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There is indication that the fallopian tubes might be involved in ovarian cancer pathogenesis and their removal reduces cancer risk. Hence, bilateral salpingectomy during hysterectomy or sterilization, so called opportunistic salpingectomy (OS), is gaining wide acceptance as a preventive strategy. Recently, it was discussed whether implementation of OS at other gynecologic surgery, e.g., cesarean section, endometriosis excision or myomectomy and even at non-gynecologic abdominal surgery such as cholecystectomy or appendectomy for women with completed family could be feasible. This modeling analysis evaluated the clinical and economic potential of OS at gynecologic and abdominal surgeries. A state transition model representing all relevant health states (healthy, healthy with hysterectomy or tubal ligation, healthy with other gynecologic or non-gynecologic abdominal surgery, healthy with hysterectomy and salpingectomy, healthy with salpingectomy, healthy with hysterectomy and salpingo-oophorectomy, ovarian cancer and death) was developed and informed with transition probabilities based on inpatient case numbers in Germany (2019). Outcomes for women aged 20-85 years were simulated over annual cycles with 1,200,000 million individuals. We compared four strategies: (I) OS at any suitable abdominal surgery, (II) OS only at any suitable gynecologic surgery, (III) OS only at hysterectomy or sterilization, and (IV) no implementation of OS. Primary outcome measures were prevented ovarian cancer cases and deaths as well as the incremental cost-effectiveness ratio (ICER). Volume of eligible interventions in strategy I was 3.5 times greater than in strategy III (286,736 versus 82,319). With strategy IV as reference, ovarian cancer cases were reduced by 15.34% in strategy I, 9.78% in II, and 5.48% in III. Setting costs for OS to €216.19 (calculated from average OS duration and operating room minute costs), implementation of OS would lead to healthcare cost savings as indicated by an ICER of €-8,685.50 per quality-adjusted life year (QALY) gained for strategy I, €-8,270.55/QALY for II, and €-4,511.86/QALY for III. Sensitivity analyses demonstrated stable results over a wide range of input parameters with strategy I being the superior approach in the majority of simulations. However, the extent of cancer risk reduction after OS appeared as the critical factor for effectiveness. Preventable ovarian cancer cases dropped to 4.07% (I versus IV), 1.90% (II versus IV), and 0.37% (III versus IV) if risk reduction would be <27% (hazard ratio [HR] > 0.73). ICER of strategies I and II was lower than the 2× gross domestic product per capita (GDP/C) (€94,366/QALY, Germany 2022) within the range of all tested parameters, but strategy III exceeded this threshold in case-risk reduction was <35% (HR > 0.65). The study is limited to data from the inpatient sector and direct medical costs. Based on our model, interdisciplinary implementation of OS in any suitable abdominal surgeries could contribute to prevention of ovarian cancer and reduction of healthcare costs. The broader implementation approach demonstrated substantially better clinical and economic effectiveness and higher robustness with parameter variation. Based on a lifetime cost saving of €20.89 per capita if OS was performed at any suitable abdominal surgery, the estimated total healthcare cost savings in Germany could be more than €10 million annually.

A randomized trial evaluated whether resection of lymph nodes that appeared macroscopically normal during surgery for ovarian cancer would lead to improved outcomes. Progression-free and overall survival were unaffected, and resection was associated with longer operations and more complications.

HPV DNA integration into the host genome is a characteristic but not an exclusive step during cervical carcinogenesis. It is still a matter of debate whether viral integration contributes to the transformation process beyond ensuring the constitutive expression of the viral oncogenes. There is mounting evidence for a non-random distribution of integration loci and the direct involvement of cellular cancer-related genes. In this study we addressed this topic by extending the existing data set by an additional 47 HPV16 and HPV18 positive cervical carcinoma. We provide supportive evidence for previously defined integration hotspots and have revealed another cluster of integration sites within the cytogenetic band 3q28. Moreover, in the vicinity of these hotspots numerous microRNAs (miRNAs) are located and may be influenced by the integrated HPV DNA. By compiling our data and published reports 9 genes could be identified which were affected by HPV integration at least twice in independent tumors. In some tumors the viral-cellular fusion transcripts were even identical with respect to the viral donor and cellular acceptor sites used. However, the exact integration sites are likely to differ since none of the integration sites analysed thus far have shown more than a few nucleotides of homology between viral and host sequences. Therefore, DNA recombination involving large stretches of homology at the integration site can be ruled out. It is however intriguing that by sequence alignment several regions of the HPV16 genome were found to have highly homologous stretches of up to 50 nucleotides to the aforementioned genes and the integration hotspots. One common region of homologies with cellular sequences is between the viral gene E5 and L2 (nucleotides positions 4100 to 4240). We speculate that this and other regions of homology are involved in the integration process. Our observations suggest that targeted disruption, possibly also of critical cellular genes, by HPV integration remains an issue to be fully resolved.

High-risk human papillomavirus (hrHPV)-DNA testing is frequently performed parallel to cytology for the detection of high-grade dysplasia and cervical cancer particularly in women above 30 years of age. Although highly sensitive, hrHPV testing cannot distinguish between HPV-positive women with or without clinically relevant lesions. However, in principle discrimination is possible on the basis of DNA methylation markers. In order to identify novel DNA regions which allow an effective triage of hrHPV-positive cases, hypermethylated DNA enriched from cervical cancers was compared with that from cervical scrapes of HPV16-positive cases with no evidence for disease by CpG island microarray hybridization. The most promising marker regions were validated by quantitative methylation-specific PCR (qMSP) using DNA from archived cervical tissues and cervical scrapes. The performance of these markers was then determined in an independent set of 217 hrHPV-positive cervical scrapes from outpatients with histopathological verification. A methylation signature comprising the 5' regions of the genes DLX1, ITGA4, RXFP3, SOX17 and ZNF671 specific for CIN3 and cervical cancer (termed CIN3+) was identified and validated. A high detection rate of CIN3+ was obtained if at least 2 of the 5 markers were methylated. In the subsequent cross-sectional study all cervical carcinomas (n = 19) and 56% (13/23) of CIN3 were identified by this algorithm. Only 10% (11/105) of hrHPV-positive women without histological evidence of cervical disease were scored positive by the methylation assay. Of note is that the detection rate of CIN3 differed between age groups. Eight of nine CIN3 were detected among women ≥30 years of age but only five of fourteen among <30 year old group (p = 0.03). The specificity for CIN3+ in the older age group was 76.6% (95% CI 65.6-85.5%). Clinical validation studies are required to determine the usefulness of these novel markers for triage after primary hrHPV testing in a cervical cancer screening setting.

The research on the anticancer potential of platinum(IV) complexes represents one strategy to circumvent the deficits of approved platinum(II) drugs. Regarding the role of inflammation during carcinogenesis, the effects of non-steroidal anti-inflammatory drug (NSAID) ligands on the cytotoxicity of platinum(IV) complexes is of special interest. The synthesis of cisplatin- and oxaliplatin-based platinum(IV) complexes with four different NSAID ligands is presented in this work. Nine platinum(IV) complexes were synthesized and characterized by use of nuclear magnetic resonance (NMR) spectroscopy (1H, 13C, 195Pt, 19F), high-resolution mass spectrometry, and elemental analysis. The cytotoxic activity of eight compounds was evaluated for two isogenic pairs of cisplatin-sensitive and -resistant ovarian carcinoma cell lines. Platinum(IV) fenamato complexes with a cisplatin core showed especially high in vitro cytotoxicity against the tested cell lines. The most promising complex, 7, was further analyzed for its stability in different buffer solutions and behavior in cell cycle and cell death experiments. Compound 7 induces a strong cytostatic effect and cell line-dependent early apoptotic or late necrotic cell death processes. Gene expression analysis suggests that compound 7 acts through a stress-response pathway integrating p21, CHOP, and ATF3.

This study evaluated factors that influence the cost-effectiveness of talazoparib, particularly for patients with a germline breast-cancer-gene-(brca)-mutation and locally advanced or metastasized breast cancer within the context of the German healthcare system. We constructed a partitioned survival model to compare medical costs and treatment effectiveness for patients with such cancers over 45 months. Transition probabilities were derived from survival data from a randomized Phase-III EMBRACA trial, utilities based on published reports, and costs in Euros, which included costs for drug acquisition, clinical monitoring, and treatment of adverse events. Willingness-to-pay thresholds were set to be multiples of the current German per capita gross domestic product. Treatment with talazoparib led to a gain of 0.32 life-years (0.22 quality-adjusted life-years). The mean total cost of €84,003 for talazoparib and €12,741 for standard therapy resulted in an incremental cost-effectiveness ratio of €223,246 per life-year and €323,932 per quality-adjusted life-year gained, indicating that talazoparib is unlikely to be cost-effective at current pricing.

Objective Symptom relief can be achieved for many patients with endometriosis by tailored individual treatment. However, therapy resistance is observed in some patients. This study surveyed patient-reported long-term outcomes after laparoscopic endometriosis surgery and evaluated potential pre-operative predictors for insufficient symptom control. Methods This retrospective study included patients with complete surgical endometriosis resection treated between 2013–2016 at the Department of Gynaecology and Reproductive Medicine, Jena University Hospital. Our 2020 survey gathered socio-demographic, reproductive, symptom-related, and subjective general condition data from 122 patients. Overall pain intensity was assessed using a numeric rating scale (NRS) from zero (no pain) to 100 (highest imaginable pain). Clinical records provided additional information. Results Median time between surgery and interview was 6 years. Postoperatively, the proportion of patients reporting symptoms was considerably reduced (menstrual pain 32.0% vs. 85.2%, chronic pelvic pain [CPP] 40.2% vs. 67.2%, dyspareunia 34.4% vs. 59.8%, hypermenorrhea 17.2% vs. 49.2%; p < 0.001). The majority of respondents (70%) reported improved subjective general condition. Mean NRS Score significantly decreased from 77.2 to 26.6 (p < 0.001). Among pre-operatively infertile women, 45.2% reported successful pregnancies. However, 20–30% of patients did not respond to therapy in one of the analyzed domains. Multivariate logistic regression identified CPP as a strong predictor for failure in permanent pain reduction (OR 5.544, 95% CI 1.338–22.965, p = 0.018) and risk for reoperation (OR 5.191, 95% CI 1.100-24.501, p = 0.038). Higher pre-operative NRS scores and increasing age were associated with better long-term pain relief. Conclusion Patients with higher pre-operative pain scores and patients of advanced age benefit significantly from precision surgery, experiencing sustained symptom relief and improved subjective general condition. However, younger patients with CPP and moderate pre-operative pain intensity showed a higher risk for therapy resistance and require multimodal treatment strategies.

This study evaluated factors that influence the cost-effectiveness of talazoparib, particularly for patients with a germline breast-cancer-gene-(brca)-mutation and locally advanced or metastasized breast cancer within the context of the German healthcare system. We constructed a partitioned survival model to compare medical costs and treatment effectiveness for patients with such cancers over 45 months. Transition probabilities were derived from survival data from a randomized Phase-III EMBRACA trial, utilities based on published reports, and costs in Euros, which included costs for drug acquisition, clinical monitoring, and treatment of adverse events. Willingness-to-pay thresholds were set to be multiples of the current German per capita gross domestic product. Treatment with talazoparib led to a gain of 0.32 life-years (0.22 quality-adjusted life-years). The mean total cost of €84,003 for talazoparib and €12,741 for standard therapy resulted in an incremental cost-effectiveness ratio of €223,246 per life-year and €323,932 per quality-adjusted life-year gained, indicating that talazoparib is unlikely to be cost-effective at current pricing.

(1) Background: Ruthenium and osmium complexes attract increasing interest as next generation anticancer drugs. Focusing on structure-activity-relationships of this class of compounds, we report on 17 different ruthenium(II) complexes and four promising osmium(II) analogues with cinnamic acid derivatives as O,S bidentate ligands. The aim of this study was to determine the anticancer activity and the ability to evade platin resistance mechanisms for these compounds. (2) Methods: Structural characterizations and stability determinations have been carried out with standard techniques, including NMR spectroscopy and X-ray crystallography. All complexes and single ligands have been tested for cytotoxic activity on two ovarian cancer cell lines (A2780, SKOV3) and their cisplatin-resistant isogenic cell cultures, a lung carcinoma cell line (A549) as well as selected compounds on three non-cancerous cell cultures in vitro. FACS analyses and histone γH2AX staining were carried out for cell cycle distribution and cell death or DNA damage analyses, respectively. (3) Results: IC50 values show promising results, specifically a high cancer selective cytotoxicity and evasion of resistance mechanisms for Ru(II) and Os(II) compounds. Histone γH2AX foci and FACS experiments validated the high cytotoxicity but revealed diminished DNA damage-inducing activity and an absence of cell cycle disturbance thus pointing to another mode of action. (4) Conclusion: Ru(II) and Os(II) compounds with O,S-bidentate ligands show high cytotoxicity without strong effects on DNA damage and cell cycle, and this seems to be the basis to circumvent resistance mechanisms and for the high cancer cell specificity.