Endometrioid Adenocarcinoma Resembling Cutaneous Pilomatrix Carcinoma: A Case Report of an Aggressive Neoplasm in a Young Woman With Diffusely Aberrant Beta-catenin Expression and Associated Morular Metaplasia and Atypical Polypoid Adenomyoma-type Change.

Endometrioid carcinoma with histopathologic resemblance to cutaneous pilomatrix carcinoma with mutations in the gene encoding beta-catenin, CTNNB1 are rare. There are minimal numbers of reports of high-grade tumors with this divergent differentiation in the literature. We report the case of a 29-yr-old female with an unusual presentation of endometrial cancer with overall histologic appearance indicative of a recently reported aggressive subtype of Federation of Gynecology and Obstetrics (FIGO) IVB grade 3 endometrioid carcinoma with features resembling cutaneous pilomatrix carcinoma. She was treated with a primary chemotherapy regimen with an initial significant response to treatment before developing symptomatic brain metastasis for which she underwent whole-brain radiotherapy. We discuss the unusual histologic and radiologic presentation as well as her individual management throughout this case report. The apparent association with morular metaplasia and atypical polypoid adenomyoma suggests that this rare carcinoma is within a spectrum of lesions associated with aberrant beta-catenin expression/beta-catenin mutation. Its aggressive nature highlights the importance of early recognition of this rare lesion.

The impact of enhanced recovery after gynaecological surgery: A systematic review and meta-analysis.

BACKGROUND: Enhanced Recovery After Surgery programs have become the gold standard of care in many surgical specialities. OBJECTIVES: This updated systematic review and meta-analysis aims to evaluate how an ERAS program can impact outcomes across both benign and oncological gynaecological surgery to inform standard surgical practice. SEARCH STRATEGY: An electronic search of the SCOPUS, Embase and PubMed Medline databases was performed for relevant studies assessing the use of ERAS in patients undergoing gynaecological surgery compared with those without ERAS. SELECTION CRITERIA: The studies included were all trials using ERAS programs in gynaecological surgery with a clearly outlined protocol which included at least four items from the most recent guidelines and recorded one primary outcome. DATA COLLECTION AND ANALYSIS: Meta-analysis was performed on two primary endpoints; post-operative length of stay and readmission rate and one secondary endpoint; rates of ileus. Further subgroup analyses was performed to compare benign and oncological surgeries. MAIN RESULTS: Forty studies (7885 patients) were included in the meta-analysis; 15 randomised controlled trials and 25 cohort studies. 21 studies (4333 patients) were included in meta-analyses of length of stay. Patients in the ERAS group (2351 patients) had a shortened length of stay by 1.22 days (95% CI: -1.59 - -0.86, P < 0.00001) compared to those in the control group (1982 patients). Evaluation of 27 studies (6051 patients) in meta-analysis of readmission rate demonstrated a 20% reduction in readmission rate (OR: 0.80, 95% CI: 0.65-0.97). Analysis of our secondary outcome, demonstrated a 47% reduction in rate of ileus compared to the control group. CONCLUSIONS: ERAS pathways significantly reduce length of stay without increasing readmission rates or rates of ileus across benign and oncological gynaecological surgery.

A bespoke target selection tool to guide biomarker discovery in tubo-ovarian cancer.

Introduction: Cancers presenting at advanced stages inherently have poor prognosis. High grade serous carcinoma (HGSC) is the most common and aggressive form of tubo-ovarian cancer. Clinical tests to accurately diagnose and monitor this condition are lacking. Hence, development of disease-specific tests are urgently required. Methods: The molecular profile of HGSC during disease progression was investigated in a unique patient cohort. A bespoke data browser was developed to analyse gene expression and DNA methylation datasets for biomarker discovery. The Ovarian Cancer Data Browser (OCDB) is built in C# with a.NET framework using an integrated development environment of Microsoft Visual Studio and fast access files (.faf). The graphical user interface is easy to navigate between four analytical modes (gene expression; methylation; combined gene expression and methylation data; methylation clusters), with a rapid query response time. A user should first define a disease progression trend for prioritising results. Single or multiomics data are then mined to identify probes, genes and methylation clusters that exhibit the desired trend. A unique scoring system based on the percentage change in expression/methylation between disease stages is used. Results are filtered and ranked using weighting and penalties. Results: The OCDB's utility for biomarker discovery is demonstrated with the identified target OSR2. Trends in OSR2 repression and hypermethylation with HGSC disease progression were confirmed in the browser samples and an independent cohort using bioassays. The OSR2 methylation biomarker could discriminate HGSC with high specificity (95%) and sensitivity (93.18%). Conclusions: The OCDB has been refined and validated to be an integral part of a unique biomarker discovery pipeline. It may also be used independently to aid identification of novel targets. It carries the potential to identify further biomarker assays that can reduce type I and II errors within clinical diagnostics.

Epithelioid Trophoblastic Tumour: A Case with Genetic Linkage to a Child Born over Seventeen Years Prior, Successfully Treated with Surgery and Pembrolizumab.

Epithelioid trophoblastic tumours are rare neoplasms showing differentiation towards the chorion leave-type intermediate cytotrophoblast, with only a handful of cases being reported in the literature. These tumours are slow-growing and are typically confined to the uterus for extended periods of time. While the pathogenesis is unclear, they are thought to arise from a remnant intermediate trophoblast originating from prior normal pregnancies or, less frequently, gestational trophoblastic tumours. A protracted time period between the gestational event and tumour development is typical. This case describes a 49-year-old previously healthy female who presented with a completely asymptomatic uterine mass, discovered incidentally during a routine gynaecological assessment. The pathological analysis of the hysterectomy specimen confirmed an epithelioid trophoblastic tumour, involving the uterus and cervix. This is a rare gynaecological tumour. A comparative short tandem repeat analysis revealed genetic similarities to a previous healthy gestation seventeen years prior. She was successful treated with adjuvant pembrolizumab, with no evidence of disease recurrence to date.

Liquid biopsy in ovarian cancer: Catching the silent killer before it strikes.

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy in the western world. The majority of women presenting with the disease are asymptomatic and it has been dubbed the "silent killer". To date there is no effective minimally invasive method of stratifying those with the disease or screening for the disease in the general population. Recent molecular and pathological discoveries, along with the advancement of scientific technology, means there is a real possibility of having disease-specific liquid biopsies available within the clinical environment in the near future. In this review we discuss these discoveries, particularly in relation to the most common and aggressive form of EOC, and their role in making this possibility a reality.

Are trainees working in obstetrics and gynecology confident and competent in the care of frail gynecological oncology patients?

INTRODUCTION: Older patients undergoing cancer surgery are at increased risk of post-operative complications, prolonged hospital stay, and mortality. Identification of frailty can help predict patients at high risk of peri-operative complications and allow a collaborative, multidisciplinary team approach to their care. A survey was conducted to assess the confidence and knowledge of trainees in obstetrics and gynecology regarding identification and management of peri-operative issues encountered in frail gynecological oncology patients. METHODS: A web-based survey was distributed via the Audit and Research in Gynaecological Oncology (ARGO) collaborative and UK Audit and Research Collaborative in Obstetrics and Gynaecology (UKARCOG) . The survey on the management of frail peri-operative patients was disseminated to doctors-in-training (trainees) working in obstetrics and gynecology in the United Kingdom (UK) and Ireland. Specialty (ST1-7), subspecialty, and general practice trainees, non-training grade doctors, and foundation year doctors currently working in obstetrics and gynecology were eligible. Consultants were excluded. Study data were collected using REDCAP software hosted at the University of Manchester. Responses were collected over a 6-week period between January and February 2020. RESULTS: Of the 666 trainees who participated, 67% (425/666) reported inadequate training in peri-operative management of frail patients. Validated frailty assessment tools were used by only 9% (59/638) of trainees and less than 1% (4/613) were able to correctly identify all the diagnostic features of frailty. Common misconceptions included the use of chronological age and gender in frailty assessments. The majority of trainees (76.5%, 448/586) correctly answered a series of questions relating to mental capacity; however, only 6% (36/606) were able to correctly identify all three diagnostic features of delirium. A total of 87% (495/571) of trainees supported closer collaboration with geriatricians and a multidisciplinary approach. CONCLUSIONS: Obstetrics and gynecology trainees reported inadequate training in the peri-operative care of frail gynecological oncology patients, and overwhelmingly favored input from geriatricians. Routine use of validated frailty assessment tools may aid diagnosis of frailty in the peri-operative setting. There is an unmet need for formal education in the management of frail surgical patients within the UK and Irish obstetrics and gynecology curriculum.

Defining the molecular evolution of extrauterine high grade serous carcinoma.

OBJECTIVE: High grade serous carcinoma (HGSC) is the most common and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced stage disease with poor prognosis. Recent pathological evidence strongly suggests HGSC arises from the fallopian tube via the precursor lesion; serous tubal intraepithelial carcinoma (STIC). However, further definition of the molecular evolution of HGSC has major implications for both clinical management and research. This study aims to more clearly define the molecular pathogenesis of HGSC. METHODS: Six cases of HGSC were identified at the Northern Ireland Gynaecological Cancer Centre (NIGCC) that each contained ovarian HGSC (HGSC), omental HGSC (OMT), STIC, normal fallopian tube epithelium (FTE) and normal ovarian surface epithelium (OSE). The relevant formalin-fixed paraffin embedded (FFPE) tissue samples were retrieved from the pathology archive via the Northern Ireland Biobank following attaining ethical approval (NIB11:005). Full microarray-based gene expression profiling was performed on the cohort. The resulting data was analysed bioinformatically and the results were validated in a HGSC-specific in-vitro model. RESULTS: The carcinogenesis of HGSC was investigated and showed the molecular profile of HGSC to be more closely related to normal FTE than OSE. STIC lesions also clustered closely with HGSC, indicating a common molecular origin. CONCLUSION: This study provides strong evidence suggesting that extrauterine HGSC arises from the fimbria of the distal fallopian tube. Furthermore, several potential pathways were identified which could be targeted by novel therapies for HGSC. These findings have significant translational relevance for both primary prevention and clinical management of the disease.

Impact of surgical site infection (SSI) following gynaecological cancer surgery in the UK: a trainee-led multicentre audit and service evaluation.

OBJECTIVES: Surgical site infection (SSI) complicates 5% of all surgical procedures in the UK and is a major cause of postoperative morbidity and a substantial drain on healthcare resources. Little is known about the incidence of SSI and its consequences in women undergoing surgery for gynaecological cancer. Our aim was to perform the first national audit of SSI following gynaecological cancer surgery through the establishment of a UK-wide trainee-led research network. DESIGN AND SETTING: In a prospective audit, we collected data from all women undergoing laparotomy for suspected gynaecological cancer at 12 specialist oncology centres in the UK during an 8-week period in 2015. Clinicopathological data were collected, and wound complications and their sequelae were recorded during the 30 days following surgery. RESULTS: In total, 339 women underwent laparotomy for suspected gynaecological cancer during the study period. A clinical diagnosis of SSI was made in 54 (16%) women. 33% (18/54) of women with SSI had prolonged hospital stays, and 11/37 (29%) had their adjuvant treatment delayed or cancelled. Multivariate analysis found body mass index (BMI) was the strongest risk factor for SSI (OR 1.08[95% CI 1.03 to 1.14] per 1 kg/m2 increase in BMI [p=0.001]). Wound drains (OR 2.92[95% CI 1.41 to 6.04], p=0.004) and staple closure (OR 3.13[95% CI 1.50 to 6.56], p=0.002) were also associated with increased risk of SSI. CONCLUSIONS: SSI is common in women undergoing surgery for gynaecological cancer leading to delays in discharge and adjuvant treatment. Resultant delays in adjuvant treatment may impact cancer-specific survival rates. Modifiable factors, such as choice of wound closure material, offer opportunities for reducing SSI and reducing morbidity in these women. There is a clear need for new trials in SSI prevention in this patient group; our trainee-led initiative provides a platform for their successful completion.

BRCA1 and MAD2 Are Coexpressed and Are Prognostic Indicators in Tubo-ovarian High-Grade Serous Carcinoma.

OBJECTIVES: The aim of this study was to investigate the relationship between BRCA1 and mitotic arrest deficiency protein 2 (MAD2) protein expression, as determined by immunohistochemistry, and clinical outcomes in epithelial ovarian carcinoma (EOC). METHODS: A tissue microarray consisting of 94 formalin-fixed paraffin-embedded EOC with fully matched clinicopathological data were immunohistochemically stained with anti-BRCA1 and anti-MAD2 antibodies. The cores were scored in a semiquantitative manner evaluating nuclear staining intensity and extent. Coexpression of BRCA1 and MAD2 was evaluated, and patient survival analyses were undertaken. RESULTS: Coexpression of BRCA1 and MAD2 was assessed in 94 EOC samples, and survival analysis was performed on 65 high-grade serous carcinomas (HGSCs). There was a significant positive correlation between BRCA1 and MAD2 expression in this patient cohort (P < 0.0001). Both low BRCA1 and low MAD2 are independently associated with overall survival because of HGSC. Low coexpression of BRCA1 and MAD2 was also significantly associated with overall survival and was driven by BRCA1 expression. CONCLUSION: BRCA1 and MAD2 expressions are strongly correlated in EOC, but BRCA1 expression remains the stronger prognostic factor in HGSC.

Vaginal Hysterectomy using the ERBE BiClamp® Bipolar Vessel Sealing System: A Case Series.

The ERBE BiClamp® BVSS appears to be a safe and effective method of vaginal hysterectomy in this small single surgeon, single institution study; demonstrating efficient operative times, minimal blood loss and intraoperative morbidity with acceptable surgical outcomes. Its use contributes to the advancement of minimally invasive gynaecology and should be encouraged.

Role of self-expanding metal stents in the management of variceal haemorrhage: Hype or hope?

Despite the advances of medical, endoscopic and radiological therapy over recent years the mortality rates of acute variceal haemorrhage are still 16%-20% and the medium term outcome has not improved in the last 25 years. Early transjugular intrahepatic portosystemic shunt has proved to be an effective therapy for selected groups of patients with a high risk of re-bleeding and moderate liver disease. However, there is an unmet need for a therapy that can be applied in patients with a high risk of re-bleeding and advanced liver disease either as definitive therapy or as a bridge to permanent therapy. Self-expanding metal stents can be placed without the need for endoscopic or fluoroscopic control and, once in place, will provide effective haemostasis and allow a route for oral fluids and nutrition. They can remain in place whilst liver function recovers and secondary prophylaxis is initiated. We review the results of 6 case series including a total of 83 patients and the first randomised controlled trial of self-expanding metal stents vs balloon tamponade (BT) in the management of refractory variceal haemorrhage. We report that self-expanding metal stents provide effective haemostasis and perform better than BT in refractory bleeding, where they are associated with fewer complications. Whilst the most effective place for self-expanding metal stents in the management algorithm needs to be determined by further randomised controlled trials, currently they provide an effective alternative to BT in selected patients.

BRCA1 immunohistochemical staining as a prognostic indicator in uterine serous carcinoma.

OBJECTIVES: The objective of this study was to investigate the relationship between BRCA1 protein expression, as determined by immunohistochemistry, and clinical outcome in uterine serous carcinoma (USC). METHODS: A tissue microarray containing duplicate cores of 73 cases of USC was immunohistochemically stained with mouse anti-BRCA1 (Ab-1) mouse monoclonal (MS110) antibody. The cores were scored in a semiquantitative manner evaluating both the distribution and intensity of nuclear staining. BRCA1 protein expression was correlated with progression-free survival. RESULTS: Seventy-two of 73 cases were assessable, and there was a statistically significant decreased progression-free survival for those cases exhibiting tumor cell nuclei staining of 76% or greater (P = 0.0023). CONCLUSIONS: Our study illustrates that a low level of BRCA1 protein expression is a favorable prognostic indicator in USC, similar to what is observed in high-grade serous ovarian carcinoma. Further studies should focus on the BRCA1 status of USCs at a molecular level and also investigate whether BRCA1 protein expression is associated with response to chemotherapy in USC.

Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy.

Conventional cytotoxic chemotherapy has not provided clinical benefit or prolonged survival for patients with advanced HCC. This review summarizes the results of prospective clinical trials of several categories of systemic therapy, with emphasis on the more promising results from recent trials of biologically targeted therapeutic agents in HCC.

Current management of the hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a serious complication of advanced liver disease. Historically, the development of HRS was considered a pre-terminal event due to a lack of efficacious therapy. Although liver transplantation remains the optimum therapy for HRS, many patients may be unsuitable for liver grafting. In addition, organ shortage may necessitate the institution of alternative pharmacological therapies to bridge patients to transplantation or to maintain renal function. This article reviews the definitions of Types-1 and -2 HRS, and addresses strategies for the prevention of the syndrome. It will also discuss management approaches to the cirrhotic patient with renal failure, specifically, assessment of novel vasoconstrictor therapies, such as vasopressin analogues, alpha-adrenoreceptor agonists, and the use of transjugular intra-hepatic shunts either alone or in combination with other therapeutic agents.

The role of the immune system in the control of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is common, and current therapies may not be suitable for the majority of patients with advanced disease. Cases of spontaneous regression suggest that immune mechanisms are important in the control of HCC. Experiments in animal models have shown that tolerance to HCC associated antigens can be overcome and using a number of different techniques researchers have been able to prevent the growth of implanted tumours. The most promising of these techniques is based on the use of dendritic cells, which are able to process and present antigens to activate naive T cells and, when loaded with tumour antigens, can stimulate a specific and durable anti-tumour response. The success of animal studies has led to interest in the clinical applicability of HCC immunotherapy. Non-specific adoptive immunotherapy has been successful in preventing disease recurrence after resection and cellular vaccines based on dendritic cells are now entering clinical trials. The use of dendritic-cell vaccination raises exciting possibilities of preventing the formation of HCC in high-risk individuals such as those with cirrhosis.