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Anterior Cingulate Cortex Mediates Hyperalgesia and Anxiety Induced by Chronic pancreatitis in Rats

Neuroscience Bulletin 2022年第4期38卷 342-358页

作者： Dan Ren Jia-Ni Li Xin-Tong Qiu Fa-Ping Wan Zhen-Yu Wu Bo-Yuan Fan Ming-Ming Zhang Tao Chen Hui Li Yang Bai Yun-Qing Li Department of Anatomy Guangxi Medical UniversityNanning 510000China Department of Anatomy Histology and Embryology and K.K.Leung Brain Research CentreFourth Military Medical UniversityXi’an 710032China Department of Anatomy Xuzhou Medical UniversityXuzhou 221004China Department of Cardiology The Second Affiliated Hospital of Xian Jiaotong UniversityXi’an 710004China Department of Neurosurgery General Hospital of Northern Theater CommandShenyang 110016China Key Laboratory of Brain Science Research and Transformation in Tropical Environment of Hainan Province Haikou 570216China Department of Human Anatomy College of Basic MedicineDali UniversityDali 671000China

Central sensitization is essential in maintaining chronic pain induced by Chronic pancreatitis(CP),but cortical modulation of painful CP remains elusive.Here,we examined the role of the anterior cingulate cortex(ACC)in the pathogenesis of abdominal hyperalgesia in a rat model of CP induced by intraductal administration of trinitrobenzene sulfonic acid(TNBS).TNBS treatment resulted in long-term abdominal hyperalgesia and anxiety in rats.Morphological data indicated that painful CP induced a significant increase in FOS-expressing neurons in the nucleus tractus solitarii(NTS)and ACC,and some FOS-expressing neurons in the NTS projected to the ACC.In addition,a larger portion of ascending fibers from the NTS innervated pyramidal neurons,the neural subpopulation primarily expressing FOS under the condition of painful CP,rather than GABAergic neurons within the ACC.CP rats showed increased expression of vesicular glutamate transporter 1,and increased membrane trafficking and phosphorylation of the N-methyl-D-aspartate receptor(NMDAR)subunit NR2B and theα-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor(AMPAR)subunit GluR1 within the ACC.Microinjection of NMDAR and AMPAR antagonists into the ACC to block excitatory synaptic transmission significantly attenuated abdominal hyperalgesia in CP rats,which was similar to the analgesic effect of endomorphins injected into the ACC.Specifically inhibiting the excitability of ACC pyramidal cells via chemogenetics reduced both hyperalgesia and comorbid anxiety,whereas activating these neurons via optogenetics failed to aggravate hyperalgesia and anxiety in CP rats.Taken together,these findings provide neurocircuit,biochemical,and behavioral evidence for involvement of the ACC in hyperalgesia and anxiety in CP rats,as well as novel insights into the cortical modulation of painful CP,and highlights the ACC as a potential target for neuromodulatory interventions in the treatment of painful CP.

关键词： Chronic pancreatitis Anterior cingulate cortex Nucleus tractus solitaries Hyperalgesia Anxiety

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Natural history,clinical characteristics,outcomes,and long-term follow-up of pain-free Chronic pancreatitis

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Gastroenterology Report 2023年第1期11卷 309-315页

作者： Awais Ahmed Ishani Shah Rachel Bocchino Steven D.Freedman Darshan J.Kothari Sunil G.Sheth Department of Medicine Division of GastroenterologyBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Department of Medicine Division of Internal MedicineBeth Israel Deaconess Medical CenterHarvard Medical SchoolBostonMAUSA Department of Medicine Division of GastroenterologyDuke UniversityDurhamNCUSA

Background:Chronic pancreatitis(CP)is characterized by chronic abdominal pain and functional insufficiency.However,a small subset of patients with prior acute pancreatitis(AP)and/or underlying risk factors for developing CP may be pain-free at diagnosis and may have a different clinical course.We aimed to compare the clinical characteristics,outcomes,and healthcare utilization between CP patients with and without pain.Methods:Reviewed patients with established CP were followed in our Pancreas Center between January 2016 and April 2021.Patients without risk factors for developing CP and/or without AP prior to their diagnosis and only with incidental radiologic features of CP were excluded,so as tominimize confounding factors of pancreatopathy unrelated to CP.Patients were divided into painful and pain-free groups to analyze differences in demographics,outcomes,and healthcare utilization.Results:Of 368 CP patients,49(13.3%)were pain-free at diagnosis and had remained so for>9 years.There were no significant differences in body mass index,race,sex,or co-morbidities between the two groups.Pain-free patients were older at diagnosis(53.9 vs 45.7,P=0.004)and had less recurrent AP(RAP)(43.8%vs 72.5%,P<0.001)and less exocrine pancreatic insufficiency(EPI)(34.7%vs 65.7%,P<0.001).Pain-free patients had less disability(2.2%vs 22.0%,P=0.003),mental illness(20.4%vs 61.0%,P<0.001),surgery(0.0%vs 15.0%,P=0.059),and therapeutic interventions(0.0%vs 16.4%,P=0.005)for pain.Conclusions:We described a unique subset of patients with underlying risk factors for CP and/or prior AP who were painfree at diagnosis.They were older at diagnosis,had less EPI and RAP,and overall favorable outcomes with minimal resource utilization.

关键词： Chronic pancreatitis pain-free pancreatic insufficiency diabetes

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Reporting of longitudinal pancreatojejunostomy with partial pancreatic head resection(the Frey procedure) for Chronic pancreatitis: A systematic review

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Hepatobiliary & Pancreatic Diseases International 2021年第2期20卷 110-116页

作者： Minas Baltatzis Santhalingam Jegatheeswaran Ajith K Siriwardena Regional Hepato-Pancreato-Biliary Surgery Unit Manchester Royal InfirmaryOxford RoadManchester M139WLUK Faculty of Biology Medicine and HealthUniversity of ManchesterManchesterUK

Background:Longitudinal pancreatojejunostomy with partial pancreatic head resection(the Frey procedure)is accepted for surgical treatment of painful Chronic pancreatitis.However,conduct and reporting are not standardized and thus,making comparisons difficult.This study assesses the reporting standards of this procedure.Data sources:A systematic literature review was performed between January 1987 and January 2020.The keyword and Medical Subject Heading"Chronic pancreatitis"was used together with the individual operation term"Frey pancreatojejunostomy".Reports were included if they provided original information on conduct and outcome.Thirty-three papers providing information on 1205 patients constituted the study population.Risk of bias in included reports was assessed.Results:Etiology of Chronic pancreatitis(alcohol)was reported in 26 of 28(93%)studies,duration of symptoms prior to surgery in 19(58%)studies and pre-operative opiate use in 12(36%)studies.In terms of morphology,pancreatic duct diameter was reported in 17(52%)studies and diameter of the pancreatic head in 13(39%)studies.In terms of technique,three(9%)studies reported weight of excised parenchyma.There were 9(0.7%)procedure-related deaths.Post-operative follow-up ranged from 6 to 82.5 months.No studies reported post-operative portal hypertension.Conclusions:There is substantial heterogeneity between studies in reporting of clinical baseline,morphology of the diseased pancreas,operative detail and outcome after longitudinal pancreatojejunostomy with partial pancreatic head resection.This critically compromises the comparison between centers and between surgeons.Structured reporting is necessary for clinicians to assess choice of procedure and for patients to make informed choices when seeking treatment for painful Chronic pancreatitis.

关键词： Chronic pancreatitis Frey procedure Reporting Longitudinal pancreatojejunostomy

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Long-term outcome of patients with Chronic pancreatitis treated with micronutrient antioxidant therapy

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Hepatobiliary & Pancreatic Diseases International 2017年第2期16卷 209-214页

作者： Sukitha Namal Rupasinghe Ajith K Siriwardena Hepatobiliary Surgery Unit Manchester Royal Infirmary Oxford Road Manchester M13 9WL UK

BACKGROUND： Micronutrient antioxidant therapy did not relieve pain in a European randomized trial of patients with Chronic pancreatitis without malnutrition. However, intervention was undertaken only for 6 months leaving unanswered the question of whether long-term antioxidant therapy may modulate Chronic pancreatitis. The aim of this study is to assess the outcome of long-term use of micronutrient antioxidant therapy in patients with Chronic pancreatitis.METHODS： This is a single center clinical cohort report of patients with Chronic pancreatitis prescribed micronutrient antioxidant therapy and followed for up to 10 years. Data were collected on demographic detail, clinic pain assessment, insulin requirements, interventions and outcome.RESULTS： A group of 30 patients with a diagnosis of Chronic pancreatitis constitute the study population. Median age at time of diagnosis was 40 years（range 14-66）; 19（63%） were male and the median duration of symptoms was 2 years（range 0-18）. Alcohol was the dominant cause in 22（73%） patients and 16（53%） patients were Cambridge stage 1. Twenty-four（80%） patients had pain at presentation. During antioxidant treatment of 4 years（range 1-10）, pain decreased but the proportion with abdominal pain compared to those who were pain-free remained constant（P=0.16; two-way ANOVA with Bonferroni correction）. There was a significant increase in requirement for insulin（P=0.028） with time together with use of both endoscopic and surgical interventions.CONCLUSIONS： This is the first study to report long-term disease-specific outcome in patients with Chronic pancreatitis prescribed micronutrient antioxidant therapy. There appears to be no effect of intervention on outcome.

关键词： Chronic pancreatitis antioxidant therapy micronutrient Antox outcomes

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Chronic pancreatitis:Pain and computed tomography/magnetic resonance imaging findings

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World Journal of Radiology 2024年第3期16卷 40-48页

作者： Yue Feng Ling-Ji Song Bo Xiao Department of Radiology The Affilia Department of Radiology Bishan Hospital of Chongqing Medical UniversityBishan Hospital of ChongqingChongqing 402760China

Chronic pancreatitis(CP)is a fibroinflammatory disease characterized by irreversible destruction of pancreatic tissue.With the development of the disease,it may lead to exocrine and/or endocrine insufficiency.CP is one of the common diseases that cause abdominal pain,which will not get permanent spontaneous relief as the disease evolves.The American College of Gastroenterology clinical guidelines recommend computed tomography or magnetic resonance imaging as the first-line examination for the diagnosis of CP.CP common imaging findings include pancreatic atrophy,irregular dilatation of the pancreatic duct,calcification of pancreatic parenchyma,pancreatic duct stones,etc.In clinical practice,whether any correlations between CP-induced abdominal pain patterns(no pain/constant/intermittent pain)and corresponding imaging findings present are not well known.Therefore,this review aims to comprehensively sort out and analyze the relevant information by collecting lots of literature on this field,so as to construct a cross-bridge between the clinical manifestations and imaging manifestations of CP patients.Also,it provides an imaging basis and foundation for the classification and diagnosis of abdominal pain types in clinical CP patients.

关键词： Chronic pancreatitis pancreatitis Abdominal pain Computed tomography Magnetic resonance imaging

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Pancreatic head excavation for tissue diagnosis may reduce unnecessary pancreaticoduode- nectomies in the setting of Chronic pancreatitis

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Hepatobiliary & Pancreatic Diseases International 2017年第3期16卷 315-322页

作者： Alessandro Fancellu Giorgio C Ginesu Claudio F Feo Maria L Cossu Marco Puledda Antonio Pinna Alberto Porcu Department of Clinical and Experimental Medicine Unit of General Surgery 2 - Clinica Chirurgica University of Sassari V.le San Pietro 43 07100 Sassari Italy

BACKGROUND： The necessity to obtain a tissue diagnosis of cancer prior to pancreatic surgery still remains an open debate. In fact, a non-negligible percentage of patients under- going pancreaticoduodenectomy （PD） for suspected cancer has a benign lesion at final histology. We describe an approach for patients with diagnostic uncertainty between cancer and Chronic pancreatitis, with the aim of minimizing the incidence of PD for suspicious malignancy finally diagnosed as benign disease. METHODS： Eighty-eight patients （85.4%） with a clinicoradio- logical picture highly suggestive for malignancy received for- mal PD （group 1）. Fifteen patients （14.6%） in whom preopera- tive diagnosis was uncertain between pancreatic cancer and Chronic pancreatitis underwent pancreatic head excavation （PHEX） for intraoperative tissue diagnosis （group 2）： those diagnosed as having cancer received PD, whereas those with Chronic pancreatitis received pancreaticojejunostomy （P]）. RESULTS： No patient received PD for benign disease. All pa- tients in group I had adenocarcinoma on final histology. Eight patients of group 2 （53.3%） received PD after intraoperative diagnosis of cancer, whereas 7 （46.7%） received PJ because no malignancy was found at introperative frozen sections. No signs of cancer were encountered in patients receiving PHEX and PJ after a median follow-up of 42 months. Overall survival did not differ between patients receiving PD for cancer in the group 1 and those receiving PD for cancer after PHEX in the group 2 （P=0.509）. CONCLUSION： Although the described technique has been used in a very selected group of patients, our results suggest that PHEX for tissue diagnosis may reduce rates of unnecessary PD, when the preoperative diagnosis is uncertain between cancer and Chronic pancreatitis.

关键词： pancreatic carcinoma Chronic pancreatitis pancreaticoduodenectomy pancreatic head excavation

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Gut microbiota controls the development of Chronic pancreatitis:A critical role of short-chain fatty acids-producing Gram-positive bacteria

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药学学报:英文版 2023年第10期13卷 4202-4216页

作者： Li-Long Pan Zheng-Nan Ren Jun Yang Bin-Bin Li Yi-Wen Huang Dong-Xiao Song Xuan Li Jia-Jia Xu Madhav Bhatia Duo-Wu Zou Chun-Hua Zhou Jia Sun Wuxi Medical School Jiangnan UniversityWuxi 214122China School of Food Science and Technology Jiangnan UniversityWuxi 214122China State Key Laboratory of Food Science and Resources Jiangnan UniversityWuxi 214122China Department of General Surgery Affiliated Hospital of Jiangnan UniversityWuxi 214122China Department of General Medicine Beicai Community Health Service Center of Pudong New DistrictShanghai 214001China Department of Pathology University of OtagoChristchurch 8140New Zealand Department of Gastroenterology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China

Chronic pancreatitis(CP)is a progressive and irreversible fibroinflammatory disorder,accompanied by pancreatic exocrine insufficiency and dysregulated gut microbiota.Recently,accumulating evidence has supported a correlation between gut dysbiosis and CP development.However,whether gut microbiota dysbiosis contributes to CP pathogenesis remains unclear.Herein,an experimental CP was induced by repeated high-dose caerulein injections.The broad-spectrum antibiotics(ABX)and ABX targeting Gram-positive(G+)or Gram-negative bacteria(G-)were applied to explore the specific roles of these bacteria.Gut dysbiosis was observed in both mice and in CP patients,which was accompanied by a sharply reduced abundance for short-chain fatty acids(SCFAs)-producers,especially G+bacteria.Broad-spectrum ABX exacerbated the severity of CP,as evidenced by aggravated pancreatic fibrosis and gut dysbiosis,especially the depletion of SCFAs-producing G+bacteria.Additionally,depletion of SCFAs-producing G+bacteria rather than G-bacteria intensified CP progression independent of TLR4,which was attenuated by supplementation with exogenous SCFAs.Finally,SCFAs modulated pancreatic fibrosis through inhibition of macrophage infiltration and M2 phenotype switching.The study supports a critical role for SCFAs-producing G+bacteria in CP.Therefore,modulation of dietary-derived SCFAs or G+SCFAs-producing bacteria may be considered a novel interventive approach for the management of CP.

关键词： Chronic pancreatitis Antibiotic exposure Gut microbiota Short-chain fatty acids-producing bacteria Pancreatic fibrogenesis Macrophage responses Toll-like receptor 4

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Incidence,prevalence,and comorbidities of Chronic pancreatitis:A 7-year population-based study

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World Journal of Gastroenterology 2023年第30期29卷 4671-4684页

作者： Qiu-Yu Cai Kun Tan Xue-Li Zhang Xu Han Jing-Ping Pan Zhi-Yin Huang Cheng-Wei Tang Jing Li Department of Gastroenterology West China HospitalSichuan UniversityChengdu 610041Sichuan ProvinceChina Sichuan Health Information Association Chengdu 610041Sichuan ProvinceChina

BACKGROUND Chronic pancreatitis(CP)is a fibroinflammatory syndrome leading to reduced quality of life and shortened life expectancy.Population-based estimates of the incidence,prevalence,and comorbidities of CP in China are scarce.AIM To characterize the incidence,prevalence,and comorbidities of CP in Sichuan Province,China,with population-based data.METHODS Data on CP from 2015 to 2021 were obtained from the Health Information Center of Sichuan Province.During the study period,a total of 38090 individuals were diagnosed with CP in Sichuan Province.The yearly incidence rate and point prevalence rate(December 31,2021)of CP were calculated.The prevalence of comorbid conditions in CP patients was estimated.The annual number of CPrelated hospitalizations,hospital length of stay,and hospitalization costs for CP were evaluated.Yearly incidence rates were standardized for age by the direct method using the permanent population of Sichuan Province in the 2020 census as the standard population.An analysis of variance test for the linearity of scaled variables and the Cochran-Armitage trend test for categorical data were performed to investigate the yearly trends,and a two-sided test with P<0.05 was considered statistically significant.RESULTS The 38090 CP patients comprised 23280 males and 14810 females.The mean age of patients at CP diagnosis was 57.83 years,with male patients(55.87 years)being younger than female patients(60.11 years)(P<0.001).The mean incidence rate of CP during the study period was 6.81 per 100000 person-years,and the incidence of CP increased each year,from 4.03 per 100000 person-years in 2015 to 8.27 per 100000 person-years in 2021(P<0.001).The point prevalence rate of CP in 2021 was 45.52 per 100000 individuals for the total population,with rates of 55.04 per 100000 individuals for men and 35.78 per 100000 individuals for women(P<0.001).Individuals aged 65 years or older had the highest prevalence of CP(113.38 per 100000 individuals)(P<0.001).Diabetes(26.32%)was the most common comorbidity in CP pa

关键词： Chronic pancreatitis Epidemiology Incidence Prevalence Comorbidities Disease burden

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Pancreatic cancer,autoimmune or Chronic pancreatitis,beyond tissue diagnosis:Collateral imaging and clinical characteristics may differentiate them

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World Journal of Gastrointestinal Oncology 2023年第6期15卷 925-942页

作者： Ana I Tornel-Avelar Jose Antonio Velarde Ruiz-Velasco Mario Pelaez-Luna Department of Gastroenterology Hospital Civil of Guadalajara“Fray Antonio Alcalde”Guadalajara 44340JaliscoMexico Research Division School of Medicine/Department of Gastroenterology Universidad Nacional Autonoma de México/National Institute of Medical Sciences and Nutrition“Salvador Zubiran”Tlalpan 14000Mexico CityMexico

Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal malignancies and is developing into the 2nd leading cause of cancer-related death.Often,the clinical and radiological presentation of PDAC may be mirrored by other inflammatory pancreatic masses,such as autoimmune pancreatitis(AIP)and massforming Chronic pancreatitis(MFCP),making its diagnosis challenging.Differentiating AIP and MFCP from PDAC is vital due to significant therapeutic and prognostic implications.Current diagnostic criteria and tools allow the precise differentiation of benign from malignant masses;however,the diagnostic accuracy is imperfect.Major pancreatic resections have been performed in AIP cases under initial suspicion of PDAC after a diagnostic approach failed to provide an accurate diagnosis.It is not unusual that after a thorough diagnostic evaluation,the clinician is confronted with a pancreatic mass with uncertain diagnosis.In those cases,a re-evaluation must be entertained,preferably by an experienced multispecialty team including radiologists,pathologists,gastroenterologists,and surgeons,looking for disease-specific clinical,imaging,and histological hallmarks or collateral evidence that could favor a specific diagnosis.Our aim is to describe current diagnostic limitations that hinder our ability to reach an accurate diagnosis among AIP,PDAC,and MFCP and to highlight those disease-specific clinical,radiological,serological,and histological characteristics that could support the presence of any of these three disorders when facing a pancreatic mass with uncertain diagnosis after an initial diagnostic approach has been unsuccessful.

关键词： Pancreas cancer Chronic pancreatitis Autoimmune pancreatitis Pancreas mass Endoscopic ultrasound Diagnosis

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A meta-analysis of the long-term effects of Chronic pancreatitis surgical treatments： duodenum-preserving pancreatic head resection versus pancreatoduodenectomy

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Chinese Medical Journal 2013年第1期126卷 147-153页

作者： LU Wen-ping SHI Qing ZHANG Wen-zhi CAI Shou-wang JIANG Kai DONG Jia-hong Department of Hepatobiliary Surgery Chinese People's LiberationArmy General Hospital Beijing 100853 China Department of Microbiology Peking University Health ScienceCenter Beijing 100191 China

Background Surgery is regarded as the most effective treatment to relieve pain and reduce complications in Chronic pancreatitis （CP）. Two major strategies exist： duodenum-preserving pancreatic head resection （DPPHR） and pancreatoduodenectomy （PD）. Many studies suggest that DPPHR offers advantages during surgery and in the short-term; however, the long-term effects have not been thoroughly investigated. We analyzed the long-term outcomes of DPPHR and PD, over follow-up times of at least 1 year, to determine the optimal surgical treatment for CP. Methods We systemically reviewed all CP surgical treatment reports, and only included randomized controlled trials （RCT） comparing DPPHR and PD, excluding unqualified studies using several pre-specified criteria. When multiple publications of a single trial were found, the most comprehensive current data were selected. Characteristics of the study populations and long-term postoperative outcome parameters were collected. The quality of the studies and data was analyzed using RevMan 4.2 software. Results Five trials were qualified for meta-analysis, with 261 participants in total （114 in the DPPHR group and 147 in the PD group）. There were no significant differences in the age, gender, or indications for surgery of each group. At the mean of 5.7-year （1-14 years） follow-up examination, DPPHR and PD resulted in equally effective pain relief, exocrine and endocrine function, and similar mortality rates （P 〉0.05）; however, DPPHR patients had improved global quality of life and weight gain, and reduced diarrhea and fatigue （P 〈0.05）. Conclusion DPPHR and PD result in equal pain relief, mortality, and pancreatic function; however, DPPHR provides superior long-term outcomes.

关键词： Chronic pancreatitis surgical treatments long-term postoperative effect meta-analysis

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