Antiangiogenic Therapies in Non-Hodgkin's Lymphoma

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中译名非甾体类抗炎药环氧合酶多药...

刘军：环氧冶－酶一２与胃癌多药耐药相关性的实验研究英文缩写ＮＳＡ【ＤＣＯＸＭ１３ｌＲＰ—ｇｐＶＣＲＡＤＭ５．ＦＵＭＭＣＤＤＰＤＡＢＭＴＴＤＭＳＯＩＣ５０ＯＤＰＢＳＰＧＳＰＦＡＣｓ英文缩略词表英文全名ｎｏｎｓｔｅｒｏｉｄａｌａｎｔｉ—ｉｎｆｌａｎｍｍａｔｏｒｙｄｒｕｇｃｙｃｌｏｏｘｙｇｅｎａｓｅｍｕｌｆｌｄｒｕｇｒｅｓｉｓｔａｎｃｅＰ—ｇｌｙｃｏｐｒｏｔｅｉｎｖｉｎｅｒｉｓｔｉｎｅａｄｒｉａｍｙｃｉｎ５一ｆｌｕｏｒｏｕｒｃｉｌｍｉｔｏｍｙｃｉｎ－ＣＣｉｓｐｌａｔｉｎｄｉａｍｉｎｏｂｅｎｚｉｄｉｎｅｔｈｉａｚｏｌｙｌｂｌｕｅｄｉｍｅｔｈｙｌｓｕｌｆｏｘｉｄｅｉｎｈｉｂｉｔｏｒｙｃｏｎｃｅｎｔｒａｔｉｏｎ５０ｏｐｔｉｃａｌｄｅｎｓｉｔｙｐｈｏｓｐｈａｔｅｂｕｆｆｅｒｅｄＳａｌｉｏｅｐｒｏｓｔａｇｌａｎｄｉｎｓｔｒｅｐｔａｖｉｄｉｎ—ｐｅｒｏｘｉｄａｓｅｆｌｏｗｃｙｔｏｍｅｔｒｙ中译名非甾体类抗炎药环氧合酶多药耐药Ｐ一糖蛋白长春新碱阿霉素氟脲嘧啶丝列霉素顺铂３，３’一二氛基联苯胺噻唑蓝二甲基亚砜半数抑制剂量光密度磷酸盐缓冲生理盐水前列腺素链酶卵白素一过氧化物酶流式细胞仪扬州大学硕士论文环氧合酶一２与胃癌多药耐药相关性的实验研究摘要背景：在我国，胃癌是发病率及死亡率最高的恶性肿瘤之一，预后极差。

多药耐药（ＭＤＲ）的形成是胃癌难治与复发的生物学基础，寻找肿瘤耐药的形成机制及有效的逆转药物是肿瘤研究领域的一项重要课题。

近十余年来，人们发现以阿斯匹林为代表的非甾体类消炎药（ＮｓＡⅢｓ）在肿瘤，尤其是消化道肿瘤的预防与治疗中具有明显的作用，其机制可能与抑制环氧合酶－２（ＣＯＸ－２）合成有关。

环氧合酶（ｃｏｘｌ是前列腺素类合成的限速酶，已有多项研究证实其亚型ＣＯＸ．２通过多种途径参与消化道肿瘤的形成。

目前发现ＣＯＸ一２还可能与肿瘤多药耐药有关，从而进一步丰富了ＣＯＸ－２与肿瘤相关的证据，为肿瘤的防治开辟了一条崭新途径。

结外NK_T细胞淋巴瘤中体重指数与疗效及预后的相关性分析

学校代码 10459学号或申请号 ************密级公开 Array专业硕士学位论文结外NK/T细胞淋巴瘤中体重指数与疗效及预后的相关性分析作者姓名：张超导师姓名：张蕾教授学科门类：医学专业名称：肿瘤学培养院系：第一临床学院完成时间：2018年3月A thesis submitted toZhengzhou Universityfor the degree of MasterThe Correlation Analysis of body mass indexand the Curative Effect and Prognosis in the ExtranodalNK/T Cell LymphomaBy Chao ZhangSupervisor: Prof. Lei ZhangOncologyThe First Affiliated Hospital of Zhengzhou UniversityMarch 2018结外NK/T细胞淋巴瘤中体重指数与疗效及预后的相关性分析研究生：张超导师：张蕾郑州大学第一附属医院肿瘤科河南郑州 450052摘要背景与目的：结外NK/T细胞淋巴瘤（Extranodal NK/T-cell lymphoma，ENKTL)在非霍奇金淋巴瘤中较为罕见，发病率约占全部恶性淋巴瘤的6%左右，其分布有明显的地域差异，中国及东南亚国家多发，而欧洲及北美洲少见。

ENKTL原发部位常见于鼻、鼻咽、口咽、韦氏环等，少数可侵犯皮肤、胃肠道、睾丸、骨髓等结外组织，临床表现多为鼻塞、鼻出血、声嘶、鼻咽部肿物等，可在鼻腔底部形成特征性硬腭穿孔，伴有恶臭。

ENKTL为高度侵袭性恶性肿瘤，进展快、易复发转移，尚无标准治疗方案，预后不良。

体重指数（body mass index，BMI）被认为与肿瘤的预后密切相关，在乳腺癌，肾癌，胆囊癌，食管癌等都有报道显示BMI 与其预后存在相关性。

抗肿瘤靶向药物的分类_张百红

１２３０．［１９］　ＣｏｓｔａＢＭ，ＳｍｉｔｈＪＳ，ＣｈｅｎＹ，ｅｔａｌ．ＲｅｖｅｒｓｉｎｇＨＯＸＡ９ｏｎｃｏｇｅｎｅａｃｔｉｖａｔｉｏｎｂｙＰＩ３Ｋｉｎｈｉｂｉｔｉｏｎ：Ｅｐｉｇｅｎｅｔｉｃｍｅｃｈａｎｉｓｍａｎｄｐｒｏｇｎｏｓｔｉｃｓｉｇｎｉｆｉｃａｎｃｅｉｎｈｕｍａｎｇｌｉｏｂｌａｓｔｏｍａ［Ｊ］．ＣａｎｃｅｒＲｅｓ，２０１０，７０（２）：４５３－４６２．［２０］　ＶｅｒｈａａｋＲＧ，ＨｏａｄｌｅｙＫＡ，ＰｕｒｄｏｍＥ，ｅｔａｌ．ＩｎｔｅｇｒａｔｅｄｇｅｎｏｍｉｃａｎａｌｙｓｉｓｉｄｅｎｔｉｆｉｅｓｃｌｉｎｉｃａｌｌｙｒｅｌｅｖａｎｔｓｕｂｔｙｐｅｓｏｆｇｌｉｏｂｌａｓｔｏｍａｃｈａｒａｃｔｅｒｉｚｅｄｂｙａｂｎｏｒｍａｌｉｔｉｅｓｉｎＰＤＧＦＲＡ，ＩＤＨ１，ＥＧＦＲ，ａｎｄＮＦ１［Ｊ］．ＣａｎｃｅｒＣｅｌｌ，２０１０，１７（１）：９８－１１０．［２１］　ＰｏｊｏＭ，ＧｏｎｃａｌｖｅｓＣＳ，Ｘａｖｉｅｒ－ＭａｇａｌｈａｅｓＡ，ｅｔａｌ．ＡｔｒａｎｓｃｒｉｐｔｏｍｉｃｓｉｇｎａｔｕｒｅｍｅｄｉａｔｅｄｂｙＨＯＸＡ９ｐｒｏｍｏｔｅｓｈｕｍａｎｇｌｉｏｂｌａｓｔｏｍａｉｎｉｔｉａｔｉｏｎ，ａｇｇｒｅｓｓｉｖｅｎｅｓｓａｎｄｒｅｓｉｓｔａｎｃｅｔｏｔｅｍｏｚｏｌｏｍｉｄｅ［Ｊ］．Ｏｎｃｏｔａｒｇｅｔ，２０１５，６（１０）：７６５７－７６７４．［２２］　ＯｔａＴ，ＫｌａｕｓｅｎＣ，ＣｌａｒａＳａｌａｍａｎｃａＭ，ｅｔａｌ．ＥｘｐｒｅｓｓｉｏｎａｎｄｆｕｎｃｔｉｏｎｏｆＨＯＸＡｇｅｎｅｓｉｎｎｏｒｍａｌａｎｄｎｅｏｐｌａｓｔｉｃｏｖａｒｉａｎｅｐｉｔｈｅｌｉａｌｃｅｌｌｓ［Ｊ］．Ｄｉｆｆｅｒｅｎｔｉａｔｉｏｎ，２００９，７７（２）：１６２－１７１．［２３］　ＫｏＳＹ，ＢａｒｅｎｇｏＮ，ＬａｄａｎｙｉＡ，ｅｔａｌ．ＨＯＸＡ９ｐｒｏｍｏｔｅｓｏｖａｒｉａｎｃａｎｃｅｒｇｒｏｗｔｈｂｙｓｔｉｍｕｌａｔｉｎｇｃａｎｃｅｒ－ａｓｓｏｃｉａｔｅｄｆｉｂｒｏｂｌａｓｔｓ［Ｊ］．ＪＣｌｉｎｉｃａｌＩｎｖｅｓｔｉｇａｔｉｏｎ，２０１２，１２２（１０）：３６０３－３６１７．［２４］　ＫｏＳＹ，ＮａｏｒａＨ．ＨＯＸＡ９ｐｒｏｍｏｔｅｓｈｏｍｏｔｙｐｉｃａｎｄｈｅｔｅｒｏｔｙｐｉｃｃｅｌｌｉｎｔｅｒａｃｔｉｏｎｓｔｈａｔｆａｃｉｌｉｔａｔｅｏｖａｒｉａｎｃａｎｃｅｒｄｉｓｓｅｍｉｎａｔｉｏｎｖｉａｉｔｓｉｎｄｕｃｔｉｏｎｏｆＰ－ｃａｄｈｅｒｉｎ［Ｊ］．ＭｏｌＣａｎｃｅｒ，２０１４，１３：１７０．［２５］　ＷｒａｎｇｌｅＪ，ＭａｃｈｉｄａＥＯ，ＤａｎｉｌｏｖａＬ，ｅｔａｌ．Ｆｕｎｃｔｉｏｎａｌｉｄｅｎｔｉｆｉｃａｔｉｏｎｏｆｃａｎｃｅｒ－ｓｐｅｃｉｆｉｃｍｅｔｈｙｌａｔｉｏｎｏｆＣＤＯ１，ＨＯＸＡ９，ａｎｄＴＡＣ１ｆｏｒｔｈｅｄｉａｇｎｏｓｉｓｏｆｌｕｎｇｃａｎｃｅｒ［Ｊ］．ＣｌｉｎＣａｎｃｅｒＲｅｓ，２０１４，２０（７）：１８５６－１８６４．［２６］　ＨｗａｎｇＪ，ＬｅｅＢＢ，ＫｉｍＹ，ｅｔａｌ．ＨＯＸＡ９ｉｎｈｉｂｉｔｓｍｉｇｒａｔｉｏｎｏｆｌｕｎｇｃａｎｃｅｒｃｅｌｌｓａｎｄｉｔｓｈｙｐｅｒｍｅｔｈｙｌａｔｉｏｎｉｓａｓｓｏｃｉａｔｅｄｗｉｔｈｒｅｃｕｒｒｅｎｃｅｉｎｎｏｎ－ｓｍａｌｌｃｅｌｌｌｕｎｇｃａｎｃｅｒ［Ｊ］．ＭｏｌｅｃｕｌａｒＣａｒｃｉｎｏｇｅｎｅｓｉｓ，２０１５，５４（Ｓ１）：Ｅ７２－Ｅ８０．［２７］　ＲｅｙｎｏｌｄｓＰＡ，ＳｉｇａｒｏｕｄｉｎｉａＭ，ＺａｒｄｏＧ，ｅｔａｌ．Ｔｕｍｏｒｓｕｐｐｒｅｓｓｏｒｐ１６ＩＮＫ４Ａｒｅｇｕｌａｔｅｓｐｏｌｙｃｏｍｂ－ｍｅｄｉａｔｅｄＤＮＡｈｙｐｅｒｍｅｔｈｙｌａｔｉｏｎｉｎｈｕｍａｎｍａｍｍａｒｙｅｐｉｔｈｅｌｉａｌｃｅｌｌｓ［Ｊ］．ＪＢｉｏｌＣｈｅｍ，２００６，２８１（３４）：２４７９０－２４８０２．［２８］　ＰａｒｋＳＹ，ＫｗｏｎＨＪ，ＬｅｅＨＥ，ｅｔａｌ．ＰｒｏｍｏｔｅｒＣｐＧｉｓｌａｎｄｈｙｐｅｒｍｅｔｈｙｌａｔｉｏｎｄｕｒｉｎｇｂｒｅａｓｔｃａｎｃｅｒｐｒｏｇｒｅｓｓｉｏｎ［Ｊ］．ＶｉｒｃｈｏｗｓＡｒｃｈ，２０１１，４５８（１）：７３－８４．［２９］　ＳｕｎＭ，ＳｏｎｇＣＸ，ＨｕａｎｇＨ，ｅｔａｌ．ＨＭＧＡ２／ＴＥＴ１／ＨＯＸＡ９ｓｉｇｎａｌｉｎｇｐａｔｈｗａｙｒｅｇｕｌａｔｅｓｂｒｅａｓｔｃａｎｃｅｒｇｒｏｗｔｈａｎｄｍｅｔａｓｔａｓｉｓ［Ｊ］．ＰｒｏｃｅｅｄｉｎｇｓｏｆｔｈｅＮａｔｉｏｎａｌＡｃａｄｅｍｙｏｆＳｃｉｅｎｃｅｓ，２０１３，１１０（２４）：９９２０－９９２５．［３０］　ＬｖＪ，ＣａｏＸＦ，ＪｉＬ，ｅｔａｌ．Ａｓｓｏｃｉａｔｉｏｎｏｆｂｅｔａ－ｃａｔｅｎｉｎ，Ｗｎｔ１，Ｓｍａｄ４，Ｈｏｘａ９，ａｎｄＢｍｉ－１ｗｉｔｈｔｈｅｐｒｏｇｎｏｓｉｓｏｆｅｓｏｐｈａｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａ［Ｊ］．ＭｅｄＯｎｃｏｌ，２０１２，２９（１）：１５１－１６０．［３１］　ＳｕｎＸ，ＬｉｕＢ，ＪｉＷ，ｅｔａｌ．ＴｈｅｒｏｌｅｏｆＨＯＸＡ９ｉｎｈｕｍａｎｌａｒｙｎｇｅａｌｓｑｕａｍｏｕｓｃｅｌｌｃａｒｃｉｎｏｍａ［Ｊ］．ＯｎｃｏｌｏｇｙＲｅｓｅａｒｃｈＦｅａｔｕｒｉｎｇＰｒｅｃｌｉｎｉｃａｌａｎｄＣｌｉｎｉｃａｌＣａｎｃｅｒＴｈｅｒａｐｅｕｔｉｃｓ，２０１２，２０（１０）：４６７－４７２．［３２］　ＫｉｍＹ，ＹｏｏｎＨ，ＫｉｍＪＳ，ｅｔａｌ．ＨＯＸＡ９，ＩＳＬ１ａｎｄＡＬＤＨ１Ａ３ｍｅｔｈｙｌａｔｉｏｎｐａｔｔｅｒｎｓａｓｐｒｏｇｎｏｓｔｉｃｍａｒｋｅｒｓｆｏｒｎｏｎｍｕｓｃｌｅｉｎｖａｓｉｖｅｂｌａｄｄｅｒｃａｎｃｅｒ：Ａｒｒａｙ－ｂａｓｅｄＤＮＡｍｅｔｈｙｌａｔｉｏｎａｎｄｅｘｐｒｅｓｓｉｏｎｐｒｏｆｉｌｉｎｇ［Ｊ］．ＩｎｔｅｒｎａｔｉｏｎａｌＪＣａｎｃｅｒ，２０１３，１３３（５）：１１３５－１１４２．［３３］　ＫｕｏＣ，ＬｉｎＣ，ＳｈｉｈＹ，ｅｔａｌ．ＦｒｅｑｕｅｎｔｍｅｔｈｙｌａｔｉｏｎｏｆＨＯＸＡ９ｇｅｎｅｉｎｔｕｍｏｒｔｉｓｓｕｅｓａｎｄｐｌａｓｍａｓａｍｐｌｅｓｆｒｏｍｈｕｍａｎｈｅｐａｔｏｃｅｌｌｕｌａｒｃａｒｃｉｎｏｍａｓ［Ｊ］．ＣｌｉｎｉｃａｌＣｈｅｍｉｓｔｒｙａｎｄＬａｂｏｒａｔｏｒｙＭｅｄｉｃｉｎｅ（ＣＣＬＭ），２０１４，５２（８）：１２３５－１２４５．（编校：张西敏）抗肿瘤靶向药物的分类张百红１，岳红云２ＡｎｅｗｃｌａｓｓｉｆｉｃａｔｉｏｎｆｏｒｔａｒｇｅｔｅｄａｎｔｉｃａｎｃｅｒａｇｅｎｔｓＺｈａｎｇＢａｉｈｏｎｇ１，ＹｕｅＨｏｎｇｙｕｎ２１ＤｅｐａｒｔｍｅｎｔｏｆＯｎｃｏｌｏｇｙ；２ＤｅｐａｒｔｍｅｎｔｏｆＯｐｈｔｈａｌｍｏｌｏｇｙ，ＬａｎｚｈｏｕＧｅｎｅｒａｌＨｏｓｐｉｔａｌ，ＬａｎｚｈｏｕＭｉｌｉｔａｒｙＡｒｅａＣｏｍｍａｎｄ，ＰＬＡ，ＧａｎｓｕＬａｎｚｈｏｕ７３００５０，Ｃｈｉｎａ．【Ａｂｓｔｒａｃｔ】Ｔｈｅｃｌａｓｓｉｆｉｃａｔｉｏｎｏｆｔａｒｇｅｔｅｄａｎｔｉｃａｎｃｅｒａｇｅｎｔｓｉｓｅｌｕｓｉｖｅ．Ａｃｃｏｒｄｉｎｇｔｏｔｈｅｒａｐｅｕｔｉｃｔａｒｇｅｔｓ，ｗｅｐｒｏｐｏｓｅａｎｅｗｃｌａｓｓｉｆｉｃａｔｉｏｎｆｏｒｔｈｅｓｅａｇｅｎｔｓｔｏｅｖａｌｕａｔｅｔｈｅｍ：Ｍｏｌｅｃｕｌａｒｔａｒｇｅｔｅｄａｇｅｎｔｓ，ｖａｓｃｕｌａｒｔａｒｇｅｔｅｄａｇｅｎｔｓ，ｉｍｍｕｎｏｍｏｄｕｌａｔｏｒｙａｇｅｎｔｓａｎｄｃｅｌｌｕｌａｒｔａｒｇｅｔｅｄａｇｅｎｔｓ．Ｔｈｉｓｃｌａｓｓｉｆｉｃａｔｉｏｎｆｏｒｔａｒｇｅｔｅｄａｇｅｎｔｓａｃｃｏｕｎｔｉｎｇｆｏｒｏｐｔｉｍａｌｔａｒｇｅｔｓａｎｄｐｒｅｃｉｓｉｏｎｍｅｃｈａｎｉｓｍｓ，ｃｏｕｌｄｐｒｏｖｉｄｅｅｆｆｅｃｔｉｖｅｔｏｏｌｓｆｏｒｃｌｉｎｉｃｉａｎｓ．【Ｋｅｙｗｏｒｄｓ】ｎｅｏｐｌａｓｍｓ，ｔａｒｇｅｔｅｄａｎｔｉｃａｎｃｅｒｔｈｅｒａｐｉｅｓ，ｔａｒｇｅｔｅｄａｇｅｎｔｓ，ｃｌａｓｓｉｆｉｃａｔｉｏｎＭｏｄｅｒｎＯｎｃｏｌｏｇｙ２０１７，２５（０２）：０２９９－０３０３【收稿日期】　２０１６－０６－０７【修回日期】　２０１６－０７－１１【基金项目】　甘肃省自然科学基金项目（编号：１３０８ＲＪＺＡ１８１）【作者单位】　１兰州军区兰州总医院肿瘤科；２眼科，甘肃　兰州　７３００５０【作者简介】　张百红（１９７０－），男，河南陕县人，副主任医师，副教授，主要从事消化道肿瘤的基础和临床研究。

林桐榆-非霍奇金淋巴瘤诊治的主要进展2014 NHL

研究设计
N=61(%) 组织学（研究者）原发/继发年龄年龄＞60岁性别男/女 ECOG PS0/1/2 Ann Arbor 分期 III/IV LDH>ULN 结外浸润， >1个病灶骨髓浸润巨块结节 50(82)/11(18) 69(30-88) 52（85.2） 31（50.8）/30（49.2） 27(54)/26(43.3)/7(11.7) 15(24.6)/31(50.8) 41(68.3) 36（59），16(26.2) 13（21.3） 28（45.9）继发IPI 低/低中/中高/高危既往治疗疗程 0/1/2 3/>3 中位（范围）既往接受移植入组时情况复发/继发耐药/原发耐药原发耐药后进展的时间（0；3月）（3；6月） 9(56.3) 7(43.8) N=61(%) 12(19.7)/11(18)/25(41)/13(21.3) 1(1.6)/25(41)/17(27.9） 9(14.8) 9(14.8) 2(0-9） 12（19.7) 28(46.7)/16(26.7)/16(26.7)
6 mg/kg 5 mg/kg 4 mg/kg 3 mg/kg
D15-21时进行疗效评估在第2,4疗程及之后的每3疗程进行CT及PET-CT
2 mg/kg 1 mg/kg 0.5 mg/kg
• • •
第1疗程未出现剂量限制性毒性因为后续疗程出现的毒副作用停止6mg/kg的入组 3,4及5mg/kg组进行扩展
来那度胺联合R-CHOP21方案在老年初治弥漫大B细胞淋巴瘤：II期临床研究(REAL07)的最终结果
治疗周期来那度胺 qd d1-14
天
1
R：375mg/m2 d0
14
来那度胺在MTD 15mg qd d 1-14

利妥昔单抗获准用于常见淋巴瘤的维持疗法

中年肥胖有可能与老年痴呆症风险增高关联
首次出版的《国医学杂志》（Ｍ）网络版英ＢＪ
发表的一项基于人口的为期２７年的纵向研究的结果的痴呆诊断；Ｃｘ例风险模型对调整了年龄、性ｏ比别、种族、教育状况、吸烟、酒精摄入、婚姻状况、糖尿病、高血压、高脂血症、卒中和缺血性心脏病等因素的诊断时间进行了评价。肥胖被定义为ＢＩ至少为３ｋ／ＭＭ０ｇｍ；ＢＩ在２．５０～２．ｋ／之间被视为超重；体重正常的９９ｇｍＢ为１．２．ｋ／ＭＩ８６～４９ｇｍ。７３１例参试者（．％）在１９６９９４年１月～２００３年４月间被确诊为痴呆；与正常体重者的痴呆风险
维普资讯
国外医学情报ｏ＼ｏ ∞０ｏ

ｌ研究进■
ＩＦＯＲＥＧＮＭＥＣＬＩＦＭＡＩＶｌｍｅ２・ｕｕｔ０６ＩＤＩＡＯＲＴＯＮ・ｏｕ７Ａｇｓ２０Ｎ
利妥昔单抗获准用于常见淋巴瘤的维持疗法
抗维持疗法的快速获批反映出该药物在延长患者生
病率将与乳腺癌、直肠癌、肺癌和皮肤癌的发生率
不相上下；惰性ＮＬ是一种慢性癌症，该疾病患者Ｈ
命方面可为患者带来极大的益处，从而为该疾病的
控制带来新的希望。利妥昔单抗此前已在欧盟获准联合化学疗法用于迅速蔓延的和惰性ＮＬ首选治疗以及惰性ＮＬＨＨ的二线单一治疗；新疗法可使复发的滤泡性ＮＬ患Ｈ

诺华_依维莫司片英文说明书_2015.05.11

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZORTRESS® (everolimus) safely and effectively. See full prescribing information for ZORTRESS.ZORTRESS (everolimus) tablets for oral useInitial U.S. Approval: 2010WARNING: MALIGNANCIES AND SERIOUS INFECTIONS,KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND MORTALITY IN HEART TRANSPLANTATIONSee Full Prescribing Information for Complete Boxed Warning.• Only physicians experienced in immunosuppressive therapy and management of transplant patients should use Zortress. (5.1)• Increased susceptibility to infection and the possible development of malignancies may result from immunosuppression. (5.2, 5.3)• Increased incidence of kidney graft thrombosis. (5.4)• Reduced doses of cyclosporine are required for use in combination with Zortress in order to reduce nephrotoxicity. (2.4, 2.5, 5.6, 12.7,12.8)• Increased mortality in a heart transplant clinical trial. Use in heart transplantation is not recommended. (5.7)---------------------------RECENT MAJOR CHANGES--------------------------Dosage and Administration (2) 1/2015 Warnings and Precautions, Management ofImmunosuppression (5.1) 1/2015 Warnings and Precautions, Interstitial Lung Disease/Non-Infectious Pneumonitis (5.10) 11/2015---------------------------INDICATIONS AND USAGE---------------------------• Zortress is indicated for the prophylaxis of organ rejection in adult patients: • Kidney transplant: at low-moderate immunologic risk. Use in combination with basiliximab, cyclosporine (reduced doses) and corticosteroids. (1.1) • Liver transplant: Administer no earlier than 30 days post-transplant. Use in combination with tacrolimus (reduced doses) and corticosteroids. (1.2, 5.5) Limitations of Use (1.3)Safety and efficacy has not been established in the following:• Kidney transplant patients at high immunologic risk.• Recipients of transplanted organs other than kidney or liver• Pediatric patients (<18 years)-------------------------DOSAGE AND ADMINISTRATION--------------------• Kidney transplantation: starting oral dose of 0.75 mg twice daily as soon as possible after transplantation. (2.1)• Liver transplantation: starting oral dose of 1.0 mg twice daily starting 30 days after transplantation. (2.2)• Monitor everolimus concentrations: Adjust maintenance dose to achieve trough concentrations within the 3-8 ng/mL target range (using LC/MS/MS assay method (2.1, 2.2, 2.3)• Administer consistently with or without food at the same time as cyclosporine or tacrolimus. (2.6, 12.3)• Mild hepatic impairment: Reduce initial daily dose by one-third (2.7) • Moderate or Severe hepatic impairment: Reduce initial daily dose by one-half. (2.7, 12.6)-------------------------DOSAGE FORMS AND STRENGTHS------------------Zortress is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets. (3)----------------------------------CONTRAINDICATIONS--------------------------• Hypersensitivity to everolimus, sirolimus, or to components of the drug product. (4)----------------------------WARNINGS AND PRECAUTIONS------------------• Angioedema (increased risk with concomitant ACE inhibitors): Monitor for symptoms and treat promptly. (5.8)• Delayed Wound Healing/Fluid Accumulation: Monitor symptoms; treat promptly to minimize complications. (5.9)• Interstitial Lung Disease/Non-Infectious Pneumonitis: Monitor for symptoms or radiologic changes; manage by dose reduction or discontinuation until symptoms resolve; consider use of corticosteroids. (5.10)• Hyperlipidemia (elevations of serum cholesterol and triglycerides): Monitor and consider anti-lipid therapy. (5.11)• Proteinuria (increased risk with higher trough concentrations): Monitor urine protein. (5.12)• Polyoma Virus Infections (activation of latent viral infections; BK-virus associated nephropathy): Consider reducing immunosuppression. (5.13)• TMA/TTP/HUS (concomitant use with cyclosporine may increase risk): Monitor for hematological changes or symptoms. (5.15)• New Onset Diabetes After Transplantation: Monitor serum glucose. (5.16) • Male Infertility: Azospermia or oligospermia may occur. (5.17, 13.1)• Immunizations: Avoid live vaccines. (5.18)----------------------------------ADVERSE REACTIONS--------------------------Most common adverse reactions were as follows:Kidney transplantation (incidence ≥20%): peripheral edema, constipation, hypertension, nausea, anemia, UTI, and hyperlipidemia. (6.1);Liver transplantation (incidence>10%): diarrhea, headache, peripheral edema, hypertension, nausea, pyrexia, abdominal pain, and leukopenia (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA1088 or /medwatch.-----------------------------------DRUG INTERACTIONS-------------------------Strong-moderate CYP3A4 inhibitors (e.g., cyclosporine, ketoconazole, erythromycin, verapamil) and CYP3A4 inducers (e.g., rifampin) may affect everolimus concentrations. (7.1) Consider Zortress dose adjustment (5.14)---------------------------USE IN SPECIFIC POPULATIONS-------------------• Pregnancy: Based on animal data may cause fetal harm. (8.1)• Nursing Mothers: Discontinue drug or nursing. (8.3)See 17 for PATIENT COUNSELING INFORMATION and Medication GuideRevised: 11/2015FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: MALIGNANCIES AND SERIOUS INFECTIONS, KIDNEY GRAFT THROMBOSIS; NEPHROTOXICITY; AND MORTALITY IN HEART TRANSPLANTATION1 INDICATIONS AND USAGE1.1 Prophylaxis of Organ Rejection in Kidney Transplantation1.2 Prophylaxis of Organ Rejection in Liver Transplantation1.3 Limitations of Use2 DOSAGE AND ADMINISTRATION2.1 Dosage in Adult Kidney Transplant Patients2.2 Dosage in Adult Liver Transplant Patients2.3 Therapeutic Drug Monitoring -Everolimus2.4 Therapeutic Drug Monitoring-Cyclosporine in KidneyTransplant Patients2.5 Therapeutic Drug Monitoring-Tacrolimus in Liver TransplantPatients2.6 Administration2.7 Hepatic Impairment3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS4.1 Hypersensitivity Reactions5 WARNINGS AND PRECAUTIONS5.1 Management of Immunosuppression5.2 Lymphomas and Other Malignancies5.3 Serious Infections5.4 Kidney Graft Thrombosis5.5 Hepatic Artery Thrombosis5.6 Zortress and Calcineurin Inhibitor-Induced Nephrotoxicity5.7 Heart Transplantation5.8 Angioedema5.9 Wound Healing and Fluid Accumulation5.10 Interstitial Lung Disease/Non-Infectious Pneumonitis5.11 Hyperlipidemia5.12 Proteinuria5.13 Polyoma Virus Infections5.14 Interaction with Strong Inhibitors and Inducers of CYP3A45.15 Thrombotic Microangiopathy/Thrombotic ThrombocytopenicPurpura/Hemolytic Uremic Syndrome (TMA/TTP/HUS)5.16 New Onset Diabetes After Transplant5.17 Male Infertility5.18 Immunizations5.19 Interaction with Grapefruit Juice5.20 Patients with Hereditary Disorders/Other6 ADVERSE REACTIONS6.1 Serious and Otherwise Important Adverse Reactions6.2 Clinical Studies Experience6.3 Postmarketing Experience7 DRUG INTERACTIONS7.1 Interactions with Strong Inhibitors or Inducers of CYP3A4 and Pglycoprotein7.2 Cyclosporine (CYP3A4/P-gp Inhibitor and CYP3A4 Substrate)7.3 Ketoconazole and Other Strong CYP3A4 Inhibitors7.4 Erythromycin (Moderate CYP3A4 Inhibitor)7.5 Verapamil (CYP3A4 and P-gp Substrate)7.6 Atorvastatin (CYP3A4 substrate) and Pravastatin (P-gp substrate)7.7 Simvastatin and Lovastatin7.8 Rifampin (Strong CYP3A4/P-gp Inducers)7.9 Midazolam (CYP3A4/5 substrate)7.10 Other Possible Interactions7.11 Octreotide7.12 Tacrolimus8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Hepatic Impairment8.7 Renal Impairment10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics12.5 Drug-Drug Interactions12.6 Specific Populations12.7 Everolimus Whole Blood Concentrations Observed in Kidneyand in Liver Transplant Patients12.8 Cyclosporine Concentrations Observed in Kidney TransplantPatients12.9 Tacrolimus Concentrations in Liver Transplant13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility14 CLINICAL STUDIES14.1 Prevention of Organ Rejection after Renal Transplantation14.2 Prevention of Organ Rejection after Liver Transplantation16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATIONWARNING: MALIGNANCIES AND SERIOUS INFECTIONS, KIDNEY GRAFT THROMBOSIS;NEPHROTOXICITY; AND MORTALITY IN HEART TRANSPLANTATIONMalignancies and Serious Infections• Only physicians experienced in immunosuppressive therapy and management of transplant patients should prescribe Zortress. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have completeinformation requisite for the follow-up of the patient. [See Warnings and Precautions (5.1)]• Increased susceptibility to infection and the possible development of malignancies such as lymphoma and skin cancer may result from immunosuppression. [See Warnings and Precautions (5.2 and 5.3)]Kidney Graft Thrombosis• An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, was reported, mostly within the first 30 days post-transplantation. [See Warnings and Precautions (5.4)]Nephrotoxicity• Increased nephrotoxicity can occur with use of standard doses of cyclosporine in combination with Zortress.Therefore reduced doses of cyclosporine should be used in combination with Zortress in order to reduce renaldysfunction. It is important to monitor the cyclosporine and everolimus whole blood trough concentrations. [See Dosage and Administration (2.4 and 2.5) and Warnings and Precautions (5.6) and Clinical Pharmacology (12.7 and12.8)]Mortality in Heart Transplantation• Increased mortality, often associated with serious infections, within the first three months post-transplantation was observed in a clinical trial of de novo heart transplant patients receiving immunosuppressive regimens with or without induction therapy. Use in heart transplantation is not recommended. [See Warnings and Precautions (5.7)]1 INDICATIONS AND USAGE1.1 Prophylaxis of Organ Rejection in Kidney TransplantationZortress is indicated for the prophylaxis of organ rejection in adult patients at low-moderate immunologic risk receiving a kidney transplant. [See Clinical Studies (14.1)] Zortress is to be administered in combination with basiliximab induction and concurrently with reduced doses of cyclosporine and with corticosteroids. Therapeutic drug monitoring of everolimus and cyclosporine is recommended for all patients receiving these products. [See Dosage and Administration (2.2 and 2.3)] 1.2 Prophylaxis of Organ Rejection in Liver TransplantationZortress is indicated for the prophylaxis of allograft rejection in adult patients receiving a liver transplant. Zortress is to be administered no earlier than 30 days post-transplant concurrently in combination with reduced doses of tacrolimus and with corticosteroids [See Warnings and Precautions (5.5) and Clinical Studies (14.2)]. Therapeutic drug monitoring of everolimus and tacrolimus is recommended for all patients receiving these products. [See Dosage and Administration (2.3 and 2.5)]1.3 Limitations of UseThe safety and efficacy of Zortress has not been established in the following populations:Kidney transplant patients at high immunologic riskRecipients of transplanted organs other than kidney and liver [See Warnings and Precautions (5.7)]Pediatric patients (<18 years).2 DOSAGE AND ADMINISTRATIONPatients receiving Zortress may require dose adjustments based on everolimus blood concentrations achieved, tolerability, individual response, change in concomitant medications and the clinical situation. Optimally, dose adjustments of Zortress should be based on trough concentrations obtained 4 or 5 days after a previous dosing change. Dose adjustment is required if the trough concentration is below 3 ng/mL. The total daily dose of Zortress should be doubled using the available tablet strengths (0.25 mg, 0.5 mg or 0.75 mg). Dose adjustment is also required if the trough concentration is >8ng/mL on 2 consecutive measures; the dose of Zortress® should be decreased by 0.25 mg b.i.d. [See Therapeutic Drug Monitoring (2.3) and Clinical Pharmacology (12.3)]2.1 Dosage in Adult Kidney Transplant PatientsAn initial Zortress dose of 0.75 mg orally twice daily (1.5 mg per day) is recommended for adult kidney transplant patients in combination with reduced dose cyclosporine, administered as soon as possible after transplantation. [See Therapeutic Drug Monitoring (2.3, 2.4), Clinical Studies (14.1)]Oral prednisone should be initiated once oral medication is tolerated. Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.2.2 Dosage in Adult Liver Transplant PatientsStart Zortress at least 30 days post-transplant. An initial dose of 1.0 mg orally twice daily (2.0 mg per day) is recommended for adult liver transplant patients in combination with reduced dose tacrolimus. [See Therapeutic Drug Monitoring (2.3 and 2.5), Clinical Studies (14.2)]Steroid doses may be further tapered on an individualized basis depending on the clinical status of patient and function of graft.2.3 Therapeutic Drug Monitoring -EverolimusRoutine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients. The recommended everolimus therapeutic range is 3 to 8 ng/mL. [See Clinical Pharmacology (12.7)] Careful attention should be made to clinical signs and symptoms, tissue biopsies, and laboratory parameters. It is important to monitor everolimus blood concentrations, in patients with hepatic impairment, during concomitant administration of CYP3A4 inducers or inhibitors, when switching cyclosporine formulations and/or when cyclosporine dosing is reduced according to recommended target concentrations. [See Clinical Pharmacology (12.7, 12.8)]There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. There is little to no pharmacokinetic interaction of tacrolimus on everolimus, and thus, everolimus concentrations do not decrease if the tacrolimus exposure is reduced. [See Drug Interactions (7.2)]The everolimus recommended therapeutic range of 3 to 8 ng/mL is based on an LC/MS/MS assay method. Currently in clinical practice, everolimus whole blood trough concentrations may be measured by chromatographic or immunoassay methodologies. Because the measured everolimus whole blood trough concentrations depend on the assay used, individual patient sample concentration values from different assays may not be interchangeable. Consideration of assay results must be made with knowledge of the specific assay used. Therefore, communication should be maintained with the laboratory performing the assay.2.4 Therapeutic Drug Monitoring-Cyclosporine in Kidney Transplant PatientsBoth cyclosporine doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with Zortress, in order to minimize the risk of nephrotoxicity. [See Warnings and Precautions (5.6), Drug Interactions (7.2), Clinical Pharmacology (12.8)]The recommended cyclosporine therapeutic ranges when administered with Zortress are 100 to 200 ng/mL through Month 1 post-transplant, 75 to 150 ng/mL at Months 2 and 3 post-transplant, 50 to 100 ng/mL at Month 4 post-transplant, and 25 to 50 ng/mL from Month 6 through Month 12 post-transplant. The median trough concentrations observed in the clinical trial ranged between 161 to 185 ng/mL through Month 1 post-transplant and between 111 to 140 ng/mL at Months 2 and 3 post-transplant. The median trough concentration was 99 ng/mL at Month 4 post-transplant and ranged between 46 to 75 ng/mL from Months 6 through Month 12 post-transplant. [See Clinical Pharmacology (12.8) and Clinical Studies (14.1)] Cyclosporine, USP Modified is to be administered as oral capsules twice daily unless cyclosporine oral solution or intravenous administration of cyclosporine cannot be avoided. Cyclosporine, USP Modified should be initiated as soon as possible -and no later than 48 hours -after reperfusion of the graft and dose adjusted to target concentrations from Day 5 onwards.If impairment of renal function is progressive the treatment regimen should be adjusted. In renal transplant patients, the cyclosporine dose should be based on cyclosporine whole blood trough concentrations. [See Clinical Pharmacology (12.8)]In renal transplantation, there are limited data regarding dosing Zortress with reduced cyclosporine trough concentrations of 25 to 50 ng/mL after 12 months. Zortress has not been evaluated in clinical trials with other formulations ofcyclosporine. Prior to dose reduction of cyclosporine it should be ascertained that steady-state everolimus whole blood trough concentration is at least 3 ng/mL. There is an interaction of cyclosporine on everolimus, and consequently, everolimus concentrations may decrease if cyclosporine exposure is reduced. [See Drug Interactions (7.2)]2.5 Therapeutic Drug Monitoring-Tacrolimus in Liver Transplant PatientsBoth tacrolimus doses and the target range for whole blood trough concentrations should be reduced, when given in a regimen with Zortress, in order to minimize the potential risk of nephrotoxicity. [See Warnings and Precautions (5.6), Clinical Pharmacology (12.9)]The recommended tacrolimus therapeutic range when administered with Zortress are whole blood trough (C-0h) concentrations of 3 to 5 ng/mL by three weeks after the first dose of Zortress (approximately Month 2) and through Month 12 post transplant.The median tacrolimus trough concentrations observed in the clinical trial ranged between 8.6 to 9.5 ng/mL at Weeks 2 and 4 post-transplant (prior to initiation of everolimus). The median tacrolimus trough concentrations ranged between 7 to 8.1 ng/mL at Weeks 5 and 6 post-transplant, between 5.2 to 5.6 ng/mL at Months 2 and 3 post-transplant, and between 4.3 to 4.9 ng/mL between Months 4 and 12 post-transplant. [See Clinical Pharmacology (12.9), Clinical Studies (14.2)] Tacrolimus is to be administered as oral capsules twice daily unless intravenous administration of tacrolimus cannot be avoided.In liver transplant patients, the tacrolimus dose should be based on tacrolimus whole blood trough concentrations. [See Clinical Pharmacology (12.9)]In liver transplantation, there are limited data regarding dosing Zortress with reduced tacrolimus trough concentrations of 3 to 5 ng/mL after 12 months. Prior to dose reduction of tacrolimus it should be ascertained that the steady-state everolimus whole blood trough concentration is at least 3 ng/mL. Unlike the interaction between cyclosporine and everolimus, tacrolimus does not affect everolimus trough concentrations, and consequently, everolimus concentrations do not decrease if the tacrolimus exposure is reduced.2.6 AdministrationZortress tablets should be swallowed whole with a glass of water and not crushed before use.Administer Zortress consistently approximately 12 hours apart with or without food to minimize variability in absorption and at the same time as cyclosporine or tacrolimus. [See Clinical Pharmacology (12.3)]2.7 Hepatic ImpairmentWhole blood trough concentrations of everolimus should be closely monitored in patients with impaired hepatic function. For patients with mild hepatic impairment (Child-Pugh Class A), the initial daily dose should be reduced by approximately one-third of the normally recommended daily dose. For patients with moderate or severe hepatic impairment (Child-Pugh B or C), the initial daily dose should be reduced to approximately one-half of the normally recommended daily dose. Further dose adjustment and/or dose titration should be made if a patient’s whole blood trough concentration of everolimus, as measured by an LC/MS/MS assay, is not within the target trough concentration range of 3 to 8 ng/mL. [See Clinical Pharmacology (12.6)]3 DOSAGE FORMS AND STRENGTHSZortress is available as 0.25 mg, 0.5 mg, and 0.75 mg tablets.Table 1. Description of Zortress (everolimus) TabletsDosage Strength 0.25 mg 0.5 mg 0.75 mg Appearance White to yellowish, marbled, round, flat tablets with bevelled edgeImprint “C” on one side and “NVR”on the other “CH” on one side and“NVR” on the other“CL” on one side and“NVR” on the other4 CONTRAINDICATIONS4.1 Hypersensitivity ReactionsZortress is contraindicated in patients with known hypersensitivity to everolimus, sirolimus, or to components of the drug product.5 WARNINGS AND PRECAUTIONS5.1 Management of ImmunosuppressionOnly physicians experienced in management of systemic immunosuppressant therapy in transplantation should prescribe Zortress. Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for the maintenance therapy should have complete information requisite for the follow-up of the patient. In limited data with the complete elimination of CNI (calcineurin inhibition), there was an increased risk of acute rejection.5.2 Lymphomas and Other MalignanciesPatients receiving immunosuppressants, including Zortress, are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.5.3 Serious InfectionsPatients receiving immunosuppressants, including Zortress, are at increased risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. [See Warnings and Precautions (5.13), Adverse Reactions (6.1, 6.2)] These infections may lead to serious, including fatal, outcomes. Because of the danger of over immunosuppression, which can cause increased susceptibility to infection, combination immunosuppressant therapy should be used with caution.Antimicrobial prophylaxis for Pneumocystis jiroveci (carinii) pneumonia and prophylaxis for cytomegalovirus (CMV) is recommended in transplant recipients.5.4 Kidney Graft ThrombosisAn increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, usually within the first 30 days post-transplantation. [See Boxed Warning]5.5 Hepatic Artery ThrombosisMammalian target of rapamycin (mTOR) inhibitors are associated with an increase in hepatic artery thrombosis (HAT). Reported cases mostly have occurred within the first 30 days post-transplant and most also lead to graft loss or death. Therefore, Zortress should not be administered earlier than 30 days after liver transplant.5.6 Zortress and Calcineurin Inhibitor-Induced NephrotoxicityIn kidney transplant recipients, Zortress with standard dose cyclosporine increases the risk of nephrotoxicity resulting in a lower glomerular filtration rate. Reduced doses of cyclosporine are required for use in combination with Zortress in order to reduce renal dysfunction. [See Boxed Warning, Indications and Usage (1.1), Clinical Pharmacology (12.8)]In liver transplant recipients, Zortress has not been studied with standard dose tacrolimus. Reduced doses of tacrolimus should be used in combination with Zortress in order to minimize the potential risk of nephrotoxicity. [See Indications and Usage (1.2), Clinical Pharmacology (12.9)]Renal function should be monitored during the administration of Zortress. Consider switching to other immunosuppressive therapies if renal function does not improve after dose adjustments or if the dysfunction is thought to be drug related. Caution should be exercised when using other drugs which are known to impair renal function.5.7 Heart TransplantationIn a clinical trial of de novo heart transplant patients, Zortress in an immunosuppressive regimen with or without induction therapy, resulted in an increased mortality often associated with serious infections within the first three months post-transplantation compared to the control regimen. Use of Zortress in heart transplantation is not recommended.5.8 AngioedemaZortress has been associated with the development of angioedema. The concomitant use of Zortress with other drugs known to cause angioedema, such as angiotensin converting enzyme (ACE) inhibitors may increase the risk of developing angioedema.5.9 Wound Healing and Fluid AccumulationZortress increases the risk of delayed wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele and seroma. These wound-related complications may require more surgical intervention. Generalized fluid accumulation, including peripheral edema (e.g., lymphoedema) and other types of localized fluid collection, such as pericardial and pleural effusions and ascites have also been reported.5.10 Interstitial Lung Disease/Non-Infectious PneumonitisA diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled-out through appropriate investigations. Cases of ILD, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious etiology, some reported with pulmonary hypertension (including pulmonary arterial hypertension [PAH]) as a secondary event, have occurred in patients receiving rapamycins and their derivatives, including Zortress. Most cases generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred.5.11 HyperlipidemiaIncreased serum cholesterol and triglycerides, requiring the need for anti-lipid therapy, have been reported to occur following initiation of Zortress and the risk of hyperlipidemia is increased with higher everolimus whole blood trough concentrations. [See Adverse Reactions (6.2)] Use of anti-lipid therapy may not normalize lipid levels in patients receiving Zortress.Any patient who is administered Zortress should be monitored for hyperlipidemia. If detected, interventions, such as diet, exercise, and lipid-lowering agents should be initiated as outlined by the National Cholesterol Education Program guidelines. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen containing Zortress. Similarly, the risk/benefit of continued Zortress therapy should be reevaluated in patients with severe refractory hyperlipidemia. Zortress has not been studied in patients with baseline cholesterol levels >350 mg/dL.Due to an interaction with cyclosporine, clinical trials of Zortress and cyclosporine in kidney transplant patients strongly discouraged patients from receiving the HMG-CoA reductase inhibitors simvastatin and lovastatin. During Zortress therapy with cyclosporine, patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects, as described in the respective labeling for these agents. [See Drug Interactions (7.7)]5.12 ProteinuriaThe use of Zortress in transplant patients has been associated with increased proteinuria. The risk of proteinuria increased with higher everolimus whole blood trough concentrations. Patients receiving Zortress should be monitored for proteinuria. [See Adverse Reactions (6.2)]5.13 Polyoma Virus InfectionsPatients receiving immunosuppressants, including Zortress, are at increased risk for opportunistic infections; including polyoma virus infections. Polyoma virus infections in transplant patients may have serious, and sometimes fatal, outcomes. These include polyoma virus-associated nephropathy (PVAN), mostly due to BK virus infection, and JC virus associated progressive multiple leukoencephalopathy (PML). PVAN has been observed in patients receiving immunosuppressants, including Zortress. PVAN is associated with serious outcomes; including deteriorating renal function and kidney graft loss. [See Adverse Reactions (6.2)] Patient monitoring may help detect patients at risk for PVAN. Reductions in immunosuppression should be considered for patients who develop evidence of PVAN or PML. Physicians should also consider the risk that reduced immunosuppression represents to the functioning allograft.5.14 Interaction with Strong Inhibitors and Inducers of CYP3A4Co-administration of Zortress with strong CYP3A4-inhibitors (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, boceprevir, telaprevir) and strong CYP3A4 inducers (e.g., rifampin, rifabutin) is not recommended without close monitoring of everolimus whole blood trough concentrations. [See Drug Interactions (7)]。

淋巴瘤 gemox化疗方案

引言淋巴瘤是一种常见的血液系统肿瘤，主要发生在淋巴组织中，包括淋巴结、脾脏、骨髓和淋巴组织。

GEMOX化疗方案是一种常用于淋巴瘤治疗的综合化疗方案，该方案的药物组合主要包括Gemcitabine和Oxaliplatin。

本文将详细介绍淋巴瘤GEMOX化疗方案的相关信息，包括适应症、药物机制、治疗方案和不良反应等。

1. 适应症GEMOX化疗方案主要适用于下列类型的淋巴瘤患者：•非霍奇金淋巴瘤（NHL）的治疗，包括弥漫大B细胞淋巴瘤（DLBCL）、滨紫罗兰淋巴瘤等；•既往治疗后复发或难治性经过的患者；•作为化疗的一部分，用于治疗有限疾病阶段的患者。

2. 药物机制2.1 GemcitabineGemcitabine是一种嘌呤类似物，属于胸苷类似物，对DNA链延伸起着抑制作用。

其主要通过下述方式发挥其作用：•阻碍DNA合成过程：Gemcitabine可与DNA链相互作用，阻碍DNA链的合成和伸长；•DNA损伤诱导：Gemcitabine能够引起DNA链损伤并抑制DNA修复机制；•阻碍细胞周期：Gemcitabine可干预DNA链的修复过程，进而阻碍细胞周期的进行。

2.2 OxaliplatinOxaliplatin是一种铂类化疗药物，通过以下机制抑制癌细胞的生长和分裂：•DNA横链连接：Oxaliplatin能够与DNA形成DNA-Oxaliplatin的横链连接，从而抑制DNA的复制和转录；•DNA损伤诱导：Oxaliplatin能够引起DNA链断裂和损伤；•诱导细胞凋亡：Oxaliplatin能够引起癌细胞凋亡。

3. 治疗方案GEMOX化疗方案的具体治疗方案如下：3.1 Gemcitabine的使用•剂量：根据患者体表面积计算，一般为1000-1250 mg/m²；•给药途径：静脉滴注；•给药频次：一般为每周给药一次，连续2-3周。

3.2 Oxaliplatin的使用•剂量：根据患者体表面积计算，一般为85-100 mg/m²；•给药途径：静脉滴注；•给药频次：与Gemcitabine同时给药，每周一次，连续2-3周。

abvd方案化疗

abvd方案化疗ABVD方案化疗是一种常用的治疗霍奇金淋巴瘤(Hodgkin's lymphoma)的化疗方案。

本文将介绍ABVD方案化疗的定义、使用方法、药物成分和治疗效果等方面的信息。

一、定义ABVD是Adriamycin（阿霉素）、Bleomycin（博来霉素）、Vinblastine（长春新碱）和Dacarbazine（达卡巴嗪）四种化疗药物的缩写，这是一种联合使用的化疗方案。

它被广泛应用于霍奇金淋巴瘤的治疗，并被视为标准化疗方案。

二、使用方法ABVD方案化疗通常通过静脉输注的方式进行，治疗周期为28天，每三周进行一次化疗。

患者在医院接受输液治疗，化疗时间一般为几小时。

治疗期间，医生会对患者的身体指标进行监测，并根据需要进行剂量调整。

三、药物成分1. Adriamycin：阿霉素，是一种抗肿瘤药物，通过干扰癌细胞DNA的复制和修复来抑制癌细胞的生长和扩散。

2. Bleomycin：博来霉素，也是一种抗肿瘤药物，主要通过干扰DNA的合成和损伤癌细胞的DNA结构来发挥作用。

3. Vinblastine：长春新碱，能够阻碍肿瘤细胞的纺锤体形成，从而干扰有丝分裂过程，阻止癌细胞的增殖。

4. Dacarbazine：达卡巴嗪，通过与癌细胞DNA结合，干扰癌细胞的DNA合成，从而达到抑制癌细胞生长的效果。

四、治疗效果ABVD方案化疗在治疗霍奇金淋巴瘤方面取得了显著的疗效。

多项临床研究表明，ABVD方案化疗能够有效控制瘤体积的增长，并使患者的症状得到明显改善。

此外，ABVD方案化疗还具有较低的毒副作用，不会对患者的生活质量造成过大影响。

总结：ABVD方案化疗是一种常用的霍奇金淋巴瘤治疗方案，由四种药物组合而成。

该方案通过干扰癌细胞的DNA合成和功能，有效抑制癌细胞的生长和扩散。

临床研究证实，ABVD方案化疗具有较好的治疗效果，能够明显减轻患者的症状，并且毒副作用较小。

ABVD方案化疗在治疗霍奇金淋巴瘤的临床实践中得到广泛应用，为患者带来了希望和康复的机会。

abvd方案化疗具体用法

ABVD方案化疗具体用法什么是ABVD方案化疗？ABVD方案（Adriamycin，Bleomycin，Vinblastine，Dacarbazine）是一种常用于治疗霍奇金淋巴瘤（Hodgkin’s lymphoma）的化疗方案。

ABVD方案化疗包括四种药物的组合使用，每种药物都有特定的作用机制，以达到最佳的治疗效果。

ABVD方案化疗的具体用法因个体情况而有所不同，下面将逐步介绍ABVD方案化疗的步骤和注意事项。

第一阶段：Adriamycin（A）的使用Adriamycin是ABVD方案化疗中的第一种药物。

它通过抑制癌细胞的DNA和RNA的合成，阻断癌细胞的分裂和增殖。

Adriamycin通过静脉注射给药，通常在医院内进行。

•剂量：Adriamycin的剂量根据患者的体重和身体情况而定，通常为每平方米体表面积25-40毫克。

剂量会根据患者的耐受性和临床疗效进行调整。

•频率：Adriamycin的使用一般为每21天一次，每个周期中的第1、15天进行治疗。

第二阶段：Bleomycin（B）的使用Bleomycin是ABVD方案化疗中的第二种药物。

它通过抑制癌细胞的DNA合成，干扰癌细胞的正常功能。

Bleomycin一般通过静脉注射给药。

•剂量：Bleomycin的剂量根据患者的体重和身体情况而定，通常为每周10-20单位。

剂量会根据患者的耐受性和临床疗效进行调整。

•频率：Bleomycin的使用通常是每个周期的第1、15天进行治疗。

第三阶段：Vinblastine（V）的使用Vinblastine是ABVD方案化疗中的第三种药物。

它通过阻断癌细胞的有丝分裂，抑制癌细胞的增殖。

Vinblastine一般通过静脉注射给药。

•剂量：Vinblastine的剂量根据患者的体重和身体情况而定，通常为每平方米体表面积4-6毫克。

剂量会根据患者的耐受性和临床疗效进行调整。

•频率：Vinblastine的使用一般为每21天一次，每个周期中的第1、15天进行治疗。

淋巴瘤ice方案

引言淋巴瘤（Lymphoma）是一种恶性血液肿瘤，其特点是由淋巴细胞恶性增生引起的淋巴结肿大。

淋巴瘤是世界范围内发病率逐年上升的癌症，因此需要制定有效的治疗方案。

本文档将介绍淋巴瘤的治疗方案之一——ICE方案，包括其定义、治疗过程以及可能的副作用。

1. 方案概述ICE方案是一种常用于晚期淋巴瘤治疗的化疗方案。

ICE方案的名称是由三种化疗药物的首字母缩写而来，分别是Ifosfamide、Carboplatin和Etoposide。

这三种药物常被用于多种恶性肿瘤的治疗，其联合使用可以提高药物疗效。

2. 治疗过程ICE方案的治疗过程通常包括以下几个步骤：步骤1：化疗前准备在开始ICE方案之前，医生会对患者进行全面的身体检查，并评估患者的肝肾功能等重要指标。

此外，医生还会为患者制定个体化的治疗计划，并与患者和其家属详细沟通，解答他们可能有的疑问和顾虑。

步骤2：化疗药物注射ICE方案中的化疗药物通常通过静脉注射的方式给予患者。

根据具体情况，医生会确定药物剂量和使用频率。

治疗过程通常分为多个周期，每个周期持续一段时间（一般为2-3周）。

患者通常需要住院接受治疗，以确保他们得到充分的监测和支持。

步骤3：化疗周期间隙每个化疗周期结束后，患者需要一段恢复期。

这个间隙通常持续数周，以确保患者身体能够从化疗中充分康复。

在这个期间，医生会对患者进行定期随访，检查患者的血液指标和身体状况，以确认下一个周期的治疗是否可以开始。

步骤4：重复治疗周期根据患者的具体情况，ICE方案通常需要进行多个治疗周期，以确保彻底清除淋巴瘤细胞。

在每个周期结束后，医生会重新评估患者的疗效，并决定是否需要继续进行下一个周期的治疗。

3. 副作用ICE方案的药物具有一定的副作用，尽管在医生的指导下，大部分病人能够较好地承受。

以下是可能出现的一些常见副作用：•恶心和呕吐：由于化疗对胃肠道产生一定的刺激作用，患者可能会感到恶心和呕吐。

医生可以根据需要给予抗恶心药物来减轻这些症状。

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J. Ruan*

Center for Lymphoma and Myeloma, Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, USA

Abstract: The tumor microenvironment is critical in the initiation and progression of cancerous growth, which is dependent on the establishment of a functional vascular network supporting neoplastic proliferation. While the precise role of tumor angiogenesis in lymphoma pathogenesis remains under active investigation, emerging data on the pro-angiogenic properties of the neoplastic lymphoma cells and mechanism of vascular assembly suggest that angiogenesis is highly relevant to the biology and therapy of non-Hodgkin’s lymphoma. Antiangiogenic therapies in non-Hodgkin’s lymphoma are in various stages of clinical development aiming at distinct angiogenic pathways operative in endothelial cells and perivascular stromal cells. The major classes of available antiangiogenics include anti-VEGF, small molecule inhibitors targeting proangiogenic receptor tyrosine kinases and their downstream signal transduction pathways, as well as immunomodulatory compounds with antiangiogenic properties. Preliminary clinical data indicate therapeutic advantages associated with strategies targeting dual compartments of vascular cells and tumor cells, as well as multiple angiogenic pathways within the tumor microenvironment. This review summarizes recent applications of antiangiogenic strategies in non-Hodgkin’s lymphoma based on current understanding of the biology of lymphoma angiogenesis.

Keywords: Angiogenesis, antiangiogenic therapy, microenvironment, non-Hodgkin’s lymphoma, VEGF.

INTRODUCTION Lymphoma is the second fastest growing adult malignancy in incidence in North America. In 2010, over 65,000 new cases of non-Hodgkin’s lymphoma (NHL) were diagnosed, and more than 20,000 people died from the diseases in the US [1]. Despite the fact that multi-modality treatment including combination chemotherapy, radiation, and target-specific monoclonal antibodies can induce a high-rate of remission in many subtypes of non-Hodgkin’s lymphoma, a significant proportion of patients relapse with incurable disease [2-3]. Novel therapeutic strategies are being actively explored to overcome treatment resistance. Amongst them, anti-angiogenics has emerged as a promising treatment modality that targets tumor microenvironment in complementary to tumor cell oriented therapy.

Angiogenesis, the growth of new blood vessels, requires dynamic expansion, assembly and stabilization of vascular endothelial cells in response to pro-angiogenic stimuli. Many aspects of tumor angiogenesis have been extensively studied in the context of nonhematopoietic neoplasms in the past three decades [4-5], and anti-angiogenic strategy has become an important treatment option for solid tumors in various clinical settings including metastatic colorectal, lung, breast, renal and liver cancers [6-10]. Non-Hodgkin’s lymphoma consists of a collection of complex disease subtypes driven by monoclonal proliferation of malignant B- or T-cells, which display a spectrum of clinical behaviors, ranging from indolent subtypes with growth latency measured in years to aggressive subtypes with progression measured in weeks to months [11]. The precise role of angiogenesis in the pathogenesis of lymphoproliferative disease is under active

*Address correspondence to this author at the Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, 1300 York Avenue, Room A-605A, New York, NY 10065, USA; Tel: 646-962-2068; Fax: 646-962-1605; E-mail: jruan@med.cornell.edu

investigation. Emerging evidence, analyzing both the angiogenic properties of the neoplastic cells as well as vascular microenvironment, suggests divergent angiogenic patterns in disparate lymphoma subtypes. To date, several lines of evidence have pointed to the relevance of angiogenesis to lymphoma progression and clinical outcome. First, increased production of proangiogenic growth factors by lymphoma tumor cells as well as infiltrating stromal cells, and increased angiogenesis activity (by vessel counts) has been observed with histological progression of the lymphomas [12-14]. Secondly, expression of both vascular endothelial growth factor (VEGF) and VEGF receptors by the tumor cells in a number of lymphoma subtypes suggests autocrine and paracrine pro-angiogenic survival mechanisms. Thirdly, large-scale gene expression studies in follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) have demonstrated that genetic signatures expressed by stromal and infiltrating immune cells define distinct prognostic groups [15-16], with increased angiogenic activity associated with inferior outcome in DLBCL. Experimentation with anti-angiogenic strategies has shown early promise in selected subtypes. This review summarizes recent applications of antiangiogenic strategies in non-Hodgkin’s lymphoma based on current understanding of the biology of lymphoma angiogenesis.