bims-meluca 2025-05-25 papers

Thorac Cancer. 2025 May;16(10): e70089

Desensitizing Effect of Intra-Tumoral GDF-15 on Immunotherapy in Patients With Advanced Non-Small Cell Lung Cancer.

Naoya Nishioka, Tateaki Naito, Takashi Sugino, Koji Muramatsu, Shigeki Nishihara, Hiroki Urashima, Nobuaki Mamesaya, Haruki Kobayashi, Shota Omori, Ryo Ko, Kazushige Wakuda, Akira Ono, Hirotsugu Kenmotsu, Haruyasu Murakami, Toshiaki Takahashi.

BACKGROUND: Serum growth/differentiation factor 15 (GDF-15) suppresses anti-tumor immunity and predicts prognosis in several malignancies. Elevated GDF-15 levels are linked to cancer cachexia, characterized by weight loss and systemic inflammation, adversely affecting patient outcomes and therapy response. However, serum GDF-15 is not always derived from tumor tissues but also from multiple organs. Therefore, we evaluated whether intra-tumoral GDF-15 could be used as a biomarker for immunotherapy and its potential association with cancer cachexia.
METHOD: We retrospectively evaluated patients with advanced non-small cell lung cancer (NSCLC) who underwent treatment with programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors at the Shizuoka Cancer Center between 2017 and 2021. Patients with histologically confirmed NSCLC (stage III-IV or postoperative recurrence) who had undergone biopsy or surgery within 6 months prior to initiating immunotherapy were included. Expression of tumor-derived GDF-15 was evaluated using immunohistochemical staining of archival biopsy and surgical specimens. We analyzed the correlation between intra-tumoral GDF-15 expression and the incidence of cancer cachexia, as well as its impact on progression-free survival (PFS) and overall survival (OS).
RESULT: In 6 of 35 cases, tumor cells highly expressed GDF-15. Patients with high intra-tumoral GDF-15 expression had a higher incidence of cancer cachexia (100% vs. 41.4%, p < 0.05), shorter PFS (3.4 vs. 13.4 months, p < 0.05), and shorter OS (9.5 vs. 26.5 months, p < 0.05) than those with low intra-tumoral GDF-15 expression.
CONCLUSION: Intra-tumoral GDF-15 expression may predict the presence of cancer cachexia and the efficacy of PD-1/PD-L1 inhibitors in patients with advanced non-small cell lung cancer.

Keywords: GDF‐15; PD‐1/PD‐L1 inhibitors; cachexia; non‐small cell lung cancer; survival

DOI: https://doi.org/10.1111/1759-7714.70089

Transl Lung Cancer Res. 2025 Apr 30. 14(4): 1242-1253

Metabolic tumor volume on 18F-FDG uptake as a negative predictor after ipilimumab plus nivolumab in advanced non-small cell lung cancer.

Kosuke Hashimoto, Kyoichi Kaira, Atsuto Mouri, Ayako Shiono, Yu Miura, Ou Yamaguchi, Hisao Imai, Hiroshi Kagamu, Ichiei Kuji.

Background: Nivolumab plus ipilimumab (Nivo-Ipi) is a standard treatments for metastatic or recurrent non-small cell lung cancer (NSCLC). Unlike programmed death-1 (PD-1) inhibitor monotherapy, the possible predictors of Nivo-Ipi treatment effectiveness remain unclear. Therefore, this retrospective study evaluated the prognostic relevance of 2-deoxy-2-[fluorine-18]-fluoro-d-glucose positron emission tomography (18F-FDG PET) after Nivo-Ipi treatment in patients with advanced NSCLC.
Methods: Among 130 eligible patients with metastatic or recurrent NSCLC who received Nivo-Ipi as initial treatment and underwent 18F-FDG PET prior to the initial treatment, the maximum standardized uptake value (SUVmax), SUVpeak, metabolic tumor volume (MTV), and total lesion glycolysis (TLG) on 18F-FDG uptake were evaluated.
Results: High MTV and TLG on 18F-FDG uptake were significantly associated with poor performance status (PS), no response, high neutrophil-to-leukocyte ratio (NLR), low albumin levels, and high C-reactive protein (CRP) level, while SUVmax and SUVpeak showed no significant associations. Univariate analysis of all patients identified PS, bone metastases, NLR, MTV, and TLG as significant predictors of prognosis. By multivariate analysis, NLR and MTV were identified as independent predictors of prognosis. Sub-analysis based on histology and programmed death ligand-1 (PD-L1) expression identified MTV as an independent prognostic predictor for Nivo-Ipi treatment in patients with histological findings of adenocarcinoma (AC) and PD-L1 <1%. A high MTV with poor outcome was closely associated with a poor PS, lymph node metastases, bone metastases, high NLR, low albumin levels, and high CRP level.
Conclusions: MTV determined based on 18F-FDG uptake was a negative prognostic factor after Nivo-Ipi treatment, particularly in patients with histological findings of AC or PD-L1 <1%.

Keywords: 2-deoxy-2-[fluorine-18]-fluoro-d-glucose positron emission tomography (18F-FDG PET); Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4); metabolic tumor activity; non-small cell lung cancer (NSCLC); programmed death-1 (PD-1)

DOI: https://doi.org/10.21037/tlcr-2024-1084

Cancer Sci. 2025 May 20.

The Pro-Apoptotic Effect of Glucose Restriction in NSCLC via AMPK-Regulated Circadian Clock Gene Bmal1.

Tao Wei, Ying Cheng, Jierong Ge, Manting Zhu, Hong Chen, Qing Feng.

The circadian clock is a crucial regulator of mammalian physiology, controlling daily oscillations in key biological processes, such as cell proliferation, apoptosis, and DNA damage repair. Disruption of circadian rhythms has been identified as a significant risk factor for cancer development and progression, yet the specific molecular mechanisms linking circadian dysfunction to cancer remain poorly understood. Recent studies have increasingly focused on the role of diet in modulating circadian rhythms, highlighting the potential for dietary interventions in cancer management. However, how dietary factors like glucose restriction interact with circadian rhythms to influence cancer cell behavior remains an open question. Here, we investigate the mechanisms underlying glucose restriction-induced apoptosis in non-small cell lung cancer (NSCLC) cells, with a focus on the role of circadian clock genes. Analysis of the GEPIA database revealed that the circadian gene Bmal1 is highly expressed in normal tissues and associated with better prognosis in lung adenocarcinoma patients. In NSCLC cells, Bmal1 expression correlated with proapoptotic gene activity. In a tumor xenograft model using severe combined immunodeficiency (SCID) mice, a glucose-restricted (ketogenic) diet significantly delayed tumor growth and increased the expression of Bmal1 and proapoptotic genes. These findings suggest that glucose restriction promotes apoptosis in NSCLC cells through a Bmal1-mediated pathway, providing novel insights into the intersection between circadian regulation and cancer biology. Targeting core circadian clock genes like Bmal1 may represent a promising therapeutic strategy for managing lung cancer, broadening our understanding of how circadian rhythms can be harnessed for cancer prevention and treatment.

Keywords: AMPK; Bmal1; NSCLC; apoptosis; glucose restriction

DOI: https://doi.org/10.1111/cas.70098

Transl Cancer Res. 2025 Apr 30. 14(4): 2381-2394

Elevated levels of total cholesterol and high-density lipoprotein cholesterol are associated with better prognosis in patients with lung adenocarcinoma: a retrospective cohort study.

Zhupeng Li, Jianfeng Xu, Jiacheng Wu, Junqing Zhou, Haiyong Wang, Haixia Xu, Bin Wang, Jianyi Ding, Guangmao Yu, Peng Xu.

Background: As is well known, lipids play an important role in cellular metabolism and storage, and they have a significant impact on signal transduction during the growth and metastasis of cancer cells. Our study aimed to evaluate the role of the preoperative plasma lipid profile, including triglycerides (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in prognosis, and to develop nomograms to predict overall survival (OS) and disease-free survival (DFS) based on the preoperative plasma lipid profile for patients with lung adenocarcinoma (LUAD) after complete resection.
Methods: Clinical data, including preoperative plasma profile levels, were retrospectively collected and reviewed in 304 patients with LUAD who underwent radical lung resection between 2016-2017. Approval of the study protocol was obtained from the Academic Ethics Committee of Shaoxing People's Hospital, and follow-up on all patients was completed in the clinic or by telephone. The OS and DFS were assessed by the Kaplan-Meier method and the Cox proportional hazards regression model. Clinicopathological factors and preoperative plasma lipid profile factors were integrated to construct nomograms. Calibration plots and concordance indexes (C-indexes) were used to evaluate the accuracy and discrimination of the models.
Results: TC level was significantly related to the sex of the patient (P=0.001), history of smoking (P=0.04), and death (P=0.007), and the HDL-C level was significantly associated with sex (P=0.004), history of smoking (P=0.02), tumor recurrence (P=0.050), and death (P=0.002). TC ≤3.58 and HDL-C ≤1.01 were deemed as independent preoperative risk factors for OS, and HDL-C ≤1.01 was an independent preoperative risk factor for DFS. In the multivariate analyses involving OS and DFS, an increased TC level [hazard ratio (HR), 0.504; 95% confidence interval (CI): 0.324-0.782, P=0.002] was significantly associated with better OS. Additionally, a decreased HDL-C level was significantly associated with worse OS (HR, 0.665; 95% CI: 0.443-0.999, P=0.049) and DFS (HR, 0.619; 95% CI: 0.420-0.912, P=0.02). Preoperative plasma lipid profile factors were involved in constructing the nomograms for predicting 1-, 3-, and 5-year OS and DFS. The C-index of the final nomograms was higher than that of the tumor node metastasis (TNM) staging system for predicting OS (0.735 vs. 0.689; P=0.009). The performance of the nomograms for predicting OS (0.699 vs. 0.735; P=0.03) and DFS (0.659 vs. 0.700; P=0.002) was significantly lower when preoperative plasma lipid profile factors were excluded. These findings indicated that TC and HDL-C levels are associated with the prognosis in patients with LUAD.
Conclusions: In patients with LUAD, increased TC levels may predict better OS, while decreased levels of HDL-C may predict worse outcomes for both DFS and OS. These findings may aid in the identification of high-risk patients and allow them to take necessary measures in advance.

Keywords: Plasma lipid profile; lung adenocarcinoma (LUAD); prognosis

DOI: https://doi.org/10.21037/tcr-24-1062