Dynamic evaluation based on acute-on-chronic liver failure predicts survival of patients after liver transplantation: a cohort study.

BACKGROUND AND AIMS: Dynamic evaluation of critically ill patients is the key to predicting their outcomes. Most scores based on the Model for End-stage Liver Disease (MELD) and acute-on-chronic liver failure (ACLF) utilize point-in-time assessment. This study mainly aimed to investigate the impact of dynamic clinical course change on post-liver transplantation (LT) survival. METHODS: This study included 637 adults (overall cohort) with benign end-stage liver diseases. The authors compared the MELD scores and our ACLF-based dynamic evaluation scores. Patients enrolled or transplanted with ACLF-3 were defined as the ACLF-3 cohort ( n =158). The primary outcome was 1-year mortality. ΔMELD and ΔCLIF-OF (Chronic Liver Failure-Organ Failure) represented the respective dynamic changes in liver transplant function. Discrimination was assessed using the area under the curve. A Cox regression analysis identified independent risk factors for specific organ failure and 1-year mortality. RESULTS: Patients were grouped into three groups: the deterioration group (D), the stable group (S), and the improvement group (I). The deterioration group (ΔCLIF-OF ≥2) was more likely to receive national liver allocation ( P =0.012) but experienced longer cold ischemia time ( P =0.006) than other groups. The area under the curves for ΔCLIF-OF were 0.752 for the entire cohort and 0.767 for ACLF-3 cohorts, both superior to ΔMELD ( P <0.001 for both). Compared to the improvement group, the 1-year mortality hazard ratios (HR) of the deterioration group were 12.57 (6.72-23.48) for the overall cohort and 7.00 (3.73-13.09) for the ACLF-3 cohort. Extrahepatic organs subscore change (HR=1.783 (1.266-2.512) for neurologic; 1.653 (1.205-2.269) for circulation; 1.906 (1.324-2.743) for respiration; 1.473 (1.097-1.976) for renal) were key to transplantation outcomes in the ACLF-3 cohort. CLIF-OF at LT (HR=1.193), ΔCLIF-OF (HR=1.354), and cold ischemia time (HR=1.077) were independent risk factors of mortality for the overall cohort, while ΔCLIF-OF (HR=1.384) was the only independent risk factor for the ACLF-3 cohort. Non-ACLF-3 patients showed a higher survival rate than patients with ACLF-3 in all groups ( P =0.002 for I, P =0.005 for S, and P =0.001 for D). CONCLUSION: This was the first ACLF-based dynamic evaluation study. ΔCLIF-OF was a more powerful predictor of post-LT mortality than ΔMELD. Extrahepatic organ failures were core risk factors for ACLF-3 patients. CLIF-OF at LT, ΔCLIF-OF, and cold ischemia time were independent risk factors for post-LT mortality. Patients with a worse baseline condition and a deteriorating clinical course had the worst prognosis. Dynamic evaluation was important in risk stratification and recipient selection.

Smp24, a Scorpion-Venom Peptide, Exhibits Potent Antitumor Effects against Hepatoma HepG2 Cells via Multi-Mechanisms In Vivo and In Vitro.

Scorpion-venom-derived peptides have become a promising anticancer agent due to their cytotoxicity against tumor cells via multiple mechanisms. The suppressive effect of the cationic antimicrobial peptide Smp24, which is derived from the venom of Scorpio Maurus palmatus, on the proliferation of the hepatoma cell line HepG2 has been reported earlier. However, its mode of action against HepG2 hepatoma cells remains unclear. In the current research, Smp24 was discovered to suppress the viability of HepG2 cells while having a minor effect on normal LO2 cells. Moreover, endocytosis and pore formation were demonstrated to be involved in the uptake of Smp24 into HepG2 cells, which subsequently interacted with the mitochondrial membrane and caused the decrease in its potential, cytoskeleton reorganization, ROS accumulation, mitochondrial dysfunction, and alteration of apoptosis- and autophagy-related signaling pathways. The protecting activity of Smp24 in the HepG2 xenograft mice model was also demonstrated. Therefore, our data suggest that the antitumor effect of Smp24 is closely related to the induction of cell apoptosis, cycle arrest, and autophagy via cell membrane disruption and mitochondrial dysfunction, suggesting a potential alternative in hepatocellular carcinoma treatment.

Durable response to crizotinib in an advanced lung adenocarcinoma patient harboring rare CD47-MET fusion: a case report.

Background: MET fusion is a rare type of structure rearrangement, reported only in 0.26% of non-small cell lung cancer (NSCLC). Some uncommon genomic variants, including MET fusions, have been detected with advanced detection technology. Therapeutic option for MET-rearranged NSCLC remains largely uncovered. Case Description: Herein, we described a 72-year-old male patient with a 10-year history of smoking who presented to our hospital with coughing, blood-tinged sputum, chest distress, and anhelation. He was diagnosed with stage IV lung adenocarcinoma harboring a CD47 (EX7)-MET (EX15) fusion, detected by next-generation sequencing (NGS). After one month of crizotinib treatment, the patient showed partial re-expansion of the collapsed right lower lobe, shrinkages of lymph node lesions, and reduced right pleural effusion. The patient achieved partial response (PR) to first-line treatment of crizotinib with a progression-free survival (PFS) of 8 months. Cabozantinib was subsequently administrated, and a short-term PR of fewer than three months was observed. The patient retained CD47-MET fusion and acquired MET D1228E at cabozantinib progression. Conclusions: This case provided the first clinical evidence for the efficacy of crizotinib in CD47-MET rearranged NSCLC and suggested MET D1228E as a resistance mechanism. NGS is a powerful tool for identifying rare MET gene variants in patients with NSCLC, which should be encouraged in clinical practice.

Scorpion Peptide Smp24 Exhibits a Potent Antitumor Effect on Human Lung Cancer Cells by Damaging the Membrane and Cytoskeleton In Vivo and In Vitro.

Smp24, a cationic antimicrobial peptide identified from the venom gland of the Egyptian scorpion Scorpio maurus palmatus, shows variable cytotoxicity on various tumor (KG1a, CCRF-CEM and HepG2) and non-tumor (CD34+, HRECs, HACAT) cell lines. However, the effects of Smp24 and its mode of action on lung cancer cell lines remain unknown. Herein, the effect of Smp24 on the viability, membrane disruption, cytoskeleton, migration and invasion, and MMP-2/-9 and TIMP-1/-2 expression of human lung cancer cells have been evaluated. In addition, its in vivo antitumor role and acute toxicity were also assessed. In our study, Smp24 was found to suppress the growth of A549, H3122, PC-9, and H460 with IC50 values from about 4.06 to 7.07 µM and show low toxicity to normal cells (MRC-5) with 14.68 µM of IC50. Furthermore, Smp24 could induce necrosis of A549 cells via destroying the integrity of the cell membrane and mitochondrial and nuclear membranes. Additionally, Smp24 suppressed cell motility by damaging the cytoskeleton and altering MMP-2/-9 and TIMP-1/-2 expression. Finally, Smp24 showed effective anticancer protection in a A549 xenograft mice model and low acute toxicity. Overall, these findings indicate that Smp24 significantly exerts an antitumor effect due to its induction of membrane defects and cytoskeleton disruption. Accordingly, our findings will open an avenue for developing scorpion venom peptides into chemotherapeutic agents targeting lung cancer cells.

The Co-Expression of Melanoma-Antigen Family a Proteins and New York Esophageal Squamous Cell Carcinoma-1 in Breast Cancer: A Pilot Study.

OBJECTIVE: The aim of this study was to quantify the expression of melanoma-antigen family A proteins (MAGE-A) and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) in breast cancer and establish the prognosis of breast cancer patients with MAGE-A and NY-ESO-1 co-expression. METHODS: A total of 122 patients with breast cancer were recruited for this study. Their clinicopathological data were collected retrospectively, and the MAGE-A and NY-ESO-1 expressions in paraffin-embedded specimens from the 122 patients were evaluated using immunohistochemical analysis. In addition, the survival states of the patients were recorded. RESULTS: Fifty-four patients (44.26%) were MAGE-A positive and 46 (37.70%) were NY-ESO-1 positive. Interestingly, 22 of the 46 NY-ESO-1-positive cases co-expressed MAGE-A. The expression of MAGE-A was positively associated with estrogen-receptor status (χ2 = 4.026, p = 0.045) and human epidermal growth factor receptor 2 status (χ2 = 5.482, p = 0.019), while the expression of NY-ESO-1 was positively associated with p53 expression (χ2 = 4.541, p = 0.033). Of the 122 patients, the lowest survival rate was observed in patients with NY-ESO-1 (+)/MAGE-A (+), with a 5-year survival rate of 59.09% and a median survival of 97 months. CONCLUSION: The results showed that MAGE-A and NY-ESO-1 were frequently expressed in breast cancer patients. The co-expression of MAGE-A and NY-ESO-1 occurred in about 18% of these patients, and it may indicate a poor prognosis.

Identification of Mutations Related to Cisplatin-Resistance and Prognosis of Patients With Lung Adenocarcinoma.

Background: Lung adenocarcinoma (LUAD) is the most common histologic type of non-small cell lung cancer (NSCLC; approximately 60%), and platinum-based chemotherapy is the cornerstone of the treatment for patients with LUAD. However, a considerable number of patients experience tumor recurrence after developing cisplatin (cis-diamminedichloroplatinum(II) or CDDP) resistance. Therefore, it is particularly important to screen primary CDDP-resistant LUAD patient populations, which can maximize the clinical benefits for these patients. Methods: Data for 61 LUAD cell lines were downloaded from the Genomics of Drug Sensitivity in Cancer (GDSC) database to screen for mutations related to CDDP susceptibility, and we conducted whole-exome sequencing (WES) of tumors from 45 LUAD patients from Zhujiang Hospital of Southern Medical University. Subsequently, the clinical prognostic value of these mutations was verified by using The Cancer Genome Atlas (TCGA)-LUAD cohort and our cohort (n = 45). Results: Based on drug sensitivity data for the GDSC-LUAD cell lines and survival analysis of the cohorts TCGA-LUAD and Local-LUAD, we found only one gene (GREB1) with mutations related to decreased CDDP sensitivity as well as worse overall survival (OS) and progression-free survival (PFS) [OS: log-rank p = 0.038, hazard ratio (HR; 95% confidence interval (95% CI)): 2.19 (0.73-6.55); PFS: log-rank p = 0.001; HR: 4.65, 95% CI: 1.18-18.37]. The GREB1-mutant (GREB1-MT) group had a higher frequency of gene mutations. Additionally, gene set enrichment analysis (GSEA) and single-sample GSEA (ssGSEA) suggested reduced accumulation of intracellular drugs in the GREB1-MT group, in addition to increased drug efflux and enhanced DNA damage repair and intracellular detoxification. Conclusion: This study found that GREB1 mutations may mediate the primary resistance and clinical prognosis of LUAD patients undergoing treatment with CDDP. Further functional analysis showed that GREB1 mutations are related to the known mechanism of CDDP resistance. These results suggest that GREB1 mutations are potential biomarkers for screening of CDDP resistance among LUAD patients.

Yi-qi-yang-yin-tian-sui-fang enhances cisplatin-induced tumor eradication and inhibits interleukin-7 reduction in non-small cell lung cancer.

Traditional Chinese Medicine (TCM) has been recognized to be conducive to enhancing the efficiency and reducing the side effects in the whole course of cancer treatment. The mechanisms of TCM/chemotherapy combination involved with interleukin-7 (IL-7) potentially enhance immune responses against tumor. In the present study, we emphasized on a herbal formulation Yi-qi-yang-yin-tian-sui-fang or TCM for short, and investigated its roles in chemotherapy in non-small cell lung cancer (NSCLC). The mice bared with tumor were treated with cisplatin (DDP) and simultaneously administrated with/without low, medium and high doses of TCMs (effective content: 0.5, 2.0 and 8.0 g/per mice) via oral gavage. The results indicated that combination of TCM further elevated the therapy efficiency of DDP in a dose-dependent manner. The growth of tumor cells was estimated by Ki-67 stain and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) assay. The addition of TCM to the DDP treatment could significantly decrease the expression of Ki-67 and promote the apoptosis of tumor cells. In addition, the serum IL-7 level was down-regulated by DDP but restored by the treatment of TCM. The expression of IL-7 and its receptor IL-7R in tumor tissues was also recovered by TCM. Furthermore, the side effect from bone marrow suppression (myelosuppression) induced by DDP were assessed. TCM could abrogate DDP-induced apoptosis of bone marrow and also remarkably induced the expressions of IL-7 and hematopoietic growth factors including G-CSF, GM-CSF, SCF, and SDF-1 in bone marrow. These data indicated that this TCM combined with DDP showed superior anti-tumor effects with reduced myelosuppression via up-regulating IL-7.

Interleukin-7 Resensitizes Non-Small-Cell Lung Cancer to Cisplatin via Inhibition of ABCG2.

Treatment with cisplatin (DDP) is one of the standard therapies used to treat non-small-cell lung cancer (NSCLC) and fundamentally causes resistance in cancer cells, which eventually poses as an obstacle to the efficacy of chemotherapy in NSCLC. Efforts are on all over the world to explore a sensitizer of NSCLC to DDP. Here, we studied the effect of IL-7 on the resistance of NSCLC to chemotherapy. We observed that IL-7 treatment significantly enhanced DDP-induced effects in A549 and A549/DDP cells (DDP-resistant cells), including decreased cell viability and proliferation, as well as increased cell apoptosis and S arrest, indicating that IL-7 treatment resensitized DDP-resistant NSCLC cells to DDP. Subsequently, IL-7 enhanced the sensitivity of PI3K/AKT signaling and expressions of ABCG2 to DDP. By inhibiting IL-7 signaling via IL-7R knockdown or activating PI3K/AKT signaling via PI3K activation, the resensitization to DDP by IL-7 was abrogated, and the expression levels of ABCG2, p-PI3K, and p-AKT were found to be significantly higher. In vivo results also confirmed that IL-7 only in combination with DDP could remarkably induce tumor regression with reduced levels of ABCG2 in tumorous tissues. These findings indicate that IL-7, apart from its adjuvant effect, could overcome multidrug resistance of DDP to restore its chemotherapy sensitivity.

Continuous EGFR tyrosine kinase inhibitor treatment with or without chemotherapy beyond gradual progression in non-small cell lung cancer patients.

BACKGROUND: Several clinical studies have demonstrated that continuous administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could provide additional survival benefit for advanced non-small cell lung cancer (NSCLC) patients who had benefited from prior EGFR TKI therapy. However, whether EGFR TKI combined with chemotherapy could further prolong survival in patients with gradual progression is still unclear. The present study was conducted to evaluate the clinical outcome of continuous EGFR TKI treatment in combination with chemotherapy (combination group) versus continuous EGFR TKI treatment only (monotherapy group) in such a clinical setting. METHODS: We designed a cohort study to collect all chart data of NSCLC patients treated with EGFR TKI in our institution from February 2012 to December 2015 retrospectively and followed up the clinical outcome of EGFR TKI monotherapy or therapy in combination with chemotherapy until April 2017 prospectively. All eligible patients had to meet the criteria of gradual progression. The time interval of progression-free survival 1 (PFS1, gradual progression or death) to PFS2 (off-EGFR TKI progression), and overall survival (OS) between the above 2 groups were used in survival analysis. RESULTS: In all, 50 patients were included in our study. Patients' baseline characteristics were well balanced. Exon 19 deletion mutations and L858R point mutations were detected in 16 and 8 patients, respectively. Twenty, 22, and 8 patients were treated with EGFR TKI in the first, second, and third line setting, respectively. The time interval from PFS1 to PFS2 was 92 and 37 days (monotherapy vs combination), respectively (hazard ratio [HR] =1.16, 95% confidence interval [CI]: 0.61-2.21, P=0.652). The median OS in the monotherapy group and combination group was 696 and 799 days, respectively (HR =0.74, 95% CI: 0.33-1.71, P=0.501). There were no statistical differences between the 2 groups in terms of the time interval from PFS1 to PFS2 and OS. CONCLUSION: Our results suggested that compared with EGFR TKI monotherapy, its combination with chemotherapy beyond gradual progression may not confer a significant survival benefit to NSCLC patients. Further prospective studies are warranted to reinforce the results of the study.

Secondary systemic lupus erythematosus after thymoma resection misdiagnosed as medically unexplained dyspnoea: A case report.

RATIONALE: Secondary systemic lupus erythematosus (SLE) is an exceedingly rare complication of thymoma resection and is difficult to diagnose because of the insidious and nonspecific clinical manifestations. A case of SLE that occurs secondary to thymoma resection is described in this report. PATIENT CONCERNS: A 43-year-old male came to our hospital with the sole symptom of dyspnea after thymoma resection initially. However, other atypical lesions of SLE occurred over time. DIAGNOSES: Antinuclear antibody spectrum test showed positive results and the diagnosis of SLE was obtained. INTERVENTIONS: Initially the patient was treated for medically unexplained dyspnea (MUD) without much improvement. Following the diagnosis, the methylprednisolone pulse therapy and therapies of immunoglobulin and cyclophosphamide were adopted for the treatment. OUTCOMES: Finally, the patient's symptoms faded rapidly and favorable prognosis has been maintained till now. LESSONS: This case highlights the importance of a serious and comprehensive analysis before we give the diagnosis of MUD. Additionally, ignorance of secondary SLE after thymoma resection should be prevented to avoid a delayed diagnosis and treatment.

Hemorrhagic events in cancer patients treated with aflibercept: a meta-analysis.

Aflibercept (Ziv-aflibercept, VEGF Trap, AVE005) is an engineered protein that functions as a decoy receptor to bind vascular endothelial growth factor A (VEGF-A). Hemorrhagic events, including epistaxis, gastrointestinal bleeding, and pulmonary bleeding, is one of its major adverse effects, but the incidence rate and overall risk has not been systematically studied. Therefore, we conducted a meta-analysis of published clinical trials to investigate the incidence and relative risk of hemorrhagic events in cancer patients treated with aflibercept. Electronic databases including PubMed, Embase, Cochrane databases, and American Society of Clinical Oncology abstracts were searched. Eligible studies were phase II and III prospective clinical trials of cancer patients treated with aflibercept with toxicity profile on hemorrhagic events. Overall incidence rates, relative risk (RR), and 95 % confidence intervals (CI) were calculated using fixed or random effects models depending on the heterogeneity of the included studies. A total of 4,538 patients with a variety of solid tumors from 13 prospective clinical trials were included for the meta-analysis. The overall incidences of all-grade and high-grade hemorrhagic events in cancer patients were 22.1 % (95 % CI, 16.5-29.7 %) and 4.2 % (95 % CI, 3.9-4.6 %), respectively. The relative risks of hemorrhagic events of aflibercept compared to control were increased for all-grade (RR = 2.63; 95 % CI, 2.07-3.34) and high-grade (RR = 2.45, 95 % CI, 1.62-3.72) hemorrhagic events. The risk of developing high-grade hemorrhagic events with aflibercept was comparable to that of bevacizumab (RR = 1.26; 95 % CI, 0.89-1.79). Aflibercept is associated with an increased risk of developing hemorrhagic events in patients with solid tumors. Close monitoring and management of hemorrhagic events are recommended.