Concurrent EGFR-TKI and Thoracic Radiotherapy as First-Line Treatment for Stage IV Non-Small Cell Lung Cancer Harboring EGFR Active Mutations.

LESSONS LEARNED: This single-arm, phase II study shows that concurrent EGFR-tyrosine kinase inhibitor plus thoracic radiotherapy as the first-line treatment for stage IV non-small cell lung cancer harboring EGFR active mutations provides long-term control for the primary lung lesion, and 1-year progression-free survival (PFS) rate and median PFS are numerically higher than those of the erlotinib monotherapy.Serious adverse events are acceptable, although grade >3 radiation pneumonitis occurred in 20% of patients. BACKGROUND: Studies show effective local control by EGFR-tyrosine kinase inhibitor (TKI) combined with radiotherapy at metastatic sites in advanced lung cancer harboring EGFR active mutations. Salvage local radiotherapy is associated with prolonged progression-free survival (PFS) in local disease during EGFR-TKI treatment. However, no prospective study has been reported on concurrent EGFR-TKI and radiotherapy for primary lung lesions. This study investigated the efficacy and safety of first-line EGFR-TKI combined with thoracic radiotherapy in treating stage IV non-small cell lung cancer (NSCLC) harboring EGFR active mutations. METHODS: We conducted a single-arm, phase II clinical trial. Each patient received EGFR-TKI (erlotinib 150 mg or gefitinib 250 mg per day) plus thoracic radiotherapy (54-60 Gy/27-30 F/5.5-6 w) within 2 weeks of beginning EGFR-TKI therapy until either disease progression or intolerable adverse events (AEs) appeared. RESULTS: From January 2015 to March 2018, 401 patients were screened, and 10 patients (5 male and 5 female) were eligible. These patients had a median age of 55 years (40-75) and median follow-up of 19.8 months (5.8-34). The 1-year PFS rate was 57.1%, median PFS was 13 months, and median time to progression of irradiated lesion (iTTP) was 20.5 months. Objective response rate (ORR), was 50% and disease control rate (DCR) was 100%. The most common grade ≥3 AEs were radiation pneumonitis (20%) and rash (10%). One patient died after rejecting treatment for pneumonitis. The others received a full, systematic course of glucocorticoid therapy. Pneumonitis was all well controlled and did not relapse. CONCLUSION: Concurrent EGFR-TKI plus thoracic radiotherapy as the first-line treatment for stage IV NSCLC harboring EGFR active mutations shows a long-term control of primary lung lesion. The 1-year PFS rate and median PFS of this combined therapy are numerically higher than those of the erlotinib monotherapy. The risk of serious adverse events is acceptable.

A case report: delayed high fever and maculopapules during Sorafenib treatment of ectopic hepatocellular carcinoma.

BACKGROUND: Sorafenib is the standard first-line therapy for hepatocellular carcinoma (HCC) and probably ectopic hepatocellular carcinoma (EHCC) as well. No report involves a side effect of delayed high fever of sorafenib. This manuscript describes a case of EHCC in the thoracic and abdominal cavities, who showed a delayed high fever and maculopapules during sorafenib treatment. CASE PRESENTATION: The patient is a 63-year-old Chinese male with advanced EHCC, taking sorafenib 400 mg twice daily. On the tenth day, red maculopapules appeared all over the body. On the same day, the patient began to suffer from continuous high fever. Due to these effects, the patient was asked to cease sorafenib treatment, and the high fever and maculopapules were alleviated quickly. However, the symptoms were present again upon re-challenge of sorafenib. Prednisone was then administered to control the symptoms, with the dosage gradually reduced from 30 to 5 mg/day in 1.5 months. No recurrence of fever or maculopapules has been found. Tumor response reached partial response (PR) and progression free survival (PFS) reached 392 days + by the date of Apr. 14th, 2016. CONCLUSION: EHCC could be treated like orthotopic HCC by oral administration of sorafenib, which shows good tumor response and survival benefit. Delayed high fever and maculopapules are potential, rare and severe side effects of sorafenib, and could be effectively controlled by glucocorticoid.

Essential role of miR-200c in regulating self-renewal of breast cancer stem cells and their counterparts of mammary epithelium.

BACKGROUND: Breast cancer stem cells (BCSCs) have been reported as the origin of breast cancer and the radical cause of drug resistance, relapse and metastasis in breast cancer. BCSCs could be derived from mutated mammary epithelial stem cells (MaSCs). Therefore, comparing the molecular differences between BCSCs and MaSCs may clarify the mechanism underlying breast carcinogenesis and the targets for gene therapy. Specifically, the distinct miRNome data of BCSCs and MaSCs need to be analyzed to find out the key miRNAs and reveal their roles in regulating the stemness of BCSCs. METHODS: MUC1(-)ESA(+) cells were isolated from normal mammary epithelial cell line MCF-10A by fluorescence-activated cell sorting (FACS) and tested for stemness by clonogenic assay and multi-potential differentiation experiments. The miRNA profiles of MaSCs, BCSCs and breast cancer MCF-7 cells were compared to obtain the candidate miRNAs that may regulate breast tumorigenesis. An miRNA consecutively upregulated from MaSCs to BCSCs to MCF-7 cells, miR-200c, was chosen to determine its role in regulating the stemness of BCSCs and MaSCs in vitro and in vivo. Based on bioinformatics, the targets of miR-200c were validated by dual-luciferase report system, western blot and rescue experiments. RESULTS: In a 2-D clonogenic assay, MUC1(-)ESA(+) cells gave rise to multiple morphological colonies, including luminal colonies, myoepithelial colonies and mixed colonies. The clonogenic potential of MUC1(-)ESA(+) (61.5 ± 3.87 %) was significantly higher than that of non-stem MCF-10A cells (53.5 ± 3.42 %) (P < 0.05). In a 3-D matrigel culture, MUC1(-)ESA(+) cells grew into mammospheres with duct-like structures. A total of 12 miRNAs of interest were identified, 8 of which were upregulated and 4 downregulated in BCSCs compared with MaSCs. In gain- and lost-of-function assays, miR-200c was sufficient to inhibit the self-renewal of BCSCs and MaSCs in vitro and the growth of BCSCs in vivo. Furthermore, miR-200c negatively regulated programmed cell death 10 (PDCD10) in BCSCs and MaSCs. PDCD10 could rescue the tumorigenesis inhibited by miR-200c in BCSCs. DISCUSSION: Accumulating evidence shows that there is a milignant transformation from MaSCs into BCSCs. The underlying mechanism remains unclear. In present study, miRNA profiles between MaSCs and BCSCs were obtained. Then miRNA-200c, downregulated in both MaSCs and BCSCs, were verified as anti-oncogene, and played essential role in regulating self-renewal of both kinds of stem-like cells. These findings reveal a novel insights of breast tumorigenesis. CONCLUSIONS: PDCD10 is a target gene of miR-200c and also a possible mechanism by which miR-200c plays a role in regulating the stemness of BCSCs and MaSCs.

Characterization of zinc finger protein 536, a neuroendocrine regulator, using pan-cancer analysis.

BACKGROUND: Previous studies suggested that zinc finger protein 536 (ZNF536) was abundant in the central brain and regulated neuronal differentiation. However, the role of ZNF536 in cancer has remained unclear. METHODS: ZNF536 mutation, copy number alteration, DNA methylation, and RNA expression were explored using public portals. Data from The Cancer Genome Atlas (TCGA) were utilized to analyze pathways and tumor microenvironment (TME), with a focus on prognosis in both TCGA and immunotherapy pan-cancer cohorts. Methylated ZNF536 from small cell lung cancer (SCLC) cell lines were utilized to train with probes for conducting enrichment analysis. Single-cell RNA profile demonstrated the sublocalization and co-expression of ZNF536, and validated its targets by qPCR. RESULTS: Genetic alterations in ZNF536 were found to be high-frequency and a single sample could harbor different variations. ZNF536 at chromosome 19q12 exerted a bypass effect on CCNE1, supported by CRISPR data. For lung cancer, ZNF536 mutation was associated with longer survival in primary lung adenocarcinoma (LUAD), but its prognosis was poor in metastatic LUAD and SCLC. Importantly, ZNF536 mutation and amplification had opposite prognoses in Stand Up To Cancer-Mark Foundation (SU2C-MARK) LUAD cohort. ZNF536 mutation altered the patterns of genomic alterations in tumors, and had distinct impacts on the signaling pathways and TME compared to ZNF536 amplification. Additionally, ZNF536 expression was predominantly in endocrine tumors and brain tissues. High-dimensional analysis supported this finding and further revealed regulators of ZNF536. Considering that the methylation of ZNF536 was involved in the synaptic pathway associated with neuroendocrine neoplasms, demonstrating both diagnostic and prognostic value. Moreover, we experimentally verified ZNF536 upregulated neuroendocrine markers. CONCLUSIONS: Our results showed that ZNF536 alterations in cancer, including variations in copy number, mutation, and methylation. We proved the involvement of ZNF536 in neuroendocrine regulation, and identified highly altered ZNF536 as a potential biomarker for immunotherapy.

High-resolution transcriptomics analysis of CXCL13+ EPSTI1+ CDK1+ cells with a specific focus on lung adenocarcinoma.

Background: Programmed cell death ligand 1 (PD-L1) blocking therapy has transformed the treatment of lung adenocarcinoma (LUAD), which has significantly changed the landscape of immunotherapy. We aimed to explore specific cell subpopulations to understand tumor progression and identify markers of response to PD-L1 blocking therapy. Methods: Bulk, fluorescence-activated cell sorting (FACS), and single-cell RNA (scRNA) sequencing were used to profile CXCL13, EPSTI1, and CDK1. The gene set variation analysis (GSVA) R package was utilized for score calculation, and prognostic analyses included receiver operating characteristic (ROC) curves, Cox proportional hazard models, and meta-analysis. Additionally, we analyzed tumor microenvironment (TME), genomics, compound perturbations, and clinical indicators. The high-dimensional analysis captured the intrinsic characteristics of the subpopulation. Furthermore, subpopulation differential genes were used for enrichment analysis of transcription factors and compounds. Results: Literature and website analyses supported the essential role of CXCL13, CDK1, and EPSTI1 in immunotherapy. This led us to focus specifically on LUAD by representing a pan-cancer profile of immune-sensitive genes. Logically, the high-characteristic population may consist of samples positive for CXCL13, EPSTI1, and CDK1. The three-gene signature was a favorable indicator of immunotherapy response in the Stand Up to Cancer-Mark Foundation (SU2C-MARK) LUAD cohort but showed a poor prognosis before treatment in the Lung Cancer Explorer (LCE) database. Further mechanistic exploration revealed specific mutations associated with the three-gene signature in SU2C-MARK LUAD, such as STK11. In The Cancer Genome Atlas (TCGA)-LUAD cohort, the high-scoring group exhibited a higher tumor mutational burden (TMB) and global methylation but a lower fraction genome altered (FGA) and estimated tumor purity. Moreover, dasatinib demonstrated sensitivity in the high-scoring group. The co-localization of the CXCL13, EPSTI1, and CDK1 subpopulation was validated through spatial transcriptome and immunohistochemical databases. Assessment of the subpopulation depicted high-resolution intercellular communication. Maintenance of specific pathways, such as TNF, CD74, and CD44, contributed to immunotherapy sensitivity. Finally, the subpopulation-enriched targets and drugs were confirmed through ConnectivityMap (CMAP) analysis and multi-omics, respectively. Conclusions: In this study, positive samples for CXCL13, EPSTI1, and CDK1 exhibited poor prognostic significance in treatment-naïve LUAD cases but demonstrated benefits from PD-L1 blockade and dasatinib therapies.

Population-based high-dimensional analyses identify multiple intrinsic characters for cancer vaccines against lung squamous cell carcinoma.

In lung squamous cell carcinoma (LUSC), current cancer vaccines show promising effects, despite a lack of benefit for a large number of patients. We first identified the tumor antigens into shared and private antigens, and determined the population by clustering analysis in public datasets. For vaccine development, The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC) were collected. WGCNA method was furthermore applied to construct a consensus gene co-expression network based on TCGA and CPTAC datasets. The main analyses in bulk sequencing included survival, clinical features, tumor microenvironment (TME), and pathways enrichment. In addition, single-cell RNA (scRNA) analysis of cancer epithelium dissected consensus subtype. We identified the ideal population for cancer vaccines, and candidate neoantigens including AOC1, COL5A2, LGI2, and POSTN. According to subtype analysis, Lung squamous 1 (LSQ1) type exhibited a higher tumor mutational load (TMB) and copy number but no immune infiltration, whereas lung squamous 2 (LSQ2) tumors had a higher global methylation level and more fibroblasts but had less stemness. Meanwhile, trajectory analysis further revealed that the evolution of TME influenced prognosis. We emphasized specific pathways or targets with the potential for combination immunotherapy by consensus network and single-cell RNA analyses. Anti-androgen therapy has been validated in vitro experiments of LUSC as proof of concept. In conclusion, LSQ1 was linked to immune exclusion and might be utilized for vaccination, while LSQ2 was linked to immune dysfunction and could be used for programmed cell death protein 1 (PD1) blocking therapy.

Correlation of preclinical and clinical biomarkers with efficacy and toxicity of cancer immunotherapy.

Immune checkpoint inhibitors (ICIs) have revealed significant clinical values in different solid tumors and hematological malignancy, changing the landscape for the treatment of multiple types of cancer. However, only a subpopulation of patients has obvious tumor response and long-term survival after ICIs treatment, and many patients may experience other undesirable clinical features. Therefore, biomarkers are critical for patients to choose exact optimum therapy. Here, we reviewed existing preclinical and clinical biomarkers of immunotherapeutic efficacy and immune-related adverse events (irAEs). Based on efficacy prediction, pseudoprogression, hyperprogressive disease, or irAEs, these biomarkers were divided into cancer cell-derived biomarkers, tumor microenvironment-derived biomarkers, host-derived biomarkers, peripheral blood biomarkers, and multi-modal model and artificial intelligence assessment-based biomarkers. Furthermore, we describe the relation between ICIs efficacy and irAEs. This review provides the overall perspective of biomarkers of immunotherapeutic outcome and irAEs prediction during ICIs treatment.

YAP1 as a Novel Negative Biomarker of Immune Checkpoint Inhibitors for EGFR-Mutant Non-Small-Cell Lung Cancer.

Background: Immune checkpoint inhibitors (ICIs) have become a standard care in non-small-cell lung cancer (NSCLC). However, its application to epidermal growth factor receptor (EGFR)-mutant NSCLC patients is confronted with drug resistance. This study aimed to clarify the potential role of Yes1-associated transcriptional regulator (YAP1) in ICIs treatment for EGFR-mutant NSCLC population. Methods: All the clinical data of NSCLC were downloaded from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) for GSE11969 and GSE72094. Based on YAP1 expression, all the NSCLC patients including the EGFR-mutant and EGFR-wildtype (WT) patients were divided into two groups, YAP1_High and YAP1_Low. Using cBioPortal, genetic alterations were analyzed for identification of immunogenicity in EGFR-mutant NSCLC. MR analysis was used to analyze the hub gene of EGFR. The infiltration of immune cells and the expression of the identified tumor-associated antigens were identified with TIMER. By graph learning-based dimensionality reduction analysis, the immune landscape was visualized. Moreover, survival analysis was performed to verify the predictive value of YAP1 in ICIs treatment for EGFR-mutant NSCLC population using Ren's research data (NCT03513666). Results: YAP1 was a poor prognostic factor of EGFR-mutant NSCLC population rather than lung adenocarcinoma (LUAD) patients. MR analysis revealed that the EGFR gene regulated YAP1 expression. YAP1 was identified as a hub gene closely associated with immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population in TCGA LUAD. Tumors with YAP1_High showed an immune-"cold" and immunosuppressive phenotype, whereas those with YAP1_Low demonstrated an immune-"hot" and immunoactive phenotype. More importantly, it was verified that YAP1_High subpopulation had a significantly shorter progression-free survival (PFS) and overall survival (OS) after ICIs treatment in EGFR-mutant NSCLC patients in the clinical trial. Conclusions: YAP1 mediates immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population. YAP1 is a novel negative biomarker of ICIs treatment in EGFR-mutant NSCLC population. Clinical Trials. This trial is registered with NCT03513666.

Immune Response on Optimal Timing and Fractionation Dose for Hypofractionated Radiotherapy in Non-Small-Cell Lung Cancer.

Background: The intervention timing of immune checkpoint inhibitors (ICIs) and radiotherapy fractionations are critical factors in clinical efficacy. This study aims to explore dynamic changes of the tumor immune microenvironment (TIME) after hypofractionated radiotherapy (HFRT) at different timepoints and fractionation doses in non-small-cell lung cancer (NSCLC). Methods: In the implanted mouse model, the experimental groups received HFRT 3.7 Gy × 4 F, 4.6 Gy × 3 F, 6.2 Gy × 2 F, and 10 Gy × 1 F, respectively, with the same biological equivalent dose (BED) of 20Gy. Tumor volume and survival time were compared with those of the control group. Flow cytometry was performed to detect immune cells and their PD-1/PD-L1 expressions using tail-tip blood at different timepoints and tumor tissues at 48 h after radiotherapy. In NSCLC patients, immune cells, PD-1/PD-L1, and cytokines were detected in peripheral blood for 4 consecutive days after different fractionation radiotherapy with the same BED of 40Gy. Results: Tumor volumes were significantly reduced in all experimental groups compared with the control group, and the survival time in 6.2 Gy × 2 F (p < 0.05) was significantly prolonged. In tail-tip blood of mice, CD8+ T counts increased from 48 h to 3 weeks in 4.6 Gy × 3 F and 6.2 Gy × 2 F, and CD8+ PD-1 shortly increased from 48 h to 2 weeks in 6.2 Gy × 2 F and 10 Gy × 1 F (p < 0.05). Dentritic cells (DCs) were recruited from 2 to 3 weeks (p < 0.01). As for NSCLC patients, CD8+ T counts and PD-1 expression increased from 24 h in 6.2 Gy × 4 F, and CD8+ T counts increased at 96 h in 10 Gy × 2 F (p < 0.05) in peripheral blood. DC cells were tentatively recruited at 48 h and enhanced PD-L1 expression from 24 h in both 6.2 Gy × 4 F and 10 Gy × 2 F (p < 0.05). Besides, serum IL-10 increased from 24 h in 6.2 Gy × 4 F (p < 0.05). Conversely, serum IL-4 decreased at 24 and 96 h in 10 Gy × 2 F (p < 0.05). Conclusion: HFRT induces the increase in CD8+ T cells and positive immune cytokine response in specific periods and fractionation doses. It was the optimal time window from 48 h to 2 weeks for the immune response, especially in 6.2 Gy fractionation. The best immune response was 96 h later in 10 Gy fractionation, delivering twice instead of a single dose. During this time window, the intervention of immunotherapy may achieve a better effect.

Programmable dual responsive system reconstructing nerve interaction with small-diameter tissue-engineered vascular grafts and inhibiting intimal hyperplasia in diabetes.

Small-diameter tissue-engineered vascular grafts (sdTEVGs) with hyperglycemia resistance have not been constructed. The intimal hyperplasia caused by hyperglycemia remains problem to hinder the patency of sdTEVGs. Here, inspired by bionic regulation of nerve on vascular, we found the released neural exosomes could inhibit the abnormal phenotype transformation of vascular smooth muscle cells (VSMCs). The transformation was a prime culprit causing the intimal hyperplasia of sdTEVGs. To address this concern, sdTEVGs were modified with an on-demand programmable dual-responsive system of ultrathin hydrogels. An external primary Reactive Oxygen Species (ROS)-responsive Netrin-1 system was initially triggered by local inflammation to induce nerve remolding of the sdTEVGs overcoming the difficulty of nerve regeneration under hyperglycemia. Then, the internal secondary ATP-responsive DENND1A (guanine nucleotide exchange factor) system was turned on by the neurotransmitter ATP from the immigrated nerve fibers to stimulate effective release of neural exosomes. The results showed nerve fibers grow into the sdTEVGs in diabetic rats 30 days after transplantation. At day 90, the abnormal VSMCs phenotype was not detected in the sdTEVGs, which maintained long-time patency without intima hyperplasia. Our study provides new insights to construct vascular grafts resisting hyperglycemia damage.

Celecoxib Blocks Vasculogenic Mimicry via an Off-Target Effect to Radiosensitize Lung Cancer Cells: An Experimental Study.

The resistance to radiotherapy in lung cancer can be attributed to vasculogenic mimicry (VM) to some extent. Celecoxib (CXB), a selective inhibitor of cyclooxygenase-2 (COX-2), is reported as a radiosensitizer in non-small cell lung cancer (NSCLC). However, whether CXB can regulate VM formation via an off-target effect to radiosensitize NSCLC remains unclear. This study aimed to elucidate the mechanism underlying the radiosensitizing effect of CXB on NSCLC, i.e., whether CXB can inhibit VM formation via binding to newly identified targets other than COX-2. CXB radiosensitivity assay was performed in BALB/c mice bearing H460 xenografts and C57 mice bearing Lewis lung cancer (LLC) xenografts, which were divided into the control, CXB, irradiation (IR) treatment, and IR plus CXB groups. VM formation was observed using 3D Matrigel, periodic acid solution (PAS) staining, and immunofluorescence staining. The potential off-targets of CXB were screened using Protein Data Bank (PDB) database, MGLTools 1.5.6, and AutoDock Vina 1.1.2 and confirmed by Western blotting, enzyme activity assay, and RNA interference in vitro experiments and by immunohistochemistry in vivo experiments. CXB treatment almost eliminated the enhancement of VM formation by IR in vitro and in vivo, partially due to COX-2 inhibition. Four potential off-targets were predicted by molecular docking. Among them, aminopeptidase N (APN) and integrin alpha-V (ITAV) were remarkably inhibited in protein expression and enzyme activity in vitro or in vivo, consistent with the remarkable reduction of VM formation in H460 xenografts in BALB/c mice. In conclusion, CXB dramatically blocked VM through inhibiting newly identified off-targets APN and ITAV, other than COX-2, then radiosensitizing NSCLC.

Reduction and Functional Exhaustion of T Cells in Patients With Coronavirus Disease 2019 (COVID-19).

Background: The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed great threat to human health. T cells play a critical role in antiviral immunity but their numbers and functional state in COVID-19 patients remain largely unclear. Methods: We retrospectively reviewed the counts of T cells and serum cytokine concentration from data of 522 patients with laboratory-confirmed COVID-19 and 40 healthy controls. In addition, the expression of T cell exhaustion markers were measured in 14 COVID-19 cases. Results: The number of total T cells, CD4+ and CD8+ T cells were dramatically reduced in COVID-19 patients, especially in patients requiring Intensive Care Unit (ICU) care. Counts of total T cells, CD8+ T cells or CD4+ T cells lower than 800, 300, or 400/µL, respectively, were negatively correlated with patient survival. T cell numbers were negatively correlated to serum IL-6, IL-10, and TNF-α concentration, with patients in the disease resolution period showing reduced IL-6, IL-10, and TNF-α concentrations and restored T cell counts. T cells from COVID-19 patients had significantly higher levels of the exhausted marker PD-1. Increasing PD-1 and Tim-3 expression on T cells was seen as patients progressed from prodromal to overtly symptomatic stages. Conclusions: T cell counts are reduced significantly in COVID-19 patients, and the surviving T cells appear functionally exhausted. Non-ICU patients with total T cells counts lower than 800/µL may still require urgent intervention, even in the immediate absence of more severe symptoms due to a high risk for further deterioration in condition.

Clinical benefits of Livin peptide-loaded DCs/CIKs combined with chemotherapy in advanced non-small cell lung cancer.

Previous studies showed that Livin, a member of inhibitors of apoptosis protein (IAP), played an important role in drug and radiation resistance. When the expression of Livin was blocked, the sensitivity to both chemotherapy and radiotherapy was improved in lung cancer cells. A total of 79 patients diagnosed with non-small cell lung cancer (NSCLC) were enrolled into the current study from Jan 2012 to Apr 2016. The Livin and MUC-1 groups received one-cycle autologous DCs/CIKs infusion on days 11 to 14 additionally. The clinical efficacy, immune index, KPS score and adverse events were compared among the three groups. Median progression-free survival (mPFS) in Livin and MUC-1 groups was significantly longer than that in Chemo group (195 and 211 vs 138 days, P < 0.05), and the objective response rate (ORR) in Livin and MUC-1 groups was significantly higher than that in Chemo group (23.1% and 22.2% vs 5.1%, P < 0.05). The Tetramer value after treatment in Livin group was significantly higher than that before treatment (4.07 ± 3.77 vs 3.16 ± 3.82, P < 0.05). The concentration of Livin antibody in patients' peripheral blood before and after treatment in Livin group had no significant difference (P > 0.05). As for KPS score, scarce decrease was found in Livin and MUC-1 groups after chemotherapy treatment (0.77 ± 6.41 and 0.37 ± 5.18, respectively). However, obvious decrease of KPS score (P < 0.039) was recorded in Chemo group (3.85 ± 6.33). There was no significant difference in disease control rate (DCR), overall survival (OS), T cell subsets, cytokine levels (IFN-γ and IL-2) and adverse events between the three groups (P > 0.05). Livin peptide could be a novel substitute to trigger cell immunity by loading DCs in combination with chemotherapy in NSCLC.

Clinical associations and prognostic value of site-specific metastases in non-small cell lung cancer: A population-based study.

The prognosis of non-small cell lung cancer (NSCLC) is poor, particularly for patients with metastatic disease. Numerous efforts have been made to improve the prognosis of these patients; however, only a small number of studies have explored the occurrence rate and prognostic value of different patterns of distant metastasis (DM) in NSCLC systematically. To investigate these, information from patients diagnosed with NSCLC between 2010 and 2014 was collected from the Surveillance, Epidemiology and End Results database. Survival rate comparisons were performed using Kaplan-Meier analysis and log-rank tests. A Cox proportional hazard model was established to determine factors associated with improved overall survival (OS) and cancer-specific survival (CSS). The present study revealed that the most common site of single metastasis occurrence was bone, and the least common was the liver for NSCLC. As for multi-site metastases, the most common two-site metastasis involved bone and lung, and the most common three-site metastasis involved bone, liver and lung. As for NSCLC subtypes, large cell carcinoma (LCC) exhibited more specific metastatic features. The most common single metastatic site was the brain for patients with LCC, and the most common two-site metastatic combination was bone and liver. Patients with isolated liver metastasis exhibited the worst OS and CSS among patients with single metastasis. Furthermore, for patients with multi-site metastases, metastases involving the liver were associated with the worst OS and CSS among various combinations. To the best of our knowledge, the present study is the first to investigate the occurrence rate and prognostic value of different metastatic patterns of site-specific DM for NSCLC using a large population-based dataset. The findings of the present study may have vital implications for classifying patients with advanced NSCLC, thus laying a foundation for individualized precise treatment.

Clinicopathological characteristics and prognostic factors of pulmonary large cell neuroendocrine carcinoma: A large population-based analysis.

BACKGROUND: The study was conducted to compare the clinicopathological characteristics, survival outcomes, and metastatic patterns between pulmonary large cell neuroendocrine carcinoma (LCNEC) and other non-small cell lung cancer (ONSCLC), and to identify the prognostic factors of LCNEC. METHODS: Data of patients diagnosed with LCNEC and ONSCLC from 2004 to 2014 were obtained from the Surveillance, Epidemiology, and End Results dataset. Pearson's chi-square tests were used to compare differences in clinicopathological characteristics. The Kaplan-Meier method was used for survival analysis. A propensity score was used for matching and a Cox proportional hazards model was used for multivariate and subgroup analyses. RESULTS: A total of 2368 LCNEC cases and 231 672 ONSCLC cases were identified. LCNEC incidence increased slightly over time. Except for marital status, LCNEC patients had obviously different biological features to ONSCLC patients. Survival analysis showed that LCNEC had poorer outcomes than ONSCLC. Multivariate analysis revealed that female gender, black race, surgery, radiation, and chemotherapy were protective factors for LCNEC. Matched subgroup analysis further demonstrated that most subgroup factors favored ONSCLC, especially in early stage. Early-stage LCNEC patients had a higher risk of lung cancer-specific death than early-stage ONSCLC patients. Moreover, metastatic patterns were different between LCNEC and ONSCLC. LCNEC patients with isolated liver metastasis or combined invasion to other organs had poorer survival rates. CONCLUSIONS: LCNEC has totally different clinicopathological characteristics and metastatic patterns to ONSCLC. LCNEC also has poorer survival outcomes, primarily because of isolated liver metastasis or combined invasion to other organs. Most subgroup factors are adverse factors for LCNEC.

A dosimetric phantom study of thoracic radiotherapy based on three-dimensional modeling of mediastinal lymph nodes.

The aim of the present study was to investigate the optimal strategy and dosimetric measurement of thoracic radiotherapy based on three-dimensional (3D) modeling of mediastinal lymph nodes (MLNs). A 3D model of MLNs was constructed from a Chinese Visible Human female dataset. Image registration and fusion between reconstructed MLNs and original chest computed tomography (CT) images was conducted in the Eclipse™ treatment planning system (TPS). There were three plans, including 3D conformal radiotherapy (3D-CRT), intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT), which were designed based on 10 cases of simulated lung lesions (SLLs) and MLNs. The quality of these plans was evaluated via examining indexes, including conformity index (CI), homogeneity index and clinical target volume (CTV) coverage. Dose-volume histogram analysis was performed on SLL, MLNs and organs at risk (OARs). A Chengdu Dosimetric Phantom (CDP) was then drilled at specific MLNs according to 20 patients with thoracic tumors and of a medium-build. These plans were repeated on fused MLNs and CDP CT images in the Eclipse™ TPS. Radiation doses at the SLLs and MLNs of the CDP were measured and compared with calculated doses. The established 3D MLN model demonstrated the spatial location of MLNs and adjacent structures. Precise image registration and fusion were conducted between reconstructed MLNs and the original chest CT or CDP CT images. IMRT demonstrated greater values in CI, CTV coverage and OAR (lungs and spinal cord) protection, compared with 3D-CRT and VMAT (P<0.05). The deviation between the measured and calculated doses was within ± 10% at SLL, and at the 2R and 7th MLN stations. In conclusion, the 3D MLN model can benefit plan optimization and dosimetric measurement of thoracic radiotherapy, and when combined with CDP, it may provide a tool for clinical dosimetric monitoring.