Stephan L. Haas

United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis (HaPanEU)

Background There have been substantial improvements in the management of chronic pancreatitis, leading to the publication of several national guidelines during recent years. In collaboration with United European Gastroenterology, the working group on ‘Harmonizing diagnosis and treatment of chronic pancreatitis across Europe’ (HaPanEU) developed these European guidelines using an evidence-based approach. Methods Twelve multidisciplinary review groups performed systematic literature reviews to answer 101 predefined clinical questions. Recommendations were graded using the Grading of Recommendations Assessment, Development and Evaluation system and the answers were assessed by the entire group in a Delphi process online. The review groups presented their recommendations during the 2015 annual meeting of United European Gastroenterology. At this one-day, interactive conference, relevant remarks were voiced and overall agreement on each recommendation was quantified using plenary voting (Test and Evaluation Directorate). After a final round of adjustments based on these comments, a draft version was sent out to external reviewers. Results The 101 recommendations covered 12 topics related to the clinical management of chronic pancreatitis: aetiology (working party (WP)1), diagnosis of chronic pancreatitis with imaging (WP2 and WP3), diagnosis of pancreatic exocrine insufficiency (WP4), surgery in chronic pancreatitis (WP5), medical therapy (WP6), endoscopic therapy (WP7), treatment of pancreatic pseudocysts (WP8), pancreatic pain (WP9), nutrition and malnutrition (WP10), diabetes mellitus (WP11) and the natural course of the disease and quality of life (WP12). Using the Grading of Recommendations Assessment, Development and Evaluation system, 70 of the 101 (70%) recommendations were rated as ‘strong and plenary voting revealed ‘strong agreement for 99 (98%) recommendations. Conclusions The 2016 HaPanEU/United European Gastroenterology guidelines provide evidence-based recommendations concerning key aspects of the medical and surgical management of chronic pancreatitis based on current available evidence. These recommendations should serve as a reference standard for existing management of the disease and as a guide for future clinical research.

Short-term Results of a Magnetic Resonance Imaging–Based Swedish Screening Program for Individuals at Risk for Pancreatic Cancer

IMPORTANCEnPancreatic cancer is the fourth leading cause of cancer-related death in Western countries. In approximately 10% of all patients with pancreatic cancer, it is possible to define a positive family history for pancreatic cancer or for one of the other related genetic syndromes. A screening program for individuals at risk is recommended; however, surveillance modalities have not been defined yet.nnnOBJECTIVEnTo analyze the short-term results of a prospective clinical surveillance program for individuals at risk for pancreatic cancer using a noninvasive magnetic resonance imaging (MRI)-based screening protocol.nnnDESIGN, SETTING AND PARTICIPANTSnA prospective observational study of all patients with a genetic risk for developing pancreatic cancer who were referred to Karolinska University Hospital between January 1, 2010, and January 31, 2013, using an MRI-based surveillance program. All patients were investigated for the most common genetic mutations associated with pancreatic cancer.nnnEXPOSUREnA noninvasive MRI-based screening protocol.nnnMAIN OUTCOMES AND MEASURESnThe ability of MRI to identify potential precancerous or early cancers in individuals at risk for pancreatic cancer.nnnRESULTSnForty patients (24 women and 16 men) were enrolled. The mean age was 49.9 years. The mean length of follow-up was 12.9 months. The numbers of relatives affected by pancreatic cancer were 5 in 2 patients (5%), 4 in 5 patients (12.5%), 3 in 17 patients (42.5%), 2 in 14 patients (35%), and 1 in 2 patients (5%). In 4 patients (10%), a p16 mutation was found; in 3, a BRCA2 mutation (7.5%); and in 1, a BRCA1 mutation (2.5%). In 16 patients (40%), MRI revealed a pancreatic lesion: intraductal papillary mucinous neoplasia (14 patients, 35%) and pancreatic ductal adenocarcinoma (2 patients, 5%). One patient had a synchronous intraductal papillary mucinous neoplasia and pancreatic ductal adenocarcinoma. Five patients (12.5%) required surgery (3 for pancreatic ductal adenocarcinoma and 2 for intraductal papillary mucinous neoplasia), while the remaining 35 are under continued surveillance.nnnCONCLUSIONS AND RELEVANCEnDuring a median follow-up of approximately 1 year, pancreatic lesions were detected in 40% of the patients, of whom 5 underwent surgery. Although the study time was relatively short, the surveillance program in individuals at risk seems to be effective.

Outcome of probe-based confocal laser endomicroscopy (pCLE) during endoscopic retrograde cholangiopancreatography: A single-center prospective study in 45 patients.

Background Diagnosis of pre-malignant and malignant lesions in the bile duct and the pancreas is sometimes cumbersome. This applies in particular to intraductal papillary mucinous neoplasia (IPMN) and bile duct strictures in primary sclerosing cholangitis (PSC). Aims To evaluate in a prospective cohort study the sensitivity and specificity of probe-based confocal laser microscopy (pCLE) during endoscopic retrograde cholangiopancreatography (ERCP). Methods We performed pCLE together with mother-baby endoscopy (SpyGlass) during 50 ERCP sessions in 45 patients. The Miami and Paris criteria were applied. Clinical diagnosis via imaging was compared to pCLE and the final pathological diagnosis from surgically-resected, biopsy, or cytology specimens. Patients were followed up for at least 1 year. Results We were able to perform pCLE in all patients. Prior to endoscopy, the diagnosis was benign in 23 patients and undetermined (suspicious) in 16 patients, while six patients had an unequivocal diagnosis of malignancy. Sensitivity was 91% and specificity 52%. The positive (PPV) and negative predictive value (NPV) was 82% and 100%, respectively. Apart from mild post-ERCP pancreatitis in two patients, no complications occurred. Conclusions Our study showed that pCLE is a safe, expert endoscopic method with high technical feasibility, high sensitivity and high NPV. It provided diagnostic information that can be helpful for decisions on patient management, especially in the case of IPMN and unclear pancreatic lesions, in individuals whom are at increased risk for pancreatic cancer.

Bioinformatory‐assisted analysis of next‐generation sequencing data for precision medicine in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a tumor with an extremely poor prognosis, predominantly as a result of chemotherapy resistance and numerous somatic mutations. Consequently, PDAC is a prime candidate for the use of sequencing to identify causative mutations, facilitating subsequent administration of targeted therapy. In a feasibility study, we retrospectively assessed the therapeutic recommendations of a novel, evidence‐based software that analyzes next‐generation sequencing (NGS) data using a large panel of pharmacogenomic biomarkers for efficacy and toxicity. Tissue from 14 patients with PDAC was sequenced using NGS with a 620 gene panel. FASTQ files were fed into treatmentmap. The results were compared with chemotherapy in the patients, including all side effects. No changes in therapy were made. Known driver mutations for PDAC were confirmed (e.g. KRAS, TP53). Software analysis revealed positive biomarkers for predicted effective and ineffective treatments in all patients. At least one biomarker associated with increased toxicity could be detected in all patients. Patients had been receiving one of the currently approved chemotherapy agents. In two patients, toxicity could have been correctly predicted by the software analysis. The results suggest that NGS, in combination with an evidence‐based software, could be conducted within a 2‐week period, thus being feasible for clinical routine. Therapy recommendations were principally off‐label use. Based on the predominant KRAS mutations, other drugs were predicted to be ineffective. The pharmacogenomic biomarkers indicative of increased toxicity could be retrospectively linked to reported negative side effects in the respective patients. Finally, the occurrence of somatic and germline mutations in cancer syndrome‐associated genes is noteworthy, despite a high frequency of these particular variants in the background population. These results suggest software‐analysis of NGS data provides evidence‐based information on effective, ineffective and toxic drugs, potentially forming the basis for precision cancer medicine in PDAC.

The HLA-DQβ1 insertion is a strong achalasia risk factor and displays a geospatial north–south gradient among Europeans

Idiopathic achalasia is a severe motility disorder of the esophagus and is characterized by a failure of the lower esophageal sphincter to relax due to a loss of neurons in the myenteric plexus. Most recently, we identified an eight-amino-acid insertion in the cytoplasmic tail of HLA-DQβ1 as strong achalasia risk factor in a sample set from Central Europe, Italy and Spain. Here, we tested whether the HLA-DQβ1 insertion also confers achalasia risk in the Polish and Swedish population. We could replicate the initial findings and the insertion shows strong achalasia association in both samples (Poland P=1.84 × 10−04, Sweden P=7.44 × 10−05). Combining all five European data sets – Central Europe, Italy, Spain, Poland and Sweden – the insertion is achalasia associated with Pcombined=1.67 × 10−35. In addition, we observe that the frequency of the insertion shows a geospatial north–south gradient. The insertion is less common in northern (around 6–7% in patients and 2% in controls from Sweden and Poland) compared with southern Europeans (~16% in patients and 8% in controls from Italy) and shows a stronger attributable risk in the southern European population. Our study provides evidence that the prevalence of achalasia may differ between populations.

Transplantation of tissue-engineered cell sheets for stricture prevention after endoscopic submucosal dissection of the oesophagus

Background and objective Endoscopic mucosal dissection (ESD) is a treatment option for oesophagus tumours localized to the mucosa enabling en bloc removal of large lesions. The resulting larger mucosal defects have resulted in an increase in the occurrence of post-treatment strictures. Transplantation of autologous cell sheets, cultured from oral mucosa, has been shown to prevent post-ESD strictures. The aim of the study was to assess the efficacy and safety of cell sheet transplantation after oesophageal ESD in a Western patient population where reflux-associated pre-malignant and malignant conditions predominate. Methods Patients with Barrett’s oesophagus associated high-grade dysplasia or early adenocarcinoma where ESD entailed a resection >3u2009cm in length and ≥75% of the circumference were eligible for treatment under hospital exemption. Cell sheets were cultured from buccal mucosa according to Good Manufacturing Practice and were endoscopically applied to the post-ESD defect directly after resection. Patients were followed with weekly endoscopy examinations, including confocal laser microscopy, for a total of four weeks. Results Five patients were treated. ESD was extensive with resections being circumferential in three patients and 9–10u2009cm in length in two. The number of transplanted cell sheets ranged from two to six. Three patients developed strictures requiring two to five dilatation sessions. Conclusions Cell sheet transplantation shows to be safe and feasible in a Western population. Results suggest that transplantation has a protective effect on the mucosal defect after ESD, decreasing both the risk for and extent of stricture formation.

Akute Alkoholintoxikation@@@Acute alcohol intoxication: Aktuelle Aspekte zur Risikoeinschätzung, Diagnostik und Therapie@@@Current aspects in risk estimation, diagnosis, and therapy

ZusammenfassungPatienten mit akuter Alkoholintoxikation stellen für den prä- und innerklinischen Notfalldienst ein zunehmendes Problem dar. Dennoch gibt es nur wenig aussagekräftige Literaturdaten zur klinischen Risikoeinschätzung. Im Universitätsklinikum Mannheim wurden die Alkoholintoxikationen aus den Jahren 2003–2007 retrospektiv untersucht und zum Teil publiziert. Die vorliegende Arbeit stellt eine Gesamtbewertung dieser Daten mit dem Ziel einer umfassenden Risikobeurteilung alkoholintoxikierter Patienten nach definierten Kriterien dar. Die insgesamt 857 alkoholintoxikierten Patienten waren überwiegend Männer (76%) mit einem mittleren Lebensalter von 45,1xa0Jahren. Die meisten Patienten (74%) wurden ambulant behandelt, die Blutalkoholkonzentration lag im Mittel bei 2,5‰. Insgesamt ergeben unsere Daten ein niedriges klinisches Risiko für alkoholintoxikierte Patienten und unterstreichen damit die Forderung nach einer kontrollierten außerklinischen Versorgung. Um auch den wenigen potenziellen Komplikationen sowie den möglichen Differenzialdiagnosen der Bewusstseinsstörung gerecht zu werden, ist es essenziell, einen definierten diagnostischen und therapeutischen Standard vorzuhalten, der die wiederholte körperliche Untersuchung mit neurologischem Status, allgemeine und spezielle Laborbestimmungen, Monitoring und ggf. eine weitere radiologische Diagnostik einschließt. Die Entlassung darf erst erfolgen, wenn der Patient wach, orientiert und gangstabil ist. Bei Bedarf sollte eine weitere stationäre Entwöhnungstherapie vermittelt werden.AbstractDespite an increasing rate of emergency admissions with acute alcohol intoxication, specific data concerning clinical risk estimation are scarce. We performed a retrospective analysis of all 857 patients admitted to the University Medical Center Mannheim with acute alcohol intoxication between 2003 and 2007. Most patients were men (76%), the mean age was 45.1 years, mean blood alcohol concentration was 2.5 ‰. The majority of patients (74%) were discharged directly from the emergency department. The present data indicate a low clinical risk of alcohol intoxication and suggest that outpatient treatment is sufficient in the majority of cases. Nevertheless, a standardized diagnostic and therapeutic approach is essential in view of rare complications. Clinical monitoring should include repeated physical and especially neurological examination, toxicological blood tests, and radiological diagnostics. Discharge is possible provided that patients are awake, not disorientated and mobile. If necessary, patients should be encouraged to enter a withdrawal treatment program.

The Scandinavian baltic pancreatic club (SBPC) database: design, rationale and characterisation of the study cohort

Abstract Objectives: Chronic pancreatitis (CP) is a multifaceted disease associated with several risk factors and a complex clinical presentation. We established the Scandinavian Baltic Pancreatic Club (SBPC) Database to characterise and study the natural history of CP in a Northern European cohort. Here, we describe the design of the database and characteristics of the study cohort. Methods: Nine centres from six different countries in the Scandinavian-Baltic region joined the database. Patients with definitive or probable CP (M-ANNHEIM diagnostic criteria) were included. Standardised case report forms were used to collect several assessment variables including disease aetiology, duration of CP, preceding acute pancreatitis, as well as symptoms, complications, and treatments. The clinical stage of CP was characterised according to M-ANNNHEIM. Yearly follow-up is planned for all patients. Results: The study cohort comprised of 910 patients (608 men: 302 women; median age 58 (IQR: 48–67) years with definite 848 (93%) or probable CP 62 (7%). Nicotine (70%) and alcohol (59%) were the most frequent aetiologies and seen in combination in 44% of patients. A history of recurrent acute pancreatitis was seen in 49% prior to the development of CP. Pain (69%) and exocrine pancreatic insufficiency (68%) were the most common complications followed by diabetes (43%). Most patients (30%) were classified as clinical stage II (symptomatic CP with exocrine or endocrine insufficiency). Less than 10% of the patients had undergone pancreatic surgery. Conclusion: The SBPC database provides a mean for future prospective, observational studies of CP in the Northern European continent.

Diagnosis, treatment and long-term outcome of autoimmune pancreatitis in Sweden

INTRODUCTIONnAutoimmune pancreatitis (AIP) is a pancreatic inflammatory process characterized by a strong inflammatory cell infiltration and two histopathologically distinct subtypes: type 1 and type 2. Diagnosis is often challenging and requires a combination of clinical, laboratory and imaging data. AIP can mimic pancreatic tumours leading to unnecessary resections if not correctly diagnosed. Short- and long-term outcomes of AIP have been poorly investigated so far and no large series have been previously reported from Sweden.nnnMETHODSnA single-centre, retrospective, cohort study of patients with histologically confirmed or highly probable diagnosis of AIP according to ICDC criteria. Demographic, clinical and radiological characteristics, type of treatment and its outcomes were collected and analysed.nnnRESULTSnSeventy-one patients with AIP (87% with type 1), were evaluated at Karolinska University Hospital between 2004 and 2018; 49% males, mean age 49 years (range 44-53). Among them, 28% were histologically confirmed, 35% presented with jaundice, 22% with acute pancreatitis, 39% had non-specific symptoms such as weight loss or abdominal pain, 84% showed other organ involvement (OOI). Radiologically, 76% showed a focal pancreatic enlargement, 27% diffuse enlargement, 27% signs of acute pancreatitis and 10% of chronic pancreatitis. Overall, 58 patients (81%) underwent treatment with different medications: 46 (79%) cortisone, 7 (12%) azathioprine, 5 (8%) other immunosuppressive drugs. Twenty-six (36%) underwent biliary stenting and 12 (16%) were given surgery. In total, 47% of patients developed pancreatic exocrine insufficiency (PEI), of whom 76% had a severe form (faecal elastase-1u202f<u202f100u202fμg/g) and 21% of patients developed diabetes mellitus (pancreatic endocrine insufficiency), of whom 73% required insulin.nnnCONCLUSIONSnAIP is a challenging disease for diagnosis and treatment. Cortisone treatment is generally successful and provides clinical remission in the large majority of patients (>90%). In the further course of the disease, a considerable number of patients develop PEI and diabetes. Only one-quarter of patients exhibit on imaging the characteristic sausage-like pancreas (diffuse enlargement), approximately three-quarters had a focal mass that could be misdiagnosed as pancreatic malignancy.

RCAN1 is a marker of oxidative stress, induced in acute pancreatitis

BACKGROUNDnTo date, there still is a lack of specific acute pancreatitis markers and specifically an early marker that can reliably predict disease severity. The inflammatory response in acute pancreatitis is mediated in part through oxidative stress and calcineurin-NFAT (Nuclear Factor of Activated T-cells) signaling, which is inducing its own negative regulator, regulator of calcineurin 1 (RCAN1). Caerulein induction is a commonly used inxa0vivo model of experimental acute pancreatitis. Caerulein induces CN-NFAT signaling, reactive oxygen species and inflammation.nnnMETHODSnTo screen for potential markers of acute pancreatitis, we used the caerulein model of experimental acute pancreatitis (AP) in C57Bl/6u202fJ mice. Pancreata from treated and control mice were used for expression profiling. Promising gene candidates were validated in cell culture experiments using primary murine acinar cells and rat AR42J cells. These candidates were then further tested for their usefulness as biomarkers in mouse and human plasma.nnnRESULTSnWe identified a number of novel genes, including Regulator of calcineurin 1 (Rcan1) and Sestrin 2 (Sesn2) and demonstrated that they are induced by oxidative stress, by stimulation with H2O2 and by inhibiting caerulein stimulated expression with the antioxidant N-acetylcysteine. We found Rcan1 protein to be significantly elevated in AP-induced mouse plasma as well as in plasma from AP patients.nnnCONCLUSIONnWe demonstrated that Rcan1 is regulated by oxidative stress and identified RCAN1 as a potential diagnostic marker of AP.