Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

The impact of endoscopic activity on musculoskeletal disorders of high-volume endoscopists in Germany.

Physical stress is common in GI endoscopists, leading to musculoskeletal disorders. Considering the increasing complexity of interventional GI endoscopy with prolonged examination time, work-related musculoskeletal disorders have come into focus. However, data on work-related health stress in German endoscopists are elusive. The aim of this study was therefore to investigate the prevalence and consequences of work-related musculoskeletal disorders in German endoscopists. A 24-item questionnaire on endoscopy-associated musculoskeletal disorders and standardized pain assessment was developed by an interdisciplinary team of endoscopists and sports medics. The survey was distributed online by the leading German societies for gastroenterology and endoscopy. Overall, 151 German practicing endoscopists took part in the study. Regarding the average number of endoscopic procedures per week, the study collective consisted mainly of high-volume endoscopists. The survey showed that most participants suffered from general musculoskeletal disorders (82.8%) and from work-related musculoskeletal disorders (76.8%). The most affected body parts were the neck, low back, thumb, and shoulder. Temporary absence from work due to symptoms was reported by 9.9% of the respondents. Over 30% of participating endoscopists stated the need for analgesics or physiotherapy due to musculoskeletal disorders. Age, professional experience and work time were identified as relevant risk factors for musculoskeletal health issues. A high number of German endoscopists are affected by musculoskeletal disorders due to specific working postures and repetitive movements with a large impact on personal health. Further interventional studies are mandatory to improve the risk prevention of endoscopic activity.

Nal-IRI with 5-fluorouracil (5-FU) and leucovorin or gemcitabine plus cisplatin in advanced biliary tract cancer - the NIFE trial (AIO-YMO HEP-0315) an open label, non-comparative, randomized, multicenter phase II study.

BACKGROUND: Biliary tract cancer (BTC) has a high mortality. Primary diagnosis is frequently delayed due to mostly unspecific symptoms, resulting in a high number of advanced cases at the time of diagnosis. Advanced BTCs are in principle chemotherapy sensitive as determined by improved disease control, survival and quality of life (QoL). However, median OS does not exceed 11.7 months with the current standard of care gemcitabine plus cisplatin. Thereby, novel drug formulations like nanoliposomal-irinotecan (nal-IRI) in combination with 5- fluorouracil (5-FU)/leucovorin may have the potential to improve therapeutic outcomes in this disease. METHODS: NIFE is an interventional, prospective, randomized, controlled, open label, two-sided phase II study. Within the study, 2 × 46 patients with locally advanced, non-resectable or metastatic BTC are to be enrolled by two stage design of Simon. Data analysis will be done unconnected for both arms. Patients are allocated in two arms: Arm A (experimental intervention) nal-IRI mg/m2, 46 h infusion)/5-FU (2400 mg/m2, 46 h infusion)/leucovorin (400 mg/m2, 0.5 h infusion) d1 on 14 day-cycles; Arm B (standard of care) cisplatin (25 mg/m2, 1 h infusion)/gemcitabine (1000 mg/m2, 0.5 h infusion) d1 and d8 on 21 day-cycles. The randomization (1:1) is stratified for tumor site (intrahepatic vs. extrahepatic biliary tract), disease stage (advanced vs. metastatic), age (≤70 vs. > 70 years), sex (male vs. female) and WHO performance score (ECOG 0 vs. ECOG 1). Primary endpoint of the study is the progression free survival (PFS) rate at 4 months after randomization by an intention-to-treat analysis in each of the groups. Secondary endpoints are the overall PFS rate, the 3-year overall survival rate, the disease control rate after 2 months, safety and patient related outcome with quality of life. The initial assessment of tumor resectability for locally advanced BTCs is planned to be reviewed retrospectively by a central surgical board. Exploratory objectives aim at establishing novel biomarkers and molecular signatures to predict response. The study was initiated January 2018 in Germany. DISCUSSION: The NIFE trial evaluates the potential of a nanoliposomal-irinotecan/5-FU/leucovorin combination in the first line therapy of advanced BTCs and additionally offers a unique chance for translational research. TRIAL REGISTRATION: Clinicaltrials.gov NCT03044587. Registration Date February 7th 2017.

"Miniguts" from plucked human hair meet Crohn's disease.

Human pluripotent stem cells represent a powerful tool to study human embryonic development and disease but also open up novel strategies for cell replacement therapies. Their capacity to give rise to every cell type of the human body, meanwhile, enables researchers to generate high yields of mesodermal, ectodermal, but also endodermal-derived tissues such as hepatic, pancreatic, or intestinal cells. Another progress in the field came with the advent of 3-dimensional culture conditions, so-called organoids, which facilitate maturation of stem cells and in turn more faithfully recapitulate human tissue architecture. While several studies reported the derivation of organoid cultures from adult intestinal tissue, the derivation of intestinal organoids derived from plucked human hair of Crohn's disease patients has not been reported. The current research project reports such successful generation and characterization of induced pluripotent stem cells (iPSCs) derived from hair sheet keratinocyte cultures of a patient with Crohn's disease. Stepwise differentiation along the intestinal lineage showed no differences in intermediate stages such as definitive endoderm formation. We also directed the patterned primitive gut tube toward intestinal organoids resembling the cellular architecture of human "miniguts". As expected from current pathophysiological knowledge on Crohn's disease, there were no obvious morphological differences in the "miniguts" derived from healthy control and diseased patient-induced pluripotent stem cells. Taken together, our platform will enable for detailed and complementary phenotyping of the pathophysiology of Crohn's disease in a novel disease-in-a-dish format.

[Personalized tumor therapy for gastrointestinal tumors]. / Personalisierte Tumortherapie bei gastrointestinalen Tumoren.

Personalized tumor therapy or more precisely tumor-specific therapy has now become established in routine clinical oncology. Particularly for solid tumors, the emerging knowledge about pathways and signaling networks allows the establishment of new targeted therapies and hopefully a continuous improvement in patient care. Targeted therapies are now established as the standard of care as single agents or in combination with chemotherapy. Using targeted therapies, substantial improvements regarding tumor response, median progression-free survival and median overall survival can be achieved for selected gastrointestinal tumors. However, these strategies also have novel side effects that need to be addressed. Importantly, valid (positive) predictive biomarkers are needed for a rational use of these novel compounds. This review article presents the current state of targeted tumor therapy for the diagnostics and therapy of gastrointestinal tumors and provides assistance in integrating the current knowledge into the routine clinical context.

Smarter drugs emerging in pancreatic cancer therapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer death in the Western world. Owing to a lack of specific symptoms and no accessible precursor lesions, primary diagnosis is commonly delayed, resulting in only 15%-20% of patients with potentially curable disease. The standard of care in advanced pancreatic cancer has improved. Apart from gemcitabine (plus erlotinib), FOLFIRINOX and the combination of gemcitabine plus nab-paclitaxel are novel and promising therapeutic options for patients with metastatic PDAC. A better molecular understanding of pancreatic cancer has led to the identification of a variety of potential molecular therapeutic targets. Many targeted therapies are currently under clinical evaluation in combination with standard therapies for PDAC. This review highlights the current status of targeted therapies and their potential benefit for the treatment of advanced PDAC.