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In the interaction between a tumor and the immune system, immune checkpoints play an important role, and in tumor immune escape, co-inhibitory immune checkpoints are important. Immune checkpoint inhibitors (ICIs) can enhance the immune system’s killing effect on tumors. To date, impressive progress has been made in a variety of tumor treatments; PD1/PDL1 and CTLA4 inhibitors have been approved for clinical use in some tumors. However, glioblastoma (GBM) still lacks an effective treatment. Recently, a phase III clinical trial using nivolumab to treat recurrent GBM showed no significant improvement in overall survival compared to bevacizumab. Therefore, the use of immune checkpoints in the treatment of GBM still faces many challenges. First, to clarify the mechanism of action, how different immune checkpoints play roles in tumor escape needs to be determined; which biomarkers predict a benefit from ICIs treatment and the therapeutic implications for GBM based on experiences in other tumors also need to be determined. Second, to optimize combination therapies, how different types of immune checkpoints are selected for combined application and whether combinations with targeted agents or other immunotherapies exhibit increased efficacy need to be addressed. All of these concerns require extensive basic research and clinical trials. In this study, we reviewed existing knowledge with respect to the issues mentioned above and the progress made in treatments, summarized the state of ICIs in preclinical studies and clinical trials involving GBM, and speculated on the therapeutic prospects of ICIs in the treatment of GBM.

An immunoscore for colorectal cancer (CRC) has higher prognostic significance than the TNM staging system. However, the tumor immune microenvironment contains various components that affect clinical prognosis. Therefore, a broader range of immune markers is required to establish an accurate immunoprofile to assess the prognosis of patients with CRC. Using immunohistochemistry combined with multispectral immunohistochemistry and objective assessments, the infiltration of four immune cell types (CD4+/CD8+/forkhead box p3+/CD33+ cells), as well as the expression of six co-signaling molecules [programmed cell death 1 (PD1) ligand 1/PD1/T-cell immunoglobulin mucin family member 3/lymphocyte-activating 3/tumor necrosis factor receptor superfamily, member 4/inducible T-cell costimulator] and indoleamine 2,3-dioxygenase 1 were investigated in two independent cohorts of CRC. The patients' overall survival (OS) was evaluated using the Kaplan-Meier method. Using the Cox proportional hazards model, independent prognostic factors of patients were assessed and a nomogram-based immunoprofile system was developed. The predictive ability of the nomogram was determined using a concordance index (C-index) and calibration curve. To facilitate clinical application, a simplified nomogram-based immunoprofile was constructed. Using receiver operating characteristic (ROC) analysis, the predictive accuracy for OS was compared between the immunoprofile and the TNM staging system for patients with stage II/III CRC. According to multivariate analysis for the primary cohort, independent prognostic factors for OS were CD8+ tumor-infiltrating lymphocytes, CD33+ myeloid-derived suppressor cells and TNM stage, which were included in the nomogram. The C-index of the nomogram for predicting OS was 0.861 (95% CI: 0.796-0.925) for the internal validation and 0.759 (95% CI: 0.714-0.804) for the external validation cohort. The simplified nomogram-based immunoprofile system was able to separate same-stage patients into different risk subgroups, particularly for TNM stage II (P

The aim of this study was to illustrate the genomic mutational landscape, tumor mutation burden (TMB), PD-L1 expression, CD8The tumor tissues and corresponding normal tissues of 37 LCNEC patients undergoing surgical resection were collected and determined by whole exome sequencing (WES). Subsequently, the tumor samples were stained with the antibodies of PD-L1 and CD8 via multiplex immunohistochemistry (Multi IHC) to evaluate PD-L1 expression and CD8The median TMB was 5.42 mutations per megabase. Mutations in Wnt (p = 0.049) and Hippo (p = 0.005) pathways were markedly associated with higher TMB value, mutations in p53 pathway were related with higher stromal PD-L1 expression (p = 0.041). LCNEC patients with KEAP1 mutation (p = 0.044) or without adjuvant radiochemotherapy (p = 0.023) had significantly shorter OS. Multivariate analysis showed that high stromal CD8 + T cells infiltration was an independent favorable factor for disease free survival (p = 0.030). The patient stratification of KEAP1 mutation status and stroma PD-L1 expression was independent prognostic factors for overall survival (p = 0.049).The investigation of prognostic factor in resectable LCNEC may provide guidance for timely intervention and new therapy strategy for LCENC patients.

Emerging evidence indicates that cancer stem cells (CSCs) are involved in tumorigenesis, tumor recurrence, and therapeutic resistance in hepatocellular carcinoma (HCC). However, the mechanisms underlying HCC CSC regulation remain largely unknown. Here we report our analysis of 97 paraffin-embedded HCC tumor specimens. We found that protein tyrosine kinase 2 (PTK2) expression correlated with liver CSC marker expression, overall survival, and recurrence-free survival in HCC patients. Our results further showed that PTK2 activated Wnt/β-catenin signaling by promoting nuclear accumulation of β-catenin in HCC cells. In this manner, PTK2 activates CSC traits and drives tumorigenicity in HCC cells, leading to HCC recurrence and sorafenib resistance. Moreover, PTK2 expression was negatively correlated with its level of promoter methylation. PTK2 apparently acts as an oncogene by increasing CSC traits and tumorigenicity in HCC. The present data suggest that PTK2 may be a novel prognostic biomarker for HCC recurrence, and a therapeutic target for HCC treatment.

Lung cancers, the leading cause of cancer mortality worldwide, are characterized by a high metastatic potential. Growing evidence reveals that Spindlin 1 (SPIN1) is involved in tumor progression and carcinogenesis. However, the role of SPIN1 in non-small-cell lung cancer (NSCLC) and the molecular mechanisms underlying SPIN1 in human NSCLC remain undetermined. Here we examined the function of SPIN1 in human NSCLC and found that the expression of SPIN1 was closely correlated with the overall survival and poor prognosis of NSCLC patients. Aberrant regulation of microRNAs (miRNAs) has an important role in cancer progression. We revealed that miR-409 inhibits the expression of SPIN1 by binding directly to the 3′ UTR of SPIN1 using dual-luciferase reporter assays. Overexpression of miR-409 significantly suppressed cell migration, growth, and proliferation by inhibiting SPIN1 in vitro and in vivo. SPIN1 overexpression in miR-409-transfected NSCLC cells effectively rescued the suppression of cell migration, growth, and proliferation regulated by miR-409. miR-409 regulates the PI3K/AKT (protein kinase B) pathway in NSCLC. Moreover, clinical data showed that NSCLC patients with high levels of miR-409 experienced significantly better survival. miR-409 expression was also negatively associated with SPIN1 expression. Taken together, these findings highlight that the miR-409/SPIN1 axis is a useful pleiotropic regulatory network and could predict the metastatic potential in NSCLC patients early, indicating the possibility that miR-409 and SPIN1 might be attractive prognostic markers for treating NSCLC patients. Keywords: non-small lung cancer, NSCLC, miR-409, SPIN1, therapy

Antibodies against checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and its ligand anti-programmed death ligand 1 (PD-L1) have shown clinical efficacy in the treatment of multiple cancers. However, there are only a few studies on biomarkers for these targeted immunotherapies, especially in peripheral blood. We first studied the role of interferon-induced protein-10 (IP10) combined with interleukin-8 (IL-8) in peripheral blood as a biomarker of immune-combined chemotherapy for lung cancer and multiple cancers. We used the high-throughput cytokine detection platform and performed bioinformatics analysis of blood samples from 67 patients with lung cancer and 24 with multiple cancers. We selected the ratio of IP-10 to IL-8 (S2/S0, ratio of changes at 10–12 weeks after treatment to baseline) to predict the response to immunotherapy combined with chemotherapy and evaluate the survival of lung cancer patients and mixed cancer patients. In patients treated with the combination therapy, the specificity and sensitivity of IL-8 and IP10 together as predictors were improved compared with those of IL-8 and IP10 alone. Our conclusion was verified in not only lung cancer but also multiple cancer research cohorts. We then further validated the predictive effect of biomarkers in different histologic types of NSCLC and chemotherapy combined with different PD-1 drug groups. Subsequent validation should be conducted with a larger number of patients. The proposed marker IP10 (S2/S0)/IL-8 (S2/S0), as a predictive immunotherapy biomarker, has broad prospects for future clinical applications in treating patients with multiple intractable neoplasms.

Objective: To observe alveolar macrophages (AMs) in the microenvironment of patients with non-small cell lung cancer (NSCLC). Materials and Methods: 20 NSCLC patients received bronchoalveolar lavage, and the bronchial alveolar lavage fluid (BALF) was collected. The phenotypes of AMs were detected by the opal multiplex immunofluorescence assay (mIF), flow cytometry, and western blot. Results: AMs could easily be made into paraffin sections after agar pre-embedding. The mIF results showed that AMs highly expressed M1-type marker CD86, and M2-type marker CD163 under PerkinElmer Vectra microscope, while there was a significant difference between the expression of CD86 and CD163 (**P

BackgroundThe current Union International Committee on Cancer or the American Joint Committee on Cancer TNM stage system has shown valuable but insufficient estimation for subsets of gastric cancer and prediction for prognosis patients. Thus, there is an urgent need to identify diagnostic, prognostic, and predictive biomarkers to improve patients’ outcomes. Our aim was to perform an integrative analysis on publicly available datasets to identify epigenetic changes that may play key role in the initiation and progression of gastric cancer, based on which we set to develop a DNA methylation signature to improve survival prediction of gastric cancer.ResultsA total of 340 methylation-related differentially expression genes (mrDEGs) were screened in gastric cancer patients from The Cancer Genome Atlas (TCGA) project. Pathway enrichment analysis revealed that they were involved in the biological process related to initiation and progression of gastric cancer. Based on the mrDEGs identified, we developed a DNA methylation signature consisting of ten gene members (SCNN1B, NFE2L3, CLDN2, RBPMS2, JPH2, GBP6, COL4A5, SMKR1, PPP1R14A, and ARL4D) according to their methylation β value. This innovative DNA methylation signature was associated with cancer recurrence, while it showed independence of cancer recurrence and TNM stage for survival prediction. Combination of this DNA methylation signature and TNM stage improved overall survival prediction in the receiver operating characteristic analysis. We also verified that two individual genes (PPP1R14A and SCNN1B) of the identified prognostic signature were regulated by promoter region methylation in a panel of gastric cell lines.ConclusionsThis study presents a powerful DNA methylation signature by performing analyses integrating multi-source data including transcriptome, methylome, and clinical outcome of gastric cancer patients from TCGA. The identified DNA methylation signature may be used to refine the current prognostic model and facilitate further stratification of patients in the future clinical trials. Further experimental studies are warranted to unveil the regulatory mechanism and functional role of all the individual genes of the DNA methylation signature. Also, clinical investigations in large GC patient cohorts are greatly needed to validate our findings.

Additional file 3: Table S3. Clinical characteristics of 363 gastric cancer patients with both methylation data and adequate follow-up information for prognostic model construction.

The present study aimed to investigate the clinical characteristics and outcomes of patients with advanced non-small cell lung cancer (NSCLC) treated with osimertinib, and focused on the resistance mechanism to osimertinib in a real-world setting. Data from 128 patients with advanced NSCLC who were treated with osimertinib between March 2015 and November 2018 at the Chinese People's Liberation Army General Hospital (Beijing, China) were retrospectively collected, and the associations between mutation types and survival were analysed. In patients treated with osimertinib, the objective response rate reached 60.9% (78/128) and the disease control rate reached 81.3% (104/128), with a median progression-free survival (PFS) time of 12.2 months. A number of complex mutations were identified in the re-analysis after the development of osimertinib resistance, including TP53, KRAS and PIK3CA mutations, epidermal growth factor receptor (EGFR) and MYC amplifications, and mutations associated with SCLC transformation, demonstrating that these mutations may account for osimertinib resistance. The median PFS time for patients with the EGFR T790M mutation (n=41) was significantly longer than that for patients with the T790M mutation and the aforementioned complex mutations (n=13) (16.7 vs. 10.8 months; P=0.001). Patients with a single EGFR mutation (n=87) had a longer median PFS time than those with an EGFR mutation and complex mutations (n=24) (14.63 vs. 6.63 months; P

Background Immunoscore, as a prognostic tool defined to quantify in situ immune cell infiltrates, appears to be superior to the TNM staging system. In esophageal squamous cell carcinoma (ESCC), no immunoscore has been established; however, in situ tumor immunology is recognized as highly important. Our study aimed to construct a comprehensive immunoprofile for ESCC. Methods The infiltration of four immune cell types (CD8+/CD4+/Foxp3+/CD33+ cells), the expression of both inhibitory (PD-1/PD-L1/Tim-3/LAG-3) and stimulatory checkpoints (OX-40/ICOS), and IDO1 were evaluated by IHC staining and multi-color immunofluorescence in two independent cohorts (95 patients in the primary cohort and 55 patients in the validation cohort). The association with patients’ overall survival was analyzed by the Kaplan-Meier method and the Cox model. Nomogram-based immunoprofile was established using the independent prognostic variables. To determine its predictive accuracy and discriminatory capacity, the C-index and calibration curve were calculated. Results Significant correlation of PD-L1 expression in tumor cells with PD-1+ T cell infiltration was found (P = 0.035), indicating the activation of the inhibitory PD-1/PD-L1 pathway in ESCC cases. More PD-L1+ ICs, Tim-3+ ICs and LAG-3+ ICs were found in the CD8-rich tumor microenvironment, which is in accordance with the feedback nature of immune system. After adjustment by TNM stage, four immune variables including the infiltration of CD8+/Foxp3+/CD33+ cells and the PD-L1 expression by tumor cells were selected to construct a prognostic nomogram. The calibration curves showed good accuracy of the nomogram for survival prediction. To overcome the complexity of applying a nomogram in a clinical setting, a simple immunoprofile was then established according to the points of each factor from the nomogram. Our immunoprofile model could separate same-stage patients into different risk subgroups, and showed superior accuracy for survival prediction than the TNM staging system based on the C-index calculation and ROC analysis. Conclusions Our nomogram-based immunoprofile can provide more accurate prognosis prediction and is an important complement to the TNM staging system for operable ESCC patients. Electronic supplementary material The online version of this article (10.1186/s40425-018-0418-7) contains supplementary material, which is available to authorized users.

Elevated LRP16 expression is associated with poor clinical outcomes in multiple malignancies. We detected LRP16 expression in hepatocellular carcinoma (HCC) and found that it was downregulated in tumor samples and HCC cell lines. In a cohort of 80 HCC patients, high level of LRP16 expression in HCC tumors was associated with well differentiation, less lymph node metastasis, and good overall survival (OS). Overexpression of LRP16 in the HepG2 and MHCC-97L cell lines increased cell apoptosis, attenuated cell proliferation, migration, and invasion ability in vitro, and drastically diminished tumor growth and metastasis in vivo. Silencing LRP16 in HCC-LM3 and SMMC-7721 cell lines showed opposite results. Microarray evaluation of tumor cells overexpressing LRP16 revealed the effects on decreased activity in the Wnt signaling pathway. These results were confirmed by qRT-PCR and Western blots. Furthermore, inhibition of Wnt signaling decreased proliferation, migration, and invasion of HCC cell lines. Mechanism conducted showed that LRP16 overexpression could prevent β-catenin from entering the nucleus. Our study demonstrated that LRP16 suppresses tumor growth in HCC by modulating Wnt/β-catenin signaling.LRP16 was low expression in HCC tissue and cell lines. Low expression of LRP16 in HCC was associated with poor prognosis. LRP16 inhibits activation of the Wnt/β-catenin pathway in HCC. LRP16 prevents β-catenin from entering the nucleus.

Table S1. Primary antibodies used in IHC/IF. (PDF 81 kb)

Figure S1. Representative IHC images of CD8, CD4, Foxp3, CD33, PD-1, PD-L1, TIM3, LAG3, OX-40, ICOS and IDO1 staining in esophageal squamous cell carcinoma samples (Ă 200). TC, tumor cell; IC, immune cell. (PDF 416 kb)

Figure S5. Survival curves grouped by immunoprofile in all patients with ESCC (n=150). (PDF 124 kb)

Figure S4. Survival curves grouped by different T stages (A), N stages (B) and TNM stages (C) in all patients with ESCC (n=150). (PDF 162 kb)

Emerging evidence has demonstrated that cancer stem cells (CSCs) are involved in tumorigenesis, tumor recurrence and therapy resistance in hepatocellular carcinoma (HCC). However, the mechanisms underlying the regulation of CSCs in HCC remain largely unknown. Here, we report that protein tyrosine kinase 2 (PTK2) expression correlates with liver CSC marker expression, overall survival and recurrence-free survival in HCC patients. PTK2 has an activating effect on Wnt/β-catenin signaling caused by PTK2 promotion of nuclear accumulation of β-catenin protein in HCC cells. PTK2 activates CSC traits and tumorigenicity of HCC cells, leading to HCC recurrence and sorafenib resistance. Moreover, PTK2 expression negatively correlates with the methylation level of its promoter. PTK2 acts as an oncogene by increasing CSC traits and tumorigenicity in HCC. Our findings suggest PTK2 as a novel prognostic biomarker for HCC recurrence and a therapeutic target for HCC treatment. Funding Statement: This work was supported by the National Natural Science Foundation of China (81702936, 81472589, 81672602, 81402345), the Natural Science Foundation of Beijing (7172199) and a General Financial Grant from the Postdoctoral Science Foundation of China (2017M613389) and Logistics Scientific Research project (BWS16J010). Declaration of Interests: The authors declare no competing financial interests. Ethics Approval Statement: The study was conducted with informed consent of the patients and with the approval of the Institutional Review Committees of the Chinese PLA General Hospital.

Figure S2. Survival curves of patients grouped by different CD8+ T cells infiltrating status (A) and different CD4+ T cells infiltrating status (B-E) in the primary cohort. TIL, tumor-infiltrating lymphocytes. (PDF 180 kb)

Table S2. Association between TILs and clinicopathological parameters in the primary cohort. (PDF 173 kb)

To investigate the expression and relevant clinical and pathological significance of AT-rich interactive domaincontaining protein 1A (ARID1A) mRNA in endometriosis-associated ovarian cancer.The clinical and pathological data of 63 patients with ovarian clear cell carcinoma (OCCC) and of 43 patients with ovarian endometrioid adenocarcinoma (OEAC) were collected. The expression of ARID1A-encoded protein, baf250a, in ovarian cancer tissues was detected using immunohistochemistry. The ARID1A mRNA expression was detected via RNAscope hybridization in situ, and its correlation with the clinical and pathological features of patients was analyzed.The age at the onset of OEAC patients accompanied with endometriosis (CM-EAC) was lower than that of those not accompanied with endometriosis (NCM-EAC) (p0.001). For patients with OCCC, the lymph node metastasis (LNM) rate of CM-CCC patients was significantly lower compared to NCM-CCC (p=0.02) and FIGO stage was earlier (stage I and II) (p=0.013). The expression of baf250a in OCCC group was significantly lower than that in the EAC group (p=0.033). In the OCCC group, baf250a was significantly related to early FIGO staging (stage I and II) (p=0.026), while its expression was not significantly associated with FIGO staging of EAC, age, tumor size, occurrence site and LND. The mRNA expression of ARID1A was positively correlated with the expression of baf250a (in OCCC group, rp=0.936, p0.01; in OEAC group, rp=0.325, p=0.035). Analysis of prognosis showed that baf250a was an important prognostic factor rather than an independent prognostic factor, affecting the overall survival (OS) of patients with OCCC, while patients with low ARID1A mRNA expression had a longer-term OS.The decreased gene and protein expression levels of ARID1A are related to the occurrence and development of endometriosis-associated ovarian cancer, especially OCCC. The detection of ARID1A mRNA expression may be used to predict the OS of OCCC.

As an extracellular matrix protein, osteopontin (OPN) has been shown to play an important role in regulation of the immune response to tumors. Myeloid-derived suppressor cells (MDSCs), a heterogeneous population of myeloid progenitors, are major components of the immune suppressive tumor microenvironment and contribute to tumor evasion of the immune response. However, the specific regulating mechanisms underlying MDSCs expansion remain unclear. Here, we found that MDSCs accumulated in the spleen and tumors of 3LL tumor-bearing mice. Supernatant collected from 3LL cells was able to induce the expansion of MDSCs in peripheral blood mononuclear cell (PBMC) in vitro. Results of enzyme linked immunosorbent assay showed high levels of OPN and matrix metalloproteinase-9 (MMP-9) in this supernatant. Silencing OPN can effectively reduce MDSCs frequency in vivo and in vitro. Furthermore, a specific fragment of OPN, OPN-32 kDa cleaved by MMP-9 was detected in the supernatant from 3LL cells. Overexpression of OPN-32 kDa in 3LL cells induced MDSCs expansion. Inhibition of MMP-9 by monoclonal antibody and inhibitor (TIMP-1) reduced MDSCs expansion in vitro and in vivo. These findings suggest that the MMP-9-cleaved OPN fragment, OPN-32kDa, was responsible for MDSCs expansion, which may contribute to tumor's evasion of the immune response.

Myeloid-derived suppressor cells (MDSCs) serve an immunosuppressive role in human tumors. Human Lin-/low human leukocyte antigen-antigen D related (HLA-DR-) cluster of differentiation (CD)-11b+CD33+ MDSCs are closely linked with tumor staging, progression, clinical therapeutic efficacy and prognosis for various types of tumors. The present study employed multiparametric flow cytometry to measure the proportion of Lin-/lowHLA-DR-CD11b+CD33+ MDSCs in the peripheral blood of 105 cervical cancer patients and 50 healthy subjects. The level of MDSC was higher in tumor patients than in the normal control group and this was closely associated with clinical staging. Further analysis of tumor-infiltrating MDSCs was performed in 22 patients. The MDSC proportions in tumor tissue were significantly higher than those in the corresponding adjacent tissue. The phenotypic characteristics of Lin-/lowHLA-DR-CD11b+CD33+ MDSCs were then evaluated and the results revealed that they express high CD13 and CD39, and low CD115, CD117, CD124 and programmed cell death ligand 1; they were also devoid of CD14, CD15 and CD66b. MDSCs and T-cells from peripheral blood were sorted by flow cytometry for co-culture experiments. Lin-/lowHLA-DR-CD11b+CD33+ MDSCs from patients significantly inhibited the proliferation of CD4 and CD8 T-cells. Furthermore, functional analysis verified that MDSCs from cervical cancer patients could inhibit interleukin-2 and interferon-γ production from T-cells. In addition, the associations between peripheral circulating MDSCs and tumor infiltrating MDSCs, and tumor relapse and metastasis were analyzed. The number of peripheral MDSCs and MDSCs in tumor tissue were observed to be associated with relapse-free survival. Thus, MDSCs in the peripheral blood and tumors of cervical cancer patients have a significant immunosuppressive effect, and are associated with cervical cancer staging and metastasis. These results suggest that targeting MDSCs may increase antitumor immunity and increase the efficacy of cervical cancer therapies.

Dendritic cell (DC) vaccine–based immunotherapy for glioblastoma multiforme (GBM) has shown apparent benefit in animal experiments and early-phase clinical trials, but the survival benefit is variable. In this work, we analyzed the mechanism of the potent antitumor immune response induced in vivo by tumor-associated antigen (TAA)-specific DCs with an invariant natural killer T (iNKT) cell adjuvant in orthotopic glioblastoma-bearing rats vaccinated with tumor-derived exosomes and α-galactosylceramide (α-GalCer) -pulsed DCs. Compared with traditional tumor lysate, exosomes were utilized as a more potent antigen to load DCs. iNKT cells, as an effective cellular adjuvant activated by α-GalCer, strengthened TAA presentation through their interaction with DCs. Co-delivery of tumor-derived exosomes with α-GalCer on a DC-based vaccine showed powerful effects in glioblastoma immunotherapy. This vaccine induced strong activation and proliferation of tumor-specific cytotoxic T lymphocytes, synergistically breaking the immune tolerance and improving the immunosuppressive environment.

Background PD-1 antibody plus chemotherapy is a standard first-line therapy in patients with advanced lung squamous carcinoma. Previous study suggested that the combination of anti-PD-1 antibody SHR-1210 and VEGFR 2 inhibitor apatinib significantly improved antitumor effects. The aim of this study was to evaluate the efficacy and safety of SHR-1210 in combination with apatinib for advanced lung squamous carcinoma patients as a first-line treatment. Methods Stage IIIB or IV advanced lung squamous carcinoma patients were enrolled in this open-label, single-center, single-arm phase II study. Patients received SHR-1210 (200mg q2w) and apatinib (250mg po qd) until progression or unacceptable toxicity. Treatment efficacy was assessed every 3 cycles (6 weeks). The primary end point is progression-free survival (PFS). Secondary end points are objective response rate (ORR), disease control rate (DCR) and overall survival (OS), which according to RECIST 1.1. Results At data cut-off (July 8, 2019), 12 advanced lung squamous carcinoma patients were enrolled in the study, of which 7 patients were evaluable. Median age was 67 years, male accounts for 91.7% (11/12), clinical stage IV for 83.3% (10/12). All included patients at a median follow-up of 2.3 months (range 0.4-6.5 months). No patient achieved complete response (CR). Partial response (PR) was achieved by 6 (85.7%) patients and stable disease (SD) exhibited by 1 (14.3%) patient. The ORR and DCR were 85.7% and 100%, respectively. Grade II adverse events were observed in 4 (33.3%) patients with interstitial pneumonia (1 patient), hand-foot skin reaction (2 patients) or rash (1 patient). One patient (1/12) died after 6 months treatment due to interstitial pneumonia and one patient was assessed by PD after 5.5 months treatment. Four patients ever suspended treatment due to interstitial pneumonia, pyelonephritis, rash or pneumothorax. Conclusions The combination of SHR-1210 and apatinib for advanced lung squamous carcinoma patients may be a promising method as a first-line treatment. Clinical trial identification ChiCTR1800019329 (Chinese Clinical Tiral Registry). Date of Registration: 2018-11-06. Legal entity responsible for the study Jinliang, Wang. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Background: Gastric cancer (GC) is one of the most common digestive malignancies worldwide. N-myc downstream-regulated gene 2 (NDRG2) is a differentiation-related gene which is considered to be a metastasis suppressor gene. The purpose of this study was to detect the serum expression of NDRG2 and its clinical significance in the early detection of patients with GC. Methods: Serum NDRG2 expression were examined in 107 patients with GC, 52 with benign gastric disease patients, and 64 healthy volunteers using reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR) and western blot analysis at mRNA and protein level, respectively. The relationship between NDRG2 expression and clinicopathologic characteristics was analyzed by chi-square test. The diagnostic value of NDRG2 was estimated via establishing the receiver operating characteristic (ROC) curve. Results: the serum NDRG2 expression was lower in GC patients than that in patients with benign disease and healthy volunteers both at mRNA and protein level (P

Although nanoparticle-based photothermal therapy (PTT) has been intensively investigated recently, its comparative efficiency with any clinical cancer treatments has been rarely explored. Herein for the first time we report a systematic comparative study of clinical iodine-125 (125 I) interstitial brachytherapy (IBT-125-I) and interventional PTT (IPTT) in an orthotopic xenograft model of human pancreatic cancer. IPTT, based on the nanoparticles composing of anti-urokinase plasminogen activator receptor (uPAR) antibody, polyethylene glycol (PEG), and indocyanine green (ICG) modified gold nanoshells (hereinafter uIGNs), is directly applied to local pancreatic tumor deep in the abdomen. In comparison to IBT-125-I, a 25% higher median survival rate of IPTT with complete ablation by one-time intervention has been achieved. The IPTT could also inhibit pancreatic tumor metastasis which can be harnessed for effective cancer immunotherapy. All results show that this IPTT is a safe and radical treatment for eradicating tumor cells, and may benefit future clinical pancreatic cancer patients.

Endometriosis is a complex and enigmatic disease that arises from the interplay among multiple genetic and environmental factors. The defining feature of endometriosis is the deposition and growth of endometrial tissues at sites outside of the uterine cavity. Studies to date have established that endometriosis is heritable but have not addressed the causal genetic variants for this disease. Here, we conducted whole-exome sequencing to comprehensively search for somatic mutations in both eutopic and ectopic endometrium from 16 endometriosis patients and five normal control patients using laser capture microdissection. We compared the mutational landscape of ectopic endometrium with the corresponding eutopic sample from endometriosis patients compared with endometrium from normal women and identified previously unreported mutated genes and pathway alternations. Statistical analysis of exome data identified that most genes were specifically mutated in both eutopic and ectopic endometrium cells. In particular, genes that are involved in biological adhesion, cell-cell junctions, and chromatin-remodeling complex(es) were identified, which partially supports the retrograde menstruation theory that proposes that endometrial cells are refluxed through the fallopian tubes during menstruation and implanted onto the peritoneum or pelvic organs. Conspicuously, when we compared exomic mutation data for paired eutopic and ectopic endometrium, we identified a mutational signature in both endometrial types for which no overlap in somatic single nucleotide variants were observed. These mutations occurred in a mutually exclusive manner, likely because of the discrepancy in endometriosis pathology and physiology, as eutopic endometrium rapidly regrows, and ectopic endometrial growth is inert. Our findings provide, to our knowledge, an unbiased view of the landscape of genetic alterations in endometriosis and vital information for indicating that genetic alterations in cytoskeletal and chromatin-remodeling proteins could be involved in the pathogenesis of endometriosis, thus implicating a novel therapeutic possibility for endometriosis.

Despite the success of CD20 antibody rituximab in immunotherapy, acquired resistance is one of the prime obstacles for the successful treatment of B-cell malignancies. There is an urgent need to intensify efforts against resistance in cancer treatment. Growing evidence indicated that lysosomes may form an “Achilles heel” for cancer cells by sensitizing them to death pathways. Here, we uncover an important role of CD20 in initiation of ceramide/lysosomal membrane permeabilization (LMP)-mediated cell death, showing that colocalization of CD20-TNFR1 after type II CD20 antibody ligation can stimulate de novo ceramide synthesis by ceramide synthase and consequently induce remarkable lysosomal permeabilization (LMP) and lysosome-mediated cell death. Further studies show that the potent lysosome-mediated cell death induced by CD20 antibodies exhibits a profound killing effect against both rituximab-sensitive and -resistant (RR) lymphoma. Furthermore, engineering of rituximab by introducing a point mutation endows it with the ability to induce potent ceramide/LMP-mediated cell death in both RR lymphoma and primary B-cell malignancies from patients with rituximab-refractory, suggesting the potential clinical application to combat rituximab resistance.