The use of biomarkers to stratify surgical care in women with ovarian cancer: Scientific Impact Paper No. 69 May 2022.

Biomarkers may offer unforeseen insights into clinical diagnosis, as well as the likely course and outcome of a condition. In this paper, the focus is on the use of biological molecules found in body fluids or tissues for diagnosis and prediction of outcome in ovarian cancer patients. In cancer care, biomarkers are being used to develop personalised treatment plans for patients based on the unique characteristics of their tumour. This tailoring of care can be used to pursue specific targets identified by biomarkers, or treat the patient according to specific tumour characteristics. Surgery is one of the core treatments for ovarian cancer, whether it is offered in primary surgery or following chemotherapy in delayed surgery. Biomarkers already exist to guide the treatment of tumours with chemotherapy, but very little research has determined the value of biomarkers in tailoring surgical care for ovarian cancer. Such research is required to identify new biomarkers and assess their effectiveness in a clinical setting as well as to help identify specific tumour types to guide surgery. Biomarkers could help to determine the success of removing the disease surgically, or help to identify tumour deposits that persist after chemotherapy. All of these aspects would improve current practice. This Scientific Impact Paper highlights research that may pave the way towards bespoke surgery according to the biological characteristics of a tumour and aid gynaecological oncologists to provide surgical treatment according to individual need, rather than a blanket approach for all.

Uterine Transplantation: Scientific Impact Paper No. 65 April 2021.

A uterine transplant, or womb transplant, provides a potential treatment for women who cannot become pregnant or carry a pregnancy because they do not have a womb, or have a womb that is unable to maintain a pregnancy. This is estimated to affect one in 500 women. Options for those who wish to start a family include adoption and surrogacy, but these are associated with legal, cultural, ethical and religious implications that may not be appropriate for some women and their families. A womb transplant is undertaken when the woman is ready to start a family, and is removed following the completion of their family. Womb transplants have been performed all over the world, with more than 70 procedures carried out so far. At least 23 babies have been born as a result, demonstrating that womb transplants can work. While the procedure offers a different option to adoption and surrogacy, it is associated with significant risks, including multiple major surgeries and the need to take medications that help to dampen the immune system to prevent rejection of the womb. To date there has been a 30% risk of a transplant being unsuccessful. Although the number of transplants to date is still relatively small, the number being performed globally is growing, providing an opportunity to learn from the experience gained so far. This paper looks at the issues that have been encountered, which may arise at each step of the process, and proposes a framework for the future. However, long term follow-up of cases will be essential to draw reliable conclusions about any overall benefits of this procedure.

The vaginal microbiome in uterine transplantation.

Women with congenital absolute uterine factor infertility (AUFI) often need vaginal restoration to optimise sexual function. Given their lack of procreative ability, little consideration has previously been given to the resultant vaginal microbiome (VM). Uterine transplantation (UTx) now offers the opportunity to restore these women's reproductive potential. The structure of the VM is associated with clinical and reproductive implications that are intricately intertwined with the process of UTx. Consideration of how vaginal restoration methods impact VM is now warranted and assessment of the VM in future UTx procedures is essential to understand the interrelation of the VM and clinical and reproductive outcomes. TWEETABLE ABSTRACT: The vaginal microbiome has numerous implications for clinical and reproductive outcomes in the context of uterine transplantation.

Human uterine transplantation: a review of outcomes from the first 45 cases.

Uterine transplantation restores reproductive anatomy in women with absolute uterine factor infertility and allows the opportunity to conceive, experience gestation, and acquire motherhood. The number of cases being performed is increasing exponentially, with detailed outcomes from 45 cases, including nine live births, now available. In light of the data presented herein, including detailed surgical, immunosuppressive and obstetric outcomes, the feasibility of uterine transplantation is now difficult to refute. However, it is associated with significant risk with more than one-quarter of grafts removed because of complications, and one in ten donors suffering complications requiring surgical repair. TWEETABLE ABSTRACT: Uterine transplantation is feasible in women with uterine factor infertility, but is associated with significant risk of complication.

Accuracy of ultrasonography performed by examiners with varied training and experience in predicting specific pathology of adnexal masses.

OBJECTIVES: To assess the diagnostic performance of subjective assessment by Level II ultrasound examiners in predicting the specific histology of adnexal masses. METHODS: The women included in this prospective multicenter cross-sectional study were older than 16 years of age and had at least one adnexal mass. They underwent transvaginal sonography (TVS) performed by Level II examiners, all of whom were familiar with the International Ovarian Tumor Analysis (IOTA) group definitions of ultrasound features of ovarian masses. The final outcome was histology. Specific diagnoses were categorized into 16 groups. Agreement between subjective assessment and final histology was measured using unweighted kappa coefficients. Sensitivities and specificities were obtained for subjective assessment. RESULTS: Of the 1279 women who underwent TVS, 313 were included in the final analysis. Overall agreement (16 × 16 table) between subjective assessment and histology was moderate, with a Cohen's kappa coefficient of 0.59 (95% CI, 0.53-0.65). The specificity of subjective assessment ranged between 91% and 100% for all histological subgroups. Highest sensitivities were achieved in the diagnosis of simple cysts (100% (95% CI, 61-100%)), hydrosalpinges (100% (95% CI, 34-100%)), mature teratomas (88% (95% CI, 74-96%)), endometriomas (75% (95% CI, 61-85%)), ovarian fibromas (88% (95% CI, 47-100%)), tubo-ovarian abscesses (88% (95% CI, 47-100%)) and serous cystadenocarcinomas (82% (95% CI, 66-93%)). Serous cystadenomas were misdiagnosed most commonly (40.5%). The sensitivity of subjective assessment in diagnosing adnexal torsion was 54% (95% CI, 25-81%); the 17 confirmed and/or suspected cases of adnexal torsion were not included in the 313 cases examined and analyzed for diagnostic performance. CONCLUSION: Overall, subjective assessment by Level II examiners was good for the detection of simple cysts, endometriomas, mature teratomas, hydrosalpinges, fibroma, tubo-ovarian abscess and serous cystadenocarcinomas.

Radiological predictors of cytoreductive outcomes in patients with advanced ovarian cancer.

OBJECTIVE: To assess site of disease on preoperative computed tomography (CT) to predict surgical debulking in patients with ovarian cancer. DESIGN: Two-phase retrospective cohort study. SETTING: West London Gynaecological Cancer Centre, UK. POPULATION: Women with stage 3 or 4, ovarian, fallopian or primary peritoneal cancer undergoing cytoreductive surgery. METHODS: Preoperative CT images were reviewed by experienced radiologists to assess the presence or absence of disease at predetermined sites. Multivariable stepwise logistic regression models determined sites of disease which were significantly associated with surgical outcomes in the test (n = 111) and validation (n = 70) sets. MAIN OUTCOME MEASURES: Sensitivity and specificity of CT in predicting surgical outcome. RESULTS: Stepwise logistic regression identified that the presence of lung metastasis, pleural effusion, deposits on the large-bowel mesentery and small-bowel mesentery, and infrarenal para-aortic nodes were associated with debulking status. Logistic regression determined a surgical predictive score which was able to significantly predict suboptimal debulking (n = 94, P = 0.0001) with an area under the curve (AUC) of 0.749 (95% confidence interval [95% CI]: 0.652, 0.846) and a sensitivity of 69.2%, specificity of 71.4%, positive predictive value of 75.0% and negative predictive value of 65.2%. These results remained significant in a recent validation set. There was a significant difference in residual disease volume in the test and validation sets (P < 0.001) in keeping with improved optimal debulking rates. CONCLUSIONS: The presence of disease at some sites on preoperative CT scan is significantly associated with suboptimal debulking and may be an indication for a change in surgical planning.

Psychological assessment tool for patients diagnosed with absolute uterine factor infertility and planning to undergo uterine transplantation.

Uterine transplantation (UTn) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI) and who are willing to bear their own child. AUFI renders a woman 'unconditionally infertile'. For AUFI women in general, UTn may offer a way to re-discover their own femininity through the restoration of fertility. Thus, when faced with a patient who may undergo UTn, the 'holistic approach' takes on an extra meaning. This is because the psychological element is two-sided for these patients. On one side lies the psychology of infertility, and on the other and equally important, is the substantially higher prevalence of psychiatric disorders in transplant candidates and recipients than in the general population. However, the psychology of a potential recipient of a uterine graft in order to bring about fertility has not been adequately explored or reviewed scientifically. We have presented here an outline of the areas which should be included in a psychological assessment for patients wishing to undergo UTn.

The role of cytology and other prognostic factors in endometrial cancer.

The clinical and prognostic value of positive cytology in women with endometrial cancer remains uncertain. The aim of our retrospective observational study was to determine whether in women with disease confined to the uterus, positive peritoneal cytology adversely affects disease-free (DFS) or overall survival (OS); to assess whether positive or negative cytology affects survival in women irrespective of stage and to assess whether the use of hysteroscopy or Pipelle for diagnosis affected cytology positivity rates. We have shown that median DFS and OS were almost identical for tumours confined to the uterus with and without positive peritoneal cytology. Women with tumours extending to the serosa or adnexa had a non-statistically significant shorter survival in comparison with women with stage I disease and negative cytology. Out of 59 women that had their cancer diagnosis based on a Pipelle biopsy of the endometrium, five had positive peritoneal washings. A total of 150 women had pre-treatment hysteroscopy; seven of these had positive peritoneal washings. There was no significant difference in the rates of positive cytology between these groups (4.6% vs 8.4%). In our cohort of un-staged women, positive peritoneal cytology did not adversely affect prognosis when disease was confined to the uterus.

Training the trainees: an evaluation exercise using the TLH and BSO model.

Our aim was to evaluate surgical training in gynaecological oncology by assessing the time required by a trainee to complete a single laparoscopic gynaecologic-oncological operation. A total of 135 patients with a BMI < 40 kg/m2, diagnosed with endometrial cancer, underwent a total laparoscopic hysterectomy and bilateral salpingo-oophorectomy (TLH and BSO). Patients in Group I (n = 78) were operated on by a consultant gynaecological oncology surgeon and in Group II (n = 57) by sub-specialist trainees (SSTs). The mean patient age and BMI was 63.5 years and 29.6 kg/m2, respectively, in Group I and 64.5 years and 29.9 kg/m2, respectively, in Group II. Median operating times for Groups I and II were 58 and 90 min, respectively (p < 0.05). Furthermore, significant improvement was noted when comparing the average operating time between the first and second half of SST training. Even experienced gynaecological trainees take significantly longer to perform a reproducible laparoscopic operation. At the completion of training, an SST demonstrates improvement with respect to operation duration but is still not as fast as the trainer.

Multicentre external validation of IOTA prediction models and RMI by operators with varied training.

BACKGROUND: Correct characterisation of ovarian tumours is critical to optimise patient care. The purpose of this study is to evaluate the diagnostic performance of the International Ovarian Tumour Analysis (IOTA) logistic regression model (LR2), ultrasound Simple Rules (SR), the Risk of Malignancy Index (RMI) and subjective assessment (SA) for preoperative characterisation of adnexal masses, when ultrasonography is performed by examiners with different background training and experience. METHODS: A 2-year prospective multicentre cross-sectional study. Thirty-five level II ultrasound examiners contributed in three UK hospitals. Transvaginal ultrasonography was performed using a standardised approach. The final outcome was the surgical findings and histological diagnosis. To characterise the adnexal masses, the six-variable prediction model (LR2) with a cutoff of 0.1, the RMI with cutoff of 200, ten SR (five rules for malignancy and five rules for benignity) and SA were applied. The area under the curves (AUCs) for performance of LR2 and RMI were calculated. Diagnostic performance measures for all models assessed were sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-), and the diagnostic odds ratio (DOR). RESULTS: Nine-hundred and sixty-two women with adnexal masses underwent transvaginal ultrasonography, whereas 255 had surgery. Prevalence of malignancy was 29% (49 primary invasive epithelial ovarian cancers, 18 borderline ovarian tumours, and 7 metastatic tumours). The AUCs for LR2 and RMI for all masses were 0.94 (95% confidence interval (CI): 0.89-0.97) and 0.90 (95% CI: 0.83-0.94), respectively. In premenopausal women, LR2-RMI difference was 0.09 (95% CI: 0.03-0.15) compared with -0.02 (95% CI: -0.08 to 0.04) in postmenopausal women. For all masses, the DORs for LR2, RMI, SR+SA (using SA when SR inapplicable), SR+MA (assuming malignancy when SR inapplicable), and SA were 62 (95% CI: 27-142), 43 (95% CI: 19-97), 109 (95% CI: 44-274), 66 (95% CI: 27-158), and 70 (95% CI: 30-163), respectively. CONCLUSION: Overall, the test performance of IOTA prediction models and rules as well as the RMI was maintained in examiners with varying levels of training and experience.

Uterine transplantation: what else needs to be done before it can become a reality?

Uterine transplantation may be a possible treatment option in the future for absolute uterine infertility. We describe three important areas of research that we feel are important in order to move closer to a successful and, crucially, safe transplant in the human setting. With closer collaboration among the various international teams working on this project, the first human uterine transplant should be possible in the next few years.

Does the presence of a Caesarean section scar affect implantation site and early pregnancy outcome in women attending an early pregnancy assessment unit?

STUDY QUESTION: Are there any differences in the location and distance to the internal cervical ostium of the implantation site of the intrauterine gestation sacs, early pregnancy symptoms and pregnancy outcome at 12 weeks gestation between women with and without a previous Caesarean section (CS)? SUMMARY ANSWER: The presence of a CS scar affects the site of implantation, and the distance between implantation site and the scar is related to the risk of spontaneous abortion. WHAT IS KNOWN ALREADY?: Little is known about the impact of a CS scar on implantation other than the risk of Caesarean scar pregnancy (CSP). Furthermore, there is a paucity of information on how the proximity of implantation to the scar impacts on pregnancy outcome in the first trimester. STUDY DESIGN, SIZE, AND DURATION: A prospective cohort study conducted over 15 months in the early pregnancy unit of a London Teaching Hospital. Three hundred and eighty women underwent a transvaginal scan at 6-11 weeks of gestation. A total of 170 women had undergone ≥1 CS, and 210 women had no history of CS. PARTICIPANTS/MATERIALS, SETTING, METHODS: The 380 women were recruited as consecutive non-selected cases. The relationship between the implanted sac and the CS scar was assessed by quantifiable measures and by subjective impression. Logistic regression analysis was used to determine the influence of the presence of a CS scar on pregnancy outcome. The final outcome of the study was the viability of the pregnancy at 12 weeks. MAIN RESULTS AND THE ROLE OF CHANCE: Implantation was most frequently posterior (53%) in the CS group and fundal in the non-CS group (42%). Gestation sac implantation was 8.7 mm lower in the CS group (95% confidence interval (CI) 6.7-10.7, P < 0.0001). Presenting complaints differed in women with and without a previous CS (P = 0.0009). More frequent vaginal bleeding [73 versus 55%, difference -18, 95% CI (-27 to -8%] yet no clearly increased spontaneous abortion rates were noted in the CS group compared with the non-CS group (adjusted odds ratio = 1.1, 95% CI 0.6-1.9, P = 0.74). Subjective impression showed that in eight cases the implantation site crossed the scar, seven of which resulted in spontaneous abortion, while the remaining case survived to term complicated by placenta praevia and post-partum haemorrhage. The subjective impression of the examiner was supported by the measurements of distance between implantation site and CS scar. LIMITATIONS, REASONS FOR CAUTION: A weakness of the study is the lack of a reference technique to verify the location of implantation. WIDER IMPLICATIONS OF THE FINDINGS: This study adds further support to the hypothesis that the presence of a CS on the uterus impacts on the implantation site of a future pregnancy. The possibility that the CS scar has an impact on the risk of spontaneous abortion should be further studied. Caution must be exercised when implantation occurs near to, and crosses, a CS scar as this is not always associated with the diagnosis of CSP. A potential limitation of the study is that we did not examine scar dimensions and morphology.

Predicting successful vaginal birth after Cesarean section using a model based on Cesarean scar features examined by transvaginal sonography.

OBJECTIVE: To develop a model to predict the success of a trial of vaginal birth after Cesarean section (VBAC) based on sonographic measurements of Cesarean section (CS) scar features, demographic variables and previous obstetric history. METHODS: We used transvaginal sonography (TVS) to examine the CS scar of 320 consecutive pregnant women. TVS was carried out at 11-13, 19-21 and 34-36 weeks' gestation and prospective measurements of the scar were recorded at each visit according to a defined protocol. A logistic regression model to predict success of VBAC was developed for those patients with a visible scar on ultrasound and only one previous CS. The model was evaluated using bootstrap validation. RESULTS: There were 131 women with one previous CS and a visible scar, of whom 10 underwent CS prior to labor and were excluded from analysis. Successful VBAC was achieved in 74/121 (61%) of the remaining cases. The prediction model developed was based on patient age, previous history of VBAC, residual myometrial thickness (RMT) and the change in RMT from the first to the second trimester (ΔRMT). The internally validated area under the receiver-operating characteristics curve was 0.62 when measurements of RMT and ΔRMT were excluded, but 0.94 when scar information was incorporated into the model. CONCLUSION: Ultrasound measurements of CS scar, namely RMT and the change in RMT from the first to the second trimester of pregnancy, when incorporated into a mathematical model, can predict accurately a successful trial of labor in patients with one previous CS.

Chromatin H3K27me3/H3K4me3 histone marks define gene sets in high-grade serous ovarian cancer that distinguish malignant, tumour-sustaining and chemo-resistant ovarian tumour cells.

In embryonic stem (ES) cells, bivalent chromatin domains containing H3K4me3 and H3K27me3 marks silence developmental genes, while keeping them poised for activation following differentiation. We have identified gene sets associated with H3K27me3 and H3K4me3 marks at transcription start sites in a high-grade ovarian serous tumour and examined their association with epigenetic silencing and malignant progression. This revealed novel silenced bivalent marked genes, not described previously for ES cells, which are significantly enriched for the PI3K (P<10(-7)) and TGF-ß signalling pathways (P<10(-5)). We matched histone marked gene sets to gene expression sets of eight normal fallopian tubes and 499 high-grade serous malignant ovarian samples. This revealed a significant decrease in gene expression for the H3K27me3 and bivalent gene sets in malignant tissue. We then correlated H3K27me3 and bivalent gene sets to gene expression data of ovarian tumour 'stem cell-like' sustaining cells versus non-sustaining cells. This showed a significantly lower expression for the H3K27me3 and bivalent gene sets in the tumour-sustaining cells. Similarly, comparison of matched chemo-sensitive and chemo-resistant ovarian cell lines showed a significantly lower expression of H3K27me3/bivalent marked genes in the chemo-resistant compared with the chemo-sensitive cell line. Our analysis supports the hypothesis that bivalent marks are associated with epigenetic silencing in ovarian cancer. However it also suggests that additional tumour specific bivalent marks, to those known in ES cells, are present in tumours and may potentially influence the subsequent development of drug resistance and tumour progression.

Changes in Cesarean section scar dimensions during pregnancy: a prospective longitudinal study.

OBJECTIVES: To describe changes in Cesarean section (CS) scars longitudinally throughout pregnancy, and to relate initial scar measurements, demographic variables and obstetric variables to subsequent changes in scar features and to final pregnancy outcome. METHODS: In this prospective observational study we used transvaginal sonography (TVS) to examine the CS scar of 320 consecutive pregnant women at 11-13, 19-21 and 32-34 weeks' gestation. For scars visible on TVS, the hypoechoic part was measured in three dimensions and the residual myometrial thickness (RMT) was also measured. Analyses were carried out using one-way repeated measures ANOVA and mixed modeling. The incidence of subsequent scar rupture was recorded. RESULTS: The CS scar was visible in 284/320 cases (89%). Concerning length and depth of the hypoechoic part of the scar and RMT, the larger the initial scar measurement, the larger the decrease observed during pregnancy. For the hypoechoic part of the scar, the width increased on average by 1.8 mm per trimester, while the depth and length decreased by 1.8 and 1.9 mm, respectively (false discovery rate P < 0.0001). Mean RMT in the first trimester was 5.2 mm and on average decreased by 1.1 mm per trimester. Two cases (0.62%) of uterine scar rupture were confirmed following a trial of vaginal delivery; these had a mean RMT of 0.5 mm at second scan and an average decrease of 2.6 mm over the course of pregnancy. CONCLUSION: This study establishes reference data and confirms that the dimensions of CS scars change throughout pregnancy. Scar rupture was associated with a smaller RMT and greater decrease in RMT during pregnancy. There is the potential to test absolute values and observed changes in CS scar measurements as predictors of uterine scar rupture and outcome in trials of vaginal birth after Cesarean section.

Does tumour biology determine surgical success in the treatment of epithelial ovarian cancer? A systematic literature review.

BACKGROUND: Ovarian cancer is the most lethal gynaecological cancer. Progression-free and overall survival is significantly related to surgical success and residual disease volume. It is unclear whether this survival advantage is due to an intrinsic biological element of the tumour cells which enables successful surgery and improved prognosis, or alternatively the number of tumour sustaining cells remaining irrespective of differences in biology. METHODS: A systematic review of the literature was performed identifying studies that have investigated the association between biomarkers and surgical outcomes. We attempted validation of these results using The Cancer Genome Atlas ovarian cancer data sets. RESULTS: Thirty studies were identified of which sixteen determined protein expression, eight gene expression and one DNA methylation in association with surgical debulking. Individualised linear models adjusting for batch, stage and age identified only expression of the genes MTDH and insulin-like growth factor-1 receptor (IGF1R) to be significantly associated with debulking surgery (P<0.05, false discovery rate (FDR)<5%), although in the case of IGF1R this was in the opposite direction to previous findings. CONCLUSION: The majority of studies are limited by design, include heterogeneous samples and lack adjustment for major confounding factors. High quality detailed clinical annotations should be routinely collected in future to more accurately evaluate biomarkers of surgical outcome.

Total laparoscopic hysterectomy for early stage endometrial cancer in obese and morbidly obese women.

This is a retrospective observational study, where we have evaluated the role of total laparoscopic hysterectomy (TLH) in obese and morbidly obese patients with early stage endometrial cancer. Our study illustrates that low conversion rates are achievable when appropriately trained surgeons undertake this procedure. All the women with high BMI were operated on laparoscopically in preference to laparotomy, unless there was an obvious contraindication such as a very large uterus or disseminated disease. We have also shown low conversation and complication rates for our patients, in particular a low rate of wound infection. This is in contrast to the high rate of wound infection and prolonged hospital stay reported for obese patients in the literature. Our study shows that TLH for endometrial cancer in obese women is feasible, safe and is likely to be cost-effective and adds to the weight of evidence for its use in this condition.