A MgAl-LDH-CuS nanosheet-based thermo-responsive composite hydrogel with nir-responsive angiogenesis inhibitor releasing capability for multimode starvation therapy.

The rapid proliferation of tumors is highly dependent on the nutrition supply of blood vessels. Cutting off the nutrient supply to tumors is an effective strategy for cancer treatment, known as starvation therapy. Although various hydrogel-based biomaterials have been developed for starvation therapy through glucose consumption or intravascular embolization, the limitations of single-mode starvation therapy hinder their therapeutic effects. Herein, we propose a dual-function nutrition deprivation strategy that can block the nutrients delivery through extravascular gelation shrinkage and inhibit neovascularization through angiogenesis inhibitors based on a novel NIR-responsive nanocomposite hydrogel. CuS nanodots-modified MgAl-LDH nanosheets loaded with angiogenesis inhibitor (sorafenib, SOR) are incorporated into the poly(n-isopropylacrylamide) (PNIPAAm) hydrogel by radical polymerization to obtain the composite hydrogel (SOR@LDH-CuS/P). The SOR@LDH-CuS/P hydrogel can deliver hydrophobic SOR with a NIR-responsive release behavior, which could decrease the tumor vascular density and accelerate cancer cells apoptosis. Moreover, the SOR@LDH-CuS/P hydrogel exhibits higher (3.5 times) compressive strength than that of the PNIPAAm, which could squeeze blood vessels through extravascular gelation shrinkage. In vitro and in vivo assays demonstrate that the interruption of nutrient supply by gelation shrinkage and the prevention of angiogenesis by SOR is a promising strategy to inhibit tumor growth for multimode starvation therapy.

The efficacy, safety, and beneficiary population of angiogenesis inhibitor apatinib plus chemotherapy in recurrent platinum-resistant ovarian cancer patients: A comparative cohort study.

AIM: Angiogenesis inhibitor apatinib targets vascular endothelial growth factor receptors and improves the outcomes of patients with gynecologic malignancy. This study aimed to evaluate the efficacy and safety of angiogenesis inhibitor apatinib plus chemotherapy in recurrent platinum-resistant ovarian cancer (RPR-OC) patients. METHODS: This study retrieved 67 RPR-OC patients who received apatinib plus chemotherapy or chemotherapy alone and divided them into apatinib + chemo (N = 30) and chemo alone (N = 37) groups according to the actual medication. RESULTS: Objective response rate (36.7% vs. 16.2%, p = 0.056) and disease control rate (80.0% vs. 59.5%, p = 0.072) showed an increased trend in apatinib + chemo group versus chemo alone group. The progression-free survival (PFS) (p = 0.010) and overall survival (OS) (p = 0.042) were prolonged in apatinib + chemo group versus chemo alone group. The median (95%confidence interval [CI]) PFS was 5.9 (5.5-6.3) months in apatinib + chemo group and 3.8 (2.0-5.6) months in chemo alone group. The median (95%CI) OS was 20.5 (16.5-24.5) months in apatinib + chemo group and 13.6 (8.6-18.6) months in chemo alone group. Apatinib plus chemotherapy was independently related with better PFS (hazard ratio [HR]: 0.354, p < 0.001) and OS (HR: 0.116, p < 0.001). Subgroup analyses indicated that patients with a more serious disease condition might benefit more from apatinib plus chemotherapy. No difference was found in adverse events of all grade or grade ≥3 between the two groups (all p > 0.05). CONCLUSION: Angiogenesis inhibitor apatinib plus chemotherapy shows better treatment efficacy than chemotherapy alone with controllable safety profile in RPR-OC patients.

Intranasal delivery of sunitinib: A new therapeutic approach for targeting angiogenesis of glioblastoma.

Glioblastoma multiforme (GBM) is one of the most vascular among solid tumors, and despite the use of multimodal therapies, the survival of these patients is poor. In order to target angiogenesis in GBM as a promising strategy, an antiangiogenic drug is required. This study was designed to evaluate the effects of sunitinib, a multityrosine kinase inhibitor with tumor proliferation and angiogenesis inhibitory properties, on GBM-bearing rats. Given the ineffective drug delivery to the brain due to the presence of the blood-brain barrier (BBB), intra-nasal (IN) drug delivery has recently been considered as a non-invasive method to bypass BBB. Therefore, in the current study, IN was used as an ideal method for the delivery of sunitinib to the brain, and the effects of this method were also compared to the OR administration of the sunitinib. GBM was induced in the brain of male Wistar rats, and they were randomly divided into 4 groups; IN-STB (sunitinib intranasal delivery), IN-sham (placebo intranasal delivery), OR-STB (sunitinib oral delivery) and OR-sham (placebo oral delivery). After the end of the treatment period, an MRI of animals' brains showed a reduction in tumor growth in the treatment groups. Immunohistochemistry revealed that sunitinib inhibits angiogenesis in GBM in both OR and IN delivery methods. Analysis of liver tissue and enzymes showed that IN delivery of sunitinib had less hepatotoxicity than the OR method. Overall, it was found that IN sunitinib delivery could be used as a potential non-hepatotoxic alternative for the treatment of GBM.

Randomised phase II trial of trifluridine/tipiracil (FTD/TPI) plus ramucirumab (RAM) versus trifluridine/tipiracil for previously treated patients with advanced gastric or esophagogastric junction adenocarcinoma (RETRIEVE study, WJOG15822G).

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) prolongs survival in the third- or later-line treatment for advanced gastric cancer (GC), esophagogastric junction (EGJ) adenocarcinoma, and colorectal cancer. While single-arm phase II trials showed promising outcomes of FTD/TPI plus ramucirumab (RAM) as third- or later-line treatments for advanced GC or EGJ cancer, there have been no clinical trials to directly compare FTD/TPI plus RAM with FTD/TPI monotherapy. Therefore, we have started a randomised phase II trial to evaluate the efficacy and safety of FTD/TPI plus RAM compared with FTD/TPI monotherapy as third- or later-line treatments in patients with advanced GC and EGJ adenocarcinoma. METHODS: This RETREVE trial (WJOG15822G) is a prospective, open-label, randomised, multicentre phase II trial comparing FTD/TPI plus RAM versus FTD/TPI monotherapy in a third- or later-line setting. Eligibility criteria include age of > 20 years; performance status of 0 or 1; unresectable or recurrent gastric or EGJ adenocarcinoma; confirmed HER2 status; refractory or intolerant to fluoropyrimidine, taxane or irinotecan; refractory to RAM (not intolerant); and at least a measurable lesion per RECIST 1.1. FTD/TPI (35 mg/m2 twice daily, evening of day 1 to morning of day 6 and evening of day 8 to morning of day 13) was administered orally every 4 weeks, and RAM (8 mg/kg) was administered intravenously every 2 weeks. The primary endpoint is progression-free survival (PFS), and the secondary endpoints are overall survival, objective response rate, disease control rate, and safety. The expected hazard ratio of PFS is set as 0.7, assuming 4-month PFS rate of 27% in FTD/TPI monotherapy and 40% in FTD/TPI plus RAM. The number of subjects was 110, with a one-sided alpha error of 0.10 and power of 0.70. DISCUSSION: This study will clarify the additional effect of RAM continuation beyond disease progression on FTD/TPI in the third- or later-line setting for patients with advanced GC or EGJ cancer. TRIAL REGISTRATION: jRCTs041220120.

Type IV collagen-derived angiogenesis inhibitor: canstatin low expressing in brain-invasive meningiomas using liquid chromatography-mass spectrometry (LC-MS/MS).

PURPOSE: Brain invasion in meningiomas is considered an indicator of more aggressive behavior and worse prognosis. But the precise definition and the prognostic role of brain invasion remains unsolved duo to lacking a standardized workflow of surgical sampling and the histopathological detection. Searching for molecular biomarker expression correlating with brain invasion, could contribute to establish a molecular pathological diagnosis without problems of subjective interobserver variation and deeply understand the mechanism of brain invasion and develop innovative therapeutic strategies. METHODS: We utilized liquid chromatography tandem mass spectrometry to quantify protein abundances between non-invasive meningiomas (n = 21) and brain-invasive meningiomas (n = 21) spanning World Health Organization grades I and III. After proteomic discrepancies were analyzed, the 14 most up-regulated or down-regulated proteins were recorded. Immunohistochemical staining for glial fibrillary acidic protein and most likely brain invasion-related proteins was performed in both groups. RESULTS: A total of 6498 unique proteins were identified in non-invasive and brain-invasive meningiomas. Canstatin expression in the non-invasive group was 2.1-fold that of the brain-invasive group. The immunohistochemical staining showed canstatin expressed in both groups, and the non-invasive group showed stronger staining for canstatin in the tumor mass (p = 0.0132) than the brain-invasive group, which showed moderate intensity. CONCLUSION: This study demonstrated the low expression of canstatin in meningiomas with brain invasion, a finding that provide a basis for understanding the mechanism of brain invasion of meningiomas and may contribute to establish molecular pathological diagnosis and identify novel therapeutic targets for personalized care.

Immunotherapy as a later-line option for HER2-altered advanced non-small-cell lung cancer: taxane might be a favorable partner.

Aim: To assess the effectiveness of different types of taxanes, including nab-paclitaxel, paclitaxel and docetaxel, and further compare the effectiveness of taxane-based chemotherapy, taxane-based chemotherapy plus angiogenesis inhibitors or taxane-based chemotherapy plus immune checkpoint inhibitors in HER2-altered non-small-cell lung cancer in the second- or third-line setting. Materials & methods: A total of 52 patients were included in the study. Progression-free survival was compared between subgroups. Results: A clinically meaningful improvement in progression-free survival was observed among patients in the nab-paclitaxel group compared with the docetaxel group. Taxane-based chemotherapy plus immune checkpoint inhibitors achieved longer progression-free survival than taxane-based chemotherapy. There was no difference between taxane-based chemotherapy plus immune checkpoint inhibitors and taxane-based chemotherapy plus angiogenesis inhibitors. Conclusion: Nab-paclitaxel appears to be a reasonable alternative to docetaxel. Chemotherapy plus immune checkpoint inhibitors might yield more survival benefits than chemotherapy alone.

Combination strategies with PD-1/PD-L1 blockade: current advances and future directions.

Antibodies targeting programmed cell death protein-1 (PD-1) or its ligand PD-L1 rescue T cells from exhausted status and revive immune response against cancer cells. Based on the immense success in clinical trials, ten α-PD-1 (nivolumab, pembrolizumab, cemiplimab, sintilimab, camrelizumab, toripalimab, tislelizumab, zimberelimab, prolgolimab, and dostarlimab) and three α-PD-L1 antibodies (atezolizumab, durvalumab, and avelumab) have been approved for various types of cancers. Nevertheless, the low response rate of α-PD-1/PD-L1 therapy remains to be resolved. For most cancer patients, PD-1/PD-L1 pathway is not the sole speed-limiting factor of antitumor immunity, and it is insufficient to motivate effective antitumor immune response by blocking PD-1/PD-L1 axis. It has been validated that some combination therapies, including α-PD-1/PD-L1 plus chemotherapy, radiotherapy, angiogenesis inhibitors, targeted therapy, other immune checkpoint inhibitors, agonists of the co-stimulatory molecule, stimulator of interferon genes agonists, fecal microbiota transplantation, epigenetic modulators, or metabolic modulators, have superior antitumor efficacies and higher response rates. Moreover, bifunctional or bispecific antibodies containing α-PD-1/PD-L1 moiety also elicited more potent antitumor activity. These combination strategies simultaneously boost multiple processes in cancer-immunity cycle, remove immunosuppressive brakes, and orchestrate an immunosupportive tumor microenvironment. In this review, we summarized the synergistic antitumor efficacies and mechanisms of α-PD-1/PD-L1 in combination with other therapies. Moreover, we focused on the advances of α-PD-1/PD-L1-based immunomodulatory strategies in clinical studies. Given the heterogeneity across patients and cancer types, individualized combination selection could improve the effects of α-PD-1/PD-L1-based immunomodulatory strategies and relieve treatment resistance.

Study of siRNA Delivery via Polymeric Nanoparticles in Combination with Angiogenesis Inhibitor for The Treatment of AFP-Related Liver Cancer.

Angiogenesis inhibitor drugs have been explored as important pharmacological agents for cancer therapy, including hepatocellular carcinoma. These agents have several drawbacks, such as drug resistance, nonspecific toxicity, and systemic side effects. Therefore, combination therapy of the drug and small interfering RNA could be a promising option to achieve high therapeutic efficacy while allowing a lower systemic dose. Therefore, we studied adding an alpha-fetoprotein siRNA (AFP-siRNA) incorporated on polymeric nanoparticles (NPs) along with angiogenesis inhibitor drugs. The AFP siRNA-loaded NPs were successfully synthesized at an average size of 242.00 ± 2.54 nm. Combination treatment of AFP-siRNA NPs and a low dose of sunitinib produced a synergistic effect in decreasing cell viability in an in vitro hepatocellular carcinoma (HCC) model. AFP-siRNA NPs together with sorafenib or sunitinib greatly inhibited cell proliferation, showing only 39.29 ± 2.72 and 44.04 ± 3.05% cell viability, respectively. Moreover, quantitative reverse transcription PCR (qRT-PCR) demonstrated that AFP-siRNA incorporated with NPs could significantly silence AFP-mRNA expression compared to unloaded NPs. Interestingly, the expression level of AFP-mRNA was further decreased to 28.53 ± 5.10% when sunitinib was added. Therefore, this finding was considered a new promising candidate for HCC treatment in reducing cell proliferation and enhancing therapeutic outcomes.

Marine Cyanobacteria as Sources of Lead Anticancer Compounds: A Review of Families of Metabolites with Cytotoxic, Antiproliferative, and Antineoplastic Effects.

The marine environment is highly diverse, each living creature fighting to establish and proliferate. Among marine organisms, cyanobacteria are astounding secondary metabolite producers representing a wonderful source of biologically active molecules aimed to communicate, defend from predators, or compete. Studies on these molecules' origins and activities have been systematic, although much is still to be discovered. Their broad chemical diversity results from integrating peptide and polyketide synthetases and synthases, along with cascades of biosynthetic transformations resulting in new chemical structures. Cyanobacteria are glycolipid, macrolide, peptide, and polyketide producers, and to date, hundreds of these molecules have been isolated and tested. Many of these compounds have demonstrated important bioactivities such as cytotoxicity, antineoplastic, and antiproliferative activity with potential pharmacological uses. Some are currently under clinical investigation. Additionally, conventional chemotherapeutic treatments include drugs with a well-known range of side effects, making anticancer drug research from new sources, such as marine cyanobacteria, necessary. This review is focused on the anticancer bioactivities of metabolites produced by marine cyanobacteria, emphasizing the identification of each variant of the metabolite family, their chemical structures, and the mechanisms of action underlying their biological and pharmacological activities.

Multiscale modeling of tumor response to vascular endothelial growth factor (VEGF) inhibitor.

Vascular endothelial growth factor (VEGF) has been known as a key mediator of angiogenesis in cancer. Bevacizumab is anti-VEGF monoclonal antibody that has been approved by the FDA as a first-line treatment in many types of cancer. In this paper, we extend a previously validated multiscale tumor model to comprehensively include the multiple roles of VEGF during the course of angiogenesis and its binding mechanism with bevacizumab. We use the model to simulate tumor system response under various bevacizumab concentrations, both in stand-alone treatment and in combination with chemotherapy. Our simulation indicates that periodic administration of bevacizumab with lower concentration can achieve greater efficacy than a single treatment with higher concentration. The simulation of the combined therapy also shows that the continuous administration of bevacizumab during the maintenance phase can lead to antitumor activity which further suppresses its growth. Agreement with experimental results indicates the potential of the model in predicting the efficacy of anti-VEGF therapies and could therefore contribute to developing prospective clinical trials.

Awareness of Complications of Dental Treatment in Patients Treated with Drugs Affecting the Immune System : A Nationwide Questionnaire Survey of Dental Practitioners in Japan.

The aim of this study was to investigate the awareness and experience, among dental practitioners, of adverse events resulting from dental treatment of patients undergoing therapy with drugs that affect the immune system [angiogenesis inhibitors, biological agents, immunosuppressants, and disease-modifying anti-rheumatic drugs (DMARDs)]. For this purpose, a nationwide questionnaire survey was conducted. Questionnaires were sent to 2,050 dentists, of which 206 (10.1%) were completed and returned. The results showed that most dentists were aware of complications associated with dental treatment of patients treated with drugs that affect the immune system, and about half had actually experienced such complications. Delayed wound healing, osteonecrosis of the jaw (ONJ), and postoperative infections were reported. Whereas approximately 50% of dentists did not discontinue the drugs during dental treatment, about 18% did. During temporary drug discontinuation, some patients experienced aggravation of the primary disease, such as worsening of rheumatism, growth of tumors, and rejection reactions of transplanted organs. As for medical cooperation, only less than half of the dentists were asked for oral hygiene management by a physician prior to starting the drug treatment. Prospective studies are needed because evidence for dental treatments in patients treated with these drugs remains limited.

Lenvatinib in Management of Solid Tumors.

Lenvatinib is a type I tyrosine kinase inhibitor exhibiting powerful antiangiogenic activity in cancer therapy. Displaying activity in multiple solid tumors, it has been approved in differentiated thyroid cancer, hepatocellular carcinoma, and renal cell carcinoma as single agent or in combination. In addition, lenvatinib has shown promise in several other tumor types including medullary, anaplastic thyroid, adenoid cystic, and endometrial cancer. Exploring synergy between angiogenic and immune checkpoint inhibitors, the lenvatinib/pembrolizumab combination is poised to become the next pair of active drugs in endometrial, lung, and gastrointestinal malignancies. Despite robust activity, the drug can be difficult to tolerate. Optimization of dose and biomarkers for prediction of efficacy and toxicities will be of great help. IMPLICATIONS FOR PRACTICE: Readers will be presented with an update on U.S. Food and Drug Administration approval of lenvatinib and suggestions for off-label use in thyroid cancer and adenoid cystic carcinomas. They will become familiarized with the common side effects, frequency, and predicators of response. In addition, they will learn that different strengths of lenvatinib are prescribed and why. Finally, readers are pointed to the latest efforts to combine lenvatinib and pembrolizumab, as well as to unresolved issues such as long-term side effects/toxicities of this drug.

Cancer Therapeutics-Related Cardiac Dysfunction　- Insights From Bench and Bedside of Onco-Cardiology.

Improvements in the long-term survival of cancer patients have led to growing awareness of the clinical importance of cancer therapeutics-related cardiac dysfunction (CTRCD), which can have a considerable effect on the prognosis and quality of life of cancer patients and survivors. Under such circumstances, onco-cardiology/cardio-oncology has emerged as a new discipline, with the aim of best managing cardiovascular complications, including CTRCD. Despite the recent accumulation of epidemiological and clinical information regarding CTRCD, the molecular mechanisms underlying the pathogenesis of CTRCD by individual drugs remain to be determined. To achieve the goal of preventing cardiovascular complications in cancer patients and survivors, it is important to elucidate the pathogenic mechanisms and to establish diagnostic strategies with risk prediction and mechanism- and evidence-based therapies against CTRCD.

Novel VEGFR-2 inhibitors with an N-acylhydrazone scaffold.

Vascular endothelial growth factor receptor 2 (VEGFR-2) is a tyrosine kinase that mediates a large number of cell responses associated with angiogenesis. The control of the angiogenic pathway in tumorigenesis by the inhibition of VEGFR-2 is considered a promising therapeutic strategy for the prevention and control of solid tumor growth. In this study, the design, synthesis, and biological evaluation of a novel series of VEGFR-2 inhibitors with an N-acylhydrazone (NAH) scaffold (9a-h) are reported. The molecular design is validated by docking studies and by in vitro inhibitory activity assays. Compounds 9b, 9c, 9d, and 9f effectively inhibited neovascularization induced by VEGF in the chorioallantoic membrane assay. Thus, these NAH derivatives are promising antiangiogenic prototypes.

Bevacizumab Augments the Antitumor Efficacy of Infigratinib in Hepatocellular Carcinoma.

The fibroblast growth factor (FGF) signaling cascade is one of the key signaling pathways in hepatocellular carcinoma (HCC). FGF has been shown to augment vascular endothelial growth factor (VEGF)-mediated HCC development and angiogenesis, as well as to potentially lead to resistance to VEGF/VEGF receptor (VEGFR)-targeted agents. Thus, novel agents targeting FGF/FGF receptor (FGFR) signaling may enhance and/or overcome de novo or acquired resistance to VEGF-targeted agents in HCC. Mice bearing high- and low-FGFR tumors were treated with Infigratinib (i.e., a pan-FGFR kinase inhibitor) and/or Bevacizumab (i.e., an angiogenesis inhibitor). The antitumor activity of both agents was assessed individually or in combination. Tumor vasculature, intratumoral hypoxia, and downstream targets of FGFR signaling pathways were also investigated. Infigratinib, when combined with Bevacizumab, exerted a synergistic inhibitory effect on tumor growth, invasion, and lung metastasis, and it significantly improved the overall survival of mice bearing FGFR-dependent HCC. Infigratinib/Bevacizumab promoted apoptosis, inhibited cell proliferation concomitant with upregulation of p27, and reduction in the expression of FGFR2-4, p-FRS-2, p-ERK1/2, p-p70S6K/4EBP1, Cdc25C, survivin, p-Cdc2, and p-Rb. Combining Infigratinib/Bevacizumab may provide therapeutic benefits for a subpopulation of HCC patients with FGFR-dependent tumors. A high level of FGFR-2/3 may serve as a potential biomarker for patient selection to Infigratinib/Bevacizumab.

[Chinese expert consensus on antiangiogenic drugs for advanced non-small cell lung cancer (2020 Edition)].

Non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer, accounting for more than 80% of primary lung cancer. Platinum-based chemotherapy is the traditional standard for the treatment of advanced NSCLC, but the 5-years survival rate is still very low, less than 5%. Angiogenesis plays an important role in the growth, proliferation and metastasis of solid tumors. Angiogenesis inhibitors affect the tumor microenvironment, degenerate existing tumor blood vessels and inhibit tumor angiogenesis. Angiogenesis inhibitors are now one of the indispensable treatments for patients with advanced NSCLC through continuous development of new angiogenesis inhibitor and improvement of drug accessibility. This consensus is based on the "Expert consensus on anti-angiogenic drug therapy for advanced non-small cell lung cancer in China (2019 Edition)" , combines with clinical research evidence published in the past years and clinical experience. The consensus-writing group compiles a consensus of guiding clinical departments related to lung cancer treatment to use anti-angiogenic drugs in a standardized manner, and further improves the level of standardized diagnosis and treatment of lung cancer.

Complement 1q-like-3 protein inhibits insulin secretion from pancreatic ß-cells via the cell adhesion G protein-coupled receptor BAI3.

Secreted proteins are important metabolic regulators in both healthy and disease states. Here, we sought to investigate the mechanism by which the secreted protein complement 1q-like-3 (C1ql3) regulates insulin secretion from pancreatic ß-cells, a key process affecting whole-body glucose metabolism. We found that C1ql3 predominantly inhibits exendin-4- and cAMP-stimulated insulin secretion from mouse and human islets. However, to a lesser extent, C1ql3 also reduced insulin secretion in response to KCl, the potassium channel blocker tolbutamide, and high glucose. Strikingly, C1ql3 did not affect insulin secretion stimulated by fatty acids, amino acids, or mitochondrial metabolites, either at low or submaximal glucose concentrations. Additionally, C1ql3 inhibited glucose-stimulated cAMP levels, and insulin secretion stimulated by exchange protein directly activated by cAMP-2 and protein kinase A. These results suggest that C1ql3 inhibits insulin secretion primarily by regulating cAMP signaling. The cell adhesion G protein-coupled receptor, brain angiogenesis inhibitor-3 (BAI3), is a C1ql3 receptor and is expressed in ß-cells and in mouse and human islets, but its function in ß-cells remained unknown. We found that siRNA-mediated Bai3 knockdown in INS1(832/13) cells increased glucose-stimulated insulin secretion. Furthermore, incubating the soluble C1ql3-binding fragment of the BAI3 protein completely blocked the inhibitory effects of C1ql3 on insulin secretion in response to cAMP. This suggests that BAI3 mediates the inhibitory effects of C1ql3 on insulin secretion from pancreatic ß-cells. These findings demonstrate a novel regulatory mechanism by which C1ql3/BAI3 signaling causes an impairment of insulin secretion from ß-cells, possibly contributing to the progression of type 2 diabetes in obesity.

Antiresorptive Agent-Related Osteonecrosis of the Jaw (ARONJ): A Twist of Fate in the Bone.

Bisphosphonates (BPs) have been used as antiresorptive agents to treat patients with osteoporosis or metastatic bone cancer, each of which is characterized by bone loss due to the increased bone resorption. However, BPs could cause osteonecrosis of the jaw (ONJ), known as bisphosphonate-related osteonecrosis of the jaw (BRONJ). ONJ is associated with severe pain and deteriorated quality of life. ONJ is also caused by administration of denosumab, a monoclonal antibody against receptor activator of NFκB ligand (RANKL), that functions as a powerful antiresorptive agent. Accordingly, antiresorptive agent-related ONJ (ARONJ) has been advocated, the incidence of which is continuing to increase in Japan as a super-aging society. Importantly, the jawbone is more susceptible to infection compared with bones in other parts of the body, due to the unique anatomical and physiological characteristics; for example, the jawbone with a high remodeling rate is stimulated by teeth during mastication. The risk factors of ARONJ include dental infection, poor occlusal or oral hygiene status, and bone-invasive dental treatment, such as tooth extraction, dental implants, and dentures. Proper collaboration between doctors and dentists is of utmost importance to understand the current status of ARONJ and prevent developing ARONJ. It is also important to ensure that the patients treated with BPs or denosumab can receive appropriate dental treatment. More recently, angiogenesis inhibitors were reported to cause ONJ; thus, medication-related ONJ (MRONJ) has been advocated. This article overviews the concept of MRONJ by focusing on antiresorptive agents and the status of BRONJ in Japan.

[Clinical efficacy and safety of apatinib combined with chemotherapy for osteosarcoma and soft tissue sarcoma with pulmonary metastasis].

Objective: To compare the clinical efficacy and drug safety between oral apatinib combined with conventional chemotherapy and conventional chemotherapy alone for the treatment of osteosarcoma and soft tissue sarcoma patients with pulmonary metastasis. Methods: Thirty-three osteosarcoma and soft tissue sarcoma patients with pulmonary metastasis who were treated in the Department of Bone and Soft Tissue Tumor Surgery, Cancer Hospital of China Medical University from January 2015 to December 2017 were enrolled in this study. Patients with osteosarcoma received methotrexate, adriamycin (ADM), cisplatin (CDDP), ifosfamide (IFO) sequential regimen; patients with soft tissue sarcoma were treated with IFO and ADM regimen. Eighteen of these patients received an additional oral dose of apatinib. The patients were followed up regularly for changes in primary tumors and metastases, adverse reactions and prognosis. Results: Before treatment, the maximum diameter of pulmonary metastases in patients of apatinib group and routine treatment group were (4.46±1.70) cm and (4.53±2.00) cm, respectively, without significant difference (P=0.909). After treatment, the maximum diameter of pulmonary metastases in patients of apatinib group was (1.46±1.39) cm, significantly smaller than (3.02±1.20) cm of routine treatment group (P=0.002). After treatment, the maximum diameter of the primary lesions in the apatinib group and the conventional treatment group median decreased 0.31 cm and 0.12 cm, respectively, without significant difference (P=0.542). After treatment, the maximum diameter of the lung metastases in the apatinib group median decreased 0.59 cm, significantly more than 0.18 cm of the conventional treatment group (P=0.027). The median progression-free survival (PFS) was 9.4 months in the 33 patients. The median PFS was 9.6 months and 8.3 months in the apatinib group and the conventional treatment group, respectively, without significant difference (P=0.593). Specific adverse reactions both occurred in apatinib group and routine treatment group, mainly including oral mucosal reactions and digestive tract reactions (including nausea, vomiting and diarrhea). Conclusions: Apatinib can effectively reduce the volume of primary and metastatic lesions in patients with bone and soft tissue sarcoma accompanied by lung metastasis without reducing the survival rate or causing uncontrollable adverse reactions. The safety and clinical efficacy of apatinib are significant.

Curcumin analog, GO-Y078, overcomes resistance to tumor angiogenesis inhibitors.

Tumor angiogenesis inhibition is one of the most potent strategies in cancer chemotherapy. From past clinical studies, inhibition of the vascular endothelial growth factor pathway successfully treats malignant tumors. However, vascular endothelial growth factor inhibitors alone cannot cure tumors. Moreover, resistance to small molecule inhibitors has also been reported. Herein, we show the antiangiogenic potential of a newly synthesized curcumin analog, GO-Y078, that possibly functions through inhibition of actin stress fiber formation, resulting in mobility inhibition; this mechanism is different from that of vascular endothelial growth factor inhibition. In addition, we examined the detailed mechanism of action of the antiangiogenesis potential of GO-Y078 using human umbilical venous epithelial cells resistant to angiogenesis inhibitors (HUVEC-R). GO-Y078 inhibited the growth and mobility of HUVEC-R at 0.75 µmol/L concentration. Expression analyses by microarray and RT-PCR showed that expressions of genes including that of fibronectin 1 were significantly suppressed. Among these genes, fibronectin 1 is abundantly expressed and, therefore, seems to be a good target for GO-Y078. In a knockdown experiment using Si-oligo of fibronectin 1 (FN1), FN1 expression was decreased to half of that in mock experiments as well as GO-Y078. Knockdown of FN1 resulted in the suppression of HUVEC-R growth at 24 hours after treatment. Fibronectin is a key molecule contributing to angiogenesis that could be inhibited by GO-Y078. Thus, resistance to vascular endothelial growth factor inhibition can be overcome using GO-Y078.