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1.  Helical intensity-modulated Radiotherapy of the Pelvic Lymph Nodes with Integrated Boost to the Prostate Bed - Initial Results of the PLATIN 3 Trial 
BMC Cancer  2014;14:20.
Background
Adjuvant and salvage radiotherapy of the prostate bed are established treatment options for prostate cancer. While the benefit of an additional radiotherapy of the pelvic lymph nodes is still under debate, the PLATIN 3 prospective phase II clinical trial was initiated to substantiate toxicity data on postoperative IMRT of the pelvic lymph nodes and the prostate bed.
Methods
From 2009 to 2011, 40 patients with high-risk prostate cancer after prostatectomy with pT3 R0/1 M0 or pT2 R1 M0 or a PSA recurrence and either > 20% risk of lymph node involvement and inadequate lymphadenectomy or pN + were enrolled. Patients received two months of antihormonal treatment (AT) before radiotherapy. AT continuation was mandatory during radiotherapy and was recommended for another two years. IMRT of the pelvic lymph nodes (51.0 Gy) with a simultaneous integrated boost to the prostate bed (68.0 Gy) was performed in 34 fractions. PSA level, prostate-related symptoms and quality of life were assessed at regular intervals for 24 months.
Results
Of the 40 patients enrolled, 39 finished treatment as planned. Overall acute toxicity rates were low and no acute grade 3/4 toxicity occurred. Only 22.5% of patients experienced acute grade 2 gastrointestinal (GI) and genitourinary (GU) toxicity. During follow-up, 10.0% late grade 2 GI and 5.0% late grade 2 GU toxicity occurred, and one patient developed late grade 3 proctitis and enteritis. After a median observation time of 24 months the PLATIN 3 trial has shown in 97.5% of all patients sufficient safety and thus met its prospectively defined aims. After a median of 24 months, 34/38 patients were free of a PSA recurrence.
Conclusions
Postoperative whole-pelvis IMRT with an integrated boost to the prostate bed can be performed safely and without excessive toxicity.
Trial registration
Trial Numbers: ARO 2009–05, ClinicalTrials.gov: NCT01903408.
doi:10.1186/1471-2407-14-20
PMCID: PMC3893457  PMID: 24422782
Prostate; Postoperative Radiotherapy; Antihormonal treatment; Pelvic lymph nodes; IMRT; Tomotherapy
2.  Disparities of conjugating protective enzyme activities in the colon of patients with adenomas and carcinomas 
AIM: To investigate the metabolic enzymatic capacity of the colon mucosa to detoxify noxious carcinogenic compounds.
METHODS: We investigated the activity of 2 conjugating enzymes-the microsomal uridine glucuronosyltransferase (UGT) and the cytosomal glutathione S-transferase (GST) in the uninvolved mucosa of the colon transversum and sigmoideum in patients with adenomatous polyps and colorectal cancer. Biopsies were taken from the mucosa during colonoscopies which were done for clinical (diagnostic) reasons. After storage, the biopsy material was homogenized and after differential centrifugation the enzyme assays were performed with 4-nitrophenol (UGT) and 1-chloro 2,4-dinitrobenzene (GST) as substrates.
RESULTS: About 48 patients were included of which 28 had adenomas and 20 had colorectal carcinomas confirmed by histopathology. Enzyme activities were expressed as nmol/mg per minute protein for the GST and as pmol/mg per minute protein for the UGT. Analysis of variance (F-test) indicated that both enzymes were more widely distributed in adenoma than in cancer patients. The means ± SD were smaller for cancer patients: GST for adenomas 268 ± 152 vs 241 ± 69 for carcinomas and UGT for adenomas 197 ± 200 vs 150 ± 86 for carcinomas.
CONCLUSION: Compared to patients with adenomatous colon polyps those with colorectal carcinoma exhibited a lower capacity of detoxifying enzyme metabolism and their activities clustered over a smaller range.
doi:10.3748/wjg.v19.i36.6020
PMCID: PMC3785623  PMID: 24106402
Glutathione S-transferase; UDP-glucuronosyltransferase; Detoxification; Colon adenoma; Colon carcinoma
3.  Hypofractionated helical intensity-modulated radiotherapy of the prostate bed after prostatectomy with or without the pelvic lymph nodes - the PRIAMOS trial 
BMC Cancer  2012;12:504.
Background
While evidence on safety and efficacy of primary hypofractionated radiotherapy in prostate cancer is accumulating, data on postoperative hypofractionated treatment of the prostate bed and of the pelvic lymph nodes is still scarce. This phase II trial was initiated to investigate safety and feasibility of hypofractionated treatment of the prostate bed alone or with the pelvic lymph nodes.
Methods/design
A total of 80 prostate cancer patients with the indication for adjuvant radiotherapy will be enrolled, where 40 patients with a low risk of lymph node involvement (arm 1) and another 40 patients with a high risk of lymph node involvement (arm 2) will each receive 54 Gy in 18 fractions to the prostate bed. Arm 2 will be given 45 Gy to the pelvic lymph nodes additionally. Helical Tomotherapy and daily image guidance will be used.
Discussion
This trial was initiated to substantiate data on hypofractionated treatment of the prostate bed and generate first data on adjuvant hypofractionated radiotherapy of the pelvic lymph nodes.
Trial registration
ClinicalTrials.gov; NCT01620710
doi:10.1186/1471-2407-12-504
PMCID: PMC3495015  PMID: 23114055
Prostate cancer; Radiotherapy; Hypofractionation; Helical tomotherapy; Prostate bed; Pelvic lymph nodes
4.  A Clinical phase I/II trial to investigate preoperative dose-escalated intensity-modulated radiation therapy (IMRT) and intraoperative radiation therapy (IORT) in patients with retroperitoneal soft tissue sarcoma 
BMC Cancer  2012;12:287.
Background
Local control rates in patients with retroperitoneal soft tissue sarcoma (RSTS) remain disappointing even after gross total resection, mainly because wide margins are not achievable in the majority of patients. In contrast to extremity sarcoma, postoperative radiation therapy (RT) has shown limited efficacy due to its limitations in achievable dose and coverage. Although Intraoperative Radiation Therapy (IORT) has been introduced in some centers to overcome the dose limitations and resulted in increased outcome, local failure rates are still high even if considerable treatment related toxicity is accepted. As postoperative administration of RT has some general disadvantages, neoadjuvant approaches could offer benefits in terms of dose escalation, target coverage and reduction of toxicity, especially if highly conformal techniques like intensity-modulated radiation therapy (IMRT) are considered.
Methods/design
The trial is a prospective, one armed, single center phase I/II study investigating a combination of neoadjuvant dose-escalated IMRT (50–56 Gy) followed by surgery and IORT (10–12 Gy) in patients with at least marginally resectable RSTS. The primary objective is the local control rate after five years. Secondary endpoints are progression-free and overall survival, acute and late toxicity, surgical resectability and patterns of failure. The aim of accrual is 37 patients in the per-protocol population.
Discussion
The present study evaluates combined neoadjuvant dose-escalated IMRT followed by surgery and IORT concerning its value for improved local control without markedly increased toxicity.
Trial registration
NCT01566123
doi:10.1186/1471-2407-12-287
PMCID: PMC3495760  PMID: 22788989
5.  A randomized controlled trial to investigate the influence of low dose radiotherapy on immune stimulatory effects in liver metastases of colorectal cancer 
BMC Cancer  2011;11:419.
Background
Insufficient migration and activation of tumor specific effector T cells in the tumor is one of the main reasons for inadequate host anti-tumor immune response. External radiation seems to induce inflammation and activate the immune response. This phase I/II clinical trial aims to evaluate whether low dose single fraction radiotherapy can improve T cell associated antitumor immune response in patients with colorectal liver metastases.
Methods/Design
This is an investigator-initiated, prospective randomised, 4-armed, controlled Phase I/II trial. Patients undergoing elective hepatic resection due to colorectal cancer liver metastasis will be enrolled in the study. Patients will receive 0 Gy, 0.5 Gy, 2 Gy or 5 Gy radiation targeted to their liver metastasis. Radiation will be applied by external beam radiotherapy using a 6 MV linear accelerator (Linac) with intensity modulated radiotherapy (IMRT) technique two days prior to surgical resection. All patients admitted to the Department of General-, Visceral-, and Transplantion Surgery, University of Heidelberg for elective hepatic resection are consecutively screened for eligibility into this trial, and written informed consent is obtained before inclusion. The primary objective is to assess the effect of active local external beam radiation dose on, tumor infiltrating T cells as a surrogate parameter for antitumor activity. Secondary objectives include radiogenic treatment toxicity, postoperative morbidity and mortality, local tumor control and recurrence patterns, survival and quality of life. Furthermore, frequencies of systemic tumor reactive T cells in blood and bone marrow will be correlated with clinical outcome.
Discussion
This is a randomized controlled patient blinded trial to assess the safety and efficiency of low dose radiotherapy on metastasis infiltrating T cells and thus potentially enhance the antitumor immune response.
Trial registration
ClinicalTrials.gov: NCT01191632
doi:10.1186/1471-2407-11-419
PMCID: PMC3195202  PMID: 21961577
colorectal liver metastasis; low dose radiation; tumor specific T cells
6.  Phase i study evaluating the treatment of patients with hepatocellular carcinoma (HCC) with carbon ion radiotherapy: The PROMETHEUS-01 trial 
BMC Cancer  2011;11:67.
Background
Treatment options for patients with advanced hepatocellular carcinoma (HCC) are often limited. In most cases, they are not amenable to local therapies including surgery or radiofrequency ablation. The multi-kinase inhibitor sorafenib has shown to increase overall survival in this patient group for about 3 months.
Radiation therapy is a treatment alternative, however, high local doses are required for long-term local control. However, due to the relatively low radiation tolerance of liver normal tissue, even using stereotactic techniques, delivery of sufficient doses for successful local tumor control has not be achieved to date.
Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 3 depending on the HCC cell line as well as the endpoint analyzed.
Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with HCC.
Methods/Design
In the current Phase I-PROMETHEUS-01-Study, carbon ion radiotherapy will be evaluated for patients with advanced HCC. The study will be performed as a dose-escalation study evaluating the optimal carbon ion dose with respect to toxicity and tumor control.
Primary endpoint is toxicity, secondary endpoint is progression-free survival and response.
Discussion
The Prometheus-01 trial ist the first trial evaluating carbon ion radiotherapy delivered by intensity-modulated rasterscanning for the treatment of HCC. Within this Phase I dose escalation study, the optimal dose of carbon ion radiotherapy will be determined.
Trial registration
NCT 01167374
doi:10.1186/1471-2407-11-67
PMCID: PMC3045987  PMID: 21314962
7.  Treatment of patients with atypical meningiomas Simpson grade 4 and 5 with a carbon ion boost in combination with postoperative photon radiotherapy: The MARCIE Trial 
BMC Cancer  2010;10:615.
Background
Treatment standard for patients with atypical or anaplastic meningioma is neurosurgical resection. With this approach, local control ranges between 50% and 70%, depending on resection status. A series or smaller studies has shown that postoperative radiotherapy in this patient population can increase progression-free survival, which translates into increased overall survival. However, meningiomas are known to be radioresistant tumors, and radiation doses of 60 Gy or higher have been shown to be necessary for tumor control.
Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the cell line as well as the endpoint analyzed.
First data obtained within the Phase I/II trial performed at GSI in Darmstadt on carbon ion radiotherapy for patients with high-risk meningiomas has shown safety, and treatment results are promising.
Methods/design
The Phase II-MARCIE-Study will evaluate a carbon ion boost applied to the macroscopic tumor in conjunction with photon radiotherapy in patients with atypical menigiomas after incomplete resection or biopsy.
Primary endpoint is progression-free survival, secondary endpoints are overall survival, safety and toxicity.
Discussion
Based on published data on the treatment of atypical meningiomas with carbon ions at GSI, the present study will evaluate this treatment concept in a larger patient population and will compare outcome to current standard photon treatment.
Trial registration
NCT01166321
doi:10.1186/1471-2407-10-615
PMCID: PMC2996393  PMID: 21062428
8.  Randomised phase I/II study to evaluate carbon ion radiotherapy versus fractionated stereotactic radiotherapy in patients with recurrent or progressive gliomas: The CINDERELLA trial 
BMC Cancer  2010;10:533.
Background
Treatment of patients with recurrent glioma includes neurosurgical resection, chemotherapy, or radiation therapy. In most cases, a full course of radiotherapy has been applied after primary diagnosis, therefore application of re-irradiation has to be applied cauteously. With modern precision photon techniques such as fractionated stereotactic radiotherapy (FSRT), a second course of radiotherapy is safe and effective and leads to survival times of 22, 16 and 8 months for recurrent WHO grade II, III and IV gliomas.
Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the GBM cell line as well as the endpoint analyzed. Protons, however, offer an RBE which is comparable to photons.
First Japanese Data on the evaluation of carbon ion radiation therapy for the treatment of primary high-grade gliomas showed promising results in a small and heterogeneous patient collective.
Methods Design
In the current Phase I/II-CINDERELLA-trial re-irradiation using carbon ions will be compared to FSRT applied to the area of contrast enhancement representing high-grade tumor areas in patients with recurrent gliomas. Within the Phase I Part of the trial, the Recommended Dose (RD) of carbon ion radiotherapy will be determined in a dose escalation scheme. In the subsequent randomized Phase II part, the RD will be evaluated in the experimental arm, compared to the standard arm, FSRT with a total dose of 36 Gy in single doses of 2 Gy.
Primary endpoint of the Phase I part is toxicity. Primary endpoint of the randomized part II is survival after re-irradiation at 12 months, secondary endpoint is progression-free survival.
Discussion
The Cinderella trial is the first study to evaluate carbon ion radiotherapy for recurrent gliomas, and to compare this treatment to photon FSRT in a randomized setting using an ion beam delivered by intensity modulated rasterscanning.
Trial Registration
NCT01166308
doi:10.1186/1471-2407-10-533
PMCID: PMC2958944  PMID: 20925951
9.  Integrin β3 Leu33Pro polymorphism increases BRCA1‐associated ovarian cancer risk 
Journal of Medical Genetics  2007;44(6):408-411.
Integrins are heterodimeric transmembrane glycoproteins that function as key adhesion and cell signalling receptors. A functional polymorphism in the integrin β3 subunit encoded by the ITGB3 gene, Leu33Pro, has been shown to modify a variety of traits of β3‐expressing cells. To analyse the role of this functional polymorphism in modifying BRCA1‐associated ovarian and breast cancer risks, a case–control study was performed among Polish BRCA1 mutation carriers including 319 breast cancer cases, 146 ovarian cancer cases and 290 controls unaffected by breast and ovarian cancer, in situ breast cancer or any other kind of cancer. Genotyping analysis was performed using PCR‐based restriction fragment length polymorphism analysis. Odds ratios were calculated using univariate and multivariate logistic regression, taking into account a series of confounding variables, including the presence of related study subjects, that potentially could have biased any association. The results revealed that the ITGB3_Leu33Pro polymorphism was associated with a 2.5‐fold increased risk of ovarian cancer, whereas no association with breast cancer risk was found. Thus, it appears that the ITGB3_Leu33Pro polymorphism may potentially increase the risk of ovarian cancer in Polish women with an inherited BRCA1 mutation.
doi:10.1136/jmg.2006.047498
PMCID: PMC2740893  PMID: 17220212
10.  Prospective cohort comparison of flavonoid treatment in patients with resected colorectal cancer to prevent recurrence 
AIM: To investigate biological prevention with flavonoids the recurrence risk of neoplasia was studied in patients with resected colorectal cancer and after adenoma polypectomy.
METHODS: Eighty-seven patients, 36 patients with resected colon cancer and 51 patients after polypectomy, were divided into 2 groups: one group was treated with a flavonoid mixture (daily standard dose 20 mg apigenin and 20 mg epigallocathechin-gallat, n = 31) and compared with a matched control group (n = 56). Both groups were observed for 3-4 years by surveillance colonoscopy and by questionnaire.
RESULTS: Of 87 patients enrolled in this study, 36 had resected colon cancer and 29 of these patients had surveillance colonoscopy. Among the flavonoid-treated patients with resected colon cancer (n = 14), there was no cancer recurrence and one adenoma developed. In contrast the cancer recurrence rate of the 15 matched untreated controls was 20% (3 of 15) and adenomas evolved in 4 of those patients (27%). The combined recurrence rate for neoplasia was 7% (1 of 14) in the treated patients and 47% (7 of 15) in the controls (P = 0.027).
CONCLUSION: Sustained long-term treatment with a flavonoid mixture could reduce the recurrence rate of colon neoplasia in patients with resected colon cancer.
doi:10.3748/wjg.14.2187
PMCID: PMC2703843  PMID: 18407592
Flavonoids; Colorectal cancer; Recurrence risk; Intestinal neoplasia; Colon polyps
11.  Early treatment of imported falciparum malaria in the intermediate and intensive care unit setting: an 8-year single-center retrospective study 
Critical Care  2008;12(1):R22.
Introduction
Imported falciparum malaria is characterized by a broad spectrum of potentially life-threatening complications that may arise even after initiation of appropriate antimalarial drug therapy. Hence, at Heidelberg University Hospital, all patients with newly diagnosed falciparum malaria are initially treated in the intermediate care unit (IMC) or intensive care unit (ICU). The present study was undertaken to evaluate critically the benefit of this strategy, which includes daily consultation with senior specialists in tropical medicine.
Methods
We conducted a retrospective cohort study at the 14-bed combined IMC/ICU of a 1,685-bed university hospital. A cohort of 122 patients with imported falciparum malaria admitted from 1 January 1996 to 31 December 2003 was included.
Results
Thirty-four patients (27.9%) developed complications, defined according to the current World Health Organization classification. Most patients (80.3%) studied did not take the recommended chemoprophylaxis against malaria. The majority of patients (89.3% [n = 109]) could be adequately treated in the IMC. Life-threatening complications requiring ICU support occurred in 13 patients (10.7%). All complications were successfully managed. Fifty-five patients (45.1%) fulfilling recently published criteria for outpatient treatment had an excellent therapeutic response and did not require ICU support.
Conclusion
This retrospective evaluation demonstrated favourable therapeutic results in hospitalized patients with imported falciparum malaria. Both initial treatment in the medical IMC/ICU and close collaboration between intensivists and specialists in tropical medicine may improve disease outcome among affected patients. Prospective studies are needed to confirm these preliminary findings.
doi:10.1186/cc6796
PMCID: PMC2374613  PMID: 18294371
12.  Treatment of primary glioblastoma multiforme with cetuximab, radiotherapy and temozolomide (GERT) – phase I/II trial: study protocol 
BMC Cancer  2006;6:133.
Background
The implementation of combined radiochemotherapy (RCHT) with temozolomide (TMZ) has lead to a significant increase in overall survival times in patients with Glioblastoma multiforme (GBM), however, outcome still remains unsatisfactory.
The majority of GBMs show an overexpression and/or amplification of the epidermal growth factor receptor (EGFR). Therefore, addition of EGFR-inhibition with cetuximab to the current standard treatment approach with radiotherapy and TMZ seems promising.
Methods/design
GERT is a one-armed single-center phase I/II trial. In a first step, dose-escalation of TMZ from 50 mg/m2 to 75 mg/m2 together with radiotherapy and cetuximab will be performed. Should safety be proven, the phase II trial will be initiated with the standard dose of 75 mg/m2 of TMZ. Cetuximab will be applied in the standard application dose of 400 mg/m2 in week 1, thereafter at a dose of 250 mg/m2 weekly. A total of 46 patients will be included into this phase I/II trial.
Primary endpoints are feasibility and toxicity, secondary endpoints are overall and progression-free survival. An interim analysis will be performed after inclusion of 15 patients into the main study. Patients' enrolment will be performed over a period of 2 years. The observation time will end 2 years after inclusion of the last patient.
Discussion
The goal of this study is to evaluate the safety and efficacy of combined RCHT-immunotherapy with TMZ and cetuximab as first-line treatment for patients with primary GBM.
doi:10.1186/1471-2407-6-133
PMCID: PMC1524973  PMID: 16709245
13.  Corticosteroid co-treatment induces resistance to chemotherapy in surgical resections, xenografts and established cell lines of pancreatic cancer 
BMC Cancer  2006;6:61.
Background
Chemotherapy for pancreatic carcinoma often has severe side effects that limit its efficacy. The glucocorticoid (GC) dexamethasone (DEX) is frequently used as co-treatment to prevent side effects of chemotherapy such as nausea, for palliative purposes and to treat allergic reactions. While the potent pro-apoptotic properties and the supportive effects of GCs to tumour therapy in lymphoid cells are well studied, the impact of GCs to cytotoxic treatment of pancreatic carcinoma is unknown.
Methods
A prospective study of DEX-mediated resistance was performed using a pancreatic carcinoma xenografted to nude mice, 20 surgical resections and 10 established pancreatic carcinoma cell lines. Anti-apoptotic signaling in response to DEX was examined by Western blot analysis.
Results
In vitro, DEX inhibited drug-induced apoptosis and promoted the growth in all of 10 examined malignant cells. Ex vivo, DEX used in physiological concentrations significantly prevented the cytotoxic effect of gemcitabine and cisplatin in 18 of 20 freshly isolated cell lines from resected pancreatic tumours. No correlation with age, gender, histology, TNM and induction of therapy resistance by DEX co-treatment could be detected. In vivo, DEX totally prevented cytotoxicity of chemotherapy to pancreatic carcinoma cells xenografted to nude mice. Mechanistically, DEX upregulated pro-survival factors and anti-apoptotic genes in established pancreatic carcinoma cells.
Conclusion
These data show that DEX induces therapy resistance in pancreatic carcinoma cells and raise the question whether GC-mediated protection of tumour cells from cancer therapy may be dangerous for patients.
doi:10.1186/1471-2407-6-61
PMCID: PMC1434760  PMID: 16539710

Results 1-13 (13)