• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Perioperative rh-endostatin with chemotherapy improves the survival of conventional osteosarcoma patients: a prospective non-randomized controlled study

    2019-03-23 05:16:54HairongXuZhenHuangYuanLiQingZhangLinHaoXiaohuiNiu
    Cancer Biology & Medicine 2019年1期

    Hairong Xu, Zhen Huang, Yuan Li, Qing Zhang, Lin Hao, Xiaohui Niu

    Department of Orthopedic Oncology Surgery, Beijing Ji Shui Tan Hospital, Peking University, Beijing 100035, China

    ABSTRACT Objective:Anti-angiogenic drugs are an emerging treatment option against malignant tumors. The aim of this study was to determine whether the addition of perioperative rh-endostatin to chemotherapy could improve the probability of distant metastasis-free survival (DMFS) and overall survival (OS) in patients newly diagnosed with non-metastatic conventional osteosarcoma.Methods:This was a controlled non-randomized clinical study that included 388 patients without clinically detectable metastatic disease enrolled from January 2008 to April 2012. The control treatment group had 272 patients; 180 were male and 92, female,with a median age of 17 years. The treatment group had 58 patients; 36 were male and 22, female, with a median age of 16 years.The control group received preoperative chemotherapy followed by surgery and postoperative chemotherapy. The treatment group received 4 cycles of rh-endostatin perioperatively in addition to chemotherapy as per the control group. Patients were followed up from 6-101 months with a median follow-up period of 50.2 months.Results:The 5-year DMFS of the control group (61%) was significantly lower than that of the rh-endostatin group (79%)(P = 0.013). The 5-year OS of the control group (74%) was significantly lower than that of the rh-endostatin treatment group(87%) (P = 0.029). No difference in adverse drug reactions was found between these 2 groups.Conclusions:The addition of perioperative rh-endostatin to chemotherapy could significantly improve the DMFS and OS of patients with non-metastatic osteosarcoma.

    KEYWORDS Osteosarcoma; rh-endostatin; perioperative; distant metastasis; overall survival

    Introduction

    Conventional osteosarcoma is the most common malignant bone tumor in children and adolescents. Long-term survival of localized osteosarcoma has increased substantially from 10%-20% in the 1970s, when surgery was the sole treatment,up to 50%-70% in the 1980s and onwards1,2. The most common survival predictors are the presence of metastases and the histological response to preoperative chemotherapy3,4. The value of chemotherapy for the treatment of osteosarcoma is well established. The most frequently used agents against osteosarcoma include doxorubicin, cisplatin, high-dose methotrexate (HDMTX)and ifosfamide5.

    Recombinant human endostatin (rh-endostatin)(EndostarTM), expressed and purified in Escherichia coli with an additional 9-amino acid sequence forming another his-tag structure, was approved by the State Food and Drug Administration of China in 2005 for the treatment of nonsmall cell lung cancer6,7. Since anti-angiogenic drugs are directed against developing vasculature, not tumor cells, they may stabilize tumor load, rather than produce partial or complete remission. Moreover, the discontinuation of antiangiogenic therapy may allow a tumor to resume growth.Thus, anti-angiogenic treatment alone is not suitable for patients with malignant tumors. In preclinical studies,synergistic antitumor efficacy was observed in an osteosarcoma nude mouse model with the addition of rhendostatin to doxorubicin8.

    From January 2008 to April 2012 our hospital carried out a single-institution study. This was a prospective, nonrandomized, controlled, doctor-initiated clinical study in patients newly diagnosed with non-metastatic conventional osteosarcoma. The primary endpoint of this study was to evaluate whether the addition of rh-endostatin to doxorubicin, cisplatin, HDMTX, and ifosfamide chemotherapy would improve overall survival (OS). The secondary endpoints included whether the addition of rhendostatin would improve distant metastasis-free survival(DMFS) and event-free survival (EFS).

    Materials and methods

    Patients

    All enrolled patients had histologically newly diagnosed conventional osteosarcoma (pathologically high-grade).Patients had no clinically detectable metastatic disease(Enneking stage IIB9) and received no prior treatment before enrollment. Patients had to be between 6 and 65 years of age without any contraindications to chemotherapy, including those associated with peripheral blood: white blood cells≥ 3.0 × 109/L, platelets ≥ 75 × 109/L, and hemoglobin level≥ 95 g/L; liver function: blood bilirubin level ≤ 2.5 × normal upper limit and transaminase level ≤ 2.5 × normal upper limit; and renal function: serum creatinine level ≤ 2.0 ×normal upper limit and blood urea nitrogen level ≤ 2.5 ×normal upper limit. Patients were required to have a normal electrocardiogram and no untreatable cardiovascular disease or cerebrovascular disorders and should not be pregnant.Approval for this study was obtained from the institutional review board before patient enrollment. Informed consent was obtained from all patients or their guardians.

    Treatments

    There were 2 treatment arms, the control group(doxorubicin, cisplatin, HDMTX, and ifosfamide) and the rh-endostatin group (doxorubicin, cisplatin, HDMTX,ifosfamide, and rh-endostatin). Both treatment regimens were explained in detail to patients or their guardians. It was the patient's/guardians' final decision to enroll in either the control group or the rh-endostatin group. The informed consent form was completed and signed by the patient or their legal representative before the commencement of the treatment.

    Both regimens called for an initial period of chemotherapy, designated as induction therapy, that lasted about 2 months, followed by definitive resection of the primary tumor. Maintenance chemotherapy was scheduled to begin 2 weeks after the surgery but did not begin until the surgeons had determined that the surgical wound was healing adequately. However, if the initial surgical plan was amputation of the affected limb the patients received no induction therapy.

    The sequence of 1 cycle of chemotherapy was HDMTX,followed by ifosfamide, doxorubicin, cisplatin, and a repeated dose of HDMTX. HDMTX (10 g/m2) was administered as a 4-hour infusion followed by leucovorin rescue. Serum methotrexate levels and renal function were monitored daily and every 3 days, respectively. Hydration and alkalinization with leucovorin were specified in the event of delayed methotrexate excretion. Ifosfamide (15 g/m2) was administered with mesna protection for 5 days. Doxorubicin was administered at a dose of 90 mg/m2for 3 consecutive days, and cisplatin was administered during the first day of doxorubicin delivery at a dose of 120 mg/m2. One cycle of induction chemotherapy lasted about 2 months, and 4 cycles of maintenance chemotherapy lasted about 8 months.

    Rh-endostatin was administered at a dose of 15 mg for 14 consecutive days. Subsequently, the patients had a 7-day break followed by the repeated administration of rhendostatin. We specified that the administration of rhendostatin would be separated from the administration of methotrexate, ifosfamide, doxorubicin, and cisplatin by a minimum of 2 hours. Rh-endostatin was administered as a 4-6 hours infusion for a total of 4 cycles along with both induction and maintenance chemotherapy.

    Definitive surgery was performed at week 9 for limbsalvage patients and at week 1 for amputation patients.Surgery was administered with curative intent and achieved a wide or marginal margin in all cases.

    Endpoints and statistical analysis

    The primary endpoint was OS, defined as the time from study entry until death or last patient contact. Patients without events were censored at the date of last contact. The secondary endpoints included DMFS, EFS, and toxicity.DMFS was defined as the time from study entry until distant metastasis or last patient contact, whichever came first. EFS was defined as the time from study entry until an adverse event or last patient contact, whichever came first. Adverse events included disease progression, the diagnosis of a second malignant neoplasm, or death before disease progression.Disease progression included local recurrence and distant metastasis. Patients without adverse events were censored at the date of last contact. Toxicity was monitored using World Health Organization common toxicity criteria10, with special attention to hepatotoxicity and nephrotoxicity. We compared the incidence of grades III and IV adverse events for the 2 groups. OS, DMFS, and EFS were estimated using the Kaplan-Meier method. The possible risks of each factor were summarized using hazard ratios (HRs) from multivariate Cox regression models. HRs were expressed relative to patients in the baseline category of the factor of interest. An HR < 1.0 and > 1.0 indicate a lower and higher risk, respectively, of the event for patients in that category compared with the baseline category. The survival curves were drawn using Prism 7 Software. The statistical significance of the comparisons of risk for adverse events was assessed by means of the log-rank test.

    The sample size was estimated as follows. Using a power of 80% and an alpha of 0.05, the 5-year survival for the control group was approximately 60%, and that of the test group was expected to be 80%. The ratio of the test group and control group was about 1:4. The total sample size was estimated to be 250 cases. However, due to the possibility that not all cases will meet the eligibility criteria and some would be lost to follow-up, the final number of cases was estimated to be 350-380.

    Results

    Patient characteristics

    A total of 388 patients were enrolled. Among the 310 patients enrolled in the control group, 38 did not meet the eligibility criteria. Among the 78 patients enrolled in the rh-endostatin group, 20 did not meet the eligibility criteria. Finally, 330 patients were included in this study. Among them, 272 were in the control group, and 58 were in the rh-endostatin group at a ratio of 4.7:1. The control group contained 180 men and 92 women with a median age of 17 years. In the rhendostatin group, there were 36 men and 22 women with a median age of 16 years. Follow-up ranged from 6-111 months with a mean period of 56 months. There was no statistical difference in sex, age, location of the tumor, tumor volume11,surgical margin9, or surgery between the 2 groups (Table 1).

    Local recurrence and distant metastasis

    There were 26 local recurrences in the control group with a recurrence rate of 9.6% (26/272). In the rh-endostatin group,there were 3 local recurrences with a recurrence rate of 5.2%(3/58). The number of local recurrences was not significantly different between the 2 groups (P = 0.284).

    In the control group, 94 patients developed distant metastasis, including 74 lung metastases alone, 10 bone metastases alone, 7 bone and lung metastases, 1 lung and brain metastases, and 2 lung and abdominal metastases. Thedistant metastasis rate for the control group was 34.6%(94/272). In the rh-endostatin group, 12 patients developed distant metastases, including 9 lung metastases alone, 1 bone metastasis alone, and 2 bone and lung metastases. The distant metastasis rate for the rh-endostatin group was 20.7%(12/58). There was a significant difference regarding the number of distant metastases between the 2 groups (P =0.04).

    Table 1 The patient characteristics of the two groups

    Distant metastasis-free survival

    In the control group, the 2-year and 5-year DMFS rates were 71% and 61%, respectively. In the rh-endostatin group, the 2-year and 5-year DMFS rates were 82% and 79%,respectively. The 2 groups were significantly different regarding their DMFS rates (P = 0.013, log rank) (Figure 1).The relative risk of distant metastasis for patients who had received rh-endostatin was 0.478 [95% confidence interval(CI), 0.300-0.761, P = 0.014]

    Event-free survival

    In the control group, the 2-year and 5-year EFS rates were 67% and 57%, respectively. In the rh-endostatin group, the 2-year and 5-year EFS rates were 81% and 75%, respectively.There was a statistically significant difference between the 2 groups (P = 0.010, log rank) (Figure 2). The relative risk of events for patients who had received rh-endostatin was 0.490(95% CI, 0.364-0.873, P = 0.010).

    Overall survival

    In the control group, the 2-year and 5-year OS rates were 85% and 74%, respectively. In the rh-endostatin group, the 2-year and 5-year OS rates were 96% and 87%, respectively.There was a statistically significant difference between the 2 groups (P = 0.029, log rank) (Figure 3). Multivariate analyses for OS are shown in Table 2. Surgery methods (limb salvage vs. amputation) and treatment arms (with/without rh-endostatin) were both prognostic for OS. The relative risk of death for patients who underwent amputation was 2.24 (95% CI, 1.16-4.33, P = 0.006), and for patients who had received rh-endostatin, it was 0.37 (95% CI, 0.16-0.87,P = 0.016).

    Figure 1 Distant metastasis-free survival for patients according to the treatment arms.

    Figure 2 Event-free survival for patients according to the treatment arms.

    Figure 3 Overall survival for patients according to the treatment arms.

    Toxicity of therapy

    Toxicity was reported for all the patients in this study. There was no treatment-related death in either group. The most common grade III and IV adverse reactions in the control and rh-endostatin groups were leukopenia, lowered hemoglobin level, hepatic impairment, nausea, and vomiting(Table 3). No adverse cardiac toxicity was observed, and no delayed wound healing was observed in either group. There was no significant difference in adverse effects between the 2 groups. No cases of discontinuation of treatment due to adverse drug reactions were observed.

    Discussion

    Although osteosarcoma is the most common primary malignant bone tumor, its treatment is still one of the most challenging issues in bone tumor therapy and even the entire field of oncology12,13. High-dose chemotherapy using methotrexate and doxorubicin has greatly increased the OS rate of osteosarcoma since the 1970s14,15. Over the past 30 years, oncologists have tested numerous approaches to improve the OS of osteosarcoma patients, including increasing the intensity of chemotherapy, using various combinations of chemotherapeutic agents, and even incorporating immunotherapy. However, to date, no new treatments have significantly reduced the development of lung metastases, which currently occur in up to 30%-50% of osteosarcoma patients16,17. Therefore, the key to improve the survival rate of osteosarcoma is reducing the incidence of lung metastases.

    In 1971, Dr. Folkman proposed the theory of tumor angiogenesis18. He pointed out that both local tumor growth and distant metastases are dependent on tumor angiogenesis.Subsequently, anti-angiogenesis became a new field of cancertreatment. Anti-angiogenesis therapy-related research has shown that there exists a balance in the body's proangiogenic factors and angiogenesis. However, when the primary tumor is excised, the pro-angiogenic factors dominate, thus, contributing to the formation of distant metastases19. In osteosarcoma patients, a study found that the balance of systemic angiogenic factor activity and angiogenesis inhibitory factor activity was disrupted, which was associated with the occurrence of postoperative lung metastasis20. Dutour's research demonstrated that therapy using Endo cDNA/CLP is associated with a pronounced delay in tumor growth in a human-like rat orthotopic tumor model21. Endo cDNA/CLP could effectively prevent the occurrence of lung metastases in osteosarcoma. We have previously undertaken promising anti-angiogenesis research on osteosarcoma in both in vitro and in vivo models22. The combination of rh-endostatin and doxorubicin produced marked synergistic antitumor activity in a mouse osteosarcoma model8.

    Table 2 Multivariate Cox analysis for overall survival

    Prior to commencing the current research, many details of the study design were discussed by the authors. First, when is the appropriate time to administer anti-angiogenesis therapy? The metastatic patterns of osteosarcoma show that most lung metastases occurred 6-12 months after surgical treatment23. Further research revealed that the balance of pro-angiogenic factors and inhibitors was disrupted soon after the primary osteosarcoma was removed24. For this study, it was decided to administer anti-angiogenesis therapy perioperatively to prevent the imbalance of pro-angiogenic factors and inhibitors. Second, should anti-angiogenesis therapy be administered alone or in conjunction with chemotherapy? As anti-angiogenesis treatment only prevents new vascular formation, in theory, it is insufficient to destroy the tumor cells25,26. The goal of anti-angiogenesis treatment is to normalize blood vessels to ensure that more cytotoxic drugs reach the tumor cells, as it is these drugs that will eventually eliminate the tumor cells27. This may explain whyanti-angiogenesis therapy alone usually results in limited good outcomes. Third, should the target patients be newly diagnosed non-metastatic or advanced? Once osteosarcoma patients have developed metastasis, it is extremely difficult to cure the patients or to improve long-time survival28-31. The primary goal of improving OS for osteosarcoma patients is to lower the occurrence of distant metastasis at an early stage.

    Table 3 The toxicity profile of the two groups

    Although it was not possible to perform a randomized study, we attempted to minimize the differences between the groups. Previous studies have shown that age, tumor size,tumor location, and other factors are possible prognostic factors1,32. In the current study, there was no significant difference between the 2 groups in terms of age, sex, tumor location, tumor volume, and tumor margin.

    We found that the 2-year and 5-year DMFS rates were significantly improved by 11% and 18%, respectively, with the addition of anti-angiogenesis therapy. For 5-year DMFS,this represents a reduction of 46% for the 39% of patients we would normally expect to develop metastatic disease. The addition of rh-endostatin to chemotherapy resulted in an improvement in the 5-year OS rate from 74% to 87% (P =0.016; relative risk = 0.37). We considered that the improved survival can be ascribed to the decreased occurrence of distant metastasis due to the use of rh-endostatin in addition to standard multi-drug chemotherapy. The higher risk of death in the amputation group than in the limb salvage group may reflect the fact that poor responders were more likely to undergo amputation in real clinical practice.

    Regarding the safety profile, there were no more serious adverse effects in the rh-endostatin group than in the control group, consistent with previous findings for the use of other anti-angiogenic agents combined with chemotherapy in the treatment of other malignancies6,33-36.

    In summary, the addition of rh-endostatin in patients with newly diagnosed conventional osteosarcoma resulted in a significantly lower occurrence of distant metastases and an improved OS. The addition of rh-endostatin did not increase the rate of adverse effects. However, we do not know whether the addition of rh-endostatin could improve the OS of osteosarcoma patients with advanced disease. The limitations of this research include the non-randomized design and an imbalance in the number of patients between the 2 groups.The current research requires further laboratory and multicenter clinical investigations to evaluate the potential mechanisms and confirm the clinical value of antiangiogenesis therapy in the treatment of osteosarcoma.

    Acknowledgements

    Ministry of Human Resources and Social Security of the People's Republic of China (MOHRSS) (Grant No. 2017-199). We thank Dr. Conan Hall for his kind revising of this manuscript.

    Conflicts of interest statement

    No potential conflicts of interest are disclosed.

    人成视频在线观看免费观看| 老熟妇乱子伦视频在线观看| 三上悠亚av全集在线观看| 午夜福利欧美成人| 99精国产麻豆久久婷婷| 久久天躁狠狠躁夜夜2o2o| 在线观看免费午夜福利视频| 久久影院123| 国产精品乱码一区二三区的特点 | 国产成人av激情在线播放| 一本综合久久免费| 久久人人97超碰香蕉20202| 热99久久久久精品小说推荐| 天堂√8在线中文| 母亲3免费完整高清在线观看| 国产精品成人在线| av天堂久久9| 黑人操中国人逼视频| 麻豆乱淫一区二区| 午夜福利乱码中文字幕| 俄罗斯特黄特色一大片| 国产欧美日韩综合在线一区二区| 免费在线观看日本一区| 妹子高潮喷水视频| 少妇被粗大的猛进出69影院| 老鸭窝网址在线观看| 女人精品久久久久毛片| 女人爽到高潮嗷嗷叫在线视频| 悠悠久久av| av在线播放免费不卡| 亚洲av电影在线进入| 欧美亚洲 丝袜 人妻 在线| 中出人妻视频一区二区| 久久精品亚洲熟妇少妇任你| 国产一区有黄有色的免费视频| 黄色视频,在线免费观看| 久久久国产成人免费| 成人影院久久| 一边摸一边做爽爽视频免费| 国产欧美日韩一区二区三| 狠狠狠狠99中文字幕| aaaaa片日本免费| 亚洲精品久久午夜乱码| 每晚都被弄得嗷嗷叫到高潮| 亚洲av成人av| 波多野结衣一区麻豆| 色尼玛亚洲综合影院| 高清欧美精品videossex| 三上悠亚av全集在线观看| 男女床上黄色一级片免费看| 亚洲五月婷婷丁香| 欧美久久黑人一区二区| 国产一区二区三区视频了| 午夜福利欧美成人| 亚洲国产欧美一区二区综合| 最新在线观看一区二区三区| 亚洲精品av麻豆狂野| 建设人人有责人人尽责人人享有的| 99re在线观看精品视频| 天天操日日干夜夜撸| 两人在一起打扑克的视频| 精品高清国产在线一区| videos熟女内射| 久久这里只有精品19| 美女福利国产在线| 久久久国产欧美日韩av| 亚洲av熟女| 自拍欧美九色日韩亚洲蝌蚪91| 一本大道久久a久久精品| 欧美+亚洲+日韩+国产| 欧美黑人欧美精品刺激| 欧美乱妇无乱码| 在线播放国产精品三级| 曰老女人黄片| 在线永久观看黄色视频| 日韩大码丰满熟妇| 伦理电影免费视频| 黄网站色视频无遮挡免费观看| 久久精品熟女亚洲av麻豆精品| 欧美日韩亚洲综合一区二区三区_| a在线观看视频网站| 一级片'在线观看视频| 色综合婷婷激情| 国产亚洲精品久久久久久毛片 | 亚洲欧洲精品一区二区精品久久久| 亚洲精品av麻豆狂野| 亚洲五月色婷婷综合| 亚洲精品国产区一区二| 国产精品九九99| 欧美色视频一区免费| 国产高清国产精品国产三级| 成年人午夜在线观看视频| 久久国产乱子伦精品免费另类| 亚洲av电影在线进入| 69精品国产乱码久久久| 99国产精品99久久久久| 国产精品影院久久| 中文字幕人妻丝袜制服| 欧美日韩亚洲国产一区二区在线观看 | 亚洲欧美激情在线| 91精品三级在线观看| 男人的好看免费观看在线视频 | 一级黄色大片毛片| 亚洲久久久国产精品| 黄片大片在线免费观看| 我的亚洲天堂| 精品电影一区二区在线| 国产精品一区二区在线观看99| 视频区图区小说| av国产精品久久久久影院| 飞空精品影院首页| 五月开心婷婷网| 午夜精品久久久久久毛片777| 夜夜躁狠狠躁天天躁| 国产无遮挡羞羞视频在线观看| 午夜福利,免费看| 久久九九热精品免费| 丰满迷人的少妇在线观看| 日本黄色视频三级网站网址 | 久久精品国产综合久久久| 日韩欧美国产一区二区入口| 51午夜福利影视在线观看| 成年女人毛片免费观看观看9 | videosex国产| 国产区一区二久久| 曰老女人黄片| 国产欧美日韩精品亚洲av| 国产av又大| 人人妻人人添人人爽欧美一区卜| 男人舔女人的私密视频| 18禁美女被吸乳视频| 一级片'在线观看视频| 97人妻天天添夜夜摸| av欧美777| 性色av乱码一区二区三区2| 国产成人欧美在线观看 | 18在线观看网站| 欧美大码av| 在线观看免费视频日本深夜| 女性生殖器流出的白浆| 99久久综合精品五月天人人| 久久久久久免费高清国产稀缺| 久久香蕉国产精品| 亚洲成国产人片在线观看| 手机成人av网站| 1024香蕉在线观看| e午夜精品久久久久久久| 国产精品国产高清国产av | netflix在线观看网站| 国产在线观看jvid| 如日韩欧美国产精品一区二区三区| 国精品久久久久久国模美| 色在线成人网| 制服诱惑二区| 亚洲欧美一区二区三区久久| 久久人人97超碰香蕉20202| 久久久久精品人妻al黑| 亚洲七黄色美女视频| 亚洲七黄色美女视频| 欧美人与性动交α欧美精品济南到| 精品久久久久久电影网| 久99久视频精品免费| 一本一本久久a久久精品综合妖精| 美女午夜性视频免费| 久久亚洲精品不卡| 午夜福利乱码中文字幕| 亚洲精品国产区一区二| 中文字幕人妻丝袜一区二区| av网站免费在线观看视频| 亚洲综合色网址| 欧美国产精品va在线观看不卡| 亚洲国产精品sss在线观看 | 涩涩av久久男人的天堂| 亚洲精品粉嫩美女一区| 久久性视频一级片| 国产精品永久免费网站| 欧洲精品卡2卡3卡4卡5卡区| 精品一区二区三区av网在线观看| 亚洲专区字幕在线| 久久久国产精品麻豆| 国产午夜精品久久久久久| 高潮久久久久久久久久久不卡| 精品久久蜜臀av无| 黑人巨大精品欧美一区二区mp4| 俄罗斯特黄特色一大片| 欧美老熟妇乱子伦牲交| 中文亚洲av片在线观看爽 | 久久 成人 亚洲| 黑人巨大精品欧美一区二区mp4| 丰满迷人的少妇在线观看| 在线观看免费高清a一片| 亚洲欧美一区二区三区久久| av不卡在线播放| 亚洲精品粉嫩美女一区| 亚洲欧美日韩高清在线视频| 婷婷精品国产亚洲av在线 | 欧美+亚洲+日韩+国产| 老司机在亚洲福利影院| 叶爱在线成人免费视频播放| √禁漫天堂资源中文www| 免费在线观看黄色视频的| 国产精品久久久久久精品古装| 黄色女人牲交| 老鸭窝网址在线观看| 日本黄色日本黄色录像| 黑人巨大精品欧美一区二区mp4| 别揉我奶头~嗯~啊~动态视频| 人人妻,人人澡人人爽秒播| 亚洲精品国产区一区二| 久久精品成人免费网站| 久久久久久久午夜电影 | 欧美丝袜亚洲另类 | 成人精品一区二区免费| 少妇猛男粗大的猛烈进出视频| 亚洲专区字幕在线| 日日爽夜夜爽网站| av福利片在线| 又黄又粗又硬又大视频| 免费少妇av软件| 激情在线观看视频在线高清 | 国产欧美日韩一区二区三| 香蕉久久夜色| 日日夜夜操网爽| 精品国产超薄肉色丝袜足j| 国产av精品麻豆| 免费在线观看影片大全网站| 午夜精品久久久久久毛片777| 91精品国产国语对白视频| 人人妻人人添人人爽欧美一区卜| 精品一区二区三区av网在线观看| 老汉色∧v一级毛片| 欧美黄色片欧美黄色片| 男人的好看免费观看在线视频 | 亚洲一区二区三区不卡视频| 国产高清国产精品国产三级| 成熟少妇高潮喷水视频| 国产一区二区三区视频了| av网站免费在线观看视频| 一边摸一边做爽爽视频免费| 亚洲欧美日韩高清在线视频| 亚洲色图av天堂| 91成年电影在线观看| 一区福利在线观看| 中文亚洲av片在线观看爽 | 五月开心婷婷网| 满18在线观看网站| 大码成人一级视频| 巨乳人妻的诱惑在线观看| 大香蕉久久成人网| 国产精品九九99| 亚洲欧美一区二区三区黑人| 黄色怎么调成土黄色| 久久 成人 亚洲| 亚洲少妇的诱惑av| 亚洲七黄色美女视频| 国产亚洲精品久久久久久毛片 | 亚洲精品国产精品久久久不卡| 一级毛片高清免费大全| 色精品久久人妻99蜜桃| 午夜免费观看网址| 欧美人与性动交α欧美精品济南到| 国产精品一区二区精品视频观看| 日日摸夜夜添夜夜添小说| 法律面前人人平等表现在哪些方面| 国产精品一区二区在线不卡| 国产高清国产精品国产三级| 少妇猛男粗大的猛烈进出视频| 国产免费男女视频| 精品一区二区三区视频在线观看免费 | 巨乳人妻的诱惑在线观看| 亚洲第一青青草原| 黄频高清免费视频| 狂野欧美激情性xxxx| 午夜免费鲁丝| 免费不卡黄色视频| 欧美精品av麻豆av| 国产亚洲欧美98| 在线观看66精品国产| av欧美777| 久久国产精品大桥未久av| 夜夜夜夜夜久久久久| 老司机福利观看| 天天操日日干夜夜撸| 亚洲全国av大片| 免费日韩欧美在线观看| 少妇猛男粗大的猛烈进出视频| 91在线观看av| 少妇 在线观看| 国产精品影院久久| 日韩欧美一区二区三区在线观看 | 亚洲第一av免费看| 人人妻人人澡人人爽人人夜夜| 国产精品 国内视频| 久久久精品国产亚洲av高清涩受| 50天的宝宝边吃奶边哭怎么回事| 亚洲色图av天堂| 精品少妇一区二区三区视频日本电影| 午夜福利影视在线免费观看| 久久久久久久久免费视频了| 美女扒开内裤让男人捅视频| 欧美国产精品一级二级三级| 日日爽夜夜爽网站| 岛国在线观看网站| 两性午夜刺激爽爽歪歪视频在线观看 | 日韩熟女老妇一区二区性免费视频| 亚洲一码二码三码区别大吗| 狂野欧美激情性xxxx| 看片在线看免费视频| 亚洲精品一卡2卡三卡4卡5卡| 建设人人有责人人尽责人人享有的| 亚洲专区中文字幕在线| 一本大道久久a久久精品| 99久久99久久久精品蜜桃| 激情在线观看视频在线高清 | 亚洲av成人不卡在线观看播放网| 丁香欧美五月| 99国产精品免费福利视频| 精品一区二区三区四区五区乱码| 精品国内亚洲2022精品成人 | 色尼玛亚洲综合影院| 国内久久婷婷六月综合欲色啪| 国产精品永久免费网站| 美女福利国产在线| 怎么达到女性高潮| 少妇粗大呻吟视频| 亚洲一区二区三区不卡视频| 香蕉久久夜色| 高清黄色对白视频在线免费看| 老司机靠b影院| 久久婷婷成人综合色麻豆| 亚洲 国产 在线| 精品久久久久久,| 国产精品九九99| 天天添夜夜摸| 两性夫妻黄色片| 黄色片一级片一级黄色片| 天堂中文最新版在线下载| 久99久视频精品免费| av不卡在线播放| 午夜福利视频在线观看免费| 久久国产精品大桥未久av| 中文字幕人妻熟女乱码| 成人永久免费在线观看视频| 女人被躁到高潮嗷嗷叫费观| 王馨瑶露胸无遮挡在线观看| 窝窝影院91人妻| 在线播放国产精品三级| 成人18禁高潮啪啪吃奶动态图| 成人18禁在线播放| 午夜福利影视在线免费观看| 黑人巨大精品欧美一区二区mp4| 精品久久久久久,| 亚洲成人国产一区在线观看| 性色av乱码一区二区三区2| 成人影院久久| 国产一区二区三区视频了| 99精品欧美一区二区三区四区| 嫁个100分男人电影在线观看| 欧美大码av| 国产成+人综合+亚洲专区| 天天躁夜夜躁狠狠躁躁| 在线免费观看的www视频| 狠狠婷婷综合久久久久久88av| av超薄肉色丝袜交足视频| 老汉色av国产亚洲站长工具| 99re在线观看精品视频| 十八禁网站免费在线| 91av网站免费观看| 亚洲五月婷婷丁香| 国产成人啪精品午夜网站| 精品久久久久久久久久免费视频 | 欧美日韩亚洲高清精品| 国产高清激情床上av| 涩涩av久久男人的天堂| 亚洲 国产 在线| 亚洲av成人不卡在线观看播放网| 搡老岳熟女国产| 深夜精品福利| 国产成人精品久久二区二区91| 国产亚洲欧美精品永久| 女性被躁到高潮视频| 久久精品aⅴ一区二区三区四区| 国产精品久久电影中文字幕 | 在线观看一区二区三区激情| 欧美日韩中文字幕国产精品一区二区三区 | svipshipincom国产片| 中文字幕最新亚洲高清| 国产成+人综合+亚洲专区| 一区福利在线观看| 国产单亲对白刺激| 国产精品国产高清国产av | 国产成人精品无人区| av视频免费观看在线观看| 国产高清激情床上av| 国产男女超爽视频在线观看| 夜夜爽天天搞| 99久久精品国产亚洲精品| 亚洲国产欧美网| 国产又色又爽无遮挡免费看| 欧美激情高清一区二区三区| a级毛片黄视频| 99re6热这里在线精品视频| 亚洲五月婷婷丁香| 精品久久久久久久久久免费视频 | 国产欧美日韩一区二区三| 国产一区二区激情短视频| 久久午夜亚洲精品久久| 美女 人体艺术 gogo| 久久国产精品人妻蜜桃| 欧美乱码精品一区二区三区| 亚洲av美国av| 亚洲av第一区精品v没综合| 夜夜躁狠狠躁天天躁| 99国产精品一区二区三区| 成年人午夜在线观看视频| 日韩免费高清中文字幕av| 女人被狂操c到高潮| 热99re8久久精品国产| 99国产精品99久久久久| 曰老女人黄片| 欧美日韩中文字幕国产精品一区二区三区 | 国产成人系列免费观看| 飞空精品影院首页| 欧美av亚洲av综合av国产av| 女性生殖器流出的白浆| 99久久精品国产亚洲精品| 精品一区二区三区视频在线观看免费 | 久久精品亚洲熟妇少妇任你| 一进一出抽搐gif免费好疼 | 久久久国产精品麻豆| 久久中文看片网| 国产成人影院久久av| 大码成人一级视频| 女人被躁到高潮嗷嗷叫费观| 亚洲五月天丁香| 久久人妻av系列| 在线国产一区二区在线| 黄色女人牲交| 午夜福利,免费看| 日韩欧美一区二区三区在线观看 | 老熟妇乱子伦视频在线观看| 日本黄色日本黄色录像| 亚洲av成人一区二区三| 1024香蕉在线观看| 99久久精品国产亚洲精品| 欧美在线黄色| bbb黄色大片| 欧美精品av麻豆av| 日韩欧美在线二视频 | www.999成人在线观看| 日韩有码中文字幕| 日韩制服丝袜自拍偷拍| 日韩欧美免费精品| 亚洲专区国产一区二区| 亚洲av第一区精品v没综合| 久热爱精品视频在线9| 欧美日韩中文字幕国产精品一区二区三区 | 自线自在国产av| 69av精品久久久久久| 高潮久久久久久久久久久不卡| 热99久久久久精品小说推荐| 热99久久久久精品小说推荐| 久久精品国产99精品国产亚洲性色 | 一进一出抽搐gif免费好疼 | 国产熟女午夜一区二区三区| netflix在线观看网站| 久久久久久久精品吃奶| 在线十欧美十亚洲十日本专区| 亚洲五月天丁香| www日本在线高清视频| 精品免费久久久久久久清纯 | 好男人电影高清在线观看| 国产亚洲精品久久久久5区| 高清av免费在线| 天堂俺去俺来也www色官网| 纯流量卡能插随身wifi吗| 日本黄色日本黄色录像| 亚洲成国产人片在线观看| 亚洲专区国产一区二区| 黄片小视频在线播放| 欧美日韩成人在线一区二区| 欧美激情久久久久久爽电影 | 亚洲国产欧美一区二区综合| 色婷婷久久久亚洲欧美| 少妇裸体淫交视频免费看高清 | 美女高潮喷水抽搐中文字幕| 高清毛片免费观看视频网站 | 亚洲视频免费观看视频| 多毛熟女@视频| 欧美精品高潮呻吟av久久| 亚洲av电影在线进入| 大陆偷拍与自拍| 国内久久婷婷六月综合欲色啪| 新久久久久国产一级毛片| 一区二区三区精品91| 免费一级毛片在线播放高清视频 | 精品人妻熟女毛片av久久网站| 一级片'在线观看视频| 在线十欧美十亚洲十日本专区| 久久99一区二区三区| 高潮久久久久久久久久久不卡| 欧美av亚洲av综合av国产av| 国产精品一区二区在线观看99| 午夜亚洲福利在线播放| 日本vs欧美在线观看视频| 中文字幕高清在线视频| 无遮挡黄片免费观看| 亚洲国产精品一区二区三区在线| 欧美一级毛片孕妇| 黄网站色视频无遮挡免费观看| 国产蜜桃级精品一区二区三区 | cao死你这个sao货| 免费av中文字幕在线| 久久久久久久国产电影| 另类亚洲欧美激情| 国产成人啪精品午夜网站| 岛国在线观看网站| 国产精品二区激情视频| 久久香蕉激情| 水蜜桃什么品种好| 99热只有精品国产| 18禁裸乳无遮挡动漫免费视频| 一二三四在线观看免费中文在| 男女午夜视频在线观看| 亚洲,欧美精品.| 亚洲五月婷婷丁香| 高清欧美精品videossex| 久久精品国产a三级三级三级| 精品人妻1区二区| 欧美日韩亚洲综合一区二区三区_| 大片电影免费在线观看免费| 精品国产亚洲在线| 国产亚洲欧美在线一区二区| 久久久久久亚洲精品国产蜜桃av| 色婷婷久久久亚洲欧美| 99精品欧美一区二区三区四区| 精品熟女少妇八av免费久了| 女人爽到高潮嗷嗷叫在线视频| 一区福利在线观看| 啪啪无遮挡十八禁网站| 香蕉国产在线看| av天堂久久9| 丰满饥渴人妻一区二区三| 久久精品aⅴ一区二区三区四区| 成人黄色视频免费在线看| 搡老熟女国产l中国老女人| 国产高清激情床上av| 两性夫妻黄色片| 无限看片的www在线观看| 久久精品国产清高在天天线| 久久人妻av系列| 久久人妻福利社区极品人妻图片| svipshipincom国产片| 欧美乱色亚洲激情| 三上悠亚av全集在线观看| 亚洲国产欧美一区二区综合| 99国产精品99久久久久| 一a级毛片在线观看| 国产欧美日韩一区二区精品| 大片电影免费在线观看免费| 夜夜躁狠狠躁天天躁| 99久久人妻综合| 亚洲七黄色美女视频| 久久国产精品人妻蜜桃| 亚洲国产精品合色在线| 午夜福利欧美成人| 男人的好看免费观看在线视频 | 国产精品永久免费网站| 一边摸一边做爽爽视频免费| 亚洲熟妇熟女久久| 最新的欧美精品一区二区| 亚洲精品久久午夜乱码| 国产xxxxx性猛交| aaaaa片日本免费| 激情在线观看视频在线高清 | 夫妻午夜视频| 80岁老熟妇乱子伦牲交| 久久久久久亚洲精品国产蜜桃av| 91精品三级在线观看| 两个人看的免费小视频| 精品国产美女av久久久久小说| 最新在线观看一区二区三区| 亚洲五月色婷婷综合| 亚洲人成77777在线视频| 色尼玛亚洲综合影院| 日韩制服丝袜自拍偷拍| 夜夜爽天天搞| 亚洲欧美日韩另类电影网站| 国产亚洲精品久久久久5区| 人妻丰满熟妇av一区二区三区 | 人妻一区二区av| 成人影院久久| 人人妻人人爽人人添夜夜欢视频| 不卡av一区二区三区| 一级,二级,三级黄色视频| 亚洲美女黄片视频| 亚洲精品国产一区二区精华液| 亚洲欧美色中文字幕在线| 久久久国产成人精品二区 | 欧美精品人与动牲交sv欧美| 黄片播放在线免费| 在线视频色国产色| 国产97色在线日韩免费| 国产99白浆流出| 色精品久久人妻99蜜桃| 在线播放国产精品三级| 日韩欧美国产一区二区入口| 欧美色视频一区免费| 久久精品国产亚洲av香蕉五月 | 国产亚洲一区二区精品| 大码成人一级视频| 一进一出好大好爽视频| 亚洲va日本ⅴa欧美va伊人久久| 亚洲精品自拍成人| 日本欧美视频一区|