bims-meluca 2020-05-17 papers

J Clin Pharm Ther. 2020 May 14.

The effect of metformin on lung cancer risk and survival in patients with type 2 diabetes mellitus: A meta-analysis.

Kang Xiao, Fengxi Liu, Juan Liu, Jiwei Xu, Qiuyun Wu, Xiao Li.

WHAT IS KNOWN AND OBJECTIVE: Metformin has received increasing attention owing to its potential protective effect against cancer. We aimed to summarize evidence regarding the association between metformin and the risk or survival in lung cancer patients with type 2 diabetes.
METHODS: We selected observational studies examining the association between exposure to metformin and the risk or survival in lung cancer. Available publications were searched in PubMed, Cochrane Library, ScienceDirect, Wiley and SpringerLink databases. Meta-analysis was performed with hazard ratios (HRs) and 95% confidence intervals (95% CIs) as effect measures for risk or survival in lung cancer.
RESULTS: Eighteen studies (eight on lung cancer risk and ten on lung cancer survival) were included. Metformin treatment was associated with decreased lung cancer incidence (HR 0.78; 95% CI 0.70-0.86) and increased lung cancer survival (HR 0.65; 95% CI 0.55-0.77). In the subgroup analysis by ethnicity, a significant protective effect of metformin use on lung cancer risk was observed among Asian patients (HR 0.66; 95% CI 0.56-0.76), but not in European patients. On the other hand, the protective effect of metformin use on lung cancer survival was observed in both Asian (HR 0.57; 95% CI 0.49-0.66) and non-Asian (HR 0.79; 95% CI 0.71-0.88) patients. In the subgroup analysis by histology, a protective effect of metformin on lung cancer survival was observed in both non-small-cell lung cancer (HR 0.68; 95% CI 0.54-0.84) and small-cell lung cancer (HR 0.52; 95% CI 0.39-0.69). Funnel plot showed that no significant publication bias existed.
CONCLUSIONS: Our findings demonstrate that metformin is significantly associated with a decreased risk and increased survival in lung cancer.

Keywords: lung cancer incidence; lung cancer survival; meta-analysis; metformin; type 2 diabetes mellitus

DOI: https://doi.org/10.1111/jcpt.13167

J Thorac Dis. 2020 Apr;12(4): 1520-1528

The impact of immune-inflammation-nutritional parameters on the prognosis of non-small cell lung cancer patients treated with atezolizumab.

Taichi Matsubara, Shinkichi Takamori, Naoki Haratake, Ryo Toyozawa, Naoko Miura, Mototsugu Shimokawa, Masafumi Yamaguchi, Takashi Seto, Mitsuhiro Takenoyama.

Background: Immunotherapy targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has become the forefront strategy for systemic therapy in advanced non-small cell lung cancer (NSCLC) patients. PD-L1 expression on tumor cells has been reported as an eligible biomarker of response to such immunotherapies. However, useful biomarkers of response to atezolizumab, an anti PD-L1 antibody, are unestablished.
Methods: We retrospectively analyzed clinicopathological characteristics including PD-L1 expression in NSCLC patients treated with atezolizumab from January 2018 at our department. In addition, we investigated the prognostic effect of the following pretreatment immune-inflammation-nutritional parameters: prognostic nutritional index (PNI), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and modified Glasgow prognostic score (mGPS).
Results: Twenty-four patients were enrolled in this study. The median age was 64.5 (range, 49-82) years, and 17 (70.8%) were men. Among this cohort, two patients showed high PD-L1 expression (≥50%), seven showed low (1-49%) expression, and the other 15 patients showed 0% or unknown expression. Survival analyses showed that low PNI was an independent predictor of short time to treatment failure (TTF) [hazard ratio (HR) =6.87, P=0.0052], and high NLR (HR =3.53, P=0.0375) and high mGPS (HR =23.2, P=0.0038) were independent prognostic factors for overall survival (OS) after atezolizumab. Furthermore, the NLR high/mGPS high group had far worse prognosis than the NLR low/mGPS low group.
Conclusions: The therapeutic and prognostic effect of atezolizumab may depend on the host immune-nutritional status. This study provided novel but retrospective evidence, and thus further prospective studies are needed.

Keywords: Immunotherapy; modified Glasgow prognostic score (mGPS); neutrophil/lymphocyte ratio (NLR); non-small cell lung cancer (NSCLC); prognostic nutritional index (PNI)

DOI: https://doi.org/10.21037/jtd.2020.02.27

Thorac Cancer. 2020 May 12.

Cytoplasmic, but not nuclear Nrf2 expression, is associated with inferior survival and relapse rate and response to platinum-based chemotherapy in non-small cell lung cancer.

Ming-Jenn Chen, Po-Lin Lin, Lee Wang, Ya-Min Cheng, Chih-Yi Chen, Huei Lee.

BACKGROUND: Several studies have previously indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) expression may promote tumor progression when the Keap1/Nrf2 pathway is activated, but few reports have demonstrated the role of cytoplasmic Nrf2 on tumorigenesis.
METHODS: Immunohistochemistry was conducted to evaluate Nrf2 expression in 167 tumors from surgically-resected patients with non-small cell lung cancer (NSCLC). Univariate and multivariate analyses were performed to examine the association of Nrf2 expression with patients' prognosis. This study was conducted to examine the association of Nrf2 expression with tumor response to cisplatin-based chemotherapy.
RESULTS: Among these tumors, 56 and 32 of 167 tumors expressed Nrf2 in the cytoplasm (34% for C+/N-) and in the cytoplasm/nucleus (19% for C+/N+), but not in the nucleus of tumor cells. Nrf2 was negatively expressed in the remainder of the tumor samples (C-/N-, 79 of 167, 47%). Univariate analysis indicated that patients with Nrf2 positive tumors (C+/N- plus C+/N+) had worse overall survival (OS), but not relapse-free survival (RFS) than with Nrf2 negative tumors (C-/N-). However, patients with C+/N- tumors possessed worse OS and RFS than those with Nrf2 negative tumors (C-/N-). Multivariate analysis further confirmed the prognostic significance of patients with Nrf2 positive and C+/N- tumors on OS and RFS, but not on RFS for patients with Nrf2 positive tumors. Patients with Nrf2 positive and C+/N- tumors were determined to more frequently have an unfavorable response to cisplatin-based chemotherapy than those with Nrf2 negative tumors.
CONCLUSIONS: Cytoplasmic Nrf2 expression might potentially be used to predict poor prognosis and unfavorable response to cisplatin-based chemotherapy in patients with NSCLC.

Keywords: NSCLC; chemotherapeutic response; cytoplasmic Nrf2; prognosis

DOI: https://doi.org/10.1111/1759-7714.13479

Ann Palliat Med. 2020 Apr 21. pii: apm.2020.04.31. [Epub ahead of print]

The prognostic value of prognostic nutritional index (PNI) and neutrophil to lymphocyte ratio (NLR) for advanced non-small cell lung cancer treated with platinum-based chemotherapeutics.

Jian Wang, Yiqian Liu, Xiaoguang Mi, Mengting Shao, Lingxiang Liu.

BACKGROUND: The present study aimed to investigate the relationship between prognostic nutritional index (PNI) and peripheral blood neutrophil to lymphocyte ratio (NLR), and the prognosis of patients with advanced non-small cell lung cancer (NSCLC) treated with platinum-based therapeutics.
METHODS: The data of 99 advanced NSCLC patients treated with platinum chemotherapeutics between January 2011 and June 2019 were retrospectively analyzed. The association between PNI and NLR and the clinicopathological characteristics of the patients was examined. The patients were randomized into high or low groups according to PNI and NLR. The predictive value of PNI and NLR for overall survival (OS) was evaluated by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate Cox proportional hazards regression analyses were performed to investigate the prognostic factors of advanced NSCLC patients treated with platinum-based chemotherapeutics. The association between PNI and NLR and progression-free survival (PFS) or OS was determined using the Kaplan-Meier method and compared between groups using the log-rank test.
RESULTS: The ROC curve analysis determined the optimal cut-off values of PNI and NLR for predicting OS to be 52.525 and 3.525, respectively. Univariate analysis indicated that low Karnofsky performance scale (KPS) score (P=0.005), poor tumor differentiation (P=0.022), brain metastasis (P<0.001), and low PNI (P=0.001) were independent risk factors for PFS in patients with advanced NSCLC; however, there was no significant correlation observed between NLR (P=0.082) and PFS in patients with advanced NSCLC. Low KPS score (P=0.003), poor tumor differentiation (P=0.001), brain metastasis (P<0.001), low PNI (P<0.001), and high NLR (P=0.046) were significantly associated with shorter OS. Furthermore, Cox multivariate analysis revealed that brain metastasis (P=0.005) and low PNI (P=0.008) were significant independent prognostic factors for PFS, while brain metastasis (P=0.003) and low PNI (P=0.028) were also found to be significant independent risk factors for poor OS.
CONCLUSIONS: PNI is a reliable, simple, easily available, and inexpensive biomarker for predicting the prognosis of advanced NSCLC patients treated with platinum-based chemotherapeutics in routine clinical practice. Furthermore, PNI is superior to NLR in as a prognostic indicator for advanced NSCLC patients treated with platinum-based chemotherapeutics.

Keywords: Prognostic nutritional index (PNI); efficacy of chemotherapy; lung neoplasms; neutrophil to lymphocyte ratio (NLR); overall survival time (OS time)

DOI: https://doi.org/10.21037/apm.2020.04.31

Autophagy. 2020 May 13.

The anti-cancer drug ABTL0812 induces ER stress-mediated cytotoxic autophagy by increasing dihydroceramide levels in cancer cells.

ABTL0812 is a first-in-class small molecule with anti-cancer activity, which is currently in clinical evaluation in a phase 2 trial in patients with advanced endometrial and squamous non-small cell lung carcinoma (NCT03366480). Previously, we showed that ABTL0812 induces TRIB3 pseudokinase expression, resulting in the inhibition of the AKT-MTORC1 axis and macroautophagy/autophagy-mediated cancer cell death. However, the precise molecular determinants involved in the cytotoxic autophagy caused by ABTL0812 remained unclear. Using a wide range of biochemical and lipidomic analyses, we demonstrated that ABTL0812 increases cellular long-chain dihydroceramides by impairing DEGS1 (delta 4-desaturase, sphingolipid 1) activity, which resulted in sustained ER stress and activated unfolded protein response (UPR) via ATF4-DDIT3-TRIB3 that ultimately promotes cytotoxic autophagy in cancer cells. Accordingly, pharmacological manipulation to increase cellular dihydroceramides or incubation with exogenous dihydroceramides resulted in ER stress, UPR and autophagy-mediated cancer cell death. Importantly, we have optimized a method to quantify mRNAs in blood samples from patients enrolled in the ongoing clinical trial, who showed significant increased DDIT3 and TRIB3 mRNAs. This is the first time that UPR markers are reported to change in human blood in response to any drug treatment, supporting their use as pharmacodynamic biomarkers for compounds that activate ER stress in humans. Finally, we found that MTORC1 inhibition and dihydroceramide accumulation synergized to induce autophagy and cytotoxicity, phenocopying the effect of ABTL0812. Given the fact that ABTL0812 is under clinical development, our findings support the hypothesis that manipulation of dihydroceramide levels might represents a new therapeutic strategy to target cancer.

Keywords: ER stress; UPR; autophagy; cancer; clinical trial; dihydroceramide

DOI: https://doi.org/10.1080/15548627.2020.1761651