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Differential expression patterns of Topoisomerase II alpha (TOP2A) in tumor epithelial and adjacent stromal cells of advanced ovarian cancer
No full textDiese Studie analysierte die Überexpression von TOP2A in den Tumorzellen und
dem tumorassoziierten Stroma beim fortgeschrittenen Ovarialkarzinom. Die TOP2A
Expression wurde mittels nichtradioaktive in-situ Hybridisierung, TaqMan RT-
PCR an mikrodissezierten Ovarialkarzinomproben und Immunhistochemie
untersucht. Die Daten aus den Expressionsanalysen wurden deskriptiv evaluiert
und den Zusammenhang mit etablierten prognostischen Faktoren analysiert. Die
TOP2A-mRNA Amplifikation wurde in der mRNA in-situ Hybridisierung und in der
TaqMan-PCR in allen Ovarialkarzinomproben nachgewiesen, mit einem stärkeren
Amplifikationssignal in den Tumorzellen verglichen zu den assoziierten
Stromazellen. Ähnliche Expressionsstärken zeigten sich auch in der
immunhistochemischen Untersuchungsreihe. Unsere Ergebnisse beschreiben zum
ersten Mal eine präzise qualitative und quantitative Validierung der TOP2A-
Geneamplifikation und Proteinexpression auf der Zellebene. Die stärkste TOP2A
Expression wurde innerhalb der Tumorzellen von Patientinnen mit primärem
Ovarialkarzinom (Platin-naïv) erfasst. Interessanterweise zeigte sich ein
charakteristischer Wandel unter den rezidivierten Ovarialkarzinomen nach
Platin-basierter Chemotherapie: die TOP2A Expression verzeichnete einen Abfall
in den Tumorzellen der Rezidivkarzinome verglichen zu der Gruppe der Frauen
mit Primärerkrankung. Andererseits war die TOP2A Expression in den tumor-
assoziierten Stromazellen nach Carboplatin Vorbehandlung signifikant höher als
in den Stromazellen der primären Ovarialkarzinomen. Unsere Beobachtungen
repräsentieren signifikante Unterschiede in der Regulation der TOP2A-
Genaktivität auf mRNA- und Proteinebene im Verlauf der Tumorerkrankung in
Abhängigkeit vom Erkrankungsstatus und in Bezug zur Chemotherapie. Der
Expressionsanstieg von TOP2A in den Stromazellen scheint viel enger mit der
Chemotherapieresistenzentwicklung assoziiert, möglicherweise resultierend aus
einer ansteigenden Zytokin-vermittelten Aktivierung der assoziierten Stroma.
Eindeutig kommt es zu einer massiven Ausbreitung der TOP2A Genaktivität
innerhalb der heterogenen Zellgruppen des Ovarialkarzinomgewebe. Die erhöhte
TOP2A-Genaktivität zeigte eine breite Amplifikation innerhalb der Tumor- und
tumor-assoziierten Stromazellen der heterogenen Karzinomgeweben. Allerdings
war der Anstieg der Stroma-assoziierten TOP2A-Expression nicht ubiquitär in
allen Karzinomen, sondern als spezifische Charakteristik einer Subgruppe von
Patientinnen evaluierbar, was eher auf die Diversifizierung des
Expressionsverhaltens nur innerhalb bestimmter Karzinomgruppen i. S. einer
Subgruppeneigenschaft auf molekularer Ebene hindeuten soll. Die zelluläre
TOP2A-Genexpression zeigte keine Assoziation weder mit den bedeutendsten
klinisch-pathologischen Prognosefaktoren, noch mit dem Überleben. Nur der
optimale postoperative Tumorrest und wenig intraoperativer Aszites (< 500 ml)
zeigten eine unabhängige prognostische Bedeutung in der Multivarianzanalyse.
Zusammenfassend liefern unsere systematischen Analysen in allen drei
unabhängig eingesetzten Methoden einen deutlichen Nachweis der zellulären
Überexpression des TOP2A-Gens auch in den tumor-assoziierten Stromazellen. Die
differentielle Modifikation der TOP2A mRNA- und Proteinexpression von
gewebsheterogenen Ovarialkarzinomen scheint in Assoziation zu einer Platin-
basierten Chemotherapiebehandlung zu stehen. Unsere Daten bestätigen die
Bedeutung der tumor-assoziierten Stroma für die Resistenzentwicklung und
Aggressivität der Rezidiverkrankung. Eine detaillierte molekularbiologische
Charakterisierung fortgeschrittener Ovarialkarzinome erleichtert unser
Verständnis über die Zusammenhänge im Verlauf der Tumorigenese und über
potentielle therapeutische Effekte in der Behandlung des Ovarialkarzinoms
durch Identifizierung von Karzinomsubgruppen.The aim of this prospective study was to evaluate the expression of
Topoisomerase II alpha (TOP2A) in normal ovary and in tumor epithelial and
adjacent stromal cells of advanced ovarian cancer. Expression analysis was
performed using non-radioactive in-situ hybridization, quantitative real-time
reverse transcription-polymerase chain reaction (RT-PCR) after laser
microdissection and immunohistochemistry with monoclonal antibodies. The
expression data were interpreted descriptive on the mRNA and protein level and
correlated to established prognostic factors. TOP2A mRNA was detected by RNA
in situ hybridization and TaqMan RT-PCR in all ovarian cancer samples, with
stronger hybridization signals in tumor epithelial cells compared to adjacent
stromal cells. The same expression pattern was found by immunohistochemistry.
Our results described for the first time precise qualitative and quantitative
validation of the TOP2A-geneamplification and protein expression on the
cellular level. The strongest TOP2A expression was evaluated in the tumor
cells of patients with primary ovarian cancer (platinum-naïve). Interestingly,
specific change was found in recurrent ovarian cancer after platinum-based
chemotherapy: TOP2A expression decreased in tumor epithelial cells of
recurrent cancers compared to primary ovarian cancer, whereas it increased in
tumor-adjacent stromal cells in Carboplatin pre-treated recurrent tumors
compared to primary ovarian cancer. These findings were validated on both the
mRNA and protein level and suggest that modified enhancement of the TOP2A-gene
regulation correlates with disease status and response to standard
chemotherapy. The expression of TOP2A suggests much closely relationship with
development of chemotherapy resistance possibly resulting of increased
cytokine mediated activation of parts of the stromal compartment. Nevertheless
the increased TOP2A-geneexpression was disseminated in relevant parts of the
tumor epithelial but also in the stroma of heterogeneous ovarian cancer
tissues. Although the enhancement of specific stromal expression of TOP2A was
detected only partially, but not ubiquitous in all cancer samples. Thus
differential expression of TOP2A supposed to be a characteristic feature of
subgroup of ovarian cancer patients. Furthermore the cellular TOP2A-
geneexpression patterns were associated neither with important clinical and
pathological factors nor with patient survival. Only tumor residual and
intraoperatively finding of ascites (< 500 ml) presented independent factors
for survival and were associated with poor clinical outcome. Summarising TOP2A
mRNA and protein expression in ovarian cancer exhibits specific patterns in
tumor epithelial and adjacent stromal cells, which are differentially
modulated after platinum-based chemotherapy. These data support the recently
discovered importance of the stromal compartment in tumor progression and
suggest that tumor stromal cells might be relevant to the development of
chemotherapy resistance in ovarian cancer
Innovative multimodal approaches for the interdisciplinary management of gynaecological malignancies
No full textWenige Bereiche der Medizin verzeichnen so gravierende Umwandlungen, wie es die gynäkologische Onkologie aktuell erlebt - vom Paradigmenwechsel der molekulargenetischen Testung hin zur Individualisierung der operativen Radikalität und von der Einführung personalisierter Therapiestrategien bis hin zur interprofessionellen und sektorenübergreifenden Patientenversorgung.
Die hier zusammengefassten Arbeiten berichten über die Herausforderungen bei der Etablierung der innovativen Tumorkonferenz „Gynäkologische Malignome“ und stellen erste Ergebnisse einzelner Subprojekte dieser Plattform dar. In einer weiteren Arbeit wird über die praktischen Probleme und Herausforderungen beim Aufbau einer translationalen Patienten- und Biobank im Rahmen des EU-Konsortiums „Ovarian Cancer - Diagnosis of a Silent Killer“ (OVCAD), initiiert an fünf führenden gynäkologisch-onkologischen Krebszentren, berichtet.
Weitere wird über erste Erfahrungen mit dem innovativen intraperitonealen Einsatz des trifunktionalen anti-CD3X/anti-EpCAM Antikörpers Catumaxumab, zugelassen für die Behandlung des malignen Aszites, als unmittelbar intraoperative Gabe nach primär zytoreduktiver Chirurgie beim fortgeschrittenen Ovarialkarzinom berichtet. Die Behandlung des multiresistenten Ovarialkarzinomrezidivs stellt uns vor noch größeren Herausforderungen, da einerseits die Therapieoptionen limitiert sind und andererseits die klinische Symptomatik, bedingt durch das Tumorgeschehen und die vorbestehende Toxizitäten, die Lebensqualität massiv einschränken. Deshalb erscheint eine Optimierung der Patientenselektion sinnvoll, um möglichst individualisierte Therapieansätze für verschiedene Subgruppen anbieten zu können, v.a. wenn man die große Anzahl älterer oder fragiler Patientinnen mit dieser Erkrankung berücksichtigen will. In der Präferenz-Studie wurde deshalb speziell auf die Patientinnen-Perspektive als primäres Studienziel fokussiert. In der TRIAS-Studie konnten zum ersten Mal in der Ovarialkarzinom-Forschung die starke klinische Relevanz eines Tyrosinkinase-basierten Kombinations- und Erhaltungsansatzes für das Outcome demonstriert werden. Diese Ergebnisse bestätigen besonders eindrucksvoll das therapeutische Potenzial der Angiogenesehemmung als zielgerichtete Therapiestrategie beim Eierstockkrebs
Treatment strategies in patients with gynecological sarcoma: Results of the prospective intergroup real-world registry for gynecological sarcoma in Germany (REGSA-NOGGO RU1)
No full textObjective Gynecological sarcomas account for 3% of all gynecological malignancies and are associated with a poor prognosis. Due to the rarity and heterogeneity of gynecological sarcomas there is still no consensus on optimal therapeutic strategies. This study’s objective was to describe the treatment strategies used in patients with gynecological sarcomas in the primary course of disease. Methods The German prospective registry for gynecological sarcoma (REGSA) is the largest registry for gynecological sarcomas in Germany, Austria and Switzerland. Primary inclusion criteria for REGSA are histological diagnosis of sarcoma of the female genital tract, sarcoma of the breast or uterine smooth muscle tumors of uncertain malignant potential (STUMP). We evaluated data of the REGSA registry on therapeutic strategies used for primary treatment from August 2015 to February 2021. Results A total of 723 patients from 120 centers were included. Data on therapeutic strategies for primary treatment were available in 605 cases. Overall, 580 (95.9%) patients underwent primary surgery, 472 (81.4%) of whom underwent only hysterectomy. Morcellation was reported in 11.4% (n=54) of all hysterectomies. A total of 42.8% (n=202) had no further surgical interventions, whereas an additional salpingo-ophorectomy was performed in 54% (n=255) of patients. An additional lymphadenectomy was performed in 12.7% (n=60), an omentectomy in 9.5% (n=45) and intestinal resection in 6.1% (n=29) of all patients. Among 448 patients with available information, 21.4% (n=96) received chemo- or targeted therapies, more commonly as single-agent treatment than as drug combinations. Information about anti-hormonal treatment was available for 423 patients, among which 42 (9.9%) received anti-hormonal treatment, 23 (54.8%) of whom with low-grade endometrial stroma sarcomas. For radiotherapy, data of 437 patients were available, among which 29 (6.6%) patients underwent radiotherapy. Conclusion Our study showed that treatment of patients with gynecologic sarcomas is heterogeneous. Further trials are needed along with more information on treatment modalities, therapy response and patient-reported outcomes to implement new treatment strategies.http://dx.doi.org/10.13039/501100013119 PharmaMarhttp://dx.doi.org/10.13039/100004336 Novarti
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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