bims-meluca 2022-04-17 papers

J Cancer Res Clin Oncol. 2022 Apr 09.

Immunological and nutritional predictive factors in patients receiving pembrolizumab for the first-line treatment of non-small cell lung cancer.

Naoki Shijubou, Toshiyuki Sumi, Yuichi Yamada, Hisashi Nakata, Yuji Mori, Hirofumi Chiba.

PURPOSE: Immune checkpoint inhibitors (ICIs) have prolonged the survival of patients with various carcinomas, including non-small cell lung cancer (NSCLC), and have caused a paradigm shift in cancer treatment. Although programmed death-ligand 1 (PD-L1) expression in tumor cells is a predictive marker of therapeutic efficacy, additional predictive markers are required. This study aimed to explore the role of immunological and nutritional parameters in the prediction of treatment response.
METHODS: Patients diagnosed with NSCLC and treated with pembrolizumab were examined retrospectively. Body weight was measured 4-6 weeks before the start of the first treatment, immediately before treatment, and 4-6 weeks after the start of the first treatment. Progression-free survival (PFS) was defined as the time from the start of pembrolizumab treatment to the last follow-up date or until disease progression. Statistical analyses were performed to confirm the association between various factors and association between these factors and PFS.
RESULTS: Thirty-eight patients with advanced NSCLC were included. We observed a significant association of weight loss and PD-L1 expression with PFS in the multivariate analysis. A significant correlation was found between the advanced lung cancer inflammation index and neutrophil-to-lymphocyte ratio. A weight loss of > 5% after the start of treatment was significantly associated with worse PFS.
CONCLUSIONS: Weight loss is an important negative prognostic factor in patients with NSCLC receiving immunotherapy. Weight maintenance may be important for good ICI treatment efficacy, and future interventions in cancer cachexia are expected to further enhance the treatment efficacy of ICIs.

Keywords: Lung cancer; PDL-1; Pembrolizumab; Predictive factor

DOI: https://doi.org/10.1007/s00432-022-03941-2

Phytomedicine. 2022 Apr 04. pii: S0944-7113(22)00153-2. [Epub ahead of print]100 154075

Osmundacetone modulates mitochondrial metabolism in non-small cell lung cancer cells by hijacking the glutamine/glutamate/α-KG metabolic axis.

Yue Yang, Pingya He, Yuhao Hou, Zhicheng Liu, Xiaoping Zhang, Ning Li.

BACKGROUND: Osmundacetone (OSC) is a bioactive phenolic compound isolated from Phellinus igniarius and that was shown to exert cytotoxic effects on cancer cells in our previous work. The antiproliferative impact of OSC on non-small cell lung cancer (NSCLC) and the underlying mechanisms, however, have not been studied.
PURPOSE: This study aimed to explore the antiproliferative effect of OSC on NSCLC cells and the mechanisms involved.
METHODS: Cell viability, colony formation and cell cycle distribution were measured following exposure to OSC in vitro. The anticancer activity of OSC was also examined using a xenograft growth assay in vivo. Furthermore, serum metabolomics analysis by GC-MS was done to detect alterations in the metabolic profile. Next, expression of GLS1 and GLUD1, the key enzymes in glutamine metabolism, was evaluated using RT-PCR and western blot. α-KG and NADH metabolites were assessed by ELISA. Mitochondrial functions and morphology were evaluated using the JC-1 probe and transmission electron microscopy, respectively. The ATP production rate in mitochondria of cells with OSC treatment was determined using a Seahorse XFe24 Analyzer.
RESULTS: OSC selectively reduced the proliferation of A549 and H460 cells. OSC triggered G2/M cell cycle arrest and decreased the cell clone formation. A mouse xenograft model revealed that OSC inhibited tumor growth in vivo. Findings of serum metabolomics analyses indicated that the anticancer function of OSC was related to disorders of glutamine metabolism. Such a speculation was further verified by the expression level of GLUD1, which was downregulated by OSC treatment. Concentrations of the related metabolites α-KG and NADH were reduced in response to OSC treatment. Moreover, OSC led to disorganization of the mitochondrial ultrastructure and a decrease in mitochondrial membrane potential. OSC also decreased ATP production via oxidative phosphorylation (OXPHOS) but did not affect glycolysis in NSCLC cells.
CONCLUSION: The key role of OSC in mitochondrial energy metabolism in NSCLC cells is to suppress tumor development and cell proliferation downregulating GLUD1 to inhibit the glutamine/glutamate/α-KG metabolic axis and OXPHOS. It indicats that OSC might be a potential natural agent for personalized medicine and an anticancer metabolic modulator in NSCLC chemotherapy.

Keywords: Abbreviations: α-KG, α-ketoglutaric acid; Antiproliferation; Glud1; Glutamine metabolism; Nsclc; Osmundacetone

DOI: https://doi.org/10.1016/j.phymed.2022.154075

Aging (Albany NY). 2022 Apr 11. 14(undefined):

The role of fructose 1,6-bisphosphate-mediated glycolysis/gluconeogenesis genes in cancer prognosis.

Chien-Hsiu Li, Ming-Hsien Chan, Yu-Chan Chang.

Metabolic reprogramming and elevated glycolysis levels are associated with tumor progression. However, despite cancer cells selectively inhibiting or expressing certain metabolic enzymes, it is unclear whether differences in gene profiles influence patient outcomes. Therefore, identifying the differences in enzyme action may facilitate discovery of gene ontology variations to characterize tumors. Fructose-1,6-bisphosphate (F-1,6-BP) is an important intermediate in glucose metabolism, particularly in cancer. Gluconeogenesis and glycolysis require fructose-1,6-bisphosphonates 1 (FBP1) and fructose-bisphosphate aldolase A (ALDOA), which participate in F-1,6-BP conversion. Increased expression of ALDOA and decreased expression of FBP1 are associated with the progression of various forms of cancer in humans. However, the exact molecular mechanism by which ALDOA and FBP1 are involved in the switching of F-1,6-BP is not yet known. As a result of their pancancer pattern, the relationship between ALDOA and FBP1 in patient prognosis is reversed, particularly in lung adenocarcinoma (LUAD) and liver hepatocellular carcinoma (LIHC). Using The Cancer Genome Atlas (TCGA), we observed that FBP1 expression was low in patients with LUAD and LIHC tumors, which was distinct from ALDOA. A similar trend was observed in the analysis of Cancer Cell Line Encyclopedia (CCLE) datasets. By dissecting downstream networks and possible upstream regulators, using ALDOA and FBP1 as the core, we identified common signatures and interaction events regulated by ALDOA and FBP1. Notably, the identified effectors dominated by ALDOA or FBP1 were distributed in opposite patterns and can be considered independent prognostic indicators for patients with LUAD and LIHC. Therefore, uncovering the effectors between ALDOA and FBP1 will lead to novel therapeutic strategies for cancer patients.

Keywords: ALDOA; FBP1; bioinformatics; cancer metabolism; prognosis

DOI: https://doi.org/10.18632/aging.204010

Transl Cancer Res. 2022 Mar;11(3): 519-529

CircPTN promotes angiogenesis via the MiR-595/LYRM5 signaling pathway in non-small cell lung cancer.

Shengcong Guo, Zejun Mao, Guodong Zhang, Botao Xu, Xiangfeng He.

Background: Non-small cell lung carcinoma (NSCLC) is a highly malignant tumor with a poor prognosis worldwide. Some studies have demonstrated that circular pleiotrophin (circPTN) plays critical roles in tumorigenesis and tumor development. However, little is known about the role of circPTN in NSCLC.
Methods: The circPTN expression in human NSCLC tissues was measured via quantitative real-time polymerase chain reaction (qRT-PCR). The function and potential mechanisms of circPTN in NSCLC angiogenesis were also investigated. We aimed to explore the function and potential mechanisms and clinical significance of circPTN in NSCLC.
Results: We first found that circPTN was markedly upregulated in NSCLC tissues. A higher circPTN level was closely associated with angiogenesis and significantly shorter overall survival in patients with NSCLC. We then found that circPTN promoted angiogenesis in NSCLC. More importantly, we found that circPTN facilitated angiogenesis by regulating the expression of LYRM5 in NSCLC. Mechanistically, LYRM5 could be a direct target of microRNA-595 (miR-595). Additionally, we demonstrated that circPTN upregulated LYRM5 expression by sponging miR-595, which promoted NSCLC angiogenesis in NSCLC.
Conclusions: We found that circPTN serves as a competing endogenous ribonucleic acid that promotes angiogenesis via the miR-595/LYRM5 signaling pathway in NSCLC. Targeting circPTN might be a promising new therapeutic strategy for NSCLC.

Keywords: Angiogenesis; CircPTN; LYRM5; MiR-595; non-small cell lung cancer (NSCLC)

DOI: https://doi.org/10.21037/tcr-22-195

ESMO Open. 2022 Apr 07. pii: S2059-7029(22)00061-8. [Epub ahead of print]7(2): 100445

Biomarkers of systemic inflammation predict survival with first-line immune checkpoint inhibitors in non-small-cell lung cancer.

M Stares, T E Ding, C Stratton, F Thomson, M Baxter, H Cagney, K Cumming, A Swan, F Ross, C Barrie, K Maclennan, S Campbell, T Evans, A Tufail, S Harrow, H Lord, B Laird, M MacKean, I Phillips.

INTRODUCTION: Pembrolizumab is an established first-line option for patients with advanced non-small-cell lung cancer (NSCLC) expressing programmed death-ligand 1 ≥50%. Durable responses are seen in a subset of patients; however, many derive little clinical benefit. Biomarkers of the systemic inflammatory response predict survival in NSCLC. We evaluated their prognostic significance in patients receiving first-line pembrolizumab for advanced NSCLC.
METHODS: Patients treated with first-line pembrolizumab for advanced NSCLC with programmed death-ligand 1 expression ≥50% at two regional Scottish cancer centres were identified. Pretreatment inflammatory biomarkers (white cell count, neutrophil count, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albumin, prognostic nutritional index) were recorded. The relationship between these and progression-free survival (PFS) and overall survival (OS) were examined.
RESULTS: Data were available for 219 patients. On multivariate analysis, albumin and neutrophil count were independently associated with PFS (P < 0.001, P = 0.002, respectively) and OS (both P < 0.001). A simple score combining these biomarkers was explored. The Scottish Inflammatory Prognostic Score (SIPS) assigned 1 point each for albumin <35 g/l and neutrophil count >7.5 × 109/l to give a three-tier categorical score. SIPS predicted PFS [hazard ratio 2.06, 95% confidence interval (CI) 1.68-2.52 (P < 0.001)] and OS [hazard ratio 2.33, 95% CI 1.86-2.92 (P < 0.001)]. It stratified PFS from 2.5 (SIPS2), to 8.7 (SIPS1) to 17.9 months (SIPS0) (P < 0.001) and OS from 5.1 (SIPS2), to 12.4 (SIPS1) to 28.7 months (SIPS0) (P < 0.001). The relative risk of death before 6 months was 2.96 (95% CI 1.98-4.42) in patients with SIPS2 compared with those with SIPS0-1 (P < 0.001).
CONCLUSIONS: SIPS, a simple score combining albumin and neutrophil count, predicts survival in patients with NSCLC receiving first-line pembrolizumab. Unlike many proposed prognostic scores, SIPS uses only routinely collected pretreatment test results and provides a categorical score. It stratifies survival across clinically meaningful time periods that may assist clinicians and patients with treatment decisions. We advocate validation of the prognostic utility of SIPS in this and other immune checkpoint inhibitor treatment settings.

Keywords: Scottish Inflammatory Prognostic Score (SIPS); biomarker; immune checkpoint inhibitors; inflammation; non-small-cell lung cancer (NSCLC); prognosis

DOI: https://doi.org/10.1016/j.esmoop.2022.100445

Cancer Diagn Progn. 2021 May-Jun;1(2):1(2): 61-67

Visceral Adipose Mass and Radiation Pneumonitis After Concurrent Chemoradiotherapy in Patients With Non-small-cell Lung Cancer.

Kuniaki Katsui, Takeshi Ogata, Soichi Sugiyama, Kotaro Yoshio, Masahiro Kuroda, Masaomi Yamane, Takao Hiraki, Katsuyuki Kiura, Shinichi Toyooka, Susumu Kanazawa.

Aim: To investigate whether muscle and adipose mass are associated with radiation pneumonitis (RP) in patients with non-small cell lung cancer undergoing preoperative concurrent chemoradiotherapy.
Patients and Methods: We calculated body mass index and determined skeletal muscle, psoas muscle, visceral adipose tissue (VAI), and subcutaneous adipose tissue indices, and visceral-to-subcutaneous adipose tissue area ratio for patients using computed tomography. We examined their relationship with grade 2 or more RP.
Results: Among 94 patients, 28 experienced grade 2 or more RP. On multivariate analysis, only VAI was associated with grade 2 or more RP (all p=0.026). The 6-month incidence rates of grade 2 or more RP were 21.4% and 36.8% in patients with VAI <39 and ≥39 cm 2 /m 2 , respectively.
Conclusion: High visceral adipose mass is associated with grade 2 or more RP in patients undergoing preoperative concurrent chemoradiotherapy. Measuring visceral adipose mass may help to predict RP occurrence. Further studies are needed to validate our findings.

Keywords: Non-small-cell lung cancer; chemoradiotherapy; intraabdominal fat; lung neoplasms; radiation pneumonitis

DOI: https://doi.org/10.21873/cdp.10009