Prenatal diagnosis of hereditary diffuse gastric cancer: a case report.

BACKGROUND: Hereditary diffuse gastric cancer(HDGC) is a kind of malignant gastric cancer that is difficult to find in the early stage. However, this late onset and incomplete penetrance hereditary cancer, and its prenatal diagnosis have rarely been reported previously. CASE PRESENTATION: A 26-year-old woman was referred to genetic counseling for an ultrasonography of fetal choroid plexus cyst at 17 weeks of gestation. The ultrasonographic evaluation showed bilateral choroid plexus cysts(CPC) in the lateral ventricles, and the women showed a family history of gastric cancer and breast cancer. Trio copy number sequencing identified a pathogenic CDH1 deletion in the fetus and unaffected mother. The CDH1 deletion was found in three of the five family members tested, segregation among affected family members. The couple finally decided to terminate the pregnancy after genetic counseling by hospital geneticists due to the uncertainty of the occurrence of HDGC in the future. CONCLUSIONS: In prenatal diagnosis, a family history of cancer should be widely concerned, and prenatal diagnosis of hereditary tumors requires extensive cooperation between the prenatal diagnosis structure and the pathology department.

A novel CTLA-4 blocking strategy based on nanobody enhances the activity of dendritic cell vaccine-stimulated antitumor cytotoxic T lymphocytes.

Despite the great success of CTLA-4 blocking in cancer treatment, the use of anti-CTLA-4 monoclonal antibodies still faces many limitations. Now, immune checkpoint blocking coupled with adoptive cell therapy is gaining much attention. In this paper, we reported a strategy on the basis of anti-CTLA-4 nanobody (Nb)-modified liposomes to improve these obstacles. An Nb36/liposome complex was constructed and utilized as a blocker of the CTLA-4/B7 signal pathway in a combination with dendritic cell (DC)/tumor fusion vaccine to enhance the CD8+ T cell cytokine secretion, activation, proliferation, as well as specific cytotoxicity. Moreover, the CD8+ T cells induced by LPS-Nb36 and DC/tumor fusion vaccine led to higher CD8+ T cell effector function in vivo, which significantly retarded tumor growth and lengthened survival of tumor-bearing mice (HepG2, A549, and MGC-803). Our data demonstrate that the anti-CTLA-4 Nb-modified liposomes in connection with DC/tumor fusion vaccines enhance the CD8+ T cell antitumor activity in vitro and in vivo, and is expected to be an alternative therapy for patients with malignancies that have T cell dysfunction or have poor treatment against anti-CTLA-4 mAb.

PD-1 blocking strategy for enhancing the anti-tumor effect of CAR T cells targeted CD105.

Purpos: CD105 has become a promising target of immunotherapy development for highly specific expression on the neovascular surface of most types of tumor cells. In previous studies, we constructed a CAR T cell (CD105 CAR T cell) and observed significant antitumor activity. In this study, we optimized the structure of CD105 CAR to increase PD-1 antibody secretion function (CD105 × PD-1 CAR T cells). Methods: we tested whether Increased PD-1 antibody secretion with CAR T cells targeted CD105 could promote in vitro proliferation, proinflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. Results: Our data showed that the PD-1 antibody secreted by CD105 × PD-1 CAR T cells could specifically bind to the PD-1 receptor of T cells then blocked the PD-1/PD-L-1 signaling pathway, thus enhancing the activation and proliferation of CAR T cells. After incubation of CD105 × PD-1 CAR T cells with HepG2 as a hepatocellular carcinoma cell line expressing CD105, the results showed that CD105 × PD-1 CAR T cells increased the expression levels of CD69 and CD62L, enhanced the proliferation capacity of CAR T cells, and secreted more IL-2, TNF-α and IFN-γ than CD105 CAR T cells. Conclusion: These data showed that CD105 × PD-1 CAR T cells was specifically killing tumor cells in vitro and in vivo. Our findings may therefore provide a promising new strategy for the improvement of CAR T therapy for solid tumors.

A CTLA-4 blocking strategy based on Nanoboby in dendritic cell-stimulated cytokine-induced killer cells enhances their anti-tumor effects.

BACKGROUND: Cytokine-induced killer cells induced with tumor antigen-pulsed dendritic cells (DC-CIK) immunotherapy is a promising strategy for the treatment of malignant tumors. However, itsefficacy isrestricted by the immunosuppression, which is mediated by the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) pathway. In order to overcome the negative co-stimulation from these T cells,we screened a nanobody targeted for CTLA-4 (Nb36) and blocked the CTLA-4 signaling with Nb36. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected from healthy donors to beused to induce CIK cells in vitro, after which they were co-cultured with DC cells that had received tumor antigens. In addition, wetested whether blocking CTLA-4 signaling with Nb36 could promote in vitro DC-CIK cells proliferation, pro-inflammatory cytokine production and cytotoxicity,or not. For the in vivo experiments, we constructed a subcutaneously transplanted tumor model and placed it in NOD/SCID mice to verify the anti-tumor effect of this therapy. RESULTS: After stimulation with Nb36, the DC-CIK cells presented enhanced proliferation and production of IFN-γ in vitro, which strengthened the killing effect on the tumor cells. For the in vivo experiments, it was found that Nb36-treated DC-CIK cells significantly inhibited the growth of subcutaneously transplanted livercancer tumors, as well as reduced the tumor weight and prolonged the survival of tumor-bearing NOD/SCID mice. CONCLUSIONS: Ourfindings demonstrated that in response to CTLA-4 specific nanobody stimulation, DC-CIK cells exhibited a better anti-tumor effect. In fact, this Nb-based CTLA-4 blocking strategy achieved an anti-tumor efficacy close to that of monoclonal antibodies. Our findings suggest that DC-CIK cells + Nb36 have the potential totreatmalignant tumors through in vivo adoptive therapy.

Does the use of targeted agents in advanced gastroesophageal cancer increase complete response? A meta-analysis of 18 randomized controlled trials.

PURPOSE: We aimed to investigate whether the use of targeted agents (TAs) in advanced gastroesophageal cancer (GEC) increased the complete response (CR) and to assess the surrogate endpoints for survival in the targeted treatment of GEC by using a meta-analysis of randomized controlled trials (RCTs). METHODS: Eligible studies were identified using Medline, PubMed, and meeting abstracts. Searches were last updated on April 30, 2018. We calculated the incidence and Peto odds ratio (Peto OR) of CR events in patients assigned to TAs compared with controls. Simple linear regression models were fitted for median overall survival (OS) and each surrogate [median progression-free survival (PFS), CRs, objective response rate (ORR), and disease control rate (DCR), respectively]. RESULTS: A total of 7,892 GEC patients from 18 RCTs were included for analysis. The incidence of CR in GEC patients treated with TAs was 2.0% (95% CI, 1.3%-3.0%) compared with 1.7% (95% CI, 1.0%-2.7%) in the control arms. The use of TAs in advanced GEC had a tendency to improve the possibility of archiving CR (Peto OR 1.42; 95% CI, 0.98-2.04; P=0.064) compared with controls. Subgroup analysis according to treatment TAs showed that the addition of antiepidermal growth factor receptor (EGFR) agents to chemotherapy in GEC significantly improved the CR rate in comparison with control (Peto OR 1.77; 95% CI, 1.02-3.09; P=0.044), but not for other molecular TAs (P=0.49 for angiogenesis inhibitors, P=0.66 for mesenchymal-epithelial transition inhibitors). We also found that the addition of TAs to first-line therapy (Peto OR 1.41; 95% CI, 0.94-2.11; P=0.098) had a tendency to increase the chance of obtaining a CR, but not for second-line therapy (Peto OR 1.47; 95% CI, 0.60-3.55; P=0.40). In addition, correlation analysis indicates that PFS, ORR, and DCR were strongly correlated with OS for GEC patients receiving TAs (r=0.85 for PFS; r=0.86 for ORR; r=0.81 for DCR). No marked correlation was found between OS and CRs (r=0.43; P=0.18). CONCLUSION: Although the CR is a rate event in advanced GEC patients, adding the TAs to therapies, especially for anti-EGFR agents, increases the chance of archiving CR in comparison with the controls. PFS, ORR, and DCR are significantly correlated with OS and could be used as surrogate endpoints in patients with GEC who have received TA therapy, but not for CR.

PRISMA - Practical meta-analysis of applying local triamcinolone acetonide injection for stenosis after esophageal cancer surgery.

OBJECTIVES: To explore the practical method of endoscopic triamcinolone acetonide (TA) injection immediately after endoscopic surgery and combined with endoscopic dilation (ED) in the management of stenosis after esophageal cancer surgery based on their efficacy and safety. METHODS: A comprehensive search was performed in electronic databases including MEDLINE, EMBASE, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure for possible controlled studies. Meta-analyses of the included studies were completed using Reviewer Manager software and were reported based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses. RESULTS: Eight randomized studies and five controlled studies containing 575 patients were obtained. In five studies (n=282), TA injected after surgery reduced the risk of stenosis (risk difference [RD] =-0.51, 95% CI [-0.64, -0.39], P<0.01) and the required ED sessions (RD =-3.66, 95% CI [-5.87, -1.46], P<0.01). In eight studies (n=293), TA injection combined with ED reduced the risk of recurrence of stenosis (RD =-0.28, 95% CI [-0.47, -0.08], P<0.01) and the required ED sessions (RD =-0.71, 95% CI [-1.39, -0.04], P<0.05). TA injection therapy did not increase the risk of complications in seven studies (n=380; RD =-0.01, 95% CI [-0.04, 0.02], P=0.53) compared with control. CONCLUSION: TA injection therapy after esophageal cancer surgery and combined with ED are both effective and safe in the management of stenosis, as they reduce the risk of stenosis and sequentially the required ED sessions without increasing complications.

Dietary protein intake and risk of ovarian cancer: evidence from a meta-analysis of observational studies.

The association between dietary protein intake and ovarian cancer had been inconsistent in the previous epidemiological studies. The aim of the present study was to identify and synthesize all citations evaluating the relationship on ovarian cancer with protein intake. The search included PubMed, Embase, and Web of Science from inception to June 2018. Two authors independently selected studies, extracted data, and assessed risk of bias. Relative risk (RR) and 95% confidence interval (95%CI) were calculated for relationship between the dietary protein intake and ovarian cancer risk using a random-effects model. Publication bias was evaluated using Egger's test and Begg's funnel plots. At the end, ten citations with 2354 patients were included in meta-analysis. Summarized RR with 95%CI on ovarian cancer was 0.915 (95%CI = 0.821-1.021), with no between-study heterogeneity (I2 = 0.0%, P=0.708). The results were consistent both in animal protein intake and in vegetable intake on ovarian cancer. Subgroup analysis by study design did not find positive association either in cohort studies or in case-control studies. Egger's test (P=0.230) and Funnel plot suggested no publication bias. Based on the obtained results, we conclude that high dietary protein intake had no significant association on ovarian cancer risk. Besides that, it is necessary to develop high quality, large-scale studies with detailed amount of dietary protein intake for verifying our results.