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Summary Low-grade serous ovarian carcinoma (LGSOC) has recently come up as a distinct rare entity of epithelial ovarian cancer. Predictive and prognostic markers are not well studied yet. Because Ki-67 and hormone receptors (HR) have been established as relevant cancer biomarkers in several malignant tumors, we evaluated Ki-67 and HR expression rates by immunohistochemistry in 68 patients with LGSOC. We used a standardized cutoff finder algorithm to analyze prognostic significance for overall survival (OS) and progression-free survival (PFS). Cox regression showed a significant continuous decrease in OS for higher proliferation rates with an HR of 1.07% (95% confidence interval, 1.01%-3.67%; P = .048) but not in PFS (P = .86). Cutoff finder analysis revealed the best possible cutoff for OS at 6.28% (P = .04) and for PFS at 1.85% proliferative activity (P = .04). Estrogen receptors (ERs) were expressed in most LGSOC patients (n = 61; 89.7%), progesterone receptor (PR) in about half of patients (n = 33; 48.5%). For both ER/PR, a statistically significant cutoff for PFS could be determined, which was at 75% of positive tumor cells for ER (P = .02) and at 15% of positive tumor cells for PR (P = .03). For OS, HR expression showed a tendency toward better OS for HR-positive tumors but did not turn out statistically significant. Our results show that Ki-67 is a valuable prognostic marker in the subgroup of LGSOC. We could also show that most LGSOCs express HRs but that this expression is associated with a better PFS, a finding valuable in times of antihormonal therapy in LGSOC.

Infection by the new corona virus strain SARS-CoV-2 and its related syndrome COVID-19 has been associated with more than two million deaths worldwide. Patients of higher age and with preexisting chronic health conditions are at an increased risk of fatal disease outcome. However, detailed information on causes of death and the contribution of pre-existing health conditions to death yet is missing, which can be reliably established by autopsy only. We performed full body autopsies on 26 patients that had died after SARS-CoV-2 infection and COVID-19 at the Charité University Hospital Berlin, Germany, or at associated teaching hospitals. We systematically evaluated causes of death and pre-existing health conditions. Additionally, clinical records and death certificates were evaluated. We report findings on causes of death and comorbidities of 26 decedents that had clinically presented with severe COVID-19. We found that septic shock and multi organ failure was the most common immediate cause of death, often due to suppurative pulmonary infection. Respiratory failure due to diffuse alveolar damage presented as immediate cause of death in fewer cases. Several comorbidities, such as hypertension, ischemic heart disease, and obesity were present in the vast majority of patients. Our findings reveal that causes of death were directly related to COVID-19 in the majority of decedents, while they appear not to be an immediate result of preexisting health conditions and comorbidities. We therefore suggest that the majority of patients had died of COVID-19 with only contributory implications of preexisting health conditions to the mechanism of death.

Epitheliale Ovarialkarzinome stellen eine häufige gynäkologische Tumorerkrankung mit schlechter Prognose dar. In der vorliegenden Arbeit wurden daher die Marker Aldehyddehydrogenase 1 A1 (ALDH1A1), Thymosin-β15A (TMSB15A) und Poly(ADP-Ribose)-Polymerase-1 (PARP1), welche sich bereits im Mammakarzinom als Biomarker mit prädiktiver und prognostischer Relevanz erwiesen hatten, hinsichtlich ihres prognostischen Wertes in Ovarialkarzinomen untersucht. Der Schwerpunkt lag in der Untersuchung der Marker in Typ II Ovarialkarzinomen. Untersucht wurden insbesondere Korrelationen mit Überlebensdaten, wichtigen klinisch-pathologischen Faktoren sowie eine Änderung der Markerexpression im Krankheitsverlauf. Hierfür wurden Formalin- fixierte und in Paraffin eingebettete Gewebeproben von insgesamt 209 Patientinnen mit primären epithelialen Ovarialkarzinomen sowie 38 korrespondierende Rezidivtumoren untersucht. Auf mRNA-Ebene wurden die Marker mittels einer quantitativen real-time-PCR untersucht. Auf Proteinebene wurden immunhistochemische Färbungen an Tissue Microarrays durchgeführt. Es konnte gezeigt werden, dass die Proteinexpression des potentiellen Krebsstammzellmarkers ALDH1 einen signifikant ungünstigen Prognosefaktor in Typ II Ovarialkarzinomen darstellt. Darüber hinaus zeigten Tumoren die das ALDH1-Protein und den epidermalen Wachstumsfaktorrezeptor (EGFR) exprimierten die statistisch ungünstigsten Verläufe. Das aktinbindende Protein TMSB15, welches die zytoskelettgesteuerte Lokomotion und somit möglicherweise auch die Metastasierungsfähigkeit der Zelle beeinflussen kann, war lediglich univariat ein signifikant günstiger Prognosemarker. Auf mRNA-Ebene konnte kein Einfluss der TMSB15A-Expression auf das Überleben der Patientinnen beobachtet werden. Die PARP1 ist als wichtiger Mediator des Basenexzisionsweg in die DNA- Reparatur involviert. Es konnte weder auf mRNA- noch auf Proteinebene ein Einfluss von PARP1 auf die Prognose festgestellt werden. Gemessene PARP1-mRNA- und Proteinwerte waren jedoch signifikant in Rezidivtumoren gegenüber den korrespondieren Primärtumoren erhöht. Eine Assoziation von ALDH1 und EGFR wird in der Literatur bereits in BRCA1-defizienten Brustepithelien und tripel negativen Mammakarzinomen beschrieben. Die Ergebnisse der vorliegenden Arbeit weisen darauf hin, dass es sich bei ALDH1- und EGFR-exprimierenden Tumoren um eine besonders aggressive Subgruppe von Typ II Ovarialkarzinomen handelt für die alternative Therapien angezeigt sein könnten. Eine weitere Charakterisierung dieser Subgruppe zusammen mit dem BRCA1-Mutationsstatus wäre daher ein interessanter Aspekt für zukünftige Studien. Höhere PARP1-Level in Rezidivtumoren der untersuchten Patientenproben könnten durch eine erhöhte chromosomale Instabilität und somit erhöhte Aktivität des Basenexzisionsweges in diesen Tumoren erklärt werden. Die Inhibierung von PARP in Zellen, in denen die homologe Rekombination beispielsweise durch eine BRCA-Mutation gestört ist, kann zur selektiven Apoptose führen, weswegen die Wirkung von PARP- Inhibitoren derzeit in klinischen Studien untersucht wird. Dennoch ist unklar, welche Patientengruppen tatsächlich von dieser Therapie profitieren und die PARP1-Expression sollte als potentieller prädiktiver Faktor weiter untersucht werden., Epithelial ovarian carcinoma constitutes a frequent gynecologic malignancy with a poor prognosis. As aldehyde dehydrogenase 1 A1 (ALDH1A1), thymosin-β15A (TMSB15A) and poly(ADP-ribose) polymerase-1 (PARP1) have already proved to be prognostic and predictive biomarkers in breast cancer, the aim of this study was to evaluate these biomarkers in ovarian cancer with emphasis on type II ovarian carcinoma. In this context correlations with survival and clinicopathologic parameters were regarded as well as changes in marker expression during the course of disease. This study included 209 formalin- fixed and paraffin-embedded samples of patients with primary epithelial ovarian carcinoma and additional 38 specimens of corresponding relapse tumors. mRNA levels were quantified by quantitative real-time polymerase chain reaction. To determine the protein expression immunohistochemical staining was performed on tissue microarrays. In this study it was demonstrated that the potential cancer stem cell marker ALDH1 was a significant marker of poor prognosis in type II ovarian carcinoma. Furthermore ALDH1- and epidermal growth factor receptor (EGFR)-protein expressing tumors showed most unfavorable outcome compared to the other expression groups. The actin binding protein TMSB15 which is assumed to be involved in cytoskeleton mediated locomotion and metastasis was a significant favorable prognostic marker merely in univariate analysis. There was no association between TMSB15A mRNA expression and survival. As an important mediator of base excision repair pathway PARP1 is involved in DNA repair. Neither PARP1-mRNA nor cytoplasmatic or nuclear PARP-protein expression were associated with prognosis. However, PARP1 mRNA and nuclear protein expression were upregulated in relapse tumors compared to the corresponding primary tumors. A correlation of ALDH1 and EGFR expression in BRCA1-deficient breast epithelium and triple negative breast cancer has already been described in previous observations. The results of this study indicate that ALDH1 and EGFR expressing tumors represent a highly aggressive subgroup of type II ovarian carcinoma for which alternative treatment options might be indicated. Further characterization of this subgroup in combination with the BRCA mutation status represents an interesting subject for future studies. Higher PARP1 levels in relapse tumors might be explained by a higher chromosomal instability in these tumors. Inhibition of PARP in cells with defective homologous recombination due to BRCA mutation, for example, can lead to selective cell death, which is why the effect of PARP inhibitors is investigated in clinical studies to date. However it is still unclear which patients actually benefit from PARP inhibitor therapy so that the PARP1-expression should be further investigated as a predictive factor.