肿瘤代谢调节疗法培训课件.ppt

1、肿瘤代谢调节疗法肿瘤代谢调节疗法定义与背景2肿瘤代谢调节疗法K n o x L S,e t a l.A n n S u r g.1983;197(2):152-62.Lieffers JR,et al.Am J Clin Nutr.2009;89(4):1173-9.3肿瘤代谢调节疗法葡萄糖葡萄糖丙酮酸乳酸乳酸Cori 循环胞浆线粒体丙酮酸乙酰辅酶AATP三羧酸循环丙酮酸脱氢酶 50%50%4肿瘤代谢调节疗法5肿瘤代谢调节疗法脂肪脂肪6肿瘤代谢调节疗法癌从口人7肿瘤代谢调节疗法肿瘤代谢调节疗法（cancer metabolic modulation therapy,CMMT）是作者提出的一种全

2、新的肿瘤治疗方法，顾名思义它是采用不同手段调节肿瘤患者正常细胞代谢、干扰肿瘤细胞代谢，从而达到预防和治疗肿瘤的目的。它包含营养疗法，但是内容更加丰富，肿瘤营养疗法是通过营养素实施抗肿瘤治疗，而代谢调节疗法则是通过各种手段调节代谢实施抗肿瘤治疗，这些手段包括（1）营养素调节，（2）能量调节，（3）营养途径调节，（4）药物调节，（5）手术调节，（6）运动调节，（7）心理调节，（8）生物反馈调节。CMMT是另外一种疗法，是一套组合拳，其地位和作用与手术、放疗、化疗等肿瘤传统治疗方法相似，但是代谢调节疗法对机体的损伤更小，毒副反应更少，患者依从性更好。8肿瘤代谢调节疗法适应证9肿瘤代谢调节疗法一个始动

3、因素恶性肿瘤两个相互作用肿瘤对宿主宿主对肿瘤三个中心环节摄食减少（厌食）体重丢失肌肉减少四个调控机制神经内分泌激素肿瘤代谢因子炎症细胞因子自由基五个临床后果能量负债生活质量下降体力活动能力下降社会心理影响生存时间缩短10肿瘤代谢调节疗法CMMT目的并非仅仅提供能量及营养素、治疗营养不良，其更加重要的目标在于代谢调节、控制肿瘤。由于所有荷瘤患者均需要代谢调节治疗，所以，其适应证为：1）荷瘤肿瘤患者，2）营养不良的患者。11肿瘤代谢调节疗法营养素调节12肿瘤代谢调节疗法Foster R,et al.PLoS One.2012;7(9):e45061.1.减少葡萄糖供给13肿瘤代谢调节疗法Miao

4、YR,et al.Clin Cancer Res.2013;19(8):2107-16.细胞活性肿瘤重量细胞数量无病生存时间14肿瘤代谢调节疗法Tayek JA,et.al.,Metabolism.1997;46:140 145静脉注入葡萄糖后胰岛素分泌反应，(A)正常体重，(B)低体重，癌症患者胰岛素分泌显著低于正常对照组(P .05)2.维持血糖稳定 15肿瘤代谢调节疗法Proposed role of miR-451 in the regulation of LKB1 signaling in response to fluctuating glucose.Two different g

5、rowth schemes of tumor spheroids(gray filled circle)with same initial size in response to fluctuating and steady glucose(green solid line).Kim Y,et al.miR451 and AMPK mutual antagonism in glioma cell migration and proliferation:a mathematical model.PLoS One.2011;6(12):e2829316肿瘤代谢调节疗法TPP脱羧酶丙酮酸脱氢酶复合物

6、 3.促进葡萄糖氧化17肿瘤代谢调节疗法thiamine(open circle)DCA(closed circle)Hanberry BS,Berger R,Zastre JA.High-dose vitamin B1 reduces proliferation in cancer cell lines analogous to dichloroacetate.Cancer Chemother Pharmacol.2014;73(3):585-9418肿瘤代谢调节疗法Abdelwahab MG,et al.The Ketogenic Diet Is an Effective Adjuvant

7、 to Radiation Therapy for the Treatment of Malignant Glioma.PLoS One.2012;7(5):e36197 4.提高脂肪比例19肿瘤代谢调节疗法治疗前经过2个月治疗后Zuccoli G,et al.Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet:Case Report.Nutr Metab.2010,22(7):3320肿瘤代谢调节疗法Vanek VW,e

8、t al.Nutr Clin Pract.2012;27(2):150-92.Th0细胞向Th1、Th2两个方向分化，Th1淋巴细胞具备促炎作用，Th2细胞相反。-3FA对Th1细胞有特异性细胞毒作用，间接增强了Th2细胞的抗炎效能5.选择合适脂肪21肿瘤代谢调节疗法Chandi Charan Mandal CC,et al.Fish oil prevents breast cancer cell metastasis to bone.Biochem Biophys Res Commun.2010;402(4):60260722肿瘤代谢调节疗法Javier A.Menendez JA,et a

9、l.Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil.A new family of gerosuppressant agents.Cell Cycle.2013;12(4):555578.secoiridoid polyphenols，裂环烯醚萜多酚(橄榄苦苷)，具有抗衰老及外来毒物兴奋效应，从而具有预防肿瘤的作用。维生素E：、4种形式，抗氧化活性最高，其他3种相对生物活性分别为0.5、0.25、0.0123肿瘤代谢调节疗法TestDiet 505

10、88%CHO15%CHOa10%CHOaCHO55.28.015.610.6Protein23.269.458.263.5Fat21.622.626.225.9NOTE:Values are given in%kcala CHO content is 70%high amylose cornstarchTable Macronutrient breakdown of diets usedHo VW,etal.A low carbohydrate,high protein diet slows tumor growth and prevents cancer Initiation.Cancer

11、Res.2011.71(13):4484-93 6.提高蛋白质供给24肿瘤代谢调节疗法The 15%CHO diet reduces the incidence of tumors in a spontaneous mouse model of breast cancer.血糖胰岛素体重肿瘤发生率生存时间25肿瘤代谢调节疗法最新版（2009年）ESPEN指南：肿瘤病人的氨基酸需要量推荐范围最少为1g/kg/d到目标需要量的1.2-2g/kg/d之间。Bozzetti F等认为，肿瘤恶病质病人蛋白质的总摄入量（静脉+口服）应该达到1.8-2 g/kg/d，BCAA应该达到0.6 g/kg/d，E

12、AA应该增加到1.2 g/kg/d。严重营养不良肿瘤病人的短期冲击营养治疗阶段，蛋白质给予量应该达到2 g/kg/d；轻中度营养不良肿瘤病人的长期营养补充治疗阶段，蛋白质给予量应该达到1.5g/kg/d（1.25-1.7 g/kg/d）。日常饮食不足时，应该口服营养补充，口服营养补充仍然不足时，应该由静脉补充。Bozzetti F,Bozzetti V.Is the intravenous supplementation of amino acid to cancer patients adequate?A critical appraisal of literature.Clin Nutr.

13、2013;32(1):142-6.26肿瘤代谢调节疗法预消化水解蛋白配方,同时含有游离氨基酸和短肽，可充分利用人体双通道氮源吸收。且短肽和游离氨基酸在吸收过程中都不受胃，肠蛋白酶的影响。Zaloga GP.Physiologic effects of peptide-based enteral formulas.Nutr Clin Pract.1990;5(6):231-7.7.选择合适蛋白质27肿瘤代谢调节疗法编号分组动物数量处理肿瘤形成率123456假处理组肿瘤组肿瘤+WPWP肿瘤+WPHWPH101111101010盐水注射AOM+DSSAOM+DSS+WPWPAOM+DSS+WPHWP

14、H091.9%91.9%033.3%0WP，whey protein，乳清蛋白；WPH，whey protein hydrolyzate，乳清蛋白水解物AOM，azoxymethane，氧化偶氮甲烷；DSS，dextran sodium sulfate，硫酸葡聚糖钠结论：与乳清蛋白相比，乳清蛋白水解物具有更强的肿瘤预防与抑制作用Attaallah W,et al.Whey protein versus whey protein hydrolyzate for the protection of azoxymethane and dextran sodium sulfate induced co

15、lonic tumors in rats.Pathol Oncol Res.2012;18(4):817-22.28肿瘤代谢调节疗法能量调节29肿瘤代谢调节疗法Colman RJ,et al.Science.2009;325(5937):201-4.8.限制能量摄入30肿瘤代谢调节疗法Colman RJ,et al.Science.2009;325(5937):201-4.31肿瘤代谢调节疗法Colman RJ,et al.Science.2009;325(5937):201-4.32肿瘤代谢调节疗法Saleh AD,et al.Caloric restriction augments rad

16、iation efficacy in breast cancer.Cell Cycle.2013;12(12):1955-63.肿瘤体积肿瘤体积33肿瘤代谢调节疗法营养途径调节34肿瘤代谢调节疗法Median survival ratesPN=12.5(10-15)months No PN=9.0(8-10)months Shang E,et al.JPEN.2006;30(3):222-30.SPN在围手术期、放化疗、终末期肿瘤、营养不良患者的营养支持中意义特别重要。9.部分肠外营养 35肿瘤代谢调节疗法Shang E,et al.JPEN.2006;30(3):222-30.生活质量随观察

17、时间的变化*表示两组间有统计学上的显著差异（P 0.05）36肿瘤代谢调节疗法营养干预的五阶梯模式能量70%蛋白质100%37肿瘤代谢调节疗法药物调节38肿瘤代谢调节疗法10.抑制乳酸代谢 39肿瘤代谢调节疗法Sutendra G,Michelakis ED.Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology.Front Oncol.2013;3:38.40肿瘤代谢调节疗法Mei ZB,et al.Survival benefits of metformin for colorectal cancer

18、patients with diabetes:a systematic review and meta-analysis.PLoS One.2014 Mar 19;9(3):e91818.11.抑制糖异生二甲双胍 Metformin41肿瘤代谢调节疗法Noto H,et al.Latest insights into the risk of cancer in diabetes.J Diabetes Investig.2013;4(3):225232.42肿瘤代谢调节疗法Horita N,Miyazawa N,Kojima R,Inoue M,Ishigatsubo Y,Ueda A,Kane

19、ko T.Statins reduce all-cause mortality in chronic obstructive pulmonary disease:a systematic review and meta-analysis of observational studies.Respir Res.2014;15:80.12.改善脂肪代谢43肿瘤代谢调节疗法BACKGROUND:There is conflicting evidence for the role of statins in the primary prevention of colorectal cancer(CRC

20、).We conducted a case control study(N=357,702)in the non-elderly adult US population(age=18-64 years)with the primary objective to examine the association between CRC and statin use.PATIENTS AND METHODS:MarketScan databases were used to identify patients with CRC.A case was defined as having an inci

21、dent diagnosis of CRC.Up to ten individually matched controls(age,sex,region and date of diagnosis)were selected per case.Statin exposure was assessed by prescription tracking in the 12 months prior to the index date.Conditional logistic regression was used to adjust for multiple potential confounde

22、rs and calculate adjusted odds ratios(AOR).RESULTS:The mean age of participants was 54 years;52%males and 48%females.In a multivariable model,any statin use was associated with 26%reduced odds of CRC(AOR,0.74,95%confidence interval(CI),0.72-0.77,p0.001).Age-stratified analyses showed a stronger effe

23、ct of statins on CRC in participants aged 55 years or younger(AOR,0.67,95%CI,0.63-0.71,p0.001)than in participants aged above 55 years(AOR,0.79,95%CI,0.76-0.82,p0.001);the age-by-statin interaction was statistically significant(p0.001).The dose-response analyses performed with simvastatin only showe

24、d a trend towards significance between the duration of simvastatin exposure and odds of developing CRC(p=0.06).CONCLUSIONS:Statins appears to reduce the risk of CRC in non-elderly US population.Chemoprevention with statin might be more effective in non-elderly US populationSehdev A,Shih YC,Huo D,Vek

25、hter B,Lyttle C,Polite B.The Role of Statins for Primary Prevention in Non-elderly Colorectal Cancer Patients.Anticancer Res.2014 Sep;34(9):5043-50.44肿瘤代谢调节疗法外科调节45肿瘤代谢调节疗法Muzumdar R,et al.Visceral adipose tissue modulates mammalian longevity.Aging Cell.2008;7(3):438-40.Survival curve of the three g

26、roups of rats(AL-fed,dashed line;VF-removed,dotted line;and CR,solid line).能量限制自由摄食内脏脂肪切除14.切除内脏脂肪47肿瘤代谢调节疗法Huffman DM,et al.Cancer Prev Res(Phila).2013;6(3):177-87.肿瘤病灶数量肿瘤生存时间整体雌性雄性48肿瘤代谢调节疗法运动调节49肿瘤代谢调节疗法Fong DY,et al.BMJ.2012;344:e70.15.身体活动50肿瘤代谢调节疗法Gould DW,Lahart I,Carmichael AR,Koutedakis Y,

27、Metsios GS.Cancer cachexia prevention via physical exercise:molecular mechanisms.J Cachexia Sarcopenia Muscle.2013;4(2):111-24.51肿瘤代谢调节疗法生物反馈52肿瘤代谢调节疗法Fig.2 Results:change in exercise capacity(mean change in 6MWD from pre to post intervention)measured by the 6 min walk distance(6MWD)in reviewed obse

28、rvational trials.Granger CL,McDonald CF,Berney S,Chao C,Denehy L.Exercise intervention to improve exercise capacity and health related quality of life for patients with Non-small cell lung cancer:a systematic review.Lung Cancer.2011;72(2):139-5316.身心放松53肿瘤代谢调节疗法Quist M,Rrth M,Langer S,Jones LW,Laurs

29、en JH,Pappot H,Christensen KB,Adamsen L.Safety and feasibility of a combined exercise intervention for inoperable lung cancer patients undergoing chemotherapy:a pilot study.Lung Cancer.2012;75(2):203-8.Variable(n=23)Base mean(SD)Post mean(SD)Change(95%CI)p valueBMI25.1(5.0)25.3(4.8)0.2(0.3 to 0.5)0.

30、076Lung capacity FEV11.76(0.70)1.96(0.63)0.20(0.01 to 0.41)0.061Aerobic capacity VO2peak(L/min)1.48(0.41)1.57(0,41)0.09(0.02 to 0.16)0.014Functional capacity 6 MWD(m)524.7(88.5)564.0(88.6)39.3(12.5 to 66.1)0.006Muscle strength Leg press(kg)70.4(26.9)86.9(28.8)16.5(11.5 to 21.7)0.000 Chest press(kg)3

31、0.8(13.2)40.3(16.3)9.5(6.4 to 12.7)0.000 Lat machine(kg)35.8(13.8)39.2(17.6)3.4(0.0 to 6.7)0.049 Abdominal crunch(kg)24.9(10.7)29.5(11.3)4.6(3.2 to 6.0)0.000 Lower back(kg)35.3(14.1)43.1(16.2)7.8(4.8 to 10.8)0.000 Leg extension(kg)38.6(15.5)45.1(18.9)6.5(4.1 to 8.9)0.00054肿瘤代谢调节疗法疗程与疗效55肿瘤代谢调节疗法时机与疗

32、程实施CMMT越早越好，考虑到CMMT的临床效果出现较慢，建议以4周为一个疗程。疗效评价1 近期指标（实验室参数）血常规，电解质，肝功能、肾功能、炎症参数（IL-1、IL-6、TNF、CRP）、血乳酸、营养套餐（白蛋白、前白蛋白、转铁蛋白、视黄醇结合蛋白、游离脂肪酸）等，每周检测1-2次。2 中期指标 人体测量参数、人体成分分析、生活质量评估、体能评估、肿瘤病灶评估（双径法）、PET-CT代谢活性。每4-12周评估一次。3 远期指标 生存时间，每年评估一次。56肿瘤代谢调节疗法荷瘤患者的代谢调节疗法内容非常丰富，涉及营养素调节、能量调节、药物调节、手术调节、运动调节多个方面。日常生活中简便易行，切实有效的措施为：限制能量摄入，减少葡萄糖供给，提高蛋白质供给，加强运动。实验医学向临床应用转化。小 结57肿瘤代谢调节疗法58肿瘤代谢调节疗法热烈欢迎2015中国国际肿瘤营养论坛第三届全国肿瘤营养与支持治疗学术会议第一届海峡两岸肿瘤营养高峰论坛2015年5月8-10日 北京59肿瘤代谢调节疗法谢谢光临敬请批评指正60肿瘤代谢调节疗法