摘要
目的
研究表明,传统的开腹胃肠外科手术由于手术本身和麻醉的影响,术后一段时间内正常的胃肠运动会受到显著抑制,严重时出现术后胃轻瘫、假性肠梗阻等,其创伤较大而恢复较慢,且患者疼痛不适感持续时间较长,胃肠道功能恢复较慢。腹腔镜胃肠手术创伤小、恢复快、术后并发症少等优点已逐渐成为共识。有研究表明腹部手术后胃肠激素的变化与术后胃肠功能恢复有关,但有关腹腔镜手术后胃肠激素变化的研究报道目前还比较少。为此本研究以腹腔镜与开腹胃癌手术患者为研究对象,测定手术前后血浆胃动素(motilin,MTL)、血管活性肠肽(vasoactive intestine peptide,VIP)和生长抑素(somatostatin,SS)的水平,同时观察术后胃肠道功能恢复情况,探讨腹腔镜胃癌手术后胃肠激素的变化对胃肠功能恢复的影响,以完善腹腔镜胃癌手术的理论依据和为术后恢复提供一定指导意义。
方法
(1)标本收集
血浆标本取自2008年3月至10月在我科行择期手术治疗的胃癌患者,共56例(Ⅰ期-Ⅲa期),其中腹腔镜手术30例,开腹手术26例。两组患者性别、年龄、肿瘤分期、病理类型均无统计学差异。对所有受检者分别在术前、术后24,48,72h抽取空腹静脉血2-4ml,离心分离血浆并置于-80℃冰箱保存待测。所有患者均无腹部手术史,术前无肠梗阻和远处转移,肝肾功能正常,无糖尿病病史。手术前未进行放化疗,未使用影响胃肠动力和胃肠激素的药物。两组患者手术均采用全麻,手术方式均行远端胃癌D2根治术,患者均经术前胃镜和术后病理证实为胃癌。
(2)胃肠激素的测定
MTL、VIP、SS均采用放射免疫法测定,利用液相竞争抑制原理,采用非平衡法分别测定血浆样品中MTL、VIP和SS浓度。
(3)术后胃肠功能恢复情况观察
手术后每2小时听诊患者左右上下腹部四个区域,每区每次听诊3-5分钟,如在两个听诊区域发现肠鸣音≥3次/分钟认为是肠鸣音恢复,并记录时间;同时告之患者记住术后肛门最早排气的具体时间,加以记录。
结果
(1)两组患者均顺利完成腹腔镜或开腹远端胃癌D2根治术,均无并发症。术前腹腔镜组和开腹组之间MTL、VIP和SS血浆水平均无显著差异(P>0.05)。
(2)腹腔镜组术后24,48h血浆MTL水平均较术前显著下降(P<0.05),术后72h恢复至术前水平。开腹组术后24,48,72h血浆MTL水平较术前也显著下降(P<0.05)。与开腹组相比,腹腔镜组术后24,48,72h血浆MTL水平均显著高于同时相开腹组且恢复较快(P<0.05)。
(3)腹腔镜组术后24h血浆VIP水平较术前显著上升(P<0.05),术后48h恢复至术前水平。开腹组术后24,48h血浆VIP水平较术前也显著上升(P<0.05),至术后72h恢复至术前水平。与开腹组相比,腹腔镜组术后24,48h血浆VIP水平均显著低于同时相开腹组且恢复较快(P<0.05)。
(4)腹腔镜组和开腹组手术后血浆SS水平均较术前显著下降(P<0.05),术后两组之间除48h时开腹组高于腹腔镜组之外(P<0.05),其余时相无显著差异(P>0.05)。至术后72h两组血浆SS水平仍显著低于术前水平(P<0.05)。
(5)腹腔镜组术后肠鸣音恢复、首次肛门排气时间均显著早于开腹组(P<0.05)。
(6)术后两组血浆MTL水平与术后肠鸣音恢复、首次肛门排气时间均呈正相关(P<0.05)。术后血浆VIP水平与术后肠鸣音恢复、首次肛门排气时间呈负相关(P<0.05)。SS与术后肠鸣音恢复及首次肛门排气之间无显著相关性(P>0.05)。
结论
(1)腹腔镜胃癌手术对血浆MTL、VIP的影响显著小于开腹胃癌手术,术后血浆MTL、VIP水平恢复均比开腹手术快。
(2)腹腔镜胃癌手术后肠鸣音恢复和首次肛门排气时间均比开腹手术快。
(3)腹腔镜胃癌手术后胃肠功能恢复较开腹手术快,胃肠激素的变化可能是其机制之一。
Objective
Research show that postoperative inhibition of gastrointestinal movement in tradition abdominal surgery is obviously, which was affected by operation and anesthesia. Seriously, there would be postoperative gastroparesis, intestinal pseudo obstruction and so on.Which prolong the recovery time and increase physical pain of the patients. The application of laparoscopy improve the postoperative recovery from reduced trauma and postoperative complications. Reseaches have show that changes of gastrointestinal hormones correlated to the gastrointestinal movement under operation. But few reports concering about the relationship between gastrointestinal hormones and laparoscopic surgery. So we evaluated the changes of serum levels of three gastrointestinal hormones: motilin(MTL), vasoactive intestine peptide(VIP) and somatostatin(SS) in two group of gastric cancer patients, who receiving either radical laparoscopy-assisted or open gastrectomy. Meanwhile the recovery of postoperative gastrointestinal function was also recorded. The purpose of this study was to investigate the changes of gastrointestinal hormones effects on gastrointestinal function postoperative and the possible mechanism after laparoscopy-assisted gastrectomy. We want this research can provide some instructions for further application of laproscopy technology in clinical treatment and postoperative care.
METHODS
(1) Samples collection
This study included two groups of 56 patients with gastric cancer receiving gastrectomy in our department. From March to Octobe 2008, 30 patients were performed by laparoscopy, the other 26 patients received open gastrectomy. Fast venous blood was taken as follow: prior to operation,24h ,48h and 72h after operation. Samples were collected and centrifugated, then separated plasma samples were stocked -80℃until assayed. All patients have no abdominal surgery before this hospitalization, no obstruction and distant metastasis were detected preoperative. Liver and renal function were normal in all patients. Patients had no diabetes, no radiotherapy and chemotherapy preoperative. Drugs affect gastrointestinal motility and secretion of gastrointestinal hormone were permitted perioperative.Two groups were anesthetized under general anesthesia, all patients receive radical distal gastrectomy with D2 lymphadenectomy. The gastric cancer of all patients were diagnosed by endoscopy examination preoperative and pathological biopsy postoperative.
(2) Determination of gastrointestinal hormones
The serum level of MTL, VIP and SS were determined by radioimmunoassay (RIA). Serum levels of MTL,VIP and SS in samples were tested by competitive binding reaction with non-equilibrium method.
(3) Observation of the recovery of gastrointestinal function
Patients were auscultated for as long as five minutes in each of the four quadrants of the abdomen to determine whether bowl sounds were present. We presumed the recovery of bowel sounds only if the bowel sounds were auscultated more than 3 times/min in two or more of the quadrants. The first flatus postoperative was also recorded.
RESULT
(1) Radical distal gastrectomy with D2 lymphadenectomy was performed successfully in all patients either by laparoscopy-assisted or open technology. No specific postoperative complications were observed in patients in hospital. There were no significant difference of serum MTL,VIP and SS levels preoperative between two groups (P>0.05)
(2)Serum levels of MTL in both groups were significantly decreased compared with those of the preoperative period (P<0.05). However levels of MTL in laparoscopic group were higher than those in open group in 24,48 and 72 postoperative hours (P<0.05). They returned to preoperative level at 72h after operation in laparoscopic group, but we did not observe those in open group at the same time.
(3)Meanwhile serum levels of VIP in two groups were significantly higher than those of the preoperative period. The serum VIP levels in laparoscopic group were lower than those date in open group in 24 and 48 postoperative hours (P<0.05). It returned to preoperative levels at 48 hours after operation in laparoscopic group, but the recovery time is 72 hours in open group.
(4) Serum levels of SS in two groups both decreased significant with the levels of preoperative(P<0.05). There were no significant difference of levels of SS postoperative between two groups, except for open group were significant higher than those in laparoscopic group 48 postoperative hours. And the levels of SS were still significant lower than preoperative levels in both groups in 72 postoperative hours.
(5)The recovery time of bowel sounds and first flatus postoperative in laparoscopy group were both significant shorter than the time of open groups (P<0.05).
(6)Postoperative serum levels of MTL were positive correlated with the time of bowel sound recovery and first flatus after operation in two groups(P<0.05). Meanwhile postoperative serum levels of VIP were negative correlated with those date in two groups(P<0.05). But serum levels of SS has no correlation with those date in both groups(P>0.05).
CONCLUSION
(1) Laparoscopy-assisted gastrectomy had significant less effects on serum level of MTL, VIP than open gastrectomy. The recovery time of serum level of MTL and VIP in laparoscopy group were faster than those in open group.
(2) The recovery time of bowel sounds and first flatus postoperative were significant shorter in laparoscopic group.
(3)The recovery period of gastrointestinal movement was shorter in gastric cancer patients treated by laparoscopy than in those by laparotomy. One of the reasons probably correlated with the less changes of some gastrointestinal hormone.
引文
1.黄莚庭.胃肠手术应注意保护胃肠功能.中华胃肠外科杂志, 2001,4(2):69-71.
2. Andersen HK, Lewis SJ, Thomas S. Early enteral nutrition within 24h of colorectal surgery versus later commencement of feeding for postoperative complications. Cochrane Database Syst Rev, 2006(4):CD004080.
3.徐飚,王建明.胃癌流行病学研究.中华肿瘤防治杂志, 2006,13(1):1-7.
4. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol, 2006,12(3):354-62.
5. Brennan MF. Current status of surgery for gastric cancer: a review. Gastric Cancer, 2005,8(2):64-70.
6. Scheidbach H, Schneider C, Hugel O, et al. Oncological quality and preliminary long-term results in laparoscopic colorectal surgery. Surg Endosc, 2003,17(6):903-10.
7.黄志强.外科微创化:21世纪外科的趋向.解放军医学杂志, 2002,27(95-97).
8. Kitano S, Iso Y, Moriyama M, et al. Laparoscopy-assisted Billroth I gastrectomy. Surg Laparosc Endosc, 1994,4(2):146-8.
9.余佩武,罗华星.进展期胃癌腹腔镜根治术的应用进展.中华消化外科杂志, 2007,6(3):166-168.
10. Hao YX, Zhong H, Zhang C, et al. Effects of simulated carbon dioxide and helium peumoperitoneum on proliferation and apoptosis of gastric cancer cells. World J Gastroenterol, 2008,14(14):2241-5.
11. Ziprin P, Ridgway PF, Peck DH, et al. Laparoscopic enhancement of tumour cell binding to the peritoneum is inhibited by anti-intercellular adhesion molecule-1 monoclonal antibody. Surg Endosc, 2003,17(11):1812-7.
12. Leng J, Lang J, Jiang Y, et al. Impact of different pressures and exposure times of a simulated carbon dioxide pneumoperitoneum environment on proliferation and apoptosis of human ovarian cancer cell lines. Surg Endosc,2006,20(10):1556-9.
13. Sumpelmann R, Schuerholz T, Marx G, et al. Haemodynamic, acid-base and blood volume changes during prolonged low pressure pneumoperitoneum in rabbits. Br J Anaesth, 2006,96(5):563-8.
14.胡建昆,周总光,陈志新.腹腔镜结直肠癌手术对机体免疫功能的影响.中华胃肠外科杂志, 2004,7(3):242-243.
15. Ziqiang W, Feng Q, Zhimin C, et al. Comparison of laparoscopically assisted and open radical distal gastrectomy with extended lymphadenectomy for gastric cancer management. Surg Endosc, 2006,20(11):1738-43.
16. Olsson C, Holmgren S. The control of gut motility. Comp Biochem Physiol A Mol Integr Physiol, 2001,128(3):481-503.
17. Madsen D, Sebolt T, Cullen L, et al. Listening to bowel sounds: an evidence-based practice project: nurses find that a traditional practice isn't the best indicator of returning gastrointestinal motility in patients who've undergone abdominal surgery. Am J Nurs, 2005,105(12):40-9; quiz 49-50.
18. Greene FL, Kercher KW, Nelson H, et al. Minimal access cancer management. CA Cancer J Clin, 2007,57(3):130-46.
19. Chi DS, Abu-Rustum NR, Sonoda Y, et al. The safety and efficacy of laparoscopic surgical staging of apparent stage I ovarian and fallopian tube cancers. Am J Obstet Gynecol, 2005,192(5):1614-9.
20. Hasegawa H, Ishii Y, Nishibori H, et al. Short- and midterm outcomes of laparoscopic surgery compared for 131 patients with rectal and rectosigmoid cancer. Surg Endosc, 2007,21(6):920-4.
21.余佩武,王自强,钱锋,等.腹腔镜辅助胃癌根治术105例.中华外科杂志, 2006,44(19):1303-1306.
22. Azagra JS, Ibanez-Aguirre JF, Goergen M, et al. Long-term results of laparoscopic extended surgery in advanced gastric cancer: a series of 101 patients. Hepatogastroenterology, 2006,53(68):304-8.
23. Bauer AJ, Boeckxstaens GE. Mechanisms of postoperative ileus. Neurogastroenterol Motil, 2004,16 Suppl 2:54-60.
24. Mochiki E, Asao T, Kuwano H. Gastrointestinal motility after digestivesurgery. Surg Today, 2007,37(12):1023-32.
25. Hotokezaka M, Mentis EP, Schirmer BD. Gastric myoelectric activity changes following open abdominal surgery in humans. Dig Dis Sci, 1996,41(5):864-9.
26.秦新裕,孙益红,吴肇光,等.不同手术与麻醉方法对手术后胃肠动力的影响.中华医学杂志, 1998,78(4):283.
27. Miedema BW, Johnson JO. Methods for decreasing postoperative gut dysmotility. Lancet Oncol, 2003,4(6):365-72.
28. Uemura K, Tatewaki M, Harris MB, et al. Magnitude of abdominal incision affects the duration of postoperative ileus in rats. Surg Endosc, 2004,18(4):606-10.
29. Cali RL, Meade PG, Swanson MS, et al. Effect of Morphine and incision length on bowel function after colectomy. Dis Colon Rectum, 2000,43(2):163-8.
30.焉鹏.胃肠激素对胃肠运动的调节作用.见:马德胜,周斌,付博,主编.胃肠运动与临床. 1版.北京:军事医学出版社,2006. 74-84.
31.耿玮,曹月敏,常迎彬.腹腔镜与开腹胆囊切除术后胃肠动力恢复的对比研究.中华外科杂志, 1999,37(7):415-417.
32.高羽,张连阳,刘宝华,等.腹腔镜结直肠癌根治术后胃肠运动与血清胃肠激素的变化.第三军医大学学报, 2006,28(6):598-600.
33. Luiking YC, Akkermans LM, van der Reijden AC, et al. Differential effects of motilin on interdigestive motility of the human gastric antrum, pylorus, small intestine and gallbladder. Neurogastroenterol Motil, 2003, 15(2):103-11.
34. Cullen JJ, Eagon JC, Kelly KA. Gastrointestinal peptide hormones during postoperative ileus. Effect of octreotide. Dig Dis Sci, 1994,39(6):1179-84.
35. Onoue S, Misaka S, Yamada S. Structure-activity relationship of vasoactive intestinal peptide (VIP): potent agonists and potential clinical applications. Naunyn Schmiedebergs Arch Pharmacol, 2008,377(4-6):579-90.
36. De Winter BY, Robberecht P, Boeckxstaens GE, et al. Role of VIP1/PACAP receptors in postoperative ileus in rats. Br J Pharmacol, 1998,124(6):1181-6.
37. Kasparek MS, Fatima J, Iqbal CW, et al. Role of VIP and substance P in NANC innervation in the longitudinal smooth muscle of the rat jejunum - influence of extrinsic denervation. J Surg Res, 2007,141(1):22-30.
38. Foxx-Orenstein A, Camilleri M, Stephens D, et al. Effect of a somatostatin analogue on gastric motor and sensory functions in healthy humans. Gut, 2003,52(11):1555-61.
39. Tomita R, Fujisaki S, Tanjoh K, et al. Studies on gastrointestinal hormone and jejunal interdigestive migrating motor complex in patients with or without early dumping syndrome after total gastrectomy with Roux-en-Y reconstruction for early gastric cancer. Am J Surg, 2003,185(4):354-9.
40. Mochiki E, Nakabayashi T, Kamimura H, et al. Gastrointestinal recovery and outcome after laparoscopy-assisted versus conventional open distal gastrectomy for early gastric cancer. World J Surg, 2002,26(9):1145-9.
41. Luo K, Li JS, Li LT, et al. Operative stress response and energy metabolism after laparoscopic cholecystectomy compared to open surgery. World J Gastroenterol, 2003,9(4):847-50.
42.龙跃瓶,韩高雄.微创外科技术在胃肠外科中的应用及其局限性.腹部外科, 2008,21(1):13-14.
43. Baig MK, Wexner SD. Postoperative ileus: a review. Dis Colon Rectum, 2004,47(4):516-26.
44. Kehlet H. Fast-track colorectal surgery. Lancet, 2008,371(9615):791-3.
45. Shiraishi N, Yasuda K, Kitano S. Laparoscopic gastrectomy with lymph node dissection for gastric cancer. Gastric Cancer, 2006,9(3):167-76.
1.焉鹏.胃肠激素对胃肠运动的调节作用.见:马德胜,周斌,付博,主编.胃肠运动与临床. 1版.北京:军事医学出版社,2006. 74-84.
2. LijianW, Lv Z, Rui T. Role of the area postrema of medulla oblongata in the regulation of canine interdigesting migrating motor complex. ChinMed J, 2002,115(384-388).
3.工志刚,刘凤林,秦新裕.胃动素受体的研究进展. Foreign Medical Sciences on Pharmacy, 2001,10:344-346.
4. Yang M, Fang DC, Li QW, et al. Effects of gastric pacing on gastric emptying and plasma motilin. World J Gastroenterol, 2004,10(3):419-23.
5. Boivin M, Bradette M, Raymond MC, et al. Mechanisms for postprandial release of motilin in humans. Dig Dis Sci, 1992,37(10):1562-8.
6. Storr M, Sattler D, Hahn A, et al. Endogenous CCK depresses contractile activity within the ascending myenteric reflex pathway of rat ileum. Neuropharmacology, 2003,44(4):524-32.
7. Zerbib F, Bruley Des Varannes S, Scarpignato C, et al. Endogenous cholecystokinin in postprandial lower esophageal sphincter function and fundic tone in humans. Am J Physiol, 1998,275(6 Pt 1):G1266-73.
8. Wu CL, Doong ML, Wang PS. Involvement of cholecystokinin receptor in the inhibition of gastrointestinal motility by oxytocin in ovariectomized rats. Eur J Pharmacol, 2008,580(3):407-15.
9. Fornai M, Colucci R, Antonioli L, et al. Cholecystokinin CCK2 receptors mediate the peptide's inhibitory actions on the contractile activity of human distal colon via the nitric oxide pathway. Br J Pharmacol, 2007, 151(8):1246-53.
10. Guilloteau P, Le Meuth-Metzinger V, Morisset J, et al. Gastrin, cholecystokinin and gastrointestinal tract functions in mammals. Nutr Res Rev, 2006,19(2):254-83.
11. Kostic N, Ratkovic M, Novakovic R, et al. Relation between pyloric dysmotility and serum levels of gastrin, somatostatin and vasoactiveintestinal polypeptide in patients with non-insulin dependent diabetes mellitus. Med Pregl, 1995,48(5-6):149-51.
12.秦新裕,雷勇.胃肠肽激素与胃肠动力.中国实用外科杂志, 2001,21(6):229-231.
13. Kasparek MS, Fatima J, Iqbal CW, et al. Role of VIP and substance P in NANC innervation in the longitudinal smooth muscle of the rat jejunum - influence of extrinsic denervation. J Surg Res, 2007,141(1):22-30.
14. Onoue S, Misaka S, Yamada S. Structure-activity relationship of vasoactive intestinal peptide (VIP): potent agonists and potential clinical applications. Naunyn Schmiedebergs Arch Pharmacol, 2008,377(4-6):579-90.
15. De Winter BY, Robberecht P, Boeckxstaens GE, et al. Role of VIP1/PACAP receptors in postoperative ileus in rats. Br J Pharmacol, 1998,124(6):1181-6.
16. Dejda A, Sokolowska P, Nowak JZ. Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. Pharmacol Rep, 2005,57(3):307-20.
17. Green ED, Maffei M, Braden VV, et al. The human obese (OB) gene: RNA expression pattern and mapping on the physical, cytogenetic, and genetic maps of chromosome 7. Genome Res, 1995,5(1):5-12.
18. Bado A, Levasseur S, Attoub S, et al. The stomach is a source of leptin. Nature, 1998,394(6695):790-3.
19. Smedh U, Hakansson ML, Meister B, et al. Leptin injected into the fourth ventricle inhibits gastric emptying. Neuroreport, 1998,9(2):297-301.
20. Barrachina MD, Martinez V, Wei JY, et al. Leptin-induced decrease in food intake is not associated with changes in gastric emptying in lean mice. Am J Physiol, 1997,272(3 Pt 2):R1007-11.
21.周吕,袁勃,王礼建等.瘦素对大鼠胃运动功能的影响.生理通讯, 2004,23(1):7-8.
22. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 1999,402(6762):656-60.
23. Gaytan F, Barreiro ML, Caminos JE, et al. Expression of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in normal human testis and testicular tumors. J Clin Endocrinol Metab,2004,89(1):400-9.
24. Tack J, Depoortere I, Bisschops R, et al. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut, 2006,55(3):327-33.
25. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature, 2001,409(6817):194-8.
26. Qiu WC, Wang ZG, Lv R, et al. Ghrelin improves delayed gastrointestinal transit in alloxan-induced diabetic mice. World J Gastroenterol, 2008,14(16):2572-7.
27. Shinomiya T, Fukunaga M, Akamizu T, et al. Plasma acylated ghrelin levels correlate with subjective symptoms of functional dyspepsia in female patients. Scand J Gastroenterol, 2005,40(6):648-53.
28. Traverso LW, Hashimoto Y. Delayed gastric emptying: the state of the highest level of evidence. J Hepatobiliary Pancreat Surg, 2008,15(3):262-9.
29. Foxx-Orenstein A, Camilleri M, Stephens D, et al. Effect of a somatostatin analogue on gastric motor and sensory functions in healthy humans. Gut, 2003,52(11):1555-61.
30. Harris AG. Somatostatin and somatostatin analogues: pharmacokinetics and pharmacodynamic effects. Gut, 1994,35(3 Suppl):S1-4.
31. Scheurer U, Drack E, Halter F. Substance P activates rat colonic motility via excitatory and inhibitory neural pathways and direct action on muscles. J Pharmacol Exp Ther, 1994,271(1):7-13.
32. Guagnini F, Valenti M, Mukenge S, et al. Neural contractions in colonic strips from patients with diverticular disease: role of endocannabinoids and substance P. Gut, 2006,55(7):946-53.
33. Schirra J, Houck P, Wank U, et al. Effects of glucagon-like peptide-1(7-36)amide on antro-pyloro-duodenal motility in the interdigestive state and with duodenal lipid perfusion in humans. Gut, 2000,46(5):622-31.
34. Andrews CN, Bharucha AE, Camilleri M, et al. Effects of glucagon-like peptide-1 and sympathetic stimulation on gastric accommodation in humans. Neurogastroenterol Motil, 2007,19(9):716-23.
35. Hellstrom PM, Naslund E, Edholm T, et al. GLP-1 suppresses gastrointestinal motility and inhibits the migrating motor complex in healthy subjects and patients with irritable bowel syndrome. Neurogastroenterol Motil, 2008,20(6):649-59.
1. Kojima M, Hosoda H, Date Y, et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 1999,402(6762):656-60.
2. Hosoda H, Kojima M, Mizushima T, et al. Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem, 2003,278(1):64-70.
3. Jeon TY, Lee S, Kim HH, et al. Changes in plasma ghrelin concentration immediately after gastrectomy in patients with early gastric cancer. J Clin Endocrinol Metab, 2004,89(11):5392-6.
4. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab, 2002,87(6):2988.
5. Kojima M, Hosoda H, Matsuo H, et al. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol Metab, 2001,12(3):118-22.
6. Muccioli G, Tschop M, Papotti M, et al. Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol, 2002,440(2-3):235-54.
7. Frohman LA, Kineman RD, Kamegai J, et al. Secretagogues and the somatotrope: signaling and proliferation. Recent Prog Horm Res, 2000,55:269-90; discussion 290-1.
8. Nanzer AM, Khalaf S, Mozid AM, et al. Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway. Eur J Endocrinol, 2004,151(2):233-40.
9. Ostergard T, Hansen TK, Nyholm B, et al. Circulating ghrelin concentrations are reduced in healthy offspring of Type 2 diabetic subjects, and are increased in women independent of a family history of Type 2 diabetes. Diabetologia, 2003,46(1):134-6.
10. Qiu WC, Wang ZG, Lv R, et al. Ghrelin improves delayed gastrointestinaltransit in alloxan-induced diabetic mice. World J Gastroenterol, 2008,14(16):2572-7.
11. Leontiou CA, Franchi G, Korbonits M. Ghrelin in neuroendocrine organs and tumours. Pituitary, 2007,10(3):213-25.
12. Zhang YF, Wang HN, Hong TP. [Ghrelin expression in the tissues of different thyroid diseases]. Beijing Da Xue Xue Bao, 2006,38(2):193-6.
13. Volante M, Allia E, Fulcheri E, et al. Ghrelin in fetal thyroid and follicular tumors and cell lines: expression and effects on tumor growth. Am J Pathol, 2003,162(2):645-54.
14. Barreiro ML, Gaytan F, Castellano JM, et al. Ghrelin inhibits the proliferative activity of immature Leydig cells in vivo and regulates stem cell factor messenger ribonucleic acid expression in rat testis. Endocrinology, 2004,145(11):4825-34.
15. Cassoni P, Allia E, Marrocco T, et al. Ghrelin and cortistatin in lung cancer: expression of peptides and related receptors in human primary tumors and in vitro effect on the H345 small cell carcinoma cell line. J Endocrinol Invest, 2006,29(9):781-90.
16. Dixit VD, Weeraratna AT, Yang H, et al. Ghrelin and the growth hormone secretagogue receptor constitute a novel autocrine pathway in astrocytoma motility. J Biol Chem, 2006,281(24):16681-90.
17. Gaytan F, Barreiro ML, Caminos JE, et al. Expression of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in normal human testis and testicular tumors. J Clin Endocrinol Metab, 2004,89(1):400-9.
18. Jeffery PL, Herington AC, Chopin LK. Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines. J Endocrinol, 2002,172(3):R7-11.
19. Jeffery PL, Murray RE, Yeh AH, et al. Expression and function of the ghrelin axis, including a novel preproghrelin isoform, in human breast cancer tissues and cell lines. Endocr Relat Cancer, 2005,12(4):839-50.
20. Murata M, Okimura Y, Iida K, et al. Ghrelin modulates the downstreammolecules of insulin signaling in hepatoma cells. J Biol Chem, 2002,277(7):5667-74.
21. Duxbury MS, Waseem T, Ito H, et al. Ghrelin promotes pancreatic adenocarcinoma cellular proliferation and invasiveness. Biochem Biophys Res Commun, 2003,309(2):464-8.
22. Aydin S, Ozercan IH, Dagli F, et al. Ghrelin immunohistochemistry of gastric adenocarcinoma and mucoepidermoid carcinoma of salivary gland. Biotech Histochem, 2005,80(3-4):163-8.
23. Mottershead M, Karteris E, Barclay JY, et al. Immunohistochemical and quantitative mRNA assessment of ghrelin expression in gastric and oesophageal adenocarcinoma. J Clin Pathol, 2007,60(4):405-9.
24. An JY, Choi MG, Noh JH, et al. Clinical significance of ghrelin concentration of plasma and tumor tissue in patients with gastric cancer. J Surg Res, 2007,143(2):344-9.
25. Waseem T, Javaid-Ur-Rehman, Ahmad F, et al. Role of ghrelin axis in colorectal cancer: a novel association. Peptides, 2008,29(8):1369-76.
26. Waseem T. Commentary: Ghrelin's role in gastrointestinal tract cancer. Surg Oncol, 2009.
27. Espelund U, Hansen TK, Orskov H, et al. Assessment of ghrelin. APMIS Suppl, 2003(109):140-5.