Das Therapiemanagement des Ovarialkarzinoms im Zeitalter der zielgerichteten Therapiestrategien

Ohne Übertreibung lässt sich sagen, dass das Therapiemanagement des Ovarialkarzinoms voll im Zeitalter der zielgerichteten Strategien angekommen ist. Die Zulassungen des letzten Jahrzehntes beinhalten kaum noch klassische Zytostatika mehr, sondern bestehen fast ausschließlich aus zielgerichteten Therapieansätzen. Diese Entwicklung ist als sehr positiv zu bewerten und ging mit einer deutlichen Verbesserung für die Patientinnen, sowohl im Sinne der Prognoseverbesserung, als auch bezüglich des Nebenwirkungsspektrums, einher. Auch die modernen Veränderungen der chirurgischen Therapie des Ovarialkarzinoms mit einem Rückschritt in der Radikalität bei erhaltener Effektivität unterstützen erfreulicherweise diese Entwicklung. Die Neoangiogenesehemmung und die PARP-Inhibition haben sich als Therapiekonzepte bereits fest im klinischen Alltag etabliert und sorgten für eine massive Steigerung der Effektivität systemischer Therapien. Als vielversprechende und völlig neuartige Behandlungsmethode zeichnet sich die Immunonkologie in Form der Checkpoint-Inhibition ab. Die revolutionären Ergebnisse dieser neuartigen Substanzklasse konnten sich bisher nicht ohne Weiteres auf die Entität des Ovarialkarzinoms übertragen lassen. Hier wird eine der großen Herausforderung des nächsten Jahrzehntes darin liegen, durch Selektion der stark immunogenen Patientinnen und Kombination mit geeigneten Zytostatika, die Ansprechraten und Effektivität in die entsprechenden Höhen zu steigern, die bereits bei anderen Tumorentitäten das Therapiemanagement völlig revolutionierten. In der Zukunft ergeben sich durch den völlig neuen Ansatz der Immunonkologie noch viele Perspektiven und Möglichkeiten zur Kombination und Findung von Synergien. Kombinationen mit anderen immunonkologischen Substanzen wie zum Beispiel Catumaxomab, aber auch PARP-Inhibitioren und Neoangiogenesehemmer scheinen vielversprechend und werden in aktuell laufenden Studien überprüft. Auch Chemotherapie-freie Kombinationen scheinen zum ersten Mal in der Geschichte des Ovarialkarzinoms vielversprechend. Zusammenfassend lässt sich sagen, dass die Entwicklung zielgerichteter Therapien bereits einen massiven Beitrag zur Verbesserung der Behandlungsqualität in der Gynäkologischen Onkologie erreicht hat und auf absehbare Zeit auch der entscheidende Motor für die zukünftige Entwicklung in diesem Fachgebiet bleiben wird

A Prospective Substudy of a Randomized Controlled Trial

Malignant ascites (MA) is most commonly observed in patients scheduled for epithelial ovarian cancer (EOC) surgery and is supposed as a major risk factor promoting perioperative hemodynamic deterioration. We aimed to assess the hemodynamic consequences of MA on systemic circulation in patients undergoing cytoreductive EOC surgery. This study is a predefined post-hoc analysis of a randomized controlled pilot trial comparing intravenous solutions within a goal-directed algorithm to optimize hemodynamic therapy in patients undergoing cytoreductive EOC surgery. Ascites was used to stratify the EOC patients prior to randomization in the main study. We analyzed 2 groups according to the amount of ascites (NLAS: none or low ascites [<500 mL] vs HAS: high ascites group [>500 mL]). Differences in hemodynamic variables with respect to time were analyzed using nonparametric analysis for longitudinal data and multivariate generalized estimating equation adjusting the analysis for the randomized study groups of the main study. A total of 31 patients in the NLAS and 16 patients in the HAS group were analyzed. Although cardiac output was not different between groups suggesting a similar circulatory blood flow, the HAS group revealed higher heart rates and lower stroke volumes during surgery. There were no differences in pressure-based hemodynamic variables. In the HAS group, fluid demands, reflected by the time to reindication of a fluid challenge after preload optimization, increased steadily, whereas stroke volume could not be maintained at baseline resulting in hemodynamic instability after 1.5 h of surgery. In contrast, in the NLAS group fluid demands were stable and stroke volume could be maintained during surgery. Clinically relevant associations of the type of fluid replacement with hemodynamic consequences were particularly observed in the HAS group, in which transfusion of fresh frozen plasma (FFP) was associated to an improved circulatory flow and reduced vasopressor and fluid demands, whereas the administration of artificial infusion solutions was related to opposite effects. Malignant ascites >500 mL implies increased fluid demands and substantial alterations in circulatory blood flow during cancer surgery. Fresh frozen plasma transfusion promotes recovering hemodynamic stability in patients with malignant ascites >500 mL, in whom artificial infusion solutions could not prevent from hemodynamic deterioration

Real-World Evidence: How Long Do Our Patients Fast?—Results from a Prospective JAGO-NOGGO-Multicenter Analysis on Perioperative Fasting in 924 Patients with Malignant and Benign Gynecological Diseases

Simple Summary: The concept of ERAS (Enhanced Recovery After Surgery) was introduced to reduce perioperative morbidity through a multimodal approach. Optimized and shortened perioperative fasting is a fundamental part of this modern concept of perioperative patient management, as prolonged fasting before and after surgery is associated with unfavorable outcomes. So far, it remains unclear whether increasingly established ERAS protocols lead to adequate short fasting intervals in clinical routines. We therefore conducted this prospective multicenter study and collected real-world data from 924 patients to evaluate actual perioperative fasting behavior. Patients reported drastically prolonged perioperative fasting durations. Even longer fasting intervals were reported for oncological and extensive procedures. Our data suggest that modern optimized fasting management is poorly implemented in clinical routine practice. This study should draw attention to the need for adequate implementation of ERAS protocols and sensitize clinicians to appropriate patient education about perioperative fasting. Background: Despite the key role of optimized fasting in modern perioperative patient management, little current data exist on perioperative fasting intervals in routine clinical practice. Methods: In this multicenter prospective study, the length of pre- and postoperative fasting intervals was assessed with the use of a specifically developed questionnaire. Between 15 January 2021 and 31 May 2022, 924 gynecology patients were included, from 13 German gynecology departments. Results: On average, patients remained fasting for about three times as long as recommended for solid foods (17:02 +/- 06:54 h) and about five times as long as recommended for clear fluids (9:21 +/- 5:48 h). The average perioperative fasting interval exceeded one day (28:23 +/- 14:02 h). Longer fasting intervals were observed before and after oncological or extensive procedures, while shorter preoperative fasting intervals were reported in the participating university hospitals. Smoking, treatment in a non-university hospital, an increased Charlson Comorbidity Index and extensive surgery were significant predictors of longer preoperative fasting from solid foods. In general, prolonged preoperative fasting was tolerated well and quality of patient information was perceived as good. Conclusion: Perioperative fasting intervals were drastically prolonged in this cohort of 924 gynecology patients. Our data indicate the need for better patient education about perioperative fasting

Oral everolimus inhibits neointimal proliferation in prosthetic pulmonary valved stents in pigs

Einleitung: Wachstumfaktor-assoziierte Proliferation von Zellen kann nach Stentimplantation eine Intimaverdickung im Lumen des Stents verursachen. Der perkutane Ersatz von Herzklappen mittels Transkathetertechnik ist eine neu entwickelte alternative Methode zur chirurgischen Implantation von prothetischen Herzklappen mit vielversprechenden Aussichten. Erste Langzeitdaten lassen vermuten, dass die Proliferation von Neointima einen negativen Einfluss auf die Funktion von klappentragenden Stents zeigt. Viele Studien demonstrieren den erfolgreichen Einsatz von immunsupprimierenden Medikamenten zur Senkung der neointimalen Proliferation in endovaskulären Stents. Die Zielsetzung dieser Studie war die Überprüfung der Frage, ob orales Everolimus inhibierend auf die neointimale Gewebsproliferation wirkt, welche mit der Implantation eines klappentragenden Stents in Pulmonalposition verbunden ist. Material und Methoden: In 12 Schweine wurden prothetische Herzklappen mittels einer transkutanen Kathetertechnik implantiert. Die trikuspide Herzklappen wurden aus einem Polymer gefertigt, mit Titan beschichtet und in einen selbstexpandierenden Nitinolstent eingenäht. Der Herzklappenstent wurde in-vitro auf seine hämodynamischen Eigenschaften in einem Flussphantom getestet. Anschließend wurde der HKS mittels transkutaner Kathetertechnik in die Pulmonalposition der Tiere implantiert und unmittelbar nach Implantation die Klappenfunktion angiographisch überprüft, sowie eine invasive Messung des Druckgradienten über der prothetischen Klappe durchgeführt. Das Implantat verblieb für 3 Monate in situ. Bei 6 Tieren wurde eine orale Behandlung mit täglich 2 mg Everolimus durchgeführt. Die verbleibenden 6 Tiere erhielten kein Everolimus und bildeten die Kontrollgruppe. Bei beiden Gruppen wurde eine antikoagulative Behandlung mit Aspirin und Clopidogrel per os durchgeführt. Nach 3 Monaten wurde erneut die Klappenfunktion der Implantate invasiv hämodynamisch evaluiert. Zusätzlich wurden mittels MRT Blutflussmessungen durch die protethischen Herzklappen durchgeführt. Postmortem wurden die Herzklappenstents explantiert und makroskopisch, histologisch und elektronenmikroskopisch untersucht. Ergebnisse: Die in vitro Testung der prothetischen Herzklappe demonstrierte gute hämodynamische Eigenschaften. Die Implantation des HKS war bei allen 12 Tieren erfolgreich. Initiale hämodynamische Messungen im Herzkatheterlabor nach Implantation zeigten eine gute Klappenfunktion des Implantats. Die Behandlung mit Everolimus zeigte keine unerwünschten Nebenwirkungen. Gemessene Everolimus-Talspiegel im Vollblut der Tiere waren 4,2±2,4 ng/ml. Die Folgeuntersuchung im Herzkatheterlabor nach 3 Monaten zeigte eine gut erhaltene Klappenfunktion in der Everolimusgruppe und eine nur wenig schlechtere Klappenfunktion in der Kontrollgruppe. Stenosen konnten bei der invasiven Evaluation der Klappenfunktion in keiner Gruppe beobachtet werden. Magnetresonanztomographische Messungen zeigten ebenfalls eine intakte Klappenfunktion der Everolimusgruppe mit einer Regurgitationsfraktion von 4,3±3,1%, aber demonstrierten eine gestörte Funktion in der Kontrollgruppe mit einer Regurgitationsfraktion von 7,3±4,2% (p<0.01). Postmortem zeigten die explantierten Stents der Everolimusgruppe in der makroskopischen und histologischen Untersuchung nur einen dünnen Überzug der Stentmaschen mit Gewebe. Die Klappensegel waren frei von funktionsstörenden Ansammlungen von Proliferationsgewebe und die elektronenmikroskopische Untersuchung zeigte lediglich einen dünnen und kontinuierlichen Überzug mit Zellen. Im Gegensatz dazu wurde in der Kontrollgruppe erhebliche Neuformation und Verdickung von Gefäßintima festgestellt. Die Gewebsneubildung war am deutlichsten an der Basis der prothetischen Klappe, dehnte sich auf die Klappensegel aus und verursachte eine Verdickung und Verkürzung der Segel. Schlußfolgerung: Die nach Stentimplantation auftretende Proliferation von Neointima hat in der vorliegenden Studie einen negativen Einfluss auf die Klappenfunktion von perkutan implantierten Herzklappenstents. Zudem wurde gezeigt, dass die orale Gabe von Everolimus effektiv die Neubildung von Gewebe in klappentragenden Stents in der Pulmonalposition von Schweinen inhibiert.BACKGROUND AND AIM OF THE STUDY: Growth factor-dependent cell proliferation can cause in-stent neointimal hyperplasia. The study aim was to evaluate whether oral everolimus inhibits the intimal proliferation associated with the implantation of prosthetic pulmonary valved stents. METHODS: Prosthetic pulmonary valves were implanted in 12 pigs (mean bodyweight 25 kg) using a transcatheter technique. Tricuspid valves were prepared from a titanium-coated polymer and sewn into a self-expanding nitinol stent (diameter 20 mm). Valved stents were implanted in the pulmonary position, where they remained for three months. In six animals, treatment with 2 mg everolimus (Certican; Novartis) per day was started three days before implantation and continued throughout the course of the experiment. The other six pigs acted as controls. Adjuvant anticoagulation treatment consisted of acetylsalicylic acid and oral clopidogrel. After three months, hemodynamic valve function was investigated at catheterization and with MRI. At postmortem investigation the valved stents were explanted and subjected to macroscopic, histological and electron microscopic examination. RESULTS: There were no adverse side effects due to everolimus treatment. The overall mean everolimus plasma level during the study was 4.2 +/- 2.4 ng/ml. MRI revealed intact valve function with a regurgitation fraction of 7.3 +/- 4.2% in controls and 4.3 +/- 3.1% in the everolimus group (p <0.01). On macroscopic inspection and histological examination, the everolimus group showed only a thin tissue coverage of the stent struts. The valve cusps were free from intimal thickening, and electron microscopy showed a thin continuous cellular coating. In contrast, substantial neointimal formation was noted in controls. Tissue neogenesis was pronounced at the base of the valve, extended to the valve cusps, and caused valve thickening and foreshortening. CONCLUSION: The oral administration of everolimus effectively inhibits tissue neogenesis in pulmonary valved stents in pigs

Sexuality as a Prognostic Factor—Results of an Individual Patient Data NOGGO (North-Eastern German Society of Gynecological Oncology)-Meta-Analysis of 644 Recurrent Ovarian Cancer Patients Prior to Chemotherapy

Background: The aim of this study was to analyze the associations between sexuality, quality of life, treatment discontinuation, and survival in recurrent ovarian cancer (OC). Methods: Raw data from various phase II/III studies, including the questionnaires EORTC-QLQ-C30 and QLQ-OV28, were included. Data from the meta-analysis were calculated using logistic and Cox regression. Results: Data on sexuality were available for 644 patients. A total of 162 patients had an interest in sex and were sexually active (Group A). A total of 45 patients had an interest in sex and were sexually not active (Group I) and 437 patients had no interest in sex and were not sexually active (Group N). Group A was younger in median age (age at randomization), at 57 years, than Group I, at 60 years, and Group N, at 65 years (p p p p p = 0.012). In addition, Group A reported less pain, less peripheral neuropathy, and less fatigue (all p p < 0.001). Conclusions: Physicians should routinely address the topic of sexuality with ovarian cancer patients. Sexuality appears to be a marker for quality of life as well as overall survival

Can a morphological description of the peritoneal carcinomatosis in advanced ovarian cancer add prognostic information? Analysis of 1686 patients of the tumor bank ovarian cancer

BackgroundPeritoneal carcinomatosis in ovarian cancer is frequent and generally associated with higher stage and poorer outcome. The clinical features of peritoneal carcinomatosis are diverse and their relevance for surgical and long-term outcome remains unclear. We conducted this prospective study to describe intraoperatively the different features of peritoneal carcinomatosis(PC) and correlate them with clinicopathological features, progression-free(PFS) and overall survival (OS),.MethodsWe performed a systematic analysis of all patients with documented intraoperative PC and a primary diagnosis of epithelial ovarian, tubal, or peritoneal cancer from January 2001 to September 2018. All data were evaluated by using the systematic tumor bank tool. Specific PC features included texture(soft-hard), consistency(coarse-fine or both), wet vs dry(PC with ascites vs. PC without ascites), and localization(diffuse-local). PC characteristics were then evaluated for correlation with age, FIGO-stage, histology, lymph-node involvement, grade, and presence of residual tumor at primary surgery. Moreover, the influence of PC characteristics on OS and PFS was analyzed.ResultsA total of 1686 patients with PC and primary epithelial ovarian cancer were included. Majority of the patients were characterized by diffuse PC(73.9%). The majority of peritoneal nodules were fine in texture (55.3%) and hard in consistency (87.4%). Moreover, 27.6% of patients had dry PC. Diffuse PC localization was significantly associated with higher FIGO-stage (pConclusionDiffuse localization of peritoneal carcinomatosis was significant predictor of recurrence. Lower OS and PFS were associated with diffuse peritoneal localization, wet PC, and additional lymph node involvement. Further prospective trials are warranted with the inclusion of translational research aspects to better understand the different peritoneal carcinomatosis patterns

Accuracy of endometrial sampling in the diagnosis of endometrial cancer: a multicenter retrospective analysis of the JAGO-NOGGO

Abstract Background Accurate preoperative molecular and histological risk stratification is essential for effective treatment planning in endometrial cancer. However, inconsistencies between pre- and postoperative tumor histology have been reported in previous studies. To address this issue and identify risk factors related to inaccurate histologic diagnosis after preoperative endometrial evaluation, we conducted this retrospective analysis. Methods We conducted a retrospective analysis involving 375 patients treated for primary endometrial cancer in five different gynaecological departments in Germany. Histological assessments of curettage and hysterectomy specimens were collected and evaluated. Results Preoperative histologic subtype was confirmed in 89.5% of cases and preoperative tumor grading in 75.2% of cases. Higher rates of histologic subtype variations (36.84%) were observed for non-endometrioid carcinomas. Non-endometrioid (OR 4.41) histology and high-grade (OR 8.37) carcinomas were identified as predictors of diverging histologic subtypes, while intermediate (OR 5.04) and high grading (OR 3.94) predicted diverging tumor grading. Conclusion When planning therapy for endometrial cancer, the limited accuracy of endometrial sampling, especially in case of non-endometrioid histology or high tumor grading, should be carefully considered