Evaluation of Tucatinib in HER2-Positive Breast Cancer Patients With Brain Metastases: A United States-Based Cost-Effectiveness Analysis.

PURPOSE: To evaluate the cost-effectiveness of tucatinib in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) patients with brain metastases (BMs) and the subgroup of active BMs from the United States (US) payer perspective. MATERIALS AND METHODS: A 3-state Markov model was developed to compare the cost-effectiveness of 2 regimens in HER2-positive BC patients with BMs: (1) tucatinib, trastuzumab, and capecitabine (TTC); (2) placebo, trastuzumab, and capecitabine (PTC). And subgroup analysis of active BMs was also performed. Lifetime costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio (ICER) and incremental net-health benefit (INHB) were estimated. The willingness-to-pay (WTP) threshold was $200,000/QALY. The robustness of the model was tested by sensitivity analyses. Additional scenario analysis was also performed. RESULTS: Compared with PTC, the ICER yielded by TTC was $418,007.01/QALY and the INHB was -1.08 QALYs in patients with BMs. In the subgroup of active BMs, the ICER and the INHB were $324,465.03/QALY and -0.71 QALY, respectively. The results were most sensitive to the cost of tucatinib. Probabilistic sensitivity analyses suggested that the cost-effective probability of TTC was low at the current WTP threshold in the patients with BMs and the subgroup of active BMs. CONCLUSION: Tucatinib is unlikely to be cost-effective in HER2-positive BC patients with BMs from the US payer perspective but shows better economics in patients with active BMs. Selecting a favorable population, reducing the price of tucatinib or offering appropriate drug assistance policies might be considerable options to optimize the cost-effectiveness of tucatinib.

The efficacy of immune checkpoint inhibitors in advanced hepatocellular carcinoma: a meta-analysis based on 40 cohorts incorporating 3697 individuals.

BACKGROUND: This study was designed to investigate the efficacy and safety of immune checkpoint inhibitors (ICIs) in advanced hepatocellular carcinoma (HCC). METHODS: Electronic databases were scanned to identify relevant trials. The primary endpoints were overall survival (OS), progression-free survival (PFS), and their prognostic factors. Stratified analyses were accomplished on ICIs agent and evaluation criteria. RESULTS: Totally, 3697 individuals from 40 cohorts were recruited. For patients treated with ICIs, the pooled median time to progression (TTP) was 8.0 months, median PFS 4.9 months, and median OS 12.0 months; the pooled median PFS and OS of ICIs plus anti-vascular endothelial growth factor (VEGF) agents (PFS: 6.3 months, OS: 16.4 months) were longer than those of ICIs alone. Furthermore, Child-Pugh stage (HR = 1.37, P = 0.0123) and Eastern Cooperative Oncology Group (ECOG) (HR = 1.40, P = 0.0016) were prognostic factors for PFS. Hepatitis C virus (HCV) (HR = 0.71, P = 0.0356), Alpha-fetoprotein (AFP) (HR = 1.17, P < 0.0001), Child-Pugh stage (HR = 1.58, P < 0.0001), Barcelona Clinic Liver Cancer (BCLC) stage (HR = 1.23, P = 0.0005), ECOG (HR = 1.50, P = 0.0012), portal vein invasion (HR = 1.32, P = 0.0053), extrahepatic metastasis (HR = 0.84, P = 0.0047), best response (HR = 0.58, P < 0.0001), and neutrophil-to-lymphocyte ratio (NLR) (HR = 1.23, P = 0.0451) were the prognostic factors for OS. According to both RECIST 1.1 and mRECIST, the objective response rate (ORR) and disease control rate (DCR) rate of ICIs plus anti-VEGF agents were better than those of ICIs alone. The overall rate of any grade adverse events (AEs) was 0.76 (95% CI 0.61-0.89), grade 3 or higher AEs was 0.28 (95% CI 0.15-0.42), and the rate of AEs leading to treatment discontinuation was 0.09 (95% CI 0.06-0.12). CONCLUSIONS: The ICIs was promising in HCC with good efficacy and tolerated toxicity. Compared with ICIs monotherapy, the joint application of ICIs and anti-VEGF agents can contribute a lot more benefits to the survival of patients according to clinical practices.

Activity of Melatonin Against Gastric Cancer Growth in a Chick Embryo Tumor Xenograft Model.

PURPOSE: Previous studies have shown the antitumor activity of melatonin against a wide range of human cancers; however, the impact of melatonin on gastric cancer growth remains to be illustrated. This study aimed to investigate the activity of melatonin against gastric cancer growth in a chick embryo tumor xenograft model and explore the possible mechanisms. MATERIALS AND METHODS: The growth of gastric cancer SGC-7901 cells was measured using MTT assay, and a chick embryo tumor xenograft model was generated to observe the effect of melatonin on gastric cancer growth in vivo. In addition, the VEGF and angiogenin secretion was measured in the supernatant of chick embryo tumor xenograft models with ELISA. RESULTS: MLT treatment inhibited the growth of SGC-7901 cells at a concentration-dependent manner, and treatment with MLT at 1 mM was found to markedly reduce the volume and weight of tumors bearing the allantois of chicken embryos. ELISA showed that MLT at concentrations of 0.0041, 0.012, 0.037 and 0.11 had no remarkable impact on VEGF and angiopoietin secretion, while MLT at 1 mM significantly suppressed VEGF and angiopoietin production in chick embryo tumor xenograft models with SGC-7901 cells (P = 0.023). CONCLUSION: Our data demonstrate that MLT inhibits gastric cancer growth in vitro at a concentration-dependent manner, and suppresses angiogenesis of the chick embryo tumor xenograft model with SGC-7901 cells through inhibiting VEGF and angiogenin secretion. Further studies are needed to investigate the therapeutic potential of MLT for gastric cancer as compared to drugs clinically approved.

Role of transforming growth factor ß1 in the inhibition of gastric cancer cell proliferation by melatonin in vitro and in vivo.

Transforming growth factor ß (TGF­ß) is a polypeptide growth factor with various biological activities, and is widely distributed in various tissues. In mammals, TGF­ß has three isoforms: TGF­ß1, 2, and 3, of which TGF­ß1 is most abundant in the TGF­ß family. TGF­ß1 is closely related to the occurrence and development of tumors. A large number of previous studies have shown that melatonin can inhibit a variety of malignancies. Thus, the aim of the present study was to investigate the role of TGF­ß1 in the melatonin­mediated inhibition of the proliferation of gastric cancer cells in vitro and in vivo. TGF­ß1 cytokine stimulation, anti­TGF­ß1 neutralizing antibody blocking, siRNA TGF­ß1 and other means were utilized to explore the role of TGF­ß1 during the course of anti­gastric cancer by melatonin. The results showed that melatonin upregulated the expression of TGF­ß1 in tumor tissues during the process of inhibiting gastric cancer tumor growth in vivo. Melatonin inhibited the proliferation of gastric cancer cells in vitro, accompanied by increased expression of TGF­ß1 in a time­dependent manner. siRNA­mediated silencing of TGF­ß1 and anti­TGF­ß1 neutralizing antibody completely blocked the TGF­ß1 pathway, which significantly antagonized the melatonin­mediated inhibition of the growth and proliferation of gastric cancer cells, and promoted G1 phase to S phase transformation of MFC cells. Our findings suggest that TGF­ß1 is involved in the regulation of the proliferation of tumor cells. One of the ways in which melatonin inhibits the proliferation of gastric cancer cells is dependent on the TGF­ß1 signaling pathway.

Melatonin induces the apoptosis and inhibits the proliferation of human gastric cancer cells via blockade of the AKT/MDM2 pathway.

Globally, gastric cancer (GC) is one of the most common types of cancer and the third leading cause of cancer­related death. In China, gastric and liver cancers have the highest mortality rates. Melatonin, also known as N-acetyl­5-methoxytryptamine, is a hormone that is produced by the pineal gland in animals and regulates sleep and wakefulness. Melatonin has been shown to inhibit various carcinomas, including GC. There are many different hypotheses to explain the anticancer effects of melatonin, including stimulation of apoptosis, inhibition of cell growth, regulation of anticancer immunity, induction of free-radical scavenging, and the competitive inhibition of estrogen. However, the underlying mechanism by which these effects are elicited remains elusive. The aim of the present study was to investigate the effects of melatonin on human GC cells and determine the underlying molecular mechanism. We treated SGC-7901 GC cells with melatonin and analyzed the resulting protein changes using protein chip technology. Several proteins related to cell apoptosis and proliferation were identified and further tested in SGC-7901 GC cells. We found that melatonin induced cell cycle arrest and the downregulation of CDC25A, phospho-CDC25A (at Ser75), p21 (p21Cip1/p21Waf1) and phospho-p21 (at Thr145). Melatonin also induced upregulation of Bax, downregulation of Bcl-xL, an increase in cleaved caspase-9 level and activation of caspase-3, which confirmed the involvement of the mitochondria in melatonin­induced apoptosis. Upstream regulators of the above proteins, MDM2, phospho-MDM2 (at Ser166) and AKT, phospho-AKT (at Thr308) were all attenuated by melatonin, which led to an increase in p53. The present study demonstrated that the oncostatic effects of melatonin on SGC-7901 GC cells are mediated via the blockade of the AKT/MDM2 intracellular pathway.

Melatonin downregulates nuclear receptor RZR/RORγ expression causing growth-inhibitory and anti-angiogenesis activity in human gastric cancer cells in vitro and in vivo.

An adequate supply of oxygen and nutrients, derived from the formation of novel blood vessels, is critical for the growth and expansion of tumor cells. It has been demonstrated that melatonin (MLT) exhibits marked in vitro and in vivo oncostatic activities. The primary purpose of the present study was to evaluate the in vitro and in vivo antitumor activity of MLT on the growth and angiogenesis of gastric cancer cells, and explore the underlying molecular mechanisms. The present results revealed that MLT inhibited the growth of gastric cancer SGC-7901 cells in a dose- and time-dependent manner. In addition, the present study demonstrated that low concentrations (0.01, 0.1 and 1 mM) of MLT had no clear effect on vascular endothelial growth factor (VEGF) secretion, whereas a high concentration (3 mM) of MLT suppressed VEGF secretion in SGC-7901 cells. Notably, administration of MLT caused suppression of gastric cancer growth and blockade of tumor angiogenesis in tumor-bearing nude mice. Furthermore, MLT treatment reduced the expression of the MLT nuclear receptor RZR/RORγ, SUMO-specific protease 1, hypoxia-inducible factor-1α and VEGF at transcriptional and translational levels within gastric cancer cells during tumorigenesis. In conclusion, MLT nuclear receptor RZR/RORγ may be of great importance in the MLT mediated anti-angiogenesis and growth-inhibitory effect in gastric cancer cells. Since RZR/RORγ is overexpressed in multiple human cancers, MLT may be a promising agent for the treatment of cancers.

Involvement of nuclear receptor RZR/RORγ in melatonin-induced HIF-1α inactivation in SGC-7901 human gastric cancer cells.

The melatonin nuclear receptor is an orphan member of the nuclear receptor superfamily RZR/ROR, which consists of three subtypes (α, ß and γ), suggesting that immunomodulatory and antitumor effects through the intracellular action of melatonin depend on nuclear signaling. In the present study, the biological mechanisms of melatonin were elucidated in association with the RZR/RORγ pathway in SGC-7901 human gastric cancer cells under hypoxia. Melatonin suppressed the activity of RZR/RORγ and SUMO-specific protease 1 (SENP1) signaling pathway, which is essential for stabilization of hypoxia­inducible factor-1α (HIF­1α) during hypoxia. Furthermore, melatonin inhibited the stability of HIF-1α in a time- and conce-ntration-dependent manner in SGC-7901 human gastric cancer cells during hypoxia. Consistently, siRNA-RZR/RORγ effectively blocked the expression of SENP1, HIF-1α and vascular endothelial growth factor (VEGF) production in SGC-7901 cells under hypoxia, suggesting the role of nuclear receptor RZR/RORγ in melatonin-inhibited HIF-1α and VEGF accumulation. Moreover, siRNA RZR/RORγ obviously antagonized to inhibit the action of the gastric cancer cell proliferation by melatonin. Our findings suggest that melatonin suppresses HIF-1α accumulation and VEGF generation via inhibition of melatonin nuclear receptor RZR/RORγ in SGC-7901 cells under hypoxia.

The efficacy and safety of docetaxel plus thalidomide vs. docetaxel alone in patients with androgen-independent prostate cancer: a systematic review.

The aim of this systematic review was taken to investigate the efficacy and safety of docetaxel plus thalidomide vs. docetaxel alone for treating androgen-independent prostate cancer (AIPC). Data were collected from different databases independently by three researchers according to the pre-defined inclusion and exclusion criteria. Total three studies were finally included, indicating that docetaxel plus thalidomide exhibited better survival prognosis and greater prostate-specific antigen (PSA) decline than docetaxel alone. There were no significant differences of hematologic toxicities in two regimens, while the frequency of non-hematologic toxicities was higher in patients with docetaxel plus thalidomide. Briefly, the available evidence indicates potential survival advantage in docetaxel plus thalidomide over docetaxel alone.

Growth-inhibitory activity of melatonin on murine foregastric carcinoma cells in vitro and the underlying molecular mechanism.

Melatonin (MLT) is an indolic hormone produced mainly by the pineal gland. Recent human and animal studies have shown that MLT exerts obvious oncostatic activity both in vitro and in vivo. The purpose of this study was to investigate the antiproliferative effect of MLT on the murine foregastric carcinoma (MFC) cell and to determine the underlying molecular mechanism. Cell viability was determined using the Cell Counting Kit-8 (CCK-8) and the results revealed that MLT exhibited a dose- and time-dependent inhibitory effect on MFC cell growth. Our studies also demonstrated upregulation of p21 and Bax and downregulation of Bcl-2 at both the mRNA and the protein levels in response to MLT treatment of MFC cells. These changes in the expression of these molecules were consistent with the results of the CCK-8. Furthermore, the mRNA and protein expression of membranous MLT receptors was also upregulated. Taken together, these results confirm the oncostatic effect of MLT in MFC cells and the expression of membranous MLT receptors is a potential approach to tumor cells in gastric cancer therapeutic treatment.

[Inhibitory effect of photodynamic therapy combined with paclitaxel on the proliferation of esophageal carcinoma Eca-109 cells].

OBJECTIVE: To investigate the inhibitory effect of photodynamic therapy (PDT) in combination with paclitaxel (PCT) on proliferation in esophageal carcinoma Eca-109 cells line. METHODS: Eca-109 cells were treated with PCT alone, HPD alone at different doses, or their combinations. For the combined treatments, the cells were exposed to PCT for 12 h followed by incubation with HPD at high, middle or low concentrations for 4 h. PDT was then performed on these treated cells and fluorescence microscopic observation was made before and after PDT. The cell survival was measured by MTT assay, and the cell apoptosis rate analyzed by flow cytometry after a 24-h cell incubation following PDT. RESULTS: The fluorescence excitation of the cells was weakened after PDT. Combined treatments resulted in significantly lowered cell survival rate and increased cell apoptosis rates as compared to those of the control cells and the cells treated with PCT alone and low-dose HPD (P<0.01). Significant differences were also noted among the cells exposed to HPD at different concentrations (P<0.05). CONCLUSION: PDT combined with PCT have significant synergetic effects in inhibiting the proliferation of human esophageal carcinoma cells and inducing their apoptosis in vitro.

[Articular cartilage defects repaired with homograft of mesenchymal stem cells seeded onto medical collagen membrane of guided tissue regeneration].

OBJECTIVE: To investigate the curative effects of homograft of the mesenchymal stem cells (MSCs) combined with the medical collagen membrane of the guided tissue regeneration(MCMG) on the full thickness defects of the articular cartilage. METHODS: MSCs derived from New Zealand rabbits aged 3-4 months weighing 2. 1-3.4 kg were cultured in vitro with a density of 5.5 x 10 (8)/ml and seeded onto MCMG. The MSC/MCMG complex was cultured for 48 h and transplanted into the full thickness defects on the in board condyle and trochlea. Twenty-seven healthy New Zealand rabbits were randomly divided into 3 groups of 9 rabbits in each. The cartilage defects in the in board condyle and trochlea were filled with the auto bone marrow MSCs and MCMG complex (MSCs/ MCMG) in Group A (Management A), with only MCMG in Group B (Management B) and with nothing in Group C (Management C). Three rabbits were killed at 4, 8 and 12 weeks after operation in each group, and the reparative tissue samples evaluated grossly,histologically and immunohistochemically were graded according to the gross and histological scale. RESULTS: Four weeks after transplantation, the cartilage and subchondral bone were regenerated in Group A; for 12 weeks, the regenerated cartilage gradually thicker; 12 week after transplantation, the defect was repaired and the structures of the articular surface and subchondral bone was.in integrity. The defects in Group A were repaired by the hyaline-like tissue and the defects in Groups B and C were repaired by the fibrous tissues. Glycosaminoglycan and type II collagen in Groups A, B and C were reduced gradually. The statistical analysis on the gross at 12 weeks and the histological gradings at 4 weeks, 8 weeks and 12 weeks showed that the in board condylar repair had no significant difference compared with the trochlearepair(P>0. 05). Management A was significantly better than Managements B and C (P<0. 05), and Management B was better than Management C (P<0. 05). CONCLUSION: Transplantation of the MSCs combined with MCMG on the full thickness defects of the articular cartilage is a promising approach to the the treatment of cartilage defects. MCMG can satisfy the demands of the scaffold for the tissue-engineered cartilage.