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Changing climate and human interference with natural phenomena are causing unprecedented changing patterns in hydro-climatic variables. These changes can manifest as dynamic changes of the stochastic properties of the datasets over time, which pose challenges for conventional time-series modeling. These datasets are dynamic in nature, even when trend and seasonality components are eliminated. Shrinking lakes are among the most notable examples of hydro-climatic-driven phenomena. This study demonstrates a framework that can capture the underlying dynamic and non-stationary structure of such environments using a case study of Maharlou Lake, Iran. To that end, a hybrid time-series model was developed to account for volatility in the data [i.e., SARIMA (1,1,2) × (1,1,2)12/GARCH(1,0)]. A series of statistical tests (i.e., augmented Dickey–Fuller test, the Ljung-Box test, the heteroskedasticity test, and the two-sample Kolmogorov–Smirnov test) were used to create, calibrate, and assess the model in the 95% confidence interval. The results indicate the decline and depletion of the lake. This reduction manifests as a general downward trend and a widening gap between the lake’s intra-annual fluctuations. The changes could be an alarming signal, as this saline lake could be mimicking the tragic fate of similar inland water bodies like Lake Urmia or the Aral Sea.

Background Management of non-small-cell lung cancer (NSCLC) is affected by regional specificities. The present study aimed at determining diagnostic and therapeutic procedures including outcome of patients with NSCLC stage III in the real-world setting in Central European countries to define areas for improvements . Patients and methods This multicentre, prospective and non-interventional study collected data of patients with NSCLC stage III in a web-based registry and analysed them centrally. Results Between March 2014 and March 2017, patients (n=583) with the following characteristics were entered: 32% females, 7% never-smokers; ECOG performance status (PS) 0, 1, 2 and 3 in 25%, 58%, 12% and 5%, respectively; 21% prior weight loss; 53% squamous carcinoma, 38% adenocarcinoma; 10% EGFR mutations. Staging procedures included chest X-ray (97% of patients), chest CT (96%), PET-CT (27%), brain imaging (20%), bronchoscopy (89%), endobronchial ultrasound (EBUS) (13%) and CT-guided biopsy (9%). Stages IIIA/IIIB were diagnosed in 55%/45% of patients, respectively. N2/N3 nodes were diagnosed in 60%/23% and pathologically confirmed in 29% of patients. Most patients (56%) were treated by combined modalities. Surgery plus chemotherapy was administered to 20%, definitive chemoradiotherapy to 34%, chemotherapy only to 26%, radiotherapy only to 12% and best supportive care (BSC) to 5% of patients. Median survival and progression-free survival times were 16.8 (15.3;18.5) and 11.2 (10.2;12.2) months, respectively. Stage IIIA, female gender, no weight loss, pathological mediastinal lymph node verification, surgery and combined modality therapy were associated with longer survival. Conclusions The real-world study demonstrated a broad heterogeneity in the management o f stage III NSCLC in Central European countries and suggested to increase the rates of PET-CT imaging, brain imaging and invasive mediastinal staging.

Aim N8‐GP (turoctocog alfa pegol) is a glycoPEGylated, extended half‐life human recombinant factor VIII (FVIII) shown to be an efficacious treatment for patients with haemophilia A. Accurate monitoring of replacement therapy helps ensure proper dosing, leading to better patient care. The objective of this field study was to evaluate the accuracy and intra‐ and inter‐laboratory variabilities of N8‐GP and rAHF (Advate®) FVIII activity (FVIII:C) measurements in clinical laboratories using their routine methods and reagents. Methods Laboratories measured plasma samples spiked with 0.03, 0.2, 0.6 and 0.9 IU/mL N8‐GP or rAHF. Samples were blinded, and laboratories were instructed to perform evaluations using their routine FVIII activity assays and calibrators. Results Of the 67 participating laboratories from 25 countries, 60 used a one‐stage assay, 36 used a chromogenic assay, and 29 used both one‐stage and chromogenic assays. Participating laboratories used nine different activated partial thromboplastin time (aPTT) reagents, the most common being SynthASil® and Actin® FS. Most aPTT reagents recovered N8‐GP close to target. Three silica‐based aPTT reagents (APTT‐SP, TriniCLOT™ and STA® PTT‐Automate) underestimated N8‐GP, recovering 40%‐83% of target concentration. For chromogenic assays, N8‐GP and rAHF recoveries were comparable at all concentrations, with overall mean recoveries for both products close to 130%. Assay variability was similar for both assay types and both products; inter‐laboratory variability was greater than intra‐laboratory variability and highest at 0.03 IU/mL. Conclusions Most clinical laboratories accurately measured N8‐GP and rAHF when using their in‐house one‐stage or chromogenic FVIII:C assays. However, three silica‐based aPTT reagents underestimated N8‐GP recovery.

Background To increase patient safety, so-called Critical Incident Reporting Systems (CIRS) were implemented. For Austria, no data are available on how CIRS is used within a healthcare facility. Therefore, the aim of this study was to present the development of CIRS within one of the biggest hospital providers in Austria. Methods In the province of Styria, CIRS was introduced in 2012 within KAGes (holder of public hospitals) in 22 regional hospitals and one tertiary university hospital. CIRS is available in all of these hospitals using the same software solution. For reporting a CIRS case an overall guideline exists. Results As of 2013, 2.504 CIRS cases were reported. Predominantly, CIRS-cases derived from surgical and associated disciplines (ranging from 35 to 45%). According to the list of hazards (also called “risk atlas”), errors in patient identification (ranging from 7 to 12%), errors in management of medicinal products (ranging from

The treatment options for the haemostatic disorders, haemophilia A and haemophilia B, have progressed rapidly over the last decade. The introduction of extended half-life recombinant factor VIII (FVIII) and factor IX (FIX) concentrates to replace these missing clotting factors highlighted discordance between one-stage activated partial thromboplastin time (APTT)-based clotting factor assays and chromogenic factor assays with some products. This raised awareness of the importance of investigation of potential reagent or assay differences by pharmaceutical companies. In 2017, the FVIII mimetic, emicizumab, was approved as a prophylactic treatment for haemophilia A patients with anti-FVIII inhibitors. The mechanism of action of emicizumab causes interference with some commonly used haemostasis tests including the APTT and its associated one-stage APTT-based clotting assays. Chromogenic assays may also be affected but this is dependent on the particular constituents of the reagents. Chromogenic assays containing human factor IXa (FIXa) and factor X (FX) are sensitive to the presence of emicizumab but those containing bovine FIXa and FX are unaffected. Many haemostasis laboratories have been required to evaluate new assays to enable accurate monitoring of emicizumab in patient plasma. A number of gene therapy approaches have been trialled in both haemophilia A and haemophilia B but there are scant data published on the measurement of FVIII and FIX in these patients and whether there are discrepancies between reagents or assay methodologies.

It has become common knowledge that the use of virtual reality (VR) applications can very often cause typical symptoms of motion sickness such as nausea and dizziness. For this reason, however, there are also more and more attempts to contain or completely avoid the side effect, which is meanwhile called cybersickness. This paper elaborates on a pre-study of a large-scale study investigating whether the use of treadmills for real, physical movement in virtual worlds can reduce the incidence of motion sickness compared to other common VR locomotion techniques and therefore enlarge the time participants can use VR for training or simulation in companies.

Background: Stroke is a morbid and potentially mortal complication among patients hospitalized with acute medical illness. The potential of extended-duration thromboprophylaxis with the factor Xa inhibitor betrixaban to reduce the risk of stroke compared with standard-dose enoxaparin in this population was assessed in this retrospective APEX trial substudy (Acute Medically Ill Venous Thromboembolism Prevention With Extended Duration Betrixaban). Methods: Hospitalized acutely medically ill subjects (n=7513) were randomized in a double-dummy double-blind fashion to either extended-duration oral betrixaban (80 mg once daily for 35–42 days) or standard-dose subcutaneous enoxaparin (40 mg once daily for 10±4 days) for venous thromboprophylaxis. Stroke events were adjudicated by an independent, blinded event adjudication committee. Results: The mean age of study participants was 76 years; 45% were male; 13% had had a stroke; and 45% had congestive heart failure. There were fewer all-cause strokes (0.54% versus 0.97%; relative risk [RR]=0.56; 95% confidence interval, 0.32–0.96; P =0.032; adjusted RR=0.43%; number needed to treat=233) and ischemic strokes (0.48% versus 0.91%; RR=0.53; 95% confidence interval, 0.30–0.94; P =0.026; adjusted RR=0.43%; number needed to treat=233) among patients treated with betrixaban versus enoxaparin through 77 days of follow-up. Among high-risk subjects, those with congestive heart failure or ischemic stroke as their index event, betrixaban reduced the risk of all-cause stroke (0.72% versus 1.48%; RR=0.49; 95% confidence interval, 0.26–0.90; P =0.019; adjusted RR=0.76%; number needed to treat=132) and ischemic stroke (0.63% versus 1.38%; RR=0.45; 95% confidence interval, 0.24–0.87; P =0.014; adjusted RR=0.75%; number needed to treat=134) compared with enoxaparin. Conclusions: Among hospitalized medically ill patients, extended-duration betrixaban significantly reduced all-cause stroke and ischemic stroke through 77 days of follow-up Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

Aims and objectives To test the method of self- and external assessment as a feedback system to decrease illegibility and incorrectness of handwritten prescriptions and to reduce additional workload for nursing staff. Background Illegibility and incorrectness of handwritten prescriptions occur very often and are the most crucial factors affecting patient safety. Design Self- versus external assessment using a 15 items checklist. Methods Nurses randomly selected five fever charts of their wards. Each fever chart was self- as well as externally assessed. Nurses and doctors took part in the self-assessment, and the external assessment was performed by external experts. According to a monitor suspension system, assessment results were considered "green," "yellow" or "red." After the first assessment and issuing feedback of the results "red" scored wards by the external assessment, additional trainings were performed. Thereafter, a second assessment was performed to rate eligibility and completeness of prescriptions. The research and reporting methodology followed squire 2.0. Results In total, 580 fever charts were self- as well as externally assessed (290 in each of the two assessment periods). Out of the 58 participating wards, 31 were surgical and 27 were non-surgical wards. Averaging over all checklist items, surgical and non-surgical wards improved only slightly over time. Linear regression models for ward means showed that there were significant improvements over time for non-surgical wards. Conclusions This method directly involves those who commit errors and stimulate learning from errors. The approach of self- and external assessment was a useful instrument to detect inadequate prescriptions and to monitor improvements. Relevance to clinical practice Significant improvements were achieved regarding correctness and legibility of handwritten prescription and helped to decrease additional workload for nursing staff and thereby enhanced patient safety.

Objectives Bone and soft-tissue calcifications are often coincidentally diagnosed on digital panoramic radiographs (DPRs). As the use of three-dimensional (3D) images has increased in the past decade for diagnostics in the mandibular region, we evaluated 3D volume images derived from 2D panoramic images to determine if this method is suitable for early detection of calcifications in this region. Methods In this study, three investigators retrospectively and independently evaluated 822 DPRs. If one or more calcifications were present, the 3D volume image from that patient was retrospectively evaluated to confirm the incidental findings. A radiographic system with a low-dose mode and a high-resolution 3D-image function was used. The investigators focussed on the most common calcifications, including tonsilloliths (TL), idiopathic osteosclerosis (IO) of the mandible, carotid artery calcifications (CAC), calcified submandibular lymph nodes (hereafter, CSL), and sialoliths of the submandibular salivary gland (SSG). Results One or more calcifications were identified in 415 (50.5%) DPRs. In total, 718 calcifications were detected, 30.2% of which were TL, 16.3% IO, 11.3% CAC, 8.8% CSL, and 1.7% SSG. Only 287 (39.97 %) of the calcifications were confirmed on 3D volume images; of these, 29.2% were TL, 58.5% IO, 0.2% CAC, and 1.4% SSG. No CSLs were detected. Conclusions Not all areas shown on the DPRs were visible in the retrospectively obtained 3D volume images. Whereas DPRs are used to diagnose calcifications such as IO, TL, SSG, CAC, and CSL, the 3D volume images were only useful for confirming the existence of IO, TL, and SSG calcifications.

Background: Venous thromboembolism (VTE) is a major health problem, with over one million events every year in Europe. However, there is a paucity of data on the current management in real life, including factors influencing treatment pathways, patient satisfaction, quality of life (QoL), and utilization of health care resources and the corresponding costs. The PREFER in VTE registry has been designed to address this and to understand medical care and needs as well as potential gaps for improvement. Methods/design: The PREFER in VTE registry was a prospective, observational, multicenter study conducted in seven European countries including Austria, France Germany, Italy, Spain, Switzerland, and the UK to assess the characteristics and the management of patients with VTE, the use of health care resources, and to provide data to estimate the costs for 12 months treatment following a first-time and/or recurrent VTE diagnosed in hospitals or specialized or primary care centers. In addition, existing anticoagulant treatment patterns, patient pathways, clinical outcomes, treatment satisfaction, and health related QoL were documented. The centers were chosen to reflect the care environment in which patients with VTE are managed in each of the participating countries. Patients were eligible to be enrolled into the registry if they were at least 18 years old, had a symptomatic, objectively confirmed first time or recurrent acute VTE defined as either distal or proximal deep vein thrombosis, pulmonary embolism or both. After the baseline visit at the time of the acute VTE event, further follow-up documentations occurred at 1, 3, 6 and 12 months. Follow-up data was collected by either routinely scheduled visits or by telephone calls. Results: Overall, 381 centers participated, which enrolled 3,545 patients during an observational period of 1 year. Conclusion: The PREFER in VTE registry will provide valuable insights into the characteristics of patients with VTE and their acute and mid-term management, as well as into drug utilization and the use of health care resources in acute first-time and/or recurrent VTE across Europe in clinical practice. Trial registration: Registered in DRKS register, ID number: DRKS00004795

The epidermal growth factor receptor (EGFR) has been established as a clinically relevant target for the treatment of patients with advanced non-small cell lung cancer (NSCLC) (1). EGFR blockade can be achieved by either monoclonal antibodies directed against the surface of the receptor or tyrosine kinase inhibitors directed against the intracellular domain of the receptor (1,2). Monoclonal antibodies such as cetuximab and necitumumab improved outcome including overall survival, particularly in patients with squamous cell NSCLC and/or high EGFR expression or EGFR fluorescence in situ positivity (3-7). EGFR tyrosine kinase inhibitors (TKIs) have also been established for the treatment of patients with advanced NSCLC (1). While these TKIs show efficacy in non-oncogene-driven NSCLC, they have much higher efficacy in patients who harbour EGFR mutations in their tumours. EGFR mutations occur in tumours of about 40% of Asian patients and 15% of Caucasian patients with advanced NSCLC (8). Based on the results from several randomized phase 3 trials, EGFR TKIs have been established as first-line therapy in patients with advanced EGFR mutation-positive NSCLC (1).

Background Extended‐duration betrixaban showed a significant reduction in venous thromboembolism in the APEX trial (Acute Medically Ill VTE Prevention With Extended Duration Betrixaban Study). Given the variable clinical impact of different efficacy and safety events, one approach to assess net clinical outcomes is to include only those events that are either fatal or cause irreversible harm. Methods and Results This was a post hoc analysis of the APEX trial—a multicenter, double‐blind, randomized controlled trial comparing extended‐duration betrixaban versus standard‐of‐care enoxaparin. A composite of all fatal or irreversible safety (fatal bleeding or intracranial hemorrhage) and efficacy events (cardiopulmonary death, myocardial infarction, pulmonary embolism, and ischemic stroke) was evaluated in a time‐to‐first event analysis. In patients with positive D‐dimer results, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.80% versus 3.54%; hazard ratio, 0.73; absolute risk reduction, 1.26%; number needed to treat, 79 [ P =0.033]) and at study end at 77 days (6.27% versus 4.36%; hazard ratio, 0.70; absolute risk reduction, 1.91%; number needed to treat, 52 [ P =0.005]) versus enoxaparin. In all patients, betrixaban reduced fatal or irreversible events at 35 to 42 days (4.08% versus 2.90%; hazard ratio, 0.71; absolute risk reduction, 1.18%; number needed to treat, 86 [ P =0.006]) and 77 days (5.17% versus 3.64%; hazard ratio, 0.70; absolute risk reduction, 1.53%; number needed to treat, 65 [ P =0.002]). Conclusions Among hospitalized medically ill patients, extended‐duration betrixaban demonstrated an ≈30% reduction in fatal or irreversible ischemic or bleeding events compared with standard‐duration enoxaparin. A total of 65 patients would require treatment with betrixaban to prevent 1 fatal or irreversible event versus enoxaparin. Clinical Trial Registration URL : http://www.ClinicalTrials.gov . Unique identifier: NCT 01583218.

To investigate nitinol stent treatment of superficial femoral artery (SFA) lesions and the impact of different risk factors on the need for clinically driven target lesion revascularization (TLR) in a large, real-world population of claudicants.Patients presenting with symptomatic SFA stenosis70% were consecutively enrolled in the 13-center MARIS prospective registry (ClinicalTrials.gov identifier NCT01067885). There was no restriction on lesion length, thus leading to the inclusion of a real-world as well as high-risk patient cohort. The 998 participating patients (657 men; mean age 67.4±9.2 years) had 1050 lesions treated with the same nitinol stent type. The mean lesion length was 9.5±9.6 cm (range 0.5-44; median 8.0); more than a third of the lesions (450, 42.9%) were total occlusions. The primary endpoint was the need for clinically driven target lesion revascularization (TLR) at 12 months.Acute technical success was achieved in 1042 (99.2%) lesions. Restenosis occurred in 187 (23.7%) and reocclusion in 79 (10.0%) lesions at 12 months. The primary endpoint of TLR at 12 months was reached by 136 (17.2%) patients. The periprocedural complication rate was 5.4%. Independent predictors of TLR were female gender [odds ratio (OR) 0.5, 95% confidence interval (CI) 0.3 to 0.7, p0.001] and lesion length20 cm vs. 10 cm (OR 2.7, 95% CI 1.1 to 6.6, p=0.029) and 10-20 cm vs. 10 cm (OR 1.9, 95% CI 1.0 to 4.1, p=0.047).Stent implantation in the SFA is safe and associated with favorable acute and midterm results in a real-world setting. Lesion length and female gender were identified as independent risk factors for TLR.

SummaryVenous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0% were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5%). The diagnosis was deep-vein thrombosis (DVT) in 59.5% and pulmonary embolism (PE) in 40.5%. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5%), hypertension (42.3%) and dyslipidaemia (21.1%). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2%), almost half received a vitamin K antagonist (48.7%) and nearly a quarter received a DOAC (24.5%). Almost a quarter of all presentations were for recurrent VTE, with >80% of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes.

Background: Patients ≥70 years with small, low-risk breast cancer who are operated but not irradiated how local relapse rates around 4% after 4 years. With adjuvant whole breast radiotherapy (WBRT) the local relapse rate drops to 1% after 4 years under Tamoxifen. It has been demonstrated that the efficacy of radiotherapy of the tumor bed only in a selected group can be non-inferior to WBRT. Methods/Design: This prospective, multicentric single arm phase II study is based on the protocol of the international TARGIT-A study. The TARGIT-E study should confirm the efficacy of a single dose of intraoperative radiotherapy (IORT) in a well selected group of elderly patients with small breast cancer and absence of risk factors. Patients will receive IORT (20 Gy with Intrabeam system/Carl Zeiss) during breast conserving surgery. In presence of risk factors postoperative WBRT will be added to complete the radiotherapeutic treatment according to international guidelines. Endpoints are the local relapse rate (within 2 cm of the tumor bed), ipsilateral in breast relapse, cancer-specific and overall survival and contralateral breast cancer as well as documentation of quality of life and cosmetic outcome. The expected local relapse rates are 0.5/1/1.5% after 2.5/5/7.5 years, respectively. Discontinuation of the trial is scheduled if rates of local relapse rates rise to 3/4/6% after 2.5/5/7.5 years. Power calculations result in 540 patients with a calculated dropout rate of 20% and loss to follow-up of 20%, an alpha of 0.01 and a beta 0.05. There will be a pre- and a post-pathology stratum (n=270 each). Discussion: It is a pragmatic trial in which each participating centre has the option to modify entry criteria and criteria for WBRT according to this core protocol after consultation with the steering committee and local ethics committee (e.g. size, free margins). Only centers with access to the Intrabeam system (Carl Zeiss) can recruit patients into the trial. Its aim is to confirm the efficacy and toxicity of IORT in a well selected collective of elderly patients with breast cancer. Trail registration: NCT01299987 Background

Background\ud Patients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.\ud \ud Methods\ud Patients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10±4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10±4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding.\ud \ud Results\ud A total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P=0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P=0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P=0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P=0.55).\ud \ud Conclusions\ud Among acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218. opens in new tab.)

The aim was to investigate changes in the tumor bed on magnetic resonance mammography (MRM) after intraoperative radiotherapy (IORT) and whether they would limit the diagnostic value of posttherapeutic MRM. We retrospectively investigated 36 patients undergoing MRM after IORT (median interval 2.8 years, range 0.4–7.1). Wound cavities with fat necrosis were common after IORT (81%). They were associated with persisting contrast enhancement, i.e., enhancement was mostly seen irrespective of the posttherapeutic interval. It normally presented as rim enhancement and did not cause any diagnostic uncertainty if viewed together with other tissue characteristics. We do not expect a limited diagnostic value of MRM after IORT.

Objectives This study sought to assess the safety and efficacy of transcatheter valve annuloplasty in patients with mitral regurgitation (MR). Background Mitral regurgitation is associated with a worsened prognosis in patients with dilated cardiomyopathy. Surgical mitral annuloplasty reduces the septal-lateral dimension of the mitral annulus resulting in improved leaflet coaptation with a reduction in regurgitation. Percutaneous annuloplasty with the MONARC device (Edwards Lifesciences, Irvine, California) implanted within the coronary sinus is designed to reduce mitral regurgitation through a similar mechanism. Methods A total of 72 patients with MR grade ≥2 were enrolled at 8 participating centers in 4 countries. Clinical evaluation and transthoracic echocardiography were performed at baseline and at 3, 6, and 12 months. Multislice cardiac computed tomography and coronary angiography were performed at baseline and 3 months. Results The MONARC device was implanted in 59 of 72 patients (82%). The primary safety end point (freedom from death, tamponade, or myocardial infarction at 30 days) was met in 91% of patients at 30 days and in 82% at 1 year. Computed tomography imaging documented passage of the great cardiac vein over an obtuse marginal artery in 55% of patients and was associated with angiographic coronary artery compression in 15 patients and myocardial infarction in 2 patients (3.4%). At 12 months, a reduction in MR by ≥1 grade was observed in 50.0% of 22 implanted patients with matched echocardiograms and in 85.7% of 7 patients with baseline MR grade ≥3. Conclusions Implantation of the MONARC device in the coronary sinus is feasible and may reduce MR. However, coronary artery compression may occur in patients in whom the great cardiac vein passes over a coronary artery, necessitating strategies in future studies to avoid this occurrence.

Intraoperative radiotherapy (IORT) is currently being evaluated as a novel approach during breast-conserving surgery (BCS). IORT can be used either as a tumor bed boost followed by external-beam radiotherapy (EBRT) or as a single treatment. In a matched-pair study, we assessed quality of life (QoL) in 69 patients with early breast cancer treated with BCS and/or IORT and/or EBRT. Patients were matched for age and time since BCS. IORT was provided with 50 kV x-rays (Intrabeam) delivering 20 Gy at the applicator surface. EBRT (46 to 50 Gy in 2-Gy fractions in the IORT with EBRT group, and 56 Gy in 2-Gy fractions in the EBRT group) was initiated after completion of wound healing and/or chemotherapy. The mailed questionnaires included the European Organization for the Research and Treatment of Cancer QLQ-C30 and BR23, FACT-F, HADS, Body Image Scale, and Rosenberg Self-Esteem Scale. At 18 to 70 months’ follow-up (median 47 months), all patients were disease free. We found only a few differences between the three groups. There was a trend toward more pain (mean ± standard deviation; 42.8 ± 32.9 vs. 27.5 ± 34.7) and reduced QoL (57.6 ± 20.7 vs. 70.3 ± 23.9) after IORT with EBRT compared with EBRT, respectively. IORT patients reported comparable QoL (70.3 ± 23.0), and less breast symptoms and body image concerns compared to EBRT (8.6 ± 12.3 vs. 19.2 ± 23.8, and 1.7 ± 3.3 vs. 3.4 ± 4.4, respectively). IORT alone resulted in significantly fewer breast symptoms (8.6 ± 12.3; P = 0.012) and less pain (23.9 ± 24.5, P = 0.041) compared with IORT with EBRT (26.1 ± 27.6; 42.8 ± 32.9, respectively). Patients with early breast cancer after BCS and IORT with or without EBRT present with comparable QoL like patients receiving EBRT without a boost. IORT patients show the lowest rate of breast symptoms.

Intraoperative radiotherapy (IORT) during breast-conserving surgery as a boost followed by whole-breast radiotherapy is increasingly used.Between February 2002 and December 2008, a total of 197 patients were treated with IORT as a boost (20 Gy, 50 kV x-rays; Intrabeam System, Carl Zeiss Surgical, Oberkochen, Germany) during breast-conserving surgery, followed by whole-breast radiotherapy (46-50 Gy). Systemic therapy was provided according to the St. Gallen consensus. Patients were recalled every 6-12 months for follow-up. Findings were scored according to the LENT-SOMA scale.Median age was 61.8 (range 30-84) years, and median follow-up was 37 (range 5-91) months. There were T1, T2, and Tx tumors in 129, 67, and 1 patients, respectively, and N0, N1, N2, and N3 disease in 144, 36, 15, and 2 patients, respectively. Until December 2009, 5 local invasive relapses, 1 local ductal carcinoma-in-situ, 1 axillary relapse, 6 secondary cancers, and 11 distant metastases were seen, resulting in a 5-year disease-free survival of 81.0% and an overall survival of 91.3%. Local relapse-free survival (invasive cancers) at 3 and 5 years was 97.0%. After a follow-up of 5 years (n =58), only 8 patients (13.8%) had chronic skin toxicities, and 2 patients (3.4%) had a marked increase in density (fibrosis III), while 62.0% had no/barely palpable fibrosis 0-I. Other toxicities observed included severe pain (n = 4, 6.9%), retraction (n =17, 29.3%), edema of the breast (n =1, 1.7%), and lymphedema in general (n =2, 3.4%).After IORT as a tumor bed boost with low-kilovoltage x-rays followed by whole-breast radiotherapy, low local recurrence and chronic toxicity rates were seen after 5-year follow-up.

Peripheral artery disease (PAD) is associated with high cardiovascular mortality and a poor quality of life. The AT1-receptor blocker telmisartan has been shown to have pleiotropic effects and it may also improve endothelial function. The aim of this study was to analyze the effects of telmisartan on absolute walking distance (WD) and endothelial function in patients with PAD.In a single centre, single-blinded, prospective study, 36 patients with PAD at stage Fontaine II or higher and mild to moderate arterial hypertension were treated with telmisartan 40/80 mg once daily or placebo for 12 months. Primary endpoint was the improvement of the absolute treadmill WD. Flow-mediated vasodilation (FMD), carotid intima-media thickness (IMT), ankle-brachial index (ABI) and disease-related quality of life (DRQL) were examined as well.After 12 months, maximum WD increased by 26% in the telmisartan group (P0.001). However, in the placebo group it was comparable to baseline. FMD rose by 40% in the telmisartan group while it deteriorated in the placebo group (P0.001). IMT and ABI were comparable in both groups at baseline and did not change considerably after 12 months. In non-diabetic patients (72.2%), the ABI did not change in the placebo group, whereas it increased by 11% in the telmisartan group (P0.001). While the DRQL remained stable in the telmisartan group, placebo treatment was associated with a marked deterioration (P0.01).Telmisartan improves WD and endothelial function, the ABI in non-diabetic patients and it may prevent further loss of quality of life in patients with advanced PAD.

The purpose of this study was to assess mammographic and sonographic findings in a long-term follow-up (≥3 years) after breast-conserving surgery (BCS) and IORT, either applied as boost or exclusively. Follow-up-findings of 54 patients were retrospectively evaluated and compared to a control group of 48 patients, treated with BCS and whole-breast radiotherapy. After IORT patients had a higher incidence of fat necroses manifesting as oil cysts in the late follow-up mammograms ( n = 31 vs n = 8); furthermore, oil cysts were larger in the IORT group (median 4.5 vs 1.4 cm 2 ). In 25 IORT patients the oil cysts arose from partially organized hematomas/seromas, which in this group were generally more frequent ( n = 38 vs n = 9) and larger (median 3.6 vs 1.8 cm 2 ). After IORT a decreasing incidence of hematomas/seromas was reciprocal to an increasing incidence of oil cysts, and the size of both entities correlated with each other. Liquid lesions with polypoid inner wall thickening on ultrasound, attributed to organized hematomas/seromas or fat necroses, appear more frequently after IORT ( n = 15 vs n = 1). In conclusion, IORT is associated with a high incidence of large oil cysts, which arise from likewise large partially organized wound cavities. On ultrasound pronounced partial organization with polypoid inner wall thickening is a frequent finding in those cavities.

To prospectively compare the effect of prophylactic and therapeutic whole brain radiotherapy (WBRT) on memory function in patients with and without brain metastases.Adult patients with and without brain metastases (n = 44) were prospectively evaluated with serial cognitive testing, before RT (T0), after starting RT (T1), at the end of RT (T2), and 6-8 weeks (T3) after RT completion. Data were obtained from small-cell lung cancer patients treated with prophylactic cranial irradiation, patients with brain metastases treated with therapeutic cranial irradiation (TCI), and breast cancer patients treated with RT to the breast.Before therapy, prophylactic cranial irradiation patients performed worse than TCI patients or than controls on most test scores. During and after WBRT, verbal memory function was influenced by pretreatment cognitive status (p0.001) and to a lesser extent by WBRT. Acute (T1) radiation effects on verbal memory function were only observed in TCI patients (p = 0.031). Subacute (T3) radiation effects on verbal memory function were observed in both TCI and prophylactic cranial irradiation patients (p = 0.006). These effects were more pronounced in patients with above-average performance at baseline. Visual memory and attention were not influenced by WBRT.The results of our study have shown that WBRT causes cognitive dysfunction immediately after the beginning of RT in patients with brain metastases only. At 6-8 weeks after the end of WBRT, cognitive dysfunction was seen in patients with and without brain metastases. Because cognitive dysfunction after WBRT is restricted to verbal memory, patients should not avoid WBRT because of a fear of neurocognitive side effects.

Background Intraoperative radiotherapy (IORT) during breast-conserving surgery is increasingly used. We analyzed the influence of the interval between an IORT boost and external beam radiotherapy (EBRT) on late toxicity. Methods Forty-eight patients received 20 Gy IORT (50 kV X-rays (Intrabeam, Carl Zeiss, Oberkochen, Germany) followed by 46–50 Gy EBRT with a median interval of 36 days (14-197). Late toxicity was assessed with the modified LENT SOMA score after a median of 36 months. Results Twelve patients developed a higher grade fibrosis (°II–III), three teleangiectases, one a breast edema grade °II, six retractions, four hyperpigmentations and five pain (°II–III). The median interval between IORT and EBRT was significantly shorter in these patients ( n = 18) compared to the 30 patients without higher grade toxicity (29.5 days vs. 39.5 days, p = 0.023, Mann–Whitney U -test). Conclusion Starting EBRT about 5–6 weeks after IORT appears to be associated with a decreased risk of chronic late toxicity compared with a shorter interval. The impact on local recurrence of prolonged gaps between IORT and EBRT is not known.

Background. Peripheral arterial disease (PAD) indicates generalized atherosclerosis but is still underdiagnosed and undertreated. Methods. Data were collected from patients with PAD from the Department of Cardiology and Angiology, University of Heidelberg, Germany. The prevalence of cardiovascular risk factors and medication were documented. Results. Atherogenic risk factors, cardiovascular disease, and cerebrovascular disease were highly prevalent. By continuous care at the university clinic, in addition to family medicine treatment, the use of platelet inhibitors, antihypertensives, and lipid-lowering therapy was increased. Ankle—brachial index and walking distance improved. Conclusion. Long-term treatment at the university clinic had positive effects on atherogenic risk factors. The regular use of secondary preventive medication was improved. Still, this patient population remained undertreated and showed a high incidence of vascular event rates and a need for vascular interventions. This study implies the importance of both specialists and general practitioners in the care of these individuals.

Androgens, like estrogens, can be synthesized in the breast. As both active androgens and their corresponding receptors are present in breast tissue, we conclude that they play a role in breast physiology. This is supported by the fact that insufficient androgen production or sensitivity results in the development of gynecomastia. Complete androgen insensitivity due to receptor defects leads to normal female breast development in these XY women. While breast development is completely inhibited by male testosterone levels, partial but not total degradation of a developed breast by androgen treatment appears to be possible. Breast cancer in early stages seems to fulfill the prerequisites of androgen responsiveness. Androgen treatment of advanced breast cancer has shown similar effectiveness as anti-estrogen or estrogen-ablative therapy, but also considerable side effects. It has been speculated that the use of selective androgen modulators (SARMs), either alone or preferably in addition to anti-estrogens or aromatase inhibitors, may be a promising alternative to current therapy modalities in hormone-dependent breast cancer. In addition, future studies on the use of SARMs in prophylactic settings seem to be justified.

The ability of von Willebrand factor (VWF) to bind platelet GP Ib and promote platelet plug formation is measured in vitro using the ristocetin cofactor (VWF:RCo) assay. Automated assay systems make testing more accessible for diagnosis, but do not necessarily improve sensitivity and accuracy.We assessed the performance of a modified automated VWF:RCo assay protocol for the Behring Coagulation System (BCS(®) ) compared to other available assay methods.Results from different VWF:RCo assays in a number of specialized commercial and research testing laboratories were compared using plasma samples with varying VWF:RCo activities (0-1.2 IU mL(-1) ). Samples were prepared by mixing VWF concentrate or plasma standard into VWF-depleted plasma. Commercially available lyophilized standard human plasma was also studied. Emphasis was put on the low measuring range. VWF:RCo accuracy was calculated based on the expected values, whereas precision was obtained from repeated measurements.In the physiological concentration range, most of the automated tests resulted in acceptable accuracy, with varying reproducibility dependent on the method. However, several assays were inaccurate in the low measuring range. Only the modified BCS protocol showed acceptable accuracy over the entire measuring range with improved reproducibility.A modified BCS(®) VWF:RCo method can improve sensitivity and thus enhances the measuring range. Furthermore, the modified BCS(®) assay displayed good precision. This study indicates that the specific modifications - namely the combination of increased ristocetin concentration, reduced platelet content, VWF-depleted plasma as on-board diluent and a two-curve calculation mode - reduces the issues seen with current VWF:RCo activity assays.

Purpose Breast intensity modulated radiation therapy (IMRT) reduces high-dose heart volumes but increases low-dose volumes. We prospectively assessed heart changes after 3D conformal RT (3DCRT) and IMRT for left-sided breast cancer. Heart dose was analyzed individually, 3DCRT patients were moderately exposed, and IMRT was performed only in patients with unacceptably high heart doses upon 3DCRT planning. Methods and Materials In 49 patients (38 patients received 3DCRT; 11 patients received IMRT; and 20 patients received neoadjuvant or adjuvant chemotherapy) magnetic resonance imaging (MRI) and echocardiography were performed before and at 6, 12, and 24 months after treatment. Results Mean heart dose for IMRT was 12.9 ± 3.9 Gy versus 4.5 ± 2.4 Gy for 3DCRT. Heart volumes receiving >40 Gy were 2.6% (3DCRT) versus 1.3% (IMRT); doses were >50 Gy only with 3DCRT. Temporary ejection fraction (EF) decrease was observed on MRI after 6 months (63%-59%, P =.005) resolving at 24 months. Only 3 patients had pronounced largely transient changes of EF and left ventricular enddiastolic diameter (LVEDD). Mitral (M) and tricuspid (T) annular plane systolic excursion (MAPSE and TAPSE) were reduced over the whole cohort (still within normal range). After 24 months left ventricular remodeling index decreased in patients receiving chemotherapy (0.80 vs 0.70, P =.028). Neither wall motion abnormalities nor late enhancements were found. On echocardiography, in addition to EF findings that were similar to those on MRI, global strain was unchanged over the whole cohort at 24 months after a transient decrease at 6 and 12 months. Longitudinal strain decreased in the whole cohort after 24 months in some segments, whereas it increased in others. Conclusions Until 24 months after risk-adapted modern multimodal adjuvant therapy, only subclinical cardiac changes were observed in both 3DCRT patients with inclusion of small to moderate amounts of heart volume in RT tangents and in the patients treated with IMRT and reduced high-dose heart exposure.

PURPOSE: Patients undergoing breast-conserving surgery were offered boost radiotherapy with targeted intraoperative radiotherapy (TARGIT) using the Intrabeam system to test the feasibility, safety, and efficacy of the new approach. METHODS AND MATERIALS: We treated 302 cancers in 301 unselected patients. This was not a low-risk group. One-third of patients (98/301) were younger than 51 years of age. More than half of the tumors (172, 57%) were between 1 cm and 2 cm, and one-fifth (62, 21%) were >2 cm; 29% (86) had a Grade 3 tumor and, in 29% (87), axillary lymph nodes contained metastasis. After primary surgery, 20 Gy was delivered intraoperatively to the surface of the tumor bed, followed by external-beam radiotherapy (EBRT), but excluding the usual boost. RESULTS: The treatment was well tolerated. The follow-up ranged from 3 to 80 months (164 and 90 patients completed 2 and 3 years follow-up, respectively). Four patients (1.3%) had local recurrence. The Kaplan-Meier estimate of local recurrence is 2.6% (SE = 1.7) at 5 years. This compares favorably with the 4.3% recurrence rate in boosted patients from the EORTC boost study, in which only 8.1% patients were node-positive, as opposed to 29% in our series. CONCLUSION: Targeted intraoperative radiotherapy combined with EBRT results in a low local recurrence rate. This could be attributed to both accurate targeting and timeliness of the treatment. These data support the need for a randomized trial to test whether the TARGIT boost is superior to conventional external boost, especially in high-risk women.

Introduction Intraoperative radiotherapy (IORT) with low-energy X-rays (30–50 KV) is an innovative technique that can be used both for accelerated partial breast irradiation (APBI) and intraoperative boosting in patients affected by breast cancer. Immediately after tumor resection the tumor bed can be treated with low-distance X-rays by a single high dose. Whereas often a geographic miss in covering the boost target occurs with external beam boost radiotherapy (EBRT), the purpose of IORT is to cover the tumor bed safely. This report will focus on the feasibility and technical aspects of the Intrabeam™ device and will summarize our experience with side effects and local control. Materials and methods Between February 2002 and June 2003 57 breast cancer patients, all eligible for breast conserving surgery (BCS), were treated at the Mannheim Medical Center with IORT using the mobile X-ray system Intrabeam™. The patient population in this feasibility study was not homogeneous consisting of 49 patients with primary stage I or II breast cancer, seven with local recurrence after previous EBRT and one with a second primary in a previously irradiated breast. The selection criteria for referral for IORT included tumor size, tumor cavity size, margin status and absence of an extensive intraductal component. The previously irradiated patients with local recurrences and 16 others received IORT as single modality. In all other cases IORT was followed by EBRT with a total dose of 46 Gy in 2-Gy fractions. The intraoperatively delivered dose after tumor resection was 20 Gy prescribed to the applicator surface. EBRT was delivered with a standard two-tangential-field technique using linear accelerators with 6- or 18-MV photons. Patients were assessed every three months by their radiation oncologist or surgeon during the first year after treatment and every six months thereafter. Breast ultrasound for follow-up was done every six months and mammographies once yearly. Acute side effects were scored according to the CTC/EORTC score and late side effects according to the Lent-Soma classification. Results Twenty-four patients received IORT only; eight patients because they had received previous radiotherapy, 16 because of a very favorable risk profile or their own preference. Thirty-three patients with tumor sizes between 1 and 30 mm and no risk factors were treated by IORT as a boost followed by EBRT. The Intrabeam™ system was used for IORT. The Intrabeam source produces 30–50 KV X-rays and the prescribed dose is delivered in an isotropic dose distribution around spherical applicators. Treatment time ranged between 20 and 48 minutes. No severe acute side effects or complications were observed during the first postoperative days or after 12 months. One local recurrence occurred 10 months after surgery plus IORT followed by EBRT. In two patients distant metastases were diagnosed shortly after BCS. Discussion IORT with the Intrabeam system is a feasible method to deliver a single high radiation dose to breast cancer patients. As a preliminary boost it has the advantage of reducing the EBRT course by 1.5 weeks, and as APBI it might be a promising tool for patients with a low risk of recurrence. The treatment is well tolerated and does not cause greater damage than the expected late reaction in normal tissue.

A revolution is challenging the dogma that local treatment for all patients with breast cancer treated with breast conservation therapy must include postoperative radiotherapy delivered to the whole breast. Such prolonged postoperative radiotherapy is a burden to patients and hospitals and forces many women to chose mastectomy instead. Furthermore, for patients receiving chemotherapy, the start of conventional radiotherapy may be delayed so long as to increase the risk of local relapse. These problems might be eliminated if effective radiotherapy could be given as a single treatment intraoperatively, immediately after the surgery. Local recurrence after breast-conserving surgery usually occurs in the portion of the breast in the immediate proximity of the tumor, even when radiotherapy is omitted. Therefore, it should usually be possible to restrict radiotherapy to only the area adjacent to the tumor in selected women. Based on this premise, we have devised a new technique of partial breast irradiation, with the intention of completing all local treatment in a single session. In this article, we elaborate on the rationale and on the different methods of delivering intraoperative radiotherapy. If this approach is validated in ongoing randomized trials, it could save time, money, and breasts.

Purpose To establish the feasibility and efficacy of capecitabine in combination with weekly irinotecan (CAPIRI) with concurrent pelvic radiotherapy (RT) in patients with locally advanced rectal cancer. Patients and Methods Nineteen patients with rectal cancer clinical stage T3-4, Nx received weekly irinotecan 50 mg/m2 (days 1, 8, 15, 22, 29) and two doses of capecitabine (days 1 through 38; dose level [DL] I, 500 mg/m2 bid; DL II, 625 mg/m2 bid) according to phase I methodology. Three-dimensional conformal RT was given to a dose of 50.4 Gy (45 Gy + 5.4 Gy). Results On DL I, no dose-limiting toxicities occurred, whereas diarrhea grade 3 affected three of seven patients on DL II. Twelve patients were treated on DL I and received a median relative dose-intensity of 100% for both drugs. Grade 3 or 4 adverse events were observed in only one of these patients (asthenia grade 3). All patients underwent surgery and R0 resection was achieved in all patients. Pathologic complete remission was observed in four patients and another five patients had only microfoci of residual tumor. Conclusion Preoperative chemoradiotherapy with CAPIRI is feasible and well tolerated. The preliminary efficacy is good, and the tolerability is at least comparable with data for fluorouracil plus irinotecan chemoradiotherapy. Larger phase II trials of the CAPIRI-RT schedule clearly are warranted.

The purpose of this study was to model the distribution of biological effect around a miniature isotropic X-ray source incorporating spherical applicators for single-dose or hypo-fractionated partial-breast intraoperative radiotherapy. A modification of the linear-quadratic formalism was used to calculate the relative biological effectiveness (RBE) of 50 kV X rays as a function of dose and irradiation time for late-reacting normal tissue and tumor cells. The response was modeled as a function of distance in the tissue based on the distribution of equivalent dose and published dose-response data for pneumonitis and subcutaneous fibrosis after single-dose conventional irradiation. Furthermore, the spatial distribution of tumor cell inactivation was assessed. The RBE for late reactions approached unity at the applicator surface but increased as the absorbed dose decreased with increasing distance from the applicator surface. The ED50 for pneumonitis was estimated to be reached at a depth of 6-11 mm in the tissue and that for subcutaneous fibrosis at 3-6 mm, depending on the applicator diameter and whether the effect of recovery was included. Thus lung tissue would be spared because of the thickness of the thorax wall. The RBE for tumor cells was higher than for late-reacting tissue. The applicator diameter is an important parameter in determining the range of tumor cell control in the irradiated tumor bed.

To disclose possible influences of alcoholic beverages on restenosis rate in men with coronary artery disease treated with percutaneous transluminal coronary angioplasty (PTCA) and stent implantation.Retrospective cohort study.225 consecutive male patients underwent PTCA and stent implantation. All patients had a control angiography and were contacted for a questionnaire regarding their drinking habits.Mean late loss of luminal diameter, rate of coronary restenosis of 50% or more within the stented segment, and rate of repeat angioplasty.53 patients (with 80 stents) consumed50 g of alcohol a week and 172 (with 266 stents) consumed more (50-700 g a week). Baseline characteristics were similar in both groups except for a higher prevalence of reduced cardiac function and multivessel disease and a lower high density lipoprotein cholesterol concentration among patients who consumed little or no alcohol. Patients who consumedor = 50 g alcohol a week had a lower mean late loss of the luminal diameter (1.1 (0.79) mm v 1.45 (0.82) mm, p = 0.002), a lower rate of coronary restenosis within the stented segment (33.7% v 48.8%, p = 0.001), and a lower rate of repeat angioplasty (23.3% v 42.5%, p = 0.002). In multivariate analysis, only alcohol consumption and diabetes were independent and significant discriminators for late loss of luminal diameter (p = 0.005 and p = 0.01, respectively), restenosis (odds ratio 0.54 and 2.08, respectively), and repeat angioplasty (odds ratio 0.39 and 2.18, respectively).Alcohol intake is associated with reduced restenosis after PTCA and stent implantation.

Purpose Data from the randomized Intergroup Trial 116 suggest effectiveness of adjuvant radiochemotherapy in patients with advanced gastric cancer. Late toxicity, however, especially with respect to the kidneys, may pose significant longtime problems. Intensity-modulated radiotherapy (IMRT) may reduce toxicity to organs at risk. To evaluate the relative merits of different IMRT approaches, we performed a plan comparison between a step-and-shoot class solution and an AP-PA setup, a conventional box technique and the Peacock tomotherapy approach. Methods and materials Computed tomographies and structure data from 15 patients who had been treated postoperatively for advanced (T3/T4/N+) gastric cancer at our department formed the basis of our plan comparison study. For each patient data set, 5 plans or plan combinations (conventional 3D plan, AP-PA plan, step-and-shoot IMRT, tomotherapy with 1-cm or 2-cm collimation) were chosen, and evaluation was performed for a total dose of 45 Gy delivered as the median dose to the target volume for each plan or plan combination. Results Median kidney dose generated from the IMRT plans is reduced individually by >50% for the kidney with the highest exposure (usually the left kidney) from 20 to 30 Gy with conventional 3D planning down to values between 8 and 10 Gy for IMRT. On average, median dose to the right kidney is the same for the conventional box technique and IMRT (between 8 and 10 Gy) but lower for the AP-PA technique. In 3 patients, kidney dose might have been ablative for both kidneys with both the AP-PA technique and the box technique, whereas it was acceptable with IMRT. Median dose to the liver was subcritical with all modalities but lowest with AP-PA fields. Differences between step-and-shoot IMRT and tomotherapy plans are small when compared to the differences between IMRT plans and conventional conformal 3D plans. For some patients, however, their body and target diameters obviate treatment with tomotherapy. Treatment time for the step-and-shoot approach and for tomotherapy with 2-cm collimation can be kept Conclusions For postoperative radiotherapy of advanced gastric cancer, step-and-shoot IMRT as well as tomotherapy can deliver efficient doses to target volumes while delivering dose to the kidneys in a fashion that is different from a conventional technique and is clearly advantageous in a small number of patients. An advantage for the majority of patients is likely with the normal tissue complication probability data presented in this series, but, given the uncertainty of the reaction of the kidney to inhomogeneous dose distributions, cannot be considered unequivocal at the moment. Different technical limitations apply to the different IMRT techniques. The choice of approach is therefore determined by departmental circumstances.

In patients with renal failure, myocardial infarction (MI) is more frequent and the rate of death from acute MI is very high. It has been argued that ischemia tolerance of the heart is reduced in uremia, but direct evidence for this hypothesis has not been provided. It was the purpose of this study (1) to ligate the left coronary artery and to measure the nonperfused area (risk area: total infarction plus penumbra) as well as the area of total infarction in subtotally nephrectomized (SNX) rats compared with sham-operated pair-fed control rats and (2) to examine the effects of potential confounders such as BP, sympathetic overactivity, and salt retention. The left coronary artery was ligated for 60 min, followed by reperfusion for 90 min. For visualizing perfused myocardium, lissamine green ink was injected. The nonperfused area (lissamine exclusion) and the area of total infarction (triphenyltetrazolium chloride stain) were assessed in sections of the left ventricle using image analysis. Groups of SNX rats also received: antihypertensive treatment (nadolol plus hydralazine); moxonidine; high salt diet or low salt diet (1.58% versus 0.015%). In surviving animals, the nonperfused area at risk (as the proportion of total left ventricular area), presumably determined by the geometry of vascular supply, was similar in sham-operated and SNX animals (0.38 +/- 0.13 versus 0.45 +/- 0.09; NS). In contrast, the infarcted area, given as a proportion of the nonperfused risk area, was significantly (P < 0.003) higher in SNX (0.68 +/- 0.09) compared with sham-operated (0.51 +/- 0.11) rats and was not altered by any of the above interventions. The finding that a greater proportion of nonperfused myocardium undergoes total necrosis is consistent with the hypothesis of reduced ischemia tolerance of the heart in renal failure. The findings could explain the high rate of death from MI in patients with impaired renal function.

Long-term treatment with angiotensin-converting enzyme (ACE) inhibitors as well as angiotensin II type 1 (AT1) receptor antagonists and statins reduces cardiovascular mortality in patients with coronary artery disease as well as chronic heart failure. Little is known about the acute effects of these compounds on vascular reactivity of coronary resistance vessels. Coronary arterioles were obtained from patients undergoing coronary bypass operation (atherosclerosis group) or valve replacement (control group). Responses to endothelium-dependent agonists (histamine, serotonin, and acetylcholine) as well as to the endothelium-independent agonist sodium nitroprusside (SNP) were investigated under baseline conditions and after incubation (15 min) with lisinopril (ACE inhibitor), candesartan (AT1 receptor antagonist), or fluvastatin. In atherosclerotic vessels, vasorelaxation was significantly reduced to all endothelium-dependent agonists but not, however, to SNP (77 ± 8, –24 ± 16, –46 ± 24, and 98 ± 8% relaxation for histamine, serotonin, acetylcholine, and SNP, respectively). Lisinopril and fluvastatin but not candesartan significantly improved the responses to the endothelium-dependent agonists (lisinopril: 94 ± 4, 17 ± 22, and –20 ± 13%; fluvastatin: 96 ± 8, 23 ± 21, and –25 ± 18% relaxation for histamine, serotonin, and acetylcholine, repectively). The effect of lisinopril was prevented by pretreatment with a bradykinin antagonist (HOE-130) and dichloroisocoumarine, an inhibitor of kinine-forming enzymes. Pretreatment with a nitric oxide (NO) synthase inhibitor abolished the improvement of endothelial function by lisinopril and fluvastatin. Vascular reactivity in the control group was not influenced by any of the pharmacological interventions. The data demonstrate that in atherosclerosis, endothelium-dependent relaxation of coronary resistance arteries is severely compromised. The impairment can acutely be reversed by ACE inhibitors and statins via increasing the availability of NO.

Mit der intensitatsmodulierten Strahlentherapie (IMRT) zusammen mit modernen, nichtinvasiven Lokalisationsverfahren steht eine Methodik zur Verfugung, mit der die konformale Bestrahlung des Prostatakarzinoms unter optimaler Schonung des Rektums potentiell verbessert werden kann.

Background: pH monitoring has been established as the “gold standard” in the diagnosis of gastroesophageal reflux. Evaluation of experimental antireflux therapy should therefore also include this technique, but a suitable technique in an experimental model did not exist so far. The aim of our study was to establish a reliable method for the evaluation of an experimental reflux model in pigs. Methods: A total of 33 German Landrace pigs with an average body weight of 56 (50.2–67.2) kg were included. pH monitoring was performed before and after open cardiomyotomy in each animal. All manipulations were performed under general anesthesia. After manometric localization of the gastroesophageal high-pressure zone, a standard pH probe was inserted into the pharynx through a small needle-punctured canal on the side of the animal’s snout and placed under endoscopic guidance with the proximal sensor 3 cm above the lower esophageal sphincter (LES) and the distal sensor in the stomach for reference. The harness to carry the pH recorder on the animal’s back consisted of a modified belly strap that enabled the animal to move around without limitation. For analysis the same threshold levels were defined as in humans. Gastroesophageal reflux was induced by cardiomyotomy. Results: The placement of the standard pH probe was possible in all cases. Inserting the probe on the side of the snout left the animals free to nuzzle, which complies with the normal habits of pigs, without breaking the probes and without being compromised in their natural behavior. Repeated punctures for multiple measurements were easily feasible. We performed up to three examinations in each individual animal. Recording was performed for 48 h. A mean number of 67.3 (±9.7) acidic refluxes were registered. The mean number of long acidic refluxes was 3.2 (±0.75). For an average total time of 75.5 (±14.3) min the pH was below 4 accounting for a fraction time pH below 4 of 3.5% (±0.68%). Following cardiomyotomy the number of acidic refluxes increased significantly to 166.1 (±21.8) and the number of long refluxes to 17.74 (±3.35). The total time of pH below 4 increased to 371.3 (±62) min so that the fraction time pH below 4 was 14.5% (p = 0.0006). Conclusion: pH monitoring should be mandatory in any investigation of antireflux therapy. Our method is easy and secure to perform. It is suitable for other gastrointestinal investigations (Bilitec, long-term manometry) that could be carried out using the same technique. The described data represent the basis for other investigations of experimental antireflux therapy.

A reduced availability of tetrahydrobiopterin (BH4), an essential cofactor for NO-synthesis, is causally involved in the development of endothelial dysfunction associated with ischemia/reperfusion. We, therefore, investigated the effect of sepiapterin, a substrate for BH4 synthesis, on postischemic injury in myocardial infarction and myocardial stunning. In rats, myocardial stunning was induced by repetitive ischemia (5 x 10-min ligature of the left coronary artery, 5 x 20-min reperfusion) and myocardial infarction by 50-min ligature and 60-min reperfusion. Myocardial blood flow was determined by H2-clearance, regional myocardial function by pulsed Doppler and infarct size by tetrazolium staining. Myeloperoxidase (MPO) activity was measured as a marker of neutrophil extravasation. cGMP was determined in rat serum as an indicator of increased NO synthesis. In animals treated with sepiapterin, regional myocardial function was significantly improved in both myocardial stunning and infarction and infarct size was significantly reduced. MPO activity decreased with sepiapterin treatment in both models. The systemic level of cGMP was reduced both following myocardial stunning and myocardial infarction in the control group. Pretreatment with sepiapterin induced a significant increase of cGMP level at the end of the protocol in both models. Substitution of sepiapterin reduces postischemic injury both in myocardial stunning and infarction apparently by ameliorating the availability of NO, thereby attenuating the activation of neutrophils in ischemia/reperfusion.

Objective: To investigate the prognostic value of induced monomorphic ventricular tachycardia (VT) and ventricular flutter or fibrillation (VF) during programmed electrical stimulation in patients with a high risk for sudden arrhythmogenic cardiac death. Design: Prospective cohort study. Patients: 102 patients at high risk for arrhythmogenic sudden cardiac death who received an automated implantable cardioverter-defibrillator (AICD) were evaluated. 56 patients received the AICD for primary prevention and 46 for secondary prevention. 58 patients had induction of a monomorphic VT (VT group) and 44 had induction of a polymorphic VT, ventricular flutter, or ventricular fibrillation (VF group) during programmed electrical stimulation. Average follow up was 20 months in both groups. Main outcome measures: Appropriate AICD protocol. Results: In patients who received the AICD for primary prevention, 16 of 32 patients in the VT group, compared with only four of 24 patients in the VF group, received an appropriate AICD protocol (p = 0.02). In the entire study population, 479 appropriate AICD protocols were recorded in 28 (48%) patients in the VT group and 28 appropriate protocols in 11 (25%) patients in the VF group. Cumulative Kaplan-Meier event-free survival curves were significantly different (p = 0.02). Conclusion: Induction of VF during programmed electrical stimulation is of no prognostic value even in high risk patients without previously documented ventricular fibrillation.

Stenosis of the internal carotid arteries is one of the leading causes of ischemic stroke. With increasing age of the general population, both physicians and patients have to increasingly face that problem, which is often found accidentally for example in the context of a routine checkup examination. In patients over seventy years, the incidence of carotid artery stenosis is about 15%. Principally, there are three options for the treatment of carotid artery stenosis: 1) best medical treatment, 2) operative revision by endarterectomy and 3) interventional therapy via stent implantation. Based on technical development and new scientific data, there has been tremendous progress of all three treatment strategies in the last few years. Therefore, the results of prior trials must not necessarily be considered when choosing a treatment option for the patient. The choice of therapy for the individual patient must take into account a number of criteria, such as grade of stenosis, symptoms, patient age, concomitant disease, anatomical conditions and patients' preference. Recently, a number of clinical trials have been performed to compare operative versus interventional treatment. The results of these studies led to some answers, but there are questions remaining which need to be clarified. The present article gives a brief overview and comment on the current status of treatment strategies of internal carotid artery stenosis based on the recent literature.

To evaluate the 1-year patency of the 4-F Pulsar-18 self-expanding nitinol stent for treatment of femoropopliteal occlusive disease in a national, prospective, multicenter, all-comers registry.Between January and June 2012, the German PEACE I all-comers prospective registry enrolled 148 patients with symptomatic femoropopliteal lesions (Rutherford category 2-5) undergoing recanalization and implantation of the Pulsar-18 SE nitinol stent at 6 clinical centers. Thirty patients did not have the 12-month follow-up visit (18 declined reevaluation, 5 withdrew consent, and 7 died), leaving 118 patients (64 men; mean 71.9±9.6 age years) for the 1-year evaluation. The average lesion length was 111.5±71.4 mm, and 38 of the 118 lesions were classified as TASC II D. More than half the lesions (67, 56.7%) were chronic total occlusions (CTO). The popliteal segment was involved in 22 (18.7%) lesions. The mean stented length was 122.7±64.5 mm. Routine follow-up included duplex ultrasound at 6 and 12 months. Outcome measures were primary patency and no clinically driven target lesion revascularization (TLR) within 12 months.The overall primary patency rates after 6 and 12 months were 87.4% and 79.5%, respectively; in the popliteal segments, the rate was 71.4% after 12 months. The overall freedom from TLR was 93.2% after 6 months and 81% after 12 months. Ankle-brachial index, pain-free walking distance, and Rutherford category all improved significantly (p0.0001) after 6 and 12 months. The primary patency rates in patients with diabetes (p=1.0) and those with renal insufficiency (p=0.8) were not significantly lower compared to the overall rate. There was no significant difference (p=0.67) in restenosis rate for recanalization of CTOs compared to non-CTO lesions.In this all-comers registry, the use of the Pulsar-18 self-expanding nitinol stent in femoropopliteal lesions averaging 111.5 mm long showed promising primary patency and freedom from TLR after 6 and 12 months. Diabetes had no negative impact on patency. Primary patency in the popliteal segments was acceptable at 12 months.

a number of vascular pathologies leads to an alteration of the physiology of endothelial cells, which is generally described as endothelial dysfunction. Endothelial dysfunction is found in basically all known major risk factors of atherosclerosis such as hypercholesterolemia, nicotin abuse

Local recurrence following potentially curative tumor resection is a major problem in patients with gastrointestinal cancer. To augment surgical excision and to avoid the disadvantages of external beam irradiation, intraoperative radiotherapy (IORT) has been applied to primary and recurrent gastrointestinal cancer, both with curative intent and for palliation. There is ample evidence that the combination of radical surgery and IORT can improve local control. Whether this eventually can translate into improved overall survival has not yet been studied in adequately powered randomized and controlled trials. Semin. Surg. Oncol. 20:40–49, 2001. © 2001 Wiley-Liss, Inc.