No abstract

Since the discovery of the first trypsinogen mutation in families with hereditary pancreatitis, pancreatic genetics has made rapid progress. The identification of mutations in genes involved in the digestive protease-antiprotease pathway has lent additional support to the notion that pancreatitis is a disease of autodigestion. Clinical and experimental observations have provided compelling evidence that premature intrapancreatic activation of digestive proteases is critical in pancreatitis onset. However, disease course and severity are mostly governed by inflammatory cells that drive local and systemic immune responses. In this article, we review the genetics, cell biology, and immunology of pancreatitis with a focus on protease activation pathways and other early events.

In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

Background & AimsLittle is known about the pathogenic mechanisms of chronic pancreatitis. We investigated the roles of complement component 5 (C5) in pancreatic fibrogenesis in mice and patients.MethodsChronic pancreatitis was induced by ligation of the midpancreatic duct, followed by a single supramaximal intraperitoneal injection of cerulein, in C57Bl6 (control) and C5-deficient mice. Some mice were given injections of 2 different antagonists of the receptor for C5a over 21 days. In a separate model, mice were given injections of cerulein for 10 weeks to induce chronic pancreatitis. Direct effects of C5 were studied in cultured primary cells. We performed genotype analysis for the single-nucleotide polymorphisms rs 17611 and rs 2300929 in C5 in patients with pancreatitis and healthy individuals (controls). Blood cells from 976 subjects were analyzed by transcriptional profiling.ResultsDuring the initial phase of pancreatitis, levels of pancreatic damage were similar between C5-deficient and control mice. During later stages of pancreatitis, C5-deficient mice and mice given injections of C5a-receptor antagonists developed significantly less pancreatic fibrosis than control mice. Primary pancreatic stellate cells were activated in vitro by C5a. There were no differences in the rs 2300929 SNP between subjects with or without pancreatitis, but the minor allele rs17611 was associated with a significant increase in levels of C5 in whole blood.ConclusionsIn mice, loss of C5 or injection of a C5a-receptor antagonist significantly reduced the level of fibrosis of chronic pancreatitis, but this was not a consequence of milder disease in early stages of pancreatitis. C5 might be a therapeutic target for chronic pancreatitis.

Background Despite significant progress in diagnostics and therapeutics, over fifty thousand patients die from colorectal cancer annually. Hence there is urgent need for new lines of treatment. Triptolide, a natural compound isolated from the Chinese herb Tripterygium wilfordii, is effective against multiple cancers. We have synthesized a water soluble analog of triptolide, named Minnelide, which is currently in phase I trial against pancreatic cancer. The aims of the current study were to evaluate whether triptolide/Minnelide is effective against colorectal cancer and to elucidate the mechanism by which triptolide induces cell death in colorectal cancer. Methods Efficacy of Minnelide was evaluated in subcutaneous xenograft and liver metastasis model of colorectal cancer. For mechanistic studies colon cancer cell lines HCT116 and HT29 were treated with triptolide and the effect on viability, caspase activation, annexin positivity, lactate dehydrogenase(LDH) release and cell cycle progression was evaluated. Effect of triptolide on E2F transcriptional activity, mRNA levels of E2F dependent genes, E2F1-Rb binding and proteins levels of regulator of G1-S transition was also measured. DNA binding of E2F1 was evaluated by chromatin immunoprecipitation assay. Results Triptolide decreased colon cancer cell viability in a dose- and time-dependent fashion. Minnelide markedly inhibited the growth of colon cancer in the xenograft and liver metastasis model of colon cancer and more than doubles the median survival of animals with liver metastases from colon cancer. Mechanistically we demonstrate that at low concentrations, triptolide induces apoptotic cell death but at higher concentrations it induces cell cycle arrest. Our data suggest that triptolide is able to induce G1 cell cycle arrest by inhibiting transcriptional activation of E2F1. Our data also show that triptolide downregulates E2F activity by potentially modulating events downstream of DNA binding. Conclusion Triptolide and Minnelide are effective against colon cancer in multiple pre-clinical models.

Kapitel: Definition und Ätiologie der akuten Pankreatitis 427 2. Schweregradeinschätzung einer akuten Pankreatitis 431 3. Bildgebung bei akuter Pankreatitis 435 4. Volumen-und Schmerztherapie, Intensivmedizinische Therapie bei akuter Pankreatitis 438 5. Antibiotika, Probiotika und Ernährung bei akuter Pankreatitis (Prävention und Therapie infektiöser Komplikationen) 442 6. Akute biliäre Pankreatitis und Therapie biliärer Komplikationen 445 7. Indikation, Zeitpunkt und Therapieverfahren bei infizierter Nekrose 448 8. Verlaufskontrolle nach akuter Pankreatitis 452 9. Definition, Epidemiologie und Ätiologie der chronischen Pankreatitis 456 9.1. Definition 456 10. Diagnostik (Funktionstests, Bildgebung, Klassifikation) bei chronischer Pankreatitis 459 10.3. Funktionstests 459 10.4. Bildgebung 461 10.5. Klassifikation 462 11. Medikamentöse Therapie der chronischen Pankreatitis 464 11.1. Akuter Schub 464 11.2. Schmerztherapie 464 11.3. Enzymsubstitution bei chronischer Pankreatitis 467 11.4. Ernährung 470 Inhaltsverzeichnis Seite 12. Endoskopische und interventionelle Therapie 471 12.1. Indikationsstellung 471 12.2. Therapie von Pseudozysten 473 12.3. Therapie von Pseudoaneurysmen 476 12.4. Therapie von Pankreasgangveränderungen und Pankreasgangsteinen bei chronischer Pankreatitis 477 12.5. Endoskopische Therapie von Gallengangsstenosen bei chronischer Pankreatitis 479 13. Indikationsstellung und chirurgische Therapie bei chronischer Pankreatitis 480 14. Überwachung und Verlaufskontrolle 484 15. Diagnostik und Therapie der chronischen Pankreatitis im Kindesalter 486 15.2. Klinisches Bild der Pankreatitis bei Kindern und Jugendlichen 486 15.3. Ätiologie und Häufigkeitsverteilung der Pankreatitis im Kindes-und Jugendalter 486 15.4. Komplikationen der Pankreatitis bei Kindern und Jugendlichen 487 15.5. Labordiagnostik bei V. a. Pankreatitis im Kindesund Jugendalter 487 15.6. Bildgebende Diagnostik bei Pankreatitis im Kindes-und Jugendalter 488 15.7. Genetische Diagnostik bei Pankreatitis im Kindes-und Jugendalter 489 15.8. Spezifische Diagnostik zum Ausschluss einer zystischen Fibrose bei Kindern und Jugendlichen mit chronischer Pankreatitis 489 15.9. Supportive Therapiemaßnahmen bei Kindern und Jugendlichen im akuten Schub einer Pankreatitis 490 15.10. Endoskopisch-interventionelle Therapie bei Kindern und Jugendlichen mit Pankreatitis 490 15.11. Operative Therapie bei Kindern und Jugendlichen mit Pankreatitis 490 15.12. Schmerztherapie der chronischen Pankreatitis bei Kindern und Jugendlichen 490 15.13. Ernährung bei Kindern im akuten Schub einer Pankreatitis 491

Acute pancreatitis is a common indication for hospital admission, increasing in incidence, including in children, pregnancy and the elderly. Moderately severe acute pancreatitis with fluid and/or necrotic collections causes substantial morbidity, and severe disease with persistent organ failure causes significant mortality. The diagnosis requires two of upper abdominal pain, amylase/lipase ≥ 3 ×upper limit of normal, and/or cross-sectional imaging findings. Gallstones and ethanol predominate while hypertriglyceridaemia and drugs are notable among many causes. Serum triglycerides, full blood count, renal and liver function tests, glucose, calcium, transabdominal ultrasound, and chest imaging are indicated, with abdominal crosssectional imaging if there is diagnostic uncertainty. Subsequent imaging is undertaken to detect complications, for example, if C-reactive protein exceeds 150 mg/L, or rarer aetiologies. Pancreatic intracellular calcium overload, mitochondrial impairment, and inflammatory responses are critical in pathogenesis, targeted in current treatment trials, which are crucially important as there is no internationally licenced drug to treat acute pancreatitis and prevent complications. Initial priorities are intravenous fluid resuscitation, analgesia, and enteral nutrition, and when necessary, critical care and organ support, parenteral nutrition, antibiotics, pancreatic exocrine and endocrine replacement therapy; all may have adverse effects. Patients with local complications should be referred to specialist tertiary centres to guide further management, which may include drainage and/or necrosectomy. The impact of acute pancreatitis can be devastating, so prevention or reduction of the risk of recurrence and progression to chronic pancreatitis with an increased risk of pancreas cancer requires proactive management that should be long term for some patients.

No abstract