Multicenter phase II trial to investigate safety and efficacy of gemcitabine combined with cetuximab as adjuvant therapy in pancreatic cancer (ATIP).

BACKGROUND: To investigate whether addition of cetuximab to standard adjuvant chemotherapy with gemcitabine improves outcome in pancreatic cancer, specifically whether the rate of disease-free survival (DFS) at 18 months (primary end point) exceeds the previously reported 35% of gemcitabine alone. PATIENTS AND METHODS: Prospective, open-label, multicenter, nonrandomized phase II study in 76 patients with R0- or R1-resected ductal adenocarcinoma of the pancreas included between October 2006 and November 2008. Gemcitabine and cetuximab were administered for 24 weeks. Secondary end points included overall survival (OS) and toxic effect. RESULTS: Seventy-three patients received cetuximab. Median DFS was 10.0 [95% confidence interval (CI) 8.9-13.6] months and the DFS rate at month 18 of 27.1% (16.7%-37.6%) was inferior to 35%. Median OS was 22.4 (18.2-27.9) months. Subgroup analyses revealed a nonsignificant increase in DFS for patients with versus without skin toxic effect ≥ grade 2 (median 14.7 versus 8.3 months, P = 0.073) and wild-type versus mutated K-Ras (median 11.5 versus 9.3 months, P = 0.57). Grade 3/4 toxic effects included neutropenia (11.0%), thrombopenia (7%), skin toxic effect (7%) and allergic reactions (7%). CONCLUSION: Addition of cetuximab to adjuvant gemcitabine does not seem to improve DFS or OS of unstratified pancreatic cancer patients. Trends for improved DFS in patients with wild-type K-Ras and skin toxic effect remain to be confirmed.

Impact of pantoprazole on duodeno-gastro-esophageal reflux (DGER).

BACKGROUND: Duodeno-gastro-esophageal reflux (DGER) is considered as an independent risk factor for complicated reflux disease (GERD). Patients with Barrett's esophagus have significantly higher levels of DGER than patients with uncomplicated GERD. However, the clinical response to conventional high-dose PPI therapy in patients with uncomplicated GERD and DGER is largely unknown. METHODS: 30 patients with uncomplicated GERD and combined pathological reflux (acid and bile) were enrolled in the study. Clinical work-up included evaluation of clinical symptoms, esophageal manometry and upper endoscopy. After 6 - 8 weeks of treatment with Pantoprazole 80 mg/d pH measurement and Bilitec 2000 were repeated, and the pattern of symptoms was re-evaluated. RESULTS: Under treatment with Pantoprazole 80 mg/d acid reflux was normalised in 28 patients (93 %). Similarly the mean percentage of DGER (time with an absorption greater than 0.14) was significantly reduced from 19.6 % (+/- 13.7) to 5.7 % (+/- 7.7, p < 0.05). In 15 patients (50 %) an elevated DGER persisted under treatment with Pantoprazole (DGER-NR group) whereas in 15 cases (50 %) a normalisation could be achieved (DGER-R group). The DGER-NR group had significantly higher levels of bile reflux before (and under) treatment compared to the DGER-R group: 22.9 % (9.98 %) vs. 15.6 % (0.72 %), respectively. Overall, the median quality of life index (QLI) improved from 4.78 (+/- 0.86) before to 8.04 +/- 1.84) under therapy. The clinical response under treatment was marikedly reduced in the DGER-NR group compared to the DGER-R group: QLI 7.3 vs. 8.9. Particularly heartburn and nocturnal coughing persisted. CONCLUSIONS: Our data confirm that high-dose pantoprazole therapy effectively exerts acid suppression in GERD patients with combined pathological reflux. However, DGER could only normalised in 50 % of patients. High levels of DGER at diagnosis enhance the risk of persistent DGER under PPI therapy and are associated with a reduced clinical outcome.

[Prevalence of a pathological DGER (duodeno-gastric-oesophageal reflux) in patients with clinical symptoms of reflux disease]. / Prävalenz eines pathologischen Duodeno-Gastro-Osophagealen Refluxes (DGER) bei Patienten mit klinischen Beschwerden einer Refluxerkrankung.

BACKGROUND: According to recent studies DGER (duodeno-gastric-oesophageal reflux) is considered as an independent risk factor for the development of reflux esophagitis and the Barrett metaplasia. The Bilitec 2000 allows a qualitative and quantitative measurement of DGER in patients with symptoms of reflux disease. The aim of the present study was to investigate the prevalence of DGER in patients with reflux symptoms. METHODS: 146 patients with symptoms of gastro-oesophageal reflux disease were enrolled in this study. Patients underwent upper gastrointestinal endoscopy, oesophageal manometry and simultaneous 24 h oesophageal pH and bilirubin monitoring. The presence of pathological DGER and its relations to the symptom pattern, distal oesophageal acid exposure and endoscopic findings were analysed. RESULTS: In 74 out of 146 patients (51 %, 39 men, 34 women) a DGER could be detected. Twenty-eight (32 %) of these patients suffered from an isolated DGER, while 46 (32 %) had a combined acid and DGER reflux. An isolated acid reflux was found in additional 28 (19 %) patients. The degrees of both acid and DGER were significantly higher in those patients with oesophageal lesions. CONCLUSIONS: 1. There is a high prevalence of DGER in patients with the clinical symptoms of a reflux disease. 2. The combined measurement of acid reflux and DGER helps to better define the cause of reflux symptoms. 3. In analogy to the acid reflux DGER increases with the gravity of oesophageal lesions.

[Reflux-associated nutcracker oesophagus in a 49-year-old patient with non-cardiac chest pain (NCCP)]. / Reflux-assoziierter Nussknacker-Osophagus bei 49-jähriger Patientin mit nicht kardialem Thoraxschmerz (NCCP).

A 49-year-old woman was admitted to our department because of intermittent left-sided chest pain for the past 2 years. The patient reported an increasing frequency and duration of the symptoms which were independent from food intake, medication or physical exercises. A cardiac cause of the chest pain was excluded before admittance to our hospital. The initially performed upper endoscopy revealed a small oesophageal hiatal hernia but no signs of acute or chronic inflammation. Basal oesophageal manometry and pH monitoring confirmed the presence of a nutcracker oesophagus, defined by high-amplitude contractions of the distal oesophagus, in combination with a gastro-oesophageal reflux disease. The patient was treated with high-dose pantoprazole for 8 weeks before re-examination. Interestingly, the symptoms completely disappeared upon medication and the relief of the chest pain was accompanied by normalisation of the nutcracker oesophagus pattern. Thus, our observation provides evidence for a causative role of acid reflux in the pathophysiology of the nutcracker oesophagus and, in addition, suggests that effective acid suppression might be a useful therapeutic tool to deal with this painful motility disorder of the oesophagus.

Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines.

BACKGROUND & AIMS: Biglycan (PG-I), a component of the extracellular matrix (ECM), is overexpressed in pancreatic cancer. To determine possible matrix-tumor interactions, we investigated the effects of PG-I on pancreatic cancer. METHODS: PG-I expression in cell lines and tissue samples was examined by Northern blot and immunofluorescence. The effect of PG-I on proliferation was determined by measuring activity of Ras, ERK, Rb, [(3)H]-thymidine incorporation, and cell cycle analysis. Expression of cyclin A, B1, D1, E1, G1, PCNA, p21, and p27 was analyzed by Northern and Western blots. RESULTS: PG-I was overexpressed in the ECM of pancreatic cancer samples compared with normal pancreas or chronic pancreatitis tissues. Addition of transforming growth factor (TGF)-beta induced PG-I expression in HFL and HFFF2 fibroblasts as well as in the pancreatic cancer cell line PANC-1. PG-I inhibited growth of both TGF-beta-responsive and TGF-beta-unresponsive pancreatic cancer cells by inducing G1-arrest, which is accompanied by an increase of p27 and reduction of cyclin A and proliferating cell nuclear antigen. Furthermore, endogenous Ras and ERK activation was partly reduced by PG-I in vitro. CONCLUSIONS: The ECM protein PG-I inhibits growth by arresting pancreatic cancer cells in G1 and may be part of a host defense mechanism aimed at slowing down pancreatic tumor progression.

Use of DNA arrays/microarrays in pancreatic research.

In recent years, enormous technical advances in experimental protocols as well as robotic and bioinformatic techniques have allowed DNA array/microarray technology to emerge as the leading technology in the field of functional, disease-related genome analysis. Multiple applications exist for DNA arrays/microarrays including comparative genomic analysis to identify chromosomal imbalances (Matrix-CGH), the study of mutations and genetic polymorphisms, and the study of gene expression (expression profiling). Expression profiling is the most widely used application of DNA array/microarray technology and allows to measure gene expression of thousands of genes simultaneously. The present review describes the basic principles of expression profiling analyses and outlines some applications in pancreatic cancer research.

Influence of clarithromycin dosage on pantoprazole combined triple therapy for eradication of Helicobacter pylori.

BACKGROUND: Low-dose clarithromycin (250 mg b.d.) in combination with omeprazole and metronidazole has been recommended for the eradication of Helicobacter pylori. Whether the substitution of omeprazole by pantoprazole requires adjustment of the clarithromycin dose is not known. AIM: To directly compare the efficacy and tolerability of two different dosages of clarithromycin in combination with pantoprazole and metronidazole. METHODS: One hundred and sixty-three patients with endoscopically confirmed gastritis, gastric or duodenal ulcers and positive H. pylori findings in the rapid urease test were randomized and treated for 7 days with pantoprazole (40 mg b.d.). metronidazole (500 mg b.d.) and clarithromycin using either a regimen of 500 mg b.d. (group PMC 500) or 250 mg b.d. (group PMC 250). Eradication success was determined no less than 4 weeks after concluding therapy using the 13C-urea breath test. RESULTS: One-hundred and thirty-nine patients completed the study. Based on a per protocol analysis. successful eradication was documented in 63/70 patients (90.0%) in group PMC 500 and in 62/69 patients (89.9%) in group PMC 250. Based on the intention-to-treat analysis, eradication rates were 78.8% (group PMC 500) and 75.6% (group PMC 250). The incidence of adverse effects was significantly higher in patients receiving PMC 500 (50.0%) than in those receiving PMC 250 (25.4%). CONCLUSIONS: Triple therapy with pantoprazole, metronidazole and clarithromycin provides an efficient eradication regimen for H. pylori infection. A low dose of clarithromycin is equal to a higher dose in therapeutic efficacy and it offers the advantage of improved tolerance and lower cost.