[show abstract][hide abstract] ABSTRACT: Unresectable cholangiocarcinoma (CCC) has a poor prognosis. Patients with intrahepatic CCC have a very limited benefit from systemic chemotherapy (ChT). The aim of this prospective study was to evaluate the feasibility, safety, and efficacy of conventional transarterial chemoembolization (cTACE) with mitomycin-C and of irinotecan-eluting beads (iDEB-TACE), and to retrospectively compare them with ChT with oxaliplatin and gemcitabine.
Between June 2002 and June 2010, three independent prospective trials were carried out and compared retrospectively. Following predefined study protocols, 26 patients with histologically proven intrahepatic CCC were treated with iDEB-TACE (200 mg irinotecan), 10 patients were treated with cTACE using 15 mg mitomycin-C mixed with 5-10 ml of ionized oil (lipiodol), followed by embolization with gelfoam, and 31 patients received systemic ChT with gemcitabine and oxaliplatin. Treatment response and progression-free survival (PFS) were assessed by computer tomography or MRI every 2 months according to Response Evaluation Criteria in Solid Tumors. Clinical and laboratory data were assessed for side-effects according to National Cancer Institute-Common Toxicity Criteria.
iDEB-TACE resulted in PFS of 3.9 months and overall survival (OS) of 11.7 months, compared with a PFS of 1.8 months and OS of 5.7 months, respectively, in patients treated with cTACE, and a PFS of 6.2 months and OS of 11.0 months, respectively, in patients treated with oxaliplatin and gemcitabine. The medium follow-up of patients treated with iDEB-TACE was 12 months; 2 months after treatment, 13 patients (50%) had progressive disease, 11 patients (42%) had stable disease, and one patient had a partial response and became eligible for secondary liver resection. Local tumor control was achieved in 66% of patients; 4% had a partial response, 62% had stable disease, and 27% progressive disease. Common Toxicity Criteria grade III or IV toxicities for iDEB-TACE were abdominal pain (n=7), hepatic abscess (n=1), pleural empyema due to biliary leakage (n=1), and one death due to cholangitis with hepatic failure in a patient with liver cirrhosis. No hematological side-effects were observed. Almost every patient experienced a 'postembolization syndrome' with low-grade fever, nausea, and abdominal pain for up to 2 weeks.
This is the first study demonstrating that treatment of patients suffering from intrahepatic CCC with iDEB-TACE is safe in patients with normal liver function, and results in a prolongation of PFS and OS. Local tumor control, PFS and OS seem similar to systemic ChT with oxaliplatin and gemcitabine, but superior to cTACE.
European journal of gastroenterology & hepatology 04/2012; 24(4):437-43. · 1.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Adjuvant chemotherapy for 6 months is the current standard of care after potentially curative resection of pancreatic cancer and yields an overall survival of 15-20 months. Early tumor recurrence before or during adjuvant chemotherapy has not been evaluated so far. These patients may not benefit from adjuvant treatment.
Thirty-five patients with resection of ductal pancreatic carcinoma and adjuvant chemotherapy with gemcitabine were analyzed between 2005 and 2007. All patients had a computed tomography (CT) scan before and during adjuvant chemotherapy after 2-3 months, 12/35 patients had a histologically confirmed R1 resection. Recurrence of pancreatic cancer was determined by CT scan and the clinical course.
Median survival of 35 patients with resected pancreatic cancer was 19.7 months, and the 2-year survival was 44%. Thirteen (37%) of the 35 patients analyzed with a CT scan showed tumor recurrence during adjuvant chemotherapy. Overall survival of patients with tumor recurrence was 9.3 months with a 2-year survival rate of 13%, whereas median overall survival of patients without early relapse was 26.3 months (P<0.001). Local recurrence of pancreatic cancer occurred in 38% (5/13); 46% (6/13) of patients developed distant metastasis, and 38% (5/13) developed lymph node metastasis. Early tumor recurrence during or adjuvant chemotherapy did not correlate with R status (R1 vs R0, P=0.69), whereas histologically confirmed lymph node invasion (pN0 vs pN1) and grading showed a statistically significant correlation with early relapse (P<0.05).
A significant fraction of patients with resected pancreatic cancer have early relapse during adjuvant chemotherapy, especially those with lymph node metastasis. Radiologic examinations prior to and during adjuvant chemotherapy will help to identify patients with tumor recurrence who are unlikely to benefit from adjuvant treatment and will need individualized palliative chemotherapy.
Saudi Journal of Gastroenterology 03/2012; 18(2):118-21.
[show abstract][hide abstract] ABSTRACT: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression.
Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression.
Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months.
This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer.
British Journal of Cancer 02/2012; 106(6):1033-8. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Auron Misheil Therapy was developed based on similarities between carcinogenesis and inflammation. Auron Misheil Therapy is a combination of natural and synthetic compounds, including anti-inflammatory drugs and insulin, expected to exhibit synergistic effects.
Here, we report the case of a 78-year-old Caucasian male patient who presented with multifocal hepatocellular carcinoma and chronic hepatitis C virus infection. Over a four-year period our patient was treated with radiofrequency ablation and transarterial chemoembolization. After these treatments there was tumor progression, with new hyperperfused lesions without evidence of extrahepatic tumor involvement. Our patient refused sorafenib therapy. Therefore, he received twice daily intramuscular injections of Auron Misheil Therapy on an outpatient basis for two months. Partial remission of the hepatic lesions was observed eight weeks after the start of treatment, and confirmed four weeks later. Unfortunately, at that time our patient refused therapy due to dizziness. During follow-up two target lesions remained stable, but one lesion increased in size. At the latest follow-up, one year later, there was still tumor control.
While the mechanisms underlying the antitumor effects of Auron Misheil Therapy are not fully understood, stable disease and remissions have been observed in different types of tumors, including hepatocellular carcinoma.
[show abstract][hide abstract] ABSTRACT: Genetic alterations within the epidermal growth factor receptor (EGFR) pathway, including KRAS mutations, have been demonstrated to be associated with response to EGFR inhibitors like cetuximab in colorectal cancers. Mutations in the KRAS gene have been found in 70-90% of pancreatic cancers. Unfortunately, the addition of cetuximab to chemotherapy did not increase response or survival in patients with advanced pancreatic cancer in phase II and phase III studies. The aim of this study was to evaluate the relationship between KRAS mutations and response or survival in patients with metastatic pancreatic cancer treated with cetuximab plus chemotherapy.
Within a multicenter phase II trial, 64 patients with metastatic pancreatic cancer were treated with cetuximab in combination with gemcitabine and oxaliplatin until disease progression. Analyses of the EGFR pathway, including KRAS mutations, could be performed in 25 patients. Analyses were carried out following microdissection of the tumor.
Fourteen (56%) of the 25 patients examined harbored a point mutation in codon 12 of the KRAS gene. No differences between the groups were noted in median progression-free survival (104 days in KRAS wild-type patients vs. 118 days in patients with KRAS mutations). Overall survival was longer in wild-type patients compared to patients with KRAS mutations (263 vs. 162 days), but the difference did not reach statistical significance. A further analysis of our clinical phase II trial showed that the presence of a rash was significantly correlated with overall survival.
KRAS mutation in codon 12 may be associated with reduced survival compared to KRAS wild type. The role of KRAS mutations for cetuximab therapy in pancreatic cancer warrants further investigation in larger trials to exclude an epiphenomenon. Furthermore, the development of a rash is indicative of clinical benefit.
[show abstract][hide abstract] ABSTRACT: The objectives of on-orbit servicing (OOS) missions include manipulation, proximity operations and inspection of target satellites. Therefore the servicer satellite often has to be teleoperated at low latency for several minutes to fulfill these tasks. That means communication plays a crucial role for OOS missions because real time teleoperation including high data rates has to be realized. So the communication path from front end sensors on the servicer spacecraft to the operator on ground has to be optimized and the latency time has to be minimized. Furthermore a long access time from the ground station is required because continuous communication with the satellite is mandatory for most of the OOS tasks. This can be realized by an inter-satellite link via a geostationary relay satellite, which has the advantage that a satellite in Low Earth Orbit (LEO) can be accessed from one ground station for about half an orbit. To evaluate both, the requirement of a long access time from the ground station as well as the need of a short latency time, an end to end communication scenario was implemented at the Institute of Astronautics (LRT) at the Technische Universität München (TUM). This scenario includes different spacecraft sensors (e.g. stereo cameras, LIDAR systems), a Ka-Band ground station and man machine interfaces. This paper describes the setup of a realistic simulation of a communication path from a data source to an operator via space-link. Furthermore the method of latency measuring depending on the data source is described. The communication architecture is embedded in a spacecraft simulator to simulate On-Orbit Servicing scenarios like Space Debris removal and target inspection.
[show abstract][hide abstract] ABSTRACT: Telomerase plays an important role during immortalization and malignant transformation as crucial steps in the development of human cancer. In a cellular model of oral-esophageal carcinogenesis, recapitulating the human disease, immortalization occurred independent of the activation of telomerase but through the recombination-based alternative lengthening of telomeres (ALT). In this stepwise model, additional overexpression of EGFR led to in vitro transformation and activation of telomerase with homogeneous telomere elongation in already immortalized oral squamous epithelial cells (OKF6-D1_dnp53). More interestingly, EGFR overexpression activated the PI3K/AKT pathway. This strongly suggested a role for telomerase in tumor progression in addition to just elongating telomeres and inferring an immortalized state. Therefore, we sought to identify the regulatory mechanisms involved in this activation of telomerase and in vitro transformation induced by EGFR. In the present study we demonstrate that telomerase expression and activity are induced through both direct phosphorylation of hTERT by phospho-AKT as well as PI3K-dependent transcriptional regulation involving Hif1-alpha as a key transcription factor. Furthermore, EGFR overexpression enhanced cell cycle progression and proliferation via phosphorylation and translocation of p21. Whereas immortalization was induced by ALT, in vitro transformation was associated with telomerase activation, supporting an additional role for telomerase in tumor progression besides elongating telomeres.
Cancer Science 02/2011; 102(2):351-60. · 3.48 Impact Factor
[show abstract][hide abstract] ABSTRACT: Since 2008 the lightweight intersatellitelink antenna (LISA MS ) has been developed for establishing communication between low flying satellites (e.g. earth observation satellites) and geostationary relay satellites. For this development a detailed electrical design has been simulated to predict performance parameters. The paper describes the detailed component design and the comparison of the simulated values with measurements of the manufactured breadboard antenna model.
Antennas and Propagation (EuCAP), 2010 Proceedings of the Fourth European Conference on; 05/2010
[show abstract][hide abstract] ABSTRACT: In spite of various efforts perihilar cholangiocellular carcinoma (Klatskin tumour) has still a bad prognosis. The treatment of patients with inoperable Klatskin tumours by stereotactic fractionated radiotherapy (SFRT) was analysed retrospectively. PATIENTS, METHODS AND MATERIALS: In our department 13 patients were treated for Klatskin tumours by SFRT (32-56 Gy, 3 x 4 Gy/week) from 1998 to 2008. The treatment technique was developed from stereotactic body frame radiotherapy to image guided (IGRT) stereotactic radiotherapy with control of patient positioning by cone beam computer tomography (CBCT). 6/13 patients received additional chemotherapy before or after SFRT.
A median survival of 33.5 (6.6-60.4) months after diagnosis was reached by SFRT. The median time of freedom from tumour progression was 32.5 (6.1-60.4, last patient died without tumour progression) months. The therapy was tolerated very well. Nausea was the most common side effect. 5/13 patients suffered from recurrent cholangitis caused and enhanced by the primary tumour and drainages or stents in the bile ducts.
In the context of reaching local control being still the main problem of Klatskin tumour patients, SFRT seems to be a very promising method for the treatment of these tumours.
Radiotherapy and Oncology 03/2010; 95(1):99-102. · 4.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: To analyze the pathogenetic role and potential clinical usefulness of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancer (BTC).
EGFR and HER2 expression was studied in biopsy samples from 124 patients (51% women; median age 64.8 years), with advanced BTC diagnosed between 1997 and 2004. Five micrometers sections of paraffin embedded tissue were examined by standard, FDA approved immunohistochemistry. Tumors with scores of 2+ or 3+ for HER2 expression on immunochemistry were additionally tested for HER2 gene amplification by fluorescence in situ hybridisation (FISH).
34/124 patients (27.4%) had gallbladder cancer, 47 (37.9%) had intrahepatic BTC and 43 (34.7%) had extrahepatic or perihilar BTC. EGFR expression was examined in a subset of 56 samples. EGFR expression was absent in 22/56 tumors (39.3%). Of the remaining samples expression was scored as 1+ in 12 (21.5%), 2+ in 13 (23.2%) and 3+ in 9 (16%), respectively. HER2 expression was as follows: score 0 73/124 (58.8%), score 1+ 27/124 (21.8%), score 2+ 21/124 (17%) and score 3+ 4/124 (3.2%). HER2 gene amplification was present in 6/124, resulting in an overall amplification rate of 5%.
Our data suggest that routine testing and therapeutic targeting of HER2 does not seem to be useful in patients with BTC, while targeting EGFR may be promising.
World Journal of Gastroenterology 09/2009; 15(36):4511-7. · 2.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Targeting the epidermal growth factor receptor pathway in pancreatic cancer seems to be an attractive therapeutic approach. This study assessed the efficacy of cetuximab plus the combination of gemcitabine/oxaliplatin in metastatic pancreatic cancer. Eligible subjects had histological or cytological diagnosis of metastatic pancreatic adenocarcinoma. The primary end point was response according to RECIST. Patients received cetuximab 400 mg m(-2) at first infusion followed by weekly 250 mg m(-2) combined with gemcitabine 1000 mg m(-2) as a 100 min infusion on day 1 and oxaliplatin 100 mg m(-2) as a 2-h infusion on day 2 every 2 weeks. Between January 2005 and August 2006, a total of 64 patients (22 women (34%), 42 men (66%); median age 64 years (range 31-78)) were enrolled at seven study centres. On October 2007, a total of 17 patients were alive. Sixty-two patients were evaluable for baseline and 61 for assessment of response to treatment in an intention-to-treat analysis. Six patients had an incomplete drug combination within the first cycle of the treatment plan (n=4 hypersensitivity reactions to the first cetuximab infusion, n=2 refused to continue therapy). Reported grade 3/4 toxicities (% of patients) were leukopaenia 15%, anaemia 8%, thrombocytopaenia 10%, diarrhoea 7%, nausea 18%, infection 18% and allergy 7%. Cetuximab-attributable skin reactions occurred as follows: grade 0: 20%, grade 1: 41%, grade 2: 30% and grade 3: 10%. The intention-to-treat analysis of 61 evaluable patients showed an overall response rate of 33%, including 1 (2%) complete and 19 (31%) partial remissions. There were 31% patients with stable and 36% with progressive disease or discontinuation of the therapy before re-staging. The presence of a grade 2 or higher skin rash was associated with a higher likelihood of achieving objective response. Median time to progression was 118 days, with a median overall survival of 213 days. A clinical benefit response was noted in 24 of the evaluable 61 patients (39%). The addition of cetuximab to the combination of gemcitabine and oxaliplatin is well tolerated but does not increase response or survival in patients with metastatic pancreatic cancer.
British Journal of Cancer 05/2009; 100(7):1032-6. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: One of main tasks within the antenna development program LISA is to optimize manufacturing technologies to be applied best to Ka-band multifeed arrays. NC-milling, Cu electroforming, direct laser sintering (DLMS) of aluminium and laser sintering of plastics are being developed/evaluated. Some interest also is put on CFRP technology. The paper presents an intermediate status with some first results.
Antennas and Propagation, 2009. EuCAP 2009. 3rd European Conference on; 04/2009
[show abstract][hide abstract] ABSTRACT: Pancreatic cancer is the fourth most common cause of cancer related death in Western countries. Advantages in surgical techniques, radiation and chemotherapy had almost no impact on the long term survival of affected patients. Therefore, the need for better treatment strategies is urgent. HER2, a receptor tyrosine kinase of the EGFR family, involved in signal transduction pathways leading to cell growth and differentiation is overexpressed in a number of cancers, including breast and pancreatic cancer. While in breast cancer HER2 has already been successfully used as a treatment target, there are only limited data evaluating the effects of inhibiting HER2 tyrosine kinases in patients with pancreatic cancer.
Here we report the design of a prospective, non-randomized multi-centered Phase II clinical study evaluating the effects of the Fluoropyrimidine-carbamate Capecitabine (Xeloda) and the monoclonal anti-HER2 antibody Trastuzumab (Herceptin) in patients with non-resectable, HER2 overexpressing pancreatic cancer. Patients eligible for the study will receive Trastuzumab infusions on day 1, 8 and 15 concomitant to the oral intake of Capecitabine from day 1 to day 14 of each three week cycle. Cycles will be repeated until tumor progression. A total of 37 patients will be enrolled with an interim analysis after 23 patients.
Primary end point of the study is to determine the progression free survival after 12 weeks of bimodal treatment with the chemotherapeutic agent Capecitabine and the anti-HER2 antibody Trastuzumab. Secondary end points include patient's survival, toxicity analysis, quality of life, the correlation of HER2 overexpression and clinical response to Trastuzumab treatment and, finally, the correlation of CA19-9 plasma levels and progression free intervals.
[show abstract][hide abstract] ABSTRACT: Patients with UICC stage II colorectal cancer (CRC) have a risk of approximately 20% to develop disease recurrence after tumour resection. The presence and significance of micrometastases for locoregional recurrence in these patients lacking histopathological lymph node involvement on routine stained HE sections is undefined. Oestrogen receptor (ER) promoter methylation has earlier been identified in CRC. Therefore, we evaluated the methylation status of the ER promoter in lymph nodes from 49 patients with CRC UICC stage I and II as a molecular marker of micrometastases and predictor of local recurrence. DNA from 574 paraffin-embedded lymph nodes was isolated and treated with bisulphite. For the detection of methylated ER promoter sequences, quantitative real-time methylation-specific PCR was used. Of the 49 patients tested, 15 (31%) had ER methylation-positive lymph nodes. Thirteen of those (86%) remained disease free and two (14%) developed local recurrence. In the resected lymph nodes of 34 of the 49 patients (69%), no ER promoter methylation could be detected and none of these patients experienced a local relapse. The methylation status of the ER promoter in lymph nodes of UICC stage I and II CRC patients may be a useful marker for the identification of patients at a high risk for local recurrence.
British Journal of Cancer 02/2009; 100(2):360-5. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: The development of efficient and safe Life Support Systems is one of the key drivers of the Global Solar System Exploration efforts. For each task performed by Life Support Systems (LSS) a great multitude of sub-system concepts exist and the challenge is to find the optimal combination of sub-systems for a given mission scenario. On a sub-system level the Equivalent Systems Mass (ESM) trade study approach is well suited to effectively compare sub-system options. On a system level in addition to ESM data time dependent sub-system performances within an overall system must be addressed. Criteria such as system stability, controllability and effectiveness must be considered in order to be able to assess the dynamic robustness of systems designed to the averages. In an effort to establish a dynamic simulation environment for this type of LSS optimizations the “Virtual Habitat” tool (V-HAB) is being developed at the Technical University of Munich (TUM). This paper introduces the most important part of the Virtual Habitat simulation, which is the human model.
Advances in Space Research 01/2009; · 1.18 Impact Factor
[show abstract][hide abstract] ABSTRACT: Upcoming space missions utilizing hyperspectral or other high-resolution sensors will generate a vast amount of data in orbit. The average communication duration between a spacecraft in low Earth orbit (LEO) to a dedicated ground station is short and in addition, due to the high amount of data to be transferred at link times, a high-performance communication system on board of the satellite is indispensable.A solution that provides longer acquisition times with the ground station is to employ a high data-rate inter-satellite link to a geostationary relay satellite, which requires a flat, compact, steerable, light-weight yet robust antenna. Such an antenna system (antenna module plus pointing module) was developed for S-Band at the Institute of Astronautics (Technische Universität München), in cooperation with German space companies, research institutes and the German Aerospace Center (DLR). Its successful operation via the geostationary relay satellite Artemis was demonstrated in cooperation with ESA in 2007.This paper describes the evaluation of an antenna system in the Ka-Band, as a successor to be developed in the next two years for high data rates and the various applications of such an antenna system.