Abstract. Background: Carboplatin and paclitaxel

HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. HOX gene expression was determined in ovarian cancer cell lines and primary EOCs by QPCR, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one-way ANOVA and t-tests, using statistical software R and GraphPad. The analysis identified 36 of the 39 HOX genes as being overexpressed in high grade serous EOC compared to normal tissue. We detected a molecular HOX gene-signature that predicted poor outcome. Overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer. In conclusion, this study has shown the HOX genes are highly dysregulated in ovarian cancer with high expression of HOXA13, B6, C13, D1 and D13 being predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum-resistant cancer represents a potentially new therapeutic option that should be further developed and tested in clinical trials.Ovarian cancer is the 5th leading cause of cancer death in women in the western world and it is estimated there were 22,280 new cases and 15,500 deaths due to the disease in the US in 2012. 1 It is the most lethal of the gynaecological malignancies largely due to late diagnosis. Standard treatment involves debulking surgery followed by a combination of taxane and platinum-based therapy. Initially most women respond to platinum-based therapy, but the majority suffer disease recurrence due to drug resistance. It is therefore essential to introduce new therapeutic approaches to improve treatment at diagnosis and/or provide an effective second line treatment.There are different types of ovarian cancer classified by the cell type they originate from. The most common form, accounting for >90% of ovarian cancers, is epithelial ovarian cancer (EOC), and the high grade serous (HGS) subtype accounts for 80% of EOC cases.The epithelial ovarian tumours undergo M€ ullerian differentiation, which suggests that differentiation-regulatory factors may contribute to their progression. This mechanism has been shown to involve homeobox (HOX) genes 2,3 which play important roles in tissue differentiation during embryonic development. The HOX genes constitute a family of transcription factors, and in mammals 39 HOX genes have been identified. They are organised into 4 paralogous clusters (A, B, C and D) located on 4 different chromosomes. During development of the female reproductive system four HOX genes, HOXA9, HOXA10, HOXA11 and HOXA13 are expressed uniformly along the M€ uller...

No abstract

BackgroundEpithelial ovarian cancer is a common malignancy, with no clinically approved diagnostic biomarker. Engrailed-2 (EN2) is a homeodomain-containing transcription factor, essential during embryological neural development, which is dysregulated in several cancer types. We evaluated the expression of EN2 in Epithelial ovarian cancer, and reviewed its role as a biomarker.MethodsWe evaluated 8 Epithelial ovarian cancer cell lines, along with > 100 surgical specimens from the Royal Surrey County Hospital (2009–2014). In total, 108 tumours and 5 normal tissue specimens were collected. En2 mRNA was evaluated by semi-quantitative RT-PCR. Histological sub-type, and platinum-sensitive/−resistant status were compared. Protein expression was assessed in cell lines (immunofluorescence), and in > 150 tumours (immunohistochemistry).ResultsEn2 mRNA expression was elevated in serous ovarian tumours compared with normal ovary (p < 0.001), particularly in high-grade serous ovarian cancer (p < 0.0001) and in platinum-resistant tumours (p = 0.0232). Median Overall Survival and Progression-free Survival were reduced with high En2 expression (OS = 28 vs 42 months, p = 0.0329; PFS = 8 vs 27 months; p = 0.0004). Positive cytoplasmic EN2 staining was demonstrated in 78% of Epithelial ovarian cancers, with absence in normal ovary. EN2 positive high-grade serous ovarian cancer patients had a shorter PFS (10 vs 17.5 months; p = 0.0103).ConclusionThe EN2 transcription factor is a novel ovarian cancer biomarker. It demonstrates prognostic value, correlating with worse Overall Survival and Progression-free Survival. It is hoped that further work will validate its use as a biomarker, and provide insight into the role of EN2 in the development, progression and spread of ovarian cancer.

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.

We describe the first in vivo use of neutral argon plasma energy in gynaecological surgery in the UK and the largest series worldwide. The use of PlasmaJet® (PJ) in different applications in 118 selected cases in a tertiary referral centre for gynaecological oncology and minimal access surgery was assessed. The effectiveness, ease of use, ergonomics and safety of PJ in gynaecological surgery is evaluated prospectively. Following this experience, we have devised a table of recommended power settings for different applications.

Ovarian leiomyosarcomas (OLS) have a poor prognosis due to their late presentation and aggressive nature. This case illustrates that surgery alone can offer disease free survival in cases of early stage disease.

ObjectivesSurgical 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 settingIn 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.ResultsIn 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.ConclusionsSSI 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.