[Data integration centers-from a concept in the Medical Informatics Initiative to its local implementation in the Network of University Medicine]. / Die Datenintegrationszentren ­ Von der Konzeption in der Medizininformatik-Initiative zur lokalen Umsetzung in einem Netzwerk Universitätsmedizin.

As part of the Medical Informatics Initiative (MII), data integration centers (DICs) have been established at 38 university and 3 non-university locations in Germany since 2018. At DICs, research and healthcare data are collected. The DICs represent an important pillar in research and healthcare. They establish the technical, organizational, and (ethical) data protection requirements to enable cross-site research with the available routine clinical data.This article presents the three main pillars of DICs: ethical-legal framework, organization, and technology. The organization of DICs and their organizational embedding and interaction are presented, as well as the technical infrastructure. The services that a DIC provides for its own location and for external researchers are explained, and the role of the DIC as an internal and external interface for strengthening cooperation and collaboration is outlined.Legal conformity, organization, and technology form the basis for the processes and structures of a DIC and are decisive for how it is integrated into the healthcare and research landscape of a location, but also for how it can react to national and European requirements and act and function as an interface to the outside world. In this context and with regard to national developments (e.g., introduction of the electronic patient file-ePA), but also international and European initiatives (e.g., European Health Data Space-EHDS), the DIC will play a central role in the future.

A scoping review of gaze and eye tracking-based control methods for assistive robotic arms.

Background: Assistive Robotic Arms are designed to assist physically disabled people with daily activities. Existing joysticks and head controls are not applicable for severely disabled people such as people with Locked-in Syndrome. Therefore, eye tracking control is part of ongoing research. The related literature spans many disciplines, creating a heterogeneous field that makes it difficult to gain an overview. Objectives: This work focuses on ARAs that are controlled by gaze and eye movements. By answering the research questions, this paper provides details on the design of the systems, a comparison of input modalities, methods for measuring the performance of these controls, and an outlook on research areas that gained interest in recent years. Methods: This review was conducted as outlined in the PRISMA 2020 Statement. After identifying a wide range of approaches in use the authors decided to use the PRISMA-ScR extension for a scoping review to present the results. The identification process was carried out by screening three databases. After the screening process, a snowball search was conducted. Results: 39 articles and 6 reviews were included in this article. Characteristics related to the system and study design were extracted and presented divided into three groups based on the use of eye tracking. Conclusion: This paper aims to provide an overview for researchers new to the field by offering insight into eye tracking based robot controllers. We have identified open questions that need to be answered in order to provide people with severe motor function loss with systems that are highly useable and accessible.

A descriptive analysis of human milk dispensed by the Leipzig Donor Human Milk Bank for neonates between 2012 and 2019.

Background: Human milk banking has become an important aspect of Nutritional medicine. It is not just about the provision of mother's own milk (MOM) or donor human milk (DHM) in the hospital, but also a strategy to encourage breastfeeding in the clinical setting and beyond. Objective: To describe the feeding patterns of hospitalised infants including human milk dispensed by the Leipzig Donor Human Milk Bank (LMB). Design: A descriptive analysis of daily data on milk feeds dispensed by LMB for hospitalised infants distinguishing between MOM or DHM, either fresh or frozen, and raw/pasteurised milk from 2012-2019. Results: We included 2,562 infants with median hospitalisation of 23 days, for whom human milk was dispensed on median 76% of those days and other nutrition on the remaining days. Raw MOM and raw DHM comprised 52% and 8% of the dispensed milk, respectively. Dispensing exclusive DHM instead of MOM for at least one full day was required for 55% of the infants, mostly at the beginning but also later during hospitalisation. Exclusive raw DHM was dispensed on at least 1 day for 37% of the infants, in different birthweight strata <1,000 g: 10%, 1,000-1500 g: 11%, 1,500-2500 g: 13% and > 2,500 g: 3%. At discharge, MOM was dispensed for more than 60% of the infants. Conclusion: During an infant's hospital stay, LMB dispenses various human milk feeds with interspersed DHM resulting in complex intra-individual and time-variant feeding patterns. LMB dispenses raw MOM and especially raw DHM with the intention to retain the properties of human milk unlike a diet containing pasteurised DHM and/or formula. Although raw DHM comprises a small percentage of all dispensed milk, raw DHM is dispensed for a substantial portion of infants. Our results document that dispensing raw DHM, is possible in routine settings.

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.

Human-Machine Differentiation in Speed and Separation Monitoring for Improved Efficiency in Human-Robot Collaboration.

Human-robot collaborative applications have been receiving increasing attention in industrial applications. The efficiency of the applications is often quite low compared to traditional robotic applications without human interaction. Especially for applications that use speed and separation monitoring, there is potential to increase the efficiency with a cost-effective and easy to implement method. In this paper, we proposed to add human-machine differentiation to the speed and separation monitoring in human-robot collaborative applications. The formula for the protective separation distance was extended with a variable for the kind of object that approaches the robot. Different sensors for differentiation of human and non-human objects are presented. Thermal cameras are used to take measurements in a proof of concept. Through differentiation of human and non-human objects, it is possible to decrease the protective separation distance between the robot and the object and therefore increase the overall efficiency of the collaborative application.

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.

Algorithmic surveillance of ICU patients with acute respiratory distress syndrome (ASIC): protocol for a multicentre stepped-wedge cluster randomised quality improvement strategy.

INTRODUCTION: The acute respiratory distress syndrome (ARDS) is a highly relevant entity in critical care with mortality rates of 40%. Despite extensive scientific efforts, outcome-relevant therapeutic measures are still insufficiently practised at the bedside. Thus, there is a clear need to adhere to early diagnosis and sufficient therapy in ARDS, assuring lower mortality and multiple organ failure. METHODS AND ANALYSIS: In this quality improvement strategy (QIS), a decision support system as a mobile application (ASIC app), which uses available clinical real-time data, is implemented to support physicians in timely diagnosis and improvement of adherence to established guidelines in the treatment of ARDS. ASIC is conducted on 31 intensive care units (ICUs) at 8 German university hospitals. It is designed as a multicentre stepped-wedge cluster randomised QIS. ICUs are combined into 12 clusters which are randomised in 12 steps. After preparation (18 months) and a control phase of 8 months for all clusters, the first cluster enters a roll-in phase (3 months) that is followed by the actual QIS phase. The remaining clusters follow in month wise steps. The coprimary key performance indicators (KPIs) consist of the ARDS diagnostic rate and guideline adherence regarding lung-protective ventilation. Secondary KPIs include the prevalence of organ dysfunction within 28 days after diagnosis or ICU discharge, the treatment duration on ICU and the hospital mortality. Furthermore, the user acceptance and usability of new technologies in medicine are examined. To show improvements in healthcare of patients with ARDS, differences in primary and secondary KPIs between control phase and QIS will be tested. ETHICS AND DISSEMINATION: Ethical approval was obtained from the independent Ethics Committee (EC) at the RWTH Aachen Faculty of Medicine (local EC reference number: EK 102/19) and the respective data protection officer in March 2019. The results of the ASIC QIS will be presented at conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: DRKS00014330.

Hospital-wide ELectronic medical record evaluated computerised decision support system to improve outcomes of Patients with staphylococcal bloodstream infection (HELP): study protocol for a multicentre stepped-wedge cluster randomised trial.

INTRODUCTION: Staphylococci are the most commonly identified pathogens in bloodstream infections. Identification of Staphylococcus aureus in blood culture (SAB) requires a prompt and adequate clinical management. The detection of coagulase-negative staphylococci (CoNS), however, corresponds to contamination in about 75% of the cases. Nevertheless, antibiotic therapy is often initiated, which contributes to the risk of drug-related side effects. We developed a computerised clinical decision support system (HELP-CDSS) that assists physicians with an appropriate management of patients with Staphylococcus bacteraemia. The CDSS is evaluated using data of the Data Integration Centers (DIC) established at each clinic. DICs transform heterogeneous primary clinical data into an interoperable format, and the HELP-CDSS displays information according to current best evidence in bacteraemia treatment. The overall aim of the HELP-CDSS is a safe but more efficient allocation of infectious diseases specialists and an improved adherence to established guidelines in the treatment of SAB. METHODS AND ANALYSIS: The study is conducted at five German university hospitals and is designed as a stepped-wedge cluster randomised trial. Over the duration of 18 months, 135 wards will change from a control period to the intervention period in a randomised stepwise sequence. The coprimary outcomes are hospital mortality for all patients to establish safety, the 90-day disease reoccurrence-free survival for patients with SAB and the cumulative vancomycin use for patients with CoNS bacteraemia. We will use a closed, hierarchical testing procedure and generalised linear mixed modelling to test for non-inferiority of the CDSS regarding hospital mortality and 90-day disease reoccurrence-free survival and for superiority of the HELP-CDSS regarding cumulative vancomycin use. ETHICS AND DISSEMINATION: The study is approved by the ethics committee of Jena University Hospital and will start at each centre after local approval. Results will be published in a peer-reviewed journal and presented at scientific conferences. TRIAL REGISTRATION NUMBER: DRKS00014320.

Integrating Heterogeneous Data Sources for Cross-Institutional Data Sharing: Requirements Elicitation and Management in SMITH.

The digitization of health records and cross-institutional data sharing is a necessary precondition to improve clinical research and patient care. The SMITH project unites several university hospitals and medical faculties in order to provide medical informatics solutions for health data integration and cross-institutional communication. In this paper, we focus on requirements elicitation and management for extracting clinical data from heterogeneous subsystems and data integration based on eHealth standards such as HL7 FHIR and IHE profiles.

Smart Medical Information Technology for Healthcare (SMITH).

INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on the German Medical Informatics Initiative. "Smart Medical Information Technology for Healthcare (SMITH)" is one of four consortia funded by the German Medical Informatics Initiative (MI-I) to create an alliance of universities, university hospitals, research institutions and IT companies. SMITH's goals are to establish Data Integration Centers (DICs) at each SMITH partner hospital and to implement use cases which demonstrate the usefulness of the approach. OBJECTIVES: To give insight into architectural design issues underlying SMITH data integration and to introduce the use cases to be implemented. GOVERNANCE AND POLICIES: SMITH implements a federated approach as well for its governance structure as for its information system architecture. SMITH has designed a generic concept for its data integration centers. They share identical services and functionalities to take best advantage of the interoperability architectures and of the data use and access process planned. The DICs provide access to the local hospitals' Electronic Medical Records (EMR). This is based on data trustee and privacy management services. DIC staff will curate and amend EMR data in the Health Data Storage. METHODOLOGY AND ARCHITECTURAL FRAMEWORK: To share medical and research data, SMITH's information system is based on communication and storage standards. We use the Reference Model of the Open Archival Information System and will consistently implement profiles of Integrating the Health Care Enterprise (IHE) and Health Level Seven (HL7) standards. Standard terminologies will be applied. The SMITH Market Place will be used for devising agreements on data access and distribution. 3LGM2 for enterprise architecture modeling supports a consistent development process.The DIC reference architecture determines the services, applications and the standardsbased communication links needed for efficiently supporting the ingesting, data nourishing, trustee, privacy management and data transfer tasks of the SMITH DICs. The reference architecture is adopted at the local sites. Data sharing services and the market place enable interoperability. USE CASES: The methodological use case "Phenotype Pipeline" (PheP) constructs algorithms for annotations and analyses of patient-related phenotypes according to classification rules or statistical models based on structured data. Unstructured textual data will be subject to natural language processing to permit integration into the phenotyping algorithms. The clinical use case "Algorithmic Surveillance of ICU Patients" (ASIC) focusses on patients in Intensive Care Units (ICU) with the acute respiratory distress syndrome (ARDS). A model-based decision-support system will give advice for mechanical ventilation. The clinical use case HELP develops a "hospital-wide electronic medical record-based computerized decision support system to improve outcomes of patients with blood-stream infections" (HELP). ASIC and HELP use the PheP. The clinical benefit of the use cases ASIC and HELP will be demonstrated in a change of care clinical trial based on a step wedge design. DISCUSSION: SMITH's strength is the modular, reusable IT architecture based on interoperability standards, the integration of the hospitals' information management departments and the public-private partnership. The project aims at sustainability beyond the first 4-year funding period.

Role of comorbidity on outcome of head and neck cancer: a population-based study in Thuringia, Germany.

To examine the impact of comorbidity on overall survival (OS) in a population-based study of patients with head and neck cancer who were treated between 2009 and 2011. Data of 1094 patients with primary head and neck carcinomas without distant metastasis from the Thuringian cancer registries were evaluated concerning the influence of patient's characteristics and comorbidity on OS. Data on comorbidity prior to head and neck cancer diagnosis was adapted to the Charlson Comorbidity (CCI), age-adjusted CCI (ACCI), head and neck CCI (HNCCI), simplified comorbidity score (SCS), and to the Adult Comorbidity Evaluation-27 (ACE-27). Most patients were male (80%; median age: 60 years; 50% stage IV tumors). Smoking, alcohol abuse, and anemia were registered for 38%, 33%, and 23% of the patients, respectively. Predominant therapy was surgery + radiochemotherapy (30%), surgery (29%), and surgery + radiotherapy (21%). Mean CCI, ACCI, HNCCI, SCS and ACE-27 were 1.0 ± 1.5, 2.6 ± 2.1, 0.6 ± 0.8, 4.4 ± 4.2, and 0.9 ± 0.9, respectively. Median follow-up was 25.7 months. Multivariable analyses showed that higher age, higher UICC stage, no therapy, including surgery or radiotherapy, alcohol abuse, and anemia, higher comorbidity were independent risk factors for worse OS (all P < 0.05). According to the discriminatory power analysis none of the five comorbidity scores was superior to the other scores to prognosticate OS. This population-based study showed that comorbidity is frequent in German patients with head and neck cancer and is an important risk factor for poor OS. Comorbidity should be routinely assessed and taken into account in prospective clinical trials.

GEC-ESTRO multicenter phase 3-trial: Accelerated partial breast irradiation with interstitial multicatheter brachytherapy versus external beam whole breast irradiation: Early toxicity and patient compliance.

BACKGROUND AND PURPOSE: To compare early side effects and patient compliance of accelerated partial breast irradiation (APBI) with multicatheter brachytherapy to external beam whole breast irradiation (WBI) in a low-risk group of patients with breast cancer. MATERIAL AND METHODS: Between April 2004 and July 2009, 1328 patients with UICC stage 0-IIA breast cancer were randomized to receive WBI with 50Gy and a boost of 10Gy or APBI with either 32.0Gy/8 fractions, or 30.1Gy/7 fractions (HDR-brachytherapy), or 50Gy/0.60-0.80Gy per pulse (PDR-brachytherapy). This report focuses on early side-effects and patient compliance observed in 1186 analyzable patients. ClinicalTrials.gov identifier: NCT00402519. RESULTS: Patient compliance was excellent in both arms. Both WBI and APBI were well tolerated with moderate early side-effects. No grade 4 toxicity had been observed. Grade 3 side effects were exclusively seen for early skin toxicity (radiation dermatitis) with 7% vs. 0.2% (p<0.0001), and breast infection with 0% vs. 0.2% (p=n.s.) for patients treated with WBI and APBI. The incidence of grades 1-2 early side effects for WBI and APBI was 86% vs. 21% (p<0.0001) for skin toxicity, 2% vs. 20% (p<0.0001) for mild hematoma, and 2% vs. 5% (p=0.01) for mild breast infection rates, respectively. No differences had been found regarding grades 1-2 early breast pain (26% vs. 29%, p=0.23). CONCLUSIONS: APBI with interstitial multicatheter brachytherapy was tolerated very well and dramatically reduced early skin toxicity in comparison to standard WBI.

Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases-A pooled analysis of the German working group "stereotactic radiotherapy".

OBJECTIVES: The current literature on stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by small patient cohorts with heterogeneous primary tumors, metastases location and dose regimes. Hence, this study established a multi-institutional database of 700 patients treated with SBRT for pulmonary metastases to identify prognostic factors influencing survival and local control. MATERIALS AND METHODS: All German radiotherapy departments were contacted and invited to participate in this analysis. A total number of 700 patients with medically inoperable lung metastases treated with SBRT in 20 centers between 1997 and 2014 were included in a database. Primary and metastatic tumor characteristics, treatment characteristics and follow-up data including survival, local control, distant metastases, and toxicity were evaluated. Lung metastases were treated with median PTV-encompassing single doses of 12.5Gy (range 3.0-33.0Gy) in a median number of 3 fractions (range 1-13). RESULTS: After a median follow-up time of 14.3 months, 2-year local control (LC) and overall survival (OS) were 81.2% and 54.4%, respectively. In multivariate analysis, OS was most significantly influenced by pretreatment performance status, maximum metastasis diameter, primary tumor histology, time interval between primary tumor diagnosis and SBRT treatment and number of metastases. For LC, independent prognostic factors were pretreatment performance status, biological effective dose (BED) at PTV isocenter (BEDISO) and single fraction (PTV-encompassing) dose in multivariate analysis. Radiation-induced pneumonitis grade 2 or higher was observed in 6.5% of patients. The only factor significantly influencing toxicity was BEDISO (p=0.006). CONCLUSION: SBRT for medically inoperable patients with pulmonary metastases achieved excellent local control and promising overall survival. Important prognostic factors were identified for selecting patients who might benefit most from this therapy approach.

Bayesian Cure Rate Modeling of Local Tumor Control: Evaluation in Stereotactic Body Radiation Therapy for Pulmonary Metastases.

PURPOSE: Most radiobiological models for prediction of tumor control probability (TCP) do not account for the fact that many events could remain unobserved because of censoring. We therefore evaluated a set of TCP models that take into account this censoring. METHODS AND MATERIALS: We applied 2 fundamental Bayesian cure rate models to a sample of 770 pulmonary metastasis treated with stereotactic body radiation therapy at German, Austrian, and Swiss institutions: (1) the model developed by Chen, Ibrahim and Sinha (the CIS99 model); and (2) a mixture model similar to the classic model of Berkson and Gage (the BG model). In the CIS99 model the number of clonogens surviving the radiation treatment follows a Poisson distribution, whereas in the BG model only 1 dominant recurrence-competent tissue mass may remain. The dose delivered to the isocenter, tumor size and location, sex, age, and pretreatment chemotherapy were used as covariates for regression. RESULTS: Mean follow-up time was 15.5 months (range: 0.1-125). Tumor recurrence occurred in 11.6% of the metastases. Delivered dose, female sex, peripheral tumor location and having received no chemotherapy before RT were associated with higher TCP in all models. Parameter estimates of the CIS99 were consistent with the classical Cox proportional hazards model. The dose required to achieve 90% tumor control after 15.5 months was 146 (range: 114-188) Gy10 in the CIS99 and 133 (range: 101-164) Gy10 in the BG model; however, the BG model predicted lower tumor control at long (≳20 months) follow-up times and gave a suboptimal fit to the data compared to the CIS99 model. CONCLUSIONS: Biologically motivated cure rate models allow adding the time component into TCP modeling without being restricted to the follow-up period which is the case for the Cox model. In practice, application of such models to the clinical setting could allow for adaption of treatment doses depending on whether local control should be achieved in the short or longer term.

Prostate cancer treated with image-guided helical TomoTherapy® and image-guided LINAC-IMRT : Correlation between high-dose bladder volume, margin reduction, and genitourinary toxicity.

BACKGROUND: We compared different image-guidance (IG) strategies for prostate cancer with high-precision IG intensity-modulated radiation therapy (IMRT) using TomoTherapy® (Accuray Inc., Madison, WI, USA) and linear accelerator (LINAC)-IMRT and their impact on planning target volume (PTV) margin reduction. Follow-up data showed reduced bladder toxicity in TomoTherapy patients compared to LINAC-IMRT. The purpose of this study was to quantify whether the treatment delivery technique and decreased margins affect reductions in bladder toxicity. PATIENTS AND METHODS: Setup corrections from 30 patients treated with helical TomoTherapy and 30 treated with a LINAC were analyzed. These data were used to simulate three IG protocols based on setup error correction and a limited number of imaging sessions. For all patients, gastrointestinal (GI) and genitourinary (GU) toxicity was documented and correlated with the treatment delivery technique. RESULTS: For fiducial marker (FM)-based RT, a margin reduction of up to 3.1, 3.0, and 4.8 mm in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions, respectively, could be achieved with calculation of a setup correction from the first three fractions and IG every second day. Although the bladder volume was treated with mean doses of 35 Gy in the TomoTherapy group vs. 22 Gy in the LINAC group, we observed less GU toxicity after TomoTherapy. CONCLUSION: Intraprostate FMs allow for small safety margins, help decrease imaging frequency after setup correction, and minimize the dose to bladder and rectum, resulting in lower GU toxicity. In addition, IMRT delivered with TomoTherapy helps to avoid hotspots in the bladder neck, a critical anatomic structure associated with post-RT urinary toxicity.

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy.

BACKGROUND AND PURPOSE: To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. MATERIALS AND METHODS: A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. RESULTS: After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. CONCLUSIONS: Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases.

5-year results of accelerated partial breast irradiation using sole interstitial multicatheter brachytherapy versus whole-breast irradiation with boost after breast-conserving surgery for low-risk invasive and in-situ carcinoma of the female breast: a randomised, phase 3, non-inferiority trial.

BACKGROUND: In a phase 3, randomised, non-inferiority trial, accelerated partial breast irradiation (APBI) for patients with stage 0, I, and IIA breast cancer who underwent breast-conserving treatment was compared with whole-breast irradiation. Here, we present 5-year follow-up results. METHODS: We did a phase 3, randomised, non-inferiority trial at 16 hospitals and medical centres in seven European countries. 1184 patients with low-risk invasive and ductal carcinoma in situ treated with breast-conserving surgery were centrally randomised to either whole-breast irradiation or APBI using multicatheter brachytherapy. The primary endpoint was local recurrence. Analysis was done according to treatment received. This trial is registered with ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 551 patients had whole-breast irradiation with tumour-bed boost and 633 patients received APBI using interstitial multicatheter brachytherapy. At 5-year follow-up, nine patients treated with APBI and five patients receiving whole-breast irradiation had a local recurrence; the cumulative incidence of local recurrence was 1.44% (95% CI 0.51-2.38) with APBI and 0.92% (0.12-1.73) with whole-breast irradiation (difference 0.52%, 95% CI -0.72 to 1.75; p=0.42). No grade 4 late side-effects were reported. The 5-year risk of grade 2-3 late side-effects to the skin was 3.2% with APBI versus 5.7% with whole-breast irradiation (p=0.08), and 5-year risk of grade 2-3 subcutaneous tissue late side-effects was 7.6% versus 6.3% (p=0.53). The risk of severe (grade 3) fibrosis at 5 years was 0.2% with whole-breast irradiation and 0% with APBI (p=0.46). INTERPRETATION: The difference between treatments was below the relevance margin of 3 percentage points. Therefore, adjuvant APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is not inferior to adjuvant whole-breast irradiation with respect to 5-year local control, disease-free survival, and overall survival. FUNDING: German Cancer Aid.

Intensity-modulated Total Body Irradiation (TBI) with TomoDirect™.

BACKGROUND: The new TomoDirect™ modality offers a non-rotational option with discrete beam angles. We have investigated this mode for TBI with the intention to test the feasibility and to establish it as a clinical routine method. Special foci were directed onto treatment planning, dosimetric accuracy and practical aspects. PATIENTS AND METHODS: TBI plans were calculated with TomoDirect™ for a Rando™ phantom and all patients with an intended fractionated total body irradiation between November 2013 and May 2014 (n = 8). Finally, four of these patients were irradiated with TomoDirect™. Additionally we studied variations in the modulation factor, pitch, field width of Y-jaws and dose grid during optimization. Dose measurements were performed using thermoluminescent rods in the Rando™ phantom, with the Delta4® and with ionization chambers in a solid water phantom. RESULTS: For all eight calculated plans with a prescribed dose of 12 Gy Dmean was 12.09-12.33 Gy (12,25 ± 0.08 Gy), D98 11.2-11.6 Gy (11.45 ± 0.12 Gy) and D2 12.6-13.1 Gy (12.94 ± 0.13 Gy). Dmean of inner lungs was 8.73 ± 0.22 Gy on the left side and 8.69 ± 0.27 Gy on the right side. When single planning parameters are varied with otherwise constant parameters, the modulation factor showed the greatest impact on dose homogeneity and treatment time. The impact of the pitch was marginally, and almost equal homogeneity can be obtained with field width of Y-jaws 5 cm and 2.5 cm. Measurements with thermoluminescent rods (n = 25) in the Rando™ phantom showed a mean dose deviation between measured and calculated dose of 0.66 ± 2.26%. 18 of 25 TLDs had a deviation below 3%, seven of 25 TLDs between 3% and 5%. CONCLUSION: TBI with TomoDirect™ allows a superior homogeneity compared to conventional methods, where lung blocks are widely accepted. The treatment is performed only in supine position and is robust and comfortable for the patient. TomoDirect™ allows the implementation of organ-specific dose prescriptions. So the discussion about the balance between the need for aggressive treatment and limited toxicity can be renewed with the new potentials of TomoDirect™ - for children as well as for adults - and possibly yield a better clinical outcome in the future.

Incidence, treatment, and outcome of parotid carcinoma, 1996-2011: a population-based study in Thuringia, Germany.

PURPOSE: The objective of this study was to examine patterns of care and survival in a population-based sample of patients with parotid cancer who were treated in Thuringia, a federal state in Germany, between 1996 and 2011. METHODS: Data of 295 patients with primary parotid cancer from the Thuringian cancer registry were evaluated for patient's characteristics, tumor stage, incidence, and trends in treatment, cancer-specific survival (CSS), and overall survival (OS). RESULTS: Stages IV tumors and the amount of tumors in all age cohorts ≥45 years of age increased significantly during the observation period (p = 0.002; age all p < 0.05, respectively). The highest increase in crude incidence was observed for salivary duct carcinomas [relative risk per decade (RR) 5.46; 95% confidence interval (CI) 1.14-26.14] and rare carcinoma subtypes (RR 9.99; 95% CI 1.85-53.94). CSS at 5 years and at 10 years for all patients was 82.4 and 82.4%, respectively. OS at 5 years and at 10 years for all patients was 60.1 and 48.2%, respectively. CSS and OS did not improve over the time. Salivary duct carcinoma showed the lowest 5-year OS (35.6%). Acinic cell carcinoma had the highest OS rate (85.3%). Multivariate Cox models revealed that higher grading (G3/G4) was a more powerful independent predictor of decreased OS than TNM stage. CONCLUSIONS: CSS and OS did not improve during the study period. Incidence of parotid cancer increased significantly in elderly patients. It seems that grading is next to patient's age the better predictor of OS than TNM stage.