TY - JOUR AB - BACKGROUND: Differentiating chondroid tumors is crucial for proper patient management. This study aimed to develop a deep learning model (DLM) for classifying enchondromas, atypical cartilaginous tumors (ACT), and high-grade chondrosarcomas using CT images. METHODS: This retrospective study analyzed chondroid tumors from two independent cohorts. Tumors were segmented on CT images. A 2D convolutional neural network was developed and tested using split-sample and geographical validation. Four radiologists blinded to patient data and the DLM results with various levels of experience performed readings of the external test dataset for comparison. Performance metrics included accuracy, sensitivity, specificity, and area under the curve (AUC). RESULTS: CTs from 344 patients (175 women; age = 50.3 ± 14.3 years;) with diagnosed enchondroma (n = 124), ACT (n = 92) or high-grade chondrosarcoma (n = 128) were analyzed. The DLM demonstrated comparable performance to radiologists (p > 0.05), achieving an AUC of 0.88 for distinguishing enchondromas from chondrosarcomas and 0.82 for differentiating enchondromas from ACTs. The DLM and musculoskeletal expert showed similar performance in differentiating ACTs from high-grade chondrosarcomas (p = 0.26), with an AUC of 0.64 and 0.56, respectively. CONCLUSIONS: The DLM reliably differentiates benign from malignant cartilaginous tumors and is particularly useful for the differentiation between ACTs and Enchondromas, which is challenging based on CT images only. However, the differentiation between ACTs and high-grade chondrosarcomas remains difficult, reflecting known diagnostic challenges in radiology. AU - Gassert, F.G.* AU - Lang, D.M. AU - Hesse, N.* AU - Dürr, H.R.* AU - Klein, A.* AU - Kohll, L.* AU - Hinterwimmer, F.* AU - Luitjens, J.* AU - Weissinger, S.E.* AU - Peeken, J.C. AU - Mogler, C.* AU - Knebel, C.* AU - Bartzsch, S. AU - Gassert, F.T.* AU - Gersing, A.S.* C1 - 73796 C2 - 57230 CY - Campus, 4 Crinan St, London N1 9xw, England TI - A deep learning model for classification of chondroid tumors on CT images. JO - BMC Cancer VL - 25 IS - 1 PB - Bmc PY - 2025 SN - 1471-2407 ER - TY - JOUR AB - Neuroblastoma (NB), a common infantile neuroendocrine tumor, presents a substantial therapeutic challenge when MYCN is amplified. Given that the protein structure of N-Myc is disordered, we utilized Alphafold for prediction and GROMACS for optimization of the N-Myc structure, thereby improving the reliability of the predicted structure. The publicly available datasets GSE49710 and GSE73517 were adopted, which contain the transcriptome data of clinical samples from 598 NB patients. Through various machine learning algorithms, FAM13A was identified as a characteristic gene of MYCN. Cell functional experiments, including those on cell proliferation, apoptosis, and cell cycle, also indicate that FAM13A is a potential risk factor. Additionally, Alphafold and GROMACS were employed to predict and optimize the structure of FAM13A. Protein-protein docking and molecular dynamic modeling techniques were then used to validate the enhanced protein stability resulting from the interaction between N-Myc and FAM13A. Consequently, targeting FAM13A holds the potential to reduce the stability of N-Myc, hinder the proliferation of NB cells, and increase the infiltration of immune cells. This multi-faceted approach effectively combats tumor cells, making FAM13A a prospective therapeutic target for MYCN-amplified NB. AU - Yin, H.* AU - Liu, T.* AU - Wu, D.* AU - Li, X.* AU - Li, G.* AU - Song, W.* AU - Wang, X.* AU - Xin, S. AU - Liu, Y.* AU - Pan, J.* C1 - 73684 C2 - 57173 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Exploring FAM13A-N-Myc interactions to uncover potential targets in MYCN-amplified neuroblastoma: A study of protein interactions and molecular dynamics simulations. JO - BMC Cancer VL - 25 IS - 1 PB - Bmc PY - 2025 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: The brain is a common site for cancer metastases. In case of large and/or symptomatic brain metastases, neurosurgical resection is performed. Adjuvant radiotherapy is a standard procedure to minimize the risk of local recurrence and is increasingly performed as local stereotactic radiotherapy to the resection cavity. Both hypofractionated stereotactic radiotherapy (HFSRT) and single fraction stereotactic radiosurgery (SRS) can be applied in this case. Although adjuvant stereotactic radiotherapy to the resection cavity is widely used in clinical routine and recommended in international guidelines, the optimal fractionation scheme still remains unclear. The SATURNUS trial prospectively compares adjuvant HFSRT with SRS and seeks to detect the superiority of HFSRT over SRS in terms of local tumor control. METHODS: In this single center two-armed randomized phase III trial, adjuvant radiotherapy to the resection cavity of brain metastases with HFSRT (6 - 7 × 5 Gy prescribed to the surrounding isodose) is compared to SRS (1 × 12-20 Gy prescribed to the surrounding isodose). Patients are randomized 1:1 into the two different treatment arms. The primary endpoint of the trial is local control at the resected site at 12 months. The trial is based on the hypothesis that HFSRT is superior to SRS in terms of local tumor control. DISCUSSION: Although adjuvant stereotactic radiotherapy after resection of brain metastases is considered standard of care treatment, there is a need for further prospective research to determine the optimal fractionation scheme. To the best of our knowledge, the SATURNUS study is the only randomized phase III study comparing different regimes of postoperative stereotactic radiotherapy to the resection cavity adequately powered to detect the superiority of HFSRT regarding local control. TRIAL REGISTRATION: The study was retrospectively registered with ClinicalTrials.gov, number NCT05160818, on December 16, 2021. The trial registry record is available on  https://clinicaltrials.gov/study/NCT05160818 . The presented protocol refers to version V1.3 from March 21, 2021. AU - Waltenberger, M.* AU - Bernhardt, D.* AU - Diehl, C.* AU - Gempt, J.* AU - Meyer, B.* AU - Straube, C.* AU - Wiestler, B.* AU - Wilkens, J.* AU - Zimmer, C.* AU - Combs, S.E. C1 - 68050 C2 - 54528 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Hypofractionated stereotactic radiotherapy (HFSRT) versus single fraction stereotactic radiosurgery (SRS) to the resection cavity of brain metastases after surgical resection (SATURNUS): Study protocol for a randomized phase III trial. JO - BMC Cancer VL - 23 IS - 1 PB - Bmc PY - 2023 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: The standard treatment for patients with advanced HER2-positive gastric cancer is a combination of the antibody trastuzumab and platin-fluoropyrimidine chemotherapy. As some patients do not respond to trastuzumab therapy or develop resistance during treatment, the search for alternative treatment options and biomarkers to predict therapy response is the focus of research. We compared the efficacy of trastuzumab and other HER-targeting drugs such as cetuximab and afatinib. We also hypothesized that treatment-dependent regulation of a gene indicates its importance in response and that it can therefore be used as a biomarker for patient stratification. METHODS: A selection of gastric cancer cell lines (Hs746T, MKN1, MKN7 and NCI-N87) was treated with EGF, cetuximab, trastuzumab or afatinib for a period of 4 or 24 h. The effects of treatment on gene expression were measured by RNA sequencing and the resulting biomarker candidates were tested in an available cohort of gastric cancer patients from the VARIANZ trial or functionally analyzed in vitro. RESULTS: After treatment of the cell lines with afatinib, the highest number of regulated genes was observed, followed by cetuximab and trastuzumab. Although trastuzumab showed only relatively small effects on gene expression, BMF, HAS2 and SHB could be identified as candidate biomarkers for response to trastuzumab. Subsequent studies confirmed HAS2 and SHB as potential predictive markers for response to trastuzumab therapy in clinical samples from the VARIANZ trial. AREG, EREG and HBEGF were identified as candidate biomarkers for treatment with afatinib and cetuximab. Functional analysis confirmed that HBEGF is a resistance factor for cetuximab. CONCLUSION: By confirming HAS2, SHB and HBEGF as biomarkers for anti-HER therapies, we provide evidence that the regulation of gene expression after treatment can be used for biomarker discovery. TRIAL REGISTRATION: Clinical specimens of the VARIANZ study (NCT02305043) were used to test biomarker candidates. AU - Ebert, K.* AU - Haffner, I.* AU - Zwingenberger, G.* AU - Keller, S.* AU - Raimúndez, E.* AU - Geffers, R.* AU - Wirtz, R.* AU - Barbaria, E.* AU - Hollerieth, V.* AU - Arnold, R.* AU - Walch, A.K. AU - Hasenauer, J. AU - Maier, D.* AU - Lordick, F.* AU - Luber, B.* C1 - 64580 C2 - 52334 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Combining gene expression analysis of gastric cancer cell lines and tumor specimens to identify biomarkers for anti-HER therapies-the role of HAS2, SHB and HBEGF. JO - BMC Cancer VL - 22 IS - 1 PB - Bmc PY - 2022 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Invadopodia, actin-rich structures that release metallo-proteases at the interface with extra-cellular matrix, in a punctate manner are thought to be important drivers of tumour invasion. Invadopodia formation has been observed in-vitro and in-vivo in numerous metastatic cell lines derived from multiple tumour types. However, prostate cancer cell lines have not been routinely reported to generate invadopodia and the few instances have always required external stimulation. METHODS: In this study, the invasive potential of primary prostate adenocarcinoma cell lines, which have never been fully characterised before, was investigated both in-vitro invadopodia assays and in-vivo zebrafish dissemination assay. Subsequently, circulating tumour cells from prostate cancer patients were isolated and tested in the invadopodia assay. RESULTS: Retention of E-cadherin and N-cadherin expression indicated a transitional state of EMT progression, consistent with the idea of partial EMT that has been frequently observed in aggressive prostate cancer. All cell lines tested were capable of spontaneous invadopodia formation and possess a significant degradative ability in-vitro under basal conditions. These cell lines were invasive in-vivo and produced visible metastasis in the zebrafish dissemination assay. Importantly we have proceeded to demonstrate that circulating tumour cells isolated from prostate cancer patients exhibit invadopodia-like structures and degrade matrix with visible puncta. This work supports a role for invadopodia activity as one of the mechanisms of dissemination employed by prostate cancer cells. CONCLUSION: The combination of studies presented here provide clear evidence that invadopodia activity can play a role in prostate cancer progression. AU - Manuelli, V.* AU - Cahill, F.* AU - Wylie, H.* AU - Gillett, C.* AU - Corrêa, I.R.* AU - Heck, S. AU - Rimmer, A.* AU - Haire, A.* AU - van Hemelrijck, M.* AU - Rudman, S.* AU - Wells, C.M.* C1 - 64769 C2 - 52441 TI - Invadopodia play a role in prostate cancer progression. JO - BMC Cancer VL - 22 IS - 1 PY - 2022 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Hepatic metastases occur frequently in the context of many tumor entities. Patients with colorectal carcinoma have already developed liver metastases in 20% at the time of diagnosis, and 25-50% develop metastases in the further course of the disease and therapy. The frequent manifestation and the variable appearance of liver metastases result in an interdisciplinary challenge, regarding treatment management. The aim of this study was to evaluate high-precision stereotactic body radiotherapy (SBRT) for liver metastases. METHODS: A cohort of 115 patients with 150 irradiated liver metastases was analyzed. All metastases were treated between May 2004 and January 2020 using SBRT. A contrast-enhanced computed tomography (CT) was performed in all patients for treatment planning, followed by image-guided high-precision radiotherapy using cone-beam CT. A median cumulative dose of 35 Gy and a median single dose of 7 Gy was applied. RESULTS: Median OS was 20.4 months and median LC was 35.1 months with a 1-year probability of local failure of 18% (95%-CI: 12.0-24.3%). In this cohort, 18 patients were still alive at the time of evaluation. The median FU-time in total was 11.4 months and for living patients 26.6 months. 70.4% of patients suffered from acute toxicities. There were several cases of grade 1 and 2 toxicities, such as constipation (13.9%), nausea (24.4%), loss of appetite (7.8%), vomiting (10.4%), diarrhea (7.8%), and abdominal pain (16.5%). 10 patients (8.7%) suffered from grade 3 toxicities. Late toxicities affected 42.6% of patients, the majority of these affected the gastrointestinal system. CONCLUSION: SBRT is becoming increasingly important in the field of radiation oncology. It has evolved to be a highly effective treatment for primary and metastasized tumors, and offers a semi-curative treatment option also in the case of oligometastatic patients. Overall, it represents a very effective and well-tolerated therapy option to treat hepatic metastases. Based on the results of this work and the studies already available, high-precision radiotherapy should be considered as a valid and promising treatment alternative in the interdisciplinary discussion. AU - Voglhuber, T.* AU - Eitz, K.A. AU - Oechsner, M.* AU - Vogel, M.M. AU - Combs, S.E. C1 - 62532 C2 - 50908 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Analysis of using high-precision radiotherapy in the treatment of liver metastases regarding toxicity and survival. JO - BMC Cancer VL - 21 IS - 1 PB - Bmc PY - 2021 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Sarcoid lesions may mimic metastatic disease or recurrence in thyroid cancer (TC) patients as both diseases may affect the lungs and lymph nodes. We present the first study to systematically evaluate the clinical course of patients with (TC) after adjuvant radioactive iodine therapy (RIT) and concomitant sarcoidosis of the lung or the lymph nodes. METHODS: We screened 3285 patients and retrospectively identified 16 patients with TC (11 papillary thyroid cancer (PTC), 3 follicular thyroid cancer (FTC), 1 oncocytic PTC, 1 oncocytic FTC) and coexisting sarcoidosis of the lung and/or the lymph nodes treated at our institute. All patients had undergone thyroidectomy and initial adjuvant RIT. Challenges in diagnosing and the management of these patients were evaluated during long term follow-up (median 4.9 years (0.8-15.0 years)). RESULTS: Median age at first diagnosis of TC was 50.1 years (33.0-71.5 years) and of sarcoidosis 39.4 years (18.0-63.9 years). During follow-up, physicians were able to differentiate between SA and persistent or recurrent TC in 10 of 16 patients (63%). Diagnosis was complicated by initial negative thyroglobulin (Tg), positive Tg antibodies and non-specific imaging findings. Histopathology can reliably distinguish between SA and TC in patients with one suspicious lesion. CONCLUSION: Physicians should be aware of the rare coexistence of sarcoidosis and TC. Lymphadenopathy and pulmonary lesions could be metastases, sarcoidosis or even a mix of both. Therefore, this rare patient group should receive a thorough work up including histopathological clarification and, if necessary, separately for each lesion. AU - Wenter, V.* AU - Albert, N.L.* AU - Ahmaddy, F.* AU - Unterrainer, M.* AU - Hornung, J.* AU - Ilhan, H.* AU - Bartenstein, P.* AU - Spitzweg, C.* AU - Kneidinger, N. AU - Todica, A.* C1 - 61334 C2 - 50125 CY - Campus, 4 Crinan St, London N1 9xw, England TI - The diagnostic challenge of coexistent sarcoidosis and thyroid cancer - a retrospective study. JO - BMC Cancer VL - 21 IS - 1 PB - Bmc PY - 2021 SN - 1471-2407 ER - TY - JOUR AB - Background: Intraventricular neuroepithelial tumors (IVT) are rare lesions and comprise different pathological entities such as ependymomas, subependymomas and central neurocytomas. The treatment of choice is neurosurgical resection, which can be challenging due to their intraventricular location. Different surgical approaches to the ventricles are described. Here we report a large series of IVTs, its postoperative outcome at a single tertiary center and discuss suitable surgical approaches. Methods: We performed a retrospective chart review at a single tertiary neurosurgical center between 03/2009–05/2019. We included patients that underwent resection of an IVT emphasizing on surgical approach, extent of resection, clinical outcome and postoperative complications. Results: Forty five IVTs were resected from 03/2009 to 05/2019, 13 ependymomas, 21 subependymomas, 10 central neurocytomas and one glioependymal cyst. Median age was 52,5 years with 55.6% (25) male and 44.4% (20) female patients. Gross total resection was achieved in 93.3% (42/45). 84.6% (11/13) of ependymomas, 100% (12/21) of subependymomas, 90% (9/10) of central neurocytomas and one glioependymal cyst were completely removed. Postoperative rate of new neurological deficits was 26.6% (12/45). Postoperative new permanent cranial nerve deficits occurred in one case with 4th ventricle subependymoma and one in 4th ventricle ependymoma. Postoperative KPSS was 90% (IR 80–100). 31.1% of the patients improved in KPSS, 48.9% remained unchanged and 20% declined. Postoperative adverse events rate was 20.0%. Surgery-related mortality was 2.2%. The rate of shunt/cisternostomy-dependent hydrocephalus was 13.3% (6/45). 15.4% of resected ependymomas underwent adjuvant radiotherapy. Mean follow-up was 26,9 (±30.1) months. Conclusion: Our surgical findings emphasize satisfactory complete resection throughout all entities. Surgical treatment can remain feasible, if institutional experience is given. Satisfying long-term survival and cure is possible by complete removal. Gross total resection should always be performed under function-remaining aspects due to mostly benign or slow growing nature of IVTs. Further data is needed to evaluate standard of care and alternative therapy options in rare cases of tumor recurrence or in case of patient collective not suitable for operative resection. AU - Aftahy, A.K.* AU - Barz, M.* AU - Krauss, P.* AU - Liesche, F.* AU - Wiestler, B.* AU - Combs, S.E. AU - Straube, C.* AU - Meyer, B.* AU - Gempt, J.* C1 - 60473 C2 - 49471 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Intraventricular neuroepithelial tumors: Surgical outcome, technical considerations and review of literature. JO - BMC Cancer VL - 20 IS - 1 PB - Bmc PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - Background The aim of our study was to assess the feasibility and oncologic outcomes in patients treated with spinal (SI) or craniospinal irradiation (CSI) in patients with leptomeningeal metastases (LM) and to suggest a prognostic score as to which patients are most likely to benefit from this treatment. Methods Nineteen patients treated with CSI at our institution were eligible for the study. Demographic data, primary tumor characteristics, outcome and toxicity were assessed retrospectively. The extent of extra-CNS disease was defined by staging CT-scans before the initiation of CSI. Based on outcome parameters a prognostic score was developed for stratification based on patient performance status and tumor staging. Results Median follow-up and overall survival (OS) for the whole group was 3.4 months (range 0.5-61.5 months). The median overall survival (OS) for patients with LM from breast cancer was 4.7 months and from NSCLC 3.3 months. The median OS was 7.3 months, 3.3 months and 1.5 months for patients with 0, 1 and 2 risk factors according to the proposed prognostic score (KPS < 70 and the presence of extra-CNS disease) respectively. Nonhematologic toxicities were mild. Conclusion CSI demonstrated clinically meaningful survival that is comparable to the reported outcome of intrathecal chemotherapy. A simple scoring system could be used to better select patients for treatment with CSI in this palliative setting. In our opinion, the feasibility of performing CSI with modern radiotherapy techniques with better sparing of healthy tissue gives a further rationale for its use also in the palliative setting. AU - Devecka, M.* AU - Duma, M.N.* AU - Wilkens, J.J.* AU - Kampfer, S.* AU - Borm, K.J.* AU - Münch, S.* AU - Straube, C.* AU - Combs, S.E. C1 - 59325 C2 - 48780 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Craniospinal irradiation(CSI) in patients with leptomeningeal metastases: Risk-benefit-profile and development of a prognostic score for decision making in the palliative setting. JO - BMC Cancer VL - 20 IS - 1 PB - Bmc PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - Following publication of the original article [1], the authors reported an error in the labeling of Table 5. The corrected Table 5 is given below. AU - Ebert, K.* AU - Zwingenberger, G.* AU - Barbaria, E.* AU - Keller, S.* AU - Heck, C.* AU - Arnold, R.* AU - Hollerieth, V.* AU - Mattes, J.* AU - Geffers, R.* AU - Raimundez-Alvarez, E. AU - Hasenauer, J. AU - Luber, B.* C1 - 60584 C2 - 49884 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Correction to: Determining the effects of trastuzumab, cetuximab and afatinib by phosphoprotein, gene expression and phenotypic analysis in gastric cancer cell lines (BMC Cancer, (2020), 20, 1, (1039), 10.1186/s12885-020-07540-7). JO - BMC Cancer VL - 20 IS - 1 PB - Bmc PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - Background: Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer death worldwide. The molecular mechanisms of action for anti-HER-family drugs in gastric cancer cells are incompletely understood. We compared the molecular effects of trastuzumab and the other HER-family targeting drugs cetuximab and afatinib on phosphoprotein and gene expression level to gain insights into the regulated pathways. Moreover, we intended to identify genes involved in phenotypic effects of anti-HER therapies. Methods: A time-resolved analysis of downstream intracellular kinases following EGF, cetuximab, trastuzumab and afatinib treatment was performed by Luminex analysis in the gastric cancer cell lines Hs746T, MKN1, MKN7 and NCI-N87. The changes in gene expression after treatment of the gastric cancer cell lines with EGF, cetuximab, trastuzumab or afatinib for 4 or 24 h were analyzed by RNA sequencing. Significantly enriched pathways and gene ontology terms were identified by functional enrichment analysis. Furthermore, effects of trastuzumab and afatinib on cell motility and apoptosis were analyzed by time-lapse microscopy and western blot for cleaved caspase 3. Results: The Luminex analysis of kinase activity revealed no effects of trastuzumab, while alterations of AKT1, MAPK3, MEK1 and p70S6K1 activations were observed under cetuximab and afatinib treatment. On gene expression level, cetuximab mainly affected the signaling pathways, whereas afatinib had an effect on both signaling and cell cycle pathways. In contrast, trastuzumab had little effects on gene expression. Afatinib reduced average speed in MKN1 and MKN7 cells and induced apoptosis in NCI-N87 cells. Following treatment with afatinib, a list of 14 genes that might be involved in the decrease of cell motility and a list of 44 genes that might have a potential role in induction of apoptosis was suggested. The importance of one of these genes (HBEGF) as regulator of motility was confirmed by knockdown experiments. Conclusions: Taken together, we described the different molecular effects of trastuzumab, cetuximab and afatinib on kinase activity and gene expression. The phenotypic changes following afatinib treatment were reflected by altered biological functions indicated by overrepresentation of gene ontology terms. The importance of identified genes for cell motility was validated in case of HBEGF. AU - Ebert, K.* AU - Zwingenberger, G.* AU - Barbaria, E.* AU - Keller, S.* AU - Heck, C.* AU - Arnold, R.* AU - Hollerieth, V.* AU - Mattes, J.* AU - Geffers, R.* AU - Raimundez-Alvarez, E. AU - Hasenauer, J. AU - Luber, B.* C1 - 60438 C2 - 49309 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Determining the effects of trastuzumab, cetuximab and afatinib by phosphoprotein, gene expression and phenotypic analysis in gastric cancer cell lines. JO - BMC Cancer VL - 20 IS - 1 PB - Bmc PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - Objectives The present study aims to evaluate long-term side-effects and outcomes and confirm prognostic factors after stereotactic body radiotherapy (SBRT) of pulmonary lesions. This is the first work that combines the investigated data from patient charts and patient-reported outcome (PRO) up to 14 years after therapy. Materials and methods We analyzed 219 patients and 316 lung metastases treated between 2004 and 2019. The pulmonary lesions received a median dose and dose per fraction of 35 Gy (range: 14-60.5 Gy) and 8 Gy (range: 3-20 Gy) to the surrounding isodose. During the last 1.5 years of monitoring, we added PRO assessment to our follow-up routine. We sent an invitation to a web-based survey questionnaire to all living patients whose last visit was more than 6 months ago. Results Median OS was 27.6 months. Univariate analysis showed a significant influence on OS for KPS >= 90%, small gross tumor volume (GTV) and planning target volume (PTV), the absence of external metastases, <= 3 pulmonary metastases, and controlled primary tumor. The number of pulmonary metastases and age influenced local control (LC) significantly. During follow-up, physicians reported severe side-effects >= grade 3 in only 2.9% within the first 6 months and in 2.5% after 1 year. Acute symptomatic pneumonitis grade 2 was observed in 9.7%, as grade 3 in 0.5%. During PRO assessment, 39 patients were contacted, 38 patients participated, 14 participated twice during follow-up. Patients reported 15 cases of severe side effects (grade >= 3) according to PROCTCAE classification. Severe dyspnea (n = 6) was reported mostly. Conclusion We could confirm excellent local control and low toxicity rates. PROs improve and complement follow-up care. They are an essential measure in addition to the physician-reported outcomes. Future research must be conducted regarding the correct interpretation of PRO data. AU - Kessel, K.A. AU - Grosser, R.C.E.* AU - Kraus, K.M.* AU - Hoffmann, H.* AU - Oechsner, M.* AU - Combs, S.E. C1 - 59172 C2 - 48649 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Stereotactic body radiotherapy (SBRT) in patients with lung metastases-prognostic factors and long-term survival using patient self-reported outcome (PRO). JO - BMC Cancer VL - 20 IS - 1 PB - Bmc PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - Background: A substantial number of patients will develop further biochemical progression after radical prostatectomy (RP) and salvage radiotherapy (sRT). Recently published data using prostate-specific membrane antigen ligand positron emission tomography (PSMA - PET) for re-staging suggest that those recurrences are often located outside the prostate fossa and most of the patients have a limited number of metastases, making them amenable to metastasis-directed treatment (MDT). Methods: We analyzed 78 patients with biochemical progression after RP and sRT from a retrospective European multicenter database and assessed the biochemical recurrence-free survival (bRFS; PSA < nadir + 0.2 ng/ml or no PSA decline) as well as the androgen deprivation therapy- free survival (ADT-FS) using Kaplan-Meier curves. Log-rank test and multivariate analysis was performed to determine influencing factors. Results: A total of 185 PSMA - PET positive metastases were detected and all lesions were treated with radiotherapy (RT). Concurrent ADT was prescribed in 16.7% (13/78) of patients. The median PSA level before RT was 1.90 ng/mL (range, 0.1-22.1) and decreased statistically significantly to a median PSA nadir level of 0.26 ng/mL (range, 0.0-12.25; p < 0.001). The median PSA level of 0.88 ng/mL (range, 0.0-25.8) at the last follow-up was also statistically significantly lower (p = 0.008) than the median PSA level of 1.9 ng/mL (range, 0.1-22.1) before RT. The median bRFS was 17.0 months (95% CI, 14.2-19.8). After 12 months, 55.3% of patients were free of biochemical progression. Multivariate analyses showed that concurrent ADT was the most important independent factor for bRFS (p = 0.01). The median ADT-FS was not reached and exploratory statistical analyses estimated a median ADT-FS of 34.0 months (95% CI, 16.3-51.7). Multivariate analyses revealed no significant parameters for ADT-FS. Conclusions: RT as MDT based on PSMA - PET of all metastases of recurrent prostate cancer after RP and sRT represents a viable treatment option for well-informed and well-selected patients. AU - Oehus, A.K.* AU - Kroeze, S.G.C.* AU - Schmidt-Hegemann, N.S.* AU - Vogel, M.M.E.* AU - Kirste, S.* AU - Becker, J.* AU - Burger, I.A.* AU - Derlin, T.* AU - Bartenstein, P.* AU - Eiber, M.* AU - Mix, M.* AU - la Fougère, C.* AU - Belka, C.* AU - Combs, S.E. AU - Grosu, A.-L.* AU - Müller, A.C.* AU - Guckenberger, M.* AU - Christiansen, H.* AU - Henkenberens, C.* C1 - 61354 C2 - 49799 TI - Efficacy of PSMA ligand PET-based radiotherapy for recurrent prostate cancer after radical prostatectomy and salvage radiotherapy. JO - BMC Cancer VL - 20 IS - 1 PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - Background Patients with locally advanced bladder cancer (cT3/4 cN0/N+ cM0) have a poor prognosis despite radical surgical therapy and perioperative chemotherapy. Preliminary data suggest that the combination of radiation and immunotherapy does not lead to excess toxicity and may have synergistic (abscopal) anti-tumor effects. We hypothesize that the combined preoperative application of the PD-1 checkpoint-inhibitor Nivolumab with concomitant radiation therapy of the bladder and pelvic region followed by radical cystectomy with standardized lymphadenectomy is safe and feasible and might improve outcome for patients with locally advanced bladder cancer. Methods Study design: "RACE IT" (AUO AB 65/18) is an investigator initiated, prospective, multicenter, open, single arm phase II trial sponsored by Technical University Munich. Study drug and funding are provided by the company Bristol-Myers Squibb. Study treatment: Patients will receive Nivolumab 240 mg i.v. every 2 weeks for 4 cycles preoperatively with concomitant radiation therapy of bladder and pelvic region (max. 50.4 Gy). Radical cystectomy with standardized bilateral pelvic lymphadenectomy will be performed between week 11-15. Primary endpoint: Rate of patients with completed treatment consisting of radio-immunotherapy and radical cystectomy at the end of week 15. Secondary endpoints: Acute and late toxicity, therapy response and survival (1 year follow up). Main inclusion criteria: Patients with histologically confirmed, locally advanced bladder cancer (cT3/4, cN0/N+), who are ineligible for neoadjuvant, cisplatin-based chemotherapy or who refuse neoadjuvant chemotherapy. Main exclusion criteria: Patients with metastatic disease (lymph node metastasis outside pelvis or distant metastasis) or previous chemo-, immune- or radiation therapy. Planned sample size: 33 patients, interim analysis after 11 patients. Discussion This trial aims to evaluate the safety and feasibility of the combined approach of preoperative PD-1 checkpoint-inhibitor therapy with concomitant radiation of bladder and pelvic region followed by radical cystectomy. The secondary objectives of therapy response and survival are thought to provide preliminary data for further clinical evaluation after successful completion of this trial. Recruitment has started in February 2019. AU - Schmid, S.C.* AU - Koll, F.J.* AU - Rödel, C.* AU - Maisch, P.* AU - Sauter, A.* AU - Beckert, F.* AU - Seitz, A.* AU - Kübler, H.* AU - Flentje, M.* AU - Chun, F.* AU - Combs, S.E. AU - Schiller, K. AU - Gschwend, J.E.* AU - Retz, M.* C1 - 57761 C2 - 48126 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Radiation therapy before radical cystectomy combined with immunotherapy in locally advanced bladder cancer - study protocol of a prospective, single arm, multicenter phase II trial (RACE IT). JO - BMC Cancer VL - 20 IS - 1 PB - Bmc PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - Background Adrenal gland metastases are a common diagnostic finding in various tumor diseases. Due to the increased use of imaging methods, they are diagnosed more frequently, especially in asymptomatic patients. SBRT has emerged as a new, alternative treatment option in the field of radiation oncology. In the past, it was often used for treating inoperable lung, liver, prostate, and brain tumors. Meanwhile, it is also an established keystone in the treatment of oligometastatic diseases. This retrospective study aims to evaluate the effect of low-dose SBRT in patients with adrenal metastases. Methods We analyzed a group of 31 patients with 34 adrenal gland lesions treated with low-dose SBRT between July 2006 and July 2019. Treatment-planning was performed through contrast-enhanced CT, followed by image-guided stereotactic radiotherapy using cone-beam CT. The applied cumulative median dose was 35 Gy; the median single dose was 7 Gy. We focused on local control (LC), progression-free survival (PFS), overall survival (OS), as well as acute and late toxicity. Results Seven adrenal gland metastases (20.6%) experienced local failure, 80.6% of the patients faced a distant progression. Fourteen patients were still alive. Median follow-up for all patients was 9.8 months and for patients alive 14.4 months. No treatment-related side-effects >grade 2 occurred. Of all, 48.4% suffered from acute gastrointestinal disorders; 32.3% reported acute fatigue, throbbing pain in the renal area, and mild adrenal insufficiency. Altogether, 19.4% of the patients faced late-toxicities, which were as follows: Grade 1: 12.9% gastrointestinal disorders, 3.2% fatigue, Grade 2: 9.7% fatigue, 6.5% headache, 3.2% loss of weight. The 1-year OS and probability of LF were 64 and 25.9%, respectively. Conclusion Low-dose SBRT has proven as an effective and safe method with promising outcomes for treating adrenal metastases. There appeared no high-grade toxicities >grade 2, and 79.4% of treated metastases were progression-free. Thus, SBRT should be considered as a therapy option for adrenal metastases as an individual therapeutic concept in the interdisciplinary discussion as an alternative to surgical or systemic treatment. AU - Voglhuber, T.* AU - Kessel, K.A. AU - Oechsner, M.* AU - Vogel, M.M.E.* AU - Gschwend, J.E.* AU - Combs, S.E. C1 - 59329 C2 - 48745 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Single-institutional outcome-analysis of low-dose stereotactic body radiation therapy (SBRT) of adrenal gland metastases. JO - BMC Cancer VL - 20 IS - 1 PB - Bmc PY - 2020 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Oncoplastic surgery techniques lead to a rearrangement of the breast tissue and impede target definition during adjuvant radiotherapy (RT). The aim of this study was to assess local control rates after immediate oncoplastic surgery and adjuvant RT. METHODS: This study comprises 965 patients who underwent breast-conserving therapy and adjuvant RT between 01/2000 and 12/2005. 288 patients received immediate oncoplastic surgery (ONC) and 677 patients breast-conserving surgery only (NONC). All patients were treated with adjuvant external tangential-beam RT (total dose: 50/50.4 Gy; fraction dose 1.8/2.0 Gy). An additional boost dose of 10-16 Gy to the primary tumor bed was given in 900 cases (93.3%). Local control rates (LCR), Progression free survival (PFS) and overall survival (OS) were assessed retrospectively after a median follow-up period of 67 (Q25-Q75: 51-84) months. RESULTS: No significant difference was found between ONC and NONC in regard to LCR (5-yr: ONC 96.8% vs. NONC 95.3%; p = 0.25). This held also true for PFS (5-yr: ONC 92.1% vs. NONC 89.3%; p = 0.09) and OS (5-yr: ONC 96.0% vs. NONC 94.8%; p = 0.53). On univariate analyses G2-3 (p = 0.04), a younger age (p = 0.01), T-stage (p < 0.01) lymph node involvement (p < 0.01) as well as triple negative tumors (p < 0.01) were identified as risk factors for local recurrence. In a propensity score stratified Cox-regression model no significant impact of oncoplastic surgery on local control rate was found (HR: 2.05, 95% CI [0.93; 4.51], p = 0.08). CONCLUSION: Immediate oncoplastic surgery seems not to affect the effectiveness of adjuvant whole breast RT on local control rates in breast cancer patients. AU - Borm, K.J.* AU - Schönknecht, C.* AU - Nestler, A.* AU - Oechsner, M.* AU - Waschulzik, B.* AU - Combs, S.E. AU - Münch, S.* AU - Niemeyer, M.* AU - Duma, M.N.* C1 - 56893 C2 - 47417 TI - Outcomes of immediate oncoplastic surgery and adjuvant radiotherapy in breast cancer patients. JO - BMC Cancer VL - 19 IS - 1 PY - 2019 SN - 1471-2407 ER - TY - JOUR AB - BackgroundThere are different contouring guidelines for the clinical target volume (CTV) in anal cancer (AC) which vary concerning recommendations for radiation margins in different anatomical regions, especially on inguinal site. PET imaging has become more important in primary staging of AC as a very sensitive method to detect lymph node (LN) metastases. Using PET imaging, we evaluated patterns of LN spread, and examined the differences of the respective contouring guidelines on the basis of our results.MethodsWe carried out a retrospective study of thirty-seven AC patients treated with chemoradiation (CRT) who underwent FDG-PET imaging for primary staging in our department between 2011 and 2018. Patients showing PET positive LN were included in this analysis. Using a color code, LN metastases of all patients were delineated on a template with standard anatomy and were divided indicating whether their location was in- or out-field of the standard CTV as recommended by the Radiation Therapy Oncology Group (RTOG), the Australasian Gastrointestinal Trials Group (AGITG) or the British National Guidance (BNG). Furthermore, a detailed analysis of the location of LN of the inguinal region was performed.ResultsTwenty-two out of thirty-seven AC patients with pre-treatment PET imaging had PET positive LN metastases, accumulating to a total of 154 LN. The most commonly affected anatomical region was inguinal (49 LN, 32%). All para-rectal, external/internal iliac, and pre-sacral LN were covered by the recommended CTVs of the three different guidelines. Of forty-nine involved inguinal LN, fourteen (29%), seven (14%) and five (10%) were situated outside of the recommended CTVs by RTOG, AGITG and BNG. Inguinal LN could be located up to 5.7cm inferiorly to the femoral saphenous junction and 2.8cm medial or laterally to the big femoral vessels.ConclusionPelvis-related, various recommendations are largely consistent, and all LN are covered by the recommended CTVs. LN misses appear generally cranially (common iliac or para-aortic) or caudally (inguinal) to the recommended CTVs. The established guidelines differ significantly, particular regarding the inguinal region. Based on our results, we presented our suggestions for CTV definition of the inguinal region. LN involvement of a larger number of patients should be investigated to enable final recommendations. AU - Dapper, H.* AU - Schiller, K.* AU - Münch, S.* AU - Peeken, J.C. AU - Borm, K.* AU - Weber, W.* AU - Combs, S.E. C1 - 56680 C2 - 47223 CY - Campus, 4 Crinan St, London N1 9xw, England TI - Have we achieved adequate recommendations for target volume definitions in anal cancer? A PET imaging based patterns of failure analysis in the context of established contouring guidelines. JO - BMC Cancer VL - 19 IS - 1 PB - Bmc PY - 2019 SN - 1471-2407 ER - TY - JOUR AB - Purpose: Maximum (MIP) and average intensity projection (AIP) CTs allow rapid definition of internal target volumes in a 4D-CT. The purpose of this study was to assess the accuracy of these techniques in a large patient cohort in combination with simulations on a lung phantom. Methods: 4DCT data from a self-developed 3D lung phantom and from 50 patients with lung tumors were analyzed. ITVs were contoured in maximum (ITVMIP) and average intensity projection (ITVAIP) and subsequently compared to ITVs contoured in 10 phases of a 4D-CT (ITV10). In the phantom study additionally a theoretical target volume was calculated for each motion and compared to the contoured volumes. Results: ITV10overestimated the actual target volume by 9.5% whereas ITVMIPand ITVAIPlead to an underestimation of - 1.8% and - 11.4% in the phantom study. The ITVMIP(ITVAIP) was in average - 10.0% (- 18.7%) smaller compared to the ITV10. In the patient CTs deviations between ITV10and MIP/AIP were significantly larger (MIP: - 20.2% AIP: -33.7%) compared to this. Tumors adjacent to the chestwall, the mediastinum or the diaphragm showed lower conformity between ITV10and ITVMIP(ITVAIP) compared to tumors solely surrounded by lung tissue. Large tumor diameters (> 3.5 cm) and large motion amplitudes (> 1 cm) were associated with lower conformity between intensity projection CTs and ITV10-. Conclusion: The application of MIP and AIP in the clinical practice should not be a standard procedure for every patient, since relevant underestimation of tumor volumes may occur. This is especially true if the tumor borders the mediastinum, the chest wall or the diaphragm and if tumors show a large motion amplitude. AU - Borm, K.J.* AU - Oechsner, M.* AU - Wiegandt, M.* AU - Hofmeister, A.* AU - Combs, S.E. AU - Duma, M.N. C1 - 54035 C2 - 45229 TI - Moving targets in 4D-CTs versus MIP and AIP: Comparison of patients data to phantom data. JO - BMC Cancer VL - 18 IS - 1 PY - 2018 SN - 1471-2407 ER - TY - JOUR AB - Background: Glioblastoma relapses in the vast majority of cases within 1 year. Maximum safe resection of the recurrent glioblastoma can be offered in some cases. Re-irradiation has been established for the treatment of recurrent glioblastoma, too. In both cases, adjuvant treatment, mostly using temozolomide, can improve PFS and OS after these interventions. However, combining gross tumor resection and adjuvant re-radiotherapy to the resection cavity has not been tested so far. Methods/Design: In the multicenter two-armed randomized Phase II GlioCave Study, fractionated stereotactic radiotherapy to the resection cavity, after gross tumor resection of recurrent glioblastoma, will be compared to observation. Depending on the size of the target volume, a total dose of 46 Gy in 2 Gy per fraction or a total dose if 36 Gy in 3 Gy per fraction will be applied. Progression free survival will be the primary endpoint of the study. Discussion: Adjuvant treatment after gross tumor resection of recurrent glioblastoma is currently deemed to be limited to chemotherapy. However, re-irradiation has proven safety and tolerability in the treatment of macroscopic disease. Performing re-irradiation as an adjuvant measure after gross tumor resection has not been tested so far. The GlioCave Study will investigate the efficacy and the safety profile of this approach. Trial registration: The trial was prospectively registered at clinicaltrials.gov (NCT02715297, registration date February 29th, 2016). The protocol presented hereby refers to the version 1.2 of the protocol (January 11 th , 2017). AU - Straube, C.* AU - Scherb, H. AU - Gempt, J.* AU - Kirschke, J.* AU - Zimmer, C.* AU - Schmidt-Graf, F.* AU - Meyer, B.* AU - Combs, S.E. C1 - 52675 C2 - 44113 CY - London TI - Adjuvant stereotactic fractionated radiotherapy to the resection cavity in recurrent glioblastoma - the GlioCave study (NOA 17-ARO 2016/3-DKTK ROG trial). JO - BMC Cancer VL - 18 IS - 1 PB - Biomed Central Ltd PY - 2018 SN - 1471-2407 ER - TY - JOUR AB - Background: The treatment recommendations for Low-grade Gliomas (LGG) underwent profound changes due to results from RTOG 9802 published in April 2016. This work aims to investigate whether the results from the trial were already incorporated into the treatment recommendations at German oncology centers before an update of the official guidelines.Methods: An online based questionnaire with questions covering all aspects of adjuvant treatments of LGGs was generated, including three cases with distinct clinical situations. We contacted all members of the neuro-oncologic working group (NOA) of the German Cancer Society (DKG) as well as all German-speaking members of the European Low-Grade Glioma Network via E-mail.Results: We collected 38 responses. All responders were at least specialists; they predominantly worked at tertiary hospitals with a high volume of LGGs treated annually (75% with more than 10 cases per year). All responders stated to consent treatment recommendation for LGGs within interdisciplinary oncologic boards. The treatment recommendations for LGGs changed profoundly between 2015 and 12/2016. There is a trend towards PCV-based multimodal treatments, especially for oligodendroglial LGGs, as well as a trend away from watchful-waiting-policies for astrocytic LGGs.Conclusion: Neurooncologists do adapt results from clinical trials quickly. None the less, there is still an immense heterogeneity within the treatment recommendations, predominantly for astrocytic LGGs. Well planned clinical trials and concise treatment recommendations are warranted; additionally, individual counseling of patients is essential. AU - Straube, C.* AU - Kessel, K.A. AU - Schmidt-Graf, F.* AU - Krieg, S.M.* AU - Meyer, B.* AU - Gempt, J.* AU - Combs, S.E. C1 - 54397 C2 - 45548 CY - Campus, 4 Crinan St, London N1 9xw, England TI - A trend towards a more intense adjuvant treatment of low-grade-gliomas in tertiary centers in Germany after RTOG 9802-results from a multi-center survey. JO - BMC Cancer VL - 18 IS - 1 PB - Bmc PY - 2018 SN - 1471-2407 ER - TY - JOUR AB - Background: To assess the personal beliefs of radiation oncologists regarding heart sparing techniques in breast cancer patients. Methods: Between August 2015 and September 2015, a survey was sent to radiation oncology departments in Germany, Austria and Switzerland. 82 radiation oncology departments answered the questionnaire: 16 university clinics and 66 other departments. Most (87.2%) of the participants had > 10years of radiation oncology experience. Results: 89.2% of the participants felt that there is enough evidence to support heart sparing for breast cancer patients. The most important dose parameter was considered the mean heart dose (69.1%). The personal "safe" dose to the heart was considered to be 5Gy (range: 0-40Gy). The main impediment in offering all breast cancer patients heart-sparing techniques seems to be the fact that these techniques are time/ resource consuming (46.5% of the participants). Conclusions: Most radiation oncologists believe that there is enough evidence to support heart sparing for breast cancer patients. But translating this belief into a wide practice will need better dosimetric and clinical data on what patients are expected to profit most, specific guidelines for which patients' heart sparing techniques should be performed, as well as recognition of the time/resource consumption of these techniques. AU - Duma, M.N. AU - Münch, S.* AU - Oechsner, M.* AU - Combs, S.E. C1 - 51797 C2 - 43480 CY - London TI - Are heart toxicities in breast cancer patients important for radiation oncologists? A practice pattern survey in German speaking countries. JO - BMC Cancer VL - 17 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1471-2407 ER - TY - JOUR AB - Background: The impact of local tumor ablative therapy in oligometastasized prostate cancer (PC) is still under debate. To gain data for this approach, we evaluated oligometastasized PC patients receiving stereotactic body radiotherapy (SBRT) to bone metastases. Methods: In this retrospective study, 15 oligometastasized PC patients with a total of 20 bone metastases were evaluated regarding biochemical progression-free survival (PSA-PFS), time to initiation of ADT, and local control rate (LCR). Three patients received concomitant androgen deprivation therapy (ADT). Results: The median follow-up after RT was 22.5 months (range 7.0-53.7 months). The median PSA-PFS was 6.9 months (range 1.1-28.4 months). All patients showing a decrease of PSA level after RT of at least factor 10 reveal a PSA-PFS of >12 months. Median PSA-PFS of this sub-group was 23.1 months (range 12.1-28.4 months). Local PFS (LPFS) after 2 years was 100%. One patient developed a local failure after 28.4 months. Median distant PFS (DPFS) was 7.36 months (range 1.74-54.34 months). The time to initiation of ADT in patients treated without ADT was 9.3 months (range 2.6-36.1 months). In all patients, the time to intensification of systemic therapy or the time to initiation of ADT increased from 9.3 to 12.3 months (range 2.6-36.1 months). Gleason-Score, ADT or the localization of metastasis had no impact on PFS or time to intensification of systemic therapy. No SBRT related acute or late toxicities were observed. Conclusion: Our study shows that SBRT of bone metastases is a highly effective therapy with an excellent risk-benefit profile. However, PFS was limited due to a high distant failure rate implying the difficulty for patient selection for this oligometastatic concept. SBRT offers high local cancer control rates in bone oligometastases of PC and should be evaluated with the aim of curation or to delay modification of systemic treatment. AU - Habl, G.* AU - Straube, C.* AU - Schiller, K.* AU - Duma, M.N.* AU - Oechsner, M.* AU - Kessel, K.A. AU - Eiber, M.* AU - Schwaiger, M.* AU - Kübler, H.R.* AU - Gschwend, J.E.* AU - Combs, S.E. C1 - 51286 C2 - 43161 CY - London TI - Oligometastases from prostate cancer: Local treatment with stereotactic body radiotherapy (SBRT). JO - BMC Cancer VL - 17 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1471-2407 ER - TY - JOUR AB - Background: Gastric cancers frequently overexpress the epidermal growth factor receptor (EGFR), which has been implicated in pathological processes including tumor cell motility, invasion and metastasis. Targeting EGFR with the inhibitory antibody cetuximab may affect the motile and invasive behavior of tumor cells. Here, we evaluated the effects of EGFR signaling in gastric cancer cell lines to link the phenotypic behavior of the cells with their molecular characteristics. Methods: Phenotypic effects were analyzed in four gastric cancer cell lines (AGS, Hs746T, LMSU and MKN1) by time-lapse microscopy and transwell invasion assay. Effects on EGFR signaling were detected using Western blot and proteome profiler analyses. A network was constructed linking EGFR signaling to the regulation of cellular motility. Results: The analysis of the effects of treatment with epidermal growth factor (EGF) and cetuximab revealed that only one cell line (MKN1) was sensitive to cetuximab treatment in all phenotypic assays, whereas the other cell lines were either not responsive (Hs746T, LMSU) or sensitive only in certain tests (AGS). Cetuximab inhibited EGFR, MAPK and AKT activity and associated components of the EGFR signaling pathway to different degrees in cetuximab-sensitive MKN1 cells. In contrast, no such changes were observed in Hs746T cells. Thus, the different phenotypic behaviors of the cells were linked to their molecular response to treatment. Genetic alterations had different associations with response to treatment: while PIK3CA mutations and KRAS mutation or amplification were not obstructive, the MET mutation was associated with non-response. Conclusion: These results identify components of the EGFR signaling network as important regulators of the phenotypic and molecular response to cetuximab treatment. AU - Keller, S.* AU - Kneissl, J.* AU - Grabher-Meier, V.* AU - Heindl, S.* AU - Hasenauer, J. AU - Maier, D.* AU - Mattes, J.* AU - Winter, P.* AU - Luber, B.* C1 - 52585 C2 - 44105 CY - London TI - Evaluation of epidermal growth factor receptor signaling effects in gastric cancer cell lines by detailed motility-focused phenotypic characterization linked with molecular analysis. JO - BMC Cancer VL - 17 IS - 1 PB - Biomed Central Ltd PY - 2017 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: The nature of the association between occupational social prestige, social mobility, and risk of lung cancer remains uncertain. Using data from the international pooled SYNERGY case-control study, we studied the association between lung cancer and the level of time-weighted average occupational social prestige as well as its lifetime trajectory. METHODS: We included 11,433 male cases and 14,147 male control subjects. Each job was translated into an occupational social prestige score by applying Treiman's Standard International Occupational Prestige Scale (SIOPS). SIOPS scores were categorized as low, medium, and high prestige (reference). We calculated odds ratios (OR) with 95 % confidence intervals (CI), adjusting for study center, age, smoking, ever employment in a job with known lung carcinogen exposure, and education. Trajectories in SIOPS categories from first to last and first to longest job were defined as consistent, downward, or upward. We conducted several subgroup and sensitivity analyses to assess the robustness of our results. RESULTS: We observed increased lung cancer risk estimates for men with medium (OR = 1.23; 95 % CI 1.13-1.33) and low occupational prestige (OR = 1.44; 95 % CI 1.32-1.57). Although adjustment for smoking and education reduced the associations between occupational prestige and lung cancer, they did not explain the association entirely. Traditional occupational exposures reduced the associations only slightly. We observed small associations with downward prestige trajectories, with ORs of 1.13, 95 % CI 0.88-1.46 for high to low, and 1.24; 95 % CI 1.08-1.41 for medium to low trajectories. CONCLUSIONS: Our results indicate that occupational prestige is independently associated with lung cancer among men. AU - Behrens, T.* AU - Groß, I.* AU - Siemiatycki, J.* AU - Conway, D.I.* AU - Olsson, A.* AU - Stücker, I.* AU - Guida, F.* AU - Jöckel, K.-H.* AU - Pohlabeln, H.* AU - Ahrens, W.* AU - Brüske, I. AU - Wichmann, H.-E. AU - Gustavsson, P.* AU - Consonni, D.* AU - Merletti, F.* AU - Richiardi, L.* AU - Simonato, L.* AU - Fortes, C.* AU - Parent, M.E.* AU - McLaughlin, J.* AU - Demers, P.* AU - Landi, M.T.* AU - Caporaso, N.* AU - Zaridze, D.* AU - Szeszenia-Dabrowska, N.* AU - Rudnai, P.* AU - Lissowska, J.* AU - Fabianova, E.* AU - Tardón, A.* AU - Field, J.K.* AU - Dumitru, R.S.* AU - Bencko, V.* AU - Foretova, L.* AU - Janout, V.* AU - Kromhout, H.* AU - Vermeulen, R.* AU - Boffetta, P.* AU - Straif, K.* AU - Schüz, J.* AU - Hovanec, J.* AU - Kendzia, B.* AU - Pesch, B.* AU - Brüning, T* C1 - 49044 C2 - 41609 CY - London TI - Occupational prestige, social mobility and the association with lung cancer in men. JO - BMC Cancer VL - 16 IS - 1 PB - Biomed Central Ltd PY - 2016 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Triple-negative breast cancer (TNBC) with a BRCA1-like molecular signature has been demonstrated to remarkably respond to platinum-based chemotherapy and might be suited for a future treatment with poly(ADP-ribose)polymerase (PARP) inhibitors. In order to rapidly assess this signature we have previously developed a multiplex-ligation-dependent probe amplification (MLPA)-based assay. Here we present an independent validation of this assay to confirm its important clinical impact. METHODS: One-hundred-forty-four TNBC tumor specimens were analysed by the MLPA-based "BRCA1-like" test. Classification into BRCA1-like vs. non-BRCA1-like samples was performed by our formerly established nearest shrunken centroids classifier. Data were subsequently compared with the BRCA1-mutation/methylation status of the samples. T-lymphocyte infiltration and expression of the main target of PARP inhibitors, PARP1, were assessed on a subset of samples by immunohistochemistry. Data acquisition and interpretation was performed in a blinded manner. RESULTS: In the studied TNBC cohort, 63 out of 144 (44 %) tumors were classified into the BRCA1-like category. Among these, the MLPA test correctly predicted 15 out of 18 (83 %) samples with a pathogenic BRCA1-mutation and 20 of 22 (91 %) samples exhibiting BRCA1-promoter methylation. Five false-negative samples were observed. We identified high lymphocyte infiltration as one possible basis for misclassification. However, two falsely classified BRCA1-mutated tumors were also characterized by rather non-BRCA1-associated histopathological features such as borderline ER expression. The BRCA1-like vs. non-BRCA1-like signature was specifically enriched in high-grade (G3) cancers (90 % vs. 58 %, p = 0.0004) and was also frequent in tumors with strong (3+) nuclear PARP1 expression (37 % vs. 16 %; p = 0.087). CONCLUSIONS: This validation study confirmed the good performance of the initial MLPA assay which might thus serve as a valuable tool to select patients for platinum-based chemotherapy regimens. Moreover, frequent PARP1 upregulation in BRCA1-like tumors may also point to susceptibility to treatment with PARP inhibitors. Limitations are the requirement of high tumor content and high-quality DNA. AU - Gross, E.* AU - van Tinteren, H.* AU - Li, Z.* AU - Raab, S.* AU - Meul, C.* AU - Avril, S.* AU - Laddach, N.* AU - Aubele, M. AU - Propping, C.* AU - Gkazepis, A.* AU - Schmitt, M.* AU - Meindl, A.* AU - Nederlof, P.M.* AU - Kiechle, M.* AU - Lips, E.H.* C1 - 49798 C2 - 40954 CY - London TI - Identification of BRCA1-like triple-negative breast cancers by quantitative multiplex-ligation-dependent probe amplification (MLPA) analysis of BRCA1-associated chromosomal regions: A validation study. JO - BMC Cancer VL - 16 PB - Biomed Central Ltd PY - 2016 SN - 1471-2407 ER - TY - JOUR AB - Background: Galectin-7 (Gal-7) is negatively regulated in cervical cancer, and appears to be a link between the apoptotic response triggered by cancer and the anti-tumoral activity of the immune system. Our understanding of how cervical cancer cells and their molecular networks adapt in response to the expression of Gal-7 remains limited. Methods: Meta-analysis of Gal-7 expression was conducted in three cervical cancer cohort studies and TCGA. In silico prediction and bisulfite sequencing were performed to inquire epigenetic alterations. To study the effect of Gal-7 on cervical cancer, we ectopically re-expressed it in the HeLa and SiHa cervical cancer cell lines, and analyzed their transcriptome and SILAC-based proteome. We also examined the tumor and microenvironment host cell transcriptomes after xenotransplantation into immunocompromised mice. Differences between samples were assessed with the Kruskall-Wallis, Dunn's Multiple Comparison and T tests. Kaplan-Meier and log-rank tests were used to determine overall survival. Results: Gal-7 was constantly downregulated in our meta-analysis (p < 0.0001). Tumors with combined high Gal-7 and low galectin-1 expression (p = 0.0001) presented significantly better prognoses (p = 0.005). In silico and bisulfite sequencing assays showed de novo methylation in the Gal-7 promoter and first intron. Cells re-expressing Gal-7 showed a high apoptosis ratio (p < 0.05) and their xenografts displayed strong growth retardation (p < 0.001). Multiple gene modules and transcriptional regulators were modulated in response to Gal-7 reconstitution, both in cervical cancer cells and their microenvironments (FDR < 0.05 %). Most of these genes and modules were associated with tissue morphogenesis, metabolism, transport, chemokine activity, and immune response. These functional modules could exert the same effects in vitro and in vivo, even despite different compositions between HeLa and SiHa samples. Conclusions: Gal-7 re-expression affects the regulation of molecular networks in cervical cancer that are involved in diverse cancer hallmarks, such as metabolism, growth control, invasion and evasion of apoptosis. The effect of Gal-7 extends to the microenvironment, where networks involved in its configuration and in immune surveillance are particularly affected. AU - Higareda-Almaraz, J. AU - Ruiz-Moreno, J.S.* AU - Klimentova, J.* AU - Barbieri, D.* AU - Salvador-Gallego, R.* AU - Ly, R.* AU - Valtierra-Gutierrez, I.A.* AU - Dinsart, C.* AU - Rabinovich, G.A.* AU - Stulik, J.* AU - Rösl, F.* AU - Rincon-Orozco, B.* C1 - 49380 C2 - 41816 CY - London TI - Systems-level effects of ectopic galectin-7 reconstitution in cervical cancer and its microenvironment. JO - BMC Cancer VL - 16 IS - 1 PB - Biomed Central Ltd PY - 2016 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Due to lack of a targeted therapy for the triple-negative breast cancer (TNBC) patients, it is important to explore this aggressive breast cancer type in more detail and to establish novel therapeutic approaches. TNBC is defined negative for the protein expression of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). One prominent feature of this cancer type is the frequent overexpression of major components of the urokinase-type plasminogen activator system (uPAS) including uPA, its receptor uPAR and the inhibitor PAI-1, which may be valuable as therapeutic targets. METHODS: Direct interactions of uPAR with interactors were demonstrated by immunoprecipitations and proximity ligation assays. For stable knockdowns of target proteins, lentiviral vectors were used and the effects were analysed by immunoblottings and using in vitro cell viability, migration and invasion assays. Immunohistochemical and statistical analyses of biomarkers and clinical parameters were conducted in a TNBC cohort (n = 174). RESULTS: Direct tumour-promoting interactions of uPAR with uPA and the insulin-like growth factor receptor 1 (IGF1R) were shown in TNBC cells and these interactions were significantly reduced (p = 0.001) when uPAR was downregulated. The combined knockdown of uPAR and uPA or IGF1R additively and significantly reduced cell viability, migration and invasion of the model cell lines. In TNBC tissue, the complexes formed by uPAR with uPA or with IGF1R significantly correlated with the histological grade (p = 0.0019) as well as with cathepsin B and D (p ≤ 0.0001) that are implicated in cell invasion and metastasis. CONCLUSIONS: Our outcomes show that not only overexpressed biomarkers promote tumourigenesis, but rather their interactions further potentiate tumour progression. This study emphasises the potential of combined approaches targeting uPAR and its interactors with regard to an improved therapy of TNBC. AU - Huber, M. AU - Mall, R. AU - Braselmann, H. AU - Feuchtinger, A. AU - Molatore, S. AU - Lindner, K. AU - Walch, A.K. AU - Gross, E.* AU - Schmitt, M.* AU - Falkenberg, N. AU - Aubele, M. C1 - 49245 C2 - 41781 CY - London TI - uPAR enhances malignant potential of triple-negative breast cancer by directly interacting with uPA and IGF1R. JO - BMC Cancer VL - 16 IS - 1 PB - Biomed Central Ltd PY - 2016 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Radiation resistance presents a challenge to the effective treatment of cancer. If therapeutic compounds were capable of resensitizing resistant tumours then a concurrent chemo-radiation treatment could be used to overcome radiation resistance. METHODS: We have developed a phenotypic assay to investigate the response of radiation resistant breast cancer cells grown in 3D-microtissue spheroids to combinations of radiation and established chemotherapeutic drugs. The effects were quantified by real time high content imaging of GFP detection area over 14 days. Ten established chemotherapeutic drugs were tested for their ability to enhance the effects of radiation. RESULTS: Of ten analysed chemotherapeutics, vinblastine was the most effective compound, with docetaxel and doxorubicine being less effective in combination with radiation. To investigate the response in a model closer to the in vivo situation we investigated the response of heterotypic 3D microtissues containing both fibroblasts and breast cancer cells. Drug treatment of these heterotypic 3D cultures confirmed treatment with radiation plus vinblastine to be additive in causing breast cancer growth inhibition. We have validated the screen by comparing radiation sensitizing effects of known chemotherapeutic agents. In both monotypic and heterotypic models the concurrent treatment of vinblastine and radiation proved more effective inhibitors of mammary cancer cell growth. The effective concentration range of both vinblastine and radiation are within the range used in treatment, suggesting the 3D model will offer a highly relevant screen for novel compounds. CONCLUSIONS: For the first time comfortable 3D cell-based phenotypic assay is available, that allows high throughput screening of compounds with radiation therapy modulating capacity, opening the field to drug discovery. AU - Anastasov, N. AU - Höfig, I. AU - Radulovic, V. AU - Strobel, S.* AU - Salomon, M.* AU - Lichtenberg, J.* AU - Rothenaigner, I. AU - Hadian, K. AU - Kelm, J.M.* AU - Thirion, C.* AU - Atkinson, M.J. C1 - 45146 C2 - 37242 CY - London TI - A 3D-microtissue-based phenotypic screening of radiation resistant tumor cells with synchronized chemotherapeutic treatment. JO - BMC Cancer VL - 15 IS - 1 PB - Biomed Central Ltd PY - 2015 SN - 1471-2407 ER - TY - JOUR AB - Thyroid neoplasias with oncocytic features represent a specific phenotype in non-medullary thyroid cancer, reflecting the unique biological phenomenon of mitochondrial hyperplasia in the cytoplasm. Oncocytic thyroid cells are characterized by a prominent eosinophilia (or oxyphilia) caused by mitochondrial abundance. Although disruptive mutations in the mitochondrial DNA (mtDNA) are the most significant hallmark of such tumors, oncocytomas may be envisioned as heterogeneous neoplasms, characterized by multiple nuclear and mitochondrial gene lesions. We investigated the nuclear mutational profile of oncocytic tumors to pinpoint the mutations that may trigger the early oncogenic hit. Methods: Total DNA was extracted from paraffin-embedded tissues from 45 biopsies of oncocytic tumors. High-resolution melting was used for mutation screening of mitochondrial complex I subunits genes. Specific nuclear rearrangements were investigated by RT-PCR (RET/PTC) or on isolated nuclei by interphase FISH (PAX8/PPARγ). Recurrent point mutations were analyzed by direct sequencing. Results: In our oncocytic tumor samples, we identified rare TP53 mutations. The series of analyzed cases did not include poorly- or undifferentiated thyroid carcinomas, and none of the TP53 mutated cases had significant mitotic activity or high-grade features. Thus, the presence of disruptive TP53 mutations was completely unexpected. In addition, novel mutations in nuclear-encoded complex I genes were identified. Conclusions: These findings suggest that nuclear genetic lesions altering the bioenergetics competence of thyroid cells may give rise to an aberrant mitochondria-centered compensatory mechanism and ultimately to the oncocytic phenotype. AU - Evangelisti, C.* AU - de Biase, D.* AU - Kurelac, I.* AU - Ceccarelli, C.* AU - Prokisch, H. AU - Meitinger, T. AU - Caria, P.* AU - Vanni, R.* AU - Romeo, G.* AU - Tallini, G.* AU - Gasparre, G.* AU - Bonora, E.* C1 - 44085 C2 - 36819 CY - London TI - A mutation screening of oncogenes, tumor suppressor gene TP53 and nuclear encoded mitochondrial complex I genes in oncocytic thyroid tumors. JO - BMC Cancer VL - 15 IS - 1 PB - Biomed Central Ltd PY - 2015 SN - 1471-2407 ER - TY - JOUR AB - Background The aim of the trial is to demonstrate that with the use of modern IMRT/IGRT and reduction of safety margins postoperative wound complications can be reduced. Methods/ Design The trial is designed as a prospective, monocentric clinical phase II trial. The treatment is performed with helical IMRT on the Tomotherapy HiArt System© or with RapidArc© IMRT as available. All treatments are performed with 6 MV photons and daily online CT-based IGRT. A dose of 50 Gy in 2 Gy single fractions (5 fractions per week) is prescribed. Restaging including MRI of the primary tumor site as well as CT of the thorax/abdomen is planned 4 weeks after RT. PET-examinations or any other imaging can be performed as required clinically. In cases of R1 resection, brachytherapy is anticipated in the 2nd postoperative week. Brachytherapy catheters are implanted into the tumor bed depending on the size and location of the lesion. Surgery is planned 5–6 weeks after completion of neoadjuvant RT. All patients are seen for a first follow-up visit 2 weeks after wound healing is completed, thereafter every 3 months during the first 2 years. The endpoints of the study are evaluated in detail during the first (2 weeks) and second (3 months) follow-up. Functional outcome and QOL are documented prior to treatment and at year 1 and 2. Treatment response and efficacy will be scored according to the RECIST 1.1 criteria. A total patient number of 50 with an expected 20 % rate of wound complications were calculated for the study, which translates into a 95 % confidence interval of 10.0-33.7 % for wound complication rate in a binomial distribution. Discussion The present study protocol prospectively evaluates the use of IMRT/IGRT for neoadjuvant RT in patients with soft tissue sarcomas of the extremity with the primary endpoint wound complications, which is the major concern with this treatment sequence. Besides complications rates, local control rates and survival rates, as well as QOL, functional outcome and treatment response parameters (imaging and pathology) are part of the protocol. The data of the present PREMISS study will enhance the current literature and support the hypothesis that neoadjuvant RT with IMRT/IGRT offers an excellent risk-benefit ratio in this patient population. Trial registration NCT01552239   AU - Roeper, B.* AU - Heinrich, C.* AU - Kehl, V.* AU - Rechl, H.P.* AU - Specht, K.* AU - Woertler, K.* AU - Toepfer, A.* AU - Molls, M.* AU - Kampfer, S.* AU - von Eisenharth-Rothe, R.* AU - Combs, S.E. C1 - 47548 C2 - 40659 TI - Study of preoperative radiotherapy for sarcomas of the extremities with intensity-modulation, image-guidance and small safety-margins (PREMISS). JO - BMC Cancer VL - 15 IS - 1 PY - 2015 SN - 1471-2407 ER - TY - JOUR AB - Background: The Wnt inhibitor Dickkopf-1 (DKK-1) has been linked to the progression of malignant bone disease by impairing osteoblast activity. In addition, there is increasing data to suggest direct tumor promoting effects of DKK-1. The prognostic role of DKK-1 expression in prostate cancer remains unclear. Methods: A prostate cancer tissue microarray (n = 400) was stained for DKK-1 and DKK-1 serum levels were measured in 80 patients with prostate cancer. The independent prognostic value of DKK-1 expression was assessed using multivariate analyses. Results: DKK-1 tissue expression was significantly increased in prostate cancer compared to benign disease, but was not correlated with survival. However, high DKK-1 serum levels at the time of the diagnosis were associated with a significantly shorter overall and disease-specific survival. Multivariate analyses defined high serum levels of DKK-1 as an independent prognostic marker in prostate cancer (HR 3.73; 95%CI 1.44-9.66, p = 0.007). Conclusion: High DKK-1 serum levels are associated with a poor survival in patients with prostate cancer. In light of current clinical trials evaluating the efficacy of anti-DKK-1 antibody therapies in multiple myeloma and solid malignancies, the measurement of DKK-1 in prostate cancer may gain clinical relevance. AU - Rachner, T.D.* AU - Thiele, S.* AU - Goebel, A.* AU - Browne, A.* AU - Fuessel, S.* AU - Erdmann, K.* AU - Wirth, M.P.* AU - Froehner, M.* AU - Todenhoefer, T.* AU - Muders, M.H.* AU - Kieslinger, M. AU - Rauner, M.* AU - Hofbauer, L.C.* C1 - 32526 C2 - 35122 CY - London TI - High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. JO - BMC Cancer VL - 14 IS - 1 PB - Biomed Central Ltd PY - 2014 SN - 1471-2407 ER - TY - JOUR AB - Recent studies have reported associations of DNA repair pathway gene variants and risk of various cancers and precancerous lesions, such as chronic atrophic gastritis (CAG). METHODS: A nested case-control study within the German population-based ESTHER cohort was conducted, including 533 CAG cases and 1054 controls. Polymorphisms in eleven DNA repair genes (APEX1, ERCC1, ERCC2/XPD, PARP1 and XRCC1), in CD3EAP/ASE-1 and PPP1R13L were analysed. RESULTS: No association was disclosed for any of the analysed polymorphisms. Nor did stratified analyses according to ages < 65 and ≥ 65 years show any significant association with CAG risk. CONCLUSIONS: The results of this large German case-control study do not reveal associations of DNA repair pathway polymorphisms and risk of CAG. On the basis of a large number of CAG cases, they do not support associations of DNA repair pathway SNPs with CAG risk, but suggest the need of larger studies to disclose or exclude potential weak associations, or of studies with full coverage of candidate genes. AU - Frank, B.* AU - Müller, H.* AU - Weck, M.N.* AU - Klopp, N. AU - Illig, T. AU - Raum, E.* AU - Brenner, H.* C1 - 6716 C2 - 29298 TI - DNA repair gene polymorphisms and risk of chronic atrophic gastritis: A case-control study. JO - BMC Cancer VL - 11 PB - Biomed Central PY - 2011 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: The activity of the epidermal growth factor receptor (EGFR)-directed monoclonal antibody cetuximab combined with oxaliplatin/leucovorin/5-fluorouracil (FUFOX) was assessed in first-line metastatic gastric and oesophago-gastric junction (OGJ) cancer in a prospective phase II study showing a promising objective tumour response rate of 65% and a low mutation frequency of KRAS (3%). The aim of the correlative tumour tissue studies was to investigate the relationship between EGFR gene copy numbers, activation of the EGFR pathway, expression and mutation of E-cadherin, V600E BRAF mutation and clinical outcome of patients with gastric and OGJ cancer treated with cetuximab combined with FUFOX. METHODS: Patients included in this correlative study (n = 39) were a subset of patients from the clinical phase II study. The association between EGFR gene copy number, activation of the EGFR pathway, abundance and mutation of E-cadherin which plays an important role in these disorders, BRAF mutation and clinical outcome of patients was studied. EGFR gene copy number was assessed by FISH. Expression of the phosphorylated forms of EGFR and its downstream effectors Akt and MAPK, in addition to E-cadherin was analysed by immunohistochemistry. The frequency of mutant V600E BRAF was evaluated by allele-specific PCR and the mutation profile of the E-cadherin gene CDH1 was examined by DHPLC followed by direct sequence analysis. Correlations with overall survival (OS), time to progression (TTP) and overall response rate (ORR) were assessed. RESULTS: Our study showed a significant association between increased EGFR gene copy number (≥ 4.0) and OS in gastric and OGJ cancer, indicating the possibility that patients may be selected for treatment on a genetic basis. Furthermore, a significant correlation was shown between activated EGFR and shorter TTP and ORR, but not between activated EGFR and OS. No V600E BRAF mutations were identified. On the other hand, an interesting trend between high E-cadherin expression levels and better OS was observed and two CDH1 exon 9 missense mutations (A408V and D402H) were detected. CONCLUSION: Our finding that increased EGFR gene copy numbers, activated EGFR and the E-cadherin status are potentially interesting biomarkers needs to be confirmed in larger randomized clinical trials. TRIAL REGISTRATION: Multicentre clinical study with the European Clinical Trials Database number 2004-004024-12. AU - Luber, B.* AU - Deplazes, J.* AU - Keller, G.* AU - Walch, A.K. AU - Rauser, S. AU - Eichmann, M. AU - Langer, R.* AU - Höfler, H. AU - Hegewisch-Becker, S.* AU - Folprecht, G.* AU - Wöll, E.* AU - Decker, T.-M.* AU - Endlicher, E.* AU - Lorenzen, S.* AU - Fend, F.* AU - Peschel, C.* AU - Lordick, F.* C1 - 7467 C2 - 29727 TI - Biomarker analysis of cetuximab plus oxaliplatin/leucovorin/5-fluorouracil in first-line metastatic gastric and oesophago-gastric junction cancer: Results from a phase II trial of the Arbeitsgemeinschaft Internistische Onkologie (AIO). JO - BMC Cancer VL - 11 PB - BioMed Central PY - 2011 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: The validation of novel prognostic indicators is of greatest interest for the management of esophageal adenocarcinoma (Barrett's cancer), particularly for non-metastasized (stage I-IIA) disease. The prognostic role of tumor infiltrating T-lymphocytes (TILs) in Barrett's cancer has not been reported so far. Here we evaluated the impact of TILs on survival, recurrence, and metastasis in Barrett's cancer, particularly in stage I-IIA patients. METHODS: The levels of the adaptive immune markers CD3, CD8, and CD45RO were analyzed by immunohistochemistry and image analysis in tissue microarrays consisting of tumor tissues of 118 patients with primary resected Barrett's cancer. The findings were correlated with clinicopathological parameters including patient outcome. RESULTS: In multivariate analysis, a low density of intratumoral CD45RO+ immune cells was an independent unfavorable factor for disease-free survival in stages I-IIA patients (P = 0.004, RR = 4.7, 95% CI = 1.6-13.5) as well in the entire cohort (P = 0.048, RR = 2.0, 95% CI = 1.0-4.0). High CD3+ and CD45RO+ levels were associated with prolonged disease-free survival and overall survival as well with low recurrence rates of disease (P = 0.005 and P = 0.018, respectively). In addition, low CD3+ levels were correlated with a higher frequency of lymph node metastasis (P = 0.025). CONCLUSIONS: This study demonstrates that the density of CD45RO+ TILs is an independent prognostic factor in non-metastasized (stage I-IIA) Barrett's cancer patients and indicates an important role for the adaptive immunologic microenvironment. The inclusion of CD45RO+ density may help to improve the management of stage I-IIA Barrett's cancer. AU - Rauser, S. AU - Langer, R.* AU - Tschernitz, S. AU - Gais, P. AU - Jütting, U. AU - Feith, M.* AU - Höfler, H. AU - Walch, A.K. C1 - 5765 C2 - 27737 TI - High number of CD45RO+ tumor infiltrating lymphocytes is an independent prognostic factor in non-metastasized (stage I-IIA) esophageal adenocarcinoma. JO - BMC Cancer VL - 10 PB - BioMed Central Ltd. PY - 2010 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) are highly invasive tumours with frequent local and distant recurrence. Metastasis formation requires degradation of the extracellular matrix, which is fulfilled by membrane-associated proteases such as the urokinase plasminogen activator (uPA). WX-UK1 is a competitive active site inhibitor of the protease function of uPA that impairs on the capacity of tumour cells to invade in vitro. METHODS: In the present study, effects of combinations of WX-UK1 with matrix metalloprotease inhibitors (MMP, galardin) and cyclooxygenase-2 (COX-2, celecoxib) inhibitors on tumour cell proliferation, invasion, and angiogenesis induction were evaluated. Matrigel invasion chambers and a spheroid co-cultivation model with human fibroblast served to determine the invasive potential of both FaDu (SCCHN) and HeLa (cervical carcinoma) cells, each treated with combinations of Celecoxib, Galardin, and WX-UK1. RESULTS: Blocking of single protease systems resulted in a significant 50% reduction of tumour cell invasion using WX-UK1, while the triple combination was even more effective with 80% reduction of invasion. Additionally, a sprouting assay with HUVEC was used to test the anti-angiogenetic potential of the triple combination, resulting in a 40% decrease in the sprouting rate. CONCLUSIONS: A combined approach targeting different families of proteases and cyclooxygenases represents a promising adjuvant therapy. AU - Zengel, P.* AU - Ramp, D.* AU - Mack, B.* AU - Zahler, S.* AU - Berghaus, A.* AU - Muehlenweg, B.* AU - Gires, O. AU - Schmitz, S.* C1 - 5853 C2 - 27691 CY - London TI - Multimodal therapy for synergic inhibition of tumour cell invasion and tumour-induced angiogenesis. JO - BMC Cancer VL - 10 PB - BioMed Central Ltd. PY - 2010 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein, which is frequently over-expressed in simple epithelia, progenitors, embryonic and tissue stem cells, carcinoma and cancer-initiating cells. Besides functioning as a homophilic adhesion protein, EpCAM is an oncogenic receptor that requires regulated intramembrane proteolysis for activation of its signal transduction capacity. Upon cleavage, the extracellular domain EpEX is released as a soluble ligand while the intracellular domain EpICD translocates into the cytoplasm and eventually into the nucleus in combination with four-and-a-half LIM domains protein 2 (FHL2) and beta-catenin, and drives cell proliferation. METHODS: EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were investigated under varying density conditions using confocal laser scanning microscopy, immunoblotting, cell counting, and conditional cell systems. RESULTS: EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were dependent on adequate cell-to-cell contact. If cell-to-cell contact was prohibited EpCAM did not provide growth advantages. If cells were allowed to undergo contact to each other, EpCAM transmitted proliferation signals based on signal transduction-related cleavage processes. Accordingly, the pre-cleaved version EpICD was not dependent on cell-to-cell contact in order to induce c-myc and cell proliferation, but necessitated nuclear translocation. For the case of contact-inhibited cells, although cleavage of EpCAM occurred, nuclear translocation of EpICD was reduced, as were EpCAM effects. CONCLUSION: Activation of EpCAM's cleavage and oncogenic capacity is dependent on cellular interaction (juxtacrine) to provide for initial signals of regulated intramembrane proteolysis, which then support signalling via soluble EpEX (paracrine). AU - Denzel, S. AU - Maetzel, D. AU - Mack, B.* AU - Eggert, C.* AU - Bärr, G.* AU - Gires, O. C1 - 2221 C2 - 27171 TI - Initial activation of EpCAM cleavage via cell-to-cell contact. JO - BMC Cancer VL - 9 PB - BioMed Central PY - 2009 SN - 1471-2407 ER - TY - JOUR AB - Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis. METHODS: Formalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival. RESULTS: GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome.GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031). CONCLUSION: We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response. AU - Langer, R.* AU - Feith, M.* AU - Siewert, J.R.* AU - Wester, H.-J.* AU - Höfler, H. C1 - 4051 C2 - 25448 TI - Expression and clinical significance of glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in human adenocarcinomas of the esophagus. JO - BMC Cancer VL - 8 PB - BioMed Central PY - 2008 SN - 1471-2407 ER - TY - JOUR AB - Osteosarcoma is the most frequent bone tumor in childhood and adolescence. Patients with primary metastatic disease have a poor prognosis. It is therefore important to better characterize the biology of this tumor to define new prognostic markers or therapeutic targets for tailored therapy. Chemokines and their receptors have been shown to be involved in the development and progression of malignant tumors. They are thought to be active participants in the biology of osteosarcoma. The function of specific chemokines and their receptors is strongly associated with the biological context and microenvironment of their expression. In this report we characterized the expression of a series of chemokine receptors in the complex environment that defines osteosarcoma. METHODS: The overall level of chemokine receptor mRNA expression was determined using TaqMan RT-PCR of microdissected archival patient biopsy samples. Expression was then verified at the protein level by immunohistochemistry using a series of receptor specific antibody reagents to elucidate the cellular association of expression. RESULTS: Expression at the RNA level was found for most of the tested receptors. CCR1 expression was found on infiltrating mononuclear and polynuclear giant cells in the tumor. Cells associated with the lining of intratumoral vessels were shown to express CCR4. Infiltrating mononuclear cells and tumor cells both showed expression of the receptor CCR5, while CCR7 was predominantly expressed by the mononuclear infiltrate. CCR10 was only very rarely detected in few scattered infiltrating cells. CONCLUSION: Our data elucidate for the first time the cellular context of chemokine receptor expression in osteosarcoma. This is an important issue for better understanding potential chemokine/chemokine receptor function in the complex biologic processes that underlie the development and progression of osteosarcoma. Our data support the suggested involvement of chemokines and their receptors in diverse aspects of the biology of osteosarcoma, but also contradict aspects of previous reports describing the expression of these receptors in this tumor. AU - Luettichau, I. AU - Segerer, S.* AU - Wechselberger, A.* AU - Notohamiprodjo, M.* AU - Nathrath, M. AU - Kremer, M. AU - Henger, A.* AU - Djafarzadeh, R.* AU - Burdach, S.* AU - Huss, R.* AU - Nelson, P.J.* C1 - 333 C2 - 25644 TI - A complex pattern of chemokine receptor expression is seen in osteosarcoma. JO - BMC Cancer VL - 8 PB - BioMed Central PY - 2008 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: The intermediate filament forming protein keratin 8 (K8) is a tumour-associated antigen, which was shown to be over-expressed in a variety of malignancies. Here, we present a study of K8 expression in squamous epithelia of the head and neck area, including normal mucosa, hyperplastic and dysplastic leukoplakia, carcinomas of different sub-localisations, and lymph node metastases. METHODS: K8 expression was assessed upon immunohistochemistry with specific antibodies in cryosections of primary tumours of the head and neck area. RESULTS: K8 expression was characteristic of transformed tissue and marked early stages of disease, i.e. dysplastic oral leukoplakia, but not normal or hyperplastic epithelium. With the exception of carcinomas of the larynx and the tongue, K8 expression also strictly differentiated carcinomas from normal epithelium of the same origin. Furthermore, K8high was characteristic of cells, which had detached from the sites of primary tumours and had been invading the surrounding tissue at the time point of surgery. CONCLUSION: K8 is an excellent marker for head and neck malignancies, which allows for early detection as well as for visualisation of potentially disseminating tumour cells in vivo. AU - Matthias, C.* AU - Mack, B.* AU - Berghaus, A.* AU - Gires, O. C1 - 4349 C2 - 25884 TI - Keratin 8 expression in head and neck epithelia. JO - BMC Cancer VL - 8 PB - BioMed Central PY - 2008 SN - 1471-2407 ER - TY - JOUR AB - The polymorphism SNP309 (rs2279744) in the promoter region of the MDM2 gene has been shown to alter protein expression and may play a role in the susceptibility to lung cancer. The MDM2 protein is a key inhibitor of p53 and several mechanisms of MDM2/p53 interactions are presently known: modulating DNA-repair, cell-cycle control, cell growth and apoptosis.We used 635 Caucasian patients diagnosed with lung cancer before 51 years of age and 1300 healthy gender and age frequency matched population Caucasian controls to investigate the association between the MDM2 SNP309 and the risk of developing early onset lung cancer. Conditional logistic models were applied to assess the genotype-phenotype association, adjusted for smoking.Compared to the GG genotype, the adjusted ORs for the TG and TT genotype were 0.9 (95% CI: 0.7-1.5) and 1.0 (95% CI: 0.7-1.5), respectively. Also no association was found for histological subtypes of lung cancer. The strength of this study is that within young cases the genetic component to develop lung cancer may be greater. Our results indicate that the MDM2 SNP309 is not significantly associated with lung carcinogenesis but point towards gender-specific differences. AU - Mittelstraß, K. AU - Sauter, W. AU - Rosenberger, A.* AU - Illig, T. AU - Timofeeva, M.* AU - Klopp, N. AU - Dienemann, H.* AU - Meese, E.* AU - Sybrecht, G.* AU - Woelke, G. AU - Cebulla, M.* AU - Degen, M.* AU - Morr, H.* AU - Drings, P.* AU - Groeschel, A.* AU - Kreymborg, K.G.* AU - Haeussinger, K.* AU - Hoeffken, G.* AU - Schmidt, C.* AU - Jilge, B.* AU - Schmidt, W.* AU - Ko, Y.D.* AU - Taeuscher, D.* AU - Chang-Claude, J.* AU - Wichmann, H.-E. AU - Bickeboeller, H.* AU - Risch, A.* C1 - 1703 C2 - 25490 TI - Early onset lung cancer, cigarette smoking and the SNP309 of the murine double minute-2 (MDM2) gene. JO - BMC Cancer VL - 8 PB - BioMed Central PY - 2008 SN - 1471-2407 ER - TY - JOUR AB - Early onset lung cancer shows some familial aggregation, pointing to a genetic predisposition. This study was set up to investigate the role of candidate genes in the susceptibility to lung cancer patients younger than 51 years at diagnosis. METHODS: 246 patients with a primary, histologically or cytologically confirmed neoplasm, recruited from 2000 to 2003 in major lung clinics across Germany, were matched to 223 unrelated healthy controls. 11 single nucleotide polymorphisms of genes with reported associations to lung cancer have been genotyped. RESULTS: Genetic associations or gene-smoking interactions was found for GPX1(Pro200Leu) and EPHX1(His113Tyr). Carriers of the Leu-allele of GPX1(Pro200Leu) showed a significant risk reduction of OR = 0.6 (95% CI: 0.4-0.8, p = 0.002) in general and of OR = 0.3 (95% CI:0.1-0.8, p = 0.012) within heavy smokers. We could also find a risk decreasing genetic effect for His-carriers of EPHX1(His113Tyr) for moderate smokers (OR = 0.2, 95% CI:0.1-0.7, p = 0.012). Considered both variants together, a monotone decrease of the OR was found for smokers (OR of 0.20; 95% CI: 0.07-0.60) for each protective allele. CONCLUSION: Smoking is the most important risk factor for young lung cancer patients. However, this study provides some support for the T-Allel of GPX1(Pro200Leu) and the C-Allele of EPHX1(His113Tyr) to play a protective role in early onset lung cancer susceptibility. AU - Rosenberger, A.* AU - Illig, T. AU - Korb, K.* AU - Klopp, N. AU - Zietemann, V. AU - Wölke, G. AU - Meese, E.* AU - Sybrecht, G.* AU - Kronenberg, F.* AU - Cebulla, M.* AU - Degen, M.* AU - Drings, P.* AU - Gröschel, A.* AU - Konietzko, N.* AU - Kreymborg, K.G.* AU - Häussinger, K.* AU - Höffken, G.* AU - Jilge, B.* AU - Ko, Y.D.* AU - Morr, H.* AU - Schmidt, C.* AU - Schmidt, E.W.* AU - Täuscher, D.* AU - Bickeböller, H.* AU - Wichmann, H.-E. C1 - 4205 C2 - 25261 TI - Do genetic factors protect for early onset lung cancer? A case control study before the age of 50 years. JO - BMC Cancer VL - 8 PB - BioMed Central PY - 2008 SN - 1471-2407 ER - TY - JOUR AB - BACKGROUND: Gastric carcinoma is one of the most frequent cancers worldwide. Patients with gastric cancer at an advanced disease stage have a poor prognosis, due to the limited efficacy of available therapies. Therefore, the development of new therapies, like immunotherapy for the treatment of gastric cancer is of utmost importance. Since the usability of existing preclinical models for the evaluation of immunotherapies for gastric adenocarcinomas is limited, the goal of the present study was to establish murine in vivo models which allow the stepwise improvement of immunotherapies for gastric cancer. METHODS: Since no murine gastric adenocarcinoma cell lines are available we established four cell lines (424GC, mGC3, mGC5, mGC8) from spontaneously developing tumors of CEA424/SV40 T antigen (CEA424/Tag) mice and three cell lines derived from double-transgenic offsprings of CEA424/Tag mice mated with human carcinoembryonic antigen (CEA)-transgenic (CEA424/Tag-CEA) mice (mGC2CEA, mGC4CEA, mGC11CEA). CEA424/Tag is a transgenic C57BL/6 mouse strain harboring the Tag under the control of a -424/-8 bp CEA gene promoter which leads to the development of invasive adenocarcinoma in the glandular stomach. Tumor cell lines established from CEA424/Tag-CEA mice express the well defined tumor antigen CEA under the control of its natural regulatory elements. RESULTS: The epithelial origin of the tumor cells was proven by morphological criteria including the presence of mucin within the cells and the expression of the cell adhesion molecules EpCAM and CEACAM1. All cell lines consistently express the transgenes CEA and/or Tag and MHC class I molecules leading to their susceptibility to lysis by Tag-specific CTL in vitro. Despite the presentation of CTL-epitopes derived from the transgene products the tumor cell lines were tumorigenic when grafted into C57BL/6, CEA424/Tag or CEA424/Tag-CEA-transgenic hosts and no significant differences in tumor take and tumor growth were observed in the different hosts. Although no spontaneous tumor rejection was observed, vaccination of C57BL/6 mice with lysates from gastric carcinoma cell lines protected C57BL/6 mice from tumor challenge, demonstrating the tumorigenicity of the tumor cell lines in nontransgenic mice of the H-2b haplotype. CONCLUSION: These tumor cell lines grafted in different syngeneic hosts should prove to be very useful to optimize immunotherapy regimens to be finally tested in transgenic animals developing primary gastric carcinomas. AU - Nöckel, J.* AU - van den Engel, N.K.* AU - Winter, H.* AU - Hatz, R.A.* AU - Zimmermann, W.* AU - Kammerer, R. C1 - 3983 C2 - 23949 TI - Characterization of gastric adenocarcinoma cell lines established from CEA424/SV40 T antigen-transgenic mice with or without a human CEA transgene. JO - BMC Cancer VL - 6 PB - BioMed Central PY - 2006 SN - 1471-2407 ER -