bims-meluca Biomed News
on Metabolism of non-small cell lung carcinoma
Issue of 2023‒05‒21
fifteen papers selected by
the Muñoz-Pinedo/Nadal (PReTT) lab
L’Institut d’Investigació Biomèdica de Bellvitge
  1. Adenosine monophosphate-activated protein kinase is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice.
  2. Clinical roles of soluble PD-1 and PD-L1 in plasma of NSCLC patients treated with immune checkpoint inhibitors.
  3. A novel methionine metabolism-related signature predicts prognosis and immunotherapy response in lung adenocarcinoma.
  4. Impact of microvessel patterns and immune status in NSCLC: a non-angiogenic vasculature is an independent negative prognostic factor in lung adenocarcinoma.
  5. Activation of CTHRC1 by HOXB9 Promotes Angiogenesis through Fatty Acid Metabolism in Lung Adenocarcinoma.
  6. Hypoxia-mediated promotion of glucose metabolism in non-small cell lung cancer correlates with activation of the EZH2/FBXL7/PFKFB4 axis.
  7. Total Metabolic Tumor Volume on 18F-FDG PET/CT Is a Useful Prognostic Biomarker for Patients with Extensive Small-Cell Lung Cancer Undergoing First-Line Chemo-Immunotherapy.
  8. Prognostic significance of SH2D5 expression in lung adenocarcinoma and its relation to immune cell infiltration.
  9. Hypoxia Changes Energy Metabolism and Growth Rate in Non-Small Cell Lung Cancer Cells.
  10. FDG PET/CT Tumor Dissemination Characteristic Predicts the Outcome of First-Line Systemic Therapy in Non-small Cell Lung Cancer.
  11. Immune checkpoint inhibitors beyond first-line progression with prior immunotherapy in patients with advanced non-small cell lung cancer.
  12. Radiomics of Tumor Heterogeneity in 18F-FDG-PET-CT for Predicting Response to Immune Checkpoint Inhibition in Therapy-Naïve Patients with Advanced Non-Small-Cell Lung Cancer.
  13. Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy.
  14. C-reactive protein and lactate dehydrogenase serum levels potentially predict the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer.
  15. Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma.
  1. J Cachexia Sarcopenia Muscle. 2023 May 16.
    Adenosine monophosphate-activated protein kinase is elevated in human cachectic muscle and prevents cancer-induced metabolic dysfunction in mice.
    Steffen H Raun, Mona S Ali, Xiuqing Han, Carlos Henríquez-Olguín, T C Phung Pham, Roberto Meneses-Valdés, Jonas R Knudsen, Anna C H Willemsen, Steen Larsen, Thomas E Jensen, Ramon Langen, Lykke Sylow.
      BACKGROUND: Metabolic dysfunction and cachexia are associated with poor cancer prognosis. With no pharmacological treatments, it is crucial to define the molecular mechanisms causing cancer-induced metabolic dysfunction and cachexia. Adenosine monophosphate-activated protein kinase (AMPK) connects metabolic and muscle mass regulation. As AMPK could be a potential treatment target, it is important to determine the function for AMPK in cancer-associated metabolic dysfunction and cachexia. We therefore established AMPK's roles in cancer-associated metabolic dysfunction, insulin resistance and cachexia.METHODS: In vastus lateralis muscle biopsies from n = 26 patients with non-small cell lung cancer (NSCLC), AMPK signalling and protein content were examined by immunoblotting. To determine the role of muscle AMPK, male mice overexpressing a dominant-negative AMPKα2 (kinase-dead [KiDe]) specifically in striated muscle were inoculated with Lewis lung carcinoma (LLC) cells (wild type [WT]: n = 27, WT + LLC: n = 34, mAMPK-KiDe: n = 23, mAMPK-KiDe + LLC: n = 38). Moreover, male LLC-tumour-bearing mice were treated with (n = 10)/without (n = 9) 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to activate AMPK for 13 days. Littermate mice were used as controls. Metabolic phenotyping of mice was performed via indirect calorimetry, body composition analyses, glucose and insulin tolerance tests, tissue-specific 2-[3H]deoxy-d-glucose (2-DG) uptake and immunoblotting.
    RESULTS: Patients with NSCLC presented increased muscle protein content of AMPK subunits α1, α2, β2, γ1 and γ3 ranging from +27% to +79% compared with control subjects. In patients with NSCLC, AMPK subunit protein content correlated with weight loss (α1, α2, β2 and γ1), fat-free mass (α1, β2 and γ1) and fat mass (α1 and γ1). Tumour-bearing mAMPK-KiDe mice presented increased fat loss and glucose and insulin intolerance. LLC in mAMPK-KiDe mice displayed lower insulin-stimulated 2-DG uptake in skeletal muscle (quadriceps: -35%, soleus: -49%, extensor digitorum longus: -48%) and the heart (-29%) than that in non-tumour-bearing mice. In skeletal muscle, mAMPK-KiDe abrogated the tumour-induced increase in insulin-stimulated TBC1D4thr642 phosphorylation. The protein content of TBC1D4 (+26%), pyruvate dehydrogenase (PDH; +94%), PDH kinases (+45% to +100%) and glycogen synthase (+48%) was increased in skeletal muscle of tumour-bearing mice in an AMPK-dependent manner. Lastly, chronic AICAR treatment elevated hexokinase II protein content and normalized phosphorylation of p70S6Kthr389 (mTORC1 substrate) and ACCser212 (AMPK substrate) and rescued cancer-induced insulin intolerance.
    CONCLUSIONS: Protein contents of AMPK subunits were upregulated in skeletal muscle of patients with NSCLC. AMPK activation seemed protectively inferred by AMPK-deficient mice developing metabolic dysfunction in response to cancer, including AMPK-dependent regulation of multiple proteins crucial for glucose metabolism. These observations highlight the potential for targeting AMPK to counter cancer-associated metabolic dysfunction and possibly cachexia.
    Keywords:  AMP-activated protein kinase (AMPK); cancer cachexia; glucose metabolism; insulin resistance; skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.13238
  2. Cancer Immunol Immunother. 2023 May 16.
    Clinical roles of soluble PD-1 and PD-L1 in plasma of NSCLC patients treated with immune checkpoint inhibitors.
    Hidetomo Himuro, Yoshiro Nakahara, Yuka Igarashi, Taku Kouro, Naoko Higashijima, Norikazu Matsuo, Shuji Murakami, Feifei Wei, Shun Horaguchi, Kayoko Tsuji, Yasunobu Mano, Haruhiro Saito, Koichi Azuma, Tetsuro Sasada.
      INTRODUCTION: Immune checkpoint inhibitors (ICIs) have significantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can benefit from this therapy, and clinically useful predictive biomarkers remain to be elucidated.METHODS: Blood was collected from 189 patients with NSCLC before and six weeks after the initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody). Soluble PD-1 (sPD-1) and PD-L1 (sPD-L1) in plasma before and after treatment were analyzed to evaluate their clinical significance.
    RESULTS: Cox regression analysis demonstrated that higher sPD-L1 levels before treatment significantly predicted unfavorable progression-free survival (PFS; HR 15.4, 95% CI 1.10-86.7, P = 0.009) and overall survival (OS; HR 11.4, 95% CI 1.19-52.3, P = 0.007) in NSCLC patients treated with ICI monotherapy (n = 122) but not in those treated with ICIs combined with chemotherapy (n = 67: P = 0.729 and P = 0.155, respectively). In addition, higher sPD-1 levels after treatment were significantly associated with better OS (HR 0.24, 95% CI 0.06-0.91, P = 0.037) in patients treated with anti-PD-1 monotherapy, whereas higher sPD-L1 levels after treatment were significantly associated with worse PFS (HR 6.09, 95% CI 1.42-21.0, P = 0.008) and OS (HR 42.6, 95% CI 6.83-226, P < 0.001). The levels of sPD-L1 at baseline closely correlated with those of other soluble factors, such as sCD30, IL-2Ra, sTNF-R1, and sTNF-R2, which are known to be released from the cell surface by zinc-binding proteases ADAM10/17.
    CONCLUSIONS: These findings suggest the clinical significance of pretreatment sPD-L1 as well as posttreatment sPD-1 and sPD-L1 in NSCLC patients treated with ICI monotherapy.
    Keywords:  Anti-PD-1 antibody; Anti-PD-L1 antibody; Non-small cell lung cancer (NSCLC); Soluble PD-1; Soluble PD-L1
    DOI:  https://doi.org/10.1007/s00262-023-03464-w
  3. Aging (Albany NY). 2023 May 02. 15
    A novel methionine metabolism-related signature predicts prognosis and immunotherapy response in lung adenocarcinoma.
    Qing-Hua Chang, Yuan-Cui Zhang, Dong-Ying Zhang, Ting Mao, Ran Chang, Nan Wang, Yun Ye, Zi-Jun Xu.
      Recent research revealed methionine metabolism as a key mediator of tumor initiation and immune evasion. However, the relationship between methionine metabolism and tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unknown. Here, we comprehensively analyzed the genomic alterations, expression patterns, and prognostic values of 68 methionine-related regulators (MRGs) in LUAD. We found that most MRGs were highly prognostic based on 30 datasets including 5024 LUAD patients. Three distinct MRG modification patterns were identified, which showed significant differences in clinical outcomes and TME characteristics: The C2 subtype was characterized by higher immune score, while the C3 subtype had more malignant cells and worse survival. We developed a MethScore to measure the level of methionine metabolism in LUAD. MethScore was positively correlated with T-cell dysfunction and tumor-associated macrophages (TAMs), indicating a dysfunctional TME phenotype in the high MethScore group. In addition, two immunotherapy cohorts confirmed that patients with a lower MethScore exhibited significant clinical benefits. Our study highlights the important role of methionine metabolism in modeling the TME. Evaluating methionine modification patterns will enhance our understanding of TME characteristics and can guide more effective immunotherapy strategies.
    Keywords:  immunotherapy; lung adenocarcinoma; methionine metabolism; molecular subtype; tumor microenvironment
    DOI:  https://doi.org/10.18632/aging.204687
  4. Front Oncol. 2023 ;13 1157461
    Impact of microvessel patterns and immune status in NSCLC: a non-angiogenic vasculature is an independent negative prognostic factor in lung adenocarcinoma.
    Erna-Elise Paulsen, Sigve Andersen, Mehrdad Rakaee, Mona Irene Pedersen, Ana Paola Lombardi, Mette Pøhl, Thomas Kilvaer, Lill-Tove Busund, Francesco Pezzella, Tom Donnem.
      Introduction: Non-small cell lung carcinomas (NSCLC) exhibit different microvessel patterns (MVPs). Basal (BA), diffuse (DA) and papillary (PA) patterns show signs of angiogenesis (new blood vessels), while an alveolar pattern indicates that tumors are co-opting existing normal vessels (non-angiogenic alveolar, NAA). NAA tumor growth is known to exist in NSCLC, but little is known about its prognostic impact in different histological subgroups, and about associations between MVPs and immune cell infiltration.Methods: Detailed patterns of angiogenic and non-angiogenic tumor growth were evaluated by CD34 immunohistochemistry in whole tissue slides from 553 surgically treated patients with NSCLC stage I-IIIB disease. Associations with clinicopathological variables and markers related to tumor immunology-, angiogenesis- and hypoxia/metabolism were explored, and disease-specific survival (DSS) was analyzed according to histological subtypes.
    Results: The predominant MVP was angiogenic in 82% of tumors: BA 40%, DA 34%, PA 8%, while a NAA pattern dominated in 18%. A contribution of the NAA pattern >5% (NAA+), i.e., either dominant or minority, was observed in 40.1% of tumors and was associated with poor disease-specific survival (DSS) (p=0.015). When stratified by histology, a significantly decreased DSS for NAA+ was found for adenocarcinomas (LUAD) only (p< 0.003). In multivariate analyses, LUAD NAA+ pattern was a significant independent prognostic factor; HR 2.37 (CI 95%, 1.50-3.73, p< 0.001). The immune cell density (CD3, CD4, CD8, CD45RO, CD204, PD1) added prognostic value in squamous cell carcinoma (LUSC) and LUAD with 0-5% NAA (NAA-), but not in LUAD NAA+. In correlation analyses, there were several significant associations between markers related to tumor metabolism (MCT1, MCT4, GLUT1) and different MVPs.
    Conclusion: The NAA+ pattern is an independent poor prognostic factor in LUAD. In NAA+ tumors, several immunological markers add prognostic impact in LUSC but not in LUAD.
    Keywords:  angiogenesis; immune cells; immunology; non-angiogenic tumors; vessel co-option
    DOI:  https://doi.org/10.3389/fonc.2023.1157461
  5. Rev Invest Clin. 2022 ;75(2): 63-75
    Activation of CTHRC1 by HOXB9 Promotes Angiogenesis through Fatty Acid Metabolism in Lung Adenocarcinoma.
    Keqi Liu, Xiaomin Li, Zhouzhou Yang, Rong Zhang.
      Background: CTHRC1 is highly expressed in various cancers.Objectives: The aim of the study was to study the role of CTHRC1 played in lung adenocarcinoma (LUAD) development and its underlying biological functions.
    Methods: Enriched pathways and upstream transcription factors of CTHRC1 were explored by bioinformatics analysis. Dual-luciferase assay and Chromatin immunoprecipitation assay were used to verify the binding relationship between CTHRC1 and HOXB9. CCK-8 was utilized to detect cell viability. Expression levels of CTHRC1, HOXB9, and angiogenesis-related genes were assessed by quantitative real time-polymerase chain reaction. Angiogenesis assay was used to detect angiogenesis ability. Quantitative analysis of metabolites were used to detect the accumulation of neutral lipids, the levels of free fatty acids (FAs), and glycerol. Western blot was conducted to measure expression of metabolic enzymes of FA.
    Results: CTHRC1 was enriched in FA metabolic pathway, which was positively correlated and bound with HOXB9. CTHRC1 and HOXB9 expression was remarkably up-regulated in LUAD cells. Overexpression of CTHRC1 promoted FA metabolic pathway and angiogenesis, and FA inhibitor Orlistat restored it to NC group level. Meanwhile, CTHRC1 affected LUAD angiogenesis by activating HOXB9 to regulate FA metabolism.
    Conclusions: This study found that activation of CTHRC1 by HOXB9 induces angiogenesis by mediating FA metabolism. CTHRC1 may be a potential target for LUAD diagnosis.
    Keywords:  Angiogenesis; CTHRC1; Fatty acid metabolism; HOXB9; Lung adenocarcinoma
    DOI:  https://doi.org/10.24875/RIC.23000023
  6. Cell Death Dis. 2023 05 13. 14(5): 326
    Hypoxia-mediated promotion of glucose metabolism in non-small cell lung cancer correlates with activation of the EZH2/FBXL7/PFKFB4 axis.
    Jing Zhou, Yang Lin, Xiuhua Kang, Zhicheng Liu, Juntao Zou, Fei Xu.
      F-box/LRR-repeat protein 7 (FBXL7) was predicted as a differentially expressed E3 ubiquitin ligase in non-small cell lung cancer (NSCLC), which has been suggested to influence cancer growth and metastasis. In this study, we aimed to decipher the function of FBXL7 in NSCLC and delineate the upstream and downstream mechanisms. FBXL7 expression was verified in NSCLC cell lines and GEPIA-based tissue samples, after which the upstream transcription factor of FBXL7 was bioinformatically identified. The substrate PFKFB4 of the FBXL7 was screened out by tandem affinity purification coupled with mass-spectrometry (TAP/MS). FBXL7 was downregulated in NSCLC cell lines and tissue samples. FBXL7 ubiquitinated and degraded PFKFB4, thus suppressing glucose metabolism and malignant phenotypes of NSCLC cells. Hypoxia-induced HIF-1α upregulation elevated EZH2 and inhibited FBXL7 transcription and reduced its expression, thus promoting PFKFB4 protein stability. By this mechanism, glucose metabolism and the malignant phenotype were enhanced. In addition, knockdown of EZH2 impeded tumor growth through the FBXL7/PFKFB4 axis. In conclusion, our work reveals that the EZH2/FBXL7/PFKFB4 axis plays a regulatory role in glucose metabolism and tumor growth of NSCLC, which is expected to be potential biomarkers for NSCLC.
    DOI:  https://doi.org/10.1038/s41419-023-05795-z
  7. Cancers (Basel). 2023 Apr 10. pii: 2223. [Epub ahead of print]15(8):
    Total Metabolic Tumor Volume on 18F-FDG PET/CT Is a Useful Prognostic Biomarker for Patients with Extensive Small-Cell Lung Cancer Undergoing First-Line Chemo-Immunotherapy.
    Julia Grambow-Velilla, Romain-David Seban, Kader Chouahnia, Jean-Baptiste Assié, Laurence Champion, Nicolas Girard, Gerald Bonardel, Lise Matton, Michael Soussan, Christos Chouaïd, Boris Duchemann.
      Background: We aimed to evaluate the prognostic value of imaging biomarkers on 18F-FDG PET/CT in extensive-stage small-cell lung cancer (ES-SCLC) patients undergoing first-line chemo-immunotherapy. Methods: In this multicenter and retrospective study, we considered two cohorts, depending on the type of first-line therapy: chemo-immunotherapy (CIT) versus chemotherapy alone (CT). All patients underwent baseline 18-FDG PET/CT before therapy between June 2016 and September 2021. We evaluated clinical, biological, and PET parameters, and used cutoffs from previously published studies or predictiveness curves to assess the association with progression-free survival (PFS) or overall survival (OS) with Cox prediction models. Results: Sixty-eight patients were included (CIT: CT) (36: 32 patients). The median PFS was 5.9:6.5 months, while the median OS was 12.1:9.8 months. dNLR (the derived neutrophils/(leucocytes-neutrophils) ratio) was an independent predictor of short PFS and OS in the two cohorts (p < 0.05). High total metabolic tumor volume (TMTVhigh if > 241 cm3) correlated with outcomes, but only in the CIT cohort (PFS for TMTVhigh in multivariable analysis: HR 2.5; 95%CI 1.1-5.9). Conclusion: Baseline 18F-FDG PET/CT using TMTV could help to predict worse outcomes for ES-SCLC patients undergoing first-line CIT. This suggests that baseline TMTV may be used to identify patients that are unlikely to benefit from CIT.
    Keywords:  18F-FDG PET/CT; biomarker; immunotherapy; predictive; prognostic; small-cell lung cancer
    DOI:  https://doi.org/10.3390/cancers15082223
  8. PeerJ. 2023 ;11 e15238
    Prognostic significance of SH2D5 expression in lung adenocarcinoma and its relation to immune cell infiltration.
    Hao Zhou, Shengjun Li, Yuansheng Lin.
      Objective: Through analyzing the SH2D5 expression profiles, clinical features, and immune infiltration in lung adenocarcinoma (LUAD), the study was intended to discuss the correlations of SH2D5 with prognosis and immune infiltration in LUAD.Methods: We downloaded transcriptome and clinical data of LUAD patients from TCGA, GEO, and CCLE databases. Sangerbox, R language, GEPIA, UALCAN, and Kaplan-Meier Plotter were adopted to analyze the SH2D5 expression patterns, prognosis, and clinical features. Spearman correlation analysis was performed to determine the association between SH2D5 expression and immune cell infiltration and immune checkpoint genes. The miRNA-SH2D5 relations were predicted by miRDB and starbase. Lastly, quantitative PCR, IHC and Western blot were implemented for validation.
    Results: A prominent up-regulation of SH2D5 was noted in the LUAD group relative to the normal group, which was validated by quantitative PCR, IHC and Western blot. SH2D5 expression was inversely related to overall survival (OS) of LUAD patients as well as B cell immune infiltration. Additionally, SH2D5 expression was negatively correlated with dendritic cells resting (p < 0.001), plasma cells (p < 0.001), mast cells resting (p = 0.031) and T cells CD4 memory resting (p = 0.036) in LUAD patients with abundant SH2D5 expression correlated with poor prognosis. Furthermore, enrichment analysis suggested that SH2D5 was associated with lung cancer and immunity. Lastly, we investigated the relationship between the expression of SH2D5 and the use of antitumor drugs.
    Conclusion: High SH2D5 expression shares an association with unfavorable prognosis in LUAD, and SH2D5 may also provide new ideas for immunotherapy as a potential therapeutic target.
    Keywords:  Immune infiltration; Lung adenocarcinoma; Prognosis; SH2D5
    DOI:  https://doi.org/10.7717/peerj.15238
  9. Cancers (Basel). 2023 Apr 26. pii: 2472. [Epub ahead of print]15(9):
    Hypoxia Changes Energy Metabolism and Growth Rate in Non-Small Cell Lung Cancer Cells.
    Hasan Nisar, Paulina Mercedes Sanchidrián González, Melanie Brauny, Frederik M Labonté, Claudia Schmitz, Marie Denise Roggan, Bikash Konda, Christine E Hellweg.
      Hypoxia occurs in 80% of non-small cell lung carcinoma (NSCLC) cases, leading to treatment resistance. Hypoxia's effects on NSCLC energetics are not well-characterized. We evaluated changes in glucose uptake and lactate production in two NSCLC cell lines under hypoxia in conjunction with growth rate and cell cycle phase distribution. The cell lines A549 (p53 wt) and H358 (p53 null) were incubated under hypoxia (0.1% and 1% O2) or normoxia (20% O2). Glucose and lactate concentrations in supernatants were measured using luminescence assays. Growth kinetics were followed over seven days. Cell nuclei were stained with DAPI and nuclear DNA content was determined by flow cytometry to determine cell cycle phase. Gene expression under hypoxia was determined by RNA sequencing. Glucose uptake and lactate production under hypoxia were greater than under normoxia. They were also significantly greater in A549 compared to H358 cells. Faster energy metabolism in A549 cells was associated with a higher growth rate in comparison to H358 cells under both normoxia and hypoxia. In both cell lines, hypoxia significantly slowed down the growth rate compared to proliferation under normoxic conditions. Hypoxia led to redistribution of cells in the different cycle phases: cells in G1 increased and the G2 population decreased. Glucose uptake and lactate production increase under hypoxia in NSCLC cells indicated greater shunting of glucose into glycolysis rather than into oxidative phosphorylation compared to normoxia, making adenosine triphosphate (ATP) production less efficient. This may explain the redistribution of hypoxic cells in the G1 cell cycle phase and the time increase for cell doubling. Energy metabolism changes were more prominent in faster-growing A549 cells compared to slower-growing H358 cells, indicating possible roles for the p53 status and inherent growth rate of different cancer cells. In both cell lines, genes associated with cell motility, locomotion and migration were upregulated under chronic hypoxia, indicating a strong stimulus to escape hypoxic conditions.
    Keywords:  cell cycle progression; cell migration; energy metabolism; glucose; hypoxia; lactate; lung cancer; non-small cell lung cancer cell lines; p53; proliferation
    DOI:  https://doi.org/10.3390/cancers15092472
  10. Acad Radiol. 2023 May 16. pii: S1076-6332(23)00163-0. [Epub ahead of print]
    FDG PET/CT Tumor Dissemination Characteristic Predicts the Outcome of First-Line Systemic Therapy in Non-small Cell Lung Cancer.
    Weiyue Tan, Yi Zhang, Jie Wang, Zhonghang Zheng, Ligang Xing, Xiaorong Sun.
      RATIONALE AND OBJECTIVES: To explore the correlation between the tumor dissemination characteristic at 18F-fluoro-deoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images and the outcome of first-line systemic therapy for stage IV non-small cell lung cancer (NSCLC).MATERIALS AND METHODS: The current retrospective study included 101 NSCLC patients receiving first-line systemic therapy with baseline 18F-FDG PET/CT images available. The distance between the two lesions that were the farthest apart was defined as Dmax to calculate the tumor dissemination. The tumor metabolic volume (MTV) of the primary tumor and the MTV of the whole-body tumor lesions (MTVwb) were calculated using 18F-FDG PET/CT imaging. The Kaplan-Meier survival analyses and Cox predictive model were performed to assess the relationship between the parameters and survival.
    RESULTS: Dmax and MTVwb were independent prognostic factors for overall survival (OS) (p = 0.019 and p = 0.011, respectively) and progression-free survival (PFS) (p = 0.043 and p = 0.009, respectively). Poor PFS and OS were associated with high MTVwb (>54.0 cm3) and high Dmax (>48.5 cm) (p = 0.006 and p = 0.008, respectively). When MTVwb and Dmax were combined, three risk groups were stratified with no (score 0), one (score 1), or two (score 2) factors (p < 0.001 for PFS, p < 0.001 for OS). The group with a score of 0 had a considerably longer PFS and OS than those who received a score of 1 or 2 (PFS: 61.1%, 43.5%, and 21.1%, respectively, OS: 77.8%, 54.3%, and 36.8%, respectively).
    CONCLUSION: The combination of tumor dissemination characteristic (Dmax) and tumor burden (MTVwb) can further improve the prognosis stratification of NSCLC.
    Keywords:  (18)F-FDG PET/CT; Dissemination; Metabolic tumor volume; Non-small cell lung cancer
    DOI:  https://doi.org/10.1016/j.acra.2023.03.027
  11. J Thorac Dis. 2023 Apr 28. 15(4): 1648-1657
    Immune checkpoint inhibitors beyond first-line progression with prior immunotherapy in patients with advanced non-small cell lung cancer.
    Manyi Xu, Yue Hao, Xiaohong Zeng, Jinfei Si, Zhengbo Song.
      Background: Immunotherapy, monotherapy, and immunotherapy plus platinum-based chemotherapy are the standard treatments for advanced non-small cell lung cancer (NSCLC) patients with negative driver genes. However, the impact of similar continuing immunotherapy beyond progression (IBP) of first-line immunotherapy for advanced NSCLC has not yet been shown. This study aimed to estimate the impact of immunotherapy beyond first-line progression (IBF) and evaluate the factors associated with second-line efficacity.Methods: Ninety-four cases of advanced NSCLC patients with progressive disease (PD) post first-line treatment with platinum-based chemotherapy plus immunotherapy and administrated prior immune checkpoint inhibitors (ICIs) between November 2017 and July 2021 were retrospectively analyzed. Survival curves were plotted using the Kaplan-Meier method. Cox proportional hazards regression analyses were applied to determine predictive factors independently associated with second-line efficacity.
    Results: A total of 94 patients were incorporated in this study. Patients who continued the original ICIs after initial PD were defined as IBF (n=42), whereas those who discontinued immunotherapy were defined as non-IBF (n=52). The second-line objective response rates (ORR, ORR = CR + PR) of patients in the IBF and non-IBF groups were 13.5% vs. 28.6%, respectively (P=0.070). No significant survival difference was found between patients in the IBF and non-IBF groups in first-line median progression-free survival (PFS) (mPFS1, 6.2 vs. 5.1 months, P=0.490), second-line median PFS (mPFS2, 4.5 vs. 2.6 months, P=0.216), or median overall survival (OS) (mOS, 14.4 vs. 8.3 months, P=0.188). However, the benefits inPFS2 were observed in individuals performed PFS1 >6 months (group A) than those of PFS1 ≤6 months (group B) (median PFS2, 4.6 vs. 3.2 months, P=0.038). Multivariate analyses did not reveal any independent prognostic factors for efficacy.
    Conclusions: The benefits of continuing prior ICIs administration beyond first-line immunotherapy progression might not be obvious in patients with advanced NSCLC, but those first line treatment showed a longer period may receive efficacy benefits.
    Keywords:  Non-small cell lung cancer (NSCLC); efficacy; immune checkpoint inhibitors (ICIs); immunotherapy beyond progression (IBP)
    DOI:  https://doi.org/10.21037/jtd-22-1611
  12. Cancers (Basel). 2023 Apr 14. pii: 2297. [Epub ahead of print]15(8):
    Radiomics of Tumor Heterogeneity in 18F-FDG-PET-CT for Predicting Response to Immune Checkpoint Inhibition in Therapy-Naïve Patients with Advanced Non-Small-Cell Lung Cancer.
    David Ventura, Philipp Schindler, Max Masthoff, Dennis Görlich, Matthias Dittmann, Walter Heindel, Michael Schäfers, Georg Lenz, Eva Wardelmann, Michael Mohr, Peter Kies, Annalen Bleckmann, Wolfgang Roll, Georg Evers.
      We aimed to evaluate the predictive and prognostic value of baseline 18F-FDG-PET-CT (PET-CT) radiomic features (RFs) for immune checkpoint-inhibitor (CKI)-based first-line therapy in advanced non-small-cell lung cancer (NSCLC) patients. In this retrospective study 44 patients were included. Patients were treated with either CKI-monotherapy or combined CKI-based immunotherapy-chemotherapy as first-line treatment. Treatment response was assessed by the Response Evaluation Criteria in Solid Tumors (RECIST). After a median follow-up of 6.4 months patients were stratified into "responder" (n = 33) and "non-responder" (n = 11). RFs were extracted from baseline PET and CT data after segmenting PET-positive tumor volume of all lesions. A Radiomics-based model was developed based on a Radiomics signature consisting of reliable RFs that allow classification of response and overall progression using multivariate logistic regression. These RF were additionally tested for their prognostic value in all patients by applying a model-derived threshold. Two independent PET-based RFs differentiated well between responders and non-responders. For predicting response, the area under the curve (AUC) was 0.69 for "PET-Skewness" and 0.75 predicting overall progression for "PET-Median". In terms of progression-free survival analysis, patients with a lower value of PET-Skewness (threshold < 0.2014; hazard ratio (HR) 0.17, 95% CI 0.06-0.46; p < 0.001) and higher value of PET-Median (threshold > 0.5233; HR 0.23, 95% CI 0.11-0.49; p < 0.001) had a significantly lower probability of disease progression or death. Our Radiomics-based model might be able to predict response in advanced NSCLC patients treated with CKI-based first-line therapy.
    Keywords:  FDG-PET-CT; NSCLC; PD-1; PD-L1; TPS; artificial intelligence; immune checkpoint inhibition; pembrolizumab; radiomics
    DOI:  https://doi.org/10.3390/cancers15082297
  13. J Clin Oncol. 2023 May 20. 41(15): 2682-2690
    Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy.
    Nasser Hanna, Frances A Shepherd, Frank V Fossella, Jose R Pereira, Filippo De Marinis, Joachim von Pawel, Ulrich Gatzemeier, Thomas Chang Yao Tsao, Miklos Pless, Thomas Muller, Hong-Liang Lim, Christopher Desch, Klara Szondy, Radj Gervais, Shaharyar, Christian Manegold, Sofia Paul, Paolo Paoletti, Lawrence Einhorn, Paul A Bunn.
      PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy.PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m2 intravenously (IV) day 1 with vitamin B12, folic acid, and dexamethasone or docetaxel 75 mg/m2 IV day 1 with dexamethasone every 21 days. The primary end point was overall survival.
    RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P < .001), febrile neutropenia (12.7% v 1.9%; P < .001), neutropenia with infections (3.3% v 0.0%; P = .004), hospitalizations for neutropenic fever (13.4% v 1.5%; P < .001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P = .092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P < .001) and all grade alopecia (37.7% v 6.4%; P < .001) compared with patients receiving pemetrexed.
    CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.
    DOI:  https://doi.org/10.1200/JCO.22.02546
  14. J Thorac Dis. 2023 Apr 28. 15(4): 1892-1900
    C-reactive protein and lactate dehydrogenase serum levels potentially predict the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer.
    Yilun Wei, Jinhe Xu, Xiulian Huang, Siting Xie, Ping Lin, Chenxi Wang, Yuxin Guo, Shumei Zou, Zhongquan Zhao, Wen Wen, Yingfang Song, Zhenming Bao, Lei Zhang, Wei Liu, Wencui Kong, Wenwu Wang, Baochang He, Shenghang Zhang, Chengzhi Zhou, Ying Chen, Zongyang Yu.
      Background: Programmed cell death-ligand 1 (PD-L1) expression and other biomarkers are not completely reliable predictors of the response to checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC). We investigated the value of peripheral serological inflammatory indicators and their combination in predicting the prognosis of patients with advanced NSCLC treated with checkpoint inhibitors.Methods: This study retrospectively analyzed 116 NSCLC patients treated with anti-programmed cell death protein 1 (PD-1)/PD-L1 monoclonal antibodies. Clinical data of the patients were collected before treatment. X-tile plots determined the optimal cut-point for C-reactive protein (CRP) and lactate dehydrogenase (LDH). A survival analysis was performed using the Kaplan-Meier method. Multi-factor Cox regression analysis was used to evaluate the statistically significant factors identified in the univariate analysis.
    Results: The X-tile plots show the cut-points of CRP and LDH were 8 mg/L and 312 U/L, respectively. Univariate analyses showed high baseline serum LDH and low CRP levels were associated with adverse progression-free survival (PFS). Multivariate analyses indicated that CRP (HR, 0.214, 95% CI: 0.053-0.857, P=0.029) could be a predictive indicator for PFS. In addition, we evaluated the combination of CRP and LDH, and univariate analyses showed that patients with high CRP and low LDH exhibited significantly better PFS than those in the other groups.
    Conclusions: Baseline levels of serum CRP and LDH have the potential to become a convenient clinical tool to predict response to immunotherapy in advanced non-small cell lung cancer.
    Keywords:  C-reactive protein (CRP); Non-small cell lung cancer (NSCLC); checkpoint inhibitors; lactic dehydrogenase (LDH)
    DOI:  https://doi.org/10.21037/jtd-23-240
  15. Int J Mol Sci. 2023 Apr 24. pii: 7771. [Epub ahead of print]24(9):
    Metabolic Effects of New Glucose Transporter (GLUT-1) and Lactate Dehydrogenase-A (LDH-A) Inhibitors against Chemoresistant Malignant Mesothelioma.
    Marika A Franczak, Oliwia Krol, Gabriela Harasim, Agata Jedrzejewska, Nadia Zaffaroni, Carlotta Granchi, Filippo Minutolo, Amir Avan, Elisa Giovannetti, Ryszard T Smolenski, Godefridus J Peters.
      Malignant mesothelioma (MM) is a highly aggressive and resistant tumor. The prognostic role of key effectors of glycolytic metabolism in MM prompted our studies on the cytotoxicity of new inhibitors of glucose transporter type 1 (GLUT-1) and lactate dehydrogenase-A (LDH-A) in relation to ATP/NAD+ metabolism, glycolysis and mitochondrial respiration. The antiproliferative activity of GLUT-1 (PGL13, PGL14) and LDH-A (NHI-1, NHI-2) inhibitors, alone and in combination, were tested with the sulforhodamine-B assay in peritoneal (MESO-II, STO) and pleural (NCI-H2052 and NCI-H28) MM and non-cancerous (HMEC-1) cells. Effects on energy metabolism were measured by both analysis of nucleotides using RP-HPLC and evaluation of glycolysis and respiration parameters using a Seahorse Analyzer system. All compounds reduced the growth of MM cells in the µmolar range. Interestingly, in H2052 cells, PGL14 decreased ATP concentration from 37 to 23 and NAD+ from 6.5 to 2.3 nmol/mg protein. NHI-2 reduced the ATP/ADP ratio by 76%. The metabolic effects of the inhibitors were stronger in pleural MM and in combination, while in HMEC-1 ATP reduction was 10% lower compared to that of the H2052 cells, and we observed a minor influence on mitochondrial respiration. To conclude, both inhibitors showed cytotoxicity in MM cells, associated with a decrease in ATP and NAD+, and were synergistic in the cells with the highest metabolic modulation. This underlines cellular energy metabolism as a potential target for combined treatments in selected cases of MM.
    Keywords:  anticancer treatment; cancer metabolism; chemoresistance; glucose transporter type 1; lactate dehydrogenase; malignant mesothelioma
    DOI:  https://doi.org/10.3390/ijms24097771
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