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Background: Matrix metalloproteinases (MMPs) are involved in the degradation of protein components of the extracellular matrix and thus play an important role in tumor invasion and metastasis. Their expression is related to the progression of gynecological cancers (e.g. endometrial, cervical or ovarian carcinoma). In this study we investigated the expression pattern of the 23 MMPs, currently known in humans, in different gynecological cancer cell lines. Methods: In total, cell lines from three endometrium carcinomas (Ishikawa, HEC-1-A, AN3 CA), three cervical carcinomas (HeLa, Caski, SiHa), three chorioncarcinomas (JEG, JAR, BeWo), two ovarian cancers (BG-1, OAW-42) and one teratocarcinoma (PA-1) were examined. The expression of MMPs was analyzed by RT-PCR, Western blot and gelatin zymography. Results: We demonstrated that the cell lines examined can constitutively express a wide variety of MMPs on mRNA and protein level. While MMP-2, -11, -14 and -24 were widely expressed, no expression was seen for MMP-12, -16, -20, -25, -26, -27 in any of the cell lines. A broad range of 16 MMPs could be found in the PA1 cells and thus this cell line could be used as a positive control for general MMP experiments. While the three cervical cancer cell lines expressed 10-14 different MMPs, the median expression in endometrial and choriocarcinoma cells was 7 different enzymes. The two investigated ovarian cancer cell lines showed a distinctive difference in the number of expressed MMPs (2 vs. 10). Conclusions: Ishikawa, Caski, OAW-42 and BeWo cell lines could be the best choice for all future experiments on MMP regulation and their role in endometrial, cervical, ovarian or choriocarcinoma development, whereas the teratocarcinoma cell line PA1 could be used as a positive control for general MMP experiments.
Purpose
The reliable detection of tumor-infiltrated axillary lymph nodes for breast cancer [BC] patients plays a decisive role in further therapy. We aimed to find out whether cross-sectional imaging techniques could improve sensitivity for pretherapeutic axillary staging in nodal-positive BC patients compared to conventional imaging such as mammography and sonography.
Methods
Data for breast cancer patients with tumor-infiltrated axillary lymph nodes having received surgery between 2014 and 2020 were included in this study.
All examinations (sonography, mammography, computed tomography [CT] and magnetic resonance imaging [MRI]) were interpreted by board-certified specialists in radiology. The sensitivity of different imaging modalities was calculated, and binary logistic regression analyses were performed to detect variables influencing the detection of positive lymph nodes.
Results
All included 382 breast cancer patients had received conventional imaging, while 52.61% of the patients had received cross-sectional imaging.
The sensitivity of the combination of all imaging modalities was 68.89%. The combination of MRI and CT showed 63.83% and the combination of sonography and mammography showed 36.11% sensitivity.
Conclusion
We could demonstrate that cross-sectional imaging can improve the sensitivity of the detection of tumor-infiltrated axillary lymph nodes in breast cancer patients. Only the safe detection of these lymph nodes at the time of diagnosis enables the evaluation of the response to neoadjuvant therapy, thereby allowing access to prognosis and improving new post-neoadjuvant therapies.
Evaluation of clinical parameters influencing the development of bone metastasis in breast cancer
(2016)
Background
The development of metastases is a negative prognostic parameter for the clinical outcome of breast cancer. Bone constitutes the first site of distant metastases for many affected women. The purpose of this retrospective multicentre study was to evaluate if and how different variables such as primary tumour stage, biological and histological subtype, age at primary diagnosis, tumour size, the number of affected lymph nodes as well as grading influence the development of bone-only metastases.
Methods
This retrospective German multicentre study is based on the BRENDA collective and included 9625 patients with primary breast cancer recruited from 1992 to 2008. In this analysis, we investigated a subgroup of 226 patients with bone-only metastases. Association between bone-only relapse and clinico-pathological risk factors was assessed in multivariate models using the tree-building algorithms “exhausted CHAID (Chi-square Automatic Interaction Detectors)” and CART(Classification and Regression Tree), as well as radial basis function networks (RBF-net), feedforward multilayer perceptron networks (MLP) and logistic regression.
Results
Multivariate analysis demonstrated that breast cancer subtypes have the strongest influence on the development of bone-only metastases (χ2 = 28). 29.9 % of patients with luminal A or luminal B (ABC-patients) and 11.4 % with triple negative BC (TNBC) or HER2-overexpressing tumours had bone-only metastases (p < 0.001). Five different mathematical models confirmed this correlation. The second important risk factor is the age at primary diagnosis. Moreover, BC subcategories influence the overall survival from date of metastatic disease of patients with bone-only metastases. Patients with bone-only metastases and TNBC (p < 0.001; HR = 7.47 (95 % CI: 3.52–15.87) or HER2 overexpressing BC (p = 0.007; HR = 3.04 (95 % CI: 1.36–6.80) have the worst outcome compared to patients with luminal A or luminal B tumours and bone-only metastases.
Conclusion
The bottom line of different mathematical models is the prior importance of subcategories of breast cancer and the age at primary diagnosis for the appearance of osseous metastases. The primary tumour stage, histological subtype, tumour size, the number of affected lymph nodes, grading and NPI seem to have only a minor influence on the development of bone-only metastases.
Ziel dieser Arbeit war es, die psychische Belastung bei Patientinnen mit auffälligen PAP-Abstrichen oder dysplastischen Veränderungen der Zervix uteri im Rahmen der Dysplasie-Sprechstunde zu erheben. Durch Auswertung und Analyse der Daten im Rahmen des Qualitätsmanagements sollte eine Grundlage für eine verbesserte und angepasste Versorgung geschaffen werden. In dem erhobenen Fragebogen waren vier Fragen von besonderer Bedeutung - die Informationslage bei Vorstellung, die Art der Informationsbeschaffung, der mögliche Wunsch nach mehr Information und der Bildungsstand.
In der Auswertung des ausgeteilten Fragebogens konnte erhoben werden, dass 56,9% der Patientinnen bei der Erstvorstellung psychisch belastet waren. Das ist ein großer Anteil in Anbetracht der Tatsache, dass das PAP-Screening eine jährliche Vorsorgeuntersuchung für über 15 Millionen Frauen darstellt [19]. Der Großteil der in der Dysplasie-Sprechstunde erhobenen PAP-Abstriche waren auffällig und somit weiter abklärungsbedürftig. Über 70% der HPV-Tests waren „high risk“ positiv. Der Mittelwert der Verteilung des Alters lag bei 44 Jahren, was bedeutet, dass viele junge Frauen mit potenziell bestehendem Kinderwunsch oder jungen Familien betroffen sind. Die jungen Frauen sind durchschnittlich besser gebildet und psychisch belasteter als die Kohorte der älteren Patientinnen.
Ein Blick auf die Verteilung der Bildung zeigt, dass bei Betrachtung der gesamten Kohorte, schlechter gebildete Frauen verunsicherter sind. Viele der Patientinnen, 40,9%, fühlten sich vor der Erstvorstellung nicht ausreichend informiert und mehr als 53,8% der Patientinnen hätten sich mehr Informationen gewünscht. Sieht man sich die Antworten auf die Frage nach der Quelle der Informationsbeschaffung an, fällt auf, dass mit 68,5% weiterhin der/die betreuende Arzt/Ärztin die wichtigste Informationsquelle darstellt.
Zusammenfassend lässt sich sagen, dass trotz des 2020 deutschlandweit begonnenen organisierten Screenings die betroffenen Frauen anhaltend belastet sind und sich mehr Informationen wünschen. Ein wichtiger Schritt zur Vorbeugung psychischer Belastung wäre eine verbesserte Vermittlung von Information seitens der behandelnden Ärzte/Ärztinnen, auch unter Hinweis auf die online zur Verfügung stehenden Informationen des Bundesministeriums für Gesundheit.
Evaluating the value of a 3D printed model for hands-on training of gynecological pelvic examination
(2022)
Background
Simulation in the field of gynecological pelvic examination with educational purposes holds great potential. In the current manuscript we evaluate a 3D printed model of the female pelvis, which improves practical teaching of the gynecological pelvic examination for medical staff.
Methods
We evaluated the benefit of a 3D printed model of the female pelvis (Pelvisio®) as part of a seminar (“skills training”) for teaching gynecological examination to medical students. Each student was randomly assigned to Group A or B by picking a ticket from a box. Group A underwent the skills training without the 3D printed model. Group B experienced the same seminar with integration of the model. Both groups evaluated the seminar by answering five questions on Likert scales (1–10, 1 = “very little” or “very poor”, 10 equals “very much” or “very good”). Additionally, both groups answered three multiple-choice questions concerning pelvic anatomy (Question 6 to 8). Finally, Group B evaluated the 3D printed model with ten questions (Question 9 to 18, Likert scales, 1–10).
Results
Two of five questions concerning the students’ satisfaction with the seminar and their gained knowledge showed statistically significant better ratings in Group B (6.7 vs. 8.2 points and 8.1 vs. 8.9 points (p < 0.001 and p < 0.009). The other three questions showed no statistically significant differences between the traditional teaching setting vs. the 3D printed model (p < 0.411, p < 0.344 and p < 0.215, respectively). The overall mean score of Question 1 to 5 showed 8.4 points for Group B and 7.8 points for Group A (p < 0.001). All three multiple-choice questions, asking about female pelvic anatomy, were answered more often correctly by Group B (p < 0.001, p < 0.008 and p < 0.001, respectively). The mean score from the answers to Questions 9 to 18, only answered by Group B, showed a mean of 8.6 points, indicating, that the students approved of the model.
Conclusion
The presented 3D printed model Pelvisio® improves the education of female pelvic anatomy and examination for medical students. Hence, training this pivotal examination can be supported by a custom designed anatomical model tailored for interactive and explorative learning.
Background
Electrosurgical excisions are common procedures for treating cervical dysplasia and are often seen as minor surgeries. Yet, thorough training of this intervention is required, as there are considerable consequences of inadequate resections, e.g. preterm birth, the risk of recurrence, injuries and many more. Unfortunately, there is a lack of sufficiently validated possibilities of simulating electrosurgeries, which focus on high fidelity and patient safety.
Methods
A novel 3D printed simulator for examination and electrosurgical treatment of dysplastic areas of the cervix was compared with a conventional simulator. Sixty medical students experienced a seminar about cervical dysplasia. Group A underwent the seminar with the conventional and Group B with the novel simulator. After a theoretical introduction, the students were randomly assigned by picking a ticket from a box and went on to perform the hands-on training with their respective simulator. Each student first obtained colposcopic examination training. Then he or she performed five electrosurgical excisions (each). This was assessed with a validated score, to visualize their learning curve. Furthermore, adequate and inadequate resections and contacts between electrosurgical loop and vagina or speculum were counted. Both groups also assessed the seminar and their simulator with 18 questions (Likert-scales, 1–10, 1 = strongly agree / very good, 10 = strongly disagree / very bad). Group B additionally assessed the novel simulator with four questions (similar Likert-scales, 1–10).
Results
Nine of 18 questions showed statistically significant differences favoring Group B (p < 0.05). Group B also achieved more adequate R0-resections and less contacts between electrosurgical loop and vagina or speculum. The learning curves of the performed resections favored the novel simulator of Group B without statistically significant differences. The four questions focusing on certain aspects of the novel simulator indicate high appreciation of the students with a mean score of 1.6 points.
Conclusion
The presented novel simulator shows several advantages compared to the existing model. Thus, novice gynecologists can be supported with a higher quality of simulation to improve their training and thereby patient safety.
Ovarian cancer is the second most common gynecological malignancy in women. More than 70% of the cases are diagnosed at the advanced stage, presenting as primary peritoneal metastasis, which results in a poor 5-year survival rate of around 40%. Mechanisms of peritoneal metastasis, including adhesion, migration, and invasion, are still not completely understood and therapeutic options are extremely limited. Therefore, there is a strong requirement for a 3D model mimicking the in vivo situation. In this study, we describe the establishment of a 3D tissue model of the human peritoneum based on decellularized porcine small intestinal submucosa (SIS) scaffold. The SIS scaffold was populated with human dermal fibroblasts, with LP-9 cells on the apical side representing the peritoneal mesothelium, while HUVEC cells on the basal side of the scaffold served to mimic the endothelial cell layer. Functional analyses of the transepithelial electrical resistance (TEER) and the FITC-dextran assay indicated the high barrier integrity of our model. The histological, immunohistochemical, and ultrastructural analyses showed the main characteristics of the site of adhesion. Initial experiments using the SKOV-3 cell line as representative for ovarian carcinoma demonstrated the usefulness of our models for studying tumor cell adhesion, as well as the effect of tumor cells on endothelial cell-to-cell contacts. Taken together, our data show that the novel peritoneal 3D tissue model is a promising tool for studying the peritoneal dissemination of ovarian cancer.
In vitro models of the human blood-brain barrier (BBB) are highly desirable for drug development. This study aims to analyze a set of ten different BBB culture models based on primary cells, human induced pluripotent stem cells (hiPSCs), and multipotent fetal neural stem cells (fNSCs). We systematically investigated the impact of astrocytes, pericytes, and NSCs on hiPSC-derived BBB endothelial cell function and gene expression. The quadruple culture models, based on these four cell types, achieved BBB characteristics including transendothelial electrical resistance (TEER) up to 2,500 Ω cm\(^{2}\) and distinct upregulation of typical BBB genes. A complex in vivo-like tight junction (TJ) network was detected by freeze-fracture and transmission electron microscopy. Treatment with claudin-specific TJ modulators caused TEER decrease, confirming the relevant role of claudin subtypes for paracellular tightness. Drug permeability tests with reference substances were performed and confirmed the suitability of the models for drug transport studies.
Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3-13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12-124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p<0.05). In conclusion, a ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.
Ergebnisse der gynäkolgischen Descensuschirurgie unter Verwendung des GYNECARE PROLIFT® prolenemesh am Krankenhaus Agatharied
Der Descensus genitalis ist eine der häufigsten gutartigen Erkrankungen der Frau, im Jahr 2010 waren mehr als 316 Millionen Frauen weltweit betroffen. Es besteht ein Lebensrisiko von 11,1% für eine chirurgische Intervention für eine 80jährige Frau.
Die Gründe liegen v. a. in der Anzahl vaginaler (operativer) Geburten, Adiopsitas, Z.n. Hysterektomie, Überalterung und chronisch erhöhter intraabdominaler Druck.
Die klinische Symptomatik besteht aus den typischen Senkungssymptomen wie Fremdkörper- und Druckgefühl, Ulcerationen mit Blutung, Fluor, Infektionen und Schmerzen. Außerdem kann es zu anorectaler Dysfunktion und Störungen der Blasenspeicher- und entleerungsfunktion kommen. Auch werden häufig Störungen der Sexualfunktion beschrieben.
Die anatomiegerechte Beckenbodendefektbehebung mittels Polypropylene-Kunststoffnetzen (GYNECARE PROLIFT® prolenemesh) über den vaginalen Zugang wird zunehmend, neben den klassischen Descensusoperationen, zur Rekonstruktion des weiblichen Beckenbodens verwendet.
Anhand der prä- und postoperativen Anamnese und Untersuchung nach dem POP-Q Schema einschließlich intra- und postoperativer Veräufe sowie 4 etablierter Fragebögen (PFDI-20, PFIQ-7, PISQ-12 und PGI-C) zu subjektiven Einschränkungen durch den Descensus erfolgt die Evaluation des Erfolges der Netzimplantation und ein Vergleich mit Ergebnissen anderer Methoden der Descensuschirurgie.
Ergebnisse: Netzspezifische Komplikationen wie Exposition in die Scheide, Erosion in Nachbarorgane, Schrumpfung der Netze mit Schmerzen, Auftreten einer De Novo Belastungsinkontinenz oder einer Dyspareunie wurden im vorliegenden Kollektiv deutlich seltener als in der Literatur verzeichnet. Die Netzimplantation war in 81,5% (Stadium 0 oder 1) erfolgreich, es kam in 18,5% zu einem Rezidiv. Je nach Literatur und betroffenem Kompartiment liegen die Rezidivraten nach Mesheinlage zwischen 3,5 und 46% und bei 2 bis 42,5% nach klassischen Descensusoperationen. In allen 4 Fragebögen wurde eine Verbesserung der Lebensqualität, der sexuellen Zufriedenheit und der Speicher- und Entleerungsfunktion von Blase und Darm verzeichnet, jedoch war die Netzimplantation gleichwertig mit den klassischen Senkungsoperationen.