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The majority of the interviewed gynecologists are convinced about the benefit of opportunistic salpingectomy regarding OC prevention. From the economic perspective, additional costs and surgery time needed for salpingectomy at hysterectomy are neglectable compared to costs and effort of OC treatment. [Extracted from the article]

Purpose: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany.Methods: Eligible patients were adults with platinum-sensitive ROC, pretreated with ≥ 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination.Results: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving ≥ 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression-free survival was 6.3 months and median overall survival was 16.4 months.Conclusion: Trabectedin plus PLD confer clinically meaningful benefit to pre-treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The coxsackie and adenovirus receptor (CAR) is a key factor in adenoviral cancer gene therapy. Reduced expression of CAR during progression of prostate and bladder cancer has been reported. In embryonic development and tissue differentiation, CAR is also differentially expressed. This study suggests a role of CAR expression in cell adhesion and cell motility of human cancer cells. Stable CAR-expressing clones from E-cadherin-deficient A2780 ovarian and CaSki cervical cancer cells with originally low and high CAR expression levels, respectively, were established. CAR reexpression in otherwise singularly growing A2780 parental cells resulted in formation of cell–cell contacts and aggregation in cell clusters. CAR overexpression in cell adhesion-forming CaSki cells did not result in morphological changes. Migration of the A2780 CAR clones was strongly reduced as characterized by using spread-off assays. Using migration chambers, formation of satellite colonies was reduced by 97% in CAR-expressing A2780 cell clones and by 23% in CAR-expressing CaSki cell clones. Parental A2780 and CaSki cells selected for high migratory ability by using migration chambers expressed endogenous CAR on lower levels associated with lower adenoviral transduction efficiency. Our data suggest CAR as a new inhibitory factor for cancer cell migration. [Copyright &y& Elsevier]

PURPOSE:: To determine the safety, gene transfer, host immune response, and pharmacokinetics of a replication-deficient adenovirus encoding human, recombinant, wild-type p53 (SCH 58500) delivered into the peritoneal cavity (i.p.) alone and sequentially in combination with platinum-based chemotherapy, of patients with recurrent ovarian, primary peritoneal, or fallopian tube cancer containing aberrant or mutant p53. Methods: SCH 58500 was administered i.p. to three groups of patients with heavily pretreated recurrent disease. Group 1 (n=17) received a single dose of SCH 58500 escalated from 7.5×1010 to 7.5×1012 particles. Group 2 (n=9) received two or three doses of SCH 58500 given alone for one cycle, and then with chemotherapy for two cycles. The SCH 58500 dose was further escalated to 2.5×1013 particles/dose in group 2. A third group (n=15) received a 5-day regimen of SCH 58500 given at 7.5×1013 particles/dose per day i.p. alone for cycle 1 and then with intravenous carboplatin/paclitaxel chemotherapy for cycles 2 and 3. Results: No dose-limiting toxicity resulted from the delivery of 236/287 (82.2%) planned doses of SCH 58500. Fever, hypotension abdominal complaints, nausea, and vomiting were the most common adverse events. Vector-specific transgene expression in tumor was documented by RT-PCR in cells from both ascitic fluid and tissue biopsies. Despite marked increases in serum adenoviral antibody titers, transgene expression was measurable in 17 of 20 samples obtained after two or three cycles of SCH 58500. Vector was detectable in peritoneal fluid by 24 hours and persisted for as long as 7 days whereas none was detected in urine or stool. There was poor correlation between CT scans and CA125 responses. CA125 responses, defined as a greater than 50% decrement in serum CA125 from baseline, were documented in 8 of 16 women who completed three cycles of the multidose regimen. Conclusion: CT scans... [ABSTRACT FROM AUTHOR]

Objectives: To evaluate a dual-phase protocol for vaginal ablative Erbium:YAG laser treatment in pelvic floor medicine.Study Design: Data from consecutive patients undergoing vaginal Erbium:YAG laser for first-degree pelvic floor complaints at a certified university urogynecological unit were analyzed. Fractional ablative and thermal treatment with adjustable pulse duration, fluence, and pulse interval was performed in single ten-minute treatment course. Followed up interval was 6 weeks including interviews on expectations, goal setting, goal achievement, and satisfaction (EGGS), vaginal pH, and determination of the Gloria-Bachmann-Index (VHI). Post-procedural complications were classified according to definition and classification of the Clavien-Dindo system.Results: Of 84 patients treated, 71 (21% pre-, 79% post-menopausal) were evaluated. 27% had single urogynecological symptoms, 35% had three or more combined symptoms. Minor post-procedural complications occurred in three patients (CD I, n = 1; CD II, n = 3). The ranges of fluence, determined according to the atrophy state, in the first and second phases were 15-35 and 3-12 J/cm2, respectively. In patients with genitourinary syndrome of menopause, pre- and post-treatment VHI and pH differed significantly [15.3 ± 4.5 vs. 19.9 ± 2.8 (p < 0.001, Student's t test) and 5.2 ± 0.6 vs. 4.8 ± 0.4 (p =  0.024, respectively]. Overall, 82% (n = 58; mean age, 58 ± 12 years) of patients were satisfied with the treatment, 84% (47/56) post-menopausal patients were satisfied.Conclusions: Vaginal ablative Erbium:YAG laser dual-phase protocol for early urogynecological symptoms was successful and safe, with high patient satisfaction and few, minor complications. Prospective studies are needed to confirm our first data. [ABSTRACT FROM AUTHOR]

Ferrocene and its derivatives compounds have shown a significant role in medicinal organometallic chemistry as an antiparasitic or antibacterial. Therefore, we herein report on the utilization of dithioesters ferrocenyl derivatives as proligands for the synthesis of heteroleptic platinum(II) and homoleptic palladium(II) complexes bearing a conserved O,S binding moiety. The resulting complexes [Pt(L1)(DMSO)Cl] (1), [Pt(L2)(DMSO)Cl] (2), [Pt(L3)(DMSO)Cl] (3), [Pd(L1)2] (4), [Pd(L2)2] (5), and [Pd(L3)2] (6), in which HL1 = methyl 3-hydroxy-3-ferroceneprop-2-enedithioate, HL2 = ethyl 3-hydroxy-3-ferroceneprop-2-enedithioate and HL3 = propyl 3-hydroxy-3-ferroceneprop-2-enedithioate, were fully characterized employing a variety of analytical techniques (NMR spectroscopy, elemental analysis, and mass spectrometry and X-ray structure determination of complexes 2 and 6). Cytotoxicity assays of the synthesized ligands as well as the Pt/Pd metal complexes showed low toxicity towards ovarian cancer cells, but the compounds are not affected by cisplatin resistance mechanisms. Pt(II) complexes exhibited the highest activity, and the alkyl substituent strongly influenced the activity of these complexes and the free ligands. The cytotoxic activity increases with the length of the alkyl chain with 3 exhibiting a mean IC50 of 56 µM. [ABSTRACT FROM AUTHOR]

Three new series of homoleptic and heteroleptic platinum(II) β‐oxodithiocinnamic ester complexes, [Pt(L1–L9)2], [Pt(L1–L9)(DMS)Cl] and [Pt(L1–L9)(DMSO)Cl], were synthesized and characterized using elemental analysis, mass spectrometry, and different NMR spectroscopy (1H, 13C{1H} and 195Pt). The β‐oxodithiocinnamic esters coordinate towards the platinum(II) centre as O,S‐bidentate chelating ligands. The structures of HL3, [Pt(L2)2], [Pt(L6)(DMS)Cl] as well as [Pt(L2)(DMSO)Cl] have been confirmed through the X‐ray crystallography, where the platinum(II) complexes exhibit a slightly distorted square planar geometry. In this article, we also investigated the solvolysis of three representative Pt(II) complexes, as well as the interaction with 9‐methylguanine as a DNA model system, by utilizing the LC‐ESI‐MS technique. A selection of the complexes was assessed for their use as anticancer agents, and cytotoxicity assays with these complexes showed modest toxicity on both Cisplatin sensitive and resistant ovarian cancer cell lines. However, the compounds cytotoxicity was not affected by the Cisplatin resistance mechanisms and a specific selection of the ligands may modify the cell line specificity. [ABSTRACT FROM AUTHOR]

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. PAOLA1: nonBRCA HRRm tests not interchangeable with HRD genomic instability to predict olaparib plus bev benefit in 1L OC. [ABSTRACT FROM AUTHOR]

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. 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. 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 %. 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. [ABSTRACT FROM AUTHOR]

Objective: To assess patient safety and complication rates in native tissue vaginal prolapse repair combined with laparoscopically assisted vaginal hysterectomy and prophylactic salpingectomy/salpingoophorectomy.Study Design: This was a single-centre retrospective study conducted at the University Hospital, Urogynaecological Unit, with a certified urogynaecological surgeon. A cohort of 321 consecutive patients received laparoscopically assisted vaginal hysterectomy for pelvic organ prolapse grade II-IV combined with defect-specific vaginal native tissue repair. Analysis of the total cohort and subgroups according to prolapse grade and concomitant laparoscopic procedures was performed. Student's t-tests and chi-squared tests were used for descriptive statistical analysis. Surgical complications were classified using the Clavien-Dindo (CD) classification system of surgical complications.Results: Complications were classified as CD I (1.87%), CD II (13.39%), CD IIIa (0.62%), and CD IIIb (1.87%); no CD IV or CD V complication occurred. One (0.31%) intraoperative bladder lesion, but no rectal lesion, ureter lesion, or intraoperative haemorrhage requiring blood transfusion, was noted. The overall morbidity rate, including the intraoperative bladder lesion and the CD I complication, was 18.06%. All (n=321) patients underwent prophylactic salpingectomy. Additional oophorectomy was performed in 222 post-menopausal patients. Pelvic adhesions were found in 123 (38.31%) patients and 148 (46%) patients presented grade IV prolapse. Operating time was longer for grade IV than for grade II/III prolapse (p<0.01), but CD III complication rates did not differ between these groups. Operating time was longer when laparoscopic adhesiolysis was performed (p=0.025), but this factor did not affect CD III complication rates.Conclusions: The combination of vaginal site-specific prolapse repair with laparoscopically assisted hysterectomy leads to low complication rates. Prophylactic salpingectomy or salpingoophorectomy can be performed safely in combination with hysterectomy for pelvic organ prolapse. In terms of surgical safety laparoscopy seems to be a meaningful addition to vaginal native tissue prolapse surgery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

(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 β-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. [ABSTRACT FROM AUTHOR]

(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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The gold standard of axillary sentinel lymph node biopsy (SLNB) in breast cancer is the combination of radioactive colloid and blue dye injection. Worldwide, numerous hospitals without access to radioactive tracers still perform a routine complete axillary lymph node dissection (ALND). We retrospectively analyzed the false negative rate and identification rate of SLNB with injection of blue dye in the absence of radioactive colloid and compared the subareolar (SA) and the peritumoral (PT) injection. Two hundred and fourteen patients with clinically node negative unifocal breast cancer of up to 3 cm in size who underwent SLNB followed by ALND were included. Patent Blue V was injected at the SA site in 120 patients or at the PT site in 94 patients. Thirty-seven (31%) patients in the SA group and 28 (29.8%) in the PT group were node-positive by ALND. The mean number of SLNs identified was 3.1 in the SA group and 1.6 in the PT group. The SLN identification rate was 91.7% for the SA group and 80.9% for the PT group ( P = 0.017). The false negative rate was 3.6% in the SA group and 11.8% in the PT group ( P = 0.032). Our study shows an acceptable low false negative rate for the SA blue dye only injection and confirms the higher identification rate of SA versus PT localisation. This technique could have spared 67.5% (81 out of 120) of our patients the ALND and could replace ALND of early breast cancer patients in environments without access to nuclear medicine. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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+. [ABSTRACT FROM AUTHOR]

Purpose: This study was undertaken to evaluate the prevalence of endometriosis in infertile women of couples with non-male factor infertility.Methods: A retrospective validation analysis was carried out of consecutive women of infertile couples with non-male factor infertility who received combined diagnostic hysteroscopy and laparoscopy, in the period from January 2017 to August 2019 in the Department for Gynecology and Reproductive Medicine (n = 300). Type, stage and site of endometriosis were assessed and matched with the occurrence of tubal stenosis. Binary regression analysis was used to estimate the prevalence of endometriosis.Results: Endometriosis was diagnosed in 67% (n = 201). Primary infertility (OR 1.76; p = 0.036), dysmenorrhea (OR 2.47; p = 0.002), and a shorter cycle length (OR 0.972; p = 0.036) were independent risk factors for detection of endometriosis in diagnostic hystero-laparoscopy. The most frequent endometriosis sites were pelvic side wall (53.2%) and uterosacral ligaments (41.8%). Patients with endometriosis showed less often a tubal occlusion (34.32% vs. 41.4%; p = 0.205) and presented a lower rate of bilateral obstruction (9.5% vs. 18.8.%, p = 0.024). Women with endometriosis of a Fallopian tube showed a higher rate of tubal occlusion on the same side (right side p = 0.002; left side p = 0.001). Patients with rASRM score III showed the highest rate of tubal obstruction.Conclusions: The prevalence of endometriosis in infertile women was higher than expected. The indication for operative infertility diagnostics by minimal invasive techniques should be made much more generous as well as the complete clarification of the causes of female infertility. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to assess post-operative complications based on the Clavien-Dindo classification system following routine laparoscopic treatment of all stages of endometriosis.Methods: A retrospective cohort study was carried out to identify women who underwent laparoscopic complete resection of newly diagnosed endometriosis between 2013 and 2016. 401 patients were identified using hospital database search software, and electronic files were reviewed. The stages of endometriosis had been classified according to the revised score of the American Society of Reproductive Medicine (rASRM) and the Enzian classification in cases of deep infiltrating endometriosis. Post-operative complications were recorded based on the Clavien-Dindo classification. Multivariate regression analysis was used to investigate the impact of the stages of endometriosis and surgical steps on complications.Results: Grade III complications requiring surgical, endoscopic, or radiological intervention occurred in only 1.7% of patients and were significantly associated with rASRM stage IV (OR 1.8). Grade II complications (blood transfusion, total parenteral nutrition) occurred in 18.7% of patients. rASRM stage IV (OR 2.0), hysterectomy (OR 3.2), conversion to laparotomy (OR 11.1), and bowel resection (OR 27.6) were significantly associated with increased risk of grade II complications. rASRM stages I-III did not show an effect on post-operative complications or hospital stay.Conclusions: Clavien-Dindo complication grading was readily applicable to laparoscopic removal of endometriosis of all stages. Higher Clavien-Dindo grades correctly reflected clinically relevant complications and were associated with deep infiltrating endometriosis, stage IV endometriosis, bowel surgery, or hysterectomy. Clavien-Dindo classification can be recommended for evaluation of laparoscopic endometriosis surgery outcome. [ABSTRACT FROM AUTHOR]

To investigate whether automated volumetric radiomic analysis of breast cancer vascularization (VAV) can improve survival prediction in primary breast cancer. 314 consecutive patients with primary invasive breast cancer received standard clinical MRI before the initiation of treatment according to international recommendations. Diagnostic work-up, treatment, and follow-up was done at one tertiary care, academic breast-center (outcome: disease specific survival/DSS vs. disease specific death/DSD). The Nottingham Prognostic Index (NPI) was used as the reference method with which to predict survival of breast cancer. Based on the MRI scans, VAV was accomplished by commercially available, FDA-cleared software. DSD served as endpoint. Integration of VAV into the NPI gave NPIVAV. Prediction of DSD by NPIVAV compared to standard NPI alone was investigated (Cox regression, likelihood-test, predictive accuracy: Harrell's C, Kaplan Meier statistics and corresponding hazard ratios/HR, confidence intervals/CI). DSD occurred in 35 and DSS in 279 patients. Prognostication of the survival outcome by NPI (Harrell's C = 75.3%) was enhanced by VAV (NPIVAV: Harrell's C = 81.0%). Most of all, the NPIVAV identified patients with unfavourable outcome more reliably than NPI alone (hazard ratio/HR = 4.5; confidence interval/CI = 2.14-9.58; P = 0.0001). Automated volumetric radiomic analysis of breast cancer vascularization improved survival prediction in primary breast cancer. Most of all, it optimized the identification of patients at higher risk of an unfavorable outcome. Future studies should integrate MRI as a "gate keeper" in the management of breast cancer patients. Such a "gate keeper" could assist in selecting patients benefitting from more advanced diagnostic procedures (genetic profiling etc.) in order to decide whether are a more aggressive therapy (chemotherapy) is warranted. [ABSTRACT FROM AUTHOR]

Purpose: To determine the influence of endometriosis on the ovarian response during controlled ovarian hyperstimulation measured by number of oocytes retrieved and the follicular output rate (FORT).Methods: A retrospective, single center study included 96 women, who underwent ICSI treatments for male factor infertility according to World Health Organisation between 2016 until 2018. A total of 96 patients were included in the study with 205 fresh ICSI cycles. The study group included 26 patients with endometriosis after surgical and medical treatment; the control group included 70 patients without endometriosis. The women with endometriosis underwent 47 and the control group 158 ICSI cycles. Women underwent fresh intracytoplasmatic sperm injection cycles after controlled ovarian hyperstimulation following a GnRH-antagonist protocol. The FORT was calculated as the ratio of pre-ovulatory follicle count × 100/small antral follicle count at baseline.Results: A lower number of retrieved oocytes (5.89 vs. 7.25, p = 0.045), lower FORT (75.67 vs. 94.63, p = 0.046), lower number of metaphase II oocytes (4.87 vs. 6.04, p = 0.046), and lower fertilization rate after intracytoplasmatic sperm injection (40.61 vs. 57.76, p = 0.003) were found in women with endometriosis compared to women without endometriosis. The number of oocyctes retrieved was 0.71 lower in the group with endometriosis than in the group without (p = 0.026). The FORT was 24.55% lower in the group with endometriosis (p = 0.025).Conclusions: Endometriosis reduces the FORT and the number of metaphase-II oocytes after controlled ovarian hyperstimulation independly of women's age, antral follicle count and anti-Müllerian hormone. [ABSTRACT FROM AUTHOR]

Purpose: To determine risk factors for unexpected coexistent endometriosis in laparoscopic myomectomy for symptomatic uterine leiomyomas.Methods: This was a single-centre, retrospective cohort study conducted at a University Women's Hospital with a certified endometriosis centre. Data were collected from patients with symptomatic uterine leiomyomas who underwent laparoscopic myomectomy. The main outcome measured in the study was the presence of histologically confirmed endometriosis. Binary regression analysis was used to investigate risk factors for the coexistence of endometriosis. Postoperative complications were classified according to the Clavien-Dindo classification.Results: From 2014 to 2018, 223 patients underwent laparoscopic myomectomy for symptomatic leiomyomas, and 57 (25.6%) had unexpected endometriosis. Women with endometriosis significantly more frequently were nulliparous (66.7% vs. 51.2%; p = 0.04), had reported infertility (31.6% vs. 15.7%; p = 0.01) and smaller leiomyomas (mean diameter 4.92 cm) than women without endometriosis (mean diameter 6.02 cm; p = 0.006). Coexistent endometriosis significantly increased mean operative time (168.4 vs. 142.8 min; p = 0.05) while intra- and postoperative complications showed a similar distribution (p = 0.87) and length of hospital stay (p = 0.26). Binary regression analysis identified 2.3- and 2.2-fold increases in the risk of endometriosis for infertility (p = 0.042) and nulliparity (p = 0.041), respectively. Myoma size influenced the risk of endometriosis by a factor of 0.8 per cm (p = 0.037).Conclusions: Coexistent endometriosis should be expected in leiomyoma patients particularly with nulliparity, infertility or minor myoma size as independent risk factors. Preoperative counselling should incorporate surgical therapy of coexisting endometriosis. [ABSTRACT FROM AUTHOR]

Antibodies to the E6 and E7 oncoproteins of high-risk human papillomavirus (HPV) types are strongly associated with HPV-driven cancer, while antibodies against the capsid protein L1 are considered cumulative exposure markers. To test the hypothesis that L1 antibody levels are stable over time, whereas E6 and E7 levels undergo decay after cervical cancer (CxCa) treatment, we performed multiplex serology for HPV16 and 18 antigens E6, E7 and L1 in a post-treatment study of 184 patients with invasive CxCa that were characterized with a median follow-up time of 725 days, and 2-12 sera per patient. Antibody titers significantly decreased within the first six months for HPV16 E6 and E7 but not L1, and stabilized for the following 12 months on a high level, with few patients showing seroreversion. Of 67 patients seropositive for HPV16 E6 at diagnosis, 28 (41.8%) showed a decrease in antibody titers of at least 50% within the first 18 months. Similarly, of 50 HPV16 E7 seropositives, 33 (66.0%) showed decreasing antibody levels, whereas antibody decay was less frequent for HPV16 L1 (12 of 47, 25.5%). Using a power-law mathematical model to characterize antibody decay kinetics, the mean (+s.e.) durations to a 50% reduction in antibody titers within individual patients were estimated to be 56.9 (+26.1) and 56.3 (+19.0) days for HPV16 E6 and E7, respectively. In summary, HPV16 E6 and E7 antibodies undergo a slow but significant decrease in antibody titers within the first 6-18 months following CxCa treatment. However, larger studies are needed to confirm the utility of serology for prediction of disease progression and time to relapse based on antibody decay kinetics. This article is part of the theme issue 'Silent cancer agents: multidisciplinary modelling of human DNA oncoviruses'. [ABSTRACT FROM AUTHOR]

After more than 50 years of platinum-based anticancer research only three compounds are in clinical use worldwide. The use of the well-known lead compound of this class of anticancer agents, cisplatin, is limited by its side effects and varying resistance mechanisms. Therefore, we report on platinum(ii) compounds with asparagusic acid derivatives as ligands which show interesting anticancer results on cisplatin resistant cell lines. [ABSTRACT FROM AUTHOR]

Purpose: This comparative cohort study evaluated the influence of surgical route for prolapse hysterectomy (vaginal or laparoscopically assisted) on the achievement of intended elective salpingo-oophorectomy, which was a procedural goal planned with the patient before primary vaginal native-tissue prolapse surgery.Methods: Consecutive patients who underwent total vaginal hysterectomy (TVH; n = 163) or laparoscopically assisted vaginal hysterectomy (LAVH; n = 144) and vaginal native-tissue repair for pelvic organ prolapse at Jena University Hospital were enrolled.Results: Peri- and postoperative parameters, including Clavien-Dindo (CD) classification of surgical complications, were compared between groups using Student's t test, Fisher's exact test, and multivariable regression. Patient characteristics were similar, except that grade IV prolapse was more common in the LAVH group (p < 0.001). The following parameters differed between the TVH and LAVH groups: concomitant salpingectomy (1.2% vs. 34%) and salpingo-oophorectomy (45% vs. 66%), non-performance of intended salpingo-oophorectomy (36% vs. 0% OR 0.006, 95% CI < 0.001-0.083), adhesiolysis (0% vs. 44%), CD II-III complications (51% vs. 14.6% p < 0.001), operating time (153 ± 61 vs. 142 ± 27 min), and postoperative in-patient days (9.02 ± 4.9 vs. 4.99 ± 0.96; all p < 0.001).Conclusions: LAVH enabled the safe performance of planned concomitant salpingo-oophorectomy in all cases. To achieve the procedural goal in such cases, laparoscopic assistance in prolapse hysterectomy should be considered. [ABSTRACT FROM AUTHOR]

(1) Background: Epithelial ovarian cancer (EOC) is the most lethal cancer of the female reproductive system. In an earlier study, we identified multiple genes as hypermethylated in tumors of patients with poor prognosis. The most promising combination of markers to predict a patient's outcome was CaMKIINa and RUNX3. Aim of this study was to functionally validate the importance of both genes. (2) Methods: IC50 measurements, cell cycle distribution-, proliferation, and migration experiments were conducted after transgene overexpression in two EOC cell lines. (3) Results: We showed that CaMKIINa has tumor suppressive functions in vitro and reduces proliferation, migration, and colony formation. However, it had no effect on the reversion of the resistance to cisplatin. RUNX3 exhibited dualistic functions related to cisplatin sensitivity and migration capacity, depending on the respective transcript variant (TV). A2780 cells expressing RUNX3 TV2--the promoter of which harbors a CpG (50-C-phosphate-G-30) island and is potentially inactivated by hypermethylation--exhibited increased cisplatin sensitivity and reduced migration properties. However, RUNX3 TV1, not affected by CpG island methylation could be characterized as mediating resistance and enhancing migration in A2780. The higher resistance of RUNX3 TV1 transfected cells correlates with a reduction of cell proliferation. Moreover, RUNX3 TV1 expressing cells exhibit a reduced cell cycle arrest at the gap-2 or mitosis phase (G2/M) under cisplatin treatment comparable to resistant A2780 subcultures. (4) Conclusion: It appears that CaMKIINα and RUNX3 TV2 can reduce the malignant potential of EOC cells. [ABSTRACT FROM AUTHOR]

Background: Qualitative analyses showed that the presence of HPV mRNA in sentinel lymph nodes of cervical cancer patients with pN0 status is associated with significantly decreased recurrence free survival. To further address the clinical potential of the strategy and to define prognostic threshold levels it is necessary to use a quantitative assay. Here, we compare two methods of quantification: digital PCR and standard quantitative PCR. Methods: Serial dilutions of 5 ng-5 pg RNA (≙ 500-0.5 cells) of the cervical cancer cell line SiHa were prepared in 5 μg RNA of the HPV-negative human keratinocyte cell line HaCaT. Clinical samples consisted of 10 sentinel lymph nodes with varying HPV transcript levels. Reverse transcription of total RNA (5 μg RNA each) was performed in 100 μl and cDNA aliquots were analyzed by qPCR and dPCR. Digital PCR was run in the RainDrop ® Digital PCR system (RainDance Technologies) using a probe-based detection of HPV E6/E7 cDNA PCR products with 11 μl template. qPCR was done using a Rotor Gene Q 5plex HRM (Qiagen) amplifying HPV E6/E7 cDNA in a SYBR Green format with 1 μl template. Results: For the analysis of both, clinical samples and serial dilution samples, dPCR and qPCR showed comparable sensitivity. With regard to reproducibility, both methods differed considerably, especially for low template samples. Here, we found with qPCR a mean variation coefficient of 126% whereas dPCR enabled a significantly lower mean variation coefficient of 40% (p = 0.01). Generally, we saw with dPCR a substantial reduction of subsampling errors, which most likely reflects the large cDNA amounts available for analysis. Conclusions: Compared to real-time PCR, dPCR shows higher reliability. Thus, our HPV mRNA dPCR assay holds promise for the clinical evaluation of occult tumor cells in histologically tumor-free lymph nodes in future studies. [ABSTRACT FROM AUTHOR]

Background: HPV DNA testing as a primary screening marker is being implemented in several countries. Due to the high HPV prevalence in the screening population, effective triage strategies for HPV-positive cases are required. The aim of this study was to evaluate the performance of a methylation-specific real-time PCR assay (GynTect®) comprising six marker regions as a triage test. Results: An analytical sensitivity of 0.1 ng genomic DNA corresponding to 15 SiHa cells was achieved. Absolute specificity was observed in the presence of 20 ng unmethylated genomic DNA. In a clinical setting, cervical scrapes of 306 women showing abnormal colposcopy were tested for cytology, HPV positivity, and the GynTect markers ASTN1, DLX1, ITGA4, RXFP3, SOX17, and ZNF671. Of all women, histopathological data were available. The overall sensitivity for GynTect to detect CIN3+ was 67.7% (95% CI 57.3%-77.1%) whereas sensitivity was significantly higher for women of age ≥ 30 years (p = 0.04). All cancer cases (n = 5) were detected by GynTect. The overall false positive rate (= 1-specificity) for women with no CIN was 17.4% (95% CI 12.5-23.1%), with a higher proportion among HPV-positive women (24.0%, 95% CI 16.0-33.6%). In a triage screening setting, where all women underwent HPV testing and the HPV positives in addition GynTect testing, the overall sensitivity would slightly decline but specificity would reach the maximum value of 88.7% (95% CI 83.7-92.6%). Conclusion: The GynTect® assay is a robust easy to use assay with high analytical sensitivity and specificity. Moreover, the performance of the assay based on cervical scrapes provides further evidence for the usefulness of methylation markers to detect HPV-positive women with clinically relevant disease. [ABSTRACT FROM AUTHOR]

Background: HPV DNA testing as a primary screening marker is being implemented in several countries. Due to the high HPV prevalence in the screening population, effective triage strategies for HPV-positive cases are required. The aim of this study was to evaluate the performance of a methylation-specific real-time PCR assay (GynTect®) comprising six marker regions as a triage test. Results: An analytical sensitivity of 0.1 ng genomic DNA corresponding to 15 SiHa cells was achieved. Absolute specificity was observed in the presence of 20 ng unmethylated genomic DNA. In a clinical setting, cervical scrapes of 306 women showing abnormal colposcopy were tested for cytology, HPV positivity, and the GynTect markers ASTN1, DLX1, ITGA4, RXFP3, SOX17, and ZNF671. Of all women, histopathological data were available. The overall sensitivity for GynTect to detect CIN3+ was 67.7% (95% CI 57.3%-77.1%) whereas sensitivity was significantly higher for women of age ≥ 30 years (p = 0.04). All cancer cases (n = 5) were detected by GynTect. The overall false positive rate (= 1-specificity) for women with no CIN was 17.4% (95% CI 12.5-23.1%), with a higher proportion among HPV-positive women (24.0%, 95% CI 16.0-33.6%). In a triage screening setting, where all women underwent HPV testing and the HPV positives in addition GynTect testing, the overall sensitivity would slightly decline but specificity would reach the maximum value of 88.7% (95% CI 83.7-92.6%). Conclusion: The GynTect® assay is a robust easy to use assay with high analytical sensitivity and specificity. Moreover, the performance of the assay based on cervical scrapes provides further evidence for the usefulness of methylation markers to detect HPV-positive women with clinically relevant disease. [ABSTRACT FROM AUTHOR]

The development of cervical cancer is frequently accompanied by the integration of human papillomaviruses (HPV) DNA into the host genome. Viral-cellular junction sequences, which arise in consequence, are highly tumor specific. By using these fragments as markers for tumor cell origin, we examined cervical cancer clonality in the context of intra-tumor heterogeneity. Moreover, we assessed the potential of these fragments as molecular tumor markers and analyzed their suitability for the detection of circulating tumor DNA in sera of cervical cancer patients. For intra-tumor heterogeneity analyses tumors of 8 patients with up to 5 integration sites per tumor were included. Tumor islands were micro-dissected from cryosections of several tissue blocks representing different regions of the tumor. Each micro-dissected tumor area served as template for a single junction-specific PCR. For the detection of circulating tumor-DNA (ctDNA) junction-specific PCR-assays were applied to sera of 21 patients. Samples were collected preoperatively and during the course of disease. In 7 of 8 tumors the integration site(s) were shown to be homogenously distributed throughout different tumor regions. Only one tumor displayed intra-tumor heterogeneity. In 5 of 21 analyzed preoperative serum samples we specifically detected junction fragments. Junction-based detection of ctDNA was significantly associated with reduced recurrence-free survival. Our study provides evidence that HPV-DNA integration is as an early step in cervical carcinogenesis. Clonality with respect to HPV integration opens new perspectives for the application of viral-cellular junction sites as molecular biomarkers in a clinical setting such as disease monitoring. [ABSTRACT FROM AUTHOR]

This work presents platinum(II) compounds with asparagusic acid and derivatives as ligands. Examples of these derivatives were characterized using X-ray diffraction methods and the cytotoxic activity of corresponding platinum(II) complexes was measured in vitro against ovarian cancer cell lines SKOV3 and A2780 and their specially prepared cisplatin-resistant analogues. [ABSTRACT FROM PUBLISHER]

We report on platinum(ii) complexes with different cinnamic acid derivatives as ligands with cytotoxic activity against Cisplatin resistant ovarian cancer cell line subcultures of SKOV3 and A2780. A typical mechanism of action for platinum(ii) complexes as Cisplatin itself is binding to the DNA and inducing double-strand breaks. We examined the biological behavior of these potential drugs with 9-methylguanine using NMR spectroscopic methods and their DNA damage potential including γH2AX-foci analyses. X-ray diffraction methods have been used to elucidate the molecular structures of the platinum(ii) complexes. Interactions with the model protein lysozyme have been evaluated by different techniques including UV-Vis absorption spectroscopy, fluorescence and X-ray crystallography. [ABSTRACT FROM AUTHOR]

A new pseudo-octahedral π-arene ruthenium(ii) piano-stool compound, containing an O,S-bidentate ligand (compound 1) and showing significant cytotoxic activity in vitro, was synthesized and characterized. In solution stability and interaction with the model protein bovine pancreatic ribonuclease (RNase A) were investigated by using UV-Vis absorption spectroscopy. Its crystal structure and that of the adduct formed upon reaction with RNase A were obtained by X-ray crystallography. The comparison between the structure of purified compound 1 and that of the fragment bound to RNase A reveals an unusual mode of protein binding that includes ligand exchange and alteration of coordination sphere geometry. [ABSTRACT FROM AUTHOR]

Objective: To define and classify cervical elongation, to compare uterine measurements after prolapse hysterectomy with a non-prolapse control group, and to associate stage of prolapse and degree of cervical elongation.Study Design: This was a single-centre retrospective case-control study conducted at the University Hospital, Urogynaecological Unit, with a certified urogynaecological surgeon. Data were collected from patients with and without pelvic organ prolapse (POP) who underwent laparoscopically assisted vaginal hysterectomy. Post-hysterectomy uterine cervical elongation was examined using the corpus/cervix ratio (CCR), calculated from measurements taken on photographs. Cervical elongation was classified as physiological (grade 0, CCR>1.5) grade I (CCR>1 and ≤1.5) grade II (CCR>0.5 and ≤1), and grade III (CCR≤0.5).Results: Cervical elongation was detected in 288/295 (97.6%) patients in the prolapse group (grade I, 44/288 [15.2%]; grade II, 212 [73.6%]; grade III, 32 [11.1%]). Mean CCR was greater among those with stage II/III than among those with stage IV prolapse (1.0±0.4 vs. 0.8±0.2; p<0.001). Grades of cervical elongation and prolapse stages were associated (p<0.001). Grade I cervical elongation was detected in 26/69 (37.6%), grade II in 5/69, and grade III in 0/69 patients of the control group. Cervical elongation was found more often in the prolapse group compared to the control group (p<0.001). Mean total uterine length did not differ between the prolapse and control groups (8.0±1.6 vs. 8.2±1.3cm), but mean calculated cervical length was greater in the prolapse group than in the control group (4.4±1.1 vs. 3.1+0.8cm; p<0.001).Conclusions: Uterine cervical elongation is found in patients undergoing hysterectomy for pelvic organ prolapse. Cervical elongation grades and prolapse stages are correlated. Defining uterine cervical elongation based on corpus/cervix ratio with grades I-III could be a valuable basic tool for further research. [ABSTRACT FROM AUTHOR]

Objective To evaluate the safety and the subjective and objective outcomes of bilateral minimal tension sacrospinous fixation for pelvic organ prolapse. Study design This was a single-centre observational study conducted at the University Hospital, Urogynaecological Unit, with a certified urogynaecological surgeon. A cohort of 110 patients receiving modified bilateral sacrospinous fixation following a diagnosis of grade II–IV pelvic organ prolapse and defects of three pelvic compartments. Non-absorbable sutures were placed on each side of the sacrospinous ligament. The main aim was to achieve a minimal tension situation by intentionally leaving suture bridges on both sides of the suspension. The post-surgical follow-up period was 14 ± 7 months. The three characteristics of cure in functional surgery – anatomy, function, and subjective patient's judgement – were evaluated in this study. Primary outcomes were anatomic, functional, and subjective cures, that were measured pre- and postoperatively using the POP-Q system values, a validated pelvic quality-of-life questionnaire (P-QoL/D), and interviews regarding expectations, goal-setting, goal achievement, and satisfaction. Secondary outcome measures included data on surgical complications. Data analysis was performed with descriptive statistics, Wilcoxon tests, and Mann–Whitney U -tests. Results A total of 110 patients underwent anterior and posterior colporrhaphy and minimal tension bilateral sacrospinous fixation. An objective anatomic cure was reported for 94.5% of patients, and significant improvement of all prolapse symptoms was observed following surgery ( p < 0.001). Full or partial fulfilment of the criteria for a subjective cure was demonstrated in 96% of the patients. Only 5.5% of the patients experienced postoperative urinary tract infections. No other complications requiring medical or surgical interventions were reported. Conclusion Bilateral minimal tension sacrospinous fixation was associated with low morbidity, as well as excellent anatomic, functional, and subjective results at follow-up. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effectiveness of intraoperatively applied local ropivacaine added to standard analgesic therapy in reducing postoperative pain intensity and opioid requirement under routine hospital conditions. Study design In this prospective controlled cohort study, 303 consecutive patients receiving a gynaecological laparoscopic intervention at the Jena University Hospital were included. The study cohort (n = 168) received, in addition to standard pain management, a port-site (PS) infiltration with ropivacaine prior to incision and intraperitoneal (IP) instillation at the end of surgery. On the first postoperative day patients answered a validated questionnaire, and requirement of rescue analgesics was assessed. Results Pain intensity was assessed on an 11-point numeric rating scale (NRS) from 0 = no pain to 10 = most severe pain. Reported pain intensity for movement-related pain was significantly lower (p = .001) in the study group compared with the control group (4.4 (SD 2.4) vs. 5.3 (SD 2.2) respectively). Minimal pain intensity after operation was also significantly lower in the study cohort (2.6 (SD 1.7) vs. 2.1 (SD 1.8), (p = .007)). Significantly fewer patients required rescue opioids for analgesia in the ropivacaine cohort (p = .001). The requested dose of rescue opioid (piritramide) in this cohort was also lower (p = .035) with 6.5 mg (SD 4.9) vs. 8.7 mg (SD 6.6), and demanded later (p = .001) with 4.3 h after surgery vs. 3.1 h. Patients in the study cohort experienced less nausea (p = .046). Higher satisfaction scores with pain management were reported in the ropivacaine group 12.7 (SD 2.5) vs. 11.6 (SD 2.8) (p < .001) (16-point NRS with 0 = not at all, 15 = completely satisfied). Conclusion Addition of pre-emptive port-site plus intraperitoneal ropivacaine to standard postoperative analgesic therapy reduced postoperative pain intensity and opioid consumption in gynaecological laparoscopy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Genetic aberrations are required for the progression of HPV-induced cervical precancers. A prerequisite for clonal expansion of cancer cells is unlimited proliferative capacity. In a cell culture model for cervical carcinogenesis loss of genes located on chromosome 4q35→qter and chromosome 10p14-p15 were found to be associated with escape from senescence. Moreover, by LOH and I-FISH analyses a higher frequency of allele loss of these regions was also observed in cervical carcinomas as compared to CIN3. The aim of this study was to identify candidate senescence-related genes located on chromosome 4q35→qter and chromosome 10p14-p15 which may contribute to clonal expansion at the transition of CIN3 to cancer.Methods: Microarray expression analyses were used to identify candidate genes down-regulated in cervical carcinomas as compared to CIN3. In order to relate these genes with the process of senescence their respective cDNAs were overexpressed in HPV16-immortalized keratinocytes as well as in primary human fibroblasts and keratinocytes using lentivirus mediated gene transduction.Results: Overall fifteen genes located on chromosome 4q35→qter and chromosome 10p14-p15 were identified. Ten of these genes could be validated in biopsies by RT-PCR. Of interest is the novel finding that SORBS2 and TLR3 can induce senescence in primary human fibroblasts and keratinocytes but not in HPV-immortalized cell lines. Intriguingly, the endogenous expression of both genes increases during finite passaging of primary keratinocytes in vitro.Conclusions: The relevance of the genes SORBS2 and TLR3 in the process of cellular senescence warrants further investigation. In ongoing experiments we are investigating whether this increase in gene expression is also characteristic of replicative senescence. [ABSTRACT FROM AUTHOR]

Background: The AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. The objective of this study was to evaluate the safety and efficacy of epoetin alfa in a second randomization of the intense dose-dense arm.Methods: One thousand two hundred eighty-four patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group. Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non-erythropoiesis-stimulating agent (ESA) control group. Primary efficacy endpoints included change in hemoglobin level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion. Relapse-free survival, overall survival, and intramammary relapse were secondary endpoints estimated with Kaplan-Meier and Cox regression methods. Except for the primary hypothesis, all statistical tests were two-sided.Results: Epoetin alfa avoided the decrease in hemoglobin level (no decrease in the epoetin alfa group vs -2.20g/dL change for the control group; P < .001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < .0001). The incidence of thrombotic events was 7% in the epoetin alfa arm vs 3% in the control arm. After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intramammary relapse.Conclusions: Epoetin alfa resulted in improved hemoglobin levels and decreased transfusions without an impact on relapse-free or overall survival. However, epoetin alfa had an adverse effect, resulting in increased thrombosis. [ABSTRACT FROM AUTHOR]

Background The AGO-ETC trial compared 5-year relapse-free survival of intense dose-dense (IDD) sequential chemotherapy with epirubicin (E), paclitaxel (T), and cyclophosphamide (C) (IDD-ETC) every 2 weeks vs conventional scheduled epirubicin/cyclophosphamide followed by paclitaxel (EC→T) (every 3 weeks) as adjuvant treatment in high-risk breast cancer patients. The objective of this study was to evaluate the safety and efficacy of epoetin alfa in a second randomization of the intense dose-dense arm. Methods One thousand two hundred eighty-four patients were enrolled; 658 patients were randomly assigned to the IDD-ETC treatment group. Within the IDD-ETC group, 324 patients were further randomly assigned to the epoetin alfa group, and 319 were randomly assigned to the non–erythropoiesis-stimulating agent (ESA) control group. Primary efficacy endpoints included change in hemoglobin level from baseline to Cycle 9 and the percentage of subjects requiring red blood cell transfusion. Relapse-free survival, overall survival, and intramammary relapse were secondary endpoints estimated with Kaplan-Meier and Cox regression methods. Except for the primary hypothesis, all statistical tests were two-sided. Results Epoetin alfa avoided the decrease in hemoglobin level (no decrease in the epoetin alfa group vs –2.20g/dL change for the control group; P < .001) and statistically significantly reduced the percentage of subjects requiring red blood cell transfusion (12.8% vs 28.1%; P < .0001). The incidence of thrombotic events was 7% in the epoetin alfa arm vs 3% in the control arm. After a median follow-up of 62 months, epoetin alfa treatment did not affect overall survival, relapse-free survival, or intramammary relapse. Conclusions Epoetin alfa resulted in improved hemoglobin levels and decreased transfusions without an impact on relapse-free or overall survival. However, epoetin alfa had an adverse effect, resulting in increased thrombosis. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: Women in the peri- and post-menopause may ask for uterus-preserving therapy options when presenting with benign uterine disorders such as symptomatic fibroids. Laparoscopic myomectomy (LM) for patients in the peri- and post-menopause as a surgical alternative to hysterectomy is widely considered to be non-standard treatment. The aim of this study was to analyze safety and outcome of LM beyond the reproductive period. Study design: We evaluated the surgical outcome and patient satisfaction for a total of 451 patients: 85 peri- or post-menopausal women as group A and, for reference, 366 premenopausal women in group B, who received LM from 1998 to 2008 in our department. We analyzed data from our medical records and applied a patient questionnaire in September 2009. Results: The average number of fibroids removed and size of the leading fibroid were similar in both groups. Time of surgery was different in group A, at 102.8min, compared to group B, 128.6min (p <0.01). Rates of intra- (2.21% overall) and post-operative complications (6.22% overall) were comparable for both groups. Post-surgical hospitalization was shorter in group B (4.4 days) compared to group A (5.0 days) (p <0.01). Evaluation of the questionnaire showed high satisfaction with the results of LM in both subgroups with a significantly lower number of relapses in group A (3.5%) compared to group B (11.2%). Conclusion: Laparoscopic myomectomy as a surgical treatment option in the peri- and post-menopause was characterized by a low rate of complications and relapses as well as a high degree of patient satisfaction in our analysis. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

Chromosomal aberrations are a hallmark of human papillomavirus (HPV)-induced cervical carcinogenesis. The aim of this project was to identify structural chromosomal aberrations which may be characteristic for intraepithelial neoplasias (CIN) and cervical carcinomas (CxCa). Two independent HPV16 immortalized keratinocyte cell lines (HPKIA, HPKII) were used as a cell culture model system for cervical carcinogenesis. Different passages of HPKIA and HPKII were analyzed by multicolor spectral karyotyping. Several chromosomal translocations were identified in HPK cells and were validated by interphase fluorescence in situ hybridization (I-FISH). Three unbalanced whole chromosome arm translocations, der(10;14), der(7;21), and der(7;12), were cell line specific. The presence and frequency of these translocations were then examined by I-FISH in frozen tissue sections from normal cervical epithelia (n=6), CIN2/3 (n=15), and CxCa (n=15). The der(10;14) and der(7;21) were detected in 80% and 53.3% of CIN2/3, and in 60% and 46.7% of CxCa, respectively. The percentage of nuclei with translocations in individual lesions was significantly higher among CxCa. The der(7;12) could only be detected in 27% of CIN2/3. None of the translocations were detected in normal cervical epithelia. The translocated chromosomes may contribute to the clonal expansion of subpopulations in these cases and may thus be of diagnostic relevance. [ABSTRACT FROM AUTHOR]

Human papillomavirus (HPV) types 16 and 18 are known to play a major role in cervical carcinogenesis. However, additional genetic alterations are required for the development and progression of cervical cancer. Our aim was to identify genes which are consistently down-regulated in cervical cancers (CxCa) and which are likely to contribute to malignant transformation. Microarray analyses of RNA from high-grade cervical precancers (CIN2/3) and CxCa were performed to screen for putative tumour suppressor genes (TSG) in predefined regions on chromosomes 4 and 10. Validation of the candidate genes was done by quantitative reverse transcription–polymerase chain reaction (qRT–PCR) in 16 normal cervical tissues, 14 CIN2/3 and 16 CxCa. The two most promising genes, SORBS2 and CALML5, were expressed ectopically in various cell lines in order to analyse their functional activity. Reconstitution of SORBS2 expression resulted in a significant reduction in cell proliferation, colony formation and anchorage-independent growth in CaSki, HPKII and HaCaT cells, whereby anchorage-independent growth could only be investigated for CaSki cells. SORBS2 had no effect on cell migration. In contrast, reconstitution of CALML5 expression did not influence the phenotype of all cell lines tested. None of the genes could induce senescence or apoptosis. Our results underline a possible role of SORBS2 as a TSG in cervical carcinogenesis. [ABSTRACT FROM AUTHOR]

The coxsackie adenovirus receptor (CAR) is a component of the tight junction complex and involved in cell adhesion. Loss of CAR expression can affect cell adhesion which in the context of carcinogenesis may influence both invasion and metastatic spread. Functional inactivation of CAR may also result from the interaction with its soluble isoforms. To relate alterations of CAR expression to tumor progression, we aimed to establish a highly specific real-time PCR protocol for quantification of all splice variants. In the process of cloning, we identified a novel splice variant termed CAR4/6 that lacked exon 5 but retained exon 6 encoding the transmembrane domain. Localization of CAR4/6 in the cell membrane was confirmed by ectopic expression in HT1080 cells. Expression analyses using cDNA arrays revealed that most normal tissues, including those of the female genital tract, express full-length CAR (CAR6/7) but not CAR4/6. Differential expression of both CAR splice variants was validated in microdissected epithelia ( n = 66) derived from normal cervical ectodermal tissue, high-grade cervical intraepithelial neoplasia (CIN2/3) and invasive squamous cervical carcinoma. CAR4/6 was not expressed in normal cervical tissue but in 42% of CIN2/3 and in most cervical carcinomas ( p < 0.001). In contrast, CAR6/7 was detected in all of the microdissected samples. As for CAR4/6 expression levels of CAR6/7 were significantly lower in normal tissue as compared with CIN2/3 and cancer ( p < 0.01). Ectopic expression of CAR4/6 in different cell lines enhanced the proliferative and invasive properties indicating a possible role in cancer progression. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Ovarian cancer is most frequently diagnosed at a late stage with a poor prognosis. No markers for early diagnosis have been established. Aberrantly methylated DNA appears as a promising molecular cancer marker. The aim of this study was to analyze the methylation status of the proapoptotic cancer related gene death-associated protein kinase (DAPK) in ovarian cancer patients, healthy controls and in patients suffering from a benign proliferative disease such as uterine leiomyoma. Methods: Methylation-specific PCR (MSP) was used to detect DAPK methylation in primary tumor tissue and serum of both ovarian cancer (n =32) and uterine leiomyoma patients (n =17 primary tissue, n =30 serum). Serum samples from healthy women served as controls (n =20). MSP results were confirmed by restriction digest and sequencing analyses of cloned PCR products. Results: DAPK methylation was detected in 50% and 35.3% of primary tissue and 56% and 23.8% of serum samples from ovarian cancer and leiomyoma patients, respectively. However, the association of methylation frequencies in tissue and serum was low (kappa=−0.053). Sequencing experiments revealed fully methylated MSP products in sera of both ovarian cancer and leiomyoma patients. In contrast sera from control patients showed only partially methylated DAPK sequences. Conclusion: DAPK hypermethylation was neither specific for the tissue of origin nor for cancer. The high prevalence of leiomyoma compromises the utility of this gene as a serum marker for early ovarian cancer detection. These data emphasize the necessity to co-analyze controls presenting with non-cancer proliferative disease in the quest for molecular cancer markers. [Copyright &y& Elsevier]

Background: Reports on the specificity of breast MRI are heterogeneous, depending on the respective setting of the performed study. Purpose: To retrospectively estimate the sensitivity and especially the specificity of breast MRI in the non-screening setting as an adjunct to mammography sorted by breast density and to estimate the accuracy of breast MRI in cases rated BI-RADS 0 and 3 mammographically. Material and Methods: A total of 216 consecutive patients with referral to breast MRI and previously acquired mammography were enrolled in this analysis. Negative findings were followed up with a mean time of 26.7 months. The loss to follow-up was 10.8%. The single breast was regarded as the study subject (n=399, 364 cases were eligible for calculation of diagnostic accuracy). BI-RADS 1 and 2 were rated as benign, 4 and 5 as malignant. BI-RADS 0 and 3 were analyzed separately. The 95% confidence intervals (CIs) were calculated from the normally approximated binomial distribution and taken to represent significant differences for the two imaging modalities if they did not overlap. Results: Among the study population, 62 malignant neoplasms were detected. For cases rated BI-RADS 1, 2, 4, and 5 (n=251), the sensitivity of breast MRI was 95.7% (95% CI 89.9-100.0%) and 74.5% (95% CI 62.0-87.0%) for mammography, respectively. The specificity of breast MRI was 96.1% (95% CI 93.4-98.8%) and 92.2% (95% CI 88.5-95.9%) for mammography, respectively. The diagnostic accuracy of breast MRI did not depend on breast density. In cases rated BI-RADS 0, n=57 (3, n=56), breast MRI achieved a sensitivity of 100% (90.9%) and a specificity of 98.1% (88.9%). There was a significant (P< 0.01) accumulation of dense breast tissue (ACR IV) in breasts rated BI-RADS 0 in mammography. Breast MRI missed three malignant lesions, two of them being smaller than 3 mm. Conclusion: There is no rationale to criticize the low specificity of breast MRI when used as an adjunct to mammography. The independency of the diagnostic accuracy of breast MRI from breast density makes it a worthwhile choice in mammographic BI-RADS 0 cases. [ABSTRACT FROM AUTHOR]