京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22304号 / 医博第4545号 / 新制||医||1040(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 川口 義弥, 教授 坂井 義治, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Abstract Acute infected necrotizing pancreatitis (ANP) is a very complex disease with a high risk of complications and death. ANP is difficult to treat and is often associated with poor outcomes. Despite the increasing data on the technical details required to perform a mini-invasive necrosectomy for walled-off necrosis (WON), relatively few studies have focused on the presence and consequences of pancreatic duct disruption in the context of APN. Moreover, the long-term prognosis of patients with acute pancreatitis (AP) is scant. The aim of this study was to examine the diagnosis, treatment and prophylaxis of pancreatic fistulas (PFs) associated with APN. In addition, the long-term prognosis of AP was evaluated. The study population consists of the patients with AP treated at Oulu University Hospital, Finland (Studies I–IV) and Copenhagen University Hospital, Denmark (Study II) during 1995–2015. In the first part of the study, all consecutive patients following open necrosectomy for infected ANP were demonstrated to have PF. Endoscopic transpapillary pancreatic stenting (ETPS) was attempted and proven to be an effective and safe treatment for patients with PF. In Study II, prophylactic pancreatic stenting in the early stage of the disease was tested in a randomized controlled trial to the patients with ANP to prevent PFs associated with the disease. However, the study showed that the patients with ANP did not benefit from early prophylactic pancreatic ductal stenting (PPDS); instead, it seemed to be harmful for the patients. The results of Study III showed that single drain amylase level measurement after surgical necrosectomy is unreliable. According to this study, serial measurements are recommended to diagnose PFs after necrosectomy. Study IV including 1644 patients showed that AP, especially alcohol AP, was associated with a high long-term mortality. On the other hand, AP without an alcohol aetiology had a minimal impact on survival. In conclusion, in patients with infected ANP, a PF has to be considered in treatment, but the prevention of ductal leak with PPDS is not recommended. In addition, the poor long-term outcome among alcohol AP patients was due to alcohol-related diseases. / Tiivistelmä Akuutti nekrotisoiva haimatulehdus ja erityisesti siihen liittyvä bakteeri-infektio on sairaus, johon liittyy korkea komplikaatio- ja kuolleisuusriski. Tautia usein komplisoi infektion lisäksi nekroosiin liittyvä haimafisteli, joka tekee hoidosta entistä haasteellisemman. Viime aikaisissa tutkimuksissa on käsitelty runsaasti mini-invasiivista nekrosektomiaa, mutta suhteellisen vähän on tutkimuksia nekrotisoivaan haimatulehdukseen liittyvästä fisteliongelmasta. Haimatulehdus-potilaiden pitkäaikaisennuste on myös epäselvä. Tämän väitöskirjatutkimuksen tavoitteena oli selvittää nekrotisoivaan haimatulehdukseen liittyvän haimafistelin yleisyyttä, diagnostiikkaa, ehkäisyä ja hoitoa. Lisäksi tarkasteltiin akuuttiin haimatulehdukseen sairastuneiden potilaiden pitkäaikaisennustetta. Ensimmäisessä osatyössä ilmeni, että kaikille potilaille, joille suoritettiin haiman nekrosektomia kehittyi fisteli ja endoskooppinen transpapillaarinen haimateiden stenttaus (ETPS) osoittautui hyväksi ja turvalliseksi hoidoksi fistelin hoidossa. Toisessa prospektiivisessa randomoidussa kontrolloidussa osatyössä tutkittiin profylaktista haimateiden stenttausta nekrotisoivassa haimatulehduksessa. Tutkimus osoitti, etteivät potilaat hyötyneet stenttauksesta: toimenpiteestä oli enemmän haittaa kuin hyötyä. Tämän tutkimuksen mukaan protetisointia ei suositella tehtäväksi taudin alkuvaiheessa. Kolmannessa osatyössä selvitettiin haiman nekrosektomian jälkeisen haimafistelin diagnosointia. Tutkimustuloksen mukaan haimafistelin osoittamiseksi dreenieritteen amylaasitasoa mittaamalla tarvitaan useita mittauskertoja, koska yksittäisen mittauksen sensitiivisyys on matala. Neljännessä osatyössä analysoitiin Oulun yliopistollisessa sairaalassa 1995–2012 akuutin haimatulehduksen sairastaneiden työikäisten potilaiden pitkäaikaisennustetta ja kuolinsyitä. Noin kymmenen vuoden seurannassa tutkimusryhmän (n = 1 644) kuolleisuus oli yli nelinkertainen verrattuna ikä- ja sukupuolivakioituihin verrokeihin (n = 8 220). Merkittävin kuolleisuutta lisäävä tekijä oli alkoholi. Tutkimuksemme osoitti, että infektoituneen haimanekroosiin liittyvä haimafisteli on huomioitava hoidossa. Varhaisesta profylaktisesta haimateiden protetisoinnista ei tutkimuksessa osoitettu olevan hyötyä. Alkoholin aiheuttaman haimatulehduksen pitkäaikaisennusteen mortaliteetti on korkea johtuen alkoholin käytöstä ja siihen liittyvistä sairauksista.

Introdução: Os benefícios do emprego do selante de fibrina no reforço de anastomoses pancreatico-jejunais, após ressecção duodenopancreática, visando a redução da incidência de fístula pancreática pós operatória (FPPO), ainda são questionáveis. Objetivo: Avaliar a influência do emprego do selante de fibrina na anastomose pancreatico-jejunal, após duodenopancreatectomia, na incidência de fístula, bem como suas consequências clínicas e os custos hospitalares. Metodologia: Estudo retrospectivo de 62 pacientes consecutivos submetidos a duodenopancreatectomia, divididos em dois grupos: 31 pacientes utilizando o selante de fibrina (GCS) e 31 pacientes sem o emprego de selante (GSS). As variáveis estudadas foram agrupadas em epidemiológicas, clínicas, laboratoriais, com destaque para a incidência de fístula pancreática, classificada segundo a definição do International Study Group on Pancreatic Fistula, suas complicações pós operatórias catalogadas segundo a classificação de Clavien e suas repercussões na assistência e nos seus custos avaliados pelo método de absorção com rateio simples de todas as despesas, exceto a despesa com medicamentos, tratada de forma separada. Resultados: Os grupos foram homogêneos para os parâmetros epidemiológicos, clínicos, e laboratoriais e não foram registradas diferenças significativas na comparação da evolução pós operatória e dos indicadores assistenciais hospitalares. Por outro lado, os custos hospitalares foram mais elevados no GCS, em relação ao GSS (p<0,0001). Conclusão: O emprego do selante de fibrina, no reforço da anastomose pancreatico-jejunal, em pacientes submetidos a duodenopancreatectomias, nas condições estudadas, não melhorou os resultados clínicos e assistenciais e ainda aumentou os custos hospitalares. / Introduction: The benefits of fibrin sealant employment in strengthening pancreatico-jejunal anastomosis after duodenopancreatic resection, reducing the incidence of pancreatic fistula postoperative (PFPO) are still questionable. Objective: To evaluate the influence of the use of fibrin sealant in pancreatico-jejunal anastomosis after pancreaticoduodenectomy in the incidence of fistula and its clinical consequences and hospital costs. Methodology: A retrospective study of 62 consecutive patients who underwent pancreaticoduodenectomy, divided into two groups: 31 patients using fibrin sealant (GCS) and 31 patients without the sealant employment (GSS). The variables were grouped into epidemiological, clinical, laboratory, especially the incidence of pancreatic fistula classified as defined by the International Study Group on Pancreatic Fistula, their postoperative complications cataloged according to Clavien rating and its repercussions on care and its costs assessed by the absorption method with simple apportionment of all expenses except the expenditure on medicines, treated separately. Results: The groups were homogeneous for clinical, epidemiological and laboratory parameters and no significant differences were recorded in the comparison given postoperative progress and hospital assistance indicators. Moreover, hospital costs were higher in GCS, with respect to GSS (p <0.0001). Conclusion: The use of fibrin sealant in pancreatojejunal anastomosis after pancreaticoduodenectomy, in the studied conditions, did not improve the results of care and also increased hospital costs

Dans le cas d'une tumeur pancréatique, la chirurgie d'exérèse est le traitement de première intention lorsqu'elle est possible. Les pancréatectomies sont des actes à haut risque, entraînant un taux de morbidité de 50%. L'une des complications les plus graves est l'apparition de fistules pancréatiques (FP) qui surviennent dans 15 à 20 % des cas, pour lesquelles il n'existe aucune solution de prévention. Cette thèse porte sur l'élaboration d'un biomatériau pour la prévention des FP. Le cahier des charges, défini avec l'équipe chirurgicale, nous a orienté vers un dispositif médical sous forme de pansement absorbant, présentant des propriétés mécaniques adaptées, ainsi qu'une résistance aux enzymes pancréatiques serait intéressant. Un biomatériau constitué de deux couches a été imaginé : 1) une matrice absorbante constituée d'un complexe polyélectrolyte (PEC) sous forme de film, 2) une couche supérieure imperméable permettant de limiter la diffusion des enzymes pancréatiques dans le milieu péritonéal ; afin de répondre aux spécifications demandées par l'équipe médicale. La première partie de ce travail a porté sur l'optimisation de la mise en forme de la matrice sous forme de film à partir de PEC d'alginate (ALG) et de chitosane (CHI) présentant différents ratio de polymères (ALG-CHI 50/50 et ALG-CHI 63/37). L'influence de la technique d'homogénéisation des PEC, sous ultra-turrax (UT) ou au Stephan (ST) a été étudiée sur les propriétés physico-chimiques des films obtenus. Les propriétés de biodégradation, de gonflement et de cytotoxicité sont principalement influencées par le ratio des polymères. En revanche, leurs structure et propriétés mécaniques sont essentiellement influencées par la technique d'homogénéisation utilisée lors de l'élaboration du PEC. Au vu de ces résultats, le choix de la matrice au contact de l'anastomose ou de la tranche pancréatique s'est arrêté sur le PEC ALG-CHI 63/37 UT. La deuxième partie de cette thèse a été consacrée à l'incorporation d'une couche imperméable à la surface supérieure du film. Deux polymères ont été testés : l'acide polylactique (PLA) et le polycaprolactone (PCL). Ils ont été incorporés après fonctionnalisation de la surface du film. La matrice ALG-CHI 63/37 UT recouverte de PLA présente une surface plus hydrophobe, des propriétés mécaniques adaptées, une bonne résistance aux enzymes pancréatiques tout en possédant des propriétés de gonflement intéressantes. Le biomatériau ainsi obtenu est un bon candidat qui répond au cahier des charges d'un pansement indiqué pour la prévention des fistules pancréatiques. / Resection surgery is the first-line treatment indicated for pancreatic tumor. The morbidity of this surgery is high with a complication rate around 50%. One of the most serious complications is the occurrence of pancreatic fistula (PF), which occurs in 15-20% of cases. To date, no biomaterial available on the market is indicated for the prevention of the onset of PF following pancreatectomy. This project focuses on the development of a biomaterial for the prevention of PF. Specifications identified by the surgical team oriented us to ward an absorbent dressing with sufficient mechanical properties and pancreatic enzymes resistance. A biomaterial made up of two layers was designed: 1) an absorbent matrix, in the form of a film, constituted by a polyelectrolyte complex (PEC), 2) an impermeable backing layer expected to limit the diffusion of the pancreatic enzymes into the peritoneal medium; to meet surgeons' specifications. The first part of this work focused on the optimization of the preparation of the matrix, composed of alginate (ALG) and chitosan (CHI) PECs films with different polymer ratios (ALG-CHI 50/50and ALG-CHI 63/37). The influence of the technique of homogenization of PEC, ultra-turrax (UT) or Stephan (ST) was studied on the physicochemical properties of the films. Biodegradation, swelling and cytotoxicity were shown to be mainly influenced by the ratio of polymers used. On the other hand, structure and mechanical properties are mainly influenced by the homogenization technique. With these results, the choice of the matrix to pancreatic application was set as the PEC ALG-CHI 63/37 UT. The second part of the present work was devoted to the incorporation of an impermeable backing layer on the upper film surface. Two polymers were evaluated: polylactic acid (PLA) and polycaprolactone (PCL). They were incorporated after the functionalization of the film surface. The PLA-coated ALG-CHI 63/37 UT matrix led to more hydrophobic surfaces, as well as adaptated mechanical properties and resistance to pancreatic enzymes with interesting swelling properties. The obtained biomaterial is a promising candidate responding to the specifications for a dressing indicated for the prevention of PF.

Introdução: Os benefícios do emprego do selante de fibrina no reforço de anastomoses pancreatico-jejunais, após ressecção duodenopancreática, visando a redução da incidência de fístula pancreática pós operatória (FPPO), ainda são questionáveis. Objetivo: Avaliar a influência do emprego do selante de fibrina na anastomose pancreatico-jejunal, após duodenopancreatectomia, na incidência de fístula, bem como suas consequências clínicas e os custos hospitalares. Metodologia: Estudo retrospectivo de 62 pacientes consecutivos submetidos a duodenopancreatectomia, divididos em dois grupos: 31 pacientes utilizando o selante de fibrina (GCS) e 31 pacientes sem o emprego de selante (GSS). As variáveis estudadas foram agrupadas em epidemiológicas, clínicas, laboratoriais, com destaque para a incidência de fístula pancreática, classificada segundo a definição do International Study Group on Pancreatic Fistula, suas complicações pós operatórias catalogadas segundo a classificação de Clavien e suas repercussões na assistência e nos seus custos avaliados pelo método de absorção com rateio simples de todas as despesas, exceto a despesa com medicamentos, tratada de forma separada. Resultados: Os grupos foram homogêneos para os parâmetros epidemiológicos, clínicos, e laboratoriais e não foram registradas diferenças significativas na comparação da evolução pós operatória e dos indicadores assistenciais hospitalares. Por outro lado, os custos hospitalares foram mais elevados no GCS, em relação ao GSS (p<0,0001). Conclusão: O emprego do selante de fibrina, no reforço da anastomose pancreatico-jejunal, em pacientes submetidos a duodenopancreatectomias, nas condições estudadas, não melhorou os resultados clínicos e assistenciais e ainda aumentou os custos hospitalares. / Introduction: The benefits of fibrin sealant employment in strengthening pancreatico-jejunal anastomosis after duodenopancreatic resection, reducing the incidence of pancreatic fistula postoperative (PFPO) are still questionable. Objective: To evaluate the influence of the use of fibrin sealant in pancreatico-jejunal anastomosis after pancreaticoduodenectomy in the incidence of fistula and its clinical consequences and hospital costs. Methodology: A retrospective study of 62 consecutive patients who underwent pancreaticoduodenectomy, divided into two groups: 31 patients using fibrin sealant (GCS) and 31 patients without the sealant employment (GSS). The variables were grouped into epidemiological, clinical, laboratory, especially the incidence of pancreatic fistula classified as defined by the International Study Group on Pancreatic Fistula, their postoperative complications cataloged according to Clavien rating and its repercussions on care and its costs assessed by the absorption method with simple apportionment of all expenses except the expenditure on medicines, treated separately. Results: The groups were homogeneous for clinical, epidemiological and laboratory parameters and no significant differences were recorded in the comparison given postoperative progress and hospital assistance indicators. Moreover, hospital costs were higher in GCS, with respect to GSS (p <0.0001). Conclusion: The use of fibrin sealant in pancreatojejunal anastomosis after pancreaticoduodenectomy, in the studied conditions, did not improve the results of care and also increased hospital costs

Bakgrund: Pankreatikoduodenektomi är den enda kurativa behandlingen av pankreascancer och pankreasanastomosläckage (PAL) är en mycket allvarlig postoperativ komplikation. Metoder för att identifiera detta i ett tidigt skede behöver förbättras. Den postoperativa övervakningen består till stor del av vitalparametrar men sjuksköterskan observerar även andra tecken på försämring. Metod: 32 patienter som genomgått pankreatikoduodenektomi inkluderades i studie. Ett bedömningsformulär innehållande 14 parametrar togs fram och användes för att identifiera vad i sjuksköterskans observationer som kan identifiera tidiga tecken på PAL. Studien hade kvantitativ ansats. Syfte: Att identifiera tidiga tecken på PAL efter pankreatikoduodenektomi med hjälp av ett bedömningsformulär. Resultat: Bedömningsformuläret identifierade normalförloppet efter pankreatikoduodenektomi. Vid jämförelse mellan patienterna som drabbats av PAL och normalförloppet urskildes tre signifikanta skillnader. Patienterna med PAL hade innan det diagnostiserades ökat syrgasbehov, sjuksköterskan bedömde deras allmäntillstånd som dåligt istället för ganska gott och patienternas egenbedömning av allmäntillståndet visade att de mådde sämre för varje dag istället för bättre. Slutsatser: Studien indikerar att ökat syrgasbehov samt sjuksköterskans bedömning och patientens egenbedömning av allmäntillståndet är vägledande för upptäckten av pankreasanastomosläckage. / Background: Pancreaticoduodenectomy is the only curative treatment of pancreaticcancer and postoperative pancreatic fistula (POPF) is a very serious complication. Methods to identify this in an early stage must be improved. The postoperative monitoring is largely composed of vital signs, but the nurse also observes other signs of deterioration. Method: 32 patients how underwent pancreaticoduodenectomy were included in the study. An assessment form containing 14 parameters was used to identify what in the nurse's observation that can identify early signs of POPF. The study had a quantitative approach. Objective: To identify early signs of POPF after pancreaticoduodenectomy using anassessment form. Results: The assessment form identified the normal process after pancreaticoduodenectomy. In the comparison between the patients affected by POPF and the normal process, three significant differences were distinguished. The patients with POPF had before it occurred increased oxygen needs, the nurse assessed the general health as poor rather than pretty good and the patients self-assessed the general health worse by the day instead of better. Conclusions: This study indicates that increased oxygen needs and the nurse's assessment and the patient's self-assessment of general health can be indicative for the discovery of POPF.

Le 17 novembre 2016 a eu lieu la 3ème journée mondiale de lutte contre le cancer du pancréas.Cette prise en considération tardive rend compte de la dualité entre une incidence faible et un pronostic redoutable. Sa réputation de cancer rapidement mortel est attestée par un ratio incidence/mortalité proche de 1. Au 10ème rang en termes de localisations de cancers, il se hisse au 4ème rang en termes de mortalité par cancer et devrait devenir, en 2020, la 2ème cause de décès par cancer devant le cancer du côlon et juste après le cancer du poumon. Le taux de survie à 5 ans, tous stades confondus, est de 5% aux USA et en Europe.L’adénocarcinome canalaire pancréatique représente la tumeur la plus fréquente (80% des tumeurs pancréatiques exocrines). Sa localisation dans la glande pancréatique est céphalique dans 2/3 des cas.A ce jour, le traitement chirurgical reste le seul traitement potentiellement curatif. Celui-ci ne s’adresse qu’à une faible proportion de patients. En effet, seul 20% des patients présentant un adénocarcinome pancréatique céphalique sont effectivement résécables permettant d’obtenir un taux de survie globale à 5 ans d'environ 10 à 20% si la résection est suivie de chimiothérapie adjuvante ou non. Ces résultats modestes sont en outre à pondérer par la morbi-mortalité des résections pancréatiques céphaliques. Dans la série de l’Association Française de Chirurgie, reprenant les résections pancréatiques céphaliques réalisées en France entre 2004 et 2010, la mortalité était de 3,8% et la morbidité de 54%. Parmi les complications post-opératoires, la fistule pancréatique représente la principale complication en termes de mortalité (15 à 25%), génératrice de coût important dans les soins et d’une augmentation significative de la durée de séjour. La fistule pancréatique demeure la pierre angulaire de l’amélioration du pronostic des patients.L’objectif de ce travail sur l’adénocarcinome canalaire pancréatique céphalique traité chirurgicalement était d’analyser certains facteurs influençant la morbi-mortalité au trois temps de sa prise en charge :- Avant l’intervention, avec l’étude d’un facteur pronostic préopératoire, sur une cohorte de patients, pouvant influencer la survenue d’une fistule pancréatique et la mortalité- Pendant l’intervention, avec la réalisation d’une méta-analyse sur le type de reconstruction pancréatique et son influence sur la survenue d’une fistule pancréatique- Après l’intervention, avec l’étude de l’influence de la survenue d’une complication sévère sur la survie et la survie sans récidive.Au cours de cette thèse nous avons vu, que la réduction du taux de fistule pancréatique, par le seul biais de techniques peropératoires semble difficilement réalisable au regard de la multiplicité des techniques et de la difficulté à réaliser des études randomisées contrôlées méthodologiquement satisfaisantes. En revanche, la recherche des facteurs liés aux patients, prédisposant à la survenue d’une fistule pancréatique semble l’approche à privilégier. Ceci est d’autant plus primordial dès lors que nous avons mis en évidence un lien entre la survenue d’une complication sévère et la survie ou la récidive chez les patients réséqués. Ce travail souligne l’importance d’être capable d’identifier, dès la consultation, les patients à haut risque de complications sévères et de fistule post-opératoire d’une part, pour sélectionner les bons candidats à la chirurgie et d’autre part, pour être capable de leur apporter une information franche et loyale indispensable éthiquement au consentement éclairé. / The third World Day on pancreatic cancer took place the 17th November 2016. This late consideration is due to the duality between his relative scarcity and a dreadful prognosis.Its aggressiveness is underlined by a mortality rate equal to its incidence. Ranked 10th on cancer-related localization and 4th on cancer-related mortality, he will become the second cause of cancer-related deaths in 2020 just behind pulmonary cancer and before colorectal cancer. 5-yr survival rate is 5% irrespective of the stage.Pancreatic ductal adenocarcinoma is the most frequent form (80% of exocrine pancreatic tumors). He is localized in cephalic pancreas in 2/3 of cases.Although pancreatic resection provides the only chance of long-term survival, no more than 20% of patients will be eligible for surgery in curative intent leading to a 5-yr survival rate of 10 to 20%. Pancreaticoduodenectomy for pancreatic head, neck and uncinated process is still a challenging procedure. In the study of the French Surgery Association, mortality and morbidity rate were respectively 3.8% and 54%. Postoperative pancreatic fistula is considered as the Achilles’ heel of pancreaticoduodenectomy and is associated with increased post-operative mortality. Postoperative pancreatic fistula generates significant costs and prolonged hospital stay. Thus postoperative pancreatic fistula is the corner stone of patient’s prognosis improvement.The aim of this study on operated pancreatic ductal adenocarcinoma was to analyze several factors influencing morbidity and mortality.- Before surgery, by testing the impact of body surface area in a cohort of patients.- During surgery, by conducting a meta-analysis on reconstruction methods for pancreatic anastomosis.- After surgery, by evaluating the influence of severe complications on survival and recurrence.We show that the use of various surgical refinements, such as type of pancreatic anastomoses, are equivocal to decrease postoperative pancreatic fistula rate and that performing randomized controlled trials will be difficult. In contrast, the search for patient’s factors leading to postoperative pancreatic fistula seems to be the promising approach. This is of major concern as we demonstrated the causal link between the occurrence of severe postoperative complications and survival or recurrence. This work highlights the need for surgeons to distinguish during preoperative consultation high-risk patients in order to select the best candidates suitable for surgery as well as to give them a full and frank information ethically necessary for free and informed consent.