Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205.

BACKGROUND: Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. METHODS: Two dose levels (I/II) were defined: capecitabine 850/1000 mg m(-2) twice daily on days 1-14; oxaliplatin 100/130 mg m(-2) on day 1; bevacizumab 7.5 mg kg(-1) on day 1; imatinib 300 mg day(-1) on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). RESULTS: Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. CONCLUSION: The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.

Cetuximab with irinotecan, folinic acid and 5-fluorouracil as first-line treatment in advanced gastroesophageal cancer: a prospective multi-center biomarker-oriented phase II study.

BACKGROUND: Cetuximab plus irinotecan/folinic acid/5-fluorouracil (5-FU) (IF) was evaluated as first-line treatment of patients with advanced gastric cancer and gastroesophageal junction tumors. Preplanned analyses of the influence of tumor biomarkers on treatment outcome were carried out. PATIENTS AND METHODS: Patients received weekly cetuximab (400 mg/m(2) on day 1, subsequently 250 mg/m(2)) plus irinotecan (80 mg/m(2)) and a 24-hour continuous infusion of folinic acid (200 mg/m(2)) and 5-FU (1500 mg/m(2)) on days 1, 8, 15, 22, 29 and 36 of a 50-day cycle, until progressive disease (PD). RESULTS: The most common grade 3/4 toxic effects in 49 patients were diarrhea (15%) and skin toxic effects (14%). In 48 assessable patients, the overall response rate was 46% and disease control rate was 79%. Median progression-free survival (PFS) and overall survival (OS) was 9.0 months [95% confidence interval (CI) 7.1-15.6] and 16.5 months (95% CI 11.7-30.1), respectively. Tumor response was more common than nonresponse in epidermal growth factor receptor-expressing tumors (P = 0.041). Tumor PTEN expression was associated with longer PFS (P = 0.035) and OS (P = 0.0127) than no PTEN expression. CONCLUSION: Cetuximab plus IF was well tolerated and efficacy data were encouraging. This treatment combination and the role of selected biomarkers are under investigation in the ongoing phase III EXPAND trial.

Afatinib plus gemcitabine versus gemcitabine alone as first-line treatment of metastatic pancreatic cancer: The randomised, open-label phase II ACCEPT study of the Arbeitsgemeinschaft Internistische Onkologie with an integrated analysis of the 'burden of therapy' method.

BACKGROUND: Targeting the epidermal growth factor receptor pathway remains controversial in pancreatic cancer. Afatinib is an oral irreversible ErbB family blocker approved in non-small-cell lung cancer. This open-label, multicenter, randomised phase II trial evaluated gemcitabine plus afatinib (Gem/afatinib) versus gemcitabine (Gem) alone as first-line treatment for metastatic pancreatic cancer. PATIENTS AND METHODS: Patients were randomised in a 2:1 ratio to either Gem (1000 mg/m2 weekly for three weeks followed by one week of rest, repeated every four weeks) and afatinib (40 mg orally once daily) or Gem alone. Overall survival (OS) was the primary study end-point. The novel BOTh©™ methodology was implemented to derive a quantitative estimate for the 'Burden of Therapy/Toxicity' (BOTh) for each patient on every day during the clinical study. RESULTS: One hundred nineteen patients from 25 centres were randomised, 79 patients for Gem/afatinib and 40 for Gem. Median OS was 7.3 months in the Gem/afatinib arm versus 7.4 months in the Gem-alone arm (hazard ratio [HR]: 1.06, p = 0.80). Median progression-free survival was identical in both arms (3.9 months versus 3.9 months, HR: 0.85, p = 0.43). Adverse events were more frequent in the Gem/afatinib arm, especially diarrhoea (71% vs. 13%) and skin rash (65% vs. 5%). The BOTh©™ analysis revealed a significantly higher burden of toxicity in the combination arm (p = 0.0005). CONCLUSION: The addition of afatinib to Gem did not improve treatment efficacy and was more toxic. The BOTh©™ methodology allowed a detailed insight into the course of treatment-related adverse events over the study period. The trial was registered at clinicaltrials.gov (NCT01728818) and Eudra-CT (2011-004063-77).

Phase II trial of mapatumumab, a fully human agonistic monoclonal antibody that targets and activates the tumour necrosis factor apoptosis-inducing ligand receptor-1 (TRAIL-R1), in patients with refractory colorectal cancer.

BACKGROUND: Recombinant tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) induces tumour-selective apoptosis in various pre-clinical models by binding its specific receptors expressed on cancer cells. Mapatumumab is a fully human monoclonal antibody that is agonistic to the TRAIL Receptor 1 (TRAIL-R1). METHODS: This phase II multicentre study was designed to evaluate the efficacy and safety of mapatumumab in patients with colorectal cancer (CRC) who had failed to respond to, were intolerant to, or not candidates for fluoropyrimidine, oxaliplatin, and irinotecan-based regimens. All patients received two loading doses of mapatumumab (20 mg kg(-1) every 14 days), followed by maintenance therapy with 10 mg kg(-1) infused every 14 days. RESULTS: A total of 38 patients, who had progressive disease after a median of three earlier chemotherapy lines, were enrolled. No response according to the Response Evaluation Criteria in Solid Tumors was observed. A total of 12 patients (32%) achieved stable disease for a median of 2.6 months. The median progression-free survival was 1.2 months. The most common adverse events reported, regardless of relationship, were fatigue, nausea, anorexia, and abdominal pain. Plasma mapatumumab concentrations were within the range of exposures predicted by the results of phase I studies of mapatumumab. CONCLUSION: No clinical activity of single-agent mapatumumab was observed in patients with advanced refractory CRC. However, on the basis of its favourable safety profile and pre-clinical evidence of potential synergy in combination with agents commonly used in the treatment of colorectal cancer, further evaluation of mapatumumab in combination with chemotherapy is warranted.

A randomized multicenter phase II study comparing capecitabine with irinotecan or cisplatin in metastatic adenocarcinoma of the stomach or esophagogastric junction.

BACKGROUND: The combination of irinotecan with 5-fluorouracil demonstrates efficacy with tolerable safety in the first-line treatment of metastatic gastroesophageal cancer (mGC). This randomized phase II trial compared for the first time capecitabine with irinotecan or cisplatin in this setting. PATIENTS AND METHODS: Patients were randomly assigned to receive 3-week cycles of capecitabine 1000 mg/m(2), twice daily for 14 days, with on day 1 either irinotecan 250 mg/m(2) (XI) or cisplatin 80 mg/m(2) (XP). The primary end point was overall response rate (ORR) and secondary end points included progression-free survival (PFS), overall survival (OS) and safety. RESULTS: Of 118 patients recruited, 112 were eligible for safety analysis and 103 for efficacy analysis. In the XI and XP treatment arms, there were no marked differences in ORR, 37.7% versus 42.0%, and median PFS, 4.2 versus 4.8 months, although median OS was longer, 10.2 versus 7.9 months, respectively. Grade 3/4 toxicity was higher in the XP regimen for thrombocytes (18.2% versus 1.8%), nausea (23.6% versus12.3%) and vomiting (16.4% versus 1.8%) and in the XI arm for diarrhea (22.8% versus 7.3%). CONCLUSION: The comparable activity and safety of the XI and XP regimens establish XI as a relevant platinum-free first-line treatment choice for patients with mGC.

Dynamics in treatment response and disease progression of metastatic colorectal cancer (mCRC) patients with focus on BRAF status and primary tumor location: analysis of untreated RAS-wild-type mCRC patients receiving FOLFOXIRI either with or without panitumumab in the VOLFI trial (AIO KRK0109).

PURPOSE: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. METHODS: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. RESULTS: BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. CONCLUSIONS: BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.

In vivo confocal laser endomicroscopy of the human liver: a novel method for assessing liver microarchitecture in real time.

BACKGROUND AND STUDY AIMS: Confocal endomicroscopy is a unique novel tool for in vivo histology in humans. Due to limitations imposed by the form of the equipment and by sterilization workflows, its use has been limited to the gastrointestinal tract so far. We have developed a rigid miniaturized probe for confocal endomicroscopy of the human liver during laparoscopy. PATIENTS AND METHODS: To assess the feasibility and potential clinical value of this new system (diameter 6.3 mm), 25 patients with liver disease were examined during routine minilaparoscopy under conscious sedation. RESULTS: Subsurface serial images (from surface to 250 microm) were generated in real time after fluorescein injection, permitting visualization of hepatocytes, bile ducts, sinusoids, and collagen fibers in vivo. Typical appearances of liver diseases were identified. Confocal diagnosis of moderate-to-severe steatosis and pericellular fibrosis correlated well with histopathologic analysis of subsequent biopsies (83.3 % and 84.6 %, respectively). In addition, intra-abdominal structures such as gallbladder, omentum, and stomach were analyzed by endomicroscopy. CONCLUSIONS: A miniaturized imaging system for confocal laparoscopy allowed in vivo microscopic analysis of healthy and diseased human liver for the first time during ongoing minilaparoscopy. Although such in vivo imaging does not yet compete with conventional histopathology, this novel confocal laparoscopy system may be of future relevance for immediate morphodynamic analysis in liver disease and the targeting of biopsies in vivo.

Efficacy of gemcitabine plus erlotinib in rash-positive patients with metastatic pancreatic cancer selected according to eligibility for FOLFIRINOX: A prospective phase II study of the 'Arbeitsgemeinschaft Internistische Onkologie'.

INTRODUCTION: In metastatic pancreatic ductal adenocarcinoma (mPDAC) treatment, erlotinib is known to be more effective in patients developing skin rash. Treatment with the FOLFIRINOX regimen is only performed in fit patients following defined inclusion criteria. The present study investigates the efficacy of gemcitabine plus erlotinib (gem/erlotinib) in rash-positive patients fit for FOLFIRINOX. PATIENTS AND METHODS: For this prospective phase II study, 150 patients were recruited in 20 centres. All patients received gem/erlotinib for 4 weeks (run-in phase); the subsequent treatment was determined by the development of skin rash: patients with rash grades 1-4 continued with gem/erlotinib, rash-negative patients were switched to FOLFIRINOX. Primary study end-point was to achieve a 1-year survival rate in rash-positive patients ≥40%. RESULTS: Ninety patients were deemed positive for skin rash by the end of the run-in phase, showing a 1-year survival rate of 40.0% (95% confidence interval [CI] 29.8-50.9). Median overall survival (OS) was 10.1 months, progression-free survival (PFS) was 3.8 months and overall response rate (ORR) was 23.3%. Patients switched to FOLFIRINOX (n = 27) had a 1-year survival rate of 48.1% (95% CI 28.7-68.1), a median OS of 10.9 months, a median PFS of 6.6 months and an ORR of 33.3%. Rash-negative patients had a lower quality of life at baseline but seemed to experience an improved control of pain during FOLFIRINOX. CONCLUSIONS: First-line treatment with gem/erlotinib was effective in fit, rash-positive mPDAC patients achieving a 1-year survival rate comparable to previous reports for FOLFIRINOX. The study was registered at clinicaltrials.gov (NCT0172948) and Eudra-CT (2011-005471-17).

In-vivo confocal real-time mini-microscopy in animal models of human inflammatory and neoplastic diseases.

BACKGROUND AND STUDY AIMS: Although various improvements in tissue imaging modalities have recently been achieved, in-vivo molecular and subsurface imaging in the field of gastroenterology remains a technical challenge. In this study we evaluated a newly developed, handheld, miniaturized confocal laser microscopy probe for real-time in-vivo molecular and subsurface imaging in rodent models of human disease. MATERIALS AND METHODS: The minimicroscope uses a 488-nm, single line laser for fluorophore excitation. The optical slice thickness is 7 microm, the lateral resolution 0.7 microm. The range of the z-axis is 0-250 microm below the tissue surface. Imaging was performed using different fluorescent staining protocols; 5-carboxyfluorescein-labeled octreotate was synthesized for targeted molecular imaging. RESULTS: Cellular and subcellular details of the gastrointestinal tract could be visualized in vivo at high resolution. Confocal real-time microscopy allowed in-vivo identification of tumor vessels and liver metastases, as well as diagnosis of focal hepatic inflammation, necrosis, and associated perfusion anomalies. Somatostatin-receptor targeting permitted in-vivo molecular staining of AR42-J-induced carcinoma and pancreatic islet cells. CONCLUSIONS: Confocal mini-microscopy allows rapid in-vivo molecular and subsurface imaging of normal and pathological tissue in the gastrointestinal tract at high resolution. Because this technology is applicable to humans, it might impact on future in-vivo microsocpic and molecular diagnosis of diseases such as cancer and inflammation.

[Single center experience over a 5-year period with sequential transarterial chemoembolization (TACE) in the treatment of hepatocellular carcinoma (HCC)]. / Sequentielle transarterielle Chemoembolisation (TACE) des hepatozellulären Karzinoms (HCC)--Erfahrungsbericht eines einzelnen Zentrums über 5 Jahre.

PURPOSE: To analyze the course of disease of patients treated with sequential TACE and to evaluate the dependent and independent prognostic factors for patient survival using the Cox Proportional Hazard Model. MATERIALS AND METHODS: 94 patients palliatively treated with TACE. Patients were selected if they had been treated at least 3 times. The TACE procedure was carried out at 8-week intervals using a suspension consisting of a fixed dosage of Mitomycin C (10 mg) and 10 ml Lipiodol. Follow-up investigations included contrast-enhanced multislice CT before and after TACE and assessment of the laboratory test results (i. e., blood count, liver enzymes, and coagulation). RESULTS: In 66.7 % of the patients, multifocal tumors were found. In 16.0 % of the patients, the tumor load represented more then 50 % of the liver volume. In 23.4 % of the cases, a portal vein thrombosis was found in the initial CT scan. The mean survival for the total cohort was 24.1 months (95 %-CI 20.1 - 28.2). During the investigation period, 72/94 of the patients died. The cumulative 1-year, 2-year, and 3-year survival rates are 71.6 %, 33.9 %, und 17.2 %, respectively. A median of 6.0 +/- 3.1 (range 14, n total = 612 TACE) was performed in each patient. A total of 62.5 % patients died because of tumor progression whereas 18.1 % died due to progressive liver failure. Patients in whom the tumor responded to the TACE treatment and who did not develop ascites or those with Okuda stage I or unifocal tumor growth showed a survival benefit whereas the presence of portal vein thrombosis was associated with a significantly poor outcome (p < 0.05). The Child-Pugh stage was not statistically significant for the disease course; the occurrence of new tumor lesions had no influence with regard to 1-year and 2-year survival but had a significant influence on long-term survival (p < 0.05). Independent prognostic factors are (multivariate analysis; p < 0.05): number of TACE performed, tumor type (i. e., unifocal vs. multifocal), response to TACE (response vs. progression), and Okuda stage. CONCLUSION: Our results emphasize the value of TACE in the palliative treatment of HCC. Under sequential TACE therapy the course of disease in patients suffering from portal vein thrombosis was not significantly worse. Crucial prognostic factors for the course of the HCC are tumor type and extension, response to TACE, and liver function at the beginning of TACE.

Hepatocyte-specific Smad7 deletion accelerates DEN-induced HCC via activation of STAT3 signaling in mice.

TGF-ß signaling in liver cells has variant roles in the dynamics of liver diseases, including hepatocellular carcinoma (HCC). We previously found a correlation of high levels of the important endogenous negative TGF-ß signaling regulator SMAD7 with better clinical outcome in HCC patients. However, the underlying tumor-suppressive molecular mechanisms are still unclear. Here, we show that conditional (TTR-Cre) hepatocyte-specific SMAD7 knockout (KO) mice develop more tumors than wild-type and corresponding SMAD7 transgenic mice 9 months after diethylnitrosamine (DEN) challenge, verifying SMAD7 as a tumor suppressor in HCC. In line with our findings in patients, Smad7 levels in both tumor tissue as well as surrounding tissue show a significant inverse correlation with tumor numbers. SMAD7 KO mice presented with increased pSMAD2/3 levels and decreased apoptosis in the tumor tissue. Higher tumor incidence was accompanied by reduced P21 and upregulated c-MYC expression in the tumors. Activation of signal transducer and activator of transcription factor 3 signaling was found in Smad7-deficient mouse tumors and in patients with low tumoral SMAD7 expression as compared with surrounding tissue. Together, our results provide new mechanistic insights into the tumor-suppressive functions of SMAD7 in hepatocarcinogenesis.

Selected quality parameters of salmon and meat when fried with or without added fat.

AIM: To determine whether pan-frying (pork, beef and salmon) without oil or with different fats (olive oil, corn oil or a partially hydrogenated plant oil) or steaming (only salmon) have effects on the total fat content, the fatty acid pattern, lipid peroxidation, tocopherols and in particular for salmon on vitamin D(3) and astaxanthin. MATERIAL AND METHODS: Pork, beef patties and salmon were pan-fried (6 min each), beef fillet was pan-fried (5 min) with an additional braising period of 90 minutes and salmon was steamed for 12 minutes. Each pan-frying treatment was done with the above mentioned fats and without fat. Total fat was determined gravimetrically, the fatty acid pattern with GC, the tocopherols, astaxanthin and vitamin D(3) by using HPLC. RESULTS: The effects on the fat quality and quantity in the final products were related to the pan-frying fat used, however, the power of the outcome was depending on the surface to volume ratio. The highest increase in total fat was observed for pork, followed by the beef patties and the braised beef. The same has been assessed for the fatty acid pattern. Tocopherols changed according to the oil used, in particular gamma-tocopherol significantly increased for each preparation after the use of corn oil. Only in pork an increase in lipid oxidation of the oil preparations has been observed. Vitamin D(3) in salmon significantly decreased after heat treatment, however a 150 g salmon portion would provide between 13.9 and 14.7 mug Vitamin D(3) which is around five times more than the average daily intake. CONCLUSION: Pan-frying without fat can be recommended for the daily use, since the total fat intake is too high in developed countries and one main task of nutritional recommendations is to reduce the total fat intake. When pan-fried with fat, the choice of the fat is of high importance since it directly influences the quality and the flavour of the final product. In order to increase the fat quality from nutritional point of view only oils of plant or vegetable origin should be used in households. Pan-fried salmon is a good source of Vitamin D(3).

Recommendation for severity assessment following liver resection and liver transplantation in rats: Part I.

Score sheets were first introduced 30 years ago to assess pain, distress and suffering in animals. To date, however, there is still no general agreement on their use in research practice, and only a few publications can be found on this topic. In the present work, we demonstrate the use of a special score sheet for severity assessment in the first three postoperative days in two showcased studies performed on Wistar and Lewis rats undergoing liver resection or orthotopic liver transplantation, respectively. Scoring of different criteria and the total score were evaluated within each intervention. Additionally, both procedures were compared regarding their degree of severity. Suitability of these score sheets was evaluated for assessing severity of the procedures and these showed a minor severity within each investigated study. A comparison of both studies showed slightly higher scores involving liver transplantation. In contradiction to the common classification of these procedures as a moderate severity grade the score sheets applied here indicates a minor severity grade within each investigated study. Also, limitations and possible improvements in the design of our score sheets for defined interventions are reconsidered.

Hepatocellular expression of a dominant-negative mutant TGF-beta type II receptor accelerates chemically induced hepatocarcinogenesis.

The potent growth-inhibitory activity of cytokines of the transforming growth factor-beta (TGF-beta) superfamily and their widespread expression in epithelia suggest that they may play an important role in the maintenance of epithelial homeostasis. To analyse TGF-beta mediated tumor suppressor activity in the liver, we generated transgenic mice overexpressing a dominant negative type II TGF-beta receptor in hepatocytes under control of the regulatory elements of the human C-reactive protein gene promoter. Transgenic animals exhibited constitutive and liver-specific transgene expression. The functional inactivation of the TGF-beta signaling pathway in transgenic hepatocytes was shown by reduced TGF-beta induced inhibition of DNA synthesis in primary hepatocyte cultures. Liver morphology and spontaneous tumorigenesis were unchanged in transgenic mice suggesting that interruption of the signaling of all three isoforms of TGF-beta in hepatocytes does not disturb tissue homeostasis in the liver under physiological conditions. However, following initiation with the carcinogen diethylnitrosamine and tumor-promotion with phenobarbital transgenic mice exhibited a moderate albeit significant increase in the incidence, size and multiplicity of both preneoplastic tissue lesions in the liver and of hepatocellular carcinomas. These results give in vivo evidence for a tumor suppressor activity of the endogenous TGF-beta system in the liver during chemical hepatocarcinogenesis.

A novel class of aromatic vitamin D analogs.

Vitamin D analogs in which the triene moiety is replaced by an aromatic ring have been synthesized and their ability to bind to the vitamin D receptor investigated.

Minilaparoscopy in the diagnosis of peritoneal tumor spread: prospective controlled comparison with computed tomography.

BACKGROUND: Early diagnosis of peritoneal spread in malignant disease prevents unnecessary laparotomies. Minimally invasive laparoscopy with the patient under conscious sedation is a new, easily feasible diagnostic technique. This study compares prospective and controlled diagnostic minilaparoscopy with computed tomography (CT) scan for the diagnosis of peritoneal metastases. METHODS: In this study, 56 patients with malignant disease were prospectively investigated with diagnostic minilaparoscopy and CT scan. RESULTS: The study criteria were fulfilled by 54 patients. Minilaparoscopy detected peritoneal carcinosis in 28 of 54 cases, whereas CT detected the disease in 14 of 54 cases. For 36 patients, the diagnosis could be verified by histologic examination of peritoneal biopsies or laparotomy. In this group, minilaparoscopy detected peritoneal carcinosis in 25 of 36 cases, whereas CT detected the disease in 12 of 36 cases. CONCLUSIONS: Minilaparoscopy was more sensitive than CT in detecting peritoneal carcinosis (100% vs 47.8%; p < 0.01). Considering its low grade of invasiveness and superior sensitivity, minilaparoscopy should be regarded as the procedure of choice for the early detection of peritoneal carcinosis.

Autoimmune findings resembling connective tissue disease in a patient with Castleman's disease.

Multicentric angiofollicular lymphnode hyperplasia (multicentric Castleman's disease) may be associated with acute phase reaction and several autoimmune features. Since lymphadenopathy is a common feature in connective tissue disease, a clear distinction between the different disease entities may be difficult. We describe a 26-year-old male patient with predominant cervical lymphadenopathy, hepatosplenomegaly and polyserositis, diagnosed as collagen disease. He showed several autoimmune features including autoimmune haemolytic anaemia, cryoglobulinaemia, positive antinuclear and anti smooth muscle antibodies, serum immune complexes and a sensorimotor polyneuropathy. Under immunosuppressive therapy with prednisolone and azathioprine, only partial remission was achieved. Repeated lymph node biopsy together with the clinical features led to the diagnosis of multicentric Castleman's disease in this patient nine years later. Interleukin-6 (IL-6) seems to play an important role in the pathogenesis of clinical and serum biochemical features in patients with Castleman's disease.

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.

Involvement of ß3-adrenergic receptors in the control of food intake in rats.

This study examined the food intake changes evoked by intracerebroventricular (icv) injection of a selective agonist (BRL37344, 2 and 20 nmol) or antagonist (SR59230A, 10 and 50 nmol) of ß3-adrenergic receptors in 24-h fasted rats (adult male Wistar rats, 200-350 g, N = 6/treatment). The animals were also pretreated with saline icv (SAL) or SR59230A (50 nmol) followed by BRL37344 (20 nmol) or SAL in order to determine the selectivity of the effects evoked by BRL37344 on food intake or the selectivity of the effects evoked by SR59230A on risk assessment (RA) behavior. The highest dose of BRL37344 (N = 7) decreased food intake 1 h after the treatment (6.4 ± 0.5 g in SAL-treated vs 4.2 ± 0.8 g in drug-treated rats). While both doses of SR59230A failed to affect food intake (5.1 ± 1.1 g for 10 nmol and 6.0 ± 1.8 g for 50 nmol), this treatment reduced the RA frequency (number/30 min) (4 ± 2 for SAL-treated vs 1 ± 1 for 10 nmol and 0.5 ± 1 for 50 nmol SR59230A-treated rats), an ethological parameter related to anxiety. While pretreatment with SR59230A (7.0 ± 0.5 g) abolished the hypophagia induced by BRL37344 (3.6 ± 0.9 g), BRL37344 suppressed the reduction in RA frequency caused by SR59230A. These results show that the hypophagia caused by BRL37344 is selectively mediated by ß3-adrenergic receptors within the central nervous system. Moreover, they suggest the involvement of these receptors in the control of anxiety.

[Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) as primary diagnostic tool for unclear lesions in the upper gastrointestinal tract]. / Endosonographie mit Feinnadelpunktion in der Primärdiagnostik unklarer Raumforderungen im oberen Gastrointestinaltrakt.

BACKGROUND: Endoscopic Ultrasound (EUS) and the EUS guided fine-needle Aspiration (EUS-FNA) increasingly plays an important role in the diagnostic evaluation of lesions or lymph nodes in the mediastinum and upper gastrointestinal tract of unknown origin. The objective of this study was to assess safety and accuracy of EUS-FNA in two secondary and tertiary health care providers. METHODS: Prospectively, from Mai 2003 to June 2007, all patients underwent EUS with devices from Pentax (FG38UX, EC3830UT) with EUS-FNA (Cook or Mediglobe) at Johannes Gutenberg University and Catholic Hospital in Mainz. In all cases, cytology and extracted cells were histological examined by the same pathologists. In case of negative EUS results, patients were observed for at least 12 months after initial diagnosis later by reanalysis, CT-scan and follow-up clinical data to confirm the diagnosis. RESULTS: In total, 776 patients with EUS and 167 EUS-FNA (21.5 %) could be evaluated. Median age was 62 years, 68 % of patients were male. Patients underwent EUS-FNA in the mediastinum (n = 54), pancreas (73), stomach (13), liver, adrenal glands and rectum (n = 6). The complication rate of EUS-FNA was very low with only 0.6 %, mainly consistent of one minor haemorrhage at the aspiration site. A clear histological diagnosis could not be achieved in 12.5 % (21/167). Statistical analyses of all EUS-FNA revealed a sensitivity of 77.8 % (95 %CI 67,2 - 86,3) and a specificity of 98.5 % (95 % CI 92,2 - 100), with a positive and negative predictive value of 98.4 % and of 78.1 %, respectively. The overall accuracy was 87 % (95 %CI 80,4 - 92,0). CONCLUSION: EUS combined with FNA is a safe tool for first histological evaluation of unidentified lesions or lymph nodes in the mediastinum and upper gastrointestinal tract, indicative for gastrointestinal cancers.