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Background:
Concomitant radiation with BRAF inhibitor (BRAFi) therapy may increase radiation-induced side effects but also potentially improve tumour control in melanoma patients.
Methods:
A total of 155 patients with BRAF-mutated melanoma from 17 European skin cancer centres were retrospectively analysed. Out of these, 87 patients received concomitant radiotherapy and BRAFi (59 vemurafenib, 28 dabrafenib), while in 68 patients BRAFi therapy was interrupted during radiation (51 vemurafenib, 17 dabrafenib). Overall survival was calculated from the first radiation (OSRT) and from start of BRAFi therapy (OSBRAFi).
Results:
The median duration of BRAFi treatment interruption prior to radiotherapy was 4 days and lasted for 17 days. Median OSRT and OSBRAFi in the entire cohort were 9.8 and 12.6 months in the interrupted group and 7.3 and 11.5 months in the concomitant group (P=0.075/P=0.217), respectively. Interrupted vemurafenib treatment with a median OSRT and OSBRAFi of 10.1 and 13.1 months, respectively, was superior to concomitant vemurafenib treatment with a median OSRT and OSBRAFi of 6.6 and 10.9 months (P=0.004/P=0.067). Interrupted dabrafenib treatment with a median OSRT and OSBRAFi of 7.7 and 9.8 months, respectively, did not differ from concomitant dabrafenib treatment with a median OSRT and OSBRAFi of 9.9 and 11.6 months (P=0.132/P=0.404). Median local control of the irradiated area did not differ in the interrupted and concomitant BRAFi treatment groups (P=0.619). Skin toxicity of grade ≥2 (CTCAE) was significantly increased in patients with concomitant vemurafenib compared to the group with treatment interruption (P=0.002).
Conclusions:
Interruption of vemurafenib treatment during radiation was associated with better survival and less toxicity compared to concomitant treatment. Due to lower number of patients, the relevance of treatment interruption in dabrafenib treated patients should be further investigated. The results of this analysis indicate that treatment with the BRAFi vemurafenib should be interrupted during radiotherapy. Prospective studies are desperately needed.
Salivary gland (SG) hypofunction is a common post-radiotherapy complication. Besides the parenchymal damage after irradiation (IR), there are also effects on mesenchymal stem cells (MSCs) which were shown to contribute to regeneration and repair of damaged tissues by differentiating into stromal cell types or releasing vesicles and soluble factors supporting the healing processes. However, there are no adequate reports about their roles during SG damage and regeneration so far. Using an irradiated SG mouse model, we performed certain immunostainings on tissue sections of submandibular glands at different time points after IR. Immunostaining for CD31 revealed that already one day after IR, vascular impairment was induced at the level of capillaries. In addition, the expression of CD44—a marker of acinar cells—diminished gradually after IR and, by 20 weeks, almost disappeared. In contrast, the number of CD34-positive cells significantly increased 4 weeks after IR and some of the CD34-positive cells were found to reside within the adventitia of arteries and veins. Laser confocal microscopic analyses revealed an accumulation of CD34-positive cells within the area of damaged capillaries where they were in close contact to the CD31-positive endothelial cells. At 4 weeks after IR, a fraction of the CD34-positive cells underwent differentiation into α-SMA-positive cells, which suggests that they may contribute to regeneration of smooth muscle cells and/or pericytes covering the small vessels from the outside. In conclusion, SG-resident CD34-positive cells represent a population of progenitors that could contribute to new vessel formation and/or remodeling of the pre-existing vessels after IR and thus, might be an important player during SG tissue healing.
Spinning black holes in the centres of galaxies can release powerful magnetised jets. When the jets are observed at angles of less than a few degrees to the line-of-sight, they are called blazars, showing variable non-thermal emission across the electromagnetic spectrum from radio waves to gamma rays. It is commonly believed that shock waves are responsible for this dissipation of jet energy. Here we show that gamma-ray observations of the blazar 3C 279 with the space-borne telescope Fermi-LAT reveal a characteristic peak-in-peak variability pattern on time scales of minutes expected if the particle acceleration is instead due to relativistic magnetic reconnection. The absence of gamma-ray pair attenuation shows that particle acceleration takes place at a distance of ten thousand gravitational radii from the black hole where the fluid dynamical kink instability drives plasma turbulence.
Das Ziel der vorliegenden Arbeit war die Mikrokernbildung in Mundschleimhautzellen von 35 Patienten mit Kopf-Hals-Tumoren während einer sechswöchigen Radio-/Radiochemotherapie und sechs Wochen danach darzustellen. Die Ergebnisse der vorliegenden Arbeit zeigten, dass Patienten mit Kopf-Hals-Tumoren im Vergleich zu gesunden Probanden erhöhte Mikrokernraten aufwiesen. Ebenfalls konnte gezeigt werden, dass es zu einer vermehrten Bildung von Mikrokernen während einer sechswöchigen Radio-/Radiochemotherapie kam. Nach Therapiebeendigung sanken die Werte nach drei bis sechs Wochen und lagen unter dem Ausgangswert, in dem Bereich von spontan entstehenden Mikrokernen. In Bezug auf die Tumorgröße konnte nur in der zweiten Woche ein signifikanter Unterschied in der Mikrokernrate zwischen T1- und T4-Stadium beobachtet werden. Es konnte keine Korrelation zwischen einer zusätzlich verabreichten Chemotherapie, Grading des Tumors, Alter sowie Geschlecht der Patienten und einem Anstieg der Mikrokernrate festgestellt werden.
Eugenol is a phytochemical present in different plant products, e.g., clove oil. Traditionally, it is used against a number of different disorders and it was suggested to have anticancer activity. In this study, the activity of eugenol was evaluated in a human cervical cancer (HeLa) cell line and cell proliferation was examined after treatment with various concentrations of eugenol and different treatment durations. Cytotoxicity was tested using lactate dehydrogenase (LDH) enzyme leakage. In order to assess eugenol’s potential to act synergistically with chemotherapy and radiotherapy, cell survival was calculated after eugenol treatment in combination with cisplatin and X-rays. To elucidate its mechanism of action, caspase-3 activity was analyzed and the expression of various genes and proteins was checked by RT-PCR and western blot analyses. Eugenol clearly decreased the proliferation rate and increased LDH release in a concentration- and time-dependent manner. It showed synergistic effects with cisplatin and X-rays. Eugenol increased caspase-3 activity and the expression of Bax, cytochrome c (Cyt-c), caspase-3, and caspase-9 and decreased the expression of B-cell lymphoma (Bcl)-2, cyclooxygenase-2 (Cox-2), and interleukin-1 beta (IL-1β) indicating that eugenol mainly induced cell death by apoptosis. In conclusion, eugenol showed antiproliferative and cytotoxic effects via apoptosis and also synergism with cisplatin and ionizing radiation in the human cervical cancer cell line.
One of the major health consequences of the Chernobyl Nuclear Power Plant accident in 1986 was a dramatic increase in incidence of thyroid cancer among those who were aged less than 18 years at the time of the accident. This increase has been directly linked in several analytic epidemiological studies to iodine-131 (I-131) thyroid doses received from the accident. However, there remains limited understanding of factors that modify the I-131-related risk. Focusing on post-Chernobyl pediatric thyroid cancer in Belarus, we reviewed evidence of the effects of radiation, thyroid screening, and iodine deficiency on regional differences in incidence rates of thyroid cancer. We also reviewed current evidence on content of nitrate in groundwater and thyroid cancer risk drawing attention to high levels of nitrates in open well water in several contaminated regions of Belarus, i.e. Gomel and Brest, related to the usage of nitrogen fertilizers. In this hypothesis generating study, based on ecological data and biological plausibility, we suggest that nitrate pollution may modify the radiation-related risk of thyroid cancer contributing to regional differences in rates of pediatric thyroid cancer in Belarus. Analytic epidemiological studies designed to evaluate joint effect of nitrate content in groundwater and radiation present a promising avenue of research and may provide useful insights into etiology of thyroid cancer.
SEPServer is a three-year collaborative project funded by the seventh framework programme (FP7-SPACE) of the European Union. The objective of the project is to provide access to state-of-the-art observations and analysis tools for the scientific community on solar energetic particle (SEP) events and related electromagnetic (EM) emissions. The project will eventually lead to better understanding of the particle acceleration and transport processes at the Sun and in the inner heliosphere. These processes lead to SEP events that form one of the key elements of space weather. In this paper we present the first results from the systematic analysis work performed on the following datasets: SOHO/ERNE, SOHO/EPHIN, ACE/EPAM, Wind/WAVES and GOES X-rays. A catalogue of SEP events at 1 AU, with complete coverage over solar cycle 23, based on high-energy (similar to 68-MeV) protons from SOHO/ERNE and electron recordings of the events by SOHO/EPHIN and ACE/EPAM are presented. A total of 115 energetic particle events have been identified and analysed using velocity dispersion analysis (VDA) for protons and time-shifting analysis (TSA) for electrons and protons in order to infer the SEP release times at the Sun. EM observations during the times of the SEP event onset have been gathered and compared to the release time estimates of particles. Data from those events that occurred during the European day-time, i.e., those that also have observations from ground-based observatories included in SEPServer, are listed and a preliminary analysis of their associations is presented. We find that VDA results for protons can be a useful tool for the analysis of proton release times, but if the derived proton path length is out of a range of 1 AU < s less than or similar to 3 AU, the result of the analysis may be compromised, as indicated by the anti-correlation of the derived path length and release time delay from the associated X-ray flare. The average path length derived from VDA is about 1.9 times the nominal length of the spiral magnetic field line. This implies that the path length of first-arriving MeV to deka-MeV protons is affected by interplanetary scattering. TSA of near-relativistic electrons results in a release time that shows significant scatter with respect to the EM emissions but with a trend of being delayed more with increasing distance between the flare and the nominal footpoint of the Earth-connected field line.
SphK1 is known to play a role in tumor progression, resistance to radiochemotherapy, and migration patterns. As the overall survival rates of squamous cell carcinoma of the head and neck (HNSCC) remain poor due to limitations in surgery and irradiation and chemotherapy resistance, SphK1 is an important enzyme to investigate. The purpose of this study was to elucidate the impact of SphK1 on irradiation efficacy of HNSCC in-vitro with emphasis on EGFR signaling. By immunhistochemical staining we found a positive correlation between EGFR and SphK1 expression in patient specimens. In colony formation assays irradiation sensitive cell lines showed a poor response to cetuximab, an EGFR inhibitor, and SKI-II, a SphK1 inhibitor, and vice versa. In irradiation sensitive cells an enhanced reduction of cell migration and survival was found upon simultaneous targeting of EGFR and SphK1. In the present study, we elucidated a linkage between the two signaling pathways with regard to the efficacy of cetuximab treatment and the impact on the migration behavior of tumor cells. We investigated the biological impact of inhibiting these pathways and examined the biochemical implications after different treatments. An understanding of the processes involved could help to improve the treatment of patients with HNSCC.
Die Versorgung von Patienten mit konventioneller Prothetik stößt an ihre Grenzen, wenn diese anatomische Veränderungen der oralen Hart- und Weichgewebe aufweisen. Lippen-Kiefer-Gaumen-Spalten, Tumoren, entzündliche Erkrankungen und Traumata können mitunter erhebliche Knochendefekte in Ober- und Unterkiefer verursachen. Auch durch Atrophie kann die Fähigkeit der oralen Gewebe einen Zahnersatz zufrieden stellend zu tragen deutlich eingeschränkt werden. Durch ein chirurgisch-implantat-prothetisches Behandlungskonzept können derartig betroffene Patienten eine kaufunktionelle und ästhetische Rehabilitation erfahren. An der Klinik und Poliklinik für Mund-, Kiefer- und Gesichtschirurgie der Universität Würzburg wurden sowohl gesunden Patienten als auch Tumorpatienten Implantate vom Typ BoneLock® eingesetzt. Zahlreiche Patienten mit unzureichenden Kieferknochen erhielten zuvor eine Rekonstruktion bzw. Augmentation mit autogenen oder allogenen Knochentransplantaten. In diesem Behandlungskonzept schneidet das BoneLock®-Implantat für das gesamte Patientenkollektiv mit einer nach dem Verfahren von KAPLAN & MEIER ermittelten Erfolgsquote von 87,7 % nach 5 Jahren und 78,4 % nach 10 Jahren ähnlich gut ab wie andere Implantatsysteme. Es bestehen keine signifikanten Erfolgsunterschiede zwischen gesunden Patienten (77,4 % nach 10 Jahren) und Tumorpatienten (80,6 % nach 10 Jahren). Unter besonderer Berücksichtigung stehen in dieser Arbeit die verschiedenen Implantatlager. Weder bestrahlter (94,0 % nach 5 Jahren) noch transplantierter Knochen (96,6 % nach 5 Jahren) zeigt gegenüber nativem Kieferknochen (84,6 % nach 5 Jahren) einen signifikanten Unterschied bezüglich der Erfolgswahrscheinlichkeit. In erster Linie sind pathologische Ursachen, wie bindegewebige Einheilung (33,7 %) und Periimplantitis (26,9 %) als Gründe für einen Implantatverlust anzuführen. Um Veränderungen am Implantatlager und am periimplantären Weichgewebe rechtzeitig erkennen und beurteilen zu können, wurden verschiedene Indizes im Rahmen der Implantat-Nachsorge aufgenommen. Die Untersuchungen ergaben eine gute, aber mit der Zeit etwas nachlassende Pflege der Implantate. Durchschnittlich zeigte sich eine minimale bis geringgradige Entzündung der Mukosa, die mit einer leicht zunehmenden Taschensondierung einhergeht. Die Beurteilung des periimplantären Knochens ergab nur einen geringfügigen Abbau des Knochens. Lediglich zwischen Implantation und prothetischer Versorgung waren höhere Resorptionen zu ermitteln. Zwischen den unterschiedlichen Implantatlagern (nativ, bestrahlt, transplantiert) bestehen keine signifikanten Unterschiede. Die implantat-prothetische Versorgung ist als erfolgreiche Alternative zur konventionellen Prothetik schon seit geraumer Zeit bekannt und wird durch die aktuellen Ergebnisse erneut bestätigt. Die vorliegende Studie zeigt darüber hinaus, dass auch bei Tumorpatienten, sowohl im rekonstruierten als auch bestrahlten Knochen, ein implantatverankerter Zahnersatz mit gleich großem Erfolg möglich ist. Dadurch besteht die Möglichkeit einer weitgehenden kaufunktionellen und ästhetischen Rehabilitation dieser häufig durch die Tumorresektion in starke Mitleidenschaft gezogenen Personen. Insbesondere bei voran gegangener Radiatio ist jedoch bei diesen Patienten noch mehr Aufmerksamkeit der Planung, der Implantatinsertion, der Einheilung, der Anfertigung des Zahnersatzes und der Nachsorge zu widmen als bei gesunden Menschen. Ähnlich hohe Erfolgsaussichten gelten auch für Patienten, die wegen unzureichendem Implantatlager vor der Implantation eine Augmentation ihrer Kieferknochen erhielten.