肿瘤代谢调节疗法培训ppt课件

肿瘤代谢调节疗法肿瘤代谢调节疗法肿肿瘤代瘤代谢调节疗谢调节疗法法定义与背景2肿瘤代谢调节疗法定定义义与背景与背景2肿肿瘤代瘤代谢调节疗谢调节疗法法Knox LS,et al.Ann Surg.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Knox LS,et al.Ann Surg.1983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肿瘤代谢调节疗法葡萄糖葡萄糖丙葡萄糖葡萄糖丙酮酮酸乳酸乳酸酸乳酸乳酸Cori 循循环环胞胞浆线浆线粒体丙粒体丙酮酮酸乙酸乙酰酰5肿瘤代谢调节疗法5肿肿瘤代瘤代谢调节疗谢调节疗法法脂肪脂肪6肿瘤代谢调节疗法脂肪脂肪6肿肿瘤代瘤代谢调节疗谢调节疗法法癌从口人7肿瘤代谢调节疗法癌从口人癌从口人7肿肿瘤代瘤代谢调节疗谢调节疗法法肿瘤代谢调节疗法（cancermetabolicmodulationtherapy,CMMT）是作者提出的一种全新的肿瘤治疗方法，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肿瘤代谢调节疗法肿肿瘤代瘤代谢调节疗谢调节疗法（法（cancer metabolic modu适应证9肿瘤代谢调节疗法适适应证应证9肿肿瘤代瘤代谢调节疗谢调节疗法法一个始动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肿瘤代谢调节疗法一个始一个始动动因素因素恶恶性性肿肿瘤瘤10肿肿瘤代瘤代谢调节疗谢调节疗法法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CMMT目的并非目的并非仅仅仅仅提供能量及提供能量及营营养素、治养素、治疗营疗营养不良，其更加重养不良，其更加重营养素调节12肿瘤代谢调节疗法营营养素养素调节调节12肿肿瘤代瘤代谢调节疗谢调节疗法法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Foster R,et al.PLoS One.201Miao 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Miao YR,et al.Clin Cancer ReTayek 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Tayek JA,et.al.,Metabolism.Proposed role of miR-451 in the regulation of LKB1 signaling in response to fluctuating glucose.Two different growth 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Proposed role of miR-451 in thTPP脱羧酶丙酮酸脱氢酶复合物3.促进葡萄糖氧化17肿瘤代谢调节疗法TPP丙丙酮酮酸脱酸脱氢氢酶酶3.促促进进葡萄糖氧化葡萄糖氧化17肿肿瘤代瘤代谢调节疗谢调节疗法法thiamine(opencircle)DCA(closedcircle)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thiamine(open circle)HanberrAbdelwahab MG,et al.The Ketogenic Diet Is an Effective Adjuvant 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Abdelwahab MG,et al.The Ketog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肿瘤代谢调节疗法治治疗疗前前Zuccoli G,et al.MetabolicVanek VW,et 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Vanek VW,et al.Nutr Clin PraChandi 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Chandi Charan Mandal CC,et alJavier A.Menendez JA,et al.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.secoiridoidpolyphenols，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Javier A.Menendez JA,et al.TestDiet50588%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 Res.2011.71(13):4484-93 6.提高蛋白质供给24肿瘤代谢调节疗法TestDiet 50588%CHO15%CHOa10%The15%CHOdietreducestheincidenceoftumorsinaspontaneousmousemodelofbreastcancer.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The 15%CHO diet reduces the i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。BozzettiF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1.8-2g/kg/d，BCAA应该达到0.6g/kg/d，EAA应该增加到1.2g/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2g/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（1.25-1.7g/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.2013;32(1):142-6.26肿瘤代谢调节疗法最新版（最新版（2009年）年）ESPEN指南：指南：肿肿瘤病人的氨基酸需要量推瘤病人的氨基酸需要量推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肿瘤代谢调节疗法预预消化水解蛋白配方消化水解蛋白配方,同同时时含有游离氨基酸和短含有游离氨基酸和短肽肽，可充分利用人体，可充分利用人体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+WPHWPH091.9%91.9%033.3%0WP，wheyprotein，乳清蛋白；WPH，wheyproteinhydrolyzate，乳清蛋白水解物AOM，azoxymethane，氧化偶氮甲烷；DSS，dextransodiumsulfate，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 colonic tumors in rats.Pathol Oncol Res.2012;18(4):817-22.28肿瘤代谢调节疗法编编号分号分组动组动物数量物数量处处理理肿肿瘤形成率瘤形成率1假假处处理理组组10盐盐水注射水注射0WP，能量调节29肿瘤代谢调节疗法能量能量调节调节29肿肿瘤代瘤代谢调节疗谢调节疗法法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.200Colman RJ,et al.Science.2009;325(5937):201-4.31肿瘤代谢调节疗法Colman RJ,et al.Science.200Colman RJ,et al.Science.2009;325(5937):201-4.32肿瘤代谢调节疗法Colman RJ,et al.Science.200Saleh AD,et al.Caloric restriction augments radiation 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Saleh AD,et al.Caloric restr营养途径调节34肿瘤代谢调节疗法营营养途径养途径调节调节34肿肿瘤代瘤代谢调节疗谢调节疗法法MediansurvivalratesPN=12.5(10-15)monthsNoPN=9.0(8-10)monthsShang 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Median survival ratesShang E,Shang E,et al.JPEN.2006;30(3):222-30.生活质量随观察时间的变化*表示两组间有统计学上的显著差异（P0.05）36肿瘤代谢调节疗法Shang E,et al.JPEN.2006;30(营养干预的五阶梯模式能量70%蛋白质100%37肿瘤代谢调节疗法营营养干养干预预的五的五阶阶梯模式能量梯模式能量70%37肿肿瘤代瘤代谢调节疗谢调节疗法法药物调节38肿瘤代谢调节疗法药药物物调节调节38肿肿瘤代瘤代谢调节疗谢调节疗法法10.抑制乳酸代谢39肿瘤代谢调节疗法10.抑制乳酸代抑制乳酸代谢谢 39肿肿瘤代瘤代谢调节疗谢调节疗法法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Sutendra G,Michelakis ED.PyrMei ZB,et al.Survival benefits of metformin for colorectal cancer 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Mei ZB,et al.Survival benefiNoto 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Noto H,et al.Latest insightsHorita N,Miyazawa N,Kojima R,Inoue M,Ishigatsubo Y,Ueda A,Kaneko 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Horita N,Miyazawa N,Kojima RBACKGROUND:There is conflicting evidence for the role of statins in the primary prevention of colorectal cancer(CRC).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 incident 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 confounders 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 effect 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 showed 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,Vekhter 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BACKGROUND:There is conflicti外科调节45肿瘤代谢调节疗法外科外科调节调节45肿肿瘤代瘤代谢调节疗谢调节疗法法肿肿瘤代瘤代谢调节疗谢调节疗法培法培训训ppt课课件件Muzumdar R,et al.Visceral adipose tissue modulates mammalian longevity.Aging Cell.2008;7(3):438-40.Survival curve of the three groups 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Muzumdar R,et al.Visceral adHuffman 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Huffman DM,et al.Cancer Prev运动调节49肿瘤代谢调节疗法运运动调节动调节49肿肿瘤代瘤代谢调节疗谢调节疗法法Fong DY,et al.BMJ.2012;344:e70.15.身体活动50肿瘤代谢调节疗法Fong DY,et al.BMJ.2012;344:Gould DW,Lahart I,Carmichael AR,Koutedakis Y,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Gould DW,Lahart I,Carmichael生物反馈52肿瘤代谢调节疗法生物反生物反馈馈52肿肿瘤代瘤代谢调节疗谢调节疗法法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 observational 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Fig.2 Results:change in exerQuist M,Rrth M,Langer S,Jones LW,Laursen 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)Basemean(SD)Postmean(SD)Change(95%CI)pvalueBMI25.1(5.0)25.3(4.8)0.2(0.3to0.5)0.076LungcapacityFEV11.76(0.70)1.96(0.63)0.20(0.01to0.41)0.061AerobiccapacityVO2peak(L/min)1.48(0.41)1.57(0,41)0.09(0.02to0.16)0.014Functionalcapacity6MWD(m)524.7(88.5)564.0(88.6)39.3(12.5to66.1)0.006MusclestrengthLegpress(kg)70.4(26.9)86.9(28.8)16.5(11.5to21.7)0.000Chestpress(kg)30.8(13.2)40.3(16.3)9.5(6.4to12.7)0.000Latmachine(kg)35.8(13.8)39.2(17.6)3.4(0.0to6.7)0.049Abdominalcrunch(kg)24.9(10.7)29.5(11.3)4.6(3.2to6.0)0.000Lowerback(kg)35.3(14.1)43.1(16.2)7.8(4.8to10.8)0.000Legextension(kg)38.6(15.5)45.1(18.9)6.5(4.1to8.9)0.00054肿瘤代谢调节疗法Quist M,Rrth M,Langer S,Jo疗程与疗效55肿瘤代谢调节疗法疗疗程与程与疗疗效效55肿肿瘤代瘤代谢调节疗谢调节疗法法时机与疗程实施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肿瘤代谢调节疗法时时机与机与疗疗程程56肿肿瘤代瘤代谢调节疗谢调节疗法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肿瘤代谢调节疗法荷瘤患者的代荷瘤患者的代谢调节疗谢调节疗法内容非常丰富，涉及法内容非常丰富，涉及营营养素养素调节调节、能量、能量调节调节58肿瘤代谢调节疗法58肿肿瘤代瘤代谢调节疗谢调节疗法法热烈欢迎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肿瘤代谢调节疗法热热烈烈欢欢迎迎59肿肿瘤代瘤代谢调节疗谢调节疗法法谢谢光临敬请批评指正60肿瘤代谢调节疗法谢谢谢谢光光临临60肿肿瘤代瘤代谢调节疗谢调节疗法法