PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.

BackgroundConsidering the lack of efficient breast cancer prediction models suitable for general population screening in China. We aimed to develop a risk prediction model to identify high-risk populations, to help with primary prevention of breast cancer among Han Chinese women.MethodsA cause-specific competing risk model was used to develop the Han Chinese Breast Cancer Prediction model. Data from the Shandong Case-Control Study (328 cases and 656 controls) and Taixing Prospective Cohort Study (13,176 participants) were used to develop and validate the model. The expected/observed (E/O) ratio and C-statistic were calculated to evaluate calibration and discriminative accuracy of the model, respectively.ResultsCompared with the reference level, the relative risks (RRs) for highest level of number of abortions, age at first live birth, history of benign breast disease, body mass index (BMI), family history of breast cancer, and life satisfaction scores were 6.3, 3.6, 4.3, 1.9, 3.3, 2.4, respectively. The model showed good calibration and discriminatory accuracy with an E/O ratio of 1.03 and C-statistic of 0.64.ConclusionsWe developed a risk prediction model including fertility status and relevant disease history, as well as other modifiable risk factors. The model demonstrated good calibration and discrimination ability.Electronic supplementary materialThe online version of this article (10.1186/s12885-019-5321-1) contains supplementary material, which is available to authorized users.

Local tumor recurrence is one of the main causes for the failure of esophageal cancer treatment following radiotherapy. Previous studies have demonstrated that epidermal growth factor receptor (EGFR)-targeted therapy combined with radiotherapy is expected to become an effective means to control tumor recurrence. The aim of the present study was to investigate the effect and mechanism of nimotuzumab (an EGFR-targeted antibody) in the treatment of recurrent esophageal carcinoma. The radiation responses of two esophageal squamous carcinoma cell lines, EC109 and TE-1, with or without nimotuzumab, were first evaluated by CCK-8 assay. Colony formation and apoptosis were used to measure anti-proliferation effects. It was demonstrated that nimotuzumab arrested the cell cycle at the G2 phase in vitro. Western blotting and immunofluorescence analysis were used to determine signaling pathway changes. It was observed that nimotuzumab inhibited phosphorylation of EGFR in EC109 cells. Furthermore, recurrent tumor models were established and it was identified that the degree of tumor hypoxia was positively associated with EGFR overexpression. In EC109 cell xenografts, nimotuzumab combined with radiation led to a significant delay in recurrent tumor growth compared with that of radiation alone (P<0.001 for 0 Gy pre-irradiation, P=0.005 for 20 Gy pre-irradiation, P=0.005 for 10 Gy pre-irradiation). These results suggest that nimotuzumab combined with radiation may be an effective means to control recurrent esophageal squamous cell carcinoma with EGFR overexpression.

Although immunotherapy has achieved great clinical success in clinical outcomes, especially the anti-PD-1 or anti-PD-L1 antibodies, not all patients respond to anti-PD-1 immunotherapy. It is urgently required for a clinical diagnosis to develop non-invasive imaging meditated strategy for assessing the expression level of PD-L1 in tumors. In this work, a 68 Ga-labeled single-domain antibody tracer, 68 Ga-NOTA-Nb109, was designed for specific and noninvasive imaging of PD-L1 expression in an MC38 tumor-bearing mouse model. Comprehensive studies including Positron Emission Tomography (PET), biodistribution, blocking studies, immunohistochemistry, and immunotherapy, have been performed in differences PD-L1 expression tumor-bearing models. These results revealed that 68 Ga-NOTA-Nb109 specifically accumulated in the MC38-hPD-L1 tumor. The content of this nanobody in MC38 hPD-L1 tumor and MC38 Mixed tumor was 8.2 ± 1.3, 7.3 ± 1.2, 3.7 ± 1.5, 2.3 ± 1.2%ID/g and 7.5 ± 1.4, 3.6 ± 1.7, 1.7 ± 0.6, 1.2 ± 0.5%ID/g at 0.5, 1, 1.5, 2 hours post-injection, respectively. 68 Ga-NOTA-Nb109 has the potential to further noninvasive PET imaging and therapy effectiveness assessments based on the PD-L1 status in tumors. To explore the possible synergistic effects of immunotherapy combined with chemotherapy, MC38 xenografts with different sensitivity to PD-L1 blockade were established. In addition, we found that PD-1 blockade also had efficacy on the PD-L1 knockout tumors. RT-PCR and immunofluorescence analysis were used to detect the expression of PD-L1. It was observed that both mouse and human PD-L1 expressed among three types of MC38 tumors. These results suggest that PD-L1 on tumor cells affect the efficacy, but it on host myeloid cells might be essential for checkpoint blockade. Moreover, anti–PD-1 treatment activates tumor-reactive CD103 + CD39 + CD8+T cells (TILs) in tumor microenvironment.

Objective. This study aimed to construct a 5-year survival prediction model of coronary heart disease (CHD) induced chronic heart failure (CHF), which is supported by the traditional Chinese medicine (TCM) factor, and to verify the model. Methods. Inpatients from January 1, 2012, to December 31, 2017, in seven hospitals in Shandong Province were studied. The random number table was used to randomly divide the seven hospitals into two groups (training set and verification set). In the training set, the least absolute shrinkage selection operator regression was first used to screen the independent variables. Logistic regression was then applied to construct a survival prediction model. The following nomogram visualizes the prediction model results. Finally, C-indices, calibration curves, and decision curves were used to discriminate and calibrate the established model and evaluate its practicability in the clinic. Bootstrap resampling and the verification set were used for internal and external verification, respectively. Results. A total of 424 eligible patients were included in the model construction and verification. In this 5-year survival prediction model of patients with CHF induced by CHD, eight independent predictors were included. The series of C-indices for the training set, bootstrap resamples, and verification set was 0.885, 0.867, and 0.835, respectively, demonstrating the credibility of our model. Additionally, the receiver operating characteristic curve, calibration curve, and clinical decision curve analysis of the training and verification sets showed that this 5-year survival prediction model was good in discrimination, calibration, and clinical practicability. Conclusion. This work highlights eight independent factors affecting 5-year mortality in patients with CHF induced by CHD after discharge and further helps reallocate medical resources rationally by precisely identifying high-risk groups. The constructed prediction model not only plays a credible role in prediction but also demonstrates TCM intervention as a protective factor for the 5-year death of patients with CHF induced by CHD, thereby advancing the use of TCM in CHF.

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ObjectiveTo summarize the research progress about the dosimetry and biological predictors of radiation-induced esophagitis.MethodsWe performed a systematic literature review addressing radiation esophagitis in the treatment of lung cancer published between January 2009 and May 2015 in the PubMed full-text database index systems.ResultsTwenty-eight eligible documents were included in the final analysis. Many clinical factors were related to the risk of radiation esophagitis, such as elder patients, concurrent chemoradiotherapy, and the intense radiotherapy regimen (hyperfractionated radiotherapy or stereotactic body radiotherapy). The parameters including Dmax, Dmean, V20, V30, V50, and V55 may be valuable in predicting the occurrence of radiation esophagitis in patients receiving concurrent chemoradiotherapy. Genetic variants in inflammation-related genes are also associated with radiation-induced toxicity.ConclusionDosimetry and biological factors of radiation-induced esophagitis provide clinical information to decrease its occurrence and grade during radiotherapy. More prospective studies are warranted to confirm their prediction efficacy.