[Gangliocytic paraganglioma--a rare differential diagnosis of a submucosal duodenal tumor]. / Gangliozytisches Paragangliom--eine seltene Differenzialdiagnose eines submukösen duodenalen Tumors.

We report on the case of a 36-year-old male patient who was found to have a submucosal duodenal tumour during the diagnostic work-up of gastrointestinal bleeding. After exclusion of other tumour manifestations complete endoscopic resection was performed. Histologically a gangliocytic paraganglioma was diagnosed, a very rare type of a duodenal neuroendocrine tumour. This case report discusses the epidemiology, diagnostic work-up and therapeutic options for this rare tumour type.

Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors.

Functional inactivation of the Rb and p53 pathways appears to be a rite of passage for all cancerous cells. However, p53 and Rb alterations are rare events in neuroendocrine gastroenteropancreatic (GEP) tumors. The CDKN2 locus on chromosome 9p21 sits at the nexus of both pathways harboring tumor suppressor genes, which restrain cell growth by affecting the function of pRb and p53. Therefore, we analyzed the implication of their inactivation in 37 primary neuroendocrine GEP tumors and two cell culture models. RT-PCR analysis revealed loss of expression of at least one of the tumor suppressor genes CDKN2A/p16, CDKN2B/p15, and CDKN2D/p14 with distinct genetic profiles, most frequently in nonfunctional pancreatic tumors (57%) and small intestinal carcinoids (44%), and less commonly in insulinomas (30%) and gastrinomas (22%). DNA analysis and methylation-specific PCR attributed loss of expression to either homozygous deletion or 5'CpG island hypermethylation. 5-Aza-2-deoxycytidine treatment reversed CDKN2A/p16 and CDKN2B/p15 silencing with concurrent growth restraint. Thus, tumor suppressor genes localized in the 9p21 gene cluster are specific targets of inactivation in neuroendocrine GEP tumors, and demethylating agents might hold promise for selective therapy.

Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme.

BACKGROUND: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. PATIENTS AND METHODS: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks+1-week rest followed by once 3-weeks+1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). RESULTS: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P=0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P=0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P=0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRß expression correlated with longer PFS. CONCLUSION: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.

Efficacy and safety of sorafenib in advanced hepatocellular carcinoma under daily practice conditions.

Sorafenib has recently been shown to be effective for the treatment of advanced hepatocellular carcinoma in randomized controlled trials. Here, we report the experience with sorafenib in 25 patients with advanced HCC under daily practice conditions. Tolerance to sorafenib was acceptable and side effects were manageable, although the ECOG performance status was reduced in all patients. The most prevalent grade 2/3 side effects were fatigue (40%) and diarrhea (24%), and withdrawal from therapy occurred in 29% of patients. Disease stabilization was documented in 60% of patients. The median treatment time was 2.7 months and overall survival was 11.0 months. No significant serum alpha-fetoprotein decline was noted at the time of the first radiological control in a subgroup of patients with baseline levels >50 ng/ml who achieved stable disease. In conclusion, in daily practice sorafenib is safe and disease stabilization can be achieved in the majority of patients. However, intolerance to sorafenib can affect treatment adherence substantially.

Neoadjuvant treatment with cetuximab, 5-Fluorouracil, folinic Acid and oxaliplatin in unresectable retroperitoneal recurrent colon cancer.

Some patients with initially unresectable hepatic colorectal cancer metastases can be effectively treated with neoadjuvant chemotherapy to allow operative resection in curative intent. Here, we report on a patient with unresectable locoregional recurrence of colon cancer, which was down-staged using combination chemotherapy with infusional 5-fluorouracil, folinic acid, oxaliplatin and cetuximab. After 12 weeks of therapy a partial response was documented and 3 weeks later the tumor was completely resected without increased perioperative morbidity. Therefore, neoadjuvant treatment with molecular targeted agents in combination with chemotherapy can also be an option to enable selected patients with locoregional recurrence to undergo surgical resection in curative intent.