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Institute
- Frauenklinik und Poliklinik (141) (remove)
EU-Project number / Contract (GA) number
- 259867 (1)
Background: The majority of breast cancer patients are severely psychologically affected by breast cancer diagnosis and subsequent therapeutic procedures. The COVID-19 pandemic and associated restrictions on public life have additionally caused significant psychological distress for much of the population. It is therefore plausible that breast cancer patients might be particularly susceptible to the additional psychological stress caused by the pandemic, increasing suffering. In this study we therefore aimed to assess the level of psychological distress currently experienced by a defined group of breast cancer patients in our breast cancer centre, compared to distress levels preCOVID-19 pandemic.
Methods: Female breast cancer patients of all ages receiving either adjuvant, neoadjuvant, or palliative therapies were recruited for the study. All patients were screened for current or previous COVID-19 infection. The participants completed a self-designed COVID-19 pandemic questionnaire, the Stress and Coping Inventory (SCI), the National Comprehensive Cancer Network (R) (NCCN (R)) Distress Thermometer (DT), the European Organization for Research and Treatment of Cancer (EORTC) QLQ C30, and the BR23.
Results: Eighty-two breast cancer patients were included. Therapy status and social demographic factors did not have a significant effect on the distress caused by the COVID-19 pandemic. The results of the DT pre and during COVID-19 pandemic did not differ significantly. Using the self-designed COVID-19 pandemic questionnaire, we detected three distinct subgroups demonstrating different levels of concerns in relation to SARS-CoV-2. The subgroup with the highest levels of concern reported significantly decreased life quality, related parameters and symptoms.
Conclusions: This monocentric study demonstrated that the COVID-19 pandemic significantly affected psychological health in a subpopulation of breast cancer patients. The application of a self-created "COVID-19 pandemic questionnaire"could potentially be used to help identify breast cancer patients who are susceptible to increased psychological distress due to the COVID-19 pandemic, and therefore may need additional intensive psychological support.
Ovarian cancer currently causes ~6,000 deaths per year in Germany alone. Since only palliative treatment is available for ovarian carcinomas that have developed resistance against platinum-based chemotherapy and paclitaxel, there is a pressing medical need for the development of new therapeutic approaches. As survival is strongly influenced by immunological parameters, immunotherapeutic strategies appear promising. The research of our group thus aims at overcoming tumour immune escape by counteracting immunosuppressive mechanisms in the tumour microenvironment. In this context, we found that tumour-infiltrating myeloid-derived suppressor cells (MDSC) or tumour associated macrophages (TAM) which are abundant in ovarian cancer express high levels of the enzyme 11β-hydroxysteroid dehydrogenase1 (11-HSD1). This oxido-reductase enzyme is essential for the conversion of biologically inactive cortisone into active cortisol. In line with this observation, high endogenous cortisol levels could be detected in serum, ascitic fluid and tumour exudates from ovarian cancer patients. Considering that cortisol exerts strong anti-inflammatory and immunosuppressive effects on immune cells, it appears likely that high endogenous cortisol levels contribute to immune escape in ovarian cancer. We thus hypothesised that local activation of endogenous glucocorticoids could suppress beneficial immune responses in the tumour microenvironment and thereby prevent a successful immunotherapy. To investigate the in vivo relevance of this postulated immune escape mechanism, irradiated PTENloxP/loxP loxP-Stop-loxP-krasG12D mice were reconstituted with hematopoietic stem cells from either glucocorticoid receptor (GR) expressing mice (GRloxP/loxP) or from mice with a T cell-specific glucocorticoid receptor knock-out (lck-Cre GRloxP/loxP) mice. In the host mice, the combination of a conditional PTEN knock-out with a latent oncogenic kras leads to tumour development when a Cre-encoding adenovirus is injected into the ovarian bursa. Using this model, mice that had been reconstituted with GC-insensitive T cells showed better intratumoural T cell infiltration than control mice that had received functionally unaltered GRloxP/loxP cells via adoptive transfer. However, tumour-infiltrating T cells mostly assumed a Foxp3+ (regulatory) phenotype and survival was even shortened in mice with cortisol-insensitive T cells. Thus, endogenous cortisol seems to inhibit immune cell infiltration in ovarian cancer, but productive anti-tumour immune responses might still be prevented by further factors from the tumour microenvironment. Thus, our data did not provide a sufficiently strong rationale to further pursue the antagonisation of glucocorticoid signalling in ovarian cancer patients, Moreover, glucocorticoids are frequently administered to cancer patients to reduce inflammation and swelling and to prevent chemotherapy-related toxic side effects like nausea or hypersensitivity reactions associated with paclitaxel therapy. Thus, we decided to address the question whether specific signalling pathways in innate immune cells, preferentially in NK cells, could still be activated even in the presence of GC. A careful investigation of the various activating NK cell receptors (i.e. NKp30, NKp44, NKp46), DNAM-1 and NKG2D) was thus performed which revealed that NKp30, NKp44 and NKG2D are all down-regulated by cortisol whereas NKp46 is actually induced by cortisol. Interestingly, NKp46 is the only known receptor that is strictly confined to NK cells. Its activation via crosslinking leads to cytokine release and activation of cytotoxic activity. Stimulation of NK cells via NKp46 may contribute to immune-mediated tumour destruction by triggering the lysis of tumour cells and by altering the cytokine pattern in the tumour microenvironment, thereby generating more favourable conditions for the recruitment of antigen-specific immune cells. Accordingly, our observation that even cortisol-treated NK cells can still be activated via NKp46 and CD2 might become valuable for the design of immunotherapies that can still be applied in the presence of endogenous or therapeutically administered glucocorticoids.
Background
Mammography and ultrasound are the gold standard imaging techniques for preoperative assessment and for monitoring the efficacy of neoadjuvant chemotherapy in breast cancer. Maximum accuracy in predicting pathological tumor size non-invasively is critical for individualized therapy and surgical planning. We therefore aimed to assess the accuracy of tumor size measurement by ultrasound and mammography in a multicentered health services research study.
Methods
We retrospectively analyzed data from 6543 patients with unifocal, unilateral primary breast cancer. The maximum tumor diameter was measured by ultrasound and/or mammographic imaging. All measurements were compared to final tumor diameter determined by postoperative histopathological examination. We compared the precision of each imaging method across different patient subgroups as well as the method-specific accuracy in each patient subgroup.
Results
Overall, the correlation with histology was 0.61 for mammography and 0.60 for ultrasound. Both correlations were higher in pT2 cancers than in pT1 and pT3. Ultrasound as well as mammography revealed a significantly higher correlation with histology in invasive ductal compared to lobular cancers (p < 0.01). For invasive lobular cancers, the mammography showed better correlation with histology than ultrasound (p = 0.01), whereas there was no such advantage for invasive ductal cancers. Ultrasound was significantly superior for HR negative cancers (p < 0.001). HER2/neu positive cancers were also more precisely assessed by ultrasound (p < 0.001). The size of HER2/neu negative cancers could be more accurately predicted by mammography (p < 0.001).
Conclusion
This multicentered health services research approach demonstrates that predicting tumor size by mammography and ultrasound provides accurate results. Biological tumor features do, however, affect the diagnostic precision.
Background
The onset of mental illness such as depression and anxiety disorders in pregnancy and postpartum period is common. The coronavirus induced disease 2019 (COVID-19) pandemic and the resulting public policy responses represent an exceptional situation worldwide and there are hints for adverse psychosocial impact, hence, the study of psychological effects of the pandemic in women during hospitalization for delivery and in the postpartum period is highly relevant.
Methods
Patients who gave birth during the first wave of the COVID-19 pandemic in Germany (March to June 2020) at the Department of Obstetrics and Gynecology, University of Würzburg, Germany, were recruited at hospital admission for delivery. Biosamples were collected for analysis of SARS-CoV-2 infection and various stress hormones and interleukin-6 (IL-6). In addition to sociodemographic and medical obstetric data, survey questionnaires in relation to concerns about and fear of COVID-19, depression, stress, anxiety, loneliness, maternal self-efficacy and the mother–child bonding were administered at T1 (delivery stay) and T2 (3–6 months postpartum).
Results
In total, all 94 recruited patients had a moderate concern of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at T1 with a significant rise at T2. This concern correlated with low to low-medium general psychosocial stress levels and stress symptoms, and the women showed a significant increase of active coping from T1 to T2. Anxiety levels were low and the Edinburgh Postnatal Depression Scale showed a medium score of 5 with a significant (T1), but only week correlation with the concerns about SARS-CoV-2. In contrast to the overall good maternal bonding without correlation to SARS-CoV-2 concern, the maternal self-efficiency correlated negatively with the obstetric impairment caused by the COVID-19 pandemic.
Conclusion
Obstetric patients` concerns regarding SARS-CoV-2 and the accompanying pandemic increased during the course of the pandemic correlating positively with stress and depression. Of note is the increase in active coping over time and the overall good mother–child-bonding. Maternal self-efficacy was affected in part by the restrictions of the pandemic.
The Marketing Effect
(2010)
Wiederholte Abortgeschehen bedeuten für Frauen und deren Partner ein großes Trauma, Trauer und Verzweiflung nehmen mit jeder weiteren Fehlgeburt zu.
Daraus ergibt sich in jeder Beziehung ein großer Handlungsbedarf, den man versuchte, in den letzten Jahrzehnten durch die Entwicklung zahlreicher Behandlungsansätze mehr oder minder gerecht zu werden.
Eine dieser Behandlungsansätze ist das Leukozytenultrafiltrat LeukoNorm CytoChemia®, das aus Vollblut von Spendern gewonnen wird und bis Ende 2006 zur Behandlung des wiederholten Spontanaborts in Deutschland zugelassen war.
In dieser Arbeit wurde der Einfluss von LeukoNorm CytoChemia® auf die Schwangerschaften von 108 Frauen untersucht, die bereits drei oder mehr Aborte durchlebt hatten. Insgesamt wurden 446 Schwangerschaften ohne und 170 Schwangerschaften mit LeukoNorm CytoChemia® untersucht. Eine placebokontrollierte randomisierte Doppelblindstudie schied aufgrund der gegebenen Datenlage und insbesondere aus ehtischen Gründen und auch wegen der mangelnden Patientencompliance aus. Es wurden die Abort- bzw. die Geburtenraten ohne und mit LeukoNorm CytoChemia® verglichen. Weiterhin wurden die Zeitpunkte der Aborte bzw. der Geburten auf möglicherweise vorhandene Unterschiede verglichen. Weitere Punkte waren die Geburtsparameter Größe, Gewicht und Kopfumfang der beiden Gruppen. Schließlich wurde noch untersucht, ob adjuvante Therapien zu LeukoNorm CytoChemia® wie ASS, niedermolekulares Heparin, Progesteron oder Folsäure einen Einfluss auf die Baby-Take-Home-Rate nahmen.
Es zeigte sich, dass Frauen nach einer Therapie mit LeukoNorm CytoChemia® signifikant häufiger ein Kind lebend gebären als im Vergleich zu vor der Therapie. Ebenso wurde eine Zunahme der Mehrlingsrate unter LeukoNorm CytoChemia® festgestellt. Hinsichtlich der Zeitpunkte, in denen die Aborte und die Geburten auftraten, ergaben sich keine signifikanten Unterschiede. Auch bezüglich der Geburtsparameter ergaben sich keine wesentlichen Unterschiede zwischen der Behandlungs- und Beobachtungsgruppe. Es wurden keine schwereren, jedoch größere Kinder geboren. Dieses Ergebnis ist schwer nachvollziehbar und sollte aufgrund der geringen Anzahl der erfassten Parameter und der daraus resultierenden statistischen Ungenauigkeit zurückhaltend interpretiert werden. Eine zusätzliche Gabe von anderen Medikamenten zu LeukoNorm CytoChemia® erbrachte in unserer Studie keine weiteren Vorteile im Hinblick auf die Geburtenrate.
Wir formulieren deshalb aus unseren Ergebnissen die These, dass LeukoNorm CytoChemia® insbesondere die Implantation und den Erhalt der Frühschwangerschaft unterstützt, nicht jedoch die späteren Stadien der Schwangerschaft.
Der Wirkungsmechanismus von LeukoNorm CytoChemia® ist bis heute nicht wirklich bekannt.
Trotz der methodischen Einschränkung durch das Fehlen einer Kontrollgruppe bzw. im Sinne einer Placebogruppe zeigt ein Vorher-Nachher-Vergleich eine deutliche Steigerung der Baby-Take-Home-Rate. Um die Höhe eines Placeboeffektes bzw. der Tender-Loving-Care zu erfassen, wäre eine prospektive randomisierte Doppelblindstudie wünschenswert, sobald das Medikament wieder auf dem europäischen Markt erhältlich ist. Auch in Anbetracht der hier dokumentierten positiven Ergebnisse bleibt es weiterhin sehr zweifelhaft, ob eine solche Studie eine ethische Zulassung bekäme, von der erforderlichen Patientencompliance einmal ganz abgesehen.
Background
Overexpression of transketolase-like 1 protein TKTL1 in cancer cells has been reported to correlate with enhanced glycolysis and lactic acid production. Furthermore, enhanced TKTL1 expression was put into context with resistance to chemotherapy and ionizing radiation. Here, a panel of human malign and benign cells, which cover a broad range of chemotherapy and radiation resistance as well as reliance on glucose metabolism, was analyzed in vitro for TKTL1 expression.
Methods
17 malign and three benign cell lines were characterized according to their expression of TKTL1 on the protein level with three commercially available anti-TKTL1 antibodies utilizing immunohistochemistry and Western blot, as well as on mRNA level with three published primer pairs for RT-qPCR. Furthermore, sensitivities to paclitaxel, cisplatin and ionizing radiation were assessed in cell survival assays. Glucose consumption and lactate production were quantified as surrogates for the “Warburg effect”.
Results
Considerable amounts of tktl1 mRNA and TKTL1 protein were detected only upon stable transfection of the human embryonic kidney cell line HEK293 with an expression plasmid for human TKTL1. Beyond that, weak expression of endogenous tktl1 mRNA was measured in the cell lines JAR and U251. Western blot analysis of JAR and U251 cells did not detect TKTL1 at the expected size of 65 kDa with all three antibodies specific for TKTL1 protein and immunohistochemical staining was observed with antibody JFC12T10 only. All other cell lines tested here revealed expression of tktl1 mRNA below detection limits and were negative for TKTL1 protein. However, in all cell lines including TKTL1-negative HEK293-control cells, antibody JFC12T10 detected multiple proteins with different molecular weights. Importantly, JAR and U251 did neither demonstrate an outstanding production of lactic acid nor increased resistance against chemotherapeutics or to ionizing radiation, respectively.
Conclusion
Using RT-qPCR and three different antibodies we observed only exceptional occurrence of TKTL1 in a panel of malignant human cell lines in vitro. The presence of TKTL1 was unrelated to either the rate of glucose consumption/lactic acid production or resistance against chemo- and radiotherapy.
Objective
In this study, we investigated to which extent patients feel well informed about their disease and treatment, which areas they wish more or less information and which variables are associated with a need for information about the disease, medical tests and treatment.
Methods
In a German multi-centre prospective study, we enrolled 759 female breast cancer patients at the time of cancer diagnosis (baseline). Data on information were captured at 5 years after diagnosis with the European Organisation for Research and Treatment of Cancer (EORTC) Information Module (EORTC QLQ-INFO24). Good information predictors were analysed using linear regression models.
Results
There were 456 patients who participated at the 5-year follow-up. They reported to feel well informed about medical tests (mean score 78.5) and the disease itself (69.3) but relatively poorly about other services (44.3) and about different places of care (31.3). The survivors expressed a need for more information concerning: side effects and long-term consequences of therapy, more information in general, information about aftercare, prognosis, complementary medicine, disease and therapy. Patients with higher incomes were better informed about medical tests (β 0.26, p 0.04) and worse informed with increasing levels of fear of treatment (β − 0.11, p 0.02). Information about treatment was reported to be worse by survivors > 70 years old (β -0.34, p 0.03) and by immigrants (β -0.11, p 0.02). Survivors who had received additional written information felt better informed about disease, medical tests, treatment and other services (β 0.19/0.19/0.20/0.25; each p < 0.01).
Conclusion
Health care providers have to reconsider how and what kind of information they provide. Providing written information, in addition to oral information, may improve meeting those information needs.
Das Endometriumkarzinom ist die häufigste Neoplasie des weiblichen Genitales. Trotz guter Therapieerfolge und deutlich verbesserter Früherkennungsrate liegt die relative 5-JÜR im Stadium 4 bei unter 16%. Zur Wahl einer möglichst individuell angepassten Therapie ist es wichtig die Prognose möglichst gut einschätzen zu können, hierzu dienen die Prognosefaktoren. Neben aggressiven Eigenschaften eines Tumors wird der klinische Verlauf maßgeblich von der Immunabwehr der Patientin bestimmt. Einige Studien weisen darauf hin, dass dendritische Zellen (DC) an der Tumorimmunität teilhaben, und somit den Verlauf maligner Tumorerkrankungen beeinflussen. Wir untersuchten, ob die Tumor-Infiltration durch S100 positive dendritische Zellen ein prognostischer Marker für das Endometriumkarzinom sein könnte. In dieser retrospektiven Studie wurden 115 Gewebeproben von Endometriumkarzinomen mit bekanntem histologischem Grading, Hormonrezeptorstatus, Ki-67, Her-2/neu und p53 Expression analysiert. Die paraffinierten Gewebeschnitte wurden immunhistochemisch mit dem Antikörper S100 gefärbt. Anschließend wurde die Anzahl tumorinfiltrierender S100 positiver dendritischer Zellen mikroskopisch bestimmt und die Anzahl S100 positiver DC/cm2 Tumorgewebe berechnet. Die Ergebnisse wurden anschließend in zwei Gruppen unterteilt, wobei die erste Gruppe weniger als 10 S100 positive DC/cm2 (n=44) und die zweite Gruppe mehr als 10 S100 positive DC/cm2 (n=71) enthielt. Die Korrelation der histopathologischen und klinischen Parameter mit der Anzahl S100 positiver DC wurde mit dem Chi-Quadrat-Test berechnet. Verglichen mit Gruppe eins zeigte Gruppe zwei einen höheren Differenzierungsgrad (p=0,045), eine geringere Expression von p53 (p=0,021) und eine geringere Proliferationsrate (p=0,028). Die Infiltration durch dendritische Zellen war nicht korreliert mit Her-2/neu, Hormonrezeptorstatus und FIGO-Stage. Obwohl keine signifikante Korrelation bestand, schien die DC-arme Gruppe mit einem höheren FIGO-Stadium assoziiert zu sein als die DC-reiche Gruppe. In der uni- und multivariaten Analyse konnte die Infiltration durch dendritische Zellen als signifikanter prognostischer Marker bezüglich bereinigter Überlebensrate, jedoch nicht bezüglich Gesamtüberlebensrate bestätigt werden. Schlussfolgerung Unsere Ergebnisse zeigen, dass der immunhistochemische Nachweis S100 positiver dendritischer Zellen im Endometriumkarzinom zur Identifizierung einer High-Risk Gruppe beitragen könnte und deshalb einen guten Prognosefaktor für diese Erkrankung darstellt. Unsere Beobachtung, dass eine verstärkte Infiltration des Karzinomgewebes durch dendritische Zellen mit einer verbesserten Prognose assoziiert ist, deutet auf die wichtige Rolle der Immunantwort auf den klinischen Verlauf von Patientinnen, die an einem Endometriumkarzinom erkrankt sind hin.
Immune checkpoint blockade therapy is beneficial and even curative for some cancer patients. However, the majority don’t respond to immune therapy. Across different tumor types, pre-existing T cell infiltrates predict response to checkpoint-based immunotherapy. Based on in vitro pharmacological studies, mouse models and analyses of human melanoma patients, we show that the cytokine GDF-15 impairs LFA-1/β2-integrin-mediated adhesion of T cells to activated endothelial cells, which is a pre-requisite of T cell extravasation. In melanoma patients, GDF-15 serum levels strongly correlate with failure of PD-1-based immune checkpoint blockade therapy. Neutralization of GDF-15 improves both T cell trafficking and therapy efficiency in murine tumor models. Thus GDF-15, beside its known role in cancer-related anorexia and cachexia, emerges as a regulator of T cell extravasation into the tumor microenvironment, which provides an even stronger rationale for therapeutic anti-GDF-15 antibody development.