The PD-1/B7-H1 pathway modulates the natural killer cells versus mouse glioma stem cells.

PURPOSE: Glioblastoma multiforme (GBM) is the most malignant primary type of brain tumor in adults. There has been increased focus on the immunotherapies to treat GBM patients, the therapeutic value of natural killer (NK) cells is still unknown. Programmed death-1 (PD-1) is a major immunological checkpoint that can negatively regulate the T-cell-mediated immune response. We tested the combination of the inhibiting the PD-1/B7H1 pathway with a NK-cell mediated immune response in an orthotopic mouse model of GBM. METHODS AND MATERIALS: Mouse glioma stem cells (GL261GSCs) and mouse NK cells were isolated and identified. A lactate dehydrogenase (LDH) assay was perfomed to detect the cytotoxicity of NK cells against GL261GSCs. GL261GSCs were intracranially implanted into mice, and the mice were stratified into 3 treatment groups: 1) control, 2) NK cells treatment, and 3) PD-1 inhibited NK cells treatment group. Overall survival was quantified, and animal magnetic resonance imaging (MRI) was performed to determine tumor growth. The brains were harvested after the mice were euthanized, and immunohistochemistry against CD45 and PCNA was performed. RESULTS: The mouse NK cells were identified as 90% CD3- NK1.1+CD335+ by flow cytometric analysis. In the LDH assay, the ratios of the damaged GL261GSCs, with the E:T ratios of 2.5:1, 5:1, and 10:1, were as follows: 1) non-inhibited group: 7.42%, 11.31%, and 15.1%, 2) B7H1 inhibited group: 14.75%, 18.25% and 29.1%, 3) PD-1 inhibited group: 15.53%, 19.21% and 29.93%, 4) double inhibited group: 33.24%, 42.86% and 54.91%. In the in vivo experiments, the mice in the PD-1 inhibited NK cells treatment group and IL-2-stimulated-NK cells treatment group displayed a slowest tumor growth (F = 308.5, P<0.01) and a slower tumor growth compared with control group (F = 118.9, P<0.01), respectively. The median survival of the mice in the three groups were as follows: 1) conrol group: 29 days, 2) NK cells treatment group: 35 days (P = 0.0012), 3) PD-1 inhibited NK cells treatment group: 44 days (P = 0.0024). Immunologic data of PCNA-positive cell ratios and CD45-positive cell ratios of the tumor specimens in the three groups were as follows: 1) control group: 65.72% (PCNA) and 0.92% (CD45), 2) NK treatment group: 27.66% (PCNA) and 13.46% (CD45), and 3) PD-1 inhibited NK cells treatment group: 13.66% (PCNA) and 23.66% (CD45) (P<0.001). CONCLUSION: The results demonstrated that blockade of PD-1/B7H1 pathway could promote mouse NK cells to kill the GL261GSCs, and the PD-1-inhibited NK cells could be a feasible immune therapeutic approach against GBM.

Hyperbaric oxygen promotes malignant glioma cell growth and inhibits cell apoptosis.

Glioblastoma multiforme (GBM) is the most frequently diagnosed intracranial malignant tumor in adults. Clinical studies have indicated that hyperbaric oxygen may improve the prognosis and reduce complications in glioma patients; however, the specific mechanism by which this occurs remains unknown. The present study investigated the direct effects of hyperbaric oxygen stimulation on glioma by constructing an intracranial transplanted glioma model in congenic C57BL/6J mice. Bioluminescent imaging (BLI) was used to assess the growth of intracranial transplanted GL261-Luc glioma cells in vivo, while flow cytometric and immunohistochemical assays were used to detect and compare the expression of the biomarkers, Ki-67, CD34 and TUNEL, reflecting the cell cycle, apoptosis and angiogenesis. BLI demonstrated that hyperbaric oxygen promoted the growth of intracranially transplanted GL261-Luc glioma cells in vivo. Flow cytometric analysis indicated that hyperbaric oxygen promoted GL261-Luc glioma cell proliferation and also prevented cell cycle arrest. In addition, hyperbaric oxygen inhibited the apoptosis of the transplanted glioma cells. Immunohistochemical analysis also indicated that hyperbaric oxygen increased positive staining for Ki-67 and CD34, while reducing staining for TUNEL (a marker of apoptosis). The microvessel density was significantly increased in the hyperbaric oxygen treatment group compared with the control group. In conclusion, hyperbaric oxygen treatment promoted the growth of transplanted malignant glioma cells in vivo and also inhibited the apoptosis of these cells.

Papillary meningioma with vital abnormal vessels.

Papillary meningioma is an uncommon meningioma subtype of World Health Organization grade III. It could show some radiologic profiles pointing to malignant behavior, such as a cystic change, a heterogeneous enhancement, and an ill- defined border. However, to date, the radiologic profile described in this article has not been reported in previous literatures, and it is just the characteristic being considered as the major cause for patients' death. A 16-year-old adolescent boy with a 6-month history of headache was admitted to our department on June 28, 2012. Magnetic resonance imaging showed a giant well-defined mass in the left temporal region, with a severe flow void on T2-weighted image and an abundant stripelike enhancement on T1-weighted contrast-enhanced scan. In view of its middle cranial fossa location (one predilection site for meningioma), meningioma was suspected preoperatively. A regular left frontotemporal craniotomy was performed. Unexpectedly, extreme hemorrhage happened intraoperatively, and it was difficult to stop the bleeding. After identification of no hemorrhage in the operative cavity through intraoperative magnetic resonance imaging, the operation was finished, with an overall blood loss of 15,000 mL. The patient died of brain stem dysfunction the second day after the operation.

Clinical safety and efficacy of Kanglaite® (Coix Seed Oil) injection combined with chemotherapy in treating patients with gastric cancer.

OBJECTIVE: To observe efficacy and side effects, as well as the impact on quality of life, of Kanglaite® (Coix Seed Oil) injections combined with chemotherapy in the treatment of advanced gastric cancer patiensts. METHOD: A consecutive cohort of 60 patients were divided into two groups:the experimental group receiving Kanglaite® Injection combined with chemotherapy and the control group with chemotherapy alone. After more than two courses of treatment, efficacy, quality of life and side effects were evaluated. RESULTS: The response rate and KPS score of experimental group were significantly improved as compared with those of the control group(P<0.05). In addition, gastrointestinal reactions and bone marrow suppression were significantly lower than in the control group(P<0.05). CONCLUSIONS: Kanglaite® Injection enhanced efficacy and reduced the side effects of chemotherapy, improving quality of life of gastric cancer patients; use of Kanglaite® injections deserves to be further investigated in randomized control clinical trails.

Clinical study on safety and efficacy of Qinin® (cantharidin sodium) injection combined with chemotherapy in treating patients with gastric cancer.

OBJECTIVES: To assess the efficacy, side effects, and the impact on quality of life with Qinin® (Cantharidin sodium) injection combined with chemotherapy for gastric cancer patients. METHOD: A consecutive cohort of 70 patients were divided into two groups: experimental group with cantharidin sodium injection combined with chemotherapy, while the control group received chemotherapy alone. After more than two courses of treatment, efficacy, quality of life and side effects were evaluated. RESULTS: The response rate of experimental group was not significantly different from that of the control group (P>0.05), but differences were significant in clinical benefit response and KPS score. In addition, gastrointestinal reactions and the incidence of leukopenia were lower than in the control group (P<0.05). CONCLUSIONS: Qinin® (Cantharidin sodium) injection combined with chemotherapy enhances clinical benefit response, improving quality of life of gastric cancer patients and reducing side effects of chemotherapy. Thus Qinin® (Cantharidin sodium) injection deserves to be further investigated in randomized control clinical trails.