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Abstract Epstein‒Barr virus (EBV)-associated gastric cancer (GC) manifests an intriguing immunotherapy response. However, the cellular basis for EBV-imprinted tumour immunity and on-treatment response remains undefined. This study aimed to finely characterize the dynamic tumour immune contexture of human EBV (+) GC treated with immunochemotherapy by longitudinal scRNA-seq and paired scTCR/BCR-seq. EBV (+) GC exhibits an inflamed-immune phenotype with increased T-cell and B-cell infiltration. Immunochemotherapy triggers clonal revival and reinvigoration of effector T cells which step to determine treatment response. Typically, an antigen-specific ISG-15+CD8+ T-cell population is highly enriched in EBV (+) GC patients, which represents a transitory exhaustion state. Importantly, baseline intratumoural ISG-15+CD8+ T cells predict immunotherapy responsiveness among GC patients. Re-emerged clonotypes of pre-existing ISG-15+CD8+ T cells could be found after treatment, which gives rise to a CXCL13-expressing effector population in responsive EBV (+) tumours. However, LAG-3 retention may render the ISG-15+CD8+ T cells into a terminal exhaustion state in non-responsive EBV (+) tumours. In accordance, anti-LAG-3 therapy could effectively reduce tumour burden in refractory EBV (+) GC patients. Our results delineate a distinct implication of EBV-imprinted on-treatment T-cell immunity in GC, which could be leveraged to optimize the rational design of precision immunotherapy.

Abstract Background Capillary leak syndrome (CLS) is a rare condition characterized by recurrent episodes of generalized edema and severe hypotension associated with hypoproteinemia. Interleukin-11 (IL-11) is a promising therapeutic agent for thrombocytopenia. A direct correlation between IL-11 and CLS has never been reported previously, particularly in patients with hepatic carcinoma. Case presentation We describe two cases of CLS after IL-11 administration in two males with thrombocytopenia. Case 1 was a 46-year-old man with recurrence of hepatic carcinoma who was treated with IL-11 (3 mg per day). After four days of therapy, hypotension and hypoproteinemia were detected. The chest X-ray and B ultrasound of the abdomen showed pleural effusion and ascites. IL-11 was then discontinued, fluid resuscitation was performed, and fresh frozen plasma and packed red blood cells were transfused into this patient. The patient had recovered after 19 days of treatment. Case 2 was a 66-year-old man who had undergone radiofrequency ablation (RFA) for hepatic carcinoma. He was treated with IL-11 (3 mg per day) for thrombocytopenia. After two days of therapy, this patient complained of dyspnea with bilateral edema of the hands. Laboratory values showed hypoproteinemia. IL-11 was stopped and human albumin was transfused at a rate of 10 g per day. On the 4th day, fluid resuscitation was performed. The patient had recovered after treatment for two weeks. Conclusions The detection of IL-11-induced CLS supports the hypothesis that CLS could be a severe side effect of IL-11 treatment in some patients. These two case reports also demonstrate that patients with hepatic carcinoma who experience this rare form of CLS after treatment with IL-11 seem to respond to a therapeutic regimen that involves hydroxyethyl starch, albumin, and diuretic therapy. Liver cancer patients might be more susceptible to CLS because of poor liver function and hypersplenia. In addition, bleeding after RFA might be a further inducer of CLS.

Objective: We conducted a systematic review and meta-analysis aiming to assess the relationship between apolipoprotein E (APOE) gene ε2/ε3/ε4 polymorphism and breast cancer risk. Methods: Yun-Long Liu and Hao-Min Zhang independently completed literature retrieval and data collection, and statistical analyses were performed by Stata. Individual odds ratio (OR) and 95% confidence interval (CI) were pooled in a random-effects model using the DerSimonian-Laird method. Heterogeneity was evaluated by I² statistic at a significance level of 50%. Publication bias was assessed by Egger's test. Results: Eleven articles including 2,074 breast cancer patients and 2,372 controls were summarized. Using the most common allele ε3 as a reference, the ε2 (OR =0.87, 95% CI =0.72- 1.05, P=0.154, I²=0.0%) and ε4 (OR =1.07, 95% CI =0.80-1.42, P=0.654, I²=71.8%) alleles were not found to be significantly associated with breast cancer risk in the overall analyses. Subgroup analyses revealed that the comparison of allele ε4 with &3949;3 was significant in Asians (OR =1.58, 95% CI =1.17-6.32, P=0.003, I²=12.1%) and in studies that used the restriction fragment length polymorphism (RFLP) genotyping method (OR =1.27; 95% CI =1.01-1.61, P=0.045, I²=34.3%), and was marginally significant in hospital-based studies (OR =1.33; 95% CI =0.98-1.79, P=0.065, I²=30.2%), without heterogeneity. Moreover, the presence of the ε2 allele was significantly associated with breast cancer in small studies (total sample size <500) (OR =0.73, 95% CI =0.54-1.00, P=0.052, I²=0.0%) without heterogeneity. The Egger's test indicated low probabilities of publication bias. Conclusion: We observed a significant association between APOE gene ε4 allele and breast cancer risk in Asian populations. Moreover, the findings of our subgroup analyses suggest that source of controls, genotyping platform, and sample size might be the potential causes of heterogeneity. [ABSTRACT FROM AUTHOR]

The objective of the present study was to construct a novel type of non-viral gene delivery vector with high delivery efficiency and specific tumor cell-targeting ability. The CP9 peptide (CYGGRGDTP) containing Arg-Gly-Asp sequence was employed to be conjugated onto polyethylenimine (PEI) to act as the role of the targeting moiety. The chemical linker, N-succinimidyl-3-(2-pyridyldithio) propionate, was applied during the synthesis of the vector (CP9-PEI). The physicochemical characteristics of the vector were evaluated by the methods of ¹H-nuclear magnetic resonance, Fourier transform infrared spectroscopy, gel retardation assay, electron microscope observation and particle size detection. HepG2 cells were used to verify the gene delivery efficiency and targeting ability by gene delivery procedure and free CP9 peptide inhibition tests. The results showed that the successful synthesis of CP9-PEI and the synthesized vector may efficiently condense plasmid DNA into round particles with diameters of ~200 nm at a polymer/pDNA ratio of 10. CP9-PEI may deliver the reporter gene into HepG2 cells with higher efficiency and the efficiency may be inhibited by the free CP9 peptide. The present study suggested that the modification of PEI with the CP9 peptide is an effective method to construct a novel tumor cell-targeting non-viral vector, and that the novel vector exhibits great prospect in the field of cancer gene therapy. [ABSTRACT FROM AUTHOR]

Pancreatic cancer has one of worst prognosis among all human malignancies around the world, the development of novel and more efficient anti-cancer agents against this disease is urgent. In the current study, we tested the potential effect of INK-128, a novel mammalian target of rapamycin (mTOR) complex 1 and 2 (mTORC1/2) dual inhibitor, against pancreatic cancer cells in vitro. Our results demonstrated that INK-128 concentration- and time-dependently inhibited the survival and growth of pancreatic cancer cells (both primary cells and transformed cells). INK-128 induced pancreatic cancer cell apoptosis and necrosis simultaneously. Further, INK-128 dramatically inhibited phosphorylation of 4E-binding protein 1 (4E-BP1), ribosomal S6 kinase 1 (S6K1) and Akt at Ser 473 in pancreatic cancer cells. Meanwhile, it downregulated cyclin D1 expression and caused cell cycle arrest. Finally, we found that a low concentration of INK-128 significantly increased the sensitivity of pancreatic cancer cells to gemcitabine. Together, our in vitro results suggest that INK-128 might be further investigated as a novel anti-cancer agent or chemo-adjuvant for pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Lung cancer is a common malignancy in the world; however symptomatic colonic metastasis from primary lung cancer is rare. A 64-year-old man was originally found poorly differentiated squamous cell carcinoma of right lung and received right lower lobectomy and lymph node dissection. Three years later, the patient presented to our emergency room with the symptom of upper abdominal pain and weight loss. Abdominal palpation and computed tomography scan of the abdomen revealed a large mass measuring 7.6 cm × 8.5 cm in the ascending colon. Colonoscopy and biopsy revealed poorly differentiated squamous cell carcinoma with similar morphological pattern to that of the previous lung cancer. Chemotherapy was given and the patient died 5 mo later. Lung cancer metastatic to the colon confers a poor prognosis: overall survival ranged from 5 wk to 1 year, with a median survival of 3 mo after the diagnosis of the colonic metastasis.

Purpose: The oral mammalian target of rapamycin inhibitor everolimus demonstrated promising efficacy in a phase II study of pretreated advanced gastric cancer. This international, double-blind, phase III study compared everolimus efficacy and safety with that of best supportive care (BSC) in previously treated advanced gastric cancer., Patients and Methods: Patients with advanced gastric cancer that progressed after one or two lines of systemic chemotherapy were randomly assigned to everolimus 10 mg/d (assignment schedule: 2:1) or matching placebo, both given with BSC. Randomization was stratified by previous chemotherapy lines (one v two) and region (Asia v rest of the world [ROW]). Treatment continued until disease progression or intolerable toxicity. Primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), overall response rate, and safety., Results: Six hundred fifty-six patients (median age, 62.0 years; 73.6% male) were enrolled. Median OS was 5.4 months with everolimus and 4.3 months with placebo (hazard ratio, 0.90; 95% CI, 0.75 to 1.08; P = .124). Median PFS was 1.7 months and 1.4 months in the everolimus and placebo arms, respectively (hazard ratio, 0.66; 95% CI, 0.56 to 0.78). Common grade 3/4 adverse events included anemia, decreased appetite, and fatigue. The safety profile was similar in patients enrolled in Asia versus ROW., Conclusion: Compared with BSC, everolimus did not significantly improve overall survival for advanced gastric cancer that progressed after one or two lines of previous systemic chemotherapy. The safety profile observed for everolimus was consistent with that observed for everolimus in other cancers.

Background/aims: To investigate the expression of multi-drug resistance-related genes, MDR3 and MRP, in clinical specimens of primary liver cancer and their potential as prognostic factors in liver cancer patients., Methodology: A total of 26 patients with primary liver cancer were enrolled. The expression of MDR3 and MRP genes was measured by real-time PCR and the association between gene expression and the prognosis of patients was analyzed by the Kaplan-Meier method and COX regression model., Results: This study showed that increases in MDR3 gene expression were identified in cholangiocellular carcinoma, cirrhosis and HBsAg-positive patients, while MRP expression increased in hepatocellular carcinoma, non-cirrhosis and HBsAg-negative patients. Moreover, conjugated bilirubin and total bile acid in the serum were significantly reduced in patients with high MRP expression compared to patients with low expression. The overall survival tended to be longer in patients with high MDR3 and MRP expression compared to the control group. MRP might be an independent prognostic factor in patients with liver cancer by COX regression analysis., Conclusions: MDR3 and MRP may play important roles in liver cancer patients as prognostic factors and their underlying mechanisms in liver cancer are worthy of further investigation.