The primary diseases of the pancreas include diabetes mellitus, acute and chronic pancreatitis, as well as pancreatic carcinoma. This review presents findings and emerging questions on the diseases of the pancreas obtained by the consortium of the Collaborative Research Center 518 (SFB 518), "Inflammation, Regeneration, and Transformation in the Pancreas" at the University of Ulm. During the last 12 years, the SFB 518 contributed considerably to the understanding of the cellular and molecular basis of pancreatic diseases and established the basis for the development of new strategies for prevention and causal therapy for diabetes, pancreatitis, and pancreatic cancer. Abbreviations: AP - acute pancreatitis, AR - amphiregulin, CP - chronic pancreatitis, DFG - German Research Foundation, EAD - experimental autoimmune diabetes, ECM - extracellular matrix, EMT - epithelial-mesenchymal transition, ER - endoplasmic reticulum, FGF - fibroblast growth factor, HSC - hepatic stellate cell, IAP - inhibitor of apoptosis, IF - intermediate (keratin) filament, IFNγ - interferon γ, KOC - K-homologous (KH) domain-containing protein overexpressed in cancer, NFAT - nuclear factor of activated T cell, PanIN - pancreatic intraepithelial neoplasia, PI3-K - phosphatidyl-inositol-3 kinase, PKD - protein kinase D, PP-Ins - preproinsulin-II, PSC - pancreatic stellate cell, T1D - type 1 diabetes mellitus, TGF - transforming growth factor, TGN - trans-Golgi network, SEM - scanning electron microscopy, SFB - Collaborative Research Center
Hintergrund: Toxinbildende Clostridium-difficile-Stämme sind weltweit die häufigsten Erreger von Antibiotika-assoziierten Darmerkrankungen und nosokomialer Diarrhö. In den letzten Jahren wurden vermehrt Clostridium-difficile-Infektionen (CDI) mit besonders schweren klinischen Verläufen und damit einhergehender erhöhter Letalität beobachtet. Verläufe mit multiplen Rezidiven werden insbesondere bei Vorliegen einer Immunsuppression beobachtet. Methoden: Ziel dieser retrospektiven kontrollierten Beobachtungsstudie war die Charakterisierung einer Immunsuppression als unabhängiger Risikofaktor für CDI. Dazu wurden Symptome und klinische Merkmale von 105 Patienten mit Clostridium-difficile-Toxinnachweis im Stuhl (detektiert mittels EIA) sowie positivem Antigen-Test oder positiver Kultur, die sich zwischen 2006 und 2009 in stationärer Behandlung der Kliniken für Innere Medizin I und IV des Universitätsklinikums Halle (Saale) befanden, erfasst und ausgewertet. 55 immunsupprimierte Patienten wurden 50 Patienten ohne Immunsuppression gegenübergestellt (Durchschnittsalter 59,3 Jahre ± 16,2 vs. 69,2 Jahre ± 15,0). Für die multivariate statistische Analyse mittels binärer logistischer Regression wurde eine Kontrollgruppe von insgesamt 105 Patienten ohne CDI herangezogen. Diese Gruppe umfasste 62 Patienten ohne Immunsuppression und 43 immunsupprimierte Patienten (Durchschnittsalter 66,9 Jahre ± 12,4 vs. 56,0 Jahre ± 13,7). Ergebnisse: Bei immunsupprimierten Patienten mit CDI fand sich signifikant häufiger eine Kolonisation durch Clostridium difficile ohne klinisch fassbare Manifestation (22 vs. 2 %, p = 0,003), während es vergleichbar viele moderate (46 vs. 52 %, p = 0,503), aber weniger schwere Krankheitsverläufe (27 vs. 40 %, p = 0,167) gab. Rezidive wurden in der Gruppe der Immunsupprimierten häufiger beobachtet (14,5 vs. 6 %, p = 0,153). Die multivariate Analyse mittels logistischer Regression identifizierte das Vorliegen einer Immunsuppression als unabhängigen Risikofaktor für das Erleiden einer CDI (OR = 2,75). Darüber hinaus waren vorangegangene Antibiotikatherapie (OR = 10,15) und PPI-Einnahme (OR = 2,93) unabhängige Risikofaktoren. Schlussfolgerung: Neben dem wichtigsten Risikofaktor Antibiotikatherapie ist somit auch eine Immunsuppression als unabhängiger Risikofaktor für eine CDI zu betrachten. Eine immunsuppressive Behandlung erhöht das Kolonisations- und Infektionsrisiko für toxinbildende Clostridium-difficile-Stämme und führt zu einer erhöhten Rezidivrate bei Patienten mit CDI.
3511 Background: This trial evaluated activity and safety of mFOLFOXIRI + panitumumab vs FOLFOXIRI in ECOG 0-1, primarily non-resectable mCRC patients. The final primary endpoint was presented at ASCO and ESMO 2018. Now we report for the first time the final results regarding OS and PFS. Methods: Prospective 2:1 randomized, controlled, open label multi-center, phase II trial comparing mFOLFOXIRI (Ox 85 mg/m2, Iri 150 mg/m2, 5-FU 3000mg/m2 cont. 48h, LV 200 mg/m2) + Panitumumab 6 mg/KG (arm A) with FOLFOXIRI (Ox 85 mg/m2, Iri 165 mg/m2, 5-FU 3200mg/m2 cont. 48h, LV 200 mg/m2; arm B), both arms q2w. Prospective strata were cohort 1: irresectable mCRC (n=65), and cohort 2: chance of secondary resection of metastatic lesions (n=31). Primary endpoint was ORR, secondary endpoints were secondary resection rate (cohort 2), DCR, PFS, OS, toxicity, quality of life (QLQ-C30). Financially supported by an unrestricted grant from Amgen. Results: A total of 96 patients were randomized (63 arm A, 33 arm B). ORR was 87.3% in arm A and 60.6% in arm B (p=0.0041, OR 4.47; 95%-CI 1.614-12.376). Secondary resections of metastases in the ITT population were observed in 33·3% (arm A Pmab) versus 12·1% (arm B) (OR=3.63; 95%-CI 1.13–11.67, p=0·029) and in cohort 2 in 75% (arm A Pmab) versus 36.4% (arm B) (OR=5.25; 95%-CI 1.07–25.8, p=0.05), respectively. Median PFS was similar in the study arms (9.7 mo in both arms, HR 1.071; 95%-CI 0.689-1.665, p=0.76). OS in the ITT population showed a strong trend in favour of the Pmab-containing arm A with a median OS of 35.7 mo compared to 29.8 mo in arm B (HR: 0·67; 95%-CI 0.41-1.11, P=0·12). mOS of cohort 2 was 52.0 mo in arm A versus 41.7 mo in arm B (HR 0.413; 95%-CI 0.15-1.12, p=0.07). Further results regarding to sidedness and BRAF mutational status will be presented. Conclusions: The addition of Pmab to a mFOLFOXIRI regimen in patients with RASwildtype metastatic colorectal cancer significantly improved objective response rate and the rate of secondary resection of metastases. Although PFS was comparable, there was a strong trend towards improved OS in the Pmab arm. Future studies are warranted to confirm this trend towards improved overall survival with this regimen. Clinical trial information: NCT01328171.
204 Background: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. Methods: 15 German and Austrian centers prospectively recruited 154 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). Results: Using random forest machine learning, we developed a predictive model that discriminated between the situations of ”no progress within 100 days before radiological progress” and ”progress within 100 days before radiological progress”. Into this we incorporated a combination of ten out of the 102 CAF markers, which fulfilled this task with 81% accuracy, 72% sensitivity, and 88% specificity. Conclusions: Using artificial intelligence we identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress. Further studies are required to show its clinical value. Clinical trial information: NCT02331927 .
The 5-year survival of patients with resected pancreatic adenocarcinoma is still unsatisfying. The ESPAC-1 and the CONKO 001 trial proofed that adjuvant chemotherapy improves 5-year survival significantly from approximately 14% to 21%. In parallel, investigators from the Virginia Mason Clinic reported a 5-year survival rate of 55% in a phase II trial evaluating a combination of adjuvant chemotherapy, immunotherapy and external beam radiation (CapRI-scheme). Two other groups confirmed in phase II trials these results to a certain extent. However, these groups reported severe gastrointestinal toxicity (up to 93% grade 3 or 4 toxicity). In a randomized controlled phase III trial, called CapRI, 110 patients were enrolled from 2004 to 2007 in Germany and Italy to check for reproducibility. Interestingly, much less gastrointestinal toxicity was observed. However, dose-reduction due to haematological side effects had to be performed in nearly all patients. First clinical results are expected for the end of 2009. CapRI-2 is an open, controlled, prospective, randomized, multicentre phase II trial with three parallel arms. A de-escalation of the CapRI-scheme will be tested in two different modifications. Patients in study arm A will be treated as outpatients with the complete CapRI-scheme consisting of cisplatin, Interferon alpha-2b and external beam radiation and three cycles of 5-fluorouracil continuous infusion. In study arm B the first de-escalation will be realised by omitting cisplatin. Next, patients in study arm C will additionally not receive external beam radiation. A total of 135 patients with pathologically confirmed R0 or R1 resected pancreatic adenocarcinoma are planned to be enrolled. Primary endpoint is the comparison of the treatment groups with respect to six-month event-free-survival. An event is defined as grade 3 or grade 4 toxicity, objective tumour recurrence, or death. The aim of this clinical trial is to evaluate de-escalation of the CapRI-scheme. It is hypothesised that removal of cisplatin and radiotherapy will have no significant effect or only a minor impact on the clinical response but result in substantially lower toxicity. Current Controlled Trials ISRCTN79802092
Onkologische Therapien sind von Nebenwirkungen begleitet, die in unterschiedlichem Ausmaß die Lebensqualität einschränken und Einfluss auf die zeit- und dosisgerechte Applikation der Systemtherapie haben können. Therapieassoziierte Nebenwirkungen frühzeitig zu erkennen und zu behandeln ist daher ein entscheidender Faktor für Therapiecompliance und Lebensqualität der Patient*innen. Aktuell werden Nebenwirkungen oder Unverträglichkeiten in der Regel bei den Arztbesuchen, meist im Abstand von 14-28 Tagen erfasst. Eine Untersuchung des MSKCC zeigte, dass ein häufigeres Monitoring von Nebenwirkungen durch Patient*innen selbst die gesundheitsbezogene Lebensqualität (health related quality of life, HRQL) von Patient*innen während einer Chemotherapie verbessern kann. [1].
in der zweiten Ausgabe der Gastroenterologie up2date bieten wir Ihnen wieder Spannendes aus dem großen Spektrum der Gastroenterologie. Dieses Mal stehen die Themen Achalasie, Diagnostik von Leberläsionen, das Pankreaskarzinom und die Colitis ulcerosa im Fokus.
