Analysen zirkulierender epithelialer Tumorzellen im periphervenösen Blut bei Patientinnen mit primär nicht metastasiertem Mammakarzinom unter adjuvanter Radiotherapie

Brustkrebs ist die häufigste Krebserkrankung und krebsbedingte Todesursache bei Frauen. Die im Blutkreislauf zirkulierenden epithelialen Tumorzellen (CETC) werden als mitverantwortlich für die Metastasenbildung angesehen, weshalb deren Bedeutung als prognostische bzw. prädiktive Marker in der Tumortherapie intensiv untersucht wird. Ziel dieser Arbeit war es, anhand der CETC den systemischen Effekt der Strahlentherapie bei Patientinnen mit primär nicht metastasiertem Mammakarzinom zu untersuchen und mögliche Veränderungen der CETC bzgl. ihrer Quantität und Genexpression im Rahmen der Strahlentherapie zu analysieren. Insgesamt wurden 161 Patientinnen mit klinisch gesichertem, primär nicht metastasiertem Mammakarzinom über einen Zeitraum von 09/2002 bis 09/2012 jeweils vor und nach der Radiotherapie Blutproben entnommen und untersucht. Dabei wurde zum einen mittels des MAINTRACTM – Verfahren die Menge der CETC quantitativ im Blut bestimmt und deren peritherapeutischen Verlauf beobachtet. Zum anderen wurde bei 9 Patientinnen eine Genexpressionsanalyse von 11 ausgewählten Genen (GAPDH, EpCAM, NANOG, Bcl-2, TLR 4, COX-2, PIK3CA, Her2/neu, Vimentin, c- Met und Ki-67) durchgeführt. Kam es im Rahmen der durchgeführten Strahlentherapie zu einem Anstieg der CETC-Zellzahl, war dies mit einer signifikant schlechteren Prognose hinsichtlich der Ereignis- freien Überlebenszeit und der Wahrscheinlichkeit für das Auftreten von Fernmetastasen verbunden. Die Aktivitätsbestimmung der ausgewählten Gene erbrachte, dass es infolge der Strahlentherapie zu einer Steigerung der Expression aller untersuchten Gene kam. Die analysierten CETC zeichneten sich neben einem allgemein erhöhten Zellstoffwechsel, durch die Überexpression von Genen aus, welche eine Fernmetastasierung begünstigen. Anhand der Ergebnisse konnte gezeigt werden, dass das Verhalten der CETC mit dem tatsächlichen Krankheitsverlauf der Patientinnen korreliert und Strahlentherapie systemische Wirkungen auf Expressionsebene hat

Prospective Monitoring of Circulating Epithelial Tumor Cells (CETC) Reveals Changes in Gene Expression during Adjuvant Radiotherapy of Breast Cancer Patients

Circulating epithelial tumor cells (CETC) are considered to be responsible for the formation of metastases. Therefore, their importance as prognostic and/or predictive markers in breast cancer is being intensively investigated. Here, the reliability of single cell expression analyses in isolated and collected CETC from whole blood samples of patients with early-stage breast cancer before and after radiotherapy (RT) using the maintrac ® method was investigated. Single-cell expression analyses were performed with qRT-PCR on a panel of selected genes: GAPDH, EpCAM, NANOG, Bcl-2, TLR 4, COX-2, PIK3CA, Her-2/neu, Vimentin, c-Met, Ki-67. In all patients, viable CETC were detected prior to and at the end of radiotherapy. In 7 of the 9 (77.8%) subjects examined, the CETC number at the end of the radiotherapy series was higher than before. The majority of genes analyzed showed increased expression after completion of radiotherapy compared to baseline. Procedures and methods used in this pilot study proved to be feasible. The method is suitable for further investigation of the underlying molecular biological mechanisms occurring in cells surviving radiotherapy and possibly the development of radiation resistance

Peer review analysis in the field of radiation oncology: results from a web-based survey of the Young DEGRO working group

PURPOSE To evaluate the reviewing behaviour in the German-speaking countries in order to provide recommendations to increase the attractiveness of reviewing activity in the field of radiation oncology. METHODS In November 2019, a survey was conducted by the Young DEGRO working group (jDEGRO) using the online platform “eSurveyCreator”. The questionnaire consisted of 29 items examining a~broad range of factors that influence reviewing motivation and performance. RESULTS A total of 281 responses were received. Of these, 154 (55%) were completed and included in the evaluation. The most important factors for journal selection criteria and peer review performance in the field of radiation oncology are the scientific background of the manuscript (85%), reputation of the journal (59%) and a~high impact factor (IF; 40%). Reasons for declining an invitation to review include the scientific background of the article (60%), assumed effort (55%) and a low IF (27%). A~double-blind review process is preferred by 70% of respondents to a single-blind (16%) or an open review process (14%). If compensation was offered, 59% of participants would review articles more often. Only 12% of the participants have received compensation for their reviewing activities so far. As compensation for the effort of reviewing, 55% of the respondents would prefer free access to the journal's articles, 45% a discount for their own manuscripts, 40% reduced congress fees and 39% compensation for expenses. CONCLUSION The scientific content of the manuscript, reputation of the journal and a~high IF determine the attractiveness for peer reviewing in the field of radiation oncology. The majority of participants prefer a~double-blind peer review process and would conduct more reviews if compensation was available. Free access to journal articles, discounts for publication costs or congress fees, or an expense allowance were identified to increase attractiveness of the review process

Survey on brachytherapy training among radiation oncology residents in the German-speaking regions of Europe.

PURPOSE This survey aimed to determine the perception of brachytherapy training among residents in the DACH region, consisting of Austria, Germany and Switzerland. MATERIAL & METHODS An online questionnaire containing 22 questions related to trainee demographics (n = 5) and to brachytherapy training (n = 17) was sent in two iterations in 11/2019 and 02/2020. The following topics were evaluated: institutional support, barriers to training, extent of training, site-specific training (prostate, gynaecology, breast, gastrointestinal and skin), preferences for further training and outlook on overall development of brachytherapy. The responses were mostly based on a Likert scale of 1 to 5, thereby reflecting strength of opinion. Descriptive statistics were used to describe frequencies. RESULTS Among the 108 respondents, approximately 69% of residents considered the ability to perform brachytherapy independently to be important or somewhat important. However, only 31% of respondents reported to have a dedicated brachytherapy training during residency. The major limitation to achieve independence in performing brachytherapy was seen in a low case load in Austria, in the lack of training in Switzerland and in both of them in Germany. CONCLUSION The interest in brachytherapy training among residents in German-speaking countries was generally high, but there is a perceived lack of sufficient case volumes and partially also in formal training opportunities. Fellowships at departments with a high case load as part of a formalised curriculum and dedicated hands-on workshops at national or international conferences might help to overcome these issues

A randomized study to evaluate the effect of exercise on fatigue in people with relapsing–remitting multiple sclerosis treated with fingolimod

Background Fatigue is a major symptom of multiple sclerosis (MS) in patients, and it has been shown to improve with physical exercise. Although fingolimod might lessen fatigue, it is unclear how patients treated with fingolimod react to physical activity regarding fatigue. Objective This study evaluated the effect of an exercise intervention on fatigue in relapsing–remitting MS patients receiving fingolimod. Methods People with MS (PwMS) were randomized to either a structured internet-based exercise program (e-training) or no e-training intervention. The primary endpoint was the change in the Modified Fatigue Impact Scale (mFIS) after six months. Results The primary analysis showed no statistically significant difference between groups in the mFIS change. Subgroup analyses revealed a beneficial effect of physical exercise for PwMS with low aerobic capacity and with low aerobic capacity plus more severe fatigue. The incidence of adverse events was similar in both groups. No cardiovascular events were reported. The majority of PwMS were relapse free. Conclusion Physical exercise benefits on fatigue may depend on the physical capacity of the patient and requires individualized training. Consistent with previous studies, these results suggest that physical exercise generally does not impose a risk and that this holds true also for patients receiving fingolimod

Peer review analysis in the field of radiation oncology: results from a web-based survey of the Young DEGRO working group

Abstract Purpose To evaluate the reviewing behaviour in the German-speaking countries in order to provide recommendations to increase the attractiveness of reviewing activity in the field of radiation oncology. Methods In November 2019, a survey was conducted by the Young DEGRO working group (jDEGRO) using the online platform “eSurveyCreator”. The questionnaire consisted of 29 items examining a broad range of factors that influence reviewing motivation and performance. Results A total of 281 responses were received. Of these, 154 (55%) were completed and included in the evaluation. The most important factors for journal selection criteria and peer review performance in the field of radiation oncology are the scientific background of the manuscript (85%), reputation of the journal (59%) and a high impact factor (IF; 40%). Reasons for declining an invitation to review include the scientific background of the article (60%), assumed effort (55%) and a low IF (27%). A double-blind review process is preferred by 70% of respondents to a single-blind (16%) or an open review process (14%). If compensation was offered, 59% of participants would review articles more often. Only 12% of the participants have received compensation for their reviewing activities so far. As compensation for the effort of reviewing, 55% of the respondents would prefer free access to the journal’s articles, 45% a discount for their own manuscripts, 40% reduced congress fees and 39% compensation for expenses. Conclusion The scientific content of the manuscript, reputation of the journal and a high IF determine the attractiveness for peer reviewing in the field of radiation oncology. The majority of participants prefer a double-blind peer review process and would conduct more reviews if compensation was available. Free access to journal articles, discounts for publication costs or congress fees, or an expense allowance were identified to increase attractiveness of the review process

Design of TRUST, a non-interventional, multicenter, 3-year prospective study investigating an integrated patient management approach in patients with relapsing-remitting multiple sclerosis treated with natalizumab

Background: Natalizumab provides rapid and high-efficacy control of multiple sclerosis disease activity with long-term stabilization. However, the benefits of the drug are countered by a risk of developing progressive multifocal leukoencephalopathy in patients infected with the John Cunningham Virus. Close monitoring is required in patients with increased progressive multifocal leukoencephalopathy risk receiving natalizumab in the long-term for an optimal benefit-risk evaluation. Standardized high-quality monitoring procedures may provide a superior basis for individual benefit and risk evaluation and thus improve treatment decisions. The non-interventional study TRUST was designed to capture natalizumab effectiveness under real-life conditions and to examine alternate approaches for clinical assessments, magnetic resonance imaging monitoring and use of biomarkers for progressive multifocal leukoencephalopathy risk stratification. Methods/Design: TRUST is a non-interventional, multicenter, prospective cohort study conducted at approximately 200 German neurological centers. The study is intended to enroll 1260 relapsing-remitting multiple sclerosis patients with ongoing natalizumab therapy for at least 12 months. Patients will be followed for a period of 3 years, irrespective of treatment changes after study start. Data on clinical, subclinical and patient-centric outcomes will be documented in order to compare the effectiveness of continuous versus discontinued natalizumab treatment. Furthermore, the type and frequency of clinical, magnetic resonance imaging and biomarker assessments, reasons for continuation or discontinuation of therapy and the safety profile of natalizumab will be collected to explore the impact of a systematic patient management approach and its potential impact on patient outcome. Specifically, the role of biomarkers, the use of expert opinions, the impact of high-frequency magnetic resonance imaging assessment for early progressive multifocal leukoencephalopathy detection and the role of additional radiological and clinical expert advice will be explored. Discussion: TRUST was initiated in spring 2014 and enrollment is anticipated to be completed by mid 2016. Annual interim analyses will deliver continuous information and transparency with regard to the patient cohorts and the completeness and quality of data as well as closely monitor any safety signals in the natalizumab-treated cohort. The study’s results may provide insights into opportunities to improve the benefit-risk assessment in clinical practice and support treatment decisions

Innovative radiation oncology Together – Precise, Personalized, Human : Vision 2030 for radiotherapy & radiation oncology in Germany

Purpose Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. Methods The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives’ final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. Results The strategy retreat’s development process resulted in conception of the final vision “Innovative radiation oncology Together – Precise, Personalized, Human.” The first term “Innovative radiation oncology” comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term “together” underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. “Precise” mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. “Personalized” emphasizes biology-directed individualization of radiation treatment. Finally, “Human” underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. Conclusion The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany

Increased Circulating Epithelial Tumor Cells (CETC/CTC) over the Course of Adjuvant Radiotherapy Is a Predictor of Less Favorable Outcome in Patients with Early-Stage Breast Cancer

Background: Adjuvant radiotherapy (RT) is an integral component of a multidisciplinary treatment strategy for early-stage breast cancer. It significantly reduces the incidence of loco-regional recurrence but also of distant events. Distant events are due to tumor cells disseminated from the primary tumor into lymphatic fluid or blood, circulating epithelial tumor cells (CETC/CTC), which can reach distant tissues and regrow into metastases. The purpose of this study is to determine changes in the number of CETC/CTC in the course of adjuvant RT, and to evaluate whether they are correlated to local recurrence and distant metastases in breast cancer patients. Methods: Blood from 165 patients irradiated between 2002 and 2012 was analyzed 0–6 weeks prior to and 0–6 weeks after RT using the maintrac® method, and patients were followed over a median period of 8.97 (1.16–19.09) years. Results: Patients with an increase in CETC/CTC numbers over the course of adjuvant RT had a significantly worse disease-free survival (p = 0.004) than patients with stable or decreasing CETC/CTC numbers. CETC/CTC behavior was the most important factor in predicting subsequent relapse-free survival. In particular, patients who had received neoadjuvant chemotherapy were disproportionately more likely to develop metastases when cell counts increased over the course of RT (p = 0.003; hazard ratio 4.886). Conclusions: Using the maintrac® method, CETC/CTC were detected in almost all breast cancer patients after surgery. The increase in CETC/CTC numbers over the course of RT represents a potential predictive biomarker to judge relative risk/benefit in patients with early breast cancer. The results of this study highlight the need for prospective clinical trials on CETC/CTC status as a predictive criterion and for individualization of treatment. Clinical Trial registration: The trial is registered (2 May 2019) at trials.gov under NCT03935802

Prospective Monitoring of Circulating Epithelial Tumor Cells (CETC) Reveals Changes in Gene Expression during Adjuvant Radiotherapy of Breast Cancer Patients

Circulating epithelial tumor cells (CETC) are considered to be responsible for the formation of metastases. Therefore, their importance as prognostic and/or predictive markers in breast cancer is being intensively investigated. Here, the reliability of single cell expression analyses in isolated and collected CETC from whole blood samples of patients with early-stage breast cancer before and after radiotherapy (RT) using the maintrac® method was investigated. Single-cell expression analyses were performed with qRT-PCR on a panel of selected genes: GAPDH, EpCAM, NANOG, Bcl-2, TLR 4, COX-2, PIK3CA, Her-2/neu, Vimentin, c-Met, Ki-67. In all patients, viable CETC were detected prior to and at the end of radiotherapy. In 7 of the 9 (77.8%) subjects examined, the CETC number at the end of the radiotherapy series was higher than before. The majority of genes analyzed showed increased expression after completion of radiotherapy compared to baseline. Procedures and methods used in this pilot study proved to be feasible. The method is suitable for further investigation of the underlying molecular biological mechanisms occurring in cells surviving radiotherapy and possibly the development of radiation resistance