Aufklärung zur Strahlentherapie: Patientenerwartungen und Auswirkung auf das Erleben der Strahlenbehandlung

Die Studie befasst sich mit dem Aufklärungsgespräch zur Strahlentherapie unter besonderer Berücksichtigung der Patientenperspektive. Es handelt sich um eine Kohortenstudie mit wiederholten Messungen (vor und nach dem Aufklärungsgespräch und nach Abschluss der Therapie). Die Kohorte bestand aus Krebspatienten, die in der Universitätsklinik Marburg ambulant strahlentherapeutisch behandelt wurden. Von insgesamt 137 Patienten durchliefen 63 Patienten die Studie komplett. Die Daten wurden teils anhand standardisierter Messinstrumente (EORTC QLQ-C30, PLC) und teils anhand selbsterstellter Fragen erhoben. Die Beobachtungsgruppe unterschied sich in demographischen Basisdaten (Alter, Geschlecht) und klinischen Kriterien (Diagnose, therapeutischer Ansatz) nicht signifikant vom Rest der Kohorte. Knapp 50% der Patienten kamen schon vorinformiert zum Aufklärungsgespräch, wobei Ärzte, Angehörige und Bekannte die wichtigsten Informationsquellen darstellten. Das Internet spielte eine untergeordnete Rolle. Die Patienten sorgten sich am häufigsten um das Thema Gesundheit/Krankheit (49%), gefolgt vom Thema Nebenwirkungen (22%). Die meisten (40%) Patienten verbanden neutrale Aspekte mit Strahlentherapie, 32% hatten positive Assoziationen (Hoffnung, Heilung) und 29% negative (z.B. z.B. Angst, Krebs). Die wichtigste Erwartung an das Aufklärungsgespräch war für 25% der Patienten Informationsgewinn, für 19% Aufbau von Vertrauen zum Arzt. Emotional betonte Aspekte, wie Angst mildern oder Beruhigung spielten kaum eine Rolle. 84% der Patienten sahen ihre Erwartungen bezüglich Informationsgewinn und Aufbau an Vertrauen nach dem Gespräch erfüllt. Insgesamt zeigten sich 73% sehr zufrieden und 27% nur mäßig bis wenig zufrieden. „Technische Informationen“ wie Bestrahlungsdauer oder Begleiterscheinungen waren nach dem Gespräch fast allen gut erinnerlich, während hinsichtlich Heilungsaussichten und Therapieziel z.T. unrealistische Erwartungen bestanden: obwohl nur zwei Drittel der Patienten mit kurativer Intention bestrahlt werden sollten, erwarteten 84% der Patienten Heilung. Hinsichtlich der Lebensqualität zeigte sich, dass diese bei der untersuchten Patientengruppe schlechter war als in der Allgemeinbevölkerung. Stärkere Unterschiede fanden sich bei der „Leistungsfähigkeit in Arbeit und Haushalt“ und in den Bereichen „soziales Leben“, „Müdigkeit“ und „Schlaflosigkeit“. Im Laufe der Therapie zeigte sich eine weitere Abnahme der Lebensqualität in den Bereichen „körperliche Leistungsfähigkeit“, „Müdigkeit“, „Schmerz“ und „Diarrhö“. Zwischen der Gesprächszufriedenheit und dem Erleben der Therapie fanden wir folgenden Zusammenhang: Je besser das Gespräch empfunden wurde, um so weniger unangenehm wurde die Strahlentherapie erlebt. Hohe Gesprächszufriedenheit führte zu weniger Nebenwirkungen, weniger Appetitlosigkeit, weniger Panik und weniger Einsamkeit. Das Gefühl, ausreichend informiert zu sein und Vertrauen zum Arzt gewonnen zu haben, führte zu weniger Nebenwirkungen, weniger Appetitlosigkeit und weniger Panik. Ergänzend wurden auch multivariate Analysen durchgeführt (in Vorbereitung auf eine englischsprachige Publikation und in dieser Arbeit nicht dargestellt), in denen Variablen wie negativer Affekt, Alter und Geschlecht als potentielle konfundierende Variablen berücksichtigt wurden (hierarchische Regressionen). Es zeigte sich, dass diese Kovariaten nur einen minimalen Beitrag zur Varianzaufklärung leisteten und der Effekt der Bewertung des Aufklärungsgespräches auf die Outcomevariablen nicht abgeschwächt wurde. In einer Nebenauswertung wurden diese Analysen nochmals für kurative und palliative Patienten getrennt vorgenommen. Für letztere war "Vertrauen zum Arzt fassen" das wichtigste Ziel des Aufklärungsgespräches. Gesprächszufirdenheit konnte Gefühle von Einsamkeit während der Therapie verringern. Schlussfolgerung: Das Aufklärungsgespräch stellt weit mehr als bloße Informationsübermittlung und juristische Absicherung des Arztes dar. Sind die Patienten mit dem Gespräch zufrieden und werden die zwei wichtigsten Wünsche der Patienten (Informiert werden und Vertrauen fassen) erfüllt, birgt es das Potential, die Strahlentherapie für den Patienten erträglicher zu machen: Nebenwirkungen werden weniger intensiv erlebt und die Patienten leiden unter weniger Panik und Einsamkeit. Somit kann es einen wichtigen Beitrag zur Verbesserung der Lebensqualität leisten. Bei Patienten mit palliativem Behandlungskonzept kann durch ein gelungenes Gespräch das Gefühl von Einsamkeit verringert werden

Decreased mitochondrial DNA content in blood samples of patients with stage I breast cancer

BACKGROUND: Alterations of mitochondrial DNA (mtDNA) have been implicated in carcinogenesis. We developed an accurate multiplex quantitative real-time PCR for synchronized determination of mtDNA and nuclear DNA (nDNA). We sought to investigate whether mtDNA content in the peripheral blood of breast cancer patients is associated with clinical and pathological parameters. METHODS: Peripheral blood samples were collected from 60 patients with breast cancer and 51 age-matched healthy individuals as control. DNA was extracted from peripheral blood for the quantification of mtDNA and nDNA, using a one-step multiplex real-time PCR. A FAM labeled MGB probe and primers were used to amplify the mtDNA sequence of the ATP 8 gene, and a VIC labeled MGB probe and primers were employed to amplify the glyceraldehyde-3-phosphate-dehydrogenase gene. mtDNA content was correlated with tumor stage, menstruation status, and age of patients as well as lymph node status and the expression of estrogen receptor (ER), progesterone receptor (PR) and Her-2/neu protein. RESULTS: The content of mtDNA in stage I breast cancer patients was significantly lower than in other stages (overall P = 0.023). Reduced mtDNA was found often in post menopausal cancer group (P = 0.024). No difference in mtDNA content, in regards to age (p = 0.564), lymph node involvement (p = 0.673), ER (p = 0.877), PR (p = 0.763), and Her-2/neu expression (p = 0.335), was observed. CONCLUSION: Early detection of breast cancer has proved difficult and current detection methods are inadequate. In the present study, decreased mtDNA content in the peripheral blood of patients with breast cancer was strongly associated with stage I. The use of mtDNA may have diagnostic value and further studies are required to validate it as a potential biomarker for early detection of breast cancer

Dual PI3K/mTOR inhibitor NVP-BEZ235 enhances radiosensitivity of head and neck squamous cell carcinoma (HNSCC) cell lines due to suppressed Double-Strand Break (DSB) repair by non-homologous end joining

The PI3K/Akt/mTOR pathway is frequently altered in human papillomavirus (HPV)-positive and negative squamous cell carcinoma of the head and neck (HNSCC) and overstimulation is associated with poor prognosis. PI3K drives Akt activation and constitutive signaling acts pro-proliferative, supports cell survival, DNA repair, and contributes to radioresistance. Since the small molecule NVP-BEZ235 (BEZ235) is a potent dual inhibitor of this pathway, we were interested whether BEZ235 could be an efficient radiosensitizer. The 50 nM BEZ235 was found to abrogate endogenous and irradiation-induced phosphorylation of Akt (Ser473). The anti-proliferative capacity of the drug resulted in an increase in G1-phase cells. Repair of radiation-induced DNA double-strand breaks (DSBs) was strongly suppressed. Reduction in DSB repair was only apparent in G1- but not in G2-phase cells, suggesting that BEZ235 primarily affects non-homologous end joining. This finding was confirmed using a DSB repair reporter gene assay and could be attributed to an impaired phosphorylation of DNA-PKcs (S2056). Cellular radiosensitivity increased strongly after BEZ235 addition in all HNSCC cell lines used, especially when irradiated in the G0 or G1 phase. Our data indicate that targeting the PI3K/Akt/mTOR pathway by BEZ235 with concurrent radiotherapy may be considered an effective strategy for the treatment of HNSCC, regardless of the HPV and Akt status

Phase I/II trial evaluating carbon ion radiotherapy for the treatment of recurrent rectal cancer: the PANDORA-01 trial

<p>Abstract</p> <p>Background</p> <p>Treatment standard for patients with rectal cancer depends on the initial staging and includes surgical resection, radiotherapy as well as chemotherapy. For stage II and III tumors, radiochemotherapy should be performed in addition to surgery, preferentially as preoperative radiochemotherapy or as short-course hypofractionated radiation. Advances in surgical approaches, especially the establishment of the total mesorectal excision (TME) in combination with sophisticated radiation and chemotherapy have reduced local recurrence rates to only few percent. However, due to the high incidence of rectal cancer, still a high absolute number of patients present with recurrent rectal carcinomas, and effective treatment is therefore needed.</p> <p>Carbon ions offer physical and biological advantages. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increase relative biological effectiveness (RBE), which can be calculated between 2 and 5 depending on the cell line as well as the endpoint analyzed.</p> <p>Japanese data on the treatment of patients with recurrent rectal cancer previously not treated with radiation therapy have shown local control rates of carbon ion treatment superior to those of surgery. Therefore, this treatment concept should also be evaluated for recurrences after radiotherapy, when dose application using conventional photons is limited. Moreover, these patients are likely to benefit from the enhanced biological efficacy of carbon ions.</p> <p>Methods and design</p> <p>In the current Phase I/II-PANDORA-01-Study the recommended dose of carbon ion radiotherapy for recurrent rectal cancer will be determined in the Phase I part, and feasibilty and progression-free survival will be assessed in the Phase II part of the study.</p> <p>Within the Phase I part, increasing doses from 12 × 3 Gy E to 18 × 3 Gy E will be applied.</p> <p>The primary endpoint in the Phase I part is toxicity, the primary endpoint in the Phase II part is progression-free survival.</p> <p>Discussion</p> <p>With conventional photon irradiation treatment of recurrent rectal cancer is limited, and the clinical effect is only moderate. With carbon ions, an improved outcome can be expected due to the physical and biological characteristics of the carbon ion beam. However, the optimal dose applicable in this clincial situation as re-irradiation still has to be determined. This, as well as efficacy, is to be evaluated in the present Phase I/II trial.</p> <p>Trial registration</p> <p><a href="http://www.clinicaltrials.gov/ct2/show/NCT01528683">NCT01528683</a></p

Siah1 proteins enhance radiosensitivity of human breast cancer cells

<p>Abstract</p> <p>Background</p> <p>Siah proteins play an important role in cancer progression. We evaluated the effect of Siah1, its splice variants Siah1L and the Siah1 mutant with the RING finger deleted (Siah1ΔR) on radiosensitization of human breast cancer cells.</p> <p>Methods</p> <p>The status of Siah1 and Siah1L was analysed in five breast cancer cell lines. To establish stable cells, SKBR3 cells were transfected with Siah1, Siah-1L and Siah1ΔR. Siah1 function was suppressed by siRNA in MCF-7 cells. The impact of Siah1 overexpression and silencing on apoptosis, proliferation, survival, invasion ability and DNA repair was assessed in SKBR3 and MCF-7 cells, also in regards to radiation.</p> <p>Results</p> <p>Siah1 and Siah1L mRNA expression was absent in four of five breast cancer cells lines analysed. Overexpression of Siah1 and Siah1L enhanced radiation-induced apoptosis in stable transfected SKBR3 cells, while Siah1ΔR failed to show this effect. In addition, Siah1 and Siah1L significantly reduced cell clonogenic survival and proliferation. Siah1L sensitization enhancement ratio values were over 1.5 and 4.0 for clonogenic survival and proliferation, respectively, pointing to a highly cooperative and potentially synergistic fashion with radiation. Siah1 or Siah1L significantly reduced invasion ability of SKBR3 and suppressed Tcf/Lef factor activity. Importantly, Siah1 siRNA demonstrated opposite effects in MCF-7 cells. Siah1 and Siah1L overexpression resulted in inhibition of DNA repair as inferred by increased levels of DNA double-strand breaks in irradiated SKBR3 cells.</p> <p>Conclusion</p> <p>Our results reveal for the first time how overexpression of Siah1L and Siah1 can determine radiosensitivity of breast cancer cells. These findings suggest that development of drugs augmenting Siah1 and Siah1L activity could be a novel approach in improving tumor cell kill.</p

Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients

<p>Abstract</p> <p>Background</p> <p>Malignant gliomas are lethal cancers, highly dependent on angiogenesis and treatment options and prognosis still remain poor for patients with recurrent glioblastoma multiforme (GBM). Ephs and ephrins have many well-defined functions during embryonic development of central nervous system such as axon mapping, neural crest cell migration, hindbrain segmentation and synapse formation as well as physiological and abnormal angiogenesis. Accumulating evidence indicates that Eph and ephrins are frequently overexpressed in different tumor types including GBM. However, their role in tumorigenesis remains controversial, as both tumor growth promoter and suppressor potential have been ascribed to Eph and ephrins while the function of EphA7 in GBM pathogenesis remains largely unknown.</p> <p>Methods</p> <p>In this study, we investigated the immunohistochemical expression of EphA7 in a series of 32 primary and recurrent GBM and correlated it with clinical pathological parameters and patient outcome. In addition, intratumor microvascular density (MVD) was quantified by immunostaining for endothelial cell marker von Willebrand factor (vWF).</p> <p>Results</p> <p>Overexpression of EphA7 protein was predictive of the adverse outcome in GBM patients, independent of MVD expression (p = 0.02). Moreover, high density of MVD as well as higher EphA7 expression predicted the disease outcome more accurately than EphA7 variable alone (p = 0.01). There was no correlation between MVD and overall survival or recurrence-free survival (p > 0.05). However, a statistically significant correlation between lower MVD and tumor recurrence was observed (p = 0.003).</p> <p>Conclusion</p> <p>The immunohistochemical assessment of tissue EphA7 provides important prognostic information in GBM and would justify its use as surrogate marker to screen patients for tyrosine kinase inhibitor therapy.</p