Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Analyzing medical device connectivity and its effect on cyber security in german hospitals

Background: Modern healthcare devices can be connected to computer networks and many western healthcare institutions run those devices in networks. At the same time, cyber attacks are on the rise and there is evidence that cybercriminals do not spare critical infrastructure such as major hospitals, even if they endanger patients. Intuitively, the more and closer connected healthcare devices are to public networks, the higher the risk of getting attacked. Methods: To asses the current connectivity status of healthcare devices, we surveyed the field of German hospitals and especially University Medical Center UMCs. Results: The results show a strong correlation between the networking degree and the number of medical devices. The average number of medical devices is 25.150, with a median of networked medical devices of 3.600. Actual key users of networked medical devices are the departments Radiology, Intensive Care, Radio-Oncology RO, Nuclear Medicine NUC, and Anaesthesiology in the group of UMCs. In the next five years, the usage of networked medical devices will increase significantly in the departments of Surgery, Intensive Care, and Radiology. We detected a strong correlation between the degree of connectivity and the likelihood of being attacked. The survey answers regarding the cyber security status reveal a lack of security basics in some of the inquired hospitals. We did discover successful attacks in hospitals with separated or subsidiary departments. A fusion of competencies on an organizational level facilitates the right behavior here. Most hospitals rated themselves predominantly positively in the self-assessment but also stated the usefulness of IT security insurance. Conclusions: Concluding our results, hospitals are already facing the consequences of omitted measures within their growing pool of medical devices. Continuously relying on historically grown structures without adaption and trusting manufactures to solve vectors is a critical behavior that could seriously endanger patients

In-vivo dosimetric analysis in total skin electron beam therapy

BACKGROUND AND PURPOSE: Thermoluminescent dosimetry (TLD) is an important element of total skin electron beam therapy (TSEBT). In this study, we compare radiation dose distributions to provide data for dose variation across anatomic sites. MATERIAL AND METHODS: Retrospectively collected data on 85 patients with cutaneous lymphoma or leukemia underwent TSEBT were reviewed. Patients were irradiated on two linear accelerators, in one of two positions (standing, n=77; reclined, n=8) and 1830 in vivo TLD measurements were obtained for various locations on 76 patients. RESULTS: The TLD results showed that the two TSEBT techniques were dosimetrically heterogeneous. At several sites, the dose administered correlated with height, weight, and gender. After the first TLD measurement, fourteen patients (18%) required MU modification, with a mean 10% reduction (range,−25 to +35). Individual TLD results allowed us to customize the boost treatment for each patient. For patients who were evaluated in the standing position, the most common underdosed sites were the axilla, perineum/perianal folds, and soles (each receiving 69%, 20%, and 34% of the prescribed dose, respectively). For patients evaluated in a reclining position, surface dose distribution was more heterogeneous. The sites underdosed most commonly were the axilla and perineum/perianal folds (receiving less than one third of prescribed dose). Significant variables were detected with model building. CONCLUSION: TLD measurements were integral to quality assurance for TSEBT. Dose distribution at several anatomical sites correlated significantly with gender, height, and weight of the treated individual and might be predicted

Biophysical Analysis of Acute and Late Toxicity of Radiotherapy in Gastric Marginal Zone Lymphoma—Impact of Radiation Dose and Planning Target Volume

Successful studies on radiation therapy for gastric lymphoma led to a decrease in planning target volume (PTV) and radiation dose with low toxicities, maintaining excellent survival rates. It remains unclear as to which effects are to be expected concerning dose burden on organs at risk (OAR) by decrease in PTV vs. dose and whether a direct impact on toxicity might be expected. We evaluated 72 radiation plans, generated prospectively for a cohort of 18 patients who were treated for indolent gastric lymphoma in our department. As a prospective work, four radiation plans with different radiation doses and target volumes (40 Gy-involved field, 40 Gy-involved site, 30 Gy-involved field, 30 Gy-involved site) were generated for each patient. Mean dose burden on adjacent organs was compared between the planning groups. Cohort toxicity data served to estimate parameters for the Lyman–Kutcher–Burman (LKB) model for normal tissue complication probability (NTCP). These were used to anticipate adverse events for OAR. Literature parameters were used to estimate high-grade toxicities of OAR. Decrease of dose and/or PTV led to median dose reductions between 0.13 and 5.2 Gy, with a significant dose reduction on neighboring organs. Estimated model parameters for liver, spleen, and bowel toxicity were feasible to predict cohort toxicities. NTCP for the endpoints elevated liver enzymes, low platelet count, and diarrhea ranged between 15.9 and 22.8%, 27.6 and 32.4%, and 21.8 and 26.4% for the respective four plan variations. Field and dose reduction highly impact dose burden and NTCP for OAR during stomach radiation. Our estimated LKB model parameters offer a good approximation for low-grade toxicities in abdominal organs with modern radiation techniques

The Lymph-Sparing Quotient: A Retrospective Risk Analysis on Extremity Radiation for Soft Tissue Sarcoma Treatment

Radiation therapy (RT) for extremity soft tissue sarcoma is associated with lymphedema risk. In this study, we analyzed the influence of lymph-sparing volume on the lymphedema occurrence in patients who received adjuvant extremity RT. The lymph-sparing quotient (LSQ) was calculated by dividing the lymph-sparing volume by the total extremity volume with double weightingfor the narrowest lymph-sparing region. A total of 34 patients were enrolled in this analysis. The median applied total radiation dose was 66.3 Gy in 36 fractions. Acute lymphedema appeared in 12 patients (35%). Most of them (n = 8) were lymphedema grade 1 and five patients had grade 2 to 3 lymphedema. Chronic lymphedema appeared in 22 patients (65%). 17 of these patients had at least a grade 2 lymphedema. In 13 of 14 patients with an LSQ ≤ 0.2 and 11 of 20 patients with an LSQ > 0.2, an acute or chronic lymphedema ≥ grade 2 was observed. A Kaplan–Meier Analysis of the two groups with the endpoint of a two-year lymph edema-free survival (=2-YLEFS) was estimated with an univariate, significant result (2-YLEFS LSQ ≤ 0.2 vs. LSQ > 0.2: 0% vs. 39%; p = 0.006; hazard ratio LSQ ≤ 0.2 vs. > 0.2 2-YLEFS 2.822 (p = 0.013); 95% confidence interval (CI): 1.24–6.42). Maximizing the potential oncologically-justifiable lymph-sparing volume should be considered to reduce the risk of high-grade lymphedema when applying RT to extremities

Toxicity Reduction after Craniospinal Irradiation via Helical Tomotherapy in Patients with Medulloblastoma: A Unicentric Retrospective Analysis

Objectives: Recent trials with craniospinal irradiation (CSI) via helical Tomotherapy (HT) demonstrated encouraging medulloblastoma results. In this study, we assess the toxicity profile of different radiation techniques and estimate survival rates. Materials and Methods: We reviewed the records of 46 patients who underwent irradiation for medulloblastoma between 1999 and 2019 (27 conventional radiotherapy technique (CRT) and 19 HT). Patient, tumor, and treatment characteristics, as well as treatment outcomes—local control rate (LCR), event-free survival (EFS), and overall survival (OS)—were reviewed. Acute and late adverse events (AEs) were evaluated according to the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria. Results: In total, 43 courses of CSI and three local RT were administered to the 46 patients: 30 were male, the median age was 7 years (range 1–56). A median total RT dose of 55 Gy (range 44–68) and a median CSI dose of 35 Gy (range, 23.4–40) was delivered. During follow-up (median, 99 months), six patients (13%) developed recurrence. The EFS rate after 5 years was 84%. The overall OS rates after 5 and 10 years were 95% and 88%, respectively. There were no treatment-related deaths. Following HT, a trend towards lower grade 2/3 acute upper gastrointestinal (p = 0.07) and subacute CNS (p = 0.05) toxicity rates was detected compared to CRT-group. The risk of late CNS toxicities, mainly grade 2/3, was significantly lower following HT technique (p = 0.003). Conclusion: CSI via HT is an efficacious treatment modality in medulloblastoma patients. In all, we detected a reduced rate of several acute, subacute, and chronic toxicities following HT compared to CRT

Using Image-guided Intensity-modulated Radiotherapy on Patients With Head and Neck Soft-tissue Sarcoma

BACKGROUND: Image-guided intensity-modulated radiotherapy (IG-IMRT) is increasingly being used to treat patients with soft-tissue sarcoma (STS) of the head and neck. Although there is no comparison between IMRT and conventional radiation therapy (CRT) concerning their efficacy. In this analysis, we compared CRT and IMRT outcomes for head and neck STS. PATIENTS AND METHODS: Sixty-seven patients who underwent radiotherapy between 1994 and 2017 were identified. RESULTS: The median follow-up was 31 months. Of the 67 patients, 34% were treated with CRT technique and 66% with IG-IMRT. The locoregional relapse rate following IMRT was 21% versus 70% with CRT (p < 0.001) and the 5-year locoregional control was 69% versus 28%, respectively (p = 0.01). IG-IMRT was associated with non-significant, less acute, and chronic adverse events. In the multivariate analysis, a significant influence of radiation technique on locoregional control was confirmed (p = 0.04). CONCLUSION: IG-IMRT seems to be associated both with higher locoregional control as well as lower acute and chronic toxicities

Radiotherapy in the GHSG HD 16 and HD 17 trials – quality assurance and dosimetric analysis for Hodgkin lymphoma in the modern era

Introduction: Radiotherapy (RT) is an integral part of treatment concepts for early-stage Hodgkin lymphoma. The following analysis reports on RT-quality in the recent HD16 and 17 trials of the German Hodgkin Study Group (GHSG). Methods: All RT-plans of involved-node RT (INRT) in HD 17 were requested for analysis, along with 100 and 50 involved-field RT (IFRT) plans in HD 16 and 17, respectively. A structured assessment regarding field design and protocol adherence was performed by the reference radiation oncology panel of the GHSG. Results: Overall, 100 (HD 16) and 176 (HD 17) patients were eligible for analysis. In HD 16, 84 % of RT series were evaluated as correct, with significant improvement compared to the predecessor studies (p< 0.001). In HD 17, 76.1 % of INRT-cases revealed a correct RT design compared to 69.1 % of IFRT-cases, which was superior to prior studies (p<0.001). Comparing INRT and IFRT, no significant differences in the percentage of any deviation (p=0.418) or major deviation (p=0.466) could be found. Regarding dosimetry, INRT was accompanied by an improvement in thyroid doses. Comparing different RT techniques, intensity modulated RT showed a reduction of high doses in the lung at the expense of an increased low-dose exposure in HD 17. Discussion: The latest study generation of the GHSG demonstrates an improved quality in RT. A modern INRT design could be established without deterioration in quality. On a conceptual level, an individual consideration of the appropriate RT technique has to be performed