The Development of a Three-Dimensional Platform for Patient-Derived Ovarian Cancer Tissue Models: A Systematic Literature Review.

There is an unmet biomedical need for ex vivo tumour models that would predict drug responses and in turn help determine treatment regimens and potentially predict resistance before clinical studies. Research has shown that three dimensional models of ovarian cancer (OvCa) are more realistic than two dimensional in vitro systems as they are able to capture patient in vivo conditions in more accurate manner. The vast majority of studies aiming to recapitulate the ovarian tumour morphology, behaviors, and study chemotherapy responses have been using ovarian cancer cell lines. However, despite the advantages of utilising cancer cell lines to set up a platform, they are not as informative as systems applying patient derived cells, as cell lines are not able to recapitulate differences between each individual patient characteristics. In this review we discussed the most recent advances in the creation of 3D ovarian cancer models that have used patient derived material, the challenges to overcome and future applications.

FARGO-360: a multi-disciplinary survey of practice and perspectives on provision of care for patients with frailty presenting with gynecological cancers in the UK and Ireland.

OBJECTIVES: Frailty has been associated with worse cancer-related outcomes for people with gynecological cancers. However, the lack of clear guidance on how to assess and modify frailty prior to instigating active treatments has the potential to lead to large variations in practice and outcomes. This study aimed to evaluate current practice and perspectives of healthcare practitioners on the provision of care for patients with frailty and a gynecological cancer. METHODS: Data were collected via a questionnaire-based survey distributed by the Audit and Research in Gynecological Oncology (ARGO) collaborative to healthcare professionals who identified as working with patients with gynecological malignancies in the United Kingdom (UK) or Ireland. Study data were collected using REDCap software hosted at the University of Manchester. Responses were collected over a 16 week period between January and April 2021. RESULTS: A total of 206 healthcare professionals (30 anesthetists (14.6%), 30 pre-operative nurses (14.6%), 51 surgeons (24.8%), 34 cancer specialist nurses (16.5%), 21 medical/clinical oncologists (10.2%), 25 physiotherapists/occupational therapists (12.1%) and 15 dieticians (7.3%)) completed the survey. The respondents worked at 19 hospital trusts across the UK and Ireland. Frailty scoring was not routinely performed in 63% of care settings, yet the majority of practitioners reported modifying their practice when providing and deciding on care for patients with frailty. Only 16% of organizations surveyed had a dedicated pathway for assessment and management of patients with frailty. A total of 37% of respondents reported access to prehabilitation services, 79% to enhanced recovery, and 27% to community rehabilitation teams. CONCLUSION: Practitioners from all groups surveyed considered that appropriate training, dedicated pathways for optimization, frailty specific performance indicators and evidence that frailty scoring had an impact on clinical outcomes and patient experience could all help to improve care for frail patients.

A Systematic Comparative Assessment of the Response of Ovarian Cancer Cells to the Chemotherapeutic Cisplatin in 3D Models of Various Structural and Biochemical Configurations-Does One Model Type Fit All?

Epithelial Ovarian Cancer (EOC) is a silent, deadly and aggressive gynaecological disease with a relatively low survival rate. This has been attributed, to some extent, to EOC's high recurrence rate and resistance to currently available platinum-based chemotherapeutic treatment methods. Multiple groups have studied and reported the effect of chemotherapeutic agents on various EOC 3D in vitro models. However, there are very few studies wherein a direct comparative study has been carried out between the different in vitro 3D models of EOC and the effect of chemotherapy within them. Herein, we report, for the first time, a direct comprehensive systematic comparative study of three different 3D in vitro platforms, namely (i) spheroids, (ii) synthetic PeptiGels/hydrogels of various chemical configurations and (iii) polymeric scaffolds with coatings of various extracellular matrices (ECMs) on the cell growth and response to the chemotherapeutic (Cisplatin) for ovary-derived (A2780) and metastatic (SK-OV-3) EOC cell lines. We report that all three 3D models are able to support the growth of EOC, but for different time periods (varying from 7 days to 4 weeks). We have also reported that chemoresistance to Cisplatin, in vitro, observed especially for metastatic EOC cells, is platform-dependent, in terms of both the structural and biochemical composition of the model/platform. Our study highlights the importance of selecting an appropriate 3D platform for in vitro tumour model development. We have demonstrated that the selection of the best platform for producing in vitro tumour models depends on the cancer/cell type, the experimental time period and the application for which the model is intended.

Would extirpative pelvic surgery improve survival in gynecological metastases of lung cancer? Case report and review of the literature.

Lung cancer is the 3rd most common cancer in the UK and the numbers of new cases increase every year. In contrast to gastrointestinal tumours and breast cancer, lung cancer, metastases to the female genital tract are incredibly rare with only five cases reported with uterine metastases on review of the published English literature. We report an interesting case of successful ongoing management of metastatic lung cancer to the pelvis along with an extensive literature review. A 47-year-old lady with recurrent respiratory tract symptoms and chest pain was diagnosed with advanced stage non-small-cell lung cancer (Stage T4N2M1A). Five years following diagnosis and several cycles of chemotherapy and radiotherapy, aged 52, she complained of post-menopausal bleeding and pelvic discomfort. An endometrial biopsy confirmed a malignancy morphologically and immunohistochemically similar to her lung adenocarcinoma, in keeping with metastatic disease. She underwent robotic surgery to excise the pelvic organs and successfully gain local disease control. The patient remains clinically stable 3 years following hysterectomy. Although metastases of lung cancer to uterus are very rare, any patient with abnormal uterine bleeding with known cancer should be investigated thoroughly to rule out metastatic disease. Combined multimodal treatment as in this case may increase overall survival.

Sex Cord Tumour with Annular Tubules-An Unusual Case of Abdominal Pain.

BACKGROUND: Ovarian sex cord tumours with annular tubules (SCTAT) are a very rare type of neoplasm and account for 14% of all sex cord tumours. This tumour was first described in 1970 with histopathology characterized by the presence of both complex and simple annular tubules. The tumour may show features of either granulosa cell tumours or Sertoli cell tumours and differentiation into either type can occur. CASE: We report an interesting case of SCTAT in a 60-year-old woman who had a primary diagnosis of granulosa cell tumour. Seven years later she experienced a recurrence. Following excision and review of all pathology, the patient was found to have a SCTAT in both the recurrence and the primary tumour. CONCLUSION: SCTAT is a slow-growing tumour that occasionally exhibits malignant behaviour with metastatic potential, albeit many years following initial diagnosis. SCTAT should be included in the differential diagnosis of sex cord tumours.

The need for post-operative vasopressor infusions after major gynae-oncologic surgery within an ERAS (Enhanced Recovery After Surgery) pathway.

BACKGROUND: Hypotension following major abdominal surgery is common, and once hypovolaemia has been optimally treated, is often due to vasodilation which can be treated with vasopressor infusions. There is unpredictability in the dose and duration of post-operative vasopressor infusions, and factors associated with this have not been determined. METHODS: We present a case series of consecutive patients who received major gynae-oncology surgery delivered within an Enhanced Recovery After Surgery (ERAS) pathway at a single institution. Patients were electively admitted from theatre directly to the intensive care unit (ICU). Data was collected prospectively into electronic databases (Philips ICCA, Wardwatcher) and then retrospectively collated and appropriate statistical analyses were performed. In the absence of a consensus definition of vasoplegia, we, necessarily arbitrarily, chose a noradrenaline dose of > 0.1 mcg/kg/min at 08:00 on the first post-operative day. The rationale is that this would be more than would typically be expected to counteract the vasodilatory effects of epidural analgesia, which is commonly used at our institution. RESULTS: Data was collected from 324 patients, all treated between February 2014 and July 2016. The average age was 67 years and 39% received neoadjuvant chemotherapy. The commonest tumour type was ovarian (58%). The median estimated blood loss was 800 ml and epidural analgesia was used in 71%. Fifty per cent received post-operative vasopressor infusions: factors associated with this included epidural use and estimated blood loss. Nineteen per cent met our criteria for vasoplegia: factors associated with this included CRP on post-operative day 1 and P-POSSUM morbidity score. Hospital and ICU length of stay was prolonged in those who had vasoplegia. CONCLUSIONS: Patients commonly receive vasopressors following major gynae-oncologic surgery, and this can be at relatively high doses. Clinical factors only accounted for a minority of the variability in vasopressor usage-suggesting considerable biological variability. Optimal care of patients having major abdomino-pelvic surgery may include advanced haemodynamic monitoring and ready availability of infused vasopressors, in a suitable environment.

Primary vaginal adenocarcinoma of intestinal type or occult metastatic colon cancer: a diagnostic dilemma from a vaginal skin tag.

The presentation of a new vaginal lesion could represent a variety of diagnoses from benign warts to more sinister primary malignancies. Rarely, a new lesion could represent a metastatic deposit from a malignancy elsewhere in the body. Colonic carcinomas are the third most common malignancy, frequently metastasising to the liver and lung. There have been a small number of cases in the literature reporting vaginal metastases from colonic carcinoma and this is usually indicative of advanced disseminated disease. We present an interesting case of a 65-year-old female with a strong family history of bowel cancer who originally presented with a vaginal skin tag that was biopsied and found to be a moderately differentiated adenocarcinoma. The immunohistochemistry profile was cytokeratin (CK) 20 positive/CK 7 negative, highly suggestive of a bowel cancer primary. However, subsequent extensive radiological and endoscopic investigations failed to identify a colonic primary tumor. The vaginal lesion was successfully excised, and no systemic treatments were warranted. To date, no primary cancer has been identified; the patient remains asymptomatic with no clinical signs of disease recurrence 5 years following her initial diagnosis. This case represents a diagnostic dilemma between two very rare diagnoses of either a vaginal metastasis from an occult colonic primary tumor or a primary vaginal adenocarcinoma of endometrioid morphology demonstrating intestinal immunophenotype. Organizing colonic screening is recommended in view of the high risk of colonic adenocarcinoma.

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.

Isolated Urethral Metastasis From a Primary Ovarian Malignancy.

BACKGROUND: Epithelial ovarian cancer (EOC) is the deadliest of gynaecological cancers, often manifesting itself at a later stage (stage 3 and 4). Metastases and recurrences tend to be limited to the abdominopelvic cavity, and cutaneous metastases are rare. CASE SUMMARY: We report an interesting case of a 51-year-old who presented 2 years after her initial treatment with surgery and adjuvant chemotherapy for a stage IIB with an isolated recurrence in the external urethral meatus. CONCLUSION: This case highlights the need for clinicians and patients to remain vigilant during follow-up visits to rule out recurrences despite nonspecific symptoms reported by patients.

Lockjaw from a metastatic uterine leiomyosarcoma- case report and review of the literature.

BACKGROUND: Leiomyosarcoma (LMS) is a malignant tumour formed of cells with distinct smooth muscle features. Leiomyosarcomas rarely metastasise to the oral cavity and this literature review details all reported cases of metastasis to the mandible found in the literature. This offers a unique perspective by specifying mandible as the site of metastasis of leiomyosarcoma. CASE PRESENTATION: A 53-year-old female presented to her General Practitioner (GP) with heavy menstrual bleeding and was diagnosed with multiple fibroids. Folowing a hysterectomy and removal of both tubes and ovaries for these symptomatic uterine fibroids, an incidental diagnosis of low grade leiomyosarcoma was made. A CT scan found no evidence of residual or metastatic disease and no further treatment was deemed necessary. 6 months later she presented to A & E with a numb lower lip but it took another 6 months for the diagnosis of metastatic LMS to the mandible to be made. DISCUSSION: Leiomyosarcomas are aggressive tumours which are liable to metastasise and therefore have a poor prognosis. An extensive literature review was undertaken to explore the frequency of metastasis in the maxillo-facial region. CONCLUSIONS: Although metastasis to the oral region is very rare as suggested from the literature review, when patients present with unusual symptoms after a diagnosis of LMS, physicians should be aware of the possibility of LMS metastases.

Decidualisation of ovarian endometriomas in pregnancy: a management dilemma. A case report and review of the literature.

INTRODUCTION: Increased progesterone levels during pregnancy may cause decidualisation of endometriomas mimicking malignancies on radiology and causing management dilemmas. CASE: An ovarian cyst was detected in a 33-year-old woman at her routine 12-week gestation ultrasound scan. By 18 weeks, the unilocular mass was increasing in size with features suggestive of early ovarian malignancy. The cyst was monitored throughout pregnancy and caesarean section at 38 weeks delivered a healthy male. Histology confirmed a decidualised endometrioma and benign dermoid cyst with no evidence of malignancy. LITERATURE REVIEW: The evidence for decidualised ovarian endometriomas in pregnancy was explored; 14 papers were identified, which reported 26 cases, excluding our index case. Of the 27 cases, 19 (70%) were managed surgically, 4 of which were delayed till caesarean section with concomitant cyst excision; 8 cases were managed conservatively through serial monitoring of the cyst, which spontaneously regressed following delivery. CONCLUSION: Surgical management of the cyst provides histological diagnosis but may introduce risks to mother and fetus; a conservative approach may cause anxiety but limits interventions. Elective caesarean section following monitoring throughout pregnancy may bridge the gap between surgical and purely conservative approaches if appropriate. Limited available evidence makes a definitive decision regarding management difficult. Decidualisation should be considered as a differential for suspicious ovarian lesions in pregnancy.

Interval debulking surgery following neo-adjuvant chemotherapy for stage IVB ovarian cancer using neutral argon plasma (PlasmaJet™).

OBJECTIVE: We present a novel surgical approach to ovarian cancer debulking using neutral argon plasma (PlasmaJet™). CASE HISTORY: A 48 year-old woman diagnosed with FIGO stage IVB grade 3 serous epithelial ovarian carcinoma received three cycles of neoadjuvant chemotherapy with carboplatin and paclitaxel. OPERATIVE TECHNIQUE: Dissection and radical debulking surgery were performed using PlasmaJet™ as previously described [1,2]. This included diaphragmatic and abdominal peritoneal stripping, supra-colic omentectomy, tumour ablation on the small and large intestines and mesentery, pelvic and para-aortic lymphadenectomy. RESULTS: The only post-operative complication was a superficial wound breakdown, which healed by secondary intention. She remains well two years after surgery, with no sign of recurrence. CONCLUSION: In this case, PlasmaJet™ facilitated diaphragmatic peritoneal stripping as well as dissection of tissue close to bowel and major vessels. Further study is required to assess whether this device can reduce the need for bowel resection while achieving complete cytoreduction.

Cerebral oedema following robotic surgery: a rare complication.

INTRODUCTION: We present an unusual complication following robotic assisted radical hysterectomy. CASE REPORT: A 51-year-old female with stage 1B1 cervical cancer underwent a robotic assisted radical hysterectomy. The procedure was prolonged with difficulties dissecting the left parametrium and vaginal fornix with persistent bleeding from the left vaginal vault. Post-operatively the patient was electively sedated and ventilated. Extubation was difficult due to patient agitation but achieved on day 2. Agitation persisted and a head CT scan was performed and a diagnosis of cerebral oedema was made. DISCUSSION: Factors contributing to this case include prolonged operating time, prolonged Trendelenburg position with high pressures of CO2 pneumoperitoneum and excessive blood loss. These factors may contribute to poor cerebral venous outflow, increasing intracranial pressure leading to increased risk of cerebral oedema. CONCLUSION: The mechanics of robotic assistance may be used to reduce these risks by significantly reducing intra-abdominal pressure improving venous return. The use of robotics in surgery has been increasing over the last 10 years, and the benefits have been well documented. We present an unusual complication following robotic assisted radical hysterectomy performed for cervical cancer.

Relevance of immunohistochemical expression of p57kip2 in epithelial ovarian carcinoma- A systematic literature review.

BACKGROUND: Epithelial Ovarian Cancer (EOC) is the second most common gynaecological cancer and accounts for more deaths than all gynaecological cancers combined. Despite extensive research, progress has been slow in understanding the pathobiology. EOC is identified as a heterogeneous malignancy with various histological subtypes. It is now well known that these different histological subtypes show differences in terms of presentation, response to treatment, immunohistochemical (IHC) reactivity and molecular profiling. Cell cycle deregulation is key in cancer development and there is some evidence in the literature that this is relevant to the problem of EOC and the development of drug resistant disease. The need to identify prognostic markers has led to several gene profiling studies using tumour tissue with equivocal results. p57kip2 is one such cell cycle regulator and its functions are being explored as recent research has shown that it is more than just a negative regulator of the cell cycle. AIMS: The aim of this review is to evaluate the literature around the IHC expression of p57kip2 in EOC. METHODS: Systematic review of the literature focussing on clinical outcome and immunohistochemical expression in epithelial ovarian cancer. RESULTS: Four papers are discussed in this review and have shown great variation in IHC expression of p57kip2 in EOC. These studies incorporated different histological subtypes of EOC. However they all suggest that p57kip2 has a significant role in prognosis and its therapeutic indication needs to be studied. Multicentre collaborative studies on individual histological subtypes might provide more data and help to increase the number of cases especially for rarer tumours.

Robot assisted surgery in gynaecologic oncology - starting a program and initial learning curve from a UK tertiary referral centre: the Guildford perspective.

BACKGROUND: The paper discusses the setup and evaluation of early data following the establishment of a robotic surgery programme in a UK gynaecological oncology cancer centre. METHODS: Prospective data were collected between December 2009 and December 2011 for all women undergoing robotic assisted procedures within the gynaecological oncology department. Patient demographics, intra, peri and post-operative data were collected at a single institution, which is a tertiary referral centre for gynaecological oncology and minimal access surgery. RESULTS: In total, 104 robotically assisted cases were performed within the gynaecological oncology team. The procedures undertaken included simple and radical hysterectomy, radical trachelectomy, BSO following previous hysterectomy, pelvic and para-aortic node dissection and omentectomy. The mean blood loss was 155.24 mL and the mean hospital stay was 3 days with more than half the women being discharged on day 1 post surgery. CONCLUSIONS: These data suggest that robotic assisted surgery is well suited to treating women with principally endometrial and cervical cancers and selected cases of ovarian cancer, enabling surgical staging to be completed with many more patients benefitting from a minimal access surgery approach. Thorough preparation, appropriate case selection and preceptorship in robotic surgery is essential to minimize the associated risks associated with adopting new surgical techniques.

Use of neutral plasma coagulation in groin node dissection for vulvar malignancy: a novel technique.

Vulvar cancer is an uncommon disease with approximately 1000 cases reported annually in the UK. Lymph node involvement is an important prognostic indicator. Vulvectomy and bilateral groin node dissection are the preferred surgical treatments for early disease and increase survival. However, significant morbidity with lymphocyst formation and wound breakdown has been reported in more than 50% of cases. We report the first case following use of the PlasmaJet(®) neutral argon coagulation system to reduce postoperative lymphocyst formation.

Combined activity of oridonin and wogonin in advanced-stage ovarian cancer cells: sensitivity of ovarian cancer cells to phyto-active chemicals.

The initial response rates of advanced-stage epithelial ovarian cancer to the chemotherapeutic agents carboplatin and paclitaxel are high. However, once drug resistance develops, further chemotherapy is less effective. The objective of this study is to investigate the anti-proliferative activity of the phyto-active chemicals (PACs) oridonin and wogonin in chemo-resistant epithelial ovarian cancer cells. Primary cell cultures from the ascitic fluid of three patients at diagnosis, two patients chemo-resistant to carboplatin and paclitaxel, and one patient treated with letrozole for breast cancer were studied and compared to the ovarian cancer cell lines A2780 and PTX10, by cell viability assay (MTS). Effects on cell cycle modulation and apoptosis were examined by flow cytometry and Western blot analysis (WB). WB was further conducted to investigate protein expressions altered by PACs. The results show that IC(50) of the primary cultures ranged from 0.6 to 5.4 µg/ml for oridonin and 0.3-12.7 µg/ml for wogonin. The paclitaxel-resistant cell line PTX10 was more sensitive to each of the PACs than the chemo-sensitive cell line A2780. Of particular interest is that in combination, the two PACs were synergistic in their cytotoxicity to five of six of the primary cultures and to both the cell lines (combination indices of 0.39-0.95). The inhibition is attributable to apoptosis and cell cycle modulation induced by the PACs as demonstrated in A2780 and PTX10. Up-regulation of the functional p53 protein in A2780 and down-regulation of Akt protein in PTX10 have in part contributed to the apoptosis. These findings suggest that oridonin and wogonin may have activity in ovarian cancer following its development of resistance to carboplatin and paclitaxel.

Synchronous uterine artery embolization and laparoscopic myomectomy for massive uterine leiomyomas.

Uterine leiomyomas remain the commonest cause of menorrhagia and frequently cause pressure symptoms. Management of leiomyomas depends on the presenting symptoms, size, location, number of myomas, and the patient's desire to retain her uterus, fertility, or both. We present the first case of laparoscopic myomectomy for a fibroid measuring 30cm in maximum diameter.