Susen Burock - Academia.edu (original) (raw)

Papers by Susen Burock

Research paper thumbnail of Regional hyperthermia of the abdomen, a pilot study towards the treatment of peritoneal carcinomatosis

Radiation Oncology, 2015

Background: Peritoneal carcinomatosis occurs in different cancer subtypes and is associated with ... more Background: Peritoneal carcinomatosis occurs in different cancer subtypes and is associated with a dismal prognosis. Some doubts remain whether the whole abdomen can be treated by regional hyperthermia, therefore we analyzed feasibility conducting a pilot study. Methods: A simulation of the abdominopelvic heat distribution in 11 patients with peritoneal carcinomatosis was done using the HyperPlan software and the SIGMA-60 and SIGMA-Eye applicators. Tissue-specific region-related electrical and thermal parameters were used to solve the Maxwell's equations and the bioheat-transfer equation. Three-dimensional specific absorption rate (SAR) distributions and, additionally, estimated region-related perfusion rates were used to solve the bioheat-transfer equation. The predicted SAR and temperature distributions were compared with minimally invasive measurements in pelvic reference points. Results: In 11 patients (7 of them treated in the SIGMA-60 and 4 in the SIGMA-Eye applicator) the measured treatment variables (SAR, temperatures in the pelvic reference points) indicated that the heated volumes were higher for the SIGMA-Eye applicator. The mean computed abdominal SARs were less for the SIGMA-Eye (33 versus 44 W/kg). Nevertheless, the temperature distributions in the abdomen (peritoneal cavity) were more homogeneous in the SIGMA-Eye applicator as compared to the SIGMA-60 as indicated by higher values of T 90 (mean 40.2 versus 38.2°C) and T 50 (mean 41.1 versus 40.2°C), while the maximum temperatures were similar (in the range 41 to 43°C). Even though the mean abdominal SAR was lower in the SIGMA-Eye, the heat distribution covered a larger volume of the abdomen (in particular the upper abdomen). For the SIGMA-60 applicator the achieved T 90 appeared to be limited between 41 and 42°C, for the SIGMA Eye applicator more effective T 90 in the range 42 to 43°C were obtained. Conclusion: Our results suggest that an adequate heating of the abdomen and therefore abdominal regional hyperthermia in PC patients appears feasible. The SIGMA-Eye applicator appears to be superior compared to the SIGMA-60 applicator for abdominal hyperthermia.

Research paper thumbnail of 13LBA S100A4 transcripts in blood of colon, rectal, and gastric cancer patients: development of a new blood-based assay for improved diagnosis and prognosis

European Journal of Cancer Supplements, 2009

Background: Low oxygen tension (hypoxia) is an important determinant in tumor progression. In thi... more Background: Low oxygen tension (hypoxia) is an important determinant in tumor progression. In this study we assess the prognostic value of an in vitro derived hypoxia gene signature in neuroblastoma patients. Material and Methods: L1-L2 regularization framework has been applied on gene expression profiles of 11 neuroblastoma cell lines to define the neuroblastoma hypoxia signature. We applied k-means clustering on the expression level of the signature 62 probesets to segregate 88 neuroblastoma patients and subgroups obtained by common risk factors stratification. We analyzed the classes by Kaplan-Meier curves and logrank test for overall survival (OS) and event-free survival (EFS). Multivariate Cox analysis was performed to define the predictive power of the signature. Results: The neuroblastoma hypoxia signature distinguished two groups of neuroblastoma patients classifying them as poor prognosis (21 patients), those having OS rate of 25.5% and EFS rate of 27.7%, and as good prognosis (67 patients), those having OS rate of 73.2% and EFS rate of 67.7%. The poor prognosis patients show an over-expression of the hypoxia probesets. Multivariate Cox analysis revealed that the neuroblastoma hypoxia signature is a significant independent predictor after controlling for commonly used risk factors. When applied to MYCN not amplified patients, the hypoxia signature was capable to stratify patients with OS rate of 24.2% and EFS rate of 27.3% for the patients with poor prognosis, compared with OS rate of 81.4% and EFS rate of 74.8% for the patients with good prognosis. Conclusions: We demonstrate that the NB-hypo signature is a significant prognostic factor capable of stratify neuroblastoma patients. Furthermore, we obtained the proof of principle that the approach of hypoxia genes selection from in vitro controlled tumor cell lines, is a feasible method to identify specific contribution of the microenvironment to the tumors' biology.

Research paper thumbnail of Fluorescence Imaging of Breast Cancer with ICG

Biomedical Optics and 3-D Imaging, 2010

ABSTRACT We have investigated twenty patients with suspicious breast lesions by fluorescence mamm... more ABSTRACT We have investigated twenty patients with suspicious breast lesions by fluorescence mammography using ICG as contrast agent. Differences in early and late fluorescence mammograms offer the chance to distinguish malignant from benign lesions.

Research paper thumbnail of Integration der Hyperthermie in chirurgisch-onkologische Techniken

Der Onkologe, 2010

Unter dem Begriff Hyperthermie versteht man allgemein verschiedene Applikationsformen von Wärme i... more Unter dem Begriff Hyperthermie versteht man allgemein verschiedene Applikationsformen von Wärme im Temperaturbereich von 40°C bis 43°C, ggf. bis 45°C. Dabei unterscheidet man lokale und regionale Verfahren, Ganzkörperhyperthermie und hypertherme Perfusionstechniken. Bei Letzteren handelt es sich um eine Hyperthermieform, die meist unter Operationsbedingungen durchgeführt wird. Hierbei wird eine überwärmte Flüssigkeit eingeleitet, um ein Körperteil oder eine Körperhöhle zu erwärmen. Geeignet für diese Hyperthermieform sind sowohl präformierte Höhlen (Abdomen, Thorax) als auch Organe mit gut zugänglicher zentraler Blutversorgung (Leber, Lunge) und die Extremitäten. Dabei gilt, dass die Hyperthermie immer im Rahmen von multimodalen Therapieansätzen angewendet wird und zur Verstärkung der Wirksamkeit einer lokalen Zytostatika-oder Biotherapie dient.

Research paper thumbnail of Weichgewebssarkome

Praxis der Viszeralchirurgie Onkologische Chirurgie, 2010

ABSTRACT

Research paper thumbnail of High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients

Molecular cancer, Jan 14, 2015

The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomar... more The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III. We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P < 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P < 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) b...

Research paper thumbnail of Circulating Metastasis Associated in Colon Cancer 1 transcripts in gastric cancer patient plasma as diagnostic and prognostic biomarker

World journal of gastroenterology : WJG, Jan 7, 2015

To evaluate the diagnostic and prognostic value of circulating Metastasis Associated in Colon Can... more To evaluate the diagnostic and prognostic value of circulating Metastasis Associated in Colon Cancer 1 (MACC1) transcripts in plasma of gastric cancer patients. We provide for the first time a blood-based assay for transcript quantification of the metastasis inducer MACC1 in a prospective study of gastric cancer patient plasma. MACC1 is a strong prognostic biomarker for tumor progression and metastasis in a variety of solid cancers. We conducted a study to define the diagnostic and prognostic power of MACC1 transcripts using 76 plasma samples from gastric cancer patients, either newly diagnosed with gastric cancer, newly diagnosed with metachronous metastasis of gastric cancer, as well as follow-up patients. Findings were controlled by using plasma samples from 54 tumor-free volunteers. Plasma was separated, RNA was isolated, and levels of MACC1 as well as S100A4 transcripts were determined by quantitative RT-PCR. Based on the levels of circulating MACC1 transcripts in plasma we sig...

Research paper thumbnail of Isolierte Extremitätenperfusion bei Weichgewebesarkomen

Weichgewebetumoren, 2011

ABSTRACT

Research paper thumbnail of Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

The Journal of Molecular Diagnostics, 2011

Early detection of tumors and metastases is critical for improving treatment strategies and patie... more Early detection of tumors and metastases is critical for improving treatment strategies and patient outcomes. The development of molecular markers and simple tests that are clinically applicable for detection, prognostication, and therapy monitoring is strongly needed. The gene S100A4 has long been known to act as a metastasis inducer. High S100A4 levels in the primary tumor are prognostic for metachronous metastasis and correlate with reduced patient survival. We provide, for the first time, a plasma-based assay for transcript quantification of S100A4 in gastrointestinal patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; plasma. We conducted a study to define the diagnostic and prognostic power of S100A4 transcripts using 466 plasma samples from colon, rectal, and gastric cancer patients. Plasma was separated, RNA was isolated, and S100A4 mRNA was determined by quantitative RT-PCR. S100A4 transcripts were increased in cancer patients of each entity (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and all disease stages (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), compared with tumor-free volunteers (sensitivities of 96%, 74%, and 90% and specificities of 59%, 82%, and 71%, for colon, rectal, and gastric cancer patients, respectively). Prospectively analyzed follow-up patients who later experienced metastasis showed higher S100A4 levels than follow-up patients without metastasis. Disease-free survival was decreased in high S100A4-expressing follow-up colorectal cancer patients (P = 0.013). In summary, we developed a method for quantitative S100A4 transcript determination in plasma that allows clinical application routinely. We demonstrated the diagnostic and prognostic potential of this method for early defining cancer staging and patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; risk for metastasis.

Research paper thumbnail of A multichannel time-domain scanning fluorescence mammograph: Performance assessment and first in vivo results

Review of Scientific Instruments, 2011

We present a scanning time-domain fluorescence mammograph capable to image the distribution of a ... more We present a scanning time-domain fluorescence mammograph capable to image the distribution of a fluorescent contrast agent within a female breast, slightly compressed between two parallel glass plates, with high sensitivity. Fluorescence of the contrast agent is excited using a near infrared picosecond diode laser module. Four additional picosecond diode lasers with emission wavelengths between 660 and 1066 nm allow to measure the intrinsic optical properties of the breast tissue. By synchronously moving a source fiber and seven detection fiber bundles across the breast, distributions of times of flight of photons are recorded simultaneously for selected source-detector combinations in transmission and reflection geometry either at the fluorescence wavelength or at the selected laser wavelengths. To evaluate the performance of the mammograph, we used breastlike rectangular phantoms comprising fluorescent and absorbing objects using the fluorescent dye Omocyanine as contrast agent excited at 735 nm. We compare two-dimensional imaging of the phantom based on transmission and reflection data. Furthermore, we developed an improved tomosynthesis algorithm which permits three-dimensional reconstruction of fluorescence and absorption properties of lesions with good spatial resolution. For illustration, we present fluorescence mammograms of one patient recorded 30 min after administration of the contrast agent indocyanine green showing the carcinoma at high contrast originating from fluorescence of the extravasated dye, excited at 780 nm.

Research paper thumbnail of Breast Cancer: Early- and Late-Fluorescence Near-Infrared Imaging with Indocyanine Green—A Preliminary Study

Radiology, 2011

To assess early- and late-fluorescence near-infrared imaging, corresponding to the vascular (earl... more To assess early- and late-fluorescence near-infrared imaging, corresponding to the vascular (early-fluorescence) and extravascular (late-fluorescence) phases of indocyanine green (ICG) enhancement, for breast cancer detection and benign versus malignant breast lesion differentiation. The study was approved by the ethical review board; all participants provided written informed consent. Twenty women with 21 breast lesions were examined with near-infrared imaging before, during, and after intravenous injection of ICG. Absorption and fluorescence projection mammograms were recorded simultaneously on a prototype near-infrared imaging unit. Two blinded readers independently assessed the images and assigned visibility scores to lesions seen on the absorption and absorption-corrected fluorescence mammograms. Imaging results were compared with histopathologic findings. Lesion contrast and diameter on the fluorescence mammograms were measured, and Cohen κ, Mann-Whitney U, and Spearman ρ tests were conducted. The absorption-corrected fluorescence ratio mammograms showed high contrast (contrast value range, 0.25-0.64) between tumors and surrounding breast tissue. Malignant lesions were correctly defined in 11 (reader 1) and 12 (reader 2) of 13 cases, and benign lesions were correctly defined in six (reader 1) and five (reader 2) of eight cases with late-fluorescence imaging. Lesion visibility scores for malignant and benign lesions were significantly different on the fluorescence ratio mammograms (P = .003) but not on the absorption mammograms (P = .206). Mean sensitivity and specificity reached 92% ± 8 (standard error of mean) and 75% ± 16, respectively, for fluorescence ratio imaging compared with 100% ± 0 and 25% ± 16, respectively, for conventional mammography alone. Preliminary data suggest that early- and late-fluorescence ratio imaging after ICG administration can be used to distinguish malignant from benign breast lesions.

Research paper thumbnail of Circulating MACC1 Transcripts in Colorectal Cancer Patient Plasma Predict Metastasis and Prognosis

PLoS ONE, 2012

Background: Metastasis is the most frequent cause of treatment failure and death in colorectal ca... more Background: Metastasis is the most frequent cause of treatment failure and death in colorectal cancer. Early detection of tumors and metastases is crucial for improving treatment strategies and patient outcome. Development of reliable biomarkers and simple tests routinely applicable in the clinic for detection, prognostication, and therapy monitoring is of special interest. We recently identified the novel gene Metastasis-Associated in Colon Cancer 1 (MACC1), a key regulator of the HGF/Met-pathway. MACC1 is a strong prognostic biomarker for colon cancer metastasis and allows identification of high-risk subjects in early stages, when determined in patients' primary tumors. To overcome the limitation of a restricted number of molecular analyses in tumor tissue, the establishment of a non-invasive blood test for early identification of highrisk cancer patients, for monitoring disease course and therapy response is strongly needed.

Research paper thumbnail of Late-fluorescence mammography assesses tumor capillary permeability and differentiates malignant from benign lesions

Optics Express, 2009

Using scanning time-domain instrumentation we recorded fluorescence projection mammograms on few ... more Using scanning time-domain instrumentation we recorded fluorescence projection mammograms on few breast cancer patients prior, during and after infusion of indocyanine green (ICG), while monitoring arterial ICG concentration by transcutaneous pulse densitometry. Latefluorescence mammograms recorded after ICG had been largely cleared from the blood by the liver, showed invasive carcinomas at high contrast over a rather homogeneous background, whereas benign lesions did not produce (focused) fluorescence contrast. During infusion, tissue concentration contrast and hence fluorescence contrast is determined by intravascular contributions, whereas late-fluorescence mammograms are dominated by contributions from protein-bound ICG extravasated into the interstitium, reflecting relative microvascular permeabilities of carcinomas and normal breast tissue. We simulated intravascular and extravascular contributions to ICG tissue concentration contrast within a twocompartment unidirectional pharmacokinetic model. , "Electromagnetic breast imaging: results of a pilot study in women with abnormal mammograms," Radiology 243(2), 350-359 (2007).

Research paper thumbnail of SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer

Molecular Cancer, 2012

Background: Colorectal cancer is one of the main cancers in the Western world. About 90% of the d... more Background: Colorectal cancer is one of the main cancers in the Western world. About 90% of the deaths arise from formation of distant metastasis. The expression of the newly identified gene metastasis associated in colon cancer 1 (MACC1) is a prognostic indicator for colon cancer metastasis. Here, we analyzed for the first time the impact of single nucleotide polymorphisms (SNPs) in the coding region of MACC1 for clinical outcome of colorectal cancer patients. Additionally, we screened met proto-oncogene (Met), the transcriptional target gene of MACC1, for mutations. Methods: We sequenced the coding exons of MACC1 in 154 colorectal tumors (stages I, II and III) and the crucial exons of Met in 60 colorectal tumors (stages I, II and III). We analyzed the association of MACC1 polymorphisms with clinical data, including metachronous metastasis, UICC stages, tumor invasion, lymph node metastasis and patients' survival (n = 154, stages I, II and III). Furthermore, we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells. Results: We genotyped three MACC1 SNPs in the coding region. Thirteen % of the tumors had the genotype cg (rs4721888, L31V), 48% a ct genotype (rs975263, S515L) and 84% a gc or cc genotype (rs3735615, R804T). We found no association of these SNPs with clinicopathological parameters or with patients' survival, when analyzing the entire patients' cohort. An increased risk for a shorter metastasis-free survival of patients with a ct genotype (rs975263) was observed in younger colon cancer patients with stage I or II (P = 0.041, n = 18). In cell culture, MACC1 SNPs did not affect MACC1-induced cell motility and proliferation. Conclusion: In summary, the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients' survival compared to MACC1 expression analysis alone. The ct genotype (rs975263) might be associated with a reduced survival for younger colon cancer patients in early stages. However, further studies with larger sample sizes are needed.

Research paper thumbnail of How can innovative forms of clinical research contribute to deliver affordable cancer care in an evolving health care environment?

European Journal of Cancer, 2013

As health care costs are constantly rising and governments are reforming their healthcare systems... more As health care costs are constantly rising and governments are reforming their healthcare systems there is an urgent need to reshape the European clinical research landscape. To bridge the translational gap extensive research to understand the mechanism of the agents and of the disease has to be performed and the real benefit of drugs needs to be assessed independently. Furthermore, meaningful data for reimbursement strategies will be a major goal of future clinical trials as well. Therefore, a new integrated model of clinical cancer research is needed to optimise the R&amp;amp;amp;amp;amp;D process. Strategies to ensure that we can gather robust and relevant data about the effectiveness of various healthcare interventions have to be developed to provide optimal patient care within the limits of a healthcare budget.

Research paper thumbnail of Academia–Industry Partnerships: Are we ready for new models of partnership?

European Journal of Cancer, 2013

Research paper thumbnail of Quantitative and qualitative analysis of study-related patient information sheets in randomised neuro-oncology phase III-trials

European Journal of Cancer, 2014

In randomised controlled trials (RCTs), patient informed consent documents are an essential corne... more In randomised controlled trials (RCTs), patient informed consent documents are an essential cornerstone of the study flow. However, these documents are often oversized in format and content. Clinical experience suggests that study information sheets are often not used as an aid to decision-making due to their complexity. We analysed nine patient informed consent documents from clinical neuro-oncological phase III-studies running at a German Brain Tumour Centre with the objective to investigate the quality of these documents. Text length, formal layout, readability, application of ethical and legal requirements, scientific evidence and social aspects were used as rating categories. Results were assessed quantitatively by two independents investigators and were depicted using net diagrams. All patient informed consent documents were of insufficient quality in all categories except that ethical and legal requirements were fulfilled. Notably, graduate levels were required to read and understand five of nine consent documents. Quality deficits were consistent between the individual study information texts. Irrespective of formal aspects, a document that is intended to inform and motivate patients to participate in a study needs to be well-structured and understandable. We therefore strongly mandate to re-design patient informed consent documents in a patient-friendly way. Specifically, standardised components with a scientific foundation should be provided that could be retrieved at various times, adapted to the mode of treatment and the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s knowledge, and could weigh information dependent of the stage of treatment decision.

Research paper thumbnail of Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society

BMC Cancer, 2009

The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (L... more The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (LARC) dramatically. But a major achievement has been the development of total mesorectal excision (TME) as a surgical standard and the recognition that the surgeon is the predominant prognostic factor. The benefit of preoperative hypofractionated radiotherapy (SCRT; five fractions each of 5 Gy), initially established by the Swedish Rectal Cancer Trial, has been demonstrated in conjunction with TME by the Dutch Colorectal Cancer Group. The concept of combined neoadjuvant radiochemotherapy (conventional radiation of about 50 Gy with chemotherapy) has not been compared over surgery alone with TME. However, the German Rectal Cancer Study Group recently demonstrated that preoperative radiochemotherapy (RCT) was better than postoperative radiochemotherapy in terms of local control.

Research paper thumbnail of The dream and reality of histology agnostic cancer clinical trials

Molecular Oncology, 2014

Emerging technologies and progress in data processing allowed for new insights on gene expression... more Emerging technologies and progress in data processing allowed for new insights on gene expression, genomics and epigenomics, and mechanisms of cancer genesis and progression. The development of new therapeutic strategies should therefore be triggered by the understanding of the underlying biology through sophisticated clinical trials. Therefore, the methodology and the design of cancer clinical trials as well as the methods of their implementation are under profound changes. Targeting specific pathways has open the hope of a more focused and personalized medicine which has the potential to bring more efficient and tailored treatments to patients. It has been questioned therefore whether clinical trials traditionally designed for specific tumor types could not re-visited towards trials gathering patients based on molecular features rather than pure pathology criteria. The complexity of the cancer biology being the result of so many different interactive mechanisms whether driving or not the process of cancer cells is an additional level of complexity to approach more inclusive clinical trial access. Nevertheless, a number of innovative solutions to address biological challenges across histologies have been initiated and the question of whether histology agnostic trials could be conceived is a logical next question. This paper questions the advantages and the limits of clinical trials performed across tumor types bearing similar selected molecular features and looks further into the feasibility of such histology agnostic trials.

Research paper thumbnail of Regional hyperthermia of the abdomen, a pilot study towards the treatment of peritoneal carcinomatosis

Radiation Oncology, 2015

Background: Peritoneal carcinomatosis occurs in different cancer subtypes and is associated with ... more Background: Peritoneal carcinomatosis occurs in different cancer subtypes and is associated with a dismal prognosis. Some doubts remain whether the whole abdomen can be treated by regional hyperthermia, therefore we analyzed feasibility conducting a pilot study. Methods: A simulation of the abdominopelvic heat distribution in 11 patients with peritoneal carcinomatosis was done using the HyperPlan software and the SIGMA-60 and SIGMA-Eye applicators. Tissue-specific region-related electrical and thermal parameters were used to solve the Maxwell's equations and the bioheat-transfer equation. Three-dimensional specific absorption rate (SAR) distributions and, additionally, estimated region-related perfusion rates were used to solve the bioheat-transfer equation. The predicted SAR and temperature distributions were compared with minimally invasive measurements in pelvic reference points. Results: In 11 patients (7 of them treated in the SIGMA-60 and 4 in the SIGMA-Eye applicator) the measured treatment variables (SAR, temperatures in the pelvic reference points) indicated that the heated volumes were higher for the SIGMA-Eye applicator. The mean computed abdominal SARs were less for the SIGMA-Eye (33 versus 44 W/kg). Nevertheless, the temperature distributions in the abdomen (peritoneal cavity) were more homogeneous in the SIGMA-Eye applicator as compared to the SIGMA-60 as indicated by higher values of T 90 (mean 40.2 versus 38.2°C) and T 50 (mean 41.1 versus 40.2°C), while the maximum temperatures were similar (in the range 41 to 43°C). Even though the mean abdominal SAR was lower in the SIGMA-Eye, the heat distribution covered a larger volume of the abdomen (in particular the upper abdomen). For the SIGMA-60 applicator the achieved T 90 appeared to be limited between 41 and 42°C, for the SIGMA Eye applicator more effective T 90 in the range 42 to 43°C were obtained. Conclusion: Our results suggest that an adequate heating of the abdomen and therefore abdominal regional hyperthermia in PC patients appears feasible. The SIGMA-Eye applicator appears to be superior compared to the SIGMA-60 applicator for abdominal hyperthermia.

Research paper thumbnail of 13LBA S100A4 transcripts in blood of colon, rectal, and gastric cancer patients: development of a new blood-based assay for improved diagnosis and prognosis

European Journal of Cancer Supplements, 2009

Background: Low oxygen tension (hypoxia) is an important determinant in tumor progression. In thi... more Background: Low oxygen tension (hypoxia) is an important determinant in tumor progression. In this study we assess the prognostic value of an in vitro derived hypoxia gene signature in neuroblastoma patients. Material and Methods: L1-L2 regularization framework has been applied on gene expression profiles of 11 neuroblastoma cell lines to define the neuroblastoma hypoxia signature. We applied k-means clustering on the expression level of the signature 62 probesets to segregate 88 neuroblastoma patients and subgroups obtained by common risk factors stratification. We analyzed the classes by Kaplan-Meier curves and logrank test for overall survival (OS) and event-free survival (EFS). Multivariate Cox analysis was performed to define the predictive power of the signature. Results: The neuroblastoma hypoxia signature distinguished two groups of neuroblastoma patients classifying them as poor prognosis (21 patients), those having OS rate of 25.5% and EFS rate of 27.7%, and as good prognosis (67 patients), those having OS rate of 73.2% and EFS rate of 67.7%. The poor prognosis patients show an over-expression of the hypoxia probesets. Multivariate Cox analysis revealed that the neuroblastoma hypoxia signature is a significant independent predictor after controlling for commonly used risk factors. When applied to MYCN not amplified patients, the hypoxia signature was capable to stratify patients with OS rate of 24.2% and EFS rate of 27.3% for the patients with poor prognosis, compared with OS rate of 81.4% and EFS rate of 74.8% for the patients with good prognosis. Conclusions: We demonstrate that the NB-hypo signature is a significant prognostic factor capable of stratify neuroblastoma patients. Furthermore, we obtained the proof of principle that the approach of hypoxia genes selection from in vitro controlled tumor cell lines, is a feasible method to identify specific contribution of the microenvironment to the tumors' biology.

Research paper thumbnail of Fluorescence Imaging of Breast Cancer with ICG

Biomedical Optics and 3-D Imaging, 2010

ABSTRACT We have investigated twenty patients with suspicious breast lesions by fluorescence mamm... more ABSTRACT We have investigated twenty patients with suspicious breast lesions by fluorescence mammography using ICG as contrast agent. Differences in early and late fluorescence mammograms offer the chance to distinguish malignant from benign lesions.

Research paper thumbnail of Integration der Hyperthermie in chirurgisch-onkologische Techniken

Der Onkologe, 2010

Unter dem Begriff Hyperthermie versteht man allgemein verschiedene Applikationsformen von Wärme i... more Unter dem Begriff Hyperthermie versteht man allgemein verschiedene Applikationsformen von Wärme im Temperaturbereich von 40°C bis 43°C, ggf. bis 45°C. Dabei unterscheidet man lokale und regionale Verfahren, Ganzkörperhyperthermie und hypertherme Perfusionstechniken. Bei Letzteren handelt es sich um eine Hyperthermieform, die meist unter Operationsbedingungen durchgeführt wird. Hierbei wird eine überwärmte Flüssigkeit eingeleitet, um ein Körperteil oder eine Körperhöhle zu erwärmen. Geeignet für diese Hyperthermieform sind sowohl präformierte Höhlen (Abdomen, Thorax) als auch Organe mit gut zugänglicher zentraler Blutversorgung (Leber, Lunge) und die Extremitäten. Dabei gilt, dass die Hyperthermie immer im Rahmen von multimodalen Therapieansätzen angewendet wird und zur Verstärkung der Wirksamkeit einer lokalen Zytostatika-oder Biotherapie dient.

Research paper thumbnail of Weichgewebssarkome

Praxis der Viszeralchirurgie Onkologische Chirurgie, 2010

ABSTRACT

Research paper thumbnail of High MACC1 expression in combination with mutated KRAS G13 indicates poor survival of colorectal cancer patients

Molecular cancer, Jan 14, 2015

The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomar... more The metastasis-associated in colon cancer 1 (MACC1) gene has been identified as prognostic biomarker for colorectal cancer (CRC). Here, we aimed at the refinement of risk assessment by separate and combined survival analyses of MACC1 expression with any of the markers KRAS mutated in codon 12 (KRAS G12) or codon 13 (KRAS G13), BRAF V600 mutation and MSI status in a retrospective study of 99 CRC patients with tumors UICC staged I, II and III. We showed that only high MACC1 expression (HR: 6.09, 95% CI: 2.50-14.85, P < 0.001) and KRAS G13 mutation (HR: 5.19, 95% CI: 1.06-25.45, P = 0.042) were independent prognostic markers for shorter metastasis-free survival (MFS). Accordingly, Cox regression analysis revealed that patients with high MACC1 expression and KRAS G13 mutation exhibited the worst prognosis (HR: 14.48, 95% CI: 3.37-62.18, P < 0.001). Patients were classified based on their molecular characteristics into four clusters with significant differences in MFS (P = 0.003) b...

Research paper thumbnail of Circulating Metastasis Associated in Colon Cancer 1 transcripts in gastric cancer patient plasma as diagnostic and prognostic biomarker

World journal of gastroenterology : WJG, Jan 7, 2015

To evaluate the diagnostic and prognostic value of circulating Metastasis Associated in Colon Can... more To evaluate the diagnostic and prognostic value of circulating Metastasis Associated in Colon Cancer 1 (MACC1) transcripts in plasma of gastric cancer patients. We provide for the first time a blood-based assay for transcript quantification of the metastasis inducer MACC1 in a prospective study of gastric cancer patient plasma. MACC1 is a strong prognostic biomarker for tumor progression and metastasis in a variety of solid cancers. We conducted a study to define the diagnostic and prognostic power of MACC1 transcripts using 76 plasma samples from gastric cancer patients, either newly diagnosed with gastric cancer, newly diagnosed with metachronous metastasis of gastric cancer, as well as follow-up patients. Findings were controlled by using plasma samples from 54 tumor-free volunteers. Plasma was separated, RNA was isolated, and levels of MACC1 as well as S100A4 transcripts were determined by quantitative RT-PCR. Based on the levels of circulating MACC1 transcripts in plasma we sig...

Research paper thumbnail of Isolierte Extremitätenperfusion bei Weichgewebesarkomen

Weichgewebetumoren, 2011

ABSTRACT

Research paper thumbnail of Diagnostic and Prognostic Value of Metastasis Inducer S100A4 Transcripts in Plasma of Colon, Rectal, and Gastric Cancer Patients

The Journal of Molecular Diagnostics, 2011

Early detection of tumors and metastases is critical for improving treatment strategies and patie... more Early detection of tumors and metastases is critical for improving treatment strategies and patient outcomes. The development of molecular markers and simple tests that are clinically applicable for detection, prognostication, and therapy monitoring is strongly needed. The gene S100A4 has long been known to act as a metastasis inducer. High S100A4 levels in the primary tumor are prognostic for metachronous metastasis and correlate with reduced patient survival. We provide, for the first time, a plasma-based assay for transcript quantification of S100A4 in gastrointestinal patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; plasma. We conducted a study to define the diagnostic and prognostic power of S100A4 transcripts using 466 plasma samples from colon, rectal, and gastric cancer patients. Plasma was separated, RNA was isolated, and S100A4 mRNA was determined by quantitative RT-PCR. S100A4 transcripts were increased in cancer patients of each entity (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.0001) and all disease stages (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), compared with tumor-free volunteers (sensitivities of 96%, 74%, and 90% and specificities of 59%, 82%, and 71%, for colon, rectal, and gastric cancer patients, respectively). Prospectively analyzed follow-up patients who later experienced metastasis showed higher S100A4 levels than follow-up patients without metastasis. Disease-free survival was decreased in high S100A4-expressing follow-up colorectal cancer patients (P = 0.013). In summary, we developed a method for quantitative S100A4 transcript determination in plasma that allows clinical application routinely. We demonstrated the diagnostic and prognostic potential of this method for early defining cancer staging and patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; risk for metastasis.

Research paper thumbnail of A multichannel time-domain scanning fluorescence mammograph: Performance assessment and first in vivo results

Review of Scientific Instruments, 2011

We present a scanning time-domain fluorescence mammograph capable to image the distribution of a ... more We present a scanning time-domain fluorescence mammograph capable to image the distribution of a fluorescent contrast agent within a female breast, slightly compressed between two parallel glass plates, with high sensitivity. Fluorescence of the contrast agent is excited using a near infrared picosecond diode laser module. Four additional picosecond diode lasers with emission wavelengths between 660 and 1066 nm allow to measure the intrinsic optical properties of the breast tissue. By synchronously moving a source fiber and seven detection fiber bundles across the breast, distributions of times of flight of photons are recorded simultaneously for selected source-detector combinations in transmission and reflection geometry either at the fluorescence wavelength or at the selected laser wavelengths. To evaluate the performance of the mammograph, we used breastlike rectangular phantoms comprising fluorescent and absorbing objects using the fluorescent dye Omocyanine as contrast agent excited at 735 nm. We compare two-dimensional imaging of the phantom based on transmission and reflection data. Furthermore, we developed an improved tomosynthesis algorithm which permits three-dimensional reconstruction of fluorescence and absorption properties of lesions with good spatial resolution. For illustration, we present fluorescence mammograms of one patient recorded 30 min after administration of the contrast agent indocyanine green showing the carcinoma at high contrast originating from fluorescence of the extravasated dye, excited at 780 nm.

Research paper thumbnail of Breast Cancer: Early- and Late-Fluorescence Near-Infrared Imaging with Indocyanine Green—A Preliminary Study

Radiology, 2011

To assess early- and late-fluorescence near-infrared imaging, corresponding to the vascular (earl... more To assess early- and late-fluorescence near-infrared imaging, corresponding to the vascular (early-fluorescence) and extravascular (late-fluorescence) phases of indocyanine green (ICG) enhancement, for breast cancer detection and benign versus malignant breast lesion differentiation. The study was approved by the ethical review board; all participants provided written informed consent. Twenty women with 21 breast lesions were examined with near-infrared imaging before, during, and after intravenous injection of ICG. Absorption and fluorescence projection mammograms were recorded simultaneously on a prototype near-infrared imaging unit. Two blinded readers independently assessed the images and assigned visibility scores to lesions seen on the absorption and absorption-corrected fluorescence mammograms. Imaging results were compared with histopathologic findings. Lesion contrast and diameter on the fluorescence mammograms were measured, and Cohen κ, Mann-Whitney U, and Spearman ρ tests were conducted. The absorption-corrected fluorescence ratio mammograms showed high contrast (contrast value range, 0.25-0.64) between tumors and surrounding breast tissue. Malignant lesions were correctly defined in 11 (reader 1) and 12 (reader 2) of 13 cases, and benign lesions were correctly defined in six (reader 1) and five (reader 2) of eight cases with late-fluorescence imaging. Lesion visibility scores for malignant and benign lesions were significantly different on the fluorescence ratio mammograms (P = .003) but not on the absorption mammograms (P = .206). Mean sensitivity and specificity reached 92% ± 8 (standard error of mean) and 75% ± 16, respectively, for fluorescence ratio imaging compared with 100% ± 0 and 25% ± 16, respectively, for conventional mammography alone. Preliminary data suggest that early- and late-fluorescence ratio imaging after ICG administration can be used to distinguish malignant from benign breast lesions.

Research paper thumbnail of Circulating MACC1 Transcripts in Colorectal Cancer Patient Plasma Predict Metastasis and Prognosis

PLoS ONE, 2012

Background: Metastasis is the most frequent cause of treatment failure and death in colorectal ca... more Background: Metastasis is the most frequent cause of treatment failure and death in colorectal cancer. Early detection of tumors and metastases is crucial for improving treatment strategies and patient outcome. Development of reliable biomarkers and simple tests routinely applicable in the clinic for detection, prognostication, and therapy monitoring is of special interest. We recently identified the novel gene Metastasis-Associated in Colon Cancer 1 (MACC1), a key regulator of the HGF/Met-pathway. MACC1 is a strong prognostic biomarker for colon cancer metastasis and allows identification of high-risk subjects in early stages, when determined in patients' primary tumors. To overcome the limitation of a restricted number of molecular analyses in tumor tissue, the establishment of a non-invasive blood test for early identification of highrisk cancer patients, for monitoring disease course and therapy response is strongly needed.

Research paper thumbnail of Late-fluorescence mammography assesses tumor capillary permeability and differentiates malignant from benign lesions

Optics Express, 2009

Using scanning time-domain instrumentation we recorded fluorescence projection mammograms on few ... more Using scanning time-domain instrumentation we recorded fluorescence projection mammograms on few breast cancer patients prior, during and after infusion of indocyanine green (ICG), while monitoring arterial ICG concentration by transcutaneous pulse densitometry. Latefluorescence mammograms recorded after ICG had been largely cleared from the blood by the liver, showed invasive carcinomas at high contrast over a rather homogeneous background, whereas benign lesions did not produce (focused) fluorescence contrast. During infusion, tissue concentration contrast and hence fluorescence contrast is determined by intravascular contributions, whereas late-fluorescence mammograms are dominated by contributions from protein-bound ICG extravasated into the interstitium, reflecting relative microvascular permeabilities of carcinomas and normal breast tissue. We simulated intravascular and extravascular contributions to ICG tissue concentration contrast within a twocompartment unidirectional pharmacokinetic model. , "Electromagnetic breast imaging: results of a pilot study in women with abnormal mammograms," Radiology 243(2), 350-359 (2007).

Research paper thumbnail of SNPs in the coding region of the metastasis-inducing gene MACC1 and clinical outcome in colorectal cancer

Molecular Cancer, 2012

Background: Colorectal cancer is one of the main cancers in the Western world. About 90% of the d... more Background: Colorectal cancer is one of the main cancers in the Western world. About 90% of the deaths arise from formation of distant metastasis. The expression of the newly identified gene metastasis associated in colon cancer 1 (MACC1) is a prognostic indicator for colon cancer metastasis. Here, we analyzed for the first time the impact of single nucleotide polymorphisms (SNPs) in the coding region of MACC1 for clinical outcome of colorectal cancer patients. Additionally, we screened met proto-oncogene (Met), the transcriptional target gene of MACC1, for mutations. Methods: We sequenced the coding exons of MACC1 in 154 colorectal tumors (stages I, II and III) and the crucial exons of Met in 60 colorectal tumors (stages I, II and III). We analyzed the association of MACC1 polymorphisms with clinical data, including metachronous metastasis, UICC stages, tumor invasion, lymph node metastasis and patients' survival (n = 154, stages I, II and III). Furthermore, we performed biological assays in order to evaluate the functional impact of MACC1 SNPs on the motility of colorectal cancer cells. Results: We genotyped three MACC1 SNPs in the coding region. Thirteen % of the tumors had the genotype cg (rs4721888, L31V), 48% a ct genotype (rs975263, S515L) and 84% a gc or cc genotype (rs3735615, R804T). We found no association of these SNPs with clinicopathological parameters or with patients' survival, when analyzing the entire patients' cohort. An increased risk for a shorter metastasis-free survival of patients with a ct genotype (rs975263) was observed in younger colon cancer patients with stage I or II (P = 0.041, n = 18). In cell culture, MACC1 SNPs did not affect MACC1-induced cell motility and proliferation. Conclusion: In summary, the identification of coding MACC1 SNPs in primary colorectal tumors does not improve the prediction for metastasis formation or for patients' survival compared to MACC1 expression analysis alone. The ct genotype (rs975263) might be associated with a reduced survival for younger colon cancer patients in early stages. However, further studies with larger sample sizes are needed.

Research paper thumbnail of How can innovative forms of clinical research contribute to deliver affordable cancer care in an evolving health care environment?

European Journal of Cancer, 2013

As health care costs are constantly rising and governments are reforming their healthcare systems... more As health care costs are constantly rising and governments are reforming their healthcare systems there is an urgent need to reshape the European clinical research landscape. To bridge the translational gap extensive research to understand the mechanism of the agents and of the disease has to be performed and the real benefit of drugs needs to be assessed independently. Furthermore, meaningful data for reimbursement strategies will be a major goal of future clinical trials as well. Therefore, a new integrated model of clinical cancer research is needed to optimise the R&amp;amp;amp;amp;amp;D process. Strategies to ensure that we can gather robust and relevant data about the effectiveness of various healthcare interventions have to be developed to provide optimal patient care within the limits of a healthcare budget.

Research paper thumbnail of Academia–Industry Partnerships: Are we ready for new models of partnership?

European Journal of Cancer, 2013

Research paper thumbnail of Quantitative and qualitative analysis of study-related patient information sheets in randomised neuro-oncology phase III-trials

European Journal of Cancer, 2014

In randomised controlled trials (RCTs), patient informed consent documents are an essential corne... more In randomised controlled trials (RCTs), patient informed consent documents are an essential cornerstone of the study flow. However, these documents are often oversized in format and content. Clinical experience suggests that study information sheets are often not used as an aid to decision-making due to their complexity. We analysed nine patient informed consent documents from clinical neuro-oncological phase III-studies running at a German Brain Tumour Centre with the objective to investigate the quality of these documents. Text length, formal layout, readability, application of ethical and legal requirements, scientific evidence and social aspects were used as rating categories. Results were assessed quantitatively by two independents investigators and were depicted using net diagrams. All patient informed consent documents were of insufficient quality in all categories except that ethical and legal requirements were fulfilled. Notably, graduate levels were required to read and understand five of nine consent documents. Quality deficits were consistent between the individual study information texts. Irrespective of formal aspects, a document that is intended to inform and motivate patients to participate in a study needs to be well-structured and understandable. We therefore strongly mandate to re-design patient informed consent documents in a patient-friendly way. Specifically, standardised components with a scientific foundation should be provided that could be retrieved at various times, adapted to the mode of treatment and the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s knowledge, and could weigh information dependent of the stage of treatment decision.

Research paper thumbnail of Preoperative short-course radiotherapy versus combined radiochemotherapy in locally advanced rectal cancer: a multi-centre prospectively randomised study of the Berlin Cancer Society

BMC Cancer, 2009

The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (L... more The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer (LARC) dramatically. But a major achievement has been the development of total mesorectal excision (TME) as a surgical standard and the recognition that the surgeon is the predominant prognostic factor. The benefit of preoperative hypofractionated radiotherapy (SCRT; five fractions each of 5 Gy), initially established by the Swedish Rectal Cancer Trial, has been demonstrated in conjunction with TME by the Dutch Colorectal Cancer Group. The concept of combined neoadjuvant radiochemotherapy (conventional radiation of about 50 Gy with chemotherapy) has not been compared over surgery alone with TME. However, the German Rectal Cancer Study Group recently demonstrated that preoperative radiochemotherapy (RCT) was better than postoperative radiochemotherapy in terms of local control.

Research paper thumbnail of The dream and reality of histology agnostic cancer clinical trials

Molecular Oncology, 2014

Emerging technologies and progress in data processing allowed for new insights on gene expression... more Emerging technologies and progress in data processing allowed for new insights on gene expression, genomics and epigenomics, and mechanisms of cancer genesis and progression. The development of new therapeutic strategies should therefore be triggered by the understanding of the underlying biology through sophisticated clinical trials. Therefore, the methodology and the design of cancer clinical trials as well as the methods of their implementation are under profound changes. Targeting specific pathways has open the hope of a more focused and personalized medicine which has the potential to bring more efficient and tailored treatments to patients. It has been questioned therefore whether clinical trials traditionally designed for specific tumor types could not re-visited towards trials gathering patients based on molecular features rather than pure pathology criteria. The complexity of the cancer biology being the result of so many different interactive mechanisms whether driving or not the process of cancer cells is an additional level of complexity to approach more inclusive clinical trial access. Nevertheless, a number of innovative solutions to address biological challenges across histologies have been initiated and the question of whether histology agnostic trials could be conceived is a logical next question. This paper questions the advantages and the limits of clinical trials performed across tumor types bearing similar selected molecular features and looks further into the feasibility of such histology agnostic trials.