bims-meluca 2025-09-14 papers

Cancers (Basel). 2025 Aug 25. pii: 2765. [Epub ahead of print]17(17):

The Impact of Body Composition on Outcomes in NSCLC Patients Treated with Immune Checkpoint Inhibitors: A Systematic Review.

Carina Golban, Septimiu-Radu Susa, Norberth-Istvan Varga, Cristiana-Smaranda Ivan, Patricia Ortansa Schirta, Nicolae Călin Schirta, Alina Gabriela Negru, Sorin Saftescu, Serban Mircea Negru.

Background/Objectives: Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis have become a standard in the treatment of all stages of non-small lung cancer. Beyond tumor-intrinsic biomarkers like PD-L1 expression, evidence points to the role of patient-related factors, such as body mass index, sarcopenia, and cachexia. These body composition parameters may reflect metabolic reserve or even immune competence and could help stratify outcomes in patients treated with PD-1 and PD-L1. This systematic review aims to evaluate the impact of body composition-specifically BMI, pretreatment weight loss, sarcopenia, and cachexia-on clinical outcomes such as progression-free and overall survival in NSCLC patients treated with immune checkpoint inhibitors. Methods: A systematic literature search was conducted across multiple databases including PubMed, Google Scholar, and Science Direct. We included full-text original research articles (1 January 2020-1 May 2025) reporting clinical outcomes of NSCLC patients treated with PD-1 or PD-L1 inhibitors, in relation to body composition factors (BMI, pretreatment weight loss, sarcopenia, cachexia). Eligible studies involved adults (>18 years) and included observational cohorts or controlled trials; animal or in vitro studies were excluded. Data extraction and risk of bias assessments were performed independently by two reviewers, with discrepancies being resolved through a third one. Results: From 12,358 records identified, 21 studies met the inclusion criteria. Most were retrospective cohorts assessing the impact of pre-treatment weight loss, cachexia, and sarcopenia on ICI outcomes in NSCLC. These factors consistently predicted poorer survival and response, while BMI alone showed limited prognostic value. Considerable heterogeneity in body composition definitions and outcome reporting was observed. Conclusions: Body composition-particularly weight loss, cachexia, and sarcopenia-significantly impacts survival and response in NSCLC patients treated with ICIs. These factors reflect immune-metabolic dysfunction that may impair treatment efficacy. BMI alone is insufficient; routine assessment of muscle mass and cachexia could improve risk stratification.

Keywords: BMI; NSCLC; PD-1; PD-L1; body composition; cachexia; immune checkpoint; non-small cell lung cancer; progression-free survival; sarcopenia

DOI: https://doi.org/10.3390/cancers17172765

J Cachexia Sarcopenia Muscle. 2025 Oct;16(5): e70063

Loss of Skeletal Muscle Mass Is Associated With Reduced Cytotoxic T Cell Abundance and Poor Survival in Advanced Lung Cancer.

Xin Nie, Yan Sun, David P J van Dijk, Min Deng, Ralph Brecheisen, Zhaoqi Wang, Qingxin Xia, Steven M W Olde Damink, Sander S Rensen.

BACKGROUND: Body composition alterations such as skeletal muscle (SM) loss in cancer patients are associated with poor survival. In turn, immune cell-driven pathways have been linked to muscle wasting. We aimed to investigate the relationship between body composition, tumour-infiltrating lymphocytes and survival in patients with advanced lung cancer.
METHODS: We studied 200 patients with advanced lung cancer receiving immunotherapy (n = 81) or non-immunotherapy regimens (n = 119). Body composition including SM index (SMI) at baseline and longitudinal changes were assessed using computed tomography (CT) scans at the third lumbar vertebra. Associations between body composition parameters and overall survival (OS) were evaluated using Cox regression analysis. The median value of SMI, stratified by sex, was used as the cut-off to define groups with high and low baseline SMI. Stable SMI was defined by any increase or < 2% decrease per 100 days; loss of SMI was defined by ≥ 2% decrease per 100 days. Logistic regression analysis was applied to investigate the association between SMI and peripheral circulating immune cells. Tumour-infiltrating lymphocytes were identified by immunohistochemistry, and their relationship with SMI was evaluated.
RESULTS: SMI loss was associated with shorter OS (whole cohort: HR = 2.314, 95% CI = 1.388-3.858, p = 0.001; immunotherapy cohort: HR = 3.028, 95% CI = 1.113-8.236, p = 0.03; non-immunotherapy cohort: HR = 2.298, 95% CI = 1.191-4.435, p = 0.013). Low baseline SMI was associated with higher CD3+ T cell abundance (OR = 1.240, 95% CI = 1.080-1.424, p = 0.002) but lower CD3+ CD8+ T cell abundance (OR = 0.862, 95% CI = 0.762-0.974, p = 0.018) in peripheral blood. Subsequent SMI loss during treatment was also significantly associated with higher CD3+ T cell counts (OR = 3.414, 95% CI = 1.301-8.961, p = 0.013) and lower CD3+ CD8+ T cell abundance (OR = 0.666, 95% CI = 0.459-0.968, p = 0.033). Patients with stable SMI had a higher number of CD8+ tumour-infiltrating lymphocytes than patients with SMI loss (15.4% vs. 7.9%, p = 0.036).
CONCLUSION: SM loss is an independent predictor for survival in patients with advanced lung cancer and is associated with reduced peripheral and tumour-infiltrating cytotoxic T cell abundance. An inadequate antitumour immune response may contribute to metabolic tissue wasting in cancer.

Keywords: TILs; cytotoxic T cell; lung cancer; skeletal muscle mass; survival

DOI: https://doi.org/10.1002/jcsm.70063

Int J Mol Sci. 2025 Aug 25. pii: 8231. [Epub ahead of print]26(17):

Metabolic Signatures in Lung Cancer: Prognostic Value of Acid-Base Disruptions and Serum Indices.

Florian Ponholzer, Marie-Christin Neuschmid, Helga Komi, Christina Bogensperger, Caecilia Ng, Herbert Maier, Paolo Lucciarini, Stefan Schneeberger, Florian Augustin.

One characteristic of tumor cells is the increased anaerobic metabolism through glycolysis leading to an acidic environment of the tumor. This acidity is linked to tumor progression, invasion and metastasis, besides stimulated survival pathways in the malignant cells. The aim of our analysis is to investigate the role of systemic acid-base parameters such as the pH, bicarbonate, baseexcess and lactate in lung cancer patients. Furthermore, alterations in electrolytes and hemoglobin were investigated regarding their impact on overall survival. Data of 937 non-small-cell lung cancer (NSCLC) patients, who underwent anatomic video-assisted thoracoscopic surgery (VATS) resection, was collected in a prospectively maintained database and analyzed. To minimize confounding effects and due to the retrospective study design, we decided to use data from the first arterial blood gas analysis during surgery and the most recent lab results prior to surgery. We found significant correlations between low systemic bicarbonate (<20 mEq/L) and overall survival (p = 0.006). Hyponatremia (<135 mmol/L) correlated with lower 5-year overall survival (p = 0.004) and decreased disease-free survival (p = 0.017). Hypochloremia (<98 mmol/L) was linked to reduced overall survival (p = 0.003) and hypocalcemia (<1.15 mmol/L) with worse disease-free survival (p = 0.015). Hemoglobin under 12 g/dL for women and 13 g/dL for men was associated with poorer outcomes (p < 0.001). Other acid-base parameters such as the pH (p = 0.563), baseexcess (BE) (p = 0.290) and lactate (p = 0.527) did not show significant differences in overall or disease-free (pH: p = 0.130; BE: p = 0.148; lactate: p = 0.418) survival. Systemic bicarbonate, sodium, calcium, chloride and hemoglobin levels were found as prognostic markers and possible therapeutic targets to improve overall survival. Further investigations are necessary to develop therapeutic strategies.

Keywords: NSCLC; VATS; acid–base homeostasis; bicarbonate; electrolyte disruptions; hypocalcemia; hypochloremia; hyponatremia; lung cancer; lung tumor; pH; surgical oncology

DOI: https://doi.org/10.3390/ijms26178231

Cell Rep. 2025 Sep 09. pii: S2211-1247(25)01049-6. [Epub ahead of print]44(9): 116278

Early adipose tissue wasting in a preclinical model of human lung cancer cachexia.

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between preclinical models and human CC. To address the need for clinically relevant models of lung CC, we generated inducible, lung epithelial cell-specific KrasG12D/+ (G12D) mice. G12D mice develop CC over a protracted time course and phenocopy tissue and tumor, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. G12D mice demonstrate early loss of adipose, a phenotype that was apparent across numerous models of CC and translates to patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in CC, and adipose wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and highlight a role for early tumor metabolic reprogramming of adipose tissue in CC.

Keywords: CP: Cancer; CP: Metabolism; inflammation; lipolysis; lung neoplasms; organoids; skeletal muscle

DOI: https://doi.org/10.1016/j.celrep.2025.116278

Cancer Treat Res Commun. 2025 Sep 02. pii: S2468-2942(25)00129-7. [Epub ahead of print]45 100993

Clinical and molecular characteristics of 42 Danish patients with metastatic ALK fusion-positive lung cancer treated with first-line alectinib: A nationwide study.

Maiken Parm Ulhøi, Emma Roger Andersen, Christoffer Trier Maansson, Lars Munch Larsen, Miroslaw Stelmach, Jon Lykkegaard Andersen, Karin Holmskov Hansen, Tine McCulloch, Bo Sorensen, Peter Meldgaard.

PURPOSE: We investigated whether EML4-ALK fusions and mutations in pre-treatment plasma ctDNA predicted time to treatment discontinuation (TTD) in ALK-positive non-small cell lung cancer (ALK+ NSCLC) patients initiating first-line alectinib and evaluated clinical characteristics influencing TTD.
MATERIALS & METHODS: 42 patients from five Danish public oncology departments with previously untreated, metastatic ALK+ NSCLC were included in the study. All patients received alectinib, a second-generation ALK inhibitor, as their first-line treatment. Clinical characteristics were obtained from the patients' health records. Plasma samples were collected before treatment start and analyzed with next-generation sequencing (NGS) analysis with the AVENIO ctDNA Surveillance kit.
RESULTS: We demonstrate that alectinib is effective regardless of baseline brain metastases, EML4-ALK variant type and co-mutations. The entire cohort had a median TTD for alectinib of 35.1 months (95% CI: 10.2-52). TTD for patients with baseline brain metastasis (BM) had a median of 34.4 months (95% CI:4.1- "not estimated" (NE)), whereas patients with no BM at baseline had a median of 16.9 months (95% CI: 4.6-NE). Additionally, 57% of the cohort were smokers, and the median TTD was shorter in smokers (11.2 months) than in never-smokers (52.0 months).
CONCLUSION: In incurable ALK+ NSCLC, alectinib appears effective as first-line therapy regardless of brain metastases. EML4-ALK fusions occur in smokers, and smoking may reduce TTD. These findings, limited by the small cohort, require confirmation in larger studies but may still help guide treatment predictions and strategies.

Keywords: Brain metastasis; EML4-ALK, ALK+ NSCLC; Non-small cell lung cancer; Smoking; ctDNA

DOI: https://doi.org/10.1016/j.ctarc.2025.100993