Klinischer Stellenwert nicht-invasiver spektroskopischer in-vivo Methoden in der Behandlung onkologischer Erkrankungen

Die Haut ist als menschliches Organ leicht zugänglich und für nicht invasive in-vivo Untersuchungen besonders geeignet, zumal Ergebnisse zur Penetration systemisch applizierter Substanzen darauf schließen lassen, dass der Schweiß Substrat eines wichtigen Penetrationsprozesses ist. Insbesondere Chemotherapeutika können in Abhängigkeit von der Barrierefunktion der Haut über die Schweißsekretion auf die Hautoberfläche gelangen und von dort, wie topisch appliziert, von außen in die tieferen Hautschichten gelangen und dort kumulativ toxische Wirkungen entfalten. Nicht selten führt die kutane Toxizität zum Therapieabbruch und zur Verschlechterung der Lebensqualität und des Outcomes. Für Zytostatika wie Taxane, 5-FU oder liposomale Anthrazykline ist dies bekannt, aber auch Substanzen, wie targeted therapies, die nicht zytotoxisch wirken, führen trotz zielgerichteter Wirkweise zu einem breiten Spektrum insbesondere kutaner Nebenwirkungen. Die Kinetik dieser Prozesse war auch in Anbetracht fehlender diagnostischer Tools bis dato größtenteils unklar. Bekannt ist, dass Antioxidantien in der menschlichen Haut Schutzketten bilden und destruktive Effekte freier Radikale verhindern können. Die Detektion von Betacarotin und Lycopin in der menschlichen Haut mittels Resonanz-Raman-Spektroskopie ist ein Indikator für den Antioxidantienstatus der Haut. In Anbetracht der demographischen Entwicklung, der noch fehlenden wissenschaftlich harmonisierten Umsetzung therapeutischer Prozesse in der geriatrischen Onkologie, der Polypharmazie und auch des breiten Einsatzes von Immuntherapeutika bei teils komorbiden Patienten ist die Qualität klinischen Monitorings entscheidend. Im Alltag ist der Wechsel von Zytostatika zu Multikinaseinhibitoren und Immuncheckpoint-Inhibitoren angekommen, Maßnahmen der Prävention und des Nebenwirkungsmanagements bedürfen der Optimierung. Dank der mehrjährigen Forschung der Charité unter Nutzung spektroskopischer Verfahren besteht ein praxisnahes, im Handling einfaches Tool zur Evaluierung in vivo. Mehrere Studien haben die klinisch relevante Beeinflussung des oxidativen Status und sich ableitender therapeutischer Maßnahmen insbesondere des Hand-Fuß-Syndroms(HFS) mittels antioxidativer Salben belegt. Im Umkehrschluss konnte gezeigt werden, dass der Wirkmechanismus von Capecitabine davon different ist und somit keiner analogen Therapie bedarf. Bei Patienten mit molekularen Therapien tritt das HFS in relativ hoher Inzidenz auf, die Pathogenese ist nur teilweise verstanden. Die aktuellen Ergebnisse, welche im Rahmen der Doktorarbeit entstanden sind, belegen eine Capecitabine-vergleichbare Pathogenese. Gleichfalls bestätigen die Ergebnisse die Notwendigkeit eines klinischen, kommunikationsbasierten Monitorings einschließlich gezielter ernährungswissenschaftlicher Intervention unter Erwägung komplementärmedizinischer Maßnahmen. Weitere Studien sollten den Stellenwert des oxidativen Status als stratifizierenden Faktor für supportive Maßnahmen im multimodalen Ansatz evaluieren. Es handelt sich um eine Publikationspromotion, die auf vier Publikationen basiert.The skin as a human organ is easily accessible for non-invasive in vivo measuring, especially because studies regarding the penetration of systemically applied substances indicate that sweat is the substrate of an important penetration process. Chemotherapeutic agents in particular can, depending on the skin’s barrier function, penetrate it to the surface. From there they can, as though applied topically, reenter it from the outside, reach deeper skin layers and cause cumulative toxic effects. Often this results in termination of treatment and the worsening of life quality and outcome. This process is already well-described for cytostatics such as taxanes, 5-FU and liposomal anthracyclines, but even targeted therapy drugs, which are not cytotoxic, cause a broad spectrum of side effects. Partly due to the lack of suitable diagnostic tools, the corresponding kinetics is to date still not understood in its entirety. It has been established that antioxidants form protective chains within the skin to counteract the destructive effect of free radicals. Beta-carotene and lycopene detection in the skin using resonance Raman spectroscopy is indicative of the oxidative status of the skin. Due to the demographic development, lack of scientifically harmonious execution of therapeutic processes in geriatric oncology, polypharmacy and the widespread use of immunotherapies in patients with comorbidities, a high quality of clinical monitoring is essential. The change from cytostatics to multikinase inhibitors and immune checkpoint inhibitors has arrived in daily practice, while preventive measures and side effect management still need optimizing. Thanks to research performed by the Charité using spectroscopic measuring methods, a practical and easily usable tool exists for in-vivo evaluation. Multiple studies have demonstrated the clinical relevance of influencing the oxidative status via related therapeutic measures, particularly for Hand-Foot-Syndrome (HFS) using antioxidative ointments. Vice versa it was shown that the mechanism of action differs for capecitabine and thus doesn’t require therapy analogous to the one for traditional cytostatics. HFS occurs with high incidence in patients treated with molecular therapies, but the pathogenesis remains only partly understood. The current study results discovered during the research for this doctoral dissertation, consisting of four publications, point to a pathogenesis similar to capecitabine. At the same time, our results confirm the necessity for clinical, communication-based monitoring including targeted nutritional intervention and complementary medicine

In vivo detection of changes in cutaneous carotenoids after chemotherapy using shifted excitation resonance Raman difference and fluorescence spectroscopy

Background: Various cutaneous toxicities under chemotherapy indicate a local effect of chemotherapy by secretion after systemic application. Here, changes in the fluorescence and Raman spectral properties of the stratum corneum subsequent to intravenous chemotherapy were assessed. Methods: Twenty healthy subjects and 20 cancer patients undergoing chemotherapy were included. Measurement time points in cancer patients were before the first cycle of chemotherapy (Tbase) and immediately after intravenous application of the chemotherapy (T1). Healthy subjects were measured once without any further intervention. Measurements were conducted using an individually manufactured system consisting of a handheld probe and a wavelength-tunable diode laser-based 488 nm SHG light source. Hereby, changes in both skin fluorescence and shifted excitation resonance Raman difference spectroscopy (SERRDS) carotenoid signals were assessed. Results: Healthy subjects showed significantly (P <.001) higher mean concentrations of carotenoids compared to cancer subjects at Tbase. An increase in fluorescence intensity was detected in almost all patients after chemotherapy, especially after doxorubicin infusion. Furthermore, a decrease in the carotenoid concentration in the skin after chemotherapy was found. Conclusion: The SERRDS based noninvasive detection can be used as an indirect quantitative assessment of fluorescent chemotherapeutics. The lower carotenoid SERRDS intensities at Tbase might be due to cancerous diseases and co-medication. © 2020 The Authors. Skin Research and Technology Published by John Wiley & Sons Ltd

In vivo detection of changes in cutaneous carotenoids after chemotherapy using shifted excitation resonance Raman difference and fluorescence spectroscopy

Background: Various cutaneous toxicities under chemotherapy indicate a local effect of chemotherapy by secretion after systemic application. Here, changes in the fluorescence and Raman spectral properties of the stratum corneum subsequent to intravenous chemotherapy were assessed. Methods: Twenty healthy subjects and 20 cancer patients undergoing chemotherapy were included. Measurement time points in cancer patients were before the first cycle of chemotherapy (Tbase) and immediately after intravenous application of the chemotherapy (T1). Healthy subjects were measured once without any further intervention. Measurements were conducted using an individually manufactured system consisting of a handheld probe and a wavelength‐tunable diode laser‐based 488 nm SHG light source. Hereby, changes in both skin fluorescence and shifted excitation resonance Raman difference spectroscopy (SERRDS) carotenoid signals were assessed. Results: Healthy subjects showed significantly (P < .001) higher mean concentrations of carotenoids compared to cancer subjects at Tbase. An increase in fluorescence intensity was detected in almost all patients after chemotherapy, especially after doxorubicin infusion. Furthermore, a decrease in the carotenoid concentration in the skin after chemotherapy was found. Conclusion: The SERRDS based noninvasive detection can be used as an indirect quantitative assessment of fluorescent chemotherapeutics. The lower carotenoid SERRDS intensities at Tbase might be due to cancerous diseases and co‐medication

Intensity modulated radiotherapy (IMRT) in the treatment of children and Adolescents - a single institution's experience and a review of the literature

<p>Abstract</p> <p>Background</p> <p>While IMRT is widely used in treating complex oncological cases in adults, it is not commonly used in pediatric radiation oncology for a variety of reasons. This report evaluates our 9 year experience using stereotactic-guided, inverse planned intensity-modulated radiotherapy (IMRT) in children and adolescents in the context of the current literature.</p> <p>Methods</p> <p>Between 1999 and 2008 thirty-one children and adolescents with a mean age of 14.2 years (1.5 - 20.5) were treated with IMRT in our department. This heterogeneous group of patients consisted of 20 different tumor entities, with Ewing's sarcoma being the largest (5 patients), followed by juvenile nasopharyngeal fibroma, esthesioneuroblastoma and rhabdomyosarcoma (3 patients each). In addition a review of the available literature reporting on technology, quality, toxicity, outcome and concerns of IMRT was performed.</p> <p>Results</p> <p>With IMRT individualized dose distributions and excellent sparing of organs at risk were obtained in the most challenging cases. This was achieved at the cost of an increased volume of normal tissue receiving low radiation doses. Local control was achieved in 21 patients. 5 patients died due to progressive distant metastases. No severe acute or chronic toxicity was observed.</p> <p>Conclusion</p> <p>IMRT in the treatment of children and adolescents is feasible and was applied safely within the last 9 years at our institution. Several reports in literature show the excellent possibilities of IMRT in selective sparing of organs at risk and achieving local control. In selected cases the quality of IMRT plans increases the therapeutic ratio and outweighs the risk of potentially increased rates of secondary malignancies by the augmented low dose exposure.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe