primary tumors and brain metastases from the same patients with NSCLC, we validated genomic and tumor-microenvironmental findings and identified a cancer cell population characterized by neural features strongly enriched in brain metastases. This comprehensive analysis provides insights into human NSCLC brain metastasis biology and serves as an important resource for additional discovery.

PMID: 40016452 [Indexed for MEDLINE]

19. Nat Rev Cancer. 2025 Apr 10. doi: 10.1038/s41568-025-00803-0. Online ahead of print.

Challenges of small cell lung cancer heterogeneity and phenotypic plasticity.

Simpson KL(1)(2)(3), Rothwell DG(2)(3), Blackhall F(3)(4)(5), Dive C(6)(7)(8).

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with ~7% 5-year overall survival reflecting early metastasis and rapid acquired chemoresistance. Immunotherapy briefly extends overall survival in ~15% cases, yet predictive biomarkers are lacking. Targeted therapies are beginning to show promise, with a recently approved delta-like ligand 3 (DLL3)-targeted therapy impacting the treatment landscape. The increased availability of patient-faithful models, accumulating human tumour biobanks and numerous comprehensive molecular profiling studies have collectively facilitated the mapping and understanding of substantial intertumoural and intratumoural heterogeneity. Beyond the almost ubiquitous loss of wild-type p53 and RB1, SCLC is characterized by heterogeneously mis-regulated expression of MYC family members, yes-associated protein 1 (YAP1), NOTCH pathway signalling, anti-apoptotic BCL2 and epigenetic regulators. Molecular subtypes are based on the neurogenic transcription factors achaete-scute homologue 1 (ASCL1) and neurogenic differentiation factor 1 (NEUROD1), the rarer non-neuroendocrine transcription factor POU class 2 homeobox 3 (POU2F3), and immune- and inflammation-related signatures. Furthermore, SCLC shows phenotypic plasticity, including neuroendocrine-to-non-neuroendocrine transition driven by NOTCH signalling, which is associated with disease progression, chemoresistance and immune modulation and, in mouse models, with metastasis. Although these features pose substantial challenges, understanding the molecular vulnerabilities of transcription factor subtypes, the functional relevance of plasticity and cell cooperation offer opportunities for personalized therapies informed by liquid and tissue biomarkers.

PMID: 40211072

20. Nat Med. 2025 Apr 10. doi: 10.1038/s41591-025-03638-2. Online ahead of print.

Sacituzumab tirumotecan in advanced non-small-cell lung cancer with or without EGFR mutations: phase 1/2 and phase 2 trials.

Zhao S(#)(1), Cheng Y(#)(2), Wang Q(#)(3)(4), Li X(#)(5), Liao J(#)(1), Rodon J(#)(6)

Trophoblast cell-surface antigen 2 (TROP2)-directed antibody-drug conjugate (ADC) is a promising anticancer agent that has shown remarkable efficacy in several malignancies. However, in lung cancer, two phase 3 trials on TROP2-ADCs in unselected patients with advanced non-small-cell lung cancer (NSCLC) have both failed. Sacituzumab tirumotecan (sac-TMT) is a novel TROP2-directed ADC. Here we report the efficacy and safety of sac-TMT in previously treated, advanced NSCLC with or without activating EGFR mutations from the phase 1/2 KL264-01 and phase 2 SKB264-II-08 studies. Primary endpoint was objective response rate (ORR). KL264-01 enrolled EGFR-wild-type and EGFR-mutant NSCLC (n = 43). Confirmed ORR was 40% (17 of 43; 95% confidence interval (CI), 25-56). Median progression-free survival (PFS) was 6.2 months (95% CI, 5.3-11.3). Post-hoc subgroup analyses found better outcomes in the EGFR-mutant subset (22 of 43, 51%) with a confirmed ORR of 55% (12 of 22) and median PFS of 11.1 months. These findings were independently supported by results from SKB264-II-08, where sac-TMT led to confirmed ORR of 34% (22 of 64; 95% CI, 23-47) and median PFS of 9.3 months (95% CI, 7.6-11.4) in 64 patients with EGFR-mutant NSCLC. For a total of 107 patients receiving sac-TMT, the most common treatment-related adverse events were hematologic toxicities. Diarrhea (4%) and interstitial lung disease (1%) were uncommon. Exploration of potential mechanisms revealed that the presence of EGFR mutation substantially increased the internalization and activity of sac-TMT in vitro. Overall, sac-TMT showed encouraging single-agent activity and manageable tolerability in previously treated, advanced NSCLC with EGFR mutations. Randomized phase 3 trials in treatment-naive and previously treated patients with EGFR-mutant NSCLC are ongoing. ClinicalTrials.gov Identifiers: NCT04152499, NCT05631262 .

PMID: 40210967

21. Cancer Commun (Lond). 2025 Apr;45(4):442-455. doi: 10.1002/cac2.12654. Epub 2025 Jan 10.

Efficacy and safety of first-line sintilimab plus anlotinib versus chemotherapy for metastatic non-small cell lung cancer: a phase II, open-label, randomized controlled trial.

Chu T(1), Zhong H(1), Yu Z(2), Wang J(2), Zhao Y(3), Mu X(3), Yu X(4), Shi X(4)

BACKGROUND: The prognosis for non-small cell lung cancer (NSCLC) patients treated with standard platinum-based chemotherapy was suboptimal, with safety concerns. Following encouraging results from a preliminary phase I study, this phase II trial investigated the efficacy and safety of first-line sintilimab and anlotinib in metastatic NSCLC.

METHODS: In this open-label, randomized controlled trial (NCT04124731), metastatic NSCLC without epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or proto-oncogene tyrosine-protein kinase ROS (ROS1) mutations, and previous treatments for metastatic disease were enrolled. Participants were randomly assigned in a 1:1 ratio to either sintilimab (200 mg every 3 weeks) plus anlotinib (12 mg D1-14 every 3 weeks) or a standard platinum-based chemotherapy regimen. Patients in the chemotherapy group were permitted to switch to sintilimab after disease progression. The primary endpoint was the objective response rate (ORR).

RESULTS: From November 2019 to March 2023, 99 patients were randomized into the sintilimab plus anlotinib group (n = 49) and the chemotherapy group (n = 50). The ORR was significantly higher in the sintilimab plus anlotinib group (44.9%; 95% confidence interval [CI] = 30.7%-59.8%) compared to the chemotherapy group (18.0%; 95% CI = 8.6%-31.4%, P = 0.003). Progression-free survival (PFS) was also notably longer (median: 14.4 vs. 5.6 months; hazard ratio [HR] = 0.39; 95% CI = 0.23-0.67; P < 0.001). The 24-month overall survival rate was 58.4% (95% CI = 40.4%-72.6%) and 43.2% (95% CI = 26.0%-59.2%), respectively. The rate of grade 3 or higher treatment-related adverse events was lower in the sintilimab plus anlotinib group (28.0%) than in the chemotherapy group (49.0%), especially for the hematological toxicities.

CONCLUSION: First-line sintilimab plus anlotinib showed improved ORR and PFS, alongside a superior safety profile, compared to the standard platinum-based chemotherapy for metastatic NSCLC patients.

PMID: 39791315 [Indexed for MEDLINE]

22. Nature. 2025 Apr 16. doi: 10.1038/s41586-025-08834-1. Online ahead of print.

An ultrasensitive method for detection of cell-free RNA.

Nesselbush MC(#)(1)(2)(3), Luca BA(#)(4), Jeon YJ(#)(5), Jabara I(1)(2)(6)

Sensitive methods for detection of cell-free RNA (cfRNA) could facilitate non-invasive gene expression profiling and monitoring of diseases1-6. Here we describe RARE-seq (random priming and affinity capture of cfRNA fragments for enrichment analysis by sequencing), a method optimized for cfRNA analysis. We demonstrate that platelet contamination can substantially confound cfRNA analyses and develop an approach to overcome it. In analytical validations, we find RARE-seq to be approximately 50-fold more sensitive for detecting tumour-derived cfRNA than whole-transcriptome RNA sequencing (RNA-seq), with a limit of detection of 0.05%. To explore clinical utility, we profiled 437 plasma samples from 369 individuals with cancer or non-malignant conditions and controls. Detection of non-small-cell lung cancer expression signatures in cfRNA increased with stage (6 out of 20 (30%) in stage I; 5 out of 8 (63%) in stage II; 10 out of 15 (67%) in stage III; 80 out of 96 (83% sensitivity) in stage IV at 95% specificity) and RARE-seq was more sensitive than tumour-naive circulating tumour DNA (ctDNA) analysis. In patients with EGFR-mutant non-small-cell lung cancer who developed resistance to tyrosine kinase inhibitors, we detected both histological transformation and mutation-based resistance mechanisms. Finally, we demonstrate the potential utility of RARE-seq for determination of tissue of origin, assessing benign pulmonary conditions and tracking response to mRNA vaccines. These results highlight the potential value of ultrasensitive cfRNA analysis and provide proof of concept for diverse clinical applications.

PMID: 40240612

23. Ann Intern Med. 2025 Apr;178(4):479-489. doi: 10.7326/ANNALS-24-00870. Epub 2025 Feb 7.

Effectiveness and Cost-Effectiveness of Expanded Targeted Testing and Treatment of Latent Tuberculosis Infection Among the Medicare Population in 2022.

Li Y(1), Marks SM(2), Beeler Asay GR(2), Winston CA(2), Pepin D(3), McClure S(2)

BACKGROUND: In the United States, older adults have elevated prevalence of latent tuberculosis infection (LTBI) and incidence of tuberculosis (TB).

OBJECTIVE: To estimate the health benefits and cost-effectiveness of LTBI testing and treatment among the Medicare-eligible population.

DESIGN: Model-based cost-effectiveness analysis.

DATA SOURCES: Nationally representative surveys and published evidence.

TARGET POPULATION: Medicare-eligible persons aged 65 years or older with at least 1 of 15 factors associated with elevated TB risk, as identified by guidelines from the U.S. Preventive Services Task Force (USPSTF) and other organizations.

TIME HORIZON: Lifetime.

PERSPECTIVE: Societal.

INTERVENTION: One-time offer of LTBI testing and treatment versus no intervention.

OUTCOME MEASURES: Lifetime TB cases and deaths averted, quality-adjusted life-years (QALYs) gained, costs, and incremental cost-effectiveness ratios (ICERs).

RESULTS OF BASE-CASE ANALYSIS: In 2022, there were an estimated 29.9 million Medicare-eligible persons (95% uncertainty interval [UI], 28.4 to 31.6 million persons) aged 65 years or older with elevated TB risks, including 14.7 million (95% UI, 13.4 to 16.0 million) with USPSTF-recommended factors. In the target population, 4.9 million persons (95% UI, 4.0 to 5.8 million persons) (16.4% [95% UI, 13.9% to 19.1%]) were estimated to have LTBI. Testing and treatment of LTBI was estimated to prevent 10 946 TB cases (95% UI, 4684 to 20 579 cases) and 2579 TB deaths (95% UI, 1106 to 4882 deaths), with 13 234 lifetime QALYs (95% UI, 5343 to 25 519 lifetime QALYs) gained. For the overall target population and for persons with USPSTF-recommended factors, ICERs were $192 000 (95% UI, $92 000 to $503 000) and $155 000 (95% UI, $77 000 to $393 000) per QALY gained, respectively.

RESULTS OF SENSITIVITY ANALYSIS: The ICER was $109 000 (95% UI, $49 000 to $285 000) per QALY gained for 65-year-olds newly eligible for Medicare.

LIMITATION: Health benefits from averted post-TB sequelae were not estimated.

CONCLUSION: Medicare-eligible persons represent approximately one third of all U.S. persons with LTBI. Testing and treatment of LTBI in this population could lead to substantial reductions in TB and TB-related mortality, particularly among 65-year-olds newly eligible for Medicare.

PRIMARY FUNDING SOURCE: Centers for Disease Control and Prevention.

PMID: 39918348 [Indexed for MEDLINE]

24. J Clin Oncol. 2025 Apr;43(10):e2-e16. doi: 10.1200/JCO-24-02785. Epub 2025 Feb 27.

Therapy for Stage IV Non-Small Cell Lung Cancer With Driver Alterations: ASCO Living Guideline, Version 2024.3.

Owen DH(1), Ismaila N(2), Ahluwalia A(3), Feldman J(4), Gadgeel S(5), Mullane M(6)

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and 2). Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline.

PMID: 40014839 [Indexed for MEDLINE]

25. J Clin Oncol. 2025 Apr;43(10):e17-e30. doi: 10.1200/JCO-24-02786. Epub 2025 Feb 27.

Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2024.3.

Leighl NB(1), Ismaila N(2), Durm G(3), Florez N(4), Freeman-Daily J(5), Pellini B(6)

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and 2). Updates are published regularly and can be found at https://ascopubs.org/nsclc-non-da-living-guideline.

PMID: 40014838 [Indexed for MEDLINE]

26. J Clin Oncol. 2025 Apr 16: JCO2402007. doi: 10.1200/JCO-24-02007. Online ahead of print.

Pragmatic Randomized Study of Afatinib Versus Chemotherapy for Patients With Non-Small Cell Lung Cancer With Uncommon Epidermal Growth Factor Receptor Mutations: ACHILLES/TORG1834.

Miura S(1), Tanaka H(1), Misumi T(2), Yoshioka H(3), Tokito T(4), Fukuhara T(5)

PURPOSE: To our knowledge, the ACHILLES/TORG1834 trial is the first randomized study comparing afatinib and chemotherapy in patients with non-small cell lung cancer (NSCLC) harboring sensitizing uncommon epidermal growth factor receptor (EGFR) mutations.

METHODS: This randomized, open-label study was performed at 51 Japanese institutions and recruited treatment-naïve patients with nonsquamous NSCLC with uncommon EGFR mutations, excluding exon 20 insertions and T790M mutations. Patients were randomly assigned 2:1 to receive afatinib (30 or 40 mg orally, at the treating physician's discretion) or a combination of platinum (cisplatin or carboplatin) andpemetrexed, followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). Secondary end points included objective response rate (ORR), overall survival, and safety. A prespecified interim analysis was planned to provide clinically meaningful information promptly, along with a crossover recommendation if necessary.

RESULTS: A total of 109 patients were enrolled between March 2019 and February 2023. In the interim analysis, the Data and Safety Monitoring Committee recommended early study termination. The median PFS was significantly longer in patients receiving afatinib than in those undergoing chemotherapy (10.6 v 5.7 months; hazard ratio, 0.421 [95% CI, 0.251 to 0.706]; P = .0010). ORRs to afatinib were similar across the overall population and among participants with major uncommon (G719X, L861Q, and S768I), compound, and other mutations (61.7%, 55.8%, 72.7%, and 60.0%, respectively). The most common grade 3 or higher adverse events were diarrhea, paronychia, and rash for afatinib, and appetite loss and nausea for chemotherapy.

CONCLUSION: Afatinib should be considered the standard initial therapy for patients with NSCLC with sensitizing uncommon EGFR mutations.

PMID: 40239133

27. J Thorac Oncol. 2025 Apr 19: S1556-0864(25)00693-8. doi: 10.1016/j.jtho.2025.04.003. Online ahead of print.

Surveillance with [(18)F]FDG PET/CT of stage I-III lung cancer patients after completion of curative treatment (SUPE_R): a randomized controlled trial.

Guldbrandsen KF(1), Bloch M(2), Skougaard K(3), Ahlborn LB(4), Jakobsen E(5)

INTRODUCTION: Post-treatment surveillance is recommended for non-small cell lung cancer (NSCLC) due to a high risk of recurrence, but evidence on the optimal surveillance method is lacking. This trial evaluates fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) versus contrast-enhanced CT (ceCT) for surveillance in NSCLC patients.

METHODS: In this multicenter, randomized controlled trial (SUPE_R, ClinicalTrials.gov NCT03740126), patients with stage IA-IIIC NSCLC were randomized 1:1 to standard surveillance (ceCT) or surveillance with [18F]FDG PET/CT after completion of curative treatment. The primary outcome was the proportion of recurrences treated with curative intent. Secondary outcomes included time to recurrence (TTR) and overall survival (OS).

RESULTS: Between February 2019 and February 2022, 750 patients were randomized to PET/CT (n=373) or CT (n=377). Recurrences occurred in 164 patients (22%). The proportion of recurrences treated with curative intent was identical between the PET group (42 of 87) and CT group (37 of 77), both 48% (p=0.98). More recurrences were detected through scheduled follow-up in the PET group (90%) compared to the CT group (77%; p = 0.02). There were no significant differences in TTR (HR 1.12, 95% CI 0.82 - 1.52, p = 0.48) or OS (HR 0.97, 95% CI 0.66 - 1.43, p = 0.89) between groups.

CONCLUSIONS: Surveillance with [18F]FDG PET/CT did not improve rates of curatively treated recurrences, TTR, or OS compared to ceCT in NSCLC patients after curative treatment. These findings do not support the routine use of [18F]FDG PET/CT for post-treatment surveillance in this patient population.

PMID: 40258572

28. Ann Oncol. 2025 Apr;36(4):460-468. doi: 10.1016/j.annonc.2025.01.014. Epub 2025 Mar 12.

European cancer mortality predictions for the year 2025 with focus on breast cancer.

Santucci C(1), Mignozzi S(1), Levi F(2), Malvezzi M(3), Boffetta P(4), Negri E(5)

BACKGROUND: We predicted the number of cancer deaths and rates for 2025 in the European Union (EU), its five most populous countries, and the UK, focusing on breast cancer.

MATERIALS AND METHODS: We derived population data and death certificates forall cancers and major sites for the EU, France, Germany, Italy, Poland, Spain, and the UK since 1970, from the World Health Organization and United Nations databases. Estimates for 2025 were computed by linear regression on recent trends identified through Poisson joinpoint regression, considering the slope of the most recent trend segment. Deaths averted from 1989 to 2025 were calculated by applying the 1988 peak rate to subsequent population data.

RESULTS: We estimated 1 280 000 cancer deaths in the EU in 2025, corresponding to age-standardised rates (ASRs) of 120.9/100 000 males (-3.5% versus 2020) and 79.1/100 000 females (-1.2%). In the UK, we predicted 173 000 cancer deaths and ASRs of 101.2/100 000 males (-10.1%) and 82.1/100 000 females (-6.3%). In the EU, favourable trends are predicted for major neoplasms, except pancreatic cancer, in males (+2.0%) and females (+3.0%), and lung (+3.8%) and bladder (+1.9%) cancers among females. Breast cancer mortality showed favourable trends in all countries. Substantial decreases were predicted for EU females aged 50-69 years (-9.8%) and 70-79 years (-12.4%). Between 1989 and 2025, we estimated about 6.8 million averted cancer deaths in the EU, including over 373 000 breast cancer deaths. Corresponding numbers for the UK were 1 500 000 and 197 000.

CONCLUSION: EU breast cancer rates have fallen by 30% since 1990, due to advances in prevention, treatment, and early detection. Contrasting trends in lung cancer among males and females reflect differing tobacco smoking patterns. Female lung cancer mortality is still increasing in the EU, though less than in the previous decade. Persistent unfavourable pancreatic cancer trends can be related to the increasing prevalence of obesity and limited therapeutic advances, requiring continued attention.

PMID: 40074664 [Indexed for MEDLINE]

29. Annu Rev Immunol. 2025 Apr;43(1):423-450. doi: 10.1146/annurev-immunol-082323-120757. Epub 2025 Feb 27.

Macrophage Differentiation and Metabolic Adaptation in Mycobacterial Infections.

Lösslein AK(1)(2), Henneke P(1)(2)(3).

The adaptation of macrophages-the most common tissue-resident immune cells-to metabolic and microbial cues with high local variability is essential for the maintenance of organ integrity. In homeostasis, macrophages show largely predictable tissue-specific differentiation, as recently revealed by multidimensional methods. However, chronic infections with human-adapted pathogens substantially contribute to the differentiation complexity of tissue macrophages, which has been only partially resolved. Specifically, the response to mycobacterial species-which range from Mycobacterium tuberculosis (with highest specificity for humans, broad organ tropism, yet tissue-specific disease phenotypes) to environmental mycobacteria with humans as accidental hosts-may serve as a paradigm of tissue macrophage adaptation mechanisms. While mycobacterial species-specific tissue preferences are partially related to the mode of acquisition and pathogen characteristics, evolutionary convergence with macrophages driven by metabolic features of the target organ likely contributes to infection resistance and immunopathology. In this review, we unravel the mechanisms of tissue-specific macrophage differentiation and its limitations in mycobacterial infections.

PMID: 40014665 [Indexed for MEDLINE]