Association of two genomic variants with HPV type-specific risk of cervical cancer.

PROBLEM: Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18. METHODS: We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues. RESULTS: rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03-1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18-7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (pANOVA = 0.0009), with the risk allele lowering mRNA levels. CONCLUSIONS: We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies.

Robotic-assisted Gynecological Surgery in Older Patients - a Comparative Cohort Study of Perioperative Outcomes.

Study design Because of current demographic developments, a hypothesis was proposed whereby older female patients aged > 65 years can be safely operated using minimally invasive, robotic-assisted surgery, despite having more preoperative comorbidities. A comparative cohort study was designed to compare the age group ≥ 65 years (older age group, OAG) with the age group < 65 years (younger age group, YAG) after robotic-assisted gynecological surgery (RAS) in two German centers. Patients and methods Consecutive RAS procedures performed between 2016 and 2021 at the Women's University Hospital of Jena and the Robotic Center Eisenach to treat benign or oncological indications were included in the study. The age groups were compared according to their preoperative comorbidities (ASA, Charlson comorbidity index [CCI], cumulative illness rating scale - geriatric version [CIRS-G]) and perioperative parameters such as Clavien-Dindo (CD) classification of surgical complications. Analysis was performed using Welch's t -test, chi 2 test, and Fisher's exact test. Results A total of 242 datasets were identified, of which 63 (73 ± 5 years) were OAG and 179 were YAG (48 ± 10 years). Patient characteristics and the percentage of benign or oncological indications did not differ between the two age groups. Comorbidity scores and the percentage of obese patients were higher in the OAG group: CCI (2.7 ± 2.0 vs. 1.5 ± 1.3; p < 0.001), CIRS-G (9.7 ± 3.9 vs. 5.4 ± 2.9; p < 0.001), ASA class II/III (91.8% vs. 74.1%; p = 0.004), obesity (54.1% vs. 38.2%; p = 0.030). There was no difference between age groups, even grouped for benign or oncological indications, with regard to perioperative parameters such as duration of surgery (p = 0.088; p = 0.368), length of hospital stay (p = 0.786; p = 0.814), decrease in Hb levels (p = 0.811; p = 0.058), conversion rate (p = 1.000; p = 1.000) and CD complications (p = 0.433; p = 0.745). Conclusion Although preoperative comorbidity was higher in the group of older female patients, no differences were found between age groups with regard to perioperative outcomes following robotic-assisted gynecological surgery. Patient age is not a contraindication for robotic gynecological surgery.

Synthesis, Characterization and Biological Investigation of the Platinum(IV) Tolfenamato Prodrug-Resolving Cisplatin-Resistance in Ovarian Carcinoma Cell Lines.

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.

Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial.

PURPOSE: The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)-positive tumors. We explored whether mutations in non-BRCA1 or BRCA2 homologous recombination repair (non-BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. METHODS: Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non-BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non-BRCA HRR gene panels, three devised for this analysis and three previously published. RESULTS: The non-BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non-BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non-BRCA HRRm had a low median GIS; however, a GIS of > 42 was observed for tumors with mutations in five HRR genes (BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non-BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). CONCLUSION: Acknowledging limitations of small subgroup sizes, non-BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

Native-tissue pelvic organ prolapse (POP) repair with perineorrhaphy for level III support results in reduced genital hiatus size and improved quality of life in sexually active and inactive patients.

INTRODUCTION AND HYPOTHESIS: Recent findings address the importance of Level III defects with increased genital hiatus being associated with pelvic organ prolapse (POP), correlated with Level I defects and strongly related to POP recurrence. We hypothesised that concomitant perineorrhaphy in POP repair reduces genital hiatus (gh) and increases perineal body (pb), that gh would be larger with number of vaginal deliveries and that patients' QOL was not different comparing sexually active vs inactive patients with overall judgement of cure comparable to the literature at evaluation. METHODS: Retrospective observational study including consecutive patients with indications for posterior repair and Level III support between 2016 and 2018. Concomitant perineorrhaphy was indicated due to complaints of wide introitus or genital hiatus of ≥ 3.5 cm. Primary objective was to compare pre- and postoperative gh and pb according to POP-Q. Secondary objectives were preoperative gh and pb values by parity, POMs obtained with P-QOL/D comparing sexually active vs inactive patients, and subjective judgement of cure according to EGGS system. RESULTS: In n = 121 patients, mean gh value was reduced postoperatively by 29.5 % (31 ± 6 vs 44 ± 10 mm, p < 0.001), mean pb value increased by 25.5 % (47 ± 8 vs 35 ± 8 mm, p < 0.001). Influence of parity on preoperative gh (p = 0.020), but not pb values (p = 0.119) was observed. All P-QOL/D domain scores improved significantly postoperatively without differences seen in sexually active vs inactive patients. EGGS responses indicated partial/full goal achievement in 90 % and cure in 87 %. CONCLUSIONS: In the study cohort, perineorrhaphy as concomitant in POP repair led to Level III support reflected by decreased genital hiatus size. Functional QOL was improved regardless of sexual activity status and the majority of patients reported partial or full cure.

Novel Nickel(II), Palladium(II), and Platinum(II) Complexes with O,S Bidendate Cinnamic Acid Ester Derivatives: An In Vitro Cytotoxic Comparison to Ruthenium(II) and Osmium(II) Analogues.

(1) Background: Since the discovery of cisplatin's cytotoxic properties, platinum(II) compounds have attracted much interest in the field of anticancer drug development. Over the last few years, classical structure−activity relationships (SAR) have been broken by some promising new compounds based on platinum or other metals. We focus on the synthesis and characterization of 17 different complexes with ß-hydroxydithiocinnamic acid esters as O,S bidendate ligands for nickel(II), palladium(II), and platinum(II) complexes. (2) Methods: The bidendate compounds were synthesized and characterized using classical methods including NMR spectroscopy, MS spectrometry, elemental analysis, and X-ray crystallography, and their cytotoxic potential was assessed using in vitro cell culture assays. Data were compared with other recently reported platinum(II), ruthenium(II), and osmium(II) complexes based on the same main ligand system. (3) Results: SAR analyses regarding the metal ion (M), and the alkyl-chain position (P) and length (L), revealed the following order of the effect strength for in vitro activity: M > P > L. The highest activities have Pd complexes and ortho-substituted compounds. Specific palladium(II) complexes show lower IC50 values compared to cisplatin, are able to elude cisplatin resistance mechanisms, and show a higher cancer cell specificity. (4) Conclusion: A promising new palladium(II) candidate (Pd3) should be evaluated in further studies using in vivo model systems, and the identified SARs may help to target platinum-resistant tumors.

Highly Cytotoxic Osmium(II) Compounds and Their Ruthenium(II) Analogues Targeting Ovarian Carcinoma Cell Lines and Evading Cisplatin Resistance Mechanisms.

(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.

The significance of transcervical ultrasound-guided radiofrequency ablation in the treatment of symptomatic fibroids: results of an expert consensus from German-speaking countries.

Uterine fibroids are one of the most common diseases in female patients, lead mainly to bleeding disorders and lower abdominal pain, and reduce the chance of having children. In recent years we have seen a trend towards more and more pharmacotherapies and minimally invasive organ-preserving treatments. One novel and innovative procedure for an organ-preserving treatment of symptomatic uterine fibroids is the transcervical ultrasound-guided radiofrequency ablation (TRFA). TRFA has been used in Germany since 2013 and later found use in other German-speaking countries as well. There have now been more than 1200 TRFA treatments performed in Germany, Austria, and Switzerland. Experts from these three countries came together for a consensus meeting to analyze the significance of the procedure in the overall concept of the treatment of symptomatic uterine fibroids.

Synthesis and characterization of thiocarbonato-linked platinum(IV) complexes.

Herein we show the formation of new oxaliplatin-based platinum(IV) complexes by reaction with DSC-activated thiols via thiocarbonate linkage. Three model complexes based on aliphatic and aromatic thiols, as well as one complex with N-acetylcysteine as biologically active thiol were synthesized. This synthetic strategy affords the expansion of biologically active compounds other than those containing carboxylic, amine or hydroxy groups for coupling to the platinum(IV) center. The complexes were characterized by high-resolution mass spectrometry, NMR spectroscopy (1H, 13C, 195Pt) and elemental analysis. Their biological behavior was evaluated against two ovarian carcinoma cell lines and their cisplatin-resistant analogues. Remarkably, the platinum(IV) samples show modest in vitro cytotoxicity against A2780 cells and comparable effects against A2780cis cells. Two complexes in particular demonstrate improved activity against SKOV3cis cells. The reduction experiment of complex 8, investigated by UHPLC-HRMS, provides evidence of interesting platinum-species formed during reaction with ascorbic acid.

Acute postoperative pain in 23 procedures of gynaecological surgery analysed in a prospective open registry study on risk factors and consequences for the patient.

Effective perioperative pain management is essential for optimal patient recovery after surgery and reduces the risk of chronification. However, in clinical practice, perioperative analgesic treatment still needs to be improved and data availability for evidence-based procedure specific analgesic recommendations is insufficient. We aimed to identify procedures related with high pain scores, to evaluate the effect of higher pain intensity on patients and to define patient and intervention related risk factors for increased pain after standard gynaecological and obstetrical surgery. Therefore, we performed a prospective cross-sectional study based on the German registry for quality in postoperative pain (QUIPS). A cohort of 2508 patients receiving surgery between January 2011 and February 2016 in our tertiary referral centre (university departments of gynaecology and obstetrics, respectively) answered a validated pain questionnaire on the first postoperative day. Maximal pain intensity was measured by means of a 11-point numeric rating scale (NRS) and related to procedure, perioperative care as well as patient characteristics. The interventions with the highest reported pain scores were laparoscopic removal of ovarian cysts (NRS of 6.41 ± 2.12) and caesarean section (NRS of 6.98 ± 2.08). Factors associated with higher pain intensity were younger age (OR 1.75, 95% CI 1.65-1.99), chronic pain (OR 2.08, 95% CI 1.65-2.64) and surgery performed outside the regular day shift (OR 1.67, 95% CI 1.09-2.36). Shorter duration of surgery, peridural or local analgesic and preoperative sedation reduced postoperative pain. Patients reporting high pain scores (NRS ≥ 5) showed relevant impairment of daily activities and reduced satisfaction. Caesarean section and minimal invasive procedures were associated with the highest pain scores in the present ranking. Pain management of these procedures has to be reconsidered. Younger age, receiving surgery outside of the regular shifts, chronic pain and the surgical approach itself have a relevant influence on postoperative pain intensity. When reporting pain scores of 5 or more, patients were more likely to have perioperative complications like nausea or vomiting and to be impaired in mobilisation. Registry-based data are useful to identify patients, procedures and critical situations in daily clinical routine, which increase the risk for elevated post-intervention pain. Furthermore, it provides a database for evaluation of new pain management strategies.

Vaginal cysts: An important differential diagnosis in the anterior compartment.

INTRODUCTION: Benign anterior-vaginal-wall cysts (0.5-1% prevalence) often mimic other structures (e.g. cystoceles). No algorithm for their diagnosis, treatment, recurrence or complication prediction can be derived from existing data. Careful preoperative diagnosis can minimize intraoperative surprises and complications due to differences in cyst origin. METHODS: This retrospective study was performed with data from consecutive patients with anterior vaginal cysts who underwent surgery at the Pelvic Floor Centre, University Women's Hospital of Jena, within a period of 7 years. Data on patient age, symptoms, history of previous surgery, lesion characteristics, preoperative imaging findings, surgeries, postoperative stays, complications and histological and microbiological findings were collected. RESULTS: Out of 797 consecutive anterior vaginal prolapse repairs 19 (2.4%) anterior vaginal cystic lesions were found, mean age 47 [standard deviation (SD) 14, range 22-72] years. Symptoms reported were pressure (58%), voiding dysfunction (26%), dyspareunia (5%) and inflammation signs (37%); 26% of cases were asymptomatic. Two patients had received prolapse pessary treatment before. Two patients had history of previous vaginal surgery. Five cases were diagnosed preoperatively by ultrasound. Cysts were located on the medial anterior vaginal wall (42%), suburethral (42%) and the vaginal apex (16%). The mean lesion size was 2.6 (SD 0.9) cm. Eleven percent of cases showed microbiological positivity. Most (89%) vaginal cysts were excised; 11% were fenestrated, biopsied and drained. Twenty-six percent of patients underwent outpatient procedures; for inpatient procedures, the median stay was 2.7 days. Postoperative hemorrhage with no transfusion requirement occurred in one patient. All lesions were benign. CONCLUSIONS: Anterior-compartment vaginal cysts can be found incidentally during pelvic organ prolapse assessment and surgery, as they can mimic anterior-vaginal-wall prolapse. In this cohort, all excised lesions were benign.

ITIH5 shows tumor suppressive properties in cervical cancer cells grown as multicellular tumor spheroids.

Cervical cancer (CC) arises from premalignant cervical intraepithelial neoplasia (CIN) induced by a persistent infection with human papillomaviruses. The multi-stepwise disease progression is driven by genetic and epigenetic alterations. Our previous studies demonstrated a clear downregulation of inter-α-trypsin-inhibitor-heavy chain 5 (ITIH5) at mRNA and protein levels in CC compared to CIN2/3 and normal cervical tissue. Initial in vitro functional analyses revealed a suppressive effect of ITIH5 on relevant mechanisms for cancer progression in conventional two dimensional (2D) cell culture model systems. Based on these studies, we aimed to investigate the functional relevance of ITIH5 in multicellular tumor spheroid (MCTS) models, which resemble in vivo tumors more closely. We successfully established CC cell line-derived MCTS using the hanging-drop technique. ITIH5 was ectopically overexpressed in HeLa and SiHa cells and its functional relevance was investigated under three dimensional (3D) culture conditions. We found that ITIH5 re-expression significantly suppressed tumor spheroid growth and spheroid invasiveness of both HeLa and SiHa spheroids. Immunohistochemical (IHC) analyses revealed a significant reduction in Ki-67 cell proliferation index and CAIX-positive areas indicative for hypoxia and acidification. Furthermore, we observed an increase in cPARP-positive cells suggesting a higher rate of apoptosis upon ITIH5 overexpression. An effect of ITIH5 expression on the susceptibility of cervical MCTS towards cytostatic drug treatment was not observed. Collectively, these data uncover pronounced anti-proliferative effects of ITIH5 under 3D cell culture conditions and provide further functional evidence that the downregulation of ITIH5 expression during cervical carcinogenesis could support cancer development.

Radiotherapy Versus Inguinofemoral Lymphadenectomy as Treatment for Vulvar Cancer Patients With Micrometastases in the Sentinel Node: Results of GROINSS-V II.

PURPOSE: The Groningen International Study on Sentinel nodes in Vulvar cancer (GROINSS-V)-II investigated whether inguinofemoral radiotherapy is a safe alternative to inguinofemoral lymphadenectomy (IFL) in vulvar cancer patients with a metastatic sentinel node (SN). METHODS: GROINSS-V-II was a prospective multicenter phase-II single-arm treatment trial, including patients with early-stage vulvar cancer (diameter < 4 cm) without signs of lymph node involvement at imaging, who had primary surgical treatment (local excision with SN biopsy). Where the SN was involved (metastasis of any size), inguinofemoral radiotherapy was given (50 Gy). The primary end point was isolated groin recurrence rate at 24 months. Stopping rules were defined for the occurrence of groin recurrences. RESULTS: From December 2005 until October 2016, 1,535 eligible patients were registered. The SN showed metastasis in 322 (21.0%) patients. In June 2010, with 91 SN-positive patients included, the stopping rule was activated because the isolated groin recurrence rate in this group went above our predefined threshold. Among 10 patients with an isolated groin recurrence, nine had SN metastases > 2 mm and/or extracapsular spread. The protocol was amended so that those with SN macrometastases (> 2 mm) underwent standard of care (IFL), whereas patients with SN micrometastases (≤ 2 mm) continued to receive inguinofemoral radiotherapy. Among 160 patients with SN micrometastases, 126 received inguinofemoral radiotherapy, with an ipsilateral isolated groin recurrence rate at 2 years of 1.6%. Among 162 patients with SN macrometastases, the isolated groin recurrence rate at 2 years was 22% in those who underwent radiotherapy, and 6.9% in those who underwent IFL (P = .011). Treatment-related morbidity after radiotherapy was less frequent compared with IFL. CONCLUSION: Inguinofemoral radiotherapy is a safe alternative for IFL in patients with SN micrometastases, with minimal morbidity. For patients with SN macrometastasis, radiotherapy with a total dose of 50 Gy resulted in more isolated groin recurrences compared with IFL.

Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance.

PURPOSE: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. METHODS: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients' individual HPV-integration sites (vcj-PCR on the basis of NGS). RESULTS: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6-34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8-27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7-20.7%) and predicted ten of fourteen recurrences at six months. CONCLUSIONS: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.

RUNX3 Transcript Variants Have Distinct Roles in Ovarian Carcinoma and Differently Influence Platinum Sensitivity and Angiogenesis.

The prognosis of late-stage epithelial ovarian cancer (EOC) patients is affected by chemotherapy response and the malignant potential of the tumor cells. In earlier work, we identified hypermethylation of the runt-related transcription factor 3 gene (RUNX3) as a prognostic biomarker and contrary functions of transcript variants (TV1 and TV2) in A2780 and SKOV3 cells. The aim of the study was to further validate these results and to increase the knowledge about RUNX3 function in EOC. New RUNX3 overexpression models of high-grade serous ovarian cancer (HGSOC) were established and analyzed for phenotypic (IC50 determination, migration, proliferation and angiogenesis assay, DNA damage analysis) and transcriptomic consequences (NGS) of RUNX3 TV1 and TV2 overexpression. Platinum sensitivity was affected by a specific transcript variant depending on BRCA background. RUNX3 TV2 induced an increased sensitivity in BRCA1wt cells (OVCAR3), whereas TV1 increased the sensitivity and induced a G2/M arrest under treatment in BRCA1mut cells (A13-2-12). These different phenotypes relate to differences in DNA repair: homologous recombination deficient A13-2-12 cells show less γH2AX foci despite higher levels of Pt-DNA adducts. RNA-Seq analyses prove transcript variant and cell-line-specific RUNX3 effects. Pathway analyses revealed another clinically important function of RUNX3-regulation of angiogenesis. This was confirmed by thrombospondin1 analyses, HUVEC spheroid sprouting assays and proteomic profiling. Importantly, conditioned media (CM) from RUNX3 TV1 overexpressing A13-2-12 cells induced an increased HUVEC sprouting. Altogether, the presented data support the hypothesis of different functions of RUNX3 transcript variants related to the clinically relevant processes-platinum resistance and angiogenesis.

CAMK2N1/RUNX3 methylation is an independent prognostic biomarker for progression-free and overall survival of platinum-sensitive epithelial ovarian cancer patients.

BACKGROUND: To date, no predictive or prognostic molecular biomarkers except BRCA mutations are clinically established for epithelial ovarian cancer (EOC) despite being the deadliest gynecological malignancy. Aim of this biomarker study was the analysis of DNA methylation biomarkers for their prognostic value independent from clinical variables in a heterogeneous cohort of 203 EOC patients from two university medical centers. RESULTS: The marker combination CAMK2N1/RUNX3 exhibited a significant prognostic value for progression-free (PFS) and overall survival (OS) of sporadic platinum-sensitive EOC (n = 188) both in univariate Kaplan-Meier (LogRank p < 0.05) and multivariate Cox regression analysis (p < 0.05; hazard ratio HR = 1.587). KRT86 methylation showed a prognostic value only in univariate analysis because of an association with FIGO staging (Fisher's exact test p < 0.01). Thus, it may represent a marker for EOC staging. Dichotomous prognostic values were observed for KATNAL2 methylation depending on BRCA aberrations. KATNAL2 methylation exhibited a negative prognostic value for PFS in sporadic EOC patients without BRCA1 methylation (HR 1.591, p = 0.012) but positive prognostic value in sporadic EOC with BRCA1 methylation (HR 0.332, p = 0.04) or BRCA-mutated EOC (HR 0.620, n.s.). CONCLUSION: The retrospective analysis of 188 sporadic platinum-sensitive EOC proved an independent prognostic value of the methylation marker combination CAMK2N1/RUNX3 for PFS and OS. If validated prospectively this combination may identify EOC patients with worse prognosis after standard therapy potentially benefiting from intensive follow-up, maintenance therapies or inclusion in therapeutic studies. The dichotomous prognostic value of KATNAL2 should be validated in larger sample sets of EOC.

Effectiveness of Superior Hypogastric Plexus Block for Pain Control Compared to Epidural Anesthesia in Women Requiring Uterine Artery Embolization for the Treatment of Uterine Fibroids - A Retrospective Evaluation.

PURPOSE: To assess the effectiveness of pain management with superior hypogastric plexus block (SHPB) compared to epidural anesthesia (EDA) in women requiring uterine artery embolization (UAE). MATERIALS AND METHODS: In this retrospective, single-center, non-randomized trial we included 79 women with symptomatic uterine fibroids who were scheduled for percutaneous, transcatheter UAE. According to their informed decision, the women were assigned to two different approaches of pain management including either SHPB or EDA. The effectiveness outcome measure was patient reported pain using a numeric rating scale ranging from 1 to 10. The pain score was assessed at UAE, 2 hours thereafter, and at subsequent intervals of 6 hours up to 36 hours after intervention. RESULTS: Treatment groups did not differ significantly regarding age, pain score for regular menstrual cramps, uterine fibroid size, location, and symptoms of uterine fibroids. During UAE and up to 6 hours thereafter, women who received SHPB experienced stronger pain than those who received EDA (mean pain score during UAE: 3.3 vs. 1.5, p < 0.001; at 2 hours: 4.4 vs. 2.8, p = 0.012; at 6 hours: 4.4 vs. 2.6, p = 0.021). The maximum pain level was 5.8 ±â€Š2.9 with SHPB and 4.5 ±â€Š2.9 with EDA (p = 0.086). Women with a history of severe menorrhagia tended to experience worse pain than those without (regression coefficient 2.5 [95 % confidence interval -0.3 to 5.3], p = 0.076). CONCLUSION: Among women who underwent UAE, pain management including SHPB resulted in stronger pain during and after the procedure than pain treatment including EDA. KEY POINTS: · Pain control with superior hypogastric plexus block was worse than epidural anesthesia.. · Peak of pain was at 12 hours after uterine artery embolization.. · Maximum pain was independent from uterine fibroid size or location.. CITATION FORMAT: · Malouhi A, Aschenbach R, Erbe A et al. Effectiveness of Superior Hypogastric Plexus Block for Pain Control Compared to Epidural Anesthesia in Women Requiring Uterine Artery Embolization for the Treatment of Uterine Fibroids - A Retrospective Evaluation. Fortschr Röntgenstr 2021; 193: 289 - 297.

Triage of hrHPV-positive women: comparison of two commercial methylation-specific PCR assays.

AIM: High-risk human papillomavirus (hrHPV)-based screening is becoming increasingly important, either by supplementing or replacing the traditional cytology-based cervical Pap smear. However, hrHPV screening lacks specificity, because it cannot differentiate between transient virus infection and clinically relevant hrHPV-induced disease. Therefore, reliable triage methods are needed for the identification of HPV-positive women with cervical intraepithelial neoplasia (CIN) in need of treatment. Promising tools discussed for the triage of these patients are molecular diagnostic tests based on epigenetic markers. Here, we compare the performance of two commercially available DNA methylation-based diagnostic assays-GynTect® and the QIAsure Methylation Test-in physician-taken cervical scrapes from 195 subjects. FINDINGS: Both GynTect® and the QIAsure Methylation Test detected all cervical carcinoma and carcinoma in situ (CIS). The differences observed in the detection rates between both assays for the different grades of cervical lesions (QIAsure Methylation Test: CIN1 26.7%, CIN2 27.8% and CIN3 74.3%; GynTect®: CIN1 13.3%, CIN2 33.3% and CIN3 60%) were not significant. Concerning the false-positive rates, significant differences were evident. For the healthy (NILM) hrHPV-positive group, the false-positive rates were 5.7% for GynTect® and 26.4% for QIAsure Methylation Test (p = 0.003) and for the NILM hrHPV-negative group 2.2% vs. 23.9% (p = 0.006), respectively. When considering hrHPV-positive samples only for comparison (n = 149), GynTect® delivered significantly higher specificity compared to the QIAsure Methylation Test for CIN2 + (87.6% vs. 67.4% (p < 0.001)) and CIN3 + (84.1% vs. 68.2% (p = 0.002)). Overall our findings suggest that DNA methylation-based tests are suitable for the triage of hrHPV-positive women. With the goal to provide a triage test that complements the limited specificity of HPV testing in HPV-based screening, GynTect® may be preferable, due to its higher specificity for CIN2+ or CIN3+ .