【作者】 王凯旋；

【导师】 金震东； 李兆申； 邹多武； 高军；

【作者基本信息】 第二军医大学 ， 内科学， 2008， 博士

【摘要】 腹痛是胰腺癌患者最突出的症状。诊断时有75%的患者主诉有腹痛,而对于晚期胰腺癌患者腹痛出现的比例超过90%,胰腺癌疼痛往往剧烈而顽固,显著增加体力及机体消耗,生活质量差,因此,姑息性治疗的主要方面就是有效控制疼痛,改善患者生活质量。目前治疗疼痛的主要途径是基于世界卫生组织（WHO）2000年所公布的癌性疼痛三级阶梯治疗方案,但有时这种治疗并不能相应改善疼痛,或者由于阿片类药物相关副反应诸如便秘、恶心抑郁等限制了所使用药物的剂量。胰腺癌疼痛的传导是通过腹腔神经丛（celiac ganglion,CG）换元后再上传中枢从而产生疼痛感觉,因此腹腔神经丛阻滞（celiac plexus neurolysis,CPN）可通过阻断感觉神经的传导而达到止痛目的。目前神经破坏剂国内外绝大多数使用无水酒精。荟萃分析显示与口服止痛药相比,腹腔神经丛阻滞术虽能有效缓解疼痛,但视觉模拟评分较术前仅减少6%;持续时间不长,仅8周左右,65%患者临终前有中到重度疼痛,10%需要再次行腹腔神经丛阻滞术。另外由于无水酒精瞬间阻断交感神经占优势的神经丛,从而出现体位性低血压、腹泻的副反应,一些严重的并发症如截瘫、后腹膜出血等也有陆续报道。行腹腔神经丛阻滞术的方法有多种,包括开腹手术术中注射、B超引导下、CT引导下以及超声内镜引导下注射。文献报道止痛疗效在各种方法间无差异性。对行腹腔神经丛阻滞术患者尸检后发现无水酒精仅能破坏神经外膜,神经纤维内部以及神经元均完好无损,胰腺癌很容易侵犯后腹膜及腹腔干,而当腹腔干受肿瘤侵犯时会严重影响无水酒精的渗透性,对于这种病人采用无水酒精腹腔神经丛阻滞术几乎没有疗效,因此寻找一种能更好更彻底的破坏神经元而安全性更高的办法对于缓解疼痛、改善胰腺癌患者生存质量具有显著意义。胰内小神经被肿瘤细胞及免疫细胞浸润,导致神经的局部微环境的稳定性受到破坏,使其对一些致痛介质的敏感性增加是胰腺癌疼痛的重要发生机制。研究表明对胰腺癌行外照射也可有效缓解疼痛,尤其是腹腔神经丛阻滞术后腹痛又复发的患者,我们前期的研究发现在胰腺癌瘤体内种植¹²⁵I放射性粒子具有止痛效果,这些结果均说明内外照射对胰内小神经有破坏作用。¹²⁵I有很长的半衰期（59.7 d）,持续低剂量释放γ射线,不会瞬间破坏腹腔神经丛,因此理论上不会出现交感神经阻断后所出现的腹泻、体位性低血压等相关症状。¹²⁵I放射性粒子照射腹腔神经丛对神经元是否也有破坏作用目前未见报道。腹腔神经丛毗邻腹主动脉、腹腔干、胃、胰腺、肾上腺等重要器官,内照射其安全性如何尚有待进一步研究。因此本研究拟采用EUS引导下的¹²⁵I放射性粒子腹腔神经丛旁植入术进行实验及临床研究,全面评价其安全性和疗效,共分四个部分,分述如下:一、猪作为超声内镜引导下腹腔神经丛穿刺术模型的实验研究目的:我们对健康家养猪进行超声内镜引导下腹腔神经丛旁穿刺操作,探讨其可行性及应用价值。方法:5只健康家养猪用于研究,术前肌内注射盐酸氯胺酮10mg/kg镇静,动物安静后给予静脉缓慢注射3%戊巴比妥钠0.8ml/kg。麻醉稳定后进行穿刺操作并植入空粒子,术后行CT增强扫描以辅助判断穿刺是否成功。结果:两组动物都没有出现死亡,1只家猪穿刺后CT扫描发现粒子在胃腔内,隔日再行穿刺种植粒子成功,其余动物均一次穿刺成功,行CT增强扫描,发现粒子定位准确,均匀分布于腹主动脉腹腔干起始部的两侧。结论:家猪的解剖结构与人类及其相似,可作为初学者进行超声内镜引导下腹腔神经丛穿刺术培训的理想动物模型。同时通过本研究积累了较多宝贵的原始资料和经验教训,而且对操作过程中的细丛问题进行了详细描述并找到了解决方案,为进一步开展该项操作技能培训打下坚实的基础。二、超声内镜引导下碘125放射性粒子腹腔神经丛照射的安全性研究目的:选择家猪作为动物模型行超声内镜引导下¹²⁵I放射性粒子腹腔神经丛旁种植,对这种方法的安全性做一初步评估。方法:14只家猪随机分成四组:A组,n=4,拟行空粒子种植对照;B组,n=4,选择放射活度为0.4mci的¹²⁵I放射性粒子种植;C组,n=4,选择放射活度为0.8mci的¹²⁵I放射性粒子种植,D组,n=2,行无水乙醇腹腔神经丛阻滞术。A、B、C三组家猪均在静脉麻醉后行超声内镜引导下粒子双侧植入,术后摄腹部平片和CT增强扫描以及血管三维重建辅助判断种植的准确性,术前,术后24小时及7天抽血化验血常规,术前和术后随访期结束抽血检查肝肾功能、血淀粉酶以及CD4、CD8值等免疫指标。术后14天、60天分批处死解剖观察粒子有无移位、丢失,周围血管有无破裂、血肿形成,周围脏器有无炎症,渗出,穿孔,粘连等表现,取材送病理检测,D组单侧注射无水乙醇5毫升,术后7天解剖取材。结果:A组1只与C组中1只种植失败（16.7%）,隔日再行补中均成功,其余粒子均一次性植入,定位良好,除C组中1只术后7天出现白细胞升高,解剖发现局部小脓肿形成外,其余家猪血常规、肝肾功能、血淀粉酶以及CD4、CD8值穿刺前后均无差异。病理检测显示周围脏器均无异常发现,与对照组相比,经受¹²⁵I放射性粒子照射的血管外膜有变性坏死,并伴随轻微炎性反应,周围有纤维组织增生,程度随照射剂量的增加而略有加重,血管肌层、内膜及内膜弹力层均未受任何影响,血管内未见血栓形成,照射时间为60天的家猪其血管外膜的纤维组织增生较14天更为明显。CPN术的家猪解剖发现其腹腔干呈淡褐色,较正常粗大,病理发现血管外膜及周围纤维结缔组织坏死出血明显,大量炎症细胞浸润。结论:超声内镜引导下¹²⁵I放射性粒子腹腔神经丛旁种植是安全的,放射性粒子对周围脏器没有影响,不会损害其免疫功能,对血管有一定的损伤作用,但作用有限,较无水乙醇对血管的损伤小。三、超声内镜引导下碘125放射性粒子腹腔神经丛照射的有效性研究目的:观察¹²⁵I放射性粒子对腹腔神经丛及神经纤维的影响。方法:14只家猪随机分成四组:A组,n=4,拟行空粒子种植对照;B组,n=4,选择放射活度为0.4mci的¹²⁵I放射性粒子种植;C组,n=4,选择放射活度为0.8mci的¹²⁵I放射性粒子种植;D组,n=2,行无水乙醇腹腔神经丛阻滞术。A、B、C三组家猪均在静脉麻醉后行超声内镜引导下粒子双侧植入,D组单侧注射无水乙醇5毫升,术后取腹腔神经丛分别行HE染色、TUNEL、尼氏染色观察细胞坏死凋亡情况,行免疫组织化学检测白细胞介素-1β的表达情况。结果:与对照组相比,¹²⁵I组可见神经元和神经纤维细胞凋亡增加,以神经元凋亡更为明显,神经元尼氏小体减少,免疫组化发现,白细胞介素-1β主要表达于胞浆,¹²⁵I组阳性表达增加,高剂量组较低剂量组阳性表达更为明显,但14天组与60天组表达无明显差异,CPN组仅见神经丛外周少量神经元凋亡,神经纤维凋亡不明显,尼氏小体与对照组相比无差异,白细胞介素-1β轻度表达。结论:内照射可诱导腹腔神经丛以及神经纤维细胞坏死凋亡,因此通过超声内镜引导下¹²⁵I放射性粒子内照射腹腔神经丛的方法可以有效缓解疼痛,而无水乙醇对神经丛及神经纤维作用有限。四、声内镜引导下碘125放射性粒子腹腔神经丛照射治疗晚期胰腺癌疼痛的临床研究目的:选择晚期胰腺癌疼痛患者行超声内镜引导下¹²⁵I放射性粒子腹腔神经丛照射,观察止痛疗效以及相关并发症情况。方法:对3例晚期胰腺癌患者静脉麻醉下行超声内镜引导下¹²⁵I放射性粒子腹腔神经丛种植术,术后进行随访,观察视觉模拟评分、止痛药物剂量变化,并记录并发症情况,随访终点为患者死亡。结果:3例患者均为单侧种植,平均植入放射活度为0.7mci粒子3颗（2-5颗）,一例肝转移患者术后腹痛无明显改善,其余两例均在术后2周开始腹痛缓解,吗啡类止痛药物剂量明显减少,所有患者均未出现任何并发症。结论:初步研究结果显示,超声内镜引导下¹²⁵I放射性粒子腹腔神经丛照射是安全的,具有一定的止痛效果。总结:家猪解剖结构与人及其相似,可作为初学者进行超声内镜引导下腹腔神经丛穿刺术培训的理想动物模型。实验研究表明超声内镜引导下¹²⁵I放射性粒子腹腔神经丛照射是安全而有效的。居于实验研究基础上所开展的临床试验结果也初步验证了这一观点。更多还原

【Abstract】 BackgroundAbdominal discomfort is a predominant symptom in patients with pancreatic cancer. Approximately 75%have pain at diagnosis and over 90%in advanced stages.The pain has been the chief complaint of the patients with PC,which has significantly decreased their life quality.Thus,to improve the living quality of patients with PC has become the main task for palliative treatment.The standard approach to pain management is based on the World Health Organization(WHO) 3-step ladder,beginning with nonopioid analgesics, followed by weak opioids,and finally,strong opioids as necessary.Virtually all patients require escalating doses of opioids.At times,systemic analgesics do not provide adequate pain relief,or doses are limited by opioid-related adverse effects,opiates present significant number of physical and psychological complications,including drowsiness, constipation,vomiting,deteriorated communication with family and depression.Celiac ganglia can transmit pain signals from the pancreas and most of the upper abdominal viscera.Stimuli reach the thalamus and cortex of the brain,and this information is perceived as pain.Then,neurolytic celiac plexus blockade(NCPB)can inhibit the transmiting of pain signal,alcohol is favored because it induces greater neurolysis and presumably greater pain relief.meta-analysis has shown that NCPB was associated with a statistically significant improvement in pain control compared with standard treatment. The overall benefit,however,was small- a 6%reduction in mean visual analogue scale (VAS) and reduced narcotic usage and constipation compared with standard treatment,The benefit of EUS NCPB diminished at 8 weeks,65%of patients suffered moderate to severe abdominal pain before death and 10%of them need rescue NCPB.Pooled data from the RCTs showed a low rate of adverse events:diarrhea,transient hypotension,constipation, nausea and vomiting.However serious NCPB related adverse events were also reported such as paraplegina,postperitoneal hemorrhage,fistula formation,gastroparesis,anterior spinal artery syndrome,aortic dissection or pseudoaneurysm,pleural effusion,and death. Although NCPB can be guided by intraoperative,Ultrasound,Computed tomography (CT),Endoscopic ultrasound,the effect for control of pain have no difference.Post-mortem neurohistopathologic examination of the celiac plexus revealed an abnormal celiac architecture with a combination of abnormal neurons with vacuolization and normal looking neuronal structures(ganglionic structures and nerve fibers) embedded in fibrotic hyalinized tissue.This show that a neurolytic celiac plexus block with alcohol is capable of partially destroying the celiac plexus.As the invasion grade increased,the effectiveness of the procedure decreased,especially when the celiac ganglia region was totally invaded. This result indicate that the effectiveness of the procedure decreases as the grade of celiac ganglia invasion increases.Therefore,it is necessary to find a new method for better pain control and Quality Of Life(QOL) improving in patients of pancreatic cancer.Perineural cancer cell invasion is one of the most intriguing characteristics of this neoplasia and may in some cases explain the pain sensation.In addition,it is likely that macrophages and other inflammatory or immune cells play a role in initiating and maintaining pancreatic cancer pain.This can destroy the microenvironment of nerve fiber and more sensitive to some mediators such as serum P substance and capsaicine that be involved in the sensitization and activation of nociceptors in pancreatic cancer.External irradiation has some effect on pain control in patients of pancreatic cancer.We have also reported that Endoscopic ultrasound-guided interstitial implantation of iodine 125 seeds could improve in pain control.Those results demonstrate that radiotherapy can destroy mtrapancreatic nerve fibers.Iodine-125 has a very long half life time(59.7d),and continueously releaseγray in a very low dose.As far as we know,there are no report on celiac plexus radiation with iodine125 seeds in the treatment the pain of advanced pancreatic carcinoma.Celiac plexus is adjacent to celiac artery,celiac trunk,stomach and adrenal gland,the safety of celiac plexus brachytherapy need to be concerned.Present study was designed to assess the safety and curative effect Or,EUS guided celiac plexus brachytherapy and consisted of four main parts.They are as follows:1.Experimental study of porcine model for Endoscopic ultrasound guided-celiac plexus paracentesisObjective:Endoscopic ultrasound guided-celiac plexus paracentesis was performed in pigs to discuss the feasibility and applied value of it.Methods.Five healthy pigs were used in this study,3%pentobarbital(0.8ml/kg)was injected into the vein after sedation with an intramuscular injection of 10mg/kg Ketamin.When the pig was in stable anesthesia,we carded out EUS and implanted empty seeds on both side of celiac trunk.Cardiac and respiratory parameters were monitored throughout the procedures.After procedure, enhancement scanning was performed to help decide whether the procedure was successful.Results:There were no deaths in all pigs.All but one procedure were performed successfully.The seed was found in stomach wall by CT scan in one pig and was carried out EUS again in another day and the procedure was successful.All seeds were located in both side of the celiac trunk.Conclusion:Find a more simple anaesthetic method for EUS in pigs than before;The anatomic structure of pig is very similar of human and it is an excellent model for EUS guided celiac plexus paracentesis.It is feasible for novice endoscopist to learn this technique.We have also accumulated many primary data through this study which is very useful for carrying out technical skill training in china.2.Safety of Endoscopic ultrasound guided Celiac Plexus Radiation with Iodine125 Seeds in porcine modelObjective:Because important organs adjacent to celiac plexus,such as celiac artery,celiac trunk,stomach and adrenal gland,so the aim of this study was to assess safety of Endoscopic ultrasound guided- celiac plexus radiation with Iodine125 Seeds in porcine model.Methods:Fourteen healthy pigs were used in this study,All pigs were divided into four groups.In the control group,(n=4) with two non-radioactive seeds implanted in both side of celiac trunk.In Group B(n=4),the radioactivity of the seeds was 0.4 mCi,and 0.8mci in Group C(n=4),In Group D,5ml dehydrated alcohol was injected in either side of celiac plexus.The seeds or alcohol were implanted or injected near the pig’s celiac plexus by means of endoscopic ultrasound procedure.At the time of preoperative,24h,7days after implantation,blood tests were conducted.Liver and renal function,hemodiastase and CD4/CD8 were examined at the time of preoperative and the end of follow-up duration. After implantation of the seed 14days and 60days or injection of dehydrated alcohol 7days in Group D,pigs were euthanized in batch.All animals underwent a post mortem to exclude intra-abdominal hemorrhage,infection,or peritonitis.During autopsy,the liver, celiac artery,celiac trunk,stomach and adrenal were examined.Results:The procedures were succeeded in 12 pigs(85.7%).Two pigs were fall to implant in correct location.The rescue procedure was performed in another day and both were succeeded.One pig had infection surrounding the left of the seed.There were no effusion,hemorrhage or necrosis in the adjacent stomach,liver or adrenal.Effect on blood vessel was very limited.Blood tests did not detect any obvious abnormality during the follow-up period.But in animals performed alcohol injection,obvious hemorrhage external coat of celiac trunk was observed.Conclusion:These results indicated that the radiation were safe in all dose groups,Moreover,these studies suggest that it is feasible for future clinical application.3.Efficacy of Endoscopic ultrasound guided Celiac Plexus Radiation with Iodine 125 Seeds in porcine model Objective:The aim of this study was to observe the efficacy Of brachytherapy on celiac plexus and celiac plexus.Methods:Fourteen healthy pigs were used in this study,All pigs were divided into four groups.In the control group,(n=4) with two non-radioactive seeds implanted in both side of celiac trunk.In Group B(n=4),the radioactivity of the seeds was 0.4 mCi,and 0.8mci in Group C(n=4).In Group D,5ml dehydrated alcohol was injected in either side of celiac plexus.The seeds or alcohol were implanted or injected near the pig’s celiac plexus by means of endoscopic ultrasound procedure.After implantation of the seed 14days and 60days,pigs were euthanized in batch.During autopsy, celiac plexus was removed and examined by HE staining,TUNEL,and Nissl’s staining, interleukin-1β(IL-1β) was detected by immtmohistochemistry.Results:apoptosis of neuron and neurofibra were significantly increased in brachytherapy group than in control group and Nissl’s body were decreased.Immunohistochemistry demonstrated that IL-1βwere presented in ndochylema and expressed more positive in high dose group than low dose group and.But it was no difference between 14days and 60days follow-up.In CPN group,very few apoptosis of neuron and neurofibra were observed,and Nissrs body was as normal as the control group,IL-1βwere expressed a little positive in both neuron and neurofibra.Conclusion:Brachytherapy can cause apoptosis of neuron and neurofibra.It can be inferred that brachytherapy of celiac plexus could relieve the pain of advanced pancreatic cancer.4.Endoscopic Ultrasound-guided Celiac Plexus Radiation with lodine125 Seeds in the Treatment the Pain of Advanced Pancreatic Carcinoma:A PreliminaryObservation.Objective:The aim of this study was to assess the efficiency and safety of celiac plexus radiation in patients of advanced pancreatic cancer who suffered pain.Methods:Three patients with unresectable pancreatic carcinoma who suffered pain were enrolled. EUS-guided Iodine-125 seed were implanted in one side of the celiac plexus.All patients were involved in follow up after the therapy.The principal indexes of assessing the curative effect including the change of visual analogue score(VAS),dose of analgesic drug, and the complication were also observed.Results:All patients were implanted Iodine-125 seed successfully,A median of 3 seeds(range,2-5) was implanted per patient,with an average activity per seed of 2.1 mCi(1.4-3.5mci).One patient who had liver metastasis had no change of abdominal pain.Pain started to relieve after two weeks in other two patients.The dose of analgesic drug was significantly decreased,and no complications recorded.Conclusion:Endoscopic ultrasongraphy-guided celiac plexus radiation with iodine 125 Seeds in the treatment the pain of advanced pancreatic carcinoma is relatively safe and effective.In short,the anatomic structure of pig is very similar of human and it is an excellent model for EUS guided celiac plexus paracentesis.It can be concluded from our study that endoscopic ultrasound-guided celiac plexus radiation with iodine125 seeds in the treatment the pain of advanced pancreatic carcinoma is relatively safe and effective.更多还原