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Background: Topical glucocorticosteroids are the first line therapy for airway inflammation. Modern compounds with higher efficacy have been developed, but head-to-head comparison studies are sparse.
Objective: To compare the activity of two intranasal glucocorticoids, fluticasone furoate (FF) and mometasone furoate (MF) with respect to the inhibition of T helper (Th)1, Th2 and Th17 cytokine release in airway mucosa.
Methods: We used an ex-vivo human nasal mucosal tissue model and employed pre-and post-Staphylococcus aureus enterotoxin B (SEB)-challenge incubations with various time intervals and drug concentrations to mimic typical clinical situations of preventive or therapeutic use.
Results: At a fixed concentration of 10(-10) M, FF had significantly higher suppressive effects on interferon (IFN)-gamma,interleukin (IL)-2 and IL-17 release, but not IL-5 or tumor necrosis factor (TNF)-alpha, vs. MF. While the maximal suppressive activity was maintained when FF was added before or after tissue stimulation, the cytokine suppression capacity of MF appeared to be compromised when SEB-induced cell activation preceded the addition of the drug. In a pre-challenge incubation setting with removal of excess drug concentrations, MF approached inhibition of IL-5 and TNF-alpha after 6 and 24 hours while FF maximally blocked the release of these cytokines right after pre-incubation. Furthermore, FF suppressed a wider range of T helper cytokines compared to MF.
Conclusion: The study demonstrates the potential of our human mucosal model and shows marked differences in the ability to suppress the release of various cytokines in pre-and post-challenge settings between FF and MF mimicking typical clinical situations of preventive or therapeutic use.
Background and purpose
Pediatric adrenocortical carcinoma (pACC) is a rare disease with poor prognosis. Publications on radiotherapy (RT) are scarce. This review summarizes the current data on RT for pACC and possibly provides first evidence to justify its use in this setting.
Materials and methods
We searched the PubMed and Embase database for manuscripts regarding RT for pACC.
Results
We included 17 manuscripts reporting on 76 patients treated with RT, after screening 2961 references and 269 full articles. In addition, we added data of 4 unreported pACC patients treated by co-authors. All reports based on retrospective data. Median age at first diagnosis was 11.1 years (70% female); 78% of patients presented with hormonal activity. RT was mostly performed for curative intent (78%). 88% of RT were administered during primary therapy. The site of RT was predominantly the local tumor bed (76%). Doses of RT ranged from 15 to 62 Gy (median 50 Gy). Information on target volumes or fractionation were lacking. Median follow-up was 6,9 years and 64% of the patients died of disease, with 33% alive without disease. In 16 of 48 patients with available follow-up data after adjuvant RT (33%) no recurrence was reported and in 3 of 9 patients palliative RT seemed to induce some benefit for the patient.
Conclusions
Our first systematic review on RT for pACC provides too few data for any general recommendation, but adjuvant RT in patients with high risk might be considered. International collaborative studies are urgently needed to establish better evidence on the role of RT in this rare malignancy.
In der vorliegenden Arbeit erfolgte eine retrospektive Auswertung der Daten von 2078 Patienten mit Erstdiagnose eines primär hormonrezeptorpositivem Mammakarzinoms, bezüglich der Entwicklung einer Rezeptorkonversion im Rezidiv. 196 Frauen entwickelten ein Rezidiv, wovon 29,1% eine Rezeptorveränderung im Östrogen-, Progesteron-, oder HER2-neu-Rezeptor zeigten. Ein niedriger Tumordifferenzierungsgrad und eine axilläre Lymphknotenbeteiligung zeigten ein erhöhtes Risiko für das Auftreten einer Rezeptorkonversion. Eine prämenopausale Tamoxifentherapie oder die Applikation einer Chemotherapie war mit einem geringerem Risiko für die Entwicklung eines östrogenrezeptornegativen Rezidivs assoziiert. Der Verlust der Rezeptorpositivität zeigte einen Trend zu einem geringeren Gesamtüberleben.
Objective
As native cartilage consists of different phenotypical zones, this study aims to fabricate different types of neocartilage constructs from collagen hydrogels and human mesenchymal stromal cells (MSCs) genetically modified to express different chondrogenic factors.
Design
Human MSCs derived from bone-marrow of osteoarthritis (OA) hips were genetically modified using adenoviral vectors encoding sex-determining region Y-type high-mobility-group-box (SOX)9,transforming growth factor beta (TGFB) 1or bone morphogenetic protein (BMP) 2cDNA, placed in type I collagen hydrogels and maintained in serum-free chondrogenic media for three weeks. Control constructs contained unmodified MSCs or MSCs expressing GFP. The respective constructs were analyzed histologically, immunohistochemically, biochemically, and by qRT-PCR for chondrogenesis and hypertrophy.
Results
Chondrogenesis in MSCs was consistently and strongly induced in collagen I hydrogels by the transgenesSOX9,TGFB1andBMP2as evidenced by positive staining for proteoglycans, chondroitin-4-sulfate (CS4) and collagen (COL) type II, increased levels of glycosaminoglycan (GAG) synthesis, and expression of mRNAs associated with chondrogenesis. The control groups were entirely non-chondrogenic. The levels of hypertrophy, as judged by expression of alkaline phosphatase (ALP) and COL X on both the protein and mRNA levels revealed different stages of hypertrophy within the chondrogenic groups (BMP2>TGFB1>SOX9).
Conclusions
Different types of neocartilage with varying levels of hypertrophy could be generated from human MSCs in collagen hydrogels by transfer of genes encoding the chondrogenic factorsSOX9,TGFB1andBMP2. This technology may be harnessed for regeneration of specific zones of native cartilage upon damage.
Aneurysmal subarachnoid hemorrhage (aSAH) remains a disease with high mortality and morbidity. Since treating vasospasm has not inevitably led to an improvement in outcome, the actual emphasis is on finding neuroprotective therapies in the early phase following aSAH to prevent secondary brain injury in the later phase of disease. Within the early phase, neuroinflammation, thromboinflammation, disturbances in brain metabolism and early neuroprotective therapies directed against delayed cerebral ischemia (DCI) came into focus. Herein, the role of neuroinflammation, thromboinflammation and metabolism in aSAH is depicted. Potential neuroprotective strategies regarding neuroinflammation target microglia activation, metalloproteases, autophagy and the pathway via Toll-like receptor 4 (TLR4), high mobility group box 1 (HMGB1), NF-κB and finally the release of cytokines like TNFα or IL-1. Following the link to thromboinflammation, potential neuroprotective therapies try to target microthrombus formation, platelets and platelet receptors as well as clot clearance and immune cell infiltration. Potential neuroprotective strategies regarding metabolism try to re-balance the mismatch of energy need and supply following aSAH, for example, in restoring fuel to the TCA cycle or bypassing distinct energy pathways. Overall, this review addresses current neuroprotective strategies in aSAH, hopefully leading to future translational therapy options to prevent secondary brain injury.
Background: Recent data suggest that cancer stem cells (CSCs) play an important role in cancer, as these cells possess enhanced tumor-forming capabilities and are responsible for relapses after apparently curative therapies have been undertaken. Hence, novel cancer therapies will be needed to test for both tumor regression and CSC targeting. The use of oncolytic vaccinia virus (VACV) represents an attractive anti-tumor approach and is currently under evaluation in clinical trials. The purpose of this study was to demonstrate whether VACV does kill CSCs that are resistant to irradiation and chemotherapy.
Methods: Cancer stem-like cells were identified and separated from the human breast cancer cell line GI-101A by virtue of increased aldehyde dehydrogenase 1 (ALDH1) activity as assessed by the ALDEFLUOR assay and cancer stem cell-like features such as chemo-resistance, irradiation-resistance and tumor-initiating were confirmed in cell culture and in animal models. VACV treatments were applied to both ALDEFLUOR-positive cells in cell culture and in xenograft tumors derived from these cells. Moreover, we identified and isolated CD44\(^+\)CD24\(^+\)ESA\(^+\) cells from GI-101A upon an epithelial-mesenchymal transition (EMT). These cells were similarly characterized both in cell culture and in animal models.
Results: We demonstrated for the first time that the oncolytic VACV GLV-1h68 strain replicated more efficiently in cells with higher ALDH1 activity that possessed stem cell-like features than in cells with lower ALDH1 activity. GLV-1h68 selectively colonized and eventually eradicated xenograft tumors originating from cells with higher ALDH1 activity. Furthermore, GLV-1h68 also showed preferential replication in CD44\(^+\)CD24\(^+\)ESA\(^+\) cells derived from GI-101A upon an EMT induction as well as in xenograft tumors originating from these cells that were more tumorigenic than CD44\(^+\)CD24\(^-\)ESA\(^+\) cells.
Conclusions: Taken together, our findings indicate that GLV-1h68 efficiently replicates and kills cancer stem-like cells. Thus, GLV-1h68 may become a promising agent for eradicating both primary and metastatic tumors, especially tumors harboring cancer stem-like cells that are resistant to chemo and/or radiotherapy and may be responsible for recurrence of tumors.
Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial
(2013)
Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B).
Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences. Results: During one year of natural course, muscle strength declined about 2% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects.
Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis.
Im Rahmen der Zusammenarbeit des Missionsärztlichen Instituts in Würzburg mit dem Sacred Heart Hospital (Nigeria) wurden vor Ort im Hinblick auf das Problem der Arzneimittelfälschungen in Nigeria und dem Auftreten von einzelnen Resistenzen gegen Artemisinin-Derivate Untersuchungen bezüglich der aktuellen Situation im Kampf gegen Malaria im Großraum Abeokuta durchgeführt. Der Kenntnisstand über Malaria und das Gesundheitsverhalten einer für die nigerianische Bevölkerung möglichst repräsentativen Probandengruppe (n=100) wurden mithilfe eines Fragebogens erfasst. Ebenfalls mithilfe eines Fragebogens wurden die Therapiestrategien der einheimischen Ärzte (n=34) gegen Malaria untersucht und die Verfügbarkeit und Qualität von Artemisinin- Derivaten im Untersuchungsgebiet durch den Erwerb von Medikamenten-Samples (n=29) und anschließende Labortests überprüft. Die Befragung der Bevölkerung ergab, dass Wissen bezüglich der Ursachen, Symptome und Prävention der Malaria durchaus vorhanden ist, wobei große Unterschiede abhängig vom Bildungsstand bestanden. Vor allem ältere Menschen verfügten über wesentlich geringere Schulbildung und verließen sich deshalb sehr viel mehr auf die traditionelle Medizin. Darüber hinaus war eine oftmalige Bagatellisierung der Malaria auffällig, weshalb viele Probanden (53%) sich im Krankheitsfall gegen das Aufsuchen eines Krankenhauses entschieden. Die Befragung bezüglich der Therapiestrategien der einheimischen Ärzte zeigte, dass die Richtlinien der WHO bezüglich der Verwendung von ACT offensichtlich optimal angenommen und angewandt werden. Als mögliches Problem stellte sich die von 76,7% der Ärzte nur selten angewandte Labordiagnostik dar, eine Tatsache, die Fehldiagnosen begünstigt. Bei der Testung der Medikamente erwiesen sich 14,3% der Proben als minderwertig oder sogar gefälscht, was offiziellen Angaben entspricht. Zudem handelte es sich bei 37,9% der Arzneimittelproben um Monopräparate, was im Hinblick auf Resistenzbildung mehr als bedenklich ist. Diese Resultate weisen darauf hin, dass im Südwesten Nigerias die Malaria-Problematik noch immer nicht adäquat gelöst ist. Immer noch erhalten viel zu wenige Menschen eine optimale Therapie, was zu einem großen Teil an fehlendem Wissen und damit verbundenem falschem Gesundheitsverhalten, an dem großen Einfluss der traditionellen Medizin und an der Präsenz von gefälschten, wirkungslosen Arzneimitteln auf dem Markt liegt.
Background
Adrenalectomies are rare procedures especially in childhood. So far, no large cohort study on this topic has been published with data on to age distribution, operative procedures, hospital volume and operative outcome.
Methods
This is a retrospective analysis of anonymized nationwide hospital billing data (DRG data, 2009-2017). All adrenal surgeries (defined by OPS codes) of patients between the age 0 and 21 years in Germany were included.
Results
A total of 523 patient records were identified. The mean age was 8.6 ± 7.7 years and 262 patients were female (50.1%). The majority of patients were between 0 and 5 years old (52% overall), while 11.1% were between 6 and 11 and 38.8% older than 12 years. The most common diagnoses were malignant neoplasms of the adrenal gland (56%, mostly neuroblastoma) with the majority being younger than 5 years. Benign neoplasms in the adrenal gland (D350) account for 29% of all cases with the majority of affected patients being 12 years or older. 15% were not defined regarding tumor behavior. Overall complication rate was 27% with a clear higher complication rate in resection for malignant neoplasia of the adrenal gland. Bleeding occurrence and transfusions are the main complications, followed by the necessary of relaparotomy. There was an uneven patient distribution between hospital tertiles (low volume, medium and high volume tertile). While 164 patients received surgery in 85 different “low volume” hospitals (0.2 cases per hospital per year), 205 patients received surgery in 8 different “high volume” hospitals (2.8 cases per hospital per year; p<0.001). Patients in high volume centers were significant younger, had more extended resections and more often malignant neoplasia. In multivariable analysis younger age, extended resections and open procedures were independent predictors for occurrence of postoperative complications.
Conclusion
Overall complication rate of adrenalectomies in the pediatric population in Germany is low, demonstrating good therapeutic quality. Our analysis revealed a very uneven distribution of patient volume among hospitals.
In North Korea, the prevalence of hepatitis B is high due to natural factors, gaps in vaccination, and the lack of antiviral treatment. Aid projects are urgently needed, however impeded by North Korea's political and economical situation and isolation. The feasibility of a joint North Korean and German humanitarian hepatitis B prevention program was assessed. Part 1: Hepatitis B vaccination catch-up campaign. Part 2: Implementation of endoscopic ligation of esophageal varices (EVL) by trainings in Germany and North Korea. By vaccinating 7 million children between 2010 and 2012, the hepatitis B vaccination gap was closed. Coverage of 99.23% was reached. A total of 11 hepatitis B-induced liver cirrhosis patients (mean age 41.1 yr) with severe esophageal varices and previous bleedings were successfully treated by EVL without major complications. A clinical standard operating procedure, a feedback system and a follow-up plan were developed. The bi-modal preventive strategy was implemented successfully. Parts of the project can serve as an example for other low-income countries, however its general transferability is limited due to the special circumstances in North Korea.
Im Rahmen der vorliegenden Arbeit erfolgte eine retrospektive Analyse von 86 Patienten der Chirurgischen Universitätsklinik Würzburg die von 02/1995 bis 07/2002 aufgrund mesenterialer Ischämien therapiert werden mussten. Ziel der Untersuchung war eine Bewertung aktueller diagnostischer und therapeutischer Möglichkeiten und deren Einfluss auf die Erfolgsprognose der Erkrankung. Das klinische Erscheinungsbild der akuten Verschlussformen war gerade in der entscheidenden Frühphase sehr uncharakteristisch. Daher kommt der sorgfältigen Anamneseerhebung eine große Bedeutung zu. Bei der chronischen mesenterialen Ischämie kommt es zu postprandialen Schmerzen und Gewichtsverlust, meist als akute Verschlimmerung eines Dauerschmerzes etwa 10 - 30 Minuten nach einer Mahlzeit mit Regredienz innerhalb der nächsten Stunden. Als diagnostische Verfahren kamen Sonografie, Nativaufnahme, Duplex-, Farbduplexsonografie und Computertomografie zum Einsatz. Alleine mit Hilfe der intraarteriellen Subtraktionsangiografie gelang ein zuverlässiger Nachweis akuter oder chronischer viszeraler Ischämien. Ist die angiografische Abklärung aufgrund mangelnder apparativer Ausstattung nicht möglich, muss zügig eine diagnostische Laparoskopie durchgeführt werden. Eine typische Konstellation von Laborparametern konnte zu diesem Zeitpunkt nicht erhoben werden. Lediglich dem Serumlaktat kam eine Bedeutung zu, jedoch ließ die Höhe keine Rückschlüsse auf die Ausdehnung der ischämischen Bezirke zu. Operative Therapieverfahren haben die möglichst schnelle Strombahnwiederherstellung und Revaskularisiation der infarktbedrohten Darmabschnitte zum Ziel. Die alleinige Darmresektion ist angezeigt, wenn eine Gefäßrekonstruktion technisch nicht möglich erscheint. Arterielle Rekonstruktionsverfahren wie Embolektomie oder Methoden mit Gefäßersatz- bzw. Transplantatmaterial sind indiziert, wenn die Möglichkeit einer Restitutio nach Perfusionswiederherstellung besteht. Eine prophylaktische Rekonstruktion bei asymptomatischen Viszeralarterienverschluss scheint bei der chronischen Verlaufsform nicht sinnvoll. Die Indikation für eine second - look Operation sollte großzügig gestellt werden! Bei kurzstreckiger Verschlussmorphologie erscheinen Stenosen der Viszeralarterien auch für perkutane transluminale Angioplastie geeignet. Bei der nicht okklusiven Form der Mesenterialischämie haben kardiologisch - intensivmedizinische Maßnahmen als alleinige Therapie Vorrang. Der wichtigste prognostische Faktor für die erfolgreiche Behandlung und damit auch für die Gesamtprognose der akuten Verlaufsform ist die frühzeitige Diagnosestellung und Behandlung.
Diagnosis and therapy of Mycobacterium marinum: a single-center 21-year retrospective analysis
(2022)
Background and Objectives
In Europe, infections with Mycobacterium (M.) marinum are rare. We conducted a retrospective single-center study to assess the clinical spectrum of M. marinum infection and its diagnosis, treatment and outcome under real-world conditions.
Patients and Methods
Eighteen patients presenting with M. marinum infections between 1998 and 2018 were identified in the data warehouse of the University Hospital Würzburg and considered for detailed analysis.
Results
Twelve patients reported aquatic exposure. In 16/18 cases the upper extremities were affected. No invasive infections were detected. Mean time to diagnosis was 15 weeks. Histology revealed granulomatous inflammation in 14 patients while mycobacterial cultures were positive for M. marinum in 16 cases. Most patients received antibiotic monotherapy (14/18) while combination therapy was administered in four cases. Treatment (with a median duration of 10 weeks) was successful in 13 patients. Five patients were lost to follow-up.
Conclusions
Our retrospective analysis of M. marinum infections at a German tertiary referral center revealed a considerable diagnostic delay and the relevance of microbiological culture, PCR and histology for diagnosis. Monotherapy with clarithromycin (rather than doxycycline) appeared as a reasonable treatment option while immunosuppressed or -compromised patients and those with extended disease received combination therapy.
Background:
The vital importance of imaging techniques in radiation oncology now extends beyond diagnostic evaluation and treatment planning. Recent technical advances have enabled the integration of various imaging modalities into the everyday practice of radiotherapy directly at the linear accelerator, improving the management of inter-and intrafractional variations.
Methods:
We present the topic of image-guided radiotherapy (IGRT) on the basis of a selective review of the literature.
Results:
IGRT can be performed with the aid of ultrasound, 2D X-ray devices, and computed tomography. It enables instant correction for positioning deviations and thereby improves the precision of daily radiotherapy fractions. It also enables immediate adjustment for changes in the position and filling status of the internal organs. Anatomical changes that take place over the course of radiotherapy, such as weight loss, tumor shrinkage, and the opening of atelectases, can be detected as they occur and accounted for in dosimetric calculations. There have not yet been any randomized controlled trials showing that IGRT causes fewer adverse effects or improves tumor control compared to conventional radiotherapy.
Conclusion:
IGRT is more precise and thus potentially safer than conventional radiotherapy. It also enables the application of special radiotherapeutic techniques with narrow safety margins in the vicinity of radiosensitive organs. Proper patient selection for IGRT must take account of the goals of treatment and the planning characteristics, as well as the available technical and human resources. IGRT should be used for steep dose gradients near organs at risk, for highly conformal dose distributions in the gastrointestinal tract where adjustment for filling variations is needed, for high-precision dose escalation to avoid geographic miss, and for patients who cannot lie perfectly still because of pain or claustrophobia.
Onkologische Patienten sind während der Phase der Chemotherapie-bedingten Knochenmarkdepression besonders durch Infektionen bedroht. Da bisher keine Parameter bekannt sind, die eine schwerwiegende bakterielle Infektion zu Beginn einer Fieberepisode von anderen Fieberursachen sicher differenziert, werden diese Patienten bei Fieber und Neutropenie trotz der damit verbundenen Nachteile und Risiken, wie z.B. mögliche Resistenzbildung, Toxizität der Antibiotika, Risiko nosokomialer Infektionen, psychische Belastung der kleinen Patienten und deren Eltern, sofort stationär aufgenommen und intravenös mit Antibiotika behandelt. In der vorliegenden Studie wurde der diagnostische Wert der Interleukine 6 und –8 für die Früherkennung schwerer Infektionen bei pädiatrischen Patienten mit Fieber und Chemotherapie-bedingter Neutropenie untersucht und mit dem diagnostischen Wert des CrP verglichen. In einem Beobachtungszeitraum von 15 Monaten wurden in 128 Fieberepisoden bei 55 Patienten mit einem breiten Spektrum onkologischer Grunderkrankungen die Konzentrationen der Parameter an den ersten Fiebertagen bestimmt. Neben 95 FUO-Episoden wurden sechs bakterielle Infektionen mit gram-negativem Erreger, 19 bakterielle Infektionen mit gram-positivem Erreger, drei Pilzinfektionen und fünf klinisch dokumentierte Infektionen behandelt. Es zeigten sich signifikant höhere IL-6 und IL-8 Konzentrationen am ersten Fiebertag bei Infektionen mit gram-negativen Bakterien, S.aureus und Pilzen, also bei potentiell schwerer verlaufenden Infektionen als bei FUO, S.epidermidis- und klinisch dokumentierten Infektionen. Schwere Infektionen konnten mit einer deutlich höheren Sensitivität und Spezifität von anderen Fieberursachen durch die Interleukine als durch das CrP unterschieden werden. Die Interleukine-6 und –8 könnten im Gegensatz zum CrP eine wertvolle Hilfe in der Frühdiagnostik von schwerwiegenden Infektionen bei pädiatrischen Patienten mit chemotherapiebedingter Neutropenie und Fieber sein. Die in dieser Arbeit dargestellten Ergebnisse müssen jedoch vor einem routinemäßigen Einsatz im Klinikalltag in großen, prospektiven Studien validiert werden. Ein weiteres Ziel dieser Studie war, den Therapieerfolg einer initialen Monotherapie mit Imipenem/Cilastat zur Behandlung von Kindern mit Fieber und Chemotherapie-bedingter Neutropenie zu untersuchen und mit dem Therapieerfolg einer initialen Therapie mit einer Ceftazidim/Teicoplanin Kombination zu vergleichen. In insgesamt 106 auswertbaren Fieberepisoden wurde 54 mal initial mit der Monotherapie und 52 mal initial mit der Kombinationstherapie behandelt. Die antibiotische Therapie wurde nach einer Mindestdauer von 72 Stunden beendet, wenn der Patient 24 Stunden fieberfrei war und die Kriterien für FUO erfüllt waren, d.h., kein Erreger nachgewiesen werden konnte und keine weiteren klinischen Zeichen einer Infektion bestanden. Keiner der Patienten verstarb infolge einer Infektion. Rund die Hälfte der Patienten entfieberten in beiden Therapiegruppen innerhalb von drei Tagen unter der Initialtherapie. Beide Therapiegruppen unterschieden sich nicht signifikant hinsichtlich der Therapiedauer, der Fieberdauer und hinsichtlich der Rezidivhäufigkeit und waren damit gleich effektiv. Lediglich bei den Infektionen mit gram-positiven Eregern zeigte sich erwartungsgemäß, dass die initiale Kombinationstherapie aufgrund des Teicoplaninanteils zu einer rascheren Entfieberung führte. Alle Patienten, die initial mit der Imipenemmonotherapie behandelt wurden, konnten nach Eintreffen des Antibiogramms erfolgreich behandelt werden. Glykopeptide sind Reserveantibiotika, die möglichst gezielt und sparsam eingesetzt werden sollten, um einer Resistenzbildung vorzubeugen. In dieser Studie konnte gezeigt werden, dass auch der verzögerte Einsatz von Teicoplanin in der Folgetherapie bzw. in Kenntnis des Antibiogramms den Therapieerfolg nicht signifikant vermindert und dadurch keine bedrohliche Situation für einen Patienten entstand. Vorteile einer Monotherapie sind außerdem eine potentiell geringere Toxizitiät, und ein potentiell geringerer Kosten- und Personalaufwand. Wir ziehen aus den genannten Gründen eine initiale Monotherapie mit Imipenem einer initialen Therapie mit einer Ceftazidim/Teicoplanin Kombination vor. Nach frühzeitiger Beendigung der antibiotischen Therapie bei Patienten mit FUO unabhängig von der Granulozytenzahl im Blutbild kam es zu keiner Häufung von Rezidiven. Mit dieser Praxis könnte sich nicht nur das Risiko einer Resistenzbildung senken lassen. Ein verkürzter stationärer Aufenthalt verbessert die Lebensqualität der Patienten, nicht zuletzt bedeutet dies auch einen geringeren Kosten- und Personalaufwand.
Background
Oncolytic viruses, including vaccinia virus (VACV), are a promising alternative to classical mono-cancer treatment methods such as surgery, chemo- or radiotherapy. However, combined therapeutic modalities may be more effective than mono-therapies. In this study, we enhanced the effectiveness of oncolytic virotherapy by matrix metalloproteinase (MMP-9)-mediated degradation of proteins of the tumoral extracellular matrix (ECM), leading to increased viral distribution within the tumors.
Methods
For this study, the oncolytic vaccinia virus GLV-1h255, containing the mmp-9 gene, was constructed and used to treat PC-3 tumor-bearing mice, achieving an intra-tumoral over-expression of MMP-9. The intra-tumoral MMP-9 content was quantified by immunohistochemistry in tumor sections. Therapeutic efficacy of GLV-1h255 was evaluated by monitoring tumor growth kinetics and intra-tumoral virus titers. Microenvironmental changes mediated by the intra-tumoral MMP-9 over-expression were investigated by microscopic quantification of the collagen IV content, the blood vessel density (BVD) and the analysis of lymph node metastasis formation.
Results
GLV-1h255-treatment of PC-3 tumors led to a significant over-expression of intra-tumoral MMP-9, accompanied by a marked decrease in collagen IV content in infected tumor areas, when compared to GLV-1h68-infected tumor areas. This led to considerably elevated virus titers in GLV-1h255 infected tumors, and to enhanced tumor regression. The analysis of the BVD, as well as the lumbar and renal lymph node volumes, revealed lower BVD and significantly smaller lymph nodes in both GLV-1h68- and GLV-1h255- injected mice compared to those injected with PBS, indicating that MMP-9 over-expression does not alter the metastasis-reducing effect of oncolytic VACV.
Conclusions
Taken together, these results indicate that a GLV-1h255-mediated intra-tumoral over-expression of MMP-9 leads to a degradation of collagen IV, facilitating intra-tumoral viral dissemination, and resulting in accelerated tumor regression. We propose that approaches which enhance the oncolytic effect by increasing the intra-tumoral viral load, may be an effective way to improve therapeutic outcome.
Molecular-based subclassifications of breast cancer are important for identifying treatment options and stratifying the prognosis in breast cancer. This study aimed to assess the prognosis relative to disease-free survival (DFS) and overall survival (OS) in patients with triple-negative breast cancer (TNBC) and other subtypes, using a biomarker panel including cytokeratin 5 (CK5), cluster of differentiation 117 (CD117), and epidermal growth factor receptor (EGFR). This cohort–case study included histologically confirmed breast carcinomas as cohort arm. From a total of 894 patients, 572 patients with early breast cancer, sufficient clinical data, and archived tumor tissue were included. Using the immunohistochemical markers CK5, CD117, and EGFR, two subgroups were formed: one with all three biomarkers negative (TBN) and one with at least one of those three biomarkers positive (non-TBN). There were significant differences between the two biomarker subgroups (TBN versus non-TBN) in TNBC for DFS (p = 0.04) and OS (p = 0.02), with higher survival rates (DFS and OS) in the non-TBN subgroup. In this study, we found the non-TBN subgroup of TNBC lesions with at least one positive biomarker of CK5, CD117, and/or EGFR, to be associated with longer DFS and OS.
Malaria is a challenging infection with increasing and wide-spread treatment failure risk due to resistance. With a estimated death toll of 1-3 Million per year, most cases of Malaria affect children under the age of five years in Sub-Saharan Africa. In this thesis, I analyse the current status of malaria control (focussing on diagnosis and therapy) in Burkina Faso to show how this disease burdens public health in endemic countries and to identify possible approaches to improvement. MB is discussed as a therapeutic option under these circumstances.
Burkina Faso is used as a representative example for a country in Sub-Saharan Africa with high endemicity for malaria and is here portrayed, its health system characterised and discussed under socioeconomic aspects.
More than half of this country’s population live in absolute poverty. The burden that malaria, especially treatment cost, poses on these people cannot be under-estimated.
A retrospective study of case files from the university pediatric hospital in Burkina Faso’s capital, Ouagadougou, shows that the case load is huge, and especially the specific diagnosis of severe malaria is difficult to apply in the hospital’s daily routine. Treatment policy as proposed by WHO is not satisfactorily implemented neither in home treatment nor in health services, as data for pretreatment clearly show.
In the face of growing resistance in malaria parasites, pharmacological combination therapies are important. Artemisinins currently are the last resort of malaria therapy. As I show with homology models, even this golden bullet is not beyond resistance development. Inconsidered mass use has rendered other drugs virtually useless before. Artemisinins should thus be protected similar to reserve antibiotics against multi-resistant bacteria.
There is accumulating evidence that MB is an effective drug against malaria. Here the biological effects of both MB alone and in combination therapy is explored via modeling and experimental data. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, CQ resistance based on Pfmdr1 and PfCRT transporters as well as SP resistance were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs, given their correct application.
Also from the economic point of view MB shows great potential: in terms of production price, it can be compared to CQ, which could help to diminuish the costs of malaria treatment to affordable ranges for those most affected and struk by poverty.
Malaria control is feasible, but suboptimal diagnosis and treatment are often hindering the achievment of this goal. In order to achieve malaria control, more effort has to be made to implement better adjusted and available primary treatment strategies for uncomplicated malaria that are highly standardised. Unfortunately, campaigns against malaria are chronically underfinanced. In order to maximize the effect of available funds, a cheap treatment option is most important, especially as pharmaceuticals represent the biggest single matter of expense in the fight against malaria.
Background. Fast progression of the transaortic mean gradient (P-mean) is relevant for clinical decision making of valve replacement in patients with moderate and severe aortic stenosis (AS) patients. However, there is currently little knowledge regarding the determinants affecting progression of transvalvular gradient in AS patients. Methods. This monocentric retrospective study included consecutive patients presenting with at least two transthoracic echocardiography examinations covering a time interval of one year or more between April 2006 and February 2016 and diagnosed as moderate or severe aortic stenosis at the final echocardiographic examination. Laboratory parameters, medication, and prevalence of eight known cardiac comorbidities and risk factors (hypertension, diabetes, coronary heart disease, peripheral artery occlusive disease, cerebrovascular disease, renal dysfunction, body mass index >= 30 Kg/m(2), and history of smoking) were analyzed. Patients were divided into slow (P-mean < 5 mmHg/year) or fast (P-mean >= 5 mmHg/year) progression groups. Results. A total of 402 patients (mean age 78 +/- 9.4 years, 58% males) were included in the study. Mean follow-up duration was 3.4 +/- 1.9 years. The average number of cardiac comorbidities and risk factors was 3.1 +/- 1.6. Average number of cardiac comorbidities and risk factors was higher in patients in slow progression group than in fast progression group (3.3 +/- 1.5 vs 2.9 +/- 1.7; P = 0.036). Patients in slow progression group had more often coronary heart disease (49.2% vs 33.6%; P = 0.003) compared to patients in fast progression group. LDL-cholesterol values were lower in the slow progression group (100 +/- 32.6 mg/dl vs 110.8 +/- 36.6 mg/dl; P = 0.005). Conclusion. These findings suggest that disease progression of aortic valve stenosis is faster in patients with fewer cardiac comorbidities and risk factors, especially if they do not have coronary heart disease. Further prospective studies are warranted to investigate the outcome of patients with slow versus fast progression of transvalvular gradient with regards to comorbidities and risk factors.