Meta-Analysis of the Efficacy and Safety of Pembrolizumab in the Treatment of Advanced Gastric Cancer and Gastroesophageal Junction Cancer.

INTRODUCTION: Pembrolizumab has been approved for the first-line treatment of patients with advanced gastric cancer (GC) and gastroesophageal junction (GEJ) cancer. However, the results of several clinical trials are not entirely consistent, and the dominant population of first-line immunotherapy for advanced GC/GEJ still needs to be precisely determined. PURPOSE: The aim of this meta-analysis was to assess the efficacy and safety of pembrolizumab in the treatment of advanced GC/GEJ. METHODS: We conducted computerized searches across multiple databases, including PubMed, Cochrane Library, Web of Science, and Embase. We established the inclusion criteria to comprise randomized clinical trials examining the efficacy of pembrolizumab in late-stage GC/GCJ cancer. We conducted a meta-analysis of outcome measures using STATA 14.0 software. RESULTS: A total of six studies involving 1,448 cases were included in this analysis. The results of the meta-analysis indicate that, when compared to chemotherapy, patients in the pembrolizumab group experienced a significant reduction in the risk of mortality in terms of overall survival (OS) (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.65-0.79, p < 0.01). In terms of progression-free survival (PFS), pembrolizumab was associated with a similar PFS as compared to chemotherapy (HR = 0.88, 95% CI: 0.73-1.07, p = 0.206). Subgroup analyses based on PD-L1 expression levels indicated a significantly longer PFS with pembrolizumab in subgroups of patients with PD-L1 CPS ≥10 but not in those with PD-L1 CPS ≥1 and PD-L1 CPS ≥5. Subgroup analyses based on distinct geographical regions revealed a comparable effect of PFS in patients residing in Asia or the USA Subgroup analysis based on tumor sites consistently demonstrated a similar effect of PFS in patients with EC/GEJ tumors and GC patients. CONCLUSION: Our findings demonstrated that pembrolizumab led to a significant extension in OS and objective response rate, along with a favorable tolerability profile compared to chemotherapy. Furthermore, the observed survival benefits were particularly pronounced in subgroup patients with a CPS of ≥10. Given the potential limitations inherent in our study, it is imperative to underscore the necessity for further large-scale RCTs to corroborate our results.

Prior frequency guided diffusion model for limited angle (LA)-CBCT reconstruction.

Objective.Cone-beam computed tomography (CBCT) is widely used in image-guided radiotherapy. Reconstructing CBCTs from limited-angle acquisitions (LA-CBCT) is highly desired for improved imaging efficiency, dose reduction, and better mechanical clearance. LA-CBCT reconstruction, however, suffers from severe under-sampling artifacts, making it a highly ill-posed inverse problem. Diffusion models can generate data/images by reversing a data-noising process through learned data distributions; and can be incorporated as a denoiser/regularizer in LA-CBCT reconstruction. In this study, we developed a diffusion model-based framework, prior frequency-guided diffusion model (PFGDM), for robust and structure-preserving LA-CBCT reconstruction.Approach.PFGDM uses a conditioned diffusion model as a regularizer for LA-CBCT reconstruction, and the condition is based on high-frequency information extracted from patient-specific prior CT scans which provides a strong anatomical prior for LA-CBCT reconstruction. Specifically, we developed two variants of PFGDM (PFGDM-A and PFGDM-B) with different conditioning schemes. PFGDM-A applies the high-frequency CT information condition until a pre-optimized iteration step, and drops it afterwards to enable both similar and differing CT/CBCT anatomies to be reconstructed. PFGDM-B, on the other hand, continuously applies the prior CT information condition in every reconstruction step, while with a decaying mechanism, to gradually phase out the reconstruction guidance from the prior CT scans. The two variants of PFGDM were tested and compared with current available LA-CBCT reconstruction solutions, via metrics including peak signal-to-noise ratio (PSNR) and structural similarity index measure (SSIM).Main results.PFGDM outperformed all traditional and diffusion model-based methods. The mean(s.d.) PSNR/SSIM were 27.97(3.10)/0.949(0.027), 26.63(2.79)/0.937(0.029), and 23.81(2.25)/0.896(0.036) for PFGDM-A, and 28.20(1.28)/0.954(0.011), 26.68(1.04)/0.941(0.014), and 23.72(1.19)/0.894(0.034) for PFGDM-B, based on 120°, 90°, and 30° orthogonal-view scan angles respectively. In contrast, the PSNR/SSIM was 19.61(2.47)/0.807(0.048) for 30° for DiffusionMBIR, a diffusion-based method without prior CT conditioning.Significance. PFGDM reconstructs high-quality LA-CBCTs under very-limited gantry angles, allowing faster and more flexible CBCT scans with dose reductions.

Prior Frequency Guided Diffusion Model for Limited Angle (LA)-CBCT Reconstruction.

Cone-beam computed tomography (CBCT) is widely used in image-guided radiotherapy. Reconstructing CBCTs from limited-angle acquisitions (LA-CBCT) is highly desired for improved imaging efficiency, dose reduction, and better mechanical clearance. LA-CBCT reconstruction, however, suffers from severe under-sampling artifacts, making it a highly ill-posed inverse problem. Diffusion models can generate data/images by reversing a data-noising process through learned data distributions; and can be incorporated as a denoiser/regularizer in LA-CBCT reconstruction. In this study, we developed a diffusion model-based framework, prior frequency-guided diffusion model (PFGDM), for robust and structure-preserving LA-CBCT reconstruction. PFGDM uses a conditioned diffusion model as a regularizer for LA-CBCT reconstruction, and the condition is based on high-frequency information extracted from patient-specific prior CT scans which provides a strong anatomical prior for LA-CBCT reconstruction. Specifically, we developed two variants of PFGDM (PFGDM-A and PFGDM-B) with different conditioning schemes. PFGDM-A applies the high-frequency CT information condition until a pre-optimized iteration step, and drops it afterwards to enable both similar and differing CT/CBCT anatomies to be reconstructed. PFGDM-B, on the other hand, continuously applies the prior CT information condition in every reconstruction step, while with a decaying mechanism, to gradually phase out the reconstruction guidance from the prior CT scans. The two variants of PFGDM were tested and compared with current available LA-CBCT reconstruction solutions, via metrics including PSNR and SSIM. PFGDM outperformed all traditional and diffusion model-based methods. PFGDM reconstructs high-quality LA-CBCTs under very-limited gantry angles, allowing faster and more flexible CBCT scans with dose reductions.

A novel lung cancer stem cell extracellular vesicles lncRNA ROLLCSC modulate non-stemness cancer cell plasticity through miR-5623-3p and miR-217-5p targeting lipid metabolism.

BACKGROUND: The high mortality rate of lung cancer is largely attributed to metastasis. Lung cancer stem cells (CSC) are conducive to cancer heterogeneity. Long noncoding RNAs are known to participate in various biological processes regulating the development of lung cancer. However, characterization of the role and mechanisms of lncRNA in lung cancer metastasis remains a challenge. RESULTS: We demonstrate that ROLLCSC, a highly expressed lncRNA in LLC-SDs, promotes the metastasis of the low metastatic LLCs both in vitro and in vivo. ROLLCSC can be transferred from LLC-SD to LLC through encapsulation in extracellular vesicles (EVs), ultimately leading to the enhancement of the metastatic phenotype of LLCs. Mechanistically, we demonstrate that the pro-metastatic activity of ROLLCSC is achieved through its function as a competing endogenous RNA (ceRNA) of miR-5623-3p and miR-217-5p to stimulate lipid metabolism. CONCLUSION: In this study, we have characterized ROLLCSC, a novel lncRNA, as a pivotal regulator in the metastasis of lung cancer, highlighting its potential as a therapeutic target. Specifically, we show that ROLLCSC is encapsulated by the EVs of LLC-SDs and transmitted to the LLCs, where it acts as a ceRNA of miR-5623-3p and miR-217-5p to stimulate lipid metabolism and ultimately augments metastatic colonization of LLCs.

Novel lncRNA Gm33149 modulates metastatic heterogeneity in melanoma by regulating the miR-5623-3p/Wnt axis via exosomal transfer.

The high mortality rate associated with melanoma primarily results from metastasis and recurrence. However, the precise mechanisms driving these processes remain poorly understood. Intercellular communication between cancer cells and non-cancer cells significantly influences the tumor microenvironment and plays a crucial role in metastasis. Therefore, our current study aims to investigate the role and mechanism of long non-coding RNAs (lncRNAs) in regulating the interaction between melanoma cancer stem cells (CSCs) and non-CSCs during the metastatic colonization process. This study has characterized a novel lncRNA called Gm33149. Importantly, we provide evidence for the first time that Gm33149, originating from highly metastatic melanoma stem cells (OL-SD), can be packaged into exosomes and transferred to low-metastatic nonstem cells (OL). Once internalized by OL cells, Gm33149 exerts its function through a competitive endogenous RNA mechanism (ceRNA) involving miR-5623-3p. Specifically, Gm33149 competitively binds to miR-5623-3p, thereby activating the Wnt signaling pathway and promoting the acquisition of a more aggressive metastatic phenotype by OL cells. In summary, our findings suggest that targeting lncRNA Gm33149 within extracellular vesicles could potentially serve as a therapeutic strategy for the treatment of metastatic melanoma. Schematic representation of the mechanisms underlying the pro-metastatic activity of lncRNA Gm33149 mediated by exosomal transfer. The figure illustrates the key mechanisms involved in the pro-metastatic activity of lncRNA Gm33149 through exosomal transfer. Melanoma stem cells (OLSD) release exosomes containing lncRNA Gm33149. These exosomes are taken up by non-stem melanoma cells (OL), delivering lncRNA Gm33149 to the recipient cells. Within OL cells, lncRNA Gm33149 functions as a competitive endogenous RNA (ceRNA), sequestering miR-5623-3p. This sequestration prevents miR-5623-3p from binding to its target genes, thereby activating the Wnt signaling pathway. The activated Wnt signaling pathway enhances the migration, invasion, and metastatic colonization capabilities of OL cells. The transfer of lncRNA Gm33149 via exosomes contributes to OL cells acquiring "metastatic competency" while promoting their metastatic colonization. These findings underscore the importance of lncRNA Gm33149 in intercellular communication and the metastatic progression of melanoma.

Metabolite profiling analysis of hepatitis B virus-induced liver cirrhosis patients with minimal hepatic encephalopathy using gas chromatography-time-of-flight mass spectrometry and ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry.

This study used gas chromatography-time-of-flight mass spectrometry (GC-TOFMS) and ultra-performance liquid chromatography-quadrupole TOFMS (UPLC-QTOFMS) metabonomic analytical techniques in combination with bioinformatics and pattern recognition analysis methods to analyze the serum metabolite profiling of hepatitis B virus (HBV)-induced liver cirrhosis patients with minimal hepatic encephalopathy (MHE), to find the specific biomarkers of MHE, to reveal the pathogenesis of MHE, and to determine a promising approach for early diagnosis of MHE. Serum samples of 100 normal controls (NC group), 29 HBV-induced liver cirrhosis patients with MHE (MHE group), and 24 HBV-induced liver cirrhosis patients without MHE [comprising 12 cases of compensated cirrhosis (CS group) and 12 cases of decompensated cirrhosis (DS group)] were collected and employed into GC-TOFMS and UPLC-QTOFMS platforms for serum metabolite detection; the outcome data were then analyzed using principal component analysis and orthogonal partial least squares-discriminant analysis (OPLS-DA). There were no significant differential metabolites between the NC group and the CS group. A series of key differential metabolites were detected. According to the variable influence in projection values and P-values, 60 small-molecule metabolites were considered to be dysregulated in the MHE group (compared to the NC group); 27 of these 60 dysregulated differential metabolites were considered to be the potential biomarkers (see Table 4, marked in bold); 66 small-molecule metabolites were considered to be dysregulated in the DS group (compared to the NC group); 34 of these 66 dysregulated differential metabolites were considered to be the potential biomarkers (see Table 5, marked in bold). According to the fold-change values, 9 of these 27 metabolites, namely valine, oxalic acid, erythro-sphingosine, 4,7,10,13,16,19-docosahexaenoic acid, isoleucine, allo-isoleucine, thyroxine, rac-octanoyl carnitine, and tocopherol (vitamin E), were downregulated in the MHE group (compared to the NC group); the other 18, namely adenine, glycochenodeoxycholic acid, fucose, allothreonine, glycohyocholic acid, glycoursodeoxycholic acid, tyrosine, taurocheno-deoxycholate, phenylalanine, 2-hydroxy-3-methyl-butanoic acid, hydroxyacetic acid, taurocholate, sorbitol, rhamnose, tauroursodeoxycholate, tolbutamide, pyroglutamic acid, and malic acid, were upregulated; 6 of these 34 metabolites were downregulated in the DS group (compared to the NC group), and the other 28 were upregulated, as shown in Table 5. (a) GC-TOFMS and UPLC-QTOFMS metabonomic analytical platforms can detect a range of metabolites in the serum; this might be of great help to study the pathogenesis of MHE and may provide a new approach for the early diagnosis of MHE. (b) Metabonomics analysis in combination with pattern recognition analysis might have great potential to distinguish the HBV-induced liver cirrhosis patients who have MHE from the normal healthy population and HBV-induced liver cirrhosis patients without MHE.