bims-meluca 2024-06-23 papers

on Metabolism of non-small cell lung carcinoma

Issue of 2024‒06‒23
twelve papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab, L’Institut d’Investigació Biomèdica de Bellvitge

Evaluation of the combination of gemcitabine, carboplatin, and lactate dehydrogenase A inhibitor on malignant mesothelioma.
Increasing serum complement component 1q is associated with worse prognosis in advanced non-small cell lung cancer treated with immune checkpoint inhibitors: a single-center, retrospective study.
[18F]FDG-PET/CT atypical response patterns to immunotherapy in non-small cell lung cancer patients: long term prognosis assessment and clinical management proposal.
Lipocalin-2 as a prognostic biomarker and its association with systemic inflammation in small cell lung cancer.
Predictive value of pre-operative prognostic nutritional index and systemic immune-inflammation index for efficacy and survival in patients with non-small cell lung cancer undergoing neoadjuvant chemotherapy.
KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma.
Comparison of FDG-PET/CT and CT for evaluation of tumor response to nivolumab plus ipilimumab combination therapy and prognosis prediction in patients with unresectable malignant pleural mesothelioma.
Inhibition of non-small cell lung cancer metastasis by knocking down APE1 through regulating myeloid-derived suppressor cells-induced immune disorders.
Melittin inactivates YAP/HIF-1α pathway via up-regulation of LATS2 to inhibit hypoxia-induced proliferation, glycolysis and angiogenesis in NSCLC.
Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.
Association between PD-L1 expression with EGFR, ALK, and ROS1 driver oncogene mutations in non-small cell lung cancer.
A novel signature based on twelve programmed cell death patterns to predict the prognosis of lung adenocarcinoma.

Nucleosides Nucleotides Nucleic Acids. 2024 Jun 20. 1-8

Evaluation of the combination of gemcitabine, carboplatin, and lactate dehydrogenase A inhibitor on malignant mesothelioma.

Marika A Frańczak, Federica Borea, Ryszard T Smoleński, Carlotta Granchi, Filippo Minutolo, Elisa Giovannetti, Godefridus J Peters.

  OBJECTIVES: Lactate dehydrogenase A (LDH-A) catalyzes the last step of glycolysis: supplying cells rapidly but inefficiently with ATP. Many tumors, including malignant mesothelioma (MM), have a high expression of LDH-A, which is associated with cancer aggressiveness. We aimed to determine whether the efficacy of the gemcitabine/carboplatin (Gem + Carbo) combination, widely used to treat this disease, could be increased by inhibition of LDH-A (by NHI-2). To this aim, we analyzed the growth inhibition of pleural and peritoneal MM by multiple combinations.METHODS: The 72 h sulforhodamine B assay (SRB) was used to test the cytotoxicity of the combination of gemcitabine (in the range 0.1 - 400 nM) and carboplatin (0.01 - 40 µM) with a fixed concentration of NHI-2 (at IC25). We used pleural (H2452) and primary peritoneal (STO, MESO-II) MM cell lines, cultured at normoxic conditions.
RESULTS: NHI-2 did not increase the cytotoxicity of the combination of 100 nM gemcitabine and 10 µM carboplatin in peritoneal MM cell lines. The cell growth inhibition was 10% smaller after the triple combination than the Gem + Carbo treatment.
CONCLUSIONS: Inhibition of LDH-A did not increase the efficacy of gemcitabine and carboplatin in MM under normoxic conditions.

Keywords:  Lactate dehydrogenase A inhibitor; carboplatin; gemcitabine; malignant mesothelioma

DOI:  https://doi.org/10.1080/15257770.2024.2356201
J Thorac Dis. 2024 May 31. 16(5): 3251-3259

Increasing serum complement component 1q is associated with worse prognosis in advanced non-small cell lung cancer treated with immune checkpoint inhibitors: a single-center, retrospective study.

Jiazhuo Tang, Yang Fu, Yuxiao Song, Jiaxin Yin, Jun Wang, Hugo Arasanz, Bicheng Zhang.

  Background: There is a lack of readily available clinical markers of non-small cell lung cancer (NSCLC) immunotherapy efficacy. Previous studies have found that overexpressed complement component 1q (C1q) promotes macrophage M2 polarization and an immunosuppressive tumor microenvironment. This study aimed to evaluate the association between serum C1q and the efficacy of immune checkpoint inhibitors (ICIs) in patients with advanced NSCLC.Methods: A total of 168 patients with advanced NSCLC who received ICIs in the Renmin Hospital of Wuhan University were included in this study. Serum C1q levels were collected before and 3 weeks after immunotherapy treatment, together with other data on clinical and demographic characteristics. The primary outcome was overall survival (OS) (months from first dose of ICIs to death, censored at date of last follow-up). Secondary outcome was progression-free survival (PFS) [defined as months from first dose of ICIs to clinical or radiographic progression by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) or death, censored at date of last follow-up] and objective response rate (ORR) which was defined as rate of complete response (CR) or partial response (PR) at best response by RECIST 1.1.
Results: A total of 168 patients were included in this study, including 127 males (75.60%) and 41 females (24.40%). Thirty-nine patients achieved objective response (2 CR, 37 PR), and 111 patients (66.07%) had stable disease (SD) as best response. The ORR was 23.21% and the disease control rate was 89.28%. The upward trends of serum C1q levels between baseline and post-treatment were strongly associated with the shorter PFS [hazard ratio (HR) =1.554, 95% confidence interval (CI): 1.07-2.10, P=0.01] and OS (HR =1.444, 95% CI: 1.01-1.98, P=0.03). Moreover, taking the median OS 18.9 months as the cut-off of prognosis, receiver operating characteristic (ROC) analysis showed that serum baseline C1q yielded an area under the ROC curve of 0.785 (95% CI: 0.711-0.869). The optimal serum baseline C1q cut-off point to predict immunotherapy prognosis was 216.2 mg/L.
Conclusions: These findings suggested that elevated serum C1q after ICIs treatment was related to a worse prognosis in NSCLC. Monitoring the baseline and dynamic data of C1q during hospitalization showed the potential to predict the prognosis of NSCLC patients.

Keywords:  Complement component 1q (C1q); Eastern Cooperative Oncology Group performance status (ECOG-PS); immune checkpoint inhibitors (ICIs); non-small cell lung cancer (NSCLC); survival

DOI:  https://doi.org/10.21037/jtd-24-304
Eur J Nucl Med Mol Imaging. 2024 Jun 19.

[18F]FDG-PET/CT atypical response patterns to immunotherapy in non-small cell lung cancer patients: long term prognosis assessment and clinical management proposal.

Mathilde Masse, David Chardin, Pierre Tricarico, Victoria Ferrari, Nicolas Martin, Josiane Otto, Jacques Darcourt, Victor Comte, Olivier Humbert.

  AIM: To determine the long-term prognosis of immune-related response profiles (pseudoprogression and dissociated response), not covered by conventional PERCIST criteria, in patients with non-small-cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ICPIs).METHODS: 109 patients were prospectively included and underwent [18F]FDG-PET/CT at baseline, after 7 weeks (PETinterim1), and 3 months (PETinterim2) of treatment. On PETinterim1, tumor response was assessed using standard PERCIST criteria. In the event of PERCIST progression at this time-point, the study design provided for continued immunotherapy for 6 more weeks. Additional response patterns were then considered on PETinterim2: pseudo-progression (PsPD, subsequent metabolic response); dissociated response (DR, coexistence of responding and non-responding lesions), and confirmed progressive metabolic disease (cPMD, subsequent homogeneous progression of lesions). Patients were followed up for at least 12 months.
RESULTS: Median follow-up was 21 months. At PETinterim1, PERCIST progression was observed in 60% (66/109) of patients and ICPI was continued in 59/66. At the subsequent PETinterim2, 14% of patients showed PsPD, 11% DR, 35% cPMD, and 28% had a sustained metabolic response. Median overall survival (OS) and progression-free-survival (PFS) did not differ between PsPD and DR (27 vs 29 months, p = 1.0; 17 vs 12 months, p = 0.2, respectively). The OS and PFS of PsPD/DR patients were significantly better than those with cPMD (29 vs 9 months, p < 0.02; 16 vs 2 months, p < 0.001), but worse than those with sustained metabolic response (p < 0.001). This 3-group prognostic stratification enabled better identification of true progressors, outperforming the prognostic value of standard PERCIST criteria (p = 0.03).
CONCLUSION: [18F]FDG-PET/CT enables early assessment of response to immunotherapy. The new wsPERCIST ("wait and see") PET criteria proposed, comprising immune-related atypical response patterns, can refine conventional prognostic stratification based on PERCIST criteria.
TRIAL REGISTRATION: HDH F20230309081206. Registered 20 April 2023. Retrospectively registered.

Keywords:  Atypical response; Dissociated response; Immunotherapy; PET/CT; Pseudoprogression

DOI:  https://doi.org/10.1007/s00259-024-06794-8
Thorac Cancer. 2024 Jun 17.

Lipocalin-2 as a prognostic biomarker and its association with systemic inflammation in small cell lung cancer.

Se-Il Go, Jung Wook Yang, Woo Je Lee, Eun Jeong Jeong, Sungwoo Park, Gyeong-Won Lee.

  BACKGROUND: Systemic inflammation is believed to contribute to small cell lung cancer (SCLC) progression, but the underlying relationship remains unclear. Lipocalin-2, a potential biomarker of inflammation, has been implicated in various cancers but its prognostic value in SCLC is underexplored.METHODS: We retrospectively analyzed 191 patients with SCLC (72 with limited-stage [LD] and 119 with extensive-stage) treated using platinum-based chemotherapy. Lipocalin-2 expression was evaluated using immunohistochemistry. Optimal cutoff values for lipocalin-2 and neutrophil-to-lymphocyte ratio (NLR) were determined using time-dependent receiver operating characteristic curve analysis. The pectoralis muscle index was used to assess sarcopenia.
RESULTS: In LD-SCLC, high lipocalin-2 expression was associated with worse progression-free survival (PFS; median: 7.0 vs. 15.9 months, p = 0.015) and overall survival (OS; median: 12.9 vs. 30.3 months, p = 0.035) compared with low lipocalin-2 expression. Patients were stratified into three prognostic groups by combining lipocalin-2 with NLR: low lipocalin-2/low NLR, high lipocalin-2/low NLR or low lipocalin-2/high NLR, and high lipocalin-2/high NLR (median PFS: 17.3 vs. 11.0 vs. 6.3 months, p = 0.004; median OS: 30.5 vs. 17.3 vs. 8.6 months, p = 0.002). Similar trends were observed when combining lipocalin-2 with the pectoralis muscle index. High lipocalin-2 expression was also associated with lower complete response rates (18.9% vs. 34.3%, p = 0.035). No significant prognostic implications were found for lipocalin-2 in extensive-stage SCLC.
CONCLUSIONS: High lipocalin-2 expression is potentially associated with poorer survival in LD-SCLC. Combining lipocalin-2 with other inflammation-related markers could improve prognostic stratification.

Keywords:  biomarkers; inflammation; lipocalin‐2; sarcopenia; small cell lung carcinoma

DOI:  https://doi.org/10.1111/1759-7714.15389
Am J Transl Res. 2024 ;16(5): 2024-2033

Predictive value of pre-operative prognostic nutritional index and systemic immune-inflammation index for efficacy and survival in patients with non-small cell lung cancer undergoing neoadjuvant chemotherapy.

Jiaqi Lan, Wencong Lin, Yanjun Lai, Jiaxiang Zhang.

  OBJECTIVE: To explore the predictive value of preoperative prognostic nutritional index (PNI) and systemic immune inflammation index (SII) in relation to the efficacy and prognosis in patients with non-small cell lung cancer (NSCLC) undergoing neoadjuvant chemotherapy (NACT).METHODS: Data of patients with stage IIIA-N2 NSCLC who received NACT in the 910th Hospital of Chinese People's Liberation Army from January 2017 to April 2020 were retrospectively analysed. Patients undergoing NACT were divided into the pCR group (80 cases with complete remission or partial remission) and the non-pCR group (46 cases with stable disease or progressive disease) in accordance with their treatment outcome. The pathologic and clinical data of the patients were collected and analysed to identify the factors affecting efficacy of NACT for stage IIIa-N2 NSCLC, and to evaluate the predictive value of PNI and SII in determining the efficacy of NACT. The patients were followed up for 3 years to observe the overall survival, and Cox regression analysis was employed to identify the risk factors affecting patient survival. Furthermore, the effect of PNI and SII on the survival time was analysed.
RESULTS: Multivariate regression analysis showed that tumor diameter, PNI, and SII were influencing factors for poor efficacy of NACT in patients with stage IIIa-N2 NSCLC. The non-pCR group exhibited a higher mortality within 3 years, thus a lower 3-year overall survival rate than the pCR group (P<0.05). Cox regression analysis revealed that both PNI and SII were risk factors for poor prognosis in patients with stage IIIa-N2 NSCLC undergoing NACT. Further analysis found a lower 3-year survival rate in patients with low PNI and high SII than in counterparts (P<0.05).
CONCLUSION: Tumor diameter, PNI and SII are risk factors for poor efficacy in patients with stage IIIa-N2 NSCLC undergoing NACT. Low PNI and high SII can indicate a poor prognosis in these patients.

Keywords:  Non-small cell lung cancer; correlation; efficacy; prognosis; prognostic nutritional index; systemic immune-inflammation index

DOI:  https://doi.org/10.62347/RRVR5429
Br J Cancer. 2024 Jun 12.

KRAS and TP53 co-mutation predicts benefit of immune checkpoint blockade in lung adenocarcinoma.

Jan Budczies, Eva Romanovsky, Martina Kirchner, Olaf Neumann, Miriam Blasi, Johannes Schnorbach, Rajiv Shah, Farastuk Bozorgmehr, Rajkumar Savai, Thorsten Stiewe, Solange Peters, Peter Schirmacher, Michael Thomas, Daniel Kazdal, Petros Christopoulos, Albrecht Stenzinger.

BACKGROUND: Predictive biomarkers in use for immunotherapy in advanced non-small cell lung cancer are of limited sensitivity and specificity. We analysed the potential of activating KRAS and pathogenic TP53 mutations to provide additional predictive information.METHODS: The study cohort included 713 consecutive immunotherapy patients with advanced lung adenocarcinomas, negative for actionable genetic alterations. Additionally, two previously published immunotherapy and two surgical patient cohorts were analyzed. Therapy benefit was stratified by KRAS and TP53 mutations. Molecular characteristics underlying KRASmut/TP53mut tumours were revealed by the analysis of TCGA data.
RESULTS: An interaction between KRAS and TP53 mutations was observed in univariate and multivariate analyses of overall survival (Hazard ratio [HR] = 0.56, p = 0.0044 and HR = 0.53, p = 0.0021) resulting in a stronger benefit for KRASmut/TP53mut tumours (HR = 0.71, CI 0.55-0.92). This observation was confirmed in immunotherapy cohorts but not observed in surgical cohorts. Tumour mutational burden, proliferation, and PD-L1 mRNA were significantly higher in TP53-mutated tumours, regardless of KRAS status. Genome-wide expression analysis revealed 64 genes, including CX3CL1 (fractalkine), as specific transcriptomic characteristic of KRASmut/TP53mut tumours.
CONCLUSIONS: KRAS/TP53 co-mutation predicts ICI benefit in univariate and multivariate survival analyses and is associated with unique molecular tumour features. Mutation testing of the two genes can be easily implemented using small NGS panels.

DOI: https://doi.org/10.1038/s41416-024-02746-z
Oncotarget. 2024 Jun 20. 15 408-417

Comparison of FDG-PET/CT and CT for evaluation of tumor response to nivolumab plus ipilimumab combination therapy and prognosis prediction in patients with unresectable malignant pleural mesothelioma.

Kazuhiro Kitajima, Kozo Kuribayashi, Toshiyuki Minami, Hiroyuki Yokoyama, Akifumi Nakamura, Masaki Hashimoto, Takashi Kijima, Seiki Hasegawa, Hayato Kaida, Koichiro Yamakado.

  OBJECTIVES: Results for malignant pleural mesothelioma (MPM) patients following first-line treatment with nivolumab plus ipilimumab obtained with immunotherapy-modified PERCIST (imPERCIST), shown by [18F]fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), and modified RECIST (mRECIST), shown by CT, were compared for response evaluation and prognosis prediction.RESULTS: imPERCIST indicated nine progressive metabolic disease (PMD), eight stable metabolic disease (SMD), four partial metabolic response (PMR), and five complete metabolic response (CMR) cases. mRECIST showed nine with progressive disease (PD), nine stable disease (SD), seven partial response (PR), and one complete response (CR). Although high concordance was noted (κ = 0.827), imPERCIST correctly judged a greater percentage with CMR (15.4%). Following a median 10.0 months, 15 patients showed progression and eight died from MPM. With both, progression-free survival (PFS) and overall survival (OS) were significantly longer in patients without progression (CMR/PMR/SMD, CR/PR/SD, respectively) as compared to PMD/PD patients (imPERCIST p < 0.0001 and p = 0.015, respectively; mRECIST p < 0.0001 and p = 0.015, respectively).
METHODS: Twenty-six patients (23 males, 3 females; median 73.5 years) with histologically proven MPM and no curative surgery received nivolumab plus ipilimumab combination therapy. FDG-PET/CT and diagnostic CT scanning at the baseline, and after 2-4 cycles (2 in three, 3 in 17, 4 in six patients) were performed. Therapeutic response findings evaluated using imPERCIST and mRECIST were compared. PFS and OS analyses were done using log-rank and Cox methods.
CONCLUSION: For unresectable MPM patient examinations, FDG-PET and CT provide accurate findings for evaluating tumor response and also prognosis prediction following first-line nivolumab plus ipilimumab immunotherapy (approximately three cycles).

Keywords:  FDG (fluorodeoxyglucose); PET-CT (positron emission tomography-computed tomography); immunotherapy; immunotherapy-modified PERCIST (positron emission tomography response criteria in solid tumors); mesothelioma

DOI:  https://doi.org/10.18632/oncotarget.28594
Aging (Albany NY). 2024 Jun 14. 16

Inhibition of non-small cell lung cancer metastasis by knocking down APE1 through regulating myeloid-derived suppressor cells-induced immune disorders.

Zhenlong Zhang, Yuchen Lin, Xiaojie Pan, Shuchen Chen.

  BACKGROUND: Non-small cell lung cancer (NSCLC) represents a highly immunogenic malignancy. Immunologic tolerance facilitated by myeloid-derived suppressor cells (MDSCs) is implicated in primary or secondary resistance mechanisms in NSCLC. The potential role of APE1 in regulating NSCLC metastasis by targeting MDSCs remains uncertain.METHODS: This study utilized a plasmid, Plxpsp-mGM-CSF, to induce elevated granulocyte-macrophage colony-stimulating factor (GM-CSF) expression in A549 cells. Tumor transplantation experiments involved A549, A549+GM-CSF, and A549+GM-CSF-siAPE1 cell lines. Evaluation encompassed MDSCs, Treg cells, IgG, CD3, and CD8 levels.
RESULTS: Notably, lung cancer tissues and cells displayed markedly reduced APE1 expression. siAPE1 transfection significantly curtailed tumor growth compared to the A549+GM-CSF group. APE1 knockdown orchestrated immune system modulation in lung tumor mice, characterized by diminished MDSCs but augmented Treg cells, IgG, CD3, and CD8. Additionally, APE1 knockdown led to reduced levels of pro-MDSC cytokines (HGF, CCL5, IL-6, CCL12) and a concurrent upregulation of the anti-MDSC cytokine IL-1ra. Furthermore, APE1 knockdown impeded cell viability in both A549 and H1650 cells.
CONCLUSIONS: Transplantation of A549-GM-CSF amplified MDSC levels, fostering accelerated tumor growth, while mitigating MDSC levels through APE1 knockdown hindered tumor progression and alleviated inflammatory infiltration in lung cancer tissues. Strategies targeting the APE1/MDSC axis offer a promising approach for lung cancer prevention and treatment, presenting novel insights for NSCLC management.

Keywords:  A549; APE1; MDSCs; NSCLC; tumor immune

DOI:  https://doi.org/10.18632/aging.205938
Clinics (Sao Paulo). 2024 ;pii: S1807-5932(24)00084-X. [Epub ahead of print]79 100407

Melittin inactivates YAP/HIF-1α pathway via up-regulation of LATS2 to inhibit hypoxia-induced proliferation, glycolysis and angiogenesis in NSCLC.

Hao Li.

  BACKGROUND: NSCLC is one of the most common causes of death. The hypoxia microenvironment contributes to cancer progression. The purpose was to explore the effects and mechanism of melittin on NSCLC cells in the hypoxic microenvironment.METHODS: NSCLC cell lines (A549 and H1299) were cultured in normoxia or hypoxia conditions with or without melittin treatment. The viability of the cells was detected via MTT assay and the proliferation ability was evaluated by EdU assay. QRT-PCR was performed to evaluate GLUT1, LDHA, HK2, VEGF and LATS2 mRNA levels. Glucose transport was assessed by the 2-NBDG uptake assay. The angiogenesis was determined by the tubule formation assay. The protein expressions of GLUT1, LDHA, HK2, VEGF, LATS2, YAP, p-YAP and HIF-1α were detected via western blotting assay. The tumor formation assay was conducted to examine the roles of melittin and LATS2 in vivo.
RESULTS: Melittin inhibited hypoxia-induced cell viability, proliferation, glycolysis and angiogenesis as well as suppressed YAP binding to HIF-1α in NSCLC. Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2, ultimately inhibiting cancer progression of NSCLC. Moreover, melittin suppressed tumor growth via up-regulation of LATS2 in vivo.
CONCLUSION: Melittin inactivated the YAP/HIF-1α pathway via up-regulation of LATS2 to contribute to the development of NSCLC. Therefore, melittin is expected to become a potential prognostic drug for the therapy of NSCLC.

Keywords:  Angiogenesis; Glycolysis; LATS2; Melittin; Non-small cell lung cancer; Proliferation

DOI:  https://doi.org/10.1016/j.clinsp.2024.100407
Nat Commun. 2024 Jun 18. 15(1): 5190

Total and H-specific GDF-15 levels increase in caloric deprivation independently of leptin in humans.

Pavlina Chrysafi, Laura Valenzuela-Vallejo, Konstantinos Stefanakis, Theodoros Kelesidis, Margery A Connelly, Christos S Mantzoros.

Mitochondrial-secreted growth differentiation factor-15 (GDF-15) promotes weight loss in animals. Its effects in humans remain unclear, due to limited research and potential measurement interference from the H202D-variant. Our post-hoc analysis investigates total (irrespective of genetic variants) and H-specific GDF-15 (detected only in H202D-variant absence) in humans under acute and chronic energy deprivation, examining GDF-15 interaction with leptin (energy homeostasis regulator) and GDF-15 biologic activity modulation by the H202D-variant. Total and H-specific GDF-15 increased with acute starvation, and total GDF-15 increased with chronic energy deprivation, compared with healthy subjects and regardless of leptin repletion. Baseline GDF-15 positively correlated with triglyceride-rich particles and lipoproteins. During acute metabolic stress, GDF-15 associations with metabolites/lipids appeared to differ in subjects with the H202D-variant. Our findings suggest GDF-15 increases with energy deprivation in humans, questioning its proposed weight loss and suggesting its function as a mitokine, reflecting or mediating metabolic stress response.

DOI: https://doi.org/10.1038/s41467-024-49366-y
Indian J Pathol Microbiol. 2024 Jun 20.

Association between PD-L1 expression with EGFR, ALK, and ROS1 driver oncogene mutations in non-small cell lung cancer.

Dülger Onur, Yaylım İlhan, Öz Büge.

BACKGROUND: Driver mutations and immunological expressions have gained importance in recent years for targeted therapies and immunotherapies of nonsmall cell lung cancer (NSCLC).AIMS: This study examined the association between PD-L1 expression and ALK, ROS1, and EGFR driver oncogene mutations in patients with NSCLC.
MATERIALS AND METHODS: A total of 501 NSCLC patients were included for analysis. Immunohistochemistry was performed with a PD-L1 clone 22c3. EGFR mutations were detected by PCR. ALK and ROS1 rearrangement analysis was performed with FISH. Results: There was a highly statistically significant difference between PD-L1 expression and EGFR mutation. PD-L1 expression was higher in the EGFR wild-type than in mutated EGFR (P = 0.0002). There was no relationship between PD-L1 expression and ALK and ROS1 mutations (P = 0.8899, P = 0.2512, respectively). PD-L1 expression was higher in nonadenocarcinomas (non-AC) than in adenocarcinomas (AC) (P = 0.0438). The ALK rearrangement and EGFR mutations were higher in ACs (P = 0.0073, P = 0.0012, respectively). ALK, ROS1 rearrangements, and EGFR mutations were higher in nonsmokers (P < 0.05). EGFR mutations were detected more frequently in females than males (P = 0.001). There was no relationship between gender and ALK, ROS1, and PD-L1 (P > 0.05). The prevalence of EGFR, ALK, and ROS1 driver mutations in the Turkish population was 9.3%, 5.3%, and 2.4%, respectively.
CONCLUSIONS: In conclusion, PD-L1 expression and mutated EGFR status have a highly negative association. PD-L1 expression was higher in EGFR wild-type patients. Therefore, it shows that the opportunity to receive PD-L1-related treatment may be higher in these patients. We think that PD-L1 immunohistochemical evaluation will increase the clinical predictive importance in EGFR wild-type cases.

DOI: https://doi.org/10.4103/ijpm.ijpm_939_23
Am J Transl Res. 2024 ;16(5): 2082-2102

A novel signature based on twelve programmed cell death patterns to predict the prognosis of lung adenocarcinoma.

Shao-Kun Yu, Jiu Yang, Qi Zhang, Tao Yu, Kai-Hua Lu.

  Programmed cell death (PCD) plays a pivotal role in tumor initiation and progression. However, the prognostic value and clinical characteristics of PCD-related genes (PRGs) remain unclear. We collected and analyzed genes associated with twelve PCD patterns, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis, and oxeiptosis to construct a gene signature. Our analysis identified 215 differentially expressed PRGs out of 1254 in lung adenocarcinoma (LUAD) and normal lung tissues. Subsequently, we performed univariate Cox regression analysis and identified 58 prognostic PRGs. Based on LASSO Cox regression analysis, we constructed a risk score using the expression levels of seven genes: DAPK2, DDIT4, E2F2, GAPDH, MET, PIM2, and FOXF1. Patients with lower risk scores showed earlier stages of cancer, longer survival times, and better immune infiltrations and functions. Notably, we found that knockdown of DDIT4 significantly increased apoptosis and impaired the proliferation of human LUAD cell lines. Our study proposes a PRG-based prognostic signature that sheds light on the potential role of PCD-related genes in LUAD and provides valuable insights into future therapeutic strategies.

Keywords:  Programmed cell death; immune landscape; immunotherapy; lung adenocarcinoma; prognosis

DOI:  https://doi.org/10.62347/UAMN8558