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Hintergrund: Den derzeitigen Therapiestandard in der Behandlung des lokal begrenzten Prostatakarzinoms stellen die radikale Prostatektomie und perkutane Radiotherapie dar. Aufgrund der besonderen Strahlenbiologie des PCa (α-/β-Wert 1,5 Gy) ist von einer höheren Sensitivität gegenüber einer Hypofraktionierung auszugehen. Die aktuellen Literaturdaten zeigen eine Nichtunterlegenheit der moderaten Hypofraktionierung gegenüber dem konventionellen Regime, jedoch sind Langzeitergebnisse hinsichtlich der Spättoxizität noch spärlich. In dieser Arbeit werden onkologische Ergebnisse sowie GI-/ und GU-Toxizität nach moderat hypofraktionierter, intensitätsmodulierter (IMRT/VMAT) und bildgeführter (IGRT) Radiotherapie mit simultan integriertem Boost (SIB) in einem universitären Tumorzentrum untersucht.
Patienten und Methoden: In den Jahren 2010 bis 2016 wurden an der Uniklinik Frankfurt 170 Patienten mit histologisch gesichertem lokal begrenzten bis fortgeschrittenen PCa (T1-4, N0-1, M0) mittels moderat hypofraktionierter EBRT in IG-IMRT- bzw. IG-VMAT- und SIB-Technik behandelt. Alle Patienten wurden nach D’Amico-Klassifikation stratifiziert und risikoadaptiert therapiert. Die GI- und GU-Toxizität wurde gemäß CTC v4.0 wöchentlich unter der Therapie und während der Nachbeobachtungszeit erfasst. Ein biochemisches Rezidiv wurde definiert als PSA-Nadir + 2 ng/ml. Die Nachbeobachtung erfolgte 6-8 Wochen, 2-3 Monate und 6 Monate nach Radiotherapie sowie anschließend mindestens einmal jährlich. Die Datenauswertung erfolgte retrospektiv. Für die statistischen Analysen wurden die Software-Programme Excel und SPSS verwendet. Die Kaplan-Meier-Überlebensanalysen wurden mittels Log-Rank-Test verglichen und bei signifikanten Unterschieden in eine Cox-Regression-Analyse aufgenommen. Ein möglicher Zusammenhang zwischen dosimetrischen/klinischen Parametern und GI-/GU-Toxizität wurde mittels Chi-Quadrat-Test nach Pearson geprüft. Für alle durchgeführten Analysen galt ein p-Wert von <0,05 als statistisch signifikant. Ergebnisse: Patienten der low-risk- (n = 15) sowie intermediate- und high-risk-Gruppe mit Z.n. TURP (n= 14) erhielten eine GRD von 73,6 Gy für das PTV1 bzw. 58,24 Gy (PTV2) mit einer Einzeldosis von 2,3 Gy (SIB) bzw. 1,82 Gy in 32 Fraktionen. Patienten der intermediate- (n = 70) und high-risk- (n = 71) Gruppe erhielten eine GRD von 75,9 Gy (PTV1) bzw. 60,06 Gy (PTV2) mit einer Einzeldosis von 2,3 Gy (SIB) bzw. 1,82 Gy in 33 Fraktionen. Eine zusätzliche Bestrahlung des LAG (PTV3) mit einer GRD von 46,0 Gy und 1,84 Gy Einzeldosis in 25 Fraktionen erhielten alle Patienten mit radiologischer cN1-Situation bzw. im Falle eines LK-Befallsrisikos von >20% nach Roach-Formel (n = 86). Eine (neo-) adjuvante AHT erhielten insg. 98 Patienten. Die mediane Nachbeobachtungszeit betrug 36 Monate (Range: 5-84 Monate). Die 24-, 36-, und 60-Monate-ÜLR lagen in der IR-Gruppe bei 98,4%, 96,1% bzw. 89,7% (OS), 98,6% bzw. 94,9% (BC), 97% bzw. 84,5% (DFS) und 98,6% (FFM), in der HR-Gruppe bei 93,1% bzw. 88,8% (OS), 89%, 84,7% bzw. 75,3% (BC), 82,5%, 74,2% bzw. 65,9% (DFS) und 98%, 95,7% bzw. 84,8% (FFM). Weder für die AHT noch die RT des LAG konnte eine Verbesserung des OS, DFS, FFM sowie der BC gezeigt werden. Eine Akuttoxizität Grad 2 trat bei 6,5% (GI) bzw. 16,5% (GU) und Grad 3 bei 0,6% (GI) bzw. 0% (GU) auf. Eine Spättoxizität Grad 2 trat bei 2,9% (GI) bzw. 12,4% (GU) und Grad 3 bei 0,6% (GI) bzw. 1,2% (GU) auf.
Schlussfolgerung: Mit Implementierung der moderat hypofraktionierten EBRT nach o.g. Schema (73,6 Gy (79,9 Gy nach EQD2 (αβ 1,5)) bzw. 75,9 Gy (82,4 Gy nach EQD2 (αβ 1,5)) konnten im Rahmen dieser retrospektiven Kohortenstudie sehr gute Ergebnisse für intermediate- und high risk-Patienten des lokal begrenzten bis fortgeschrittenen PCa hinsichtlich der onkologischen Endpunkte sowie der GI-/GU-Toxizität, vergleichbar mit den besten Ergebnissen aktueller Publikationen, erzielt werden. Diese Ergebnisse bekräftigen die zunehmende Anwendung dieser Bestrahlungstechnik. Die Kohorte sollte zur Validierung der Ergebnisse weiter expandiert und mit einer längeren Nachbeobachtungszeit erneut ausgewertet werden.
Objective: Severely injured patients frequently develop an immunological imbalance following the traumatic insult, which might result in infectious complications evoked by a persisting immunosuppression. Regulatory T cells (Tregs) maintain the immune homeostasis by suppressing proinflammatory responses, however, their functionality after trauma is unclear. Here, we characterized the role of Tregs in regulating the proliferation of CD4+ lymphocytes in traumatized patients (TP). Methods: Peripheral blood was obtained daily from 29 severely injured TP (Injury Severity Score, ISS ≥16) for ten days following admission to the emergency department (ED). Ten healthy volunteers (HV) served as controls. The frequency and activity of Tregs were assessed by flow cytometry. Proliferation of CD4+ cells was analyzed either in presence or absence of Tregs, or after blocking of either IL-10 or IL-10R1. Results: The frequencies of CD4+CD25high and CD4+CD25+CD127− Tregs were significantly decreased immediately upon admission of TP to the ED and during the following 10 post-injury days. Compared with HV CD4+ T cell proliferation in TP increased significantly upon their admission and on the following days. As expected, CD4+CD25+CD127− Tregs reduced the proliferation of CD4+ cells in HV, nevertheless, CD4+ proliferation in TP was increased by Tregs. Neutralization of IL-10 as well as blocking the IL-10R1 increased further CD4+ T cell proliferation in Tregs-depleted cultures, thereby confirming an IL-10-mediated mechanism of IL-10-regulated CD4+ T cell proliferation. Neutralization of IL-10 in TP decreased CD4+ T cell proliferation in Tregs-depleted cultures, whereas blocking of the IL-10R1 receptor had no significant effects. Conclusions: The frequency of Tregs in the CD4+ T lymphocyte population is reduced after trauma; however, their inductiveness is increased. The mechanisms of deregulated influence of Tregs on CD4+ T cell proliferation are mediated via IL-10 but not via the IL-10R1.
Background: Lung disease phenotype varies widely even in the F508del (homozygous) genotype. Leukocyte-driven inflammation is important for pulmonary disease pathogenesis in cystic fibrosis (CF). Blood cytokines correlate negatively with pulmonary function in F508del homozygous patients, and gap junction proteins (GJA) might be related to the influx of blood cells into the lung and influence disease course. We aimed to assess the relationship between GJA1/GJA4 genotypes and the clinical disease phenotype. Methods: One-hundred-and-sixteen homozygous F508del patients (mean age 27 years, m/f 66/50) were recruited from the CF centers of Bonn, Frankfurt, and Amsterdam. Sequence analysis was performed for GJA1 and GJA4. The clinical disease course was assessed over 3 years using pulmonary function tests, body mass index, Pseudomonas aeruginosa colonization, diabetes mellitus, survival to end-stage lung disease, blood and sputum inflammatory markers. Results: Sequence analysis revealed one clinically relevant single nucleotide polymorphism. In this GJA4 variant (rs41266431), homozygous G variant carriers (n = 84/116; 72.4%) had poorer pulmonary function (FVC% pred: mean 78/86, p < 0.040) and survival to end-stage lung disease was lower (p < 0.029). The frequency of P. aeruginosa colonization was not influenced by the genotype, but in those chronically colonized, those with the G/G genotype had reduced pulmonary function (FVC% pred: mean 67/80, p < 0.049). Serum interleukin-8 (median: 12.4/6.7 pg/ml, p < 0.052) and sputum leukocytes (2305/437.5 pg/ml, p < 0.025) were higher for the G/G genotype. Conclusions: In carriers of the A allele (27.6%) the GJA4 variant is associated with significantly better protection against end-stage lung disease and superior pulmonary function test results in F508del homozygous patients. This SNP has the potential of a modifier gene for phenotyping severity of CF lung disease, in addition to the CFTR genotype.
Clinical Trial Registration: The study was registered with ClinicalTrials.gov, number NCT04242420, retrospectively on January 24th, 2020.
Background: The number of implantable cardioverter defibrillator (ICD) infections is increasing due to an increased number of ICD implants, higher-risk patients, and more frequent replacement procedures, which carry a higher risk of infection. Reducing the morbidity, mortality, and cost of ICD-related infections requires an understanding of the current rate of this complication and its predictors.
Methods: The Shock Implant Evaluation Trial (SIMPLE) trial randomized 2500 ICD recipients to defibrillation testing or not. Over an average of 3.1 years, patients were seen every 6 months and examined for evidence of ICD infection, which was defined as requiring device removal and/or intravenous antibiotics.
Results: Within 24 months, 21 patients (0.8%) developed infection. Fourteen patients (67%) with infection presented within 30 days, 20 patients by 12 months, and only 1 patient beyond 12 months. Univariate analysis demonstrated that patients with primary electrical disorders (3 patients, P = 0.009) and those with a secondary prevention indication (13 patients, P = 0.0009) were more likely to develop infection. Among the 2.2% of patients who developed an ICD wound hematoma, 10.4% developed an infection. Among the 8.3% of patients requiring an ICD reintervention, 1.9% developed an infection.
Conclusions: This cohort of ICD recipients at high-volume centres have a low risk of device-related infection. However; strategies to reduce wound hematoma and the need for ICD reintervention could further reduce the rate of infection.
Background: A web-based malaria reporting information system (MRIS) has the potential to improve malaria reporting and management. The aim of this study was to evaluate the existing manual paper-based MRIS and to provide a way to overcome the obstacles by developing a web-based MRIS in Indonesia.
Methods: An exploratory study was conducted in 2012 in Lahat District, South Sumatra Province of Indonesia. We evaluated the current reporting system and identified the potential benefits of using a web-based MRIS by in-depth interviews on selected key informants. Feasibility study was then conducted to develop a prototype system. A web-based MRIS was developed, integrated and synchronized, with suitability ranging from Primary Healthcare Centres (PHCs) to the Lahat District Health Office.
Results: The paper-based reporting system was sub-optimal due to a lack of transportation, communication, and human capacity. We developed a web-based MRIS to replace the current one. Although the web-based system has the potential to improve the malaria reporting information system, there were some barriers to its implementation, including lack of skilled operators, computer availability and lack of internet access. Recommended ways to overcome the obstacles are by training operators, making the application in an offline mode and able to be operated by mobile phone text messaging for malaria reporting.
Conclusion: The web-based MRIS has the potential to be implemented as an enhanced malaria reporting information system and investment in the system to support timely management responses is essential for malaria elimination. The developed application can be cloned to other areas that have similar characteristics and MRIS with a built-in web base to aid its application in the 5G future.
Introduction: In patients with severe pelvic ring injuries, exsanguination still is the leading cause of death in the early post-injury phase. While mechanical pelvic ring stabilization and pre-peritoneal pelvic packing are mainly addressing venous bleeding, angio-embolization aims to control arterial bleeding. The goal of the present study was to evaluate the rate of postoperative angio-embolization after mechanical pelvic ring injury stabilization and pre-peritoneal pelvic packing. Bleeding sources detected in the angiography and the patient's outcome were investigated. Patients and Methods: Retrospective observational cohort study at a single academic level I trauma center, reviewing all patients with pelvic ring injuries admitted from 01/2010 to 12/2019. Patients with emergent mechanical pelvic ring stabilization (supraacetabular external fixator and/or pelvic C-clamp) and direct pre-peritoneal pelvic packing were further analyzed. Patients that underwent postoperative angio-embolization were compared with those that did not. All postoperative angio-embolizations were evaluated with regards to bleeding sources and type of embolization. Results: During the study period, a total of 39 patients required immediate mechanical pelvic stabilization and direct pre-peritoneal pelvic packing. Of these, 12 patients (30.8%) underwent a postoperative angio-embolization. The following vessels were identified as bleeding sources: superior gluteal artery (n = 6), obturator artery (n = 2), internal pudendal artery (n = 2), unnamed branches of the internal iliac artery (n = 3). A selective embolization was successful in 11 patients; in 1 patient, an unilateral complete occlusion of the internal iliac artery was performed to control the bleeding. Mean time from hospital admission to the surgical procedure was 52.8 ± 14.7 min and the mean time from admission to angio-embolization was 189.1 ± 55.5 min. The in-hospital mortality rate of patients with angio-embolization was 25.0% (n = 3). Of these, 2 patients died due to multiple organ failure and 1 patient due to severe head injury. Conclusion: Secondary angio-embolization after external pelvic fixation and pre-peritoneal pelvic packing was effective in controlling ongoing bleeding. The most frequently detected bleeding vessel was the superior gluteal artery, which is difficult to surgically address, further highlighting the importance of angio-embolization in the management algorithm.
NIMA (never-in-mitosis gene A)-related kinase 1 (Nek1) is shown to impact on different cellular pathways such as DNA repair, checkpoint activation, and apoptosis. Its role as a molecular target for radiation sensitization of malignant cells, however, remains elusive. Stably transduced doxycycline (Dox)-inducible Nek1 shRNA HeLa cervix and siRNA-transfected HCT-15 colorectal carcinoma cells were irradiated in vitro and 3D clonogenic radiation survival, residual DNA damage, cell cycle distribution, and apoptosis were analyzed. Nek1 knockdown (KD) sensitized both cell lines to ionizing radiation following a single dose irradiation and more pronounced in combination with a 6 h fractionation (3 × 2 Gy) regime. For preclinical analyses we focused on cervical cancer. Nek1 shRNA HeLa cells were grafted into NOD/SCID/IL-2Rγc−/− (NSG) mice and Nek1 KD was induced by Dox-infused drinking water resulting in a significant cytostatic effect if combined with a 6 h fractionation (3 × 2 Gy) regime. In addition, we correlated Nek1 expression in biopsies of patients with cervical cancer with histopathological parameters and clinical follow-up. Our results indicate that elevated levels of Nek1 were associated with an increased rate of local or distant failure, as well as with impaired cancer-specific and overall survival in univariate analyses and for most endpoints in multivariable analyses. Finally, findings from The Cancer Genome Atlas (TCGA) validation cohort confirmed a significant association of high Nek1 expression with a reduced disease-free survival. In conclusion, we consider Nek1 to represent a novel biomarker and potential therapeutic target for drug development in the context of optimized fractionation intervals.
The interleukin (IL)-1 family has been described for its numerous involvement in the regulation of inflammatory processes. Certain members are able to induce inflammation, whereas others have the capacity to inhibit inflammation. The newly discovered IL-1 family member IL-38 shows interesting and innovative properties. While most of these cytokines are pro-inflammatory mediators, IL-38 appears to enter the smaller circle of anti-inflammatory mediators. As a pattern, IL-38 appears to suppress IL-17-driven chronic or auto-inflammation by working as receptor antagonist. These properties, as well as its beneficial effects in models of inflammatory and autoimmune diseases suggest the possibility of IL-38-based therapies. Nevertheless, its role in the resolution of acute inflammation, thereby preventing chronic inflammation, remains unclear.
The first part of my thesis elucidated the role of IL-38 in the resolution of inflammation. I found that the complete absence of IL-38 in IL-38 KO mice leads to a delayed resolution of inflammation in the zymosan-induced peritonitis mouse model, compared to WT mice. This was marked by a persistent neutrophilia and a lower production of pro-resolving mediators during the resolution phase, such as TGFβ1 production from macrophages following efferocytosis of apoptotic cells. Reduced TGFβ1 production from macrophages coincided with reduced levels of regulatory T cells (Tregs), which are known to promote the resolution of inflammation. Unexpectedly, the TGFβ1 production capacity of macrophages did not influence the induction of Tregs from naïve T cells. Rather, IL-38 KO mice had an accumulation of Tregs in the thymus compared to WT mice. This was caused by an impairment of CD62L expression at the surface of Tregs, which is required for Tregs migration outside of the thymus. Higher Treg numbers in the thymus correlated with lower level of Tregs in peripheral lymphoid organs. Importantly, CD62L expression at the surface of IL-38 KO Tregs in the thymus was restored by injecting IL-38 i.p. for 24h. These data indicate a potential key function of IL-38 in the regulation of Treg migration, which is triggered in many cases of autoimmunity.
The second part of my thesis was to study the role of IL-38 in experimental autoimmune encephalomyelitis (EAE) development, given that EAE is IL-17-dependent. Unexpectedly, IL-38-deficient mice showed strongly reduced clinical scores and histological markers of EAE. This came with reduced inflammatory cell infiltrates, as well as reduced expression of inflammatory markers in the spinal cord. IL-38 mRNA was detected in the spinal cord, mainly by resident and infiltrated phagocytes, but also by other cells, such as ependymal cells. IL-38 was upregulated upon pro-inflammatory stimulation of bone marrow-derived macrophages, and its presence was necessary for a complete activation of inflammatory macrophages. My data suggest an alternative cell-intrinsic role of IL-38 in macrophages to promote inflammation in the central nervous system.
In the last part of my thesis, I initiated a project on the function of IL-38 in B cell physiology and antibody production, given the fact that IL-38 is expressed by B cells. I generated preliminary data showing that the absence of IL-38 in mice decreased antibody production. Furthermore, I showed that IL-38 is particularly expressed by plasma cells in human tonsils. This project remains open and further studies will be conducted to investigate how IL-38 regulates antibody production, both in physiological and autoimmune settings. Understanding the role of IL-38 in autoantibody production could lead to original and innovative therapy for patients suffering from auto-inflammatory disease.
In summary, the different projects of my thesis provide evidence that the pro-resolving function of IL-38 may be indirectly linked to the retention of Tregs in the thymus. Moreover, a possible intracellular role of IL-38 within macrophages was described showing opposite properties in the regulation of inflammation. This function could be causatively involved in EAE development. However, further studies remain to be done to find the mechanism of action by which IL-38 regulates Tregs egression and how it influences the EAE development. Complete understanding of the IL-38 biology and differentiation between its extra- vs potential intracellular functions could make it a promising therapeutic target for chronic inflammatory or autoimmune diseases.
Beyond their role in pathogen recognition and the initiation of immune defense, Toll-like receptors (TLRs) are known to be involved in various vascular processes in health and disease. We investigated the potential of the lipopeptide and TLR2/6 ligand macrophage activating protein of 2-kDA (MALP-2) to promote blood flow recovery in mice. Hypercholesterolemic apolipoprotein E (Apoe)-deficient mice were subjected to microsurgical ligation of the femoral artery. MALP-2 significantly improved blood flow recovery at early time points (three and seven days), as assessed by repeated laser speckle imaging, and increased the growth of pre-existing collateral arteries in the upper hind limb, along with intimal endothelial cell proliferation in the collateral wall and pericollateral macrophage accumulation. In addition, MALP-2 increased capillary density in the lower hind limb. MALP-2 enhanced endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) release from endothelial cells and improved the experimental vasorelaxation of mesenteric arteries ex vivo. In vitro, MALP-2 led to the up-regulated expression of major endothelial adhesion molecules as well as their leukocyte integrin receptors and consequently enhanced the endothelial adhesion of leukocytes. Using the experimental approach of femoral artery ligation (FAL), we achieved promising results with MALP-2 to promote peripheral blood flow recovery by collateral artery growth.
Aim: Our aim was to analyse the diagnostic workup of hospitalised infants with symptoms of congenital cytomegalovirus (CMV) infections.
Methods: This retrospective study was carried out at the University Hospital Frankfurt, Germany, from 2008 to 2017 on infants aged 4 weeks to 12 months presenting with neurological symptoms consistent with congenital CMV infections.
Results: We studied 117 infants, and workup data for CMV infections were available for 84%. Of these, 54% were immunoglobulin G‐ and immunoglobulin M‐seronegative for CMV or immunoglobulin G‐seropositive with no viral shedding. Congenital CMV infection was excluded in these cases. In 16%, the CMV workup was incomplete, precluding a definitive diagnosis. Dried blood spots (DBS) were requested from 30%. CMV polymerase chain reaction was negative in 19 of these 29 infants, and CMV deoxyribonucleic acid detection confirmed congenital CMV infections in six patients. DBS had been destroyed in line with German law in four cases. Congenital CMV infections were diagnosed (5%) or excluded (62%) in 67% of patients and unanswered in the remaining 33%.
Conclusion: Diagnoses of congenital CMV infections were widely considered and found in 5%. CMV was not stringently investigated in all patients or remained elusive due to German law on destroying DBS.