| 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.
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