Ultrasound characteristics of hepatic epithelioid hemangioendothelioma: a multi-center case series study.

AIMS: Hepatic epithelioid hemangioendothelioma (HEHE) is a rare vascular tumor that primarily affects the liver. This study aimed to analyze the characteristics of conventional ultrasound (US) and contrast-enhanced ultrasonography (CEUS) in HEHE. MATERIAL AND METHODS: This multi-center case series study enrolled patients diagnosed with HEHE from five hospitals in China between August 2004 and October 2022. Data on conventional US and CEUS characteristics were collected and analyzed. RESULTS: A total of 41 patients with HEHE were included, comprising 14 males and 27 females with a mean age of 50.62±11.43 years. The mean size of the lesion was 4.51±2.92 cm. Among these patients, 29 were confirmed through surgical resection and 12 through liver biopsy. Conventional US imaging identified three types of HEHE: multifocal type in 35 patients (85.4%), single nodular type in 1 patient (2.4%), and giant type in 5 patients (12.2%). US revealed proximity to the liver capsule in 29 patients (71%), hypoechoic appearance in 36 patients (88%), heterogeneity in 4 patients (10%), and hyperechoic appearance in 1 patient (2.4%). CEUS also demonstrated three distinct enhancement patterns: peripheral marginal enhancement with centripetal filling in the arterial phase and washout in the portal venous and venous phases (23 patients), eterogeneous enhancement in the arterial phase with washout in the subsequent phases (7 patients), and mild hyperenhancement in the arterial phase with resolution in later phases (9 patients). A hypo-enhancement pattern in the portal venous and venous phases was observed in 38 patients, suggesting a higher degree of malignancy. CONCLUSION: HEHE exhibits specific US findings, primarilypresenting as multiple hypoechoic lesions distributed under the liver capsule.

53BP1 loss elicits cGAS-STING-dependent antitumor immunity in ovarian and pancreatic cancer.

53BP1 nucleates the anti-end resection machinery at DNA double-strand breaks, thereby countering BRCA1 activity. Loss of 53BP1 leads to DNA end processing and homologous recombination in BRCA1-deficient cells. Consequently, BRCA1-mutant tumors, typically sensitive to PARP inhibitors (PARPi), become resistant in the absence of 53BP1. Here, we demonstrate that the 'leaky' DNA end resection in the absence of 53BP1 results in increased micronuclei and cytoplasmic double-stranded DNA, leading to activation of the cGAS-STING pathway and pro-inflammatory signaling. This enhances CD8+ T cell infiltration, activates macrophages and natural killer cells, and impedes tumor growth. Loss of 53BP1 correlates with a response to immune checkpoint blockade (ICB) and improved overall survival. Immunohistochemical assessment of 53BP1 in two malignancies, high grade serous ovarian cancer and pancreatic ductal adenocarcinoma, which are refractory to ICBs, reveals that lower 53BP1 levels correlate with an increased adaptive and innate immune response. Finally, BRCA1-deficient tumors that develop resistance to PARPi due to the loss of 53BP1 are susceptible to ICB. Therefore, we conclude that 53BP1 is critical for tumor immunogenicity and underpins the response to ICB. Our results support including 53BP1 expression as an exploratory biomarker in ICB trials for malignancies typically refractory to immunotherapy.

Manipulated C5aR1 over/down-expression associates with IL-6 expression during bacterial inflammation in half-smooth tongue sole (Cynoglossus semilaevis).

The complement component 5a/complement component 5 receptor 1 (C5a/C5aR1) pathway plays a crucial role in the onset and development of inflammation, but relevant studies in fish are lacking. In this study, we successfully characterized the relationship between half-smooth tongue sole (Cynoglossus semilaevis) C5aR1 (CsC5aR1) and bacterial inflammation. First, we showed that the overexpression of CsC5aR1 significantly increased bacterial pathological damage in the liver and intestine, whereas inhibition attenuated the damage. The in vitro experiments suggested that CsC5aR1 was able to positively regulate the phagocytic activity and respiratory burst of tongue sole macrophages. In terms of both transcriptional and translational levels, overexpression/inhibition of CsC5aR1 was followed by a highly consistent up-regulation/decrease of its downstream canonical inflammatory factor interleukin-6 (CsIL-6). Furthermore, we stimulated macrophages by lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and found a broad-spectrum response to bacterial infections by the C5a/C5aR1 complement pathway together with the downstream inflammatory factor CsIL-6. Subsequently, we directly elucidated that CsIL-6 is an indicator of C5a/C5aR1-mediated inflammation at different infection concentrations, different infectious bacteria (Vibrio anguillarum and Mycobacterium marinum), and different detection levels. These results might provide a new inflammation bio-marker for early warning of bacteria-induced hyperinflammation leading to fish mortality and a promising target for the treatment of bacterial inflammation in teleost.

Real-world data on the first-line immune checkpoint inhibitors or in combination with chemotherapy in older patients (aged ≥ 75 years) with advanced non-small cell lung cancer.

Purpose: The purpose of this study is to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) or plus with chemotherapy in older patients. Methods: We enrolled 110 older patients with non-small cell lung cancer (NSCLC ≥75 years) who received either chemotherapy alone (chemo), ICI plus chemotherapy (ICI + chemo), or ICI alone and ICI plus other therapies, which included anti-angiogenesis drugs or other novel ICI (ICIs). Patient characteristics, treatment response, survival, and toxicity were evaluated. Results: In total population, the ICIs group has the highest disease control rate (DCR 75%). There were no significant differences in progression-free survival (PFS) and overall survival (OS) among older patients between ICI + chemo and ICIs groups (PFS: 5.3 months vs. 5.5 months, p = 0.70, OS: 10.7 months vs. 20.3 months, p = 0.995). Meanwhile, we observed ICIs had a longer PFS and OS than chemo group (PFS: 3.9 months vs. 5.5 months, p = 0.01, OS: 10.9 months vs. 20.3 months, p = 0.05). Subgroup analysis showed that patients with programmed death ligand-1 (PD-L1) ≥ 1% had a distinct longer trend toward OS in ICIs group compared to ICI + chemo group (22.4 months vs. 10.7 months, p = 0.605), even though there was no significant difference. In terms of safety, ICIs was more tolerable and had a lower discontinuation rate than ICI + chemo group. Conclusion: In the real world, ICI + chemo is more likely to be discontinued due to adverse effects and does not significantly improve patient survival compared with ICIs treatment in total population and subgroup. Therefore, ICI alone or ICIs plus other therapies, such as anti-angiogenesis drugs or other novel ICI (ICIs) could be recommended for older cases with PD-L1 positive NSCLC.

Nivolumab combined docetaxel versus nivolumab in patients with previously treated nonsmall cell lung cancer: a phase 2 study.

The current standard second-line treatment is immune checkpoint inhibitors monotherapy for nonsmall cell lung cancer (NSCLC) patients. The objective of this phase 2 study was to evaluate the efficacy and safety of nivolumab plus docetaxel compared with nivolumab monotherapy for second-line therapy in immunotherapy-naive patients with advanced NSCLC. Progression-free survival (PFS) was the primary endpoint of this phase 2 study. Patients were randomized to receive nivolumab plus docetaxel or nivolumab monotherapy. From July 2019 to June 2022, a total of 22 patients were recruited, with significantly longer median PFS observed in the nivolumab plus docetaxel group (4.0 months) compared to the nivolumab group (2.0 months), P  = 0.0019. The study was closed in June 2022 due to slow recruitment. The objective response rate was 10.0% [95% confidence interval (CI), 0-28.6] in the nivolumab group and 25% (95% CI, 0.5-49.5) in the nivolumab + docetaxel group ( P  = 0.346). Disease control was significantly higher in the nivolumab plus docetaxel arm (40.0% versus 83.3%, P  = 0.035). There was also an improvement in overall survival (OS) in the nivolumab + docetaxel arm, but this was not statistically significant (10.0 months versus 7.2 months, P  = 0.129). The addition of docetaxel to nivolumab was well-tolerated, with adverse events more common in the combination group. Despite the small sample size, the results suggest that the addition of docetaxel to nivolumab may be a promising treatment option for NSCLC patients progressing on platinum-based chemotherapy, with trends towards improved OS observed.

Targeted inhibition of Wnt signaling with a Clostridioides difficile toxin B fragment suppresses breast cancer tumor growth.

Wnt signaling pathways are transmitted via 10 homologous frizzled receptors (FZD1-10) in humans. Reagents broadly inhibiting Wnt signaling pathways reduce growth and metastasis of many tumors, but their therapeutic development has been hampered by the side effect. Inhibitors targeting specific Wnt-FZD pair(s) enriched in cancer cells may reduce side effect, but the therapeutic effect of narrow-spectrum Wnt-FZD inhibitors remains to be established in vivo. Here, we developed a fragment of C. difficile toxin B (TcdBFBD), which recognizes and inhibits a subclass of FZDs, FZD1/2/7, and examined whether targeting this FZD subgroup may offer therapeutic benefits for treating breast cancer models in mice. Utilizing 2 basal-like and 1 luminal-like breast cancer models, we found that TcdBFBD reduces tumor-initiating cells and attenuates growth of basal-like mammary tumor organoids and xenografted tumors, without damaging Wnt-sensitive tissues such as bones in vivo. Furthermore, FZD1/2/7-positive cells are enriched in chemotherapy-resistant cells in both basal-like and luminal mammary tumors treated with cisplatin, and TcdBFBD synergizes strongly with cisplatin in inhibiting both tumor types. These data demonstrate the therapeutic value of narrow-spectrum Wnt signaling inhibitor in treating breast cancers.

Construction of an endoplasmic reticulum stress-related signature in lung adenocarcinoma by comprehensive bioinformatics analysis.

BACKGROUND: Lung Adenocarcinoma (LUAD) is a major component of lung cancer. Endoplasmic reticulum stress (ERS) has emerged as a new target for some tumor treatments. METHODS: The expression and clinical data of LUAD samples were downloaded from The Cancer Genome Atlas (TCGA) and The Gene Expression Omnibus (GEO) database, followed by acquiring ERS-related genes (ERSGs) from the GeneCards database. Differentially expressed endoplasmic reticulum stress-related genes (DE-ERSGs) were screened and used to construct a risk model by Cox regression analysis. Kaplan-Meier (K-M) curves and receiver operating characteristic (ROC) curves were plotted to determine the risk validity of the model. Moreover, enrichment analysis of differentially expressed genes (DEGs) between the high- and low- risk groups was conducted to investigate the functions related to the risk model. Furthermore, the differences in ERS status, vascular-related genes, tumor mutation burden (TMB), immunotherapy response, chemotherapy drug sensitivity and other indicators between the high- and low- risk groups were studied. Finally, quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the mRNA expression levels of prognostic model genes. RESULTS: A total of 81 DE-ERSGs were identified in the TCGA-LUAD dataset, and a risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was constructed by Cox regression analysis. K-M and ROC analyses showed that the high-risk group had a low survival, and the Area Under Curve (AUC) of ROC curves of 1-, 3- and 5-years overall survival was all greater than 0.6. In addition, functional enrichment analysis suggested that the risk model was related to collagen and extracellular matrix. Furthermore, differential analysis showed vascular-related genes FLT1, TMB, neoantigen, PD-L1 protein (CD274), Tumor Immune Dysfunction and Exclusion (TIDE), and T cell exclusion score were significantly different between the high- and low-risk groups. Finally, qRT-PCR results showed that the mRNA expression levels of 6 prognostic genes were consistent with the analysis. CONCLUSION: A novel ERS-related risk model, including HSPD1, PCSK9, GRIA1, MAOB, COL1A1, and CAV1, was developed and validated, which provided a theoretical basis and reference value for ERS-related fields in the study and treatment of LUAD.

Three tyrosine kinase inhibitors cause cardiotoxicity by inducing endoplasmic reticulum stress and inflammation in cardiomyocytes.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are anti-cancer therapeutics often prescribed for long-term treatment. Many of these treatments cause cardiotoxicity with limited cure. We aim to clarify molecular mechanisms of TKI-induced cardiotoxicity so as to find potential targets for treating the adverse cardiac complications. METHODS: Eight TKIs with different levels of cardiotoxicity reported are selected. Phenotypic and transcriptomic responses of human cardiomyocytes to TKIs at varying doses and times are profiled and analyzed. Stress responses and signaling pathways that modulate cardiotoxicity induced by three TKIs are validated in cardiomyocytes and rat hearts. RESULTS: Toxicity rank of the eight TKIs determined by measuring their effects on cell viability, contractility, and respiration is largely consistent with that derived from database or literature, indicating that human cardiomyocytes are a good cellular model for studying cardiotoxicity. When transcriptomes are measured for selected TKI treatments with different levels of toxicity in human cardiomyocytes, the data are classified into 7 clusters with mainly single-drug clusters. Drug-specific effects on the transcriptome dominate over dose-, time- or toxicity-dependent effects. Two clusters with three TKIs (afatinib, ponatinib, and sorafenib) have the top enriched pathway as the endoplasmic reticulum stress (ERS). All three TKIs induce ERS in rat primary cardiomyocytes and ponatinib activates the IRE1α-XBP1s axis downstream of ERS in the hearts of rats underwent a 7-day course of drug treatment. To look for potential triggers of ERS, we find that the three TKIs induce transient reactive oxygen species followed by lipid peroxidation. Inhibiting either PERK or IRE1α downstream of ERS blocks TKI-induced cardiac damages, represented by the induction of cardiac fetal and pro-inflammatory genes without causing more cell death. CONCLUSIONS: Our data contain rich information about phenotypic and transcriptional responses of human cardiomyocytes to eight TKIs, uncovering potential molecular mechanisms in modulating cardiotoxicity. ER stress is activated by multiple TKIs and leads to cardiotoxicity through promoting expression of pro-inflammatory factors and cardiac fetal genes. ER stress-induced inflammation is a promising therapeutic target to mitigate ponatinib- and sorafenib-induced cardiotoxicity.

Innate Immune Program in Formation of Tumor-Initiating Cells from Cells-of-Origin of Breast, Prostate, and Ovarian Cancers.

Tumor-initiating cells (TICs), also known as cancer stem cells (CSCs), are cancer cells that can initiate a tumor, possess self-renewal capacity, and can contribute to tumor heterogeneity. TICs/CSCs are developed from their cells-of-origin. In breast, prostate, and ovarian cancers, progenitor cells for mammary alveolar cells, prostate luminal (secretory) cells, and fallopian tube secretory cells are the preferred cellular origins for their corresponding cancer types. These luminal progenitors (LPs) express common innate immune program (e.g., Toll-like receptor (TLR) signaling)-related genes. Microbes such as bacteria are now found in breast, prostate, and fallopian tube tissues and their corresponding cancer types, raising the possibility that their LPs may sense the presence of microbes and trigger their innate immune/TLR pathways, leading to an inflammatory microenvironment. Crosstalk between immune cells (e.g., macrophages) and affected epithelial cells (e.g., LPs) may eventually contribute to formation of TICs/CSCs from their corresponding LPs, in part via STAT3 and/or NFκB pathways. As such, TICs/CSCs can inherit expression of innate-immunity/TLR-pathway-related genes from their cells-of-origin; the innate immune program may also represent their unique vulnerability, which can be explored therapeutically (e.g., by enhancing immunotherapy via augmenting TLR signaling).

Distinct niche structures and intrinsic programs of fallopian tube and ovarian surface epithelial cells.

Epithelial ovarian cancer (EOC) can originate from either fallopian tube epithelial (FTE) or ovarian surface epithelial (OSE) cells, but with different latencies and disease outcomes. To address the basis of these differences, we performed single cell RNA-sequencing of mouse cells isolated from the distal half of fallopian tube (FT) and surface layer of ovary. We find at the molecular level, FTE secretory stem/progenitor cells and OSE cells resemble mammary luminal progenitors and basal cells, respectively. An FT stromal subpopulation, enriched with Pdgfra + and Esr1 + cells, expresses multiple secreted factor (e.g., IGF1) and Hedgehog pathway genes and may serve as a niche for FTE cells. In contrast, Lgr5 + OSE cells express similar genes largely by themselves, raising a possibility that they serve as their own niche. The differences in intrinsic expression programs and niche organizations of FTE and OSE cells may contribute to their different courses toward the development of EOCs.

Second-line treatment options in advanced thymic carcinoma after failure of platinum-based chemotherapy: A multicenter retrospective study.

BACKGROUND: Currently there is no standard therapy recommended for second-line treatment for thymic carcinoma. Our study compared multidrug chemotherapy, single-agent chemotherapy, and PD-1 inhibitors in patients diagnosed with advanced thymic carcinoma who had previous platinum-based chemotherapy at the clinic. METHODS: The study included patients with thymic carcinoma who failed first-line platinum-based chemotherapy. Kaplan-Meier methods were applied in the study for estimating the progression-free survival (PFS) and overall survival (OS) curves. Pearson chi-square or Fisher's exact chi-square test was adopted to make comparisons of the objective response rate (ORR) between treatment groups. Cox regression was used for the multivariate analyses in PFS and OS. RESULTS: Among the 92 patients enrolled, multidrug chemotherapy was used in 51 (55.4%) patients for second-line therapy. Thirty-six patients (35.9%) received single-agent chemotherapy, and eight patients (8.7%) underwent PD-1 inhibitors. The multidrug chemotherapy group showed better efficacy than the other two groups, with an ORR of 35.3% (p = 0.006). The median PFS of multidrug chemotherapy, single-agent chemotherapy and PD-1 inhibitors were 5.0 months, 3.0 months, and 4.0 months, respectively (p = 0.008). Patients in the multidrug chemotherapy group also showed an advantage in OS in comparison with the other two treatment groups (p = 0.045), with a median OS of 30.4 months. Multivariate analysis showed that second-line treatment was independent factor for both PFS (p = 0.035) and OS (p = 0.037). Grade 3-4 AEs were mostly detected in patients receiving multidrug chemotherapy and were primarily hematologic. Treatment-related mortality was not found in any of the groups. CONCLUSIONS: Multidrug chemotherapy had a trend toward a more positive response rate and outcomes in longer survival time than single-agent chemotherapy and PD-1 inhibitors. Multidrug chemotherapy is a choice worth considering for second-line therapy in patients with thymic carcinoma if tolerable.

Circulating tumour DNA biomarkers in savolitinib-treated patients with non-small cell lung cancer harbouring MET exon 14 skipping alterations: a post hoc analysis of a pivotal phase 2 study.

Background: Savolitinib, a selective MET inhibitor, showed efficacy in patients with non-small cell lung cancer (NSCLC), including pulmonary sarcomatoid carcinoma (PSC), harbouring MET exon 14 skipping alteration (METex14). Objective: To analyse post hoc, the association between circulating tumour DNA (ctDNA) biomarkers and clinical outcomes, including resistance, with savolitinib. Design: A multicentre, single-arm, open-label phase 2 study. Methods: All enrolled patients with baseline plasma samples were included. Outcomes were objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) by baseline METex14 and post-treatment clearance, coexisting gene alterations at baseline and disease progression. Results: Among 66 patients with baseline ctDNA sequencing, 46 (70%) had detectable METex14. Frequent coexisting baseline gene alterations included TP53 and POT1 mutations. Patients with detectable baseline METex14 exhibited worse PFS [hazard ratio (HR), 1.77; 95% confidence interval (CI), 0.88-3.57; p = 0.108] and OS (HR, 3.26; 95% CI, 1.35-7.89; p = 0.006) than those without, despite showing a numerically higher ORR. Among 24 patients with baseline detectable METex14 and evaluable postbaseline samples, 13 achieved METex14 clearance post-treatment. Median time to first clearance was 1.3 months (range, 0.7-1.5). METex14 post-treatment clearance was associated with better ORR (92.3%; 95% CI, 64.0-99.8 versus 36.4%; 95% CI, 10.9-69.2; p = 0.0078), PFS (HR, 0.44; 95% CI, 0.2-1.3; p = 0.1225) and OS (HR, 0.31; 95% CI, 0.1-1.0; p = 0.0397) versus non-clearance. Among 22 patients with disease progression, 10 acquired pathway alterations (e.g. in RAS/RAF and PI3K/PTEN) alone or with secondary MET mutations (D1228H/N and Y1230C/H/S). Conclusion: ctDNA biomarkers may allow for longitudinal monitoring of clinical outcomes with savolitinib in patients with METex14-positive PSC and other NSCLC subtypes. Specifically, undetectable baseline METex14 or post-treatment clearance may predict favourable clinical outcomes, while secondary MET mutations and other acquired gene alterations may explain resistance to savolitinib. Registration: The trial was registered with ClinicalTrials.gov (NCT02897479) on 13 September 2016.

The overall survival benefit in Chinese ALK+ NSCLC patients received targeted therapies.

Background: Anaplastic lymphoma kinase (ALK) gene rearrangement is a series of mutations of non-small cell lung cancer (NSCLC) patients. Since 2011, multiple ALK inhibitors (ALKis) have been developed and launched for targeted therapy. In this study, we sought to investigate different strategies of sequential applying the ALKis and their clinical benefits to the overall survival (OS). Methods: A total of 176 patients with advanced NSCLC (stage IIIB-IV) harboring the ALK rearrangement were included in this cohort study. They were diagnosed between February 1, 2012 and November 19, 2019 at Peking University Cancer Hospital. Clinical characters were reviewed from patients' records. Strategies of drugs, progression-free survival (PFS) and OS were collected during the follow-ups. The Kaplan-Meier method and multivariate Cox proportional-hazard analysis were used to conduct the analyses survival and to examine the relationship between the variables and OS. Results: A significantly longer OS was observed either in patients treated with crizotinib [N=106, median OS (mOS): 32.9 months] or in patients treated with a next-generation ALKi [N=34, mOS: not reached (NR)] as the initial ALKi, compared with patients treated with conventional chemotherapy but no ALKi (N=36, mOS: 10.3 months, P<0.001). After disease progression with initial crizotinib, patients who received no ALKi had shorter OS than those who received only crizotinib beyond progressive disease (CBPD) (mOS: 9.7 vs. 20.3 months; P=0.015), only subsequent next-generation ALKis (mOS: 9.7 vs. 41.1 months; P<0.001), and CBPD followed with subsequent next-generation ALKis (mOS: 9.7 months vs. NR; P<0.001). Patients treated with 2 types of ALKi had better survival than those treated with 1 ALKi (mOS: 45.8 vs. 21.3 months, P=0.003), but no such survival benefit was observed in patients treated with ≥3 ALKis (P=0.366). Conclusions: ALKis have been shown to be clinically effective in treating NSCLC patients with ALK rearrangements. In the case of disease progression with crizotinib, either of CBPD or sequential other ALKis can extend patients' OS. The sequential application of multiple ALKis was found to be better than it of single ALKi in prolonging OS. However, the question of which inhibitor to select as the initial inhibitor needs to be examined further in future studies.

Deciphering a Novel Necroptosis-Related miRNA Signature for Predicting the Prognosis of Clear Cell Renal Carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common histological and devastating subtype of renal cell carcinoma. Necroptosis is a form of programmed cell death that causes prominent inflammatory responses. miRNAs play a significant role in cancer progression through necroptosis. However, the prognostic value of necroptosis-related miRNAs remains ambiguous. In this study, 39 necroptosis-related miRNAs (NRMs) were extracted and 17 differentially expressed NRMs between normal and tumor samples were identified using data form The Cancer Genome Atlas (TCGA). After applying univariate Cox proportional hazard regression analysis and LASSO Cox regression model, six necroptosis-related miRNA signatures were identified in the training cohort and their expression levels were verified by qRT-PCR. Using the expression levels of these miRNAs, all patients were divided into the high- and low-risk groups. Patients in the high-risk group showed poor overall survival (P < 0.0001). Time-dependent ROC curves confirmed the good performance of our signature. The results were verified in the testing cohort and the entire TCGA cohort. Univariate and multivariate Cox regression models demonstrated that the risk score was an independent prognostic factor. Additionally, a predictive nomogram with good performance was constructed to enhance the implementation of the constructed signature in a clinical setting. We then employed miRBD, miRTarBase, and TargetScan to predict the target genes of six necroptosis-related miRNAs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses indicated that 392 potential target genes were enriched in cell proliferation-related biological processes. Six miRNAs and 59 differentially expressed target genes were used to construct an miRNA-mRNA interaction network, and 11 hub genes were selected for survival and tumor infiltration analysis. Drug sensitivity analysis revealed potential drugs that may contribute to cancer management. Hence, necroptosis-related genes play an important role in cancer biology. We developed, for the first time, a necroptosis-related miRNA signature to predict ccRCC prognosis.

Evaluation of efficacy and toxicity of nivolumab combined with or without docetaxel in patients with advanced NSCLC.

BACKGROUND: The combination of PD-1/PD-L1 inhibitor and chemotherapy has been clinically confirmed to be beneficial as the first-line treatment of patients with advanced NSCLC. This study aimed to assess the effect of nivolumab + docetaxel versus nivolumab monotherapy in patients with NSCLC after the failure of platinum doublet chemotherapy. MATERIALS AND METHODS: The efficacy and toxicity of nivolumab + docetaxel combination therapy versus nivolumab monotherapy were compared in this retrospective study. Primary endpoint of the study was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), overall survival (OS), and toxicity. RESULTS: Between November 2017 and December 2019, 77 patients were included in this study, with 58 patients in the nivolumab group and 19 in the nivolumab + docetaxel group. The median follow-up was 18 months, and the PFS was 8 months for patients receiving nivolumab + docetaxel and 2 months for those receiving nivolumab alone (p = 0.001), respectively. Nivolumab + docetaxel showed superior OS compared with nivolumab, with the median OS unreached versus 7 months (p = 0.011). Among patients without EGFR/ALK variation, compared to nivolumab monotherapy, nivolumab + docetaxel showed better PFS (p = 0.04) and OS (p = 0.05). There was no significant difference in grade 3-4 adverse events (AEs) between the two groups (p = 0.253). CONCLUSIONS: The combination of nivolumab and docetaxel demonstrated a meaningful improvement in progression-free survival and overall survival compared to nivolumab monotherapy, in patients with NSCLC after the failure of platinum doublet chemotherapy, irrespective of EGFR/ALK variation status.

Comparison of endostatin combined with PT-DC versus bevacizumab combined with PT-DC in the first-line treatment of advanced lung adenocarcinoma: a retrospective propensity score-matched cohort study.

BACKGROUND: Endostatin and bevacizumab have been approved for the first-line treatment of advanced non-small-cell lung cancer (NSCLC) patients in China; however, the clinical outcomes for each drug combined with platinum-based doublet chemotherapy (PT-DC) have not yet been directly compared. This study sought to assess the clinical outcomes of the 2 drugs combined with PT-DC in the first-line treatment of patients with advanced lung adenocarcinoma. METHODS: This retrospective cohort study examined the clinical data of patients with metastatic or recurrent lung adenocarcinoma (LUAD) treated with endostatin or bevacizumab combined with PT-DC as the first-line treatment from October 2010 to November 2019. Propensity score matching (PSM) was performed using a 1:1 ratio nearest neighbor algorithm. The effectiveness and safety outcomes for the 2 groups were evaluated. RESULTS: A total of 202 patients were enrolled in the study. Of these, the endostatin group comprised 124 patients and the bevacizumab group comprised 78 patients; 67 pairs of patients were identified after PSM. The progression-free survival (PFS) and overall survival (OS) of patients treated with PT-DC + endostatin and PT-DC + bevacizumab were compared [(PFS: before PSM 4.8 vs. 6.5 months, P=0.741; after PSM 6.5 vs. 6.1 months, P=0.402), (OS: before PSM 21.1 vs. 39.3 months, P=0.912; after PSM 23.6 vs. 39.3 months, P=0.579)]. The objective response rates (ORRs) and disease control rates (DCRs) of the 2 groups were comparable (37.7% vs. 50.7%, P=0.094; 89.6% vs. 92.5%, P=0.545). Adverse events (AEs) ≥ grade 3 were not observed in the PT-DC + endostatin group. Three (3.8%) cases of AEs ≥ grade 3 were observed the PT-DC + bevacizumab group, comprising hypertension (n=1), proteinuria (n=1), hemoptysis (n=1). CONCLUSIONS: This retrospective analysis showed that in first-line treatments, PT-DC + endostatin and PT-DC + bevacizumab appear to produce similar anti-tumor activities in patients with metastatic or recurrent lung adenocarcinoma. PT-DC + bevacizumab tended to result in worse adverse reactions than PT-DC + endostatin.

Epidemiology of Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is a consequence of excessive alcohol use. It comprises a spectrum of histopathologic changes ranging from simple steatosis, steatohepatitis, and cirrhosis to hepatocellular carcinoma. The public health impact of ALD is growing because of an increase in the prevalence and incidence of ALD in parallel with liver transplant and mortalities. There are multiple factors involved in the pathogenesis and progression of ALD. Reducing alcohol consumption is the cornerstone of ALD management. The efforts to reduce excessive alcohol use at the individual and population levels are urgently needed to prevent adverse outcomes from ALD.

Prognostic factor analysis of patients with small cell lung cancer: Real-world data from 988 patients.

BACKGROUND: Small cell lung cancer (SCLC) is characterized by aggressive spread and poor prognosis, but has limited treatment options. Results of prognostic factors from randomized trials on treatment arrangement are conflicting and large-scale real-world analysis is lacking. METHODS: Patients diagnosed SCLC between 2008 and 2018 in Peking University Cancer Hospital were included in this study. Kaplan-Meier methods were adopted, and univariate analysis and multivariate Cox regression models were constructed to analyze prognostic factors. RESULTS: Among 1045 patients who presented to our center, 988 eligible patients were identified. Median overall survival (OS) was 16.0 months for the whole group, 24.0 months and 11.0 months for limited stage small cell lung cancer (LS-SCLC) and extensive stage small cell lung cancer (ES-SCLC), separately. Limited-stage, good performance status (PS) (ECOG 0-1), response to primary systemic treatment, and patients who received initiative irradiation and three or more lines of chemotherapy were predicted to have better OS in the whole group. Only response to first-line systemic therapy and prophylactic cranial irradiation (PCI) were independent prognostic factors of survival in LS-SCLC; while good PS (ECOG 0-1), without liver, bone, or subcutaneous metastases, response to first-line therapy, initial local irradiation, and three or more lines of systemic therapy predicted a favorable prognosis in ES-SCLC. CONCLUSIONS: The present study retrieved from large real-world data suggested that response to primary systemic therapy and aggressive radiotherapy are independent prognostic factors for SCLC. PCI and initiative irradiation for original or metastatic sites improved the OS in LS-SCLC and ES-SCLC, respectively.

Low miR-16 expression induces regulatory CD4+NKG2D+ T cells involved in colorectal cancer progression.

MiR-15a/16 is a member of the miRNA cluster that exhibits tumor suppression and immune modulation via targeting multiple genes. Decreased miR-15a/16 expression is involved in many cancer cells. Here, miR-16 had decreased expression in NK1.1-CD4+NKG2D+ T cells and bound with the 3'-UTR of NKG2D gene. MiR-15a/16-deficient mice had many CD4+NKG2D+ T cells, which produced TGF-ß1 and IL-10 and inhibited the IFN-γ production of CD8+ T cells. Adoptive transfer of NK1.1-CD4+NKG2D+ T cells from miR-15a/16-deficient mice promoted tumor growth in vivo. However, no changes for NK1.1-CD4+NKG2D+ T cells were found in the miR-15a/16-transgenic mice. Although the miR-15a/16 transgenic mice transplanted with B16BL6 or MC38 cells exhibited rapid growth, these tumor-bearing mice did not show changes in NK1.1-CD4+NKG2D+ T cell distributions in either spleens or tumors. When NK1.1-CD4+ T cells were stimulated by α-CD3/sRAE-1 ex vivo, the NKG2D expression was difficult to induce in the T cells of miR-15a/16-transgenic mice. Finally, increased frequencies of regulatory CD4+NKG2D+ T cells with low miR-16 levels were observed in patients with late-stage colorectal cancer (Duke's C, D). Thus, miR-16 modulates NK1.1-CD4+NKG2D+ T cell functions via targeting NKG2D. Low miR-16 expression in CD4+ T cells induces the regulatory CD4+NKG2D+ T subpopulation, which promotes tumor evasion via the secretion of immune-suppressive molecules.

Immune-Related Adverse Events and Their Association With the Effectiveness of PD-1/PD-L1 Inhibitors in Non-Small Cell Lung Cancer: A Real-World Study From China.

BACKGROUND: Programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) inhibitors are increasingly used in China, but no real-world data are available about the immune-related adverse events (irAEs). This real-world retrospective study aimed to assess the safety and effectiveness of PD-1/PD-L1 inhibitors in patients with non-small cell lung cancer (NSCLC) and to analyze the association between irAEs and effectiveness. METHODS: This was a retrospective study of the clinical data of patients with NSCLC treated with PD-1/PD-L1 inhibitors from August 2016 to November 2019 at Beijing Cancer Hospital. The patients were divided into the irAE or non-irAE groups. Overall adverse events, the impact of irAE on tumor response, and the association of irAEs with effectiveness were evaluated. RESULTS: One hundred and ninety-one patients were included, including 70 (36.6%) patients in the irAE group and 121 (63.4%) patients in the non-irAE group. AE, grades 3-5 AEs, and irAE occurred in 107 (56.0%), 24 (12.6%), and 70 (36.6%) of the patients, respectively. The objective response rate (ORR) and disease control rate (DCR) were higher in the irAE group compared with the non-irAE group (42.0% vs. 25.8%, P=0.038; 91.9% vs. 70.8%, P=0.002). Multivariable analyses identified that irAE were associated with progression-free survival (HR=0.62, 95%CI: 0.43-0.91; P=0.015), but not with overall survival (HR=0.76, 95%CI: 0.44-1.28; P=0.299). CONCLUSION: In NSCLC treated with PD-1/PD-L1 inhibitors, patients with irAEs showed improved effectiveness over patients without irAEs. Future studies of anti-PD-1/PD-L1 immunotherapy should explore this association and the underlying biological mechanisms of efficacy.