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Background Visceral pleural invasion (VPI) with PL1 or PL2 increases the T classification from T1 to T2 in non-small cell lung cancers (NSCLCs) ≤ 3 cm. We proposed a modified T classification based on VPI to guide adjuvant therapy. Research Question Is it reasonable to upstage PL1-positive cases from T1 to T2 for NSCLCs ≤ 3 cm? Study Design and Methods In total, 1,055 patients with resected NSCLC were retrospectively included. Tumor sections were restained with hematoxylin and eosin stain and Victoria blue elastic stain for the elastic layer. Disease-free survival (DFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Subgroup analysis and a Cox proportional hazards model were used to further determine the impact of VPI on survival. Results The extent of VPI was diagnosed as PL0 in 824 patients, PL1 in 133 patients, and PL2 in 98 patients. The 5-year DFS rates of patients with PL0, PL1, and PL2 were 62.6%, 60.2%, and 28.8% (P Interpretation In NSCLCs ≤ 3 cm, tumors with PL1 should remain defined as T1, not T2. Overtreatment by adjuvant chemotherapy in node-negative NSCLCs ≤ 3 cm might be avoided in PL1 cases.

Cadmium (Cd) is a potentially toxic trace element frequently existed in foods, water, and air, threatening liver function from its continuous bioaccumulation and induction of oxidative stress and inflammation. However, the hepatotoxicity of Cd during puberty remains unclear. In this study, pubertal mice were given cadmium chloride at a dose of 5.0 mg/kg·bw by gavage, and the liver damage was investigated at different treatment points of 10, 20, and 30 days. After Cd exposure, there is an obvious inflammatory hepatocyte infiltration accompanied by more apoptotic cells at 20 days and an increase in alanine aminotransferases and aspartate aminotransferases in circulation at 30 days. Additionally, the soaring TNF-α and MCP-1 were found in liver, and the mRNA expression of pro-inflammatory cytokines (IL-1α, IL-1β, and IL-18) and anti-inflammatory cytokines (TGF-β, IL-10, and IL-13) were both significantly upregulated. Moreover, the activated M1 and M2 macrophages were confirmed in charge of these cytokines release. Most importantly, the data validated a pivotal role of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in Cd-induced inflammation in liver at puberty. Collectively, our results suggested that low-dose Cd oral exposure can cause liver inflammation via activation of NLRP3 inflammasome and give rise to severe liver injury at puberty.

Purpose: Metastatic uveal melanoma is a lethal disease with no standard treatment. Here we studied a case with metastatic uveal melanoma (UVM) and had unexpected contrast response to PD-1 inhibitor in liver metastasis. Experimental design: Whole exome sequencing, RNA sequencing, and immunohistochemistry (IHC) and multiplex immunofluorescence imaging (MII) were conducted on the biopsied samples of intrahepatic lesions with differential responses. Combined bioinformatics analysis of the patient and public dataset including The Cancer Genome Atlas uveal melanoma (TCGA-UVM) cohort and NCBI Gene Expression Omnibus (GEO) cohorts were performed. Results: The differences in somatic mutations and tumor mutation burden between complete response (CR) and progressive disease (PD) lesion of the patient were small. IHC suggested both CR and PD lesions were PD-L1 negative and had diffuse CD8+ TILs and Foxp3+ TILs infiltration. Using ImmuCellAI, an advanced tool to estimate the abundance of 24 immune cells from gene expression dataset, PD lesion was found to have more than two times the abundance of inducible regulatory T cell (iTreg) compared with the CR lesion; the abundance of nTreg were similar. Based on GEO datasets, high abundance of iTreg was found able to predict poor response to PD-1 inhibitor and was correlated with unfavorable prognosis of advanced melanoma patients receiving PD-1 blockade therapy; high iTreg also correlates with unfavorable prognosis in TCGA-UVM cohort. Bioinformatic analysis of transcriptome data of this patient and TCGA-UVM cohort revealed iTreg may negatively impact on PD-1 blockade therapy through the IL-10-PRDM1 axis, which is confirmed by MII under microscope. Conclusion: This study provides an insight into the suppressive impact of iTreg on the efficacy of PD-1 blockade therapy and will facilitate the development of novel treatment against its tolerance in the future.

Blockade of the programmed cell death 1-programmed cell death ligand 1 pathway is a new and promising therapeutic approach in Hodgkin lymphoma (HL). To our knowledge, the impact of soluble programmed cell death ligand 1 (sPD-L1) serum levels on HL patient prognosis has not yet been investigated. In this study, the prognostic value of sPD-L1 was assessed in patients with HL. We measured serum sPD-L1 levels and identified their prognostic value in 108 newly diagnosed HL patients using an enzyme-linked immunosorbent assay (ELISA). We found higher serum sPD-L1 concentrations in HL patients than in healthy controls. The best sPD-L1 cutoff value for predicting disease progression risk was 25.1674 ng/ml. The 4-year progression-free survival (PFS) rates for the high-sPD-L1 and low-sPD-L1 groups were 78.8% and 93.3%, respectively. Multivariate survival analysis showed that advanced stage and higher sPD-L1 levels (>25.1674 ng/ml) were independent prognostic factors for shorter PFS. In addition, higher sPD-L1 levels were positively correlated with advanced stage and negatively correlated with peripheral blood monocyte number. The serum sPD-L1 level is an independent prognostic factor for PFS in HL patients and may allow identification of a subgroup of patients who require more intensive therapy and who may benefit from anti-PD-1 agents.

Primary lung cancer is the fourth most frequently diagnosed cancer, but gastric metastasis from lung cancer is extremely rare. Little is known about its clinicopathological features, prognosis and optimal treatment strategy. The present study reports a case of primary lung cancer that metastasized to the stomach and to the best of our knowledge, is the first to identify discordance in epidermal growth factor receptor (EGFR) mutation status between the primary tumor and gastric metastasis. The study also systematically searched the Medline database for similar cases to provide a literature review. Data concerning the clinicopathological features, treatment strategies and outcomes were extracted and analyzed. In total, 22 eligible cases were identified from 16 studies. The average age at presentation was 67.3 years and there was a male predominance of 90.9%. Epigastric pain (45.5%) was the most common chief complaint, followed by melena (22.7%), nausea/vomiting (13.6%) and hematemesis (9.1%). Three patients were asymptomatic. Five patients sought the initial consultation for gastrointestinal symptoms. The median time between the primary lung cancer diagnosis and the confirmation of gastric metastasis was five months. Endoscopically, gastric lesions were described as polypoid masses or volcano-like ulcers, mostly involving the gastric corpus, which were identified in 62.5% of the 16 cases in which information regarding the site of metastasis was available. Gastric metastases were reported from adenocarcinoma, squamous cell carcinoma, small cell lung cancer and pleomorphic carcinoma of the lung. The median survival following comprehensive treatment strategies was four months, and the one-year post-metastasis survival rate was 35.3%. In conclusion, although primary lung cancer metastasis to the stomach is rare, clinicians should be aware of the possibility of its occurrence. Comprehensive and personalized treatment may be beneficial to patients. EGFR tyrosine-kinase inhibitor therapy may be the treatment of choice for non-small cell lung carcinoma patients harboring an activating EGFR mutation in the metastatic lesion.

Background & Aims Adjuvant cytokine‐induced killer (CIK) cells treatment has shown potential in reducing the recurrence rate and prolonging the survival of patients with hepatocellular carcinoma (HCC). We aimed to identify the best predictive biomarker for adjuvant CIK cells treatment in patients with HCC after curative resection. Methods This study retrospectively included 145 pairs of HCC patients by one‐to‐one propensity score matching. One group received CIK cells transfusion after surgery (surgery‐CIK group); the other one group underwent surgery only (surgery‐only group). Immunohistochemistry (IHC) was used to measure PD‐1, PD‐L1, CD4, CD8 and Foxp3 expression in tumour tissues of surgery‐CIK group; IHC of PD‐1 and PD‐L1 was conducted in the surgery‐only group. Results The surgery‐CIK group had a significantly higher disease‐free survival (DFS) and overall survival (OS) rates compared to the surgery‐only group. Of all the intratumoural biomarkers, in the surgery‐CIK group, multivariate analysis showed that a high number of PD‐1+ tumour infiltrative lymphocytes (TILs) was the only factor that independently predicted favourable OS and DFS. By contrast, in the surgery‐only group, no significant correlations between PD‐1/PD‐L1 expression and survival of patients were identified. Further correlation analysis showed a high number of PD‐1+ TILs associated with a high number of both CD4+ and CD8+ TILs in surgery‐CIK group. Conclusions A high number of PD‐1+ TILs can serve as a potent biomarker for adopting CIK cells therapy in HCC patients after curative resection.

Lymphovascular invasion (LVI) is a histopathological feature that is associated with an increased risk for micrometastasis. The aim of this study was to determine the prognostic and staging value of LVI among patients with esophageal squamous cell carcinoma (ESCC) undergoing esophagectomy.A prospective database of patients with ESCC was used to retrospectively analyze 666 cases to identify the relationship between LVI and survival, and to evaluate predictive accuracy of prognosis after combining LVI and the tumor, node, and metastasis (TNM) system. Pathological slides were reassessed by gastrointestinal pathologists according to the strict criteria; 1000-bootstrap resampling was used for internal validation, and 222 cases from an independent multicenter database were used for external validation.LVI was present in 33.8% of patients, and the proportion increased with advancing T and N classification. LVI was an independent predictor of unfavorable disease-specific survival (DSS) (hazard ratio = 1.59, 95% confidence interval: 1.30-1.94) and disease-free survival (DFS) (hazard ratio = 1.62, 95% confidence interval: 1.32-1.98) after T classification. Among node-negative patients, LVI and T classification were two independent predictors of DSS and DFS (p0.001). The risk score model combing LVI and T classification improved the predictive accuracy of the TNM system for DSS and DFS by 3.5% and 4.8%, respectively (p0.001). The external validation showed congruent results. The DSS of TxN0MO disease with LVI was similar to the DSS of TxN1M0 (both p0.05). In contrast, LVI was not associated with DSS or DFS among node-positive patients.The independent prognostic significance of LVI existed only in node-negative patients with ESCC, and the combination of LVI and the TNM system enhanced the predictive accuracy of prognosis. After confirmation, node-negative patients with LVI might be considered for upstaging in pathological staging.