Publications
205 results found
Jones BP, Rajamanoharan A, Williams NJ, et al., 2021, Uterine Transplantation Using Living Donation: A Cross-sectional Study Assessing Perceptions, Acceptability, and Suitability, TRANSPLANTATION DIRECT, Vol: 7, ISSN: 2373-8731
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- Citations: 5
Sundar S, Manchanda R, Gourley C, et al., 2021, British Gynaecological Cancer Society/British Association of Gynaecological Pathology consensus for germline and tumor testing for <i>BRCA</i>1/2 variants in ovarian cancer in the United Kingdom, INTERNATIONAL JOURNAL OF GYNECOLOGICAL CANCER, Vol: 31, Pages: 272-278, ISSN: 1048-891X
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- Citations: 11
Jones BP, Rajamanoharan A, Vali S, et al., 2021, Perceptions and Motivations for Uterus Transplant in Transgender Women, JAMA NETWORK OPEN, Vol: 4, ISSN: 2574-3805
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- Citations: 16
Natoli M, Gallon J, Lu H, et al., 2021, Transcriptional analysis of multiple ovarian cancer cohorts reveals prognostic and immunomodulatory consequences of ERV expression, Journal for ImmunoTherapy of Cancer, Vol: 9, ISSN: 2051-1426
Background Endogenous retroviruses (ERVs) play a role in a variety of biological processes, including embryogenesis and cancer. DNA methyltransferase inhibitors (DNMTi)-induced ERV expression triggers interferon responses in ovarian cancer cells via the viral sensing machinery. Baseline expression of ERVs also occurs in cancer cells, though this process is poorly understood and previously unexplored in epithelial ovarian cancer (EOC). Here, the prognostic and immunomodulatory consequences of baseline ERV expression was assessed in EOC.Methods ERV expression was assessed using EOC transcriptional data from The Cancer Genome Atlas (TCGA) and from an independent cohort (Hammersmith Hospital, HH), as well as from untreated or DNMTi-treated EOC cell lines. Least absolute shrinkage and selection operator (LASSO) logistic regression defined an ERV expression score to predict patient prognosis. Immunohistochemistry (IHC) was conducted on the HH cohort. Combination of DNMTi treatment with γδ T cells was tested in vitro, using EOC cell lines and patient-derived tumor cells.Results ERV expression was found to define clinically relevant subsets of EOC patients. An ERV prognostic score was successfully generated in TCGA and validated in the independent cohort. In EOC patients from this cohort, a high ERV score was associated with better survival (log-rank p=0.0009) and correlated with infiltration of CD8+PD1+T cells (r=0.46, p=0.0001). In the TCGA dataset, a higher ERV score was found in BRCA1/2 mutant tumors, compared to wild type (p=0.015), while a lower ERV score was found in CCNE1 amplified tumors, compared to wild type (p=0.019). In vitro, baseline ERV expression dictates the level of ERV induction in response to DNMTi. Manipulation of an ERV expression threshold by DNMTi resulted in improved EOC cell killing by cytotoxic immune cells.Conclusions These findings uncover the potential for baseline ERV expression to robustly inform EOC patient prognosis, influence
Phelps DL, Saso S, Ghaem-Maghami S, 2020, Is ovarian cancer surgery stuck in the dark ages?: a commentary piece reviewing surgical technologies, BRITISH JOURNAL OF CANCER, Vol: 123, Pages: 1471-1473, ISSN: 0007-0920
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- Citations: 2
Phelps DL, Saso S, Ghaem-Maghami S, 2020, Analysis of worldwide surgical outcomes in COVID-19-infected patients: a gynecological oncology perspective, Future Science OA, Vol: 6, Pages: 1-8, ISSN: 2056-5623
Coronavirus Disease 2019 (COVID-19) guidance limits all but the most urgent surgery in the United Kingdom. We review the literature and our experience in gynecology to assess perioperative outcomes. PubMed was searched with (surg*[Title])AND(COVID[Title]), (surg*[Title])AND(2019-nCoV[Title]), and (surg*[Title])AND(SARS-CoV-2[Title]), and 67 COVID-19-positive surgical patients across ten hospitals in four countries are included. Median mortality was 33%. Cardiac and pulmonary co-morbidities associated with higher risk of COVID-19-positive postoperative death. Mortality was high in neurosurgery (80%) and the lowest in gynecological oncology surgery (none). This analysis provides an evidence base on which to consider surgical risk assessment for different specialties. Risk of perioperative death needs to be assessed in the context of patients’ co-morbidities and surgical specialty. An individualized approach toward surgical decision making is imperative.
Tzafetas M, Mitra A, Paraskevaidi M, et al., 2020, The intelligent knife (iKnife) and its intraoperative diagnostic advantage for the treatment of cervical disease (vol 117, pg 7338, 2020), PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 117, Pages: 18892-18892, ISSN: 0027-8424
Natoli M, Bonito N, Robinson JD, et al., 2020, Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade, Cancer Immunology Immunotherapy, Vol: 69, Pages: 1391-1401, ISSN: 0340-7004
Immune checkpoint blocking antibodies are currently being tested in ovarian cancer (OC) patients and have shown some responses in early clinical trials. However, it remains unclear how human OC cancer cells regulate lymphocyte activation in response to therapy. In this study, we have established and optimised an in vitro tumour-immune co-culture system (TICS), which is specifically designed to quantify the activation of multiple primary human lymphocyte subsets and human cancer cell killing in response to PD-1/L1 blockade. Human OC cell lines and treatment naïve patient ascites show differential effects on lymphocyte activation and respond differently to PD-1 blocking antibody nivolumab in TICS. Using paired OC cell lines established prior to and after chemotherapy relapse, our data reveal that the resistant cells express low levels of HLA and respond poorly to nivolumab, relative to the treatment naïve cells. In accordance, knockdown of IFNγ receptor expression compromises response to nivolumab in the treatment naïve OC cell line, while enhanced HLA expression induced by a DNA methyltransferase inhibitor promotes lymphocyte activation in TICS. Altogether, our results suggest a 'cross resistance' model, where the acquired chemotherapy resistance in cancer cells may confer resistance to immune checkpoint blockade therapy through down-regulation of antigen presentation machinery. As such, agents that can restore HLA expression may be a suitable combination partner for immunotherapy in chemotherapy-relapsed human ovarian cancer patients.
Natoli M, Bonito N, Robinson JD, et al., 2020, Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade (vol 45, pg 203, 2020), CANCER IMMUNOLOGY IMMUNOTHERAPY, Vol: 69, Pages: 1403-1408, ISSN: 0340-7004
Du Bois A, Sehouli J, Vergote I, et al., 2020, Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: Final analysis of AGO DESKTOP III/ENGOT-ov20., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
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- Citations: 89
Jones BP, Vali S, Saso S, et al., 2020, Endometrial autotransplantation in rabbits: Potential for fertility restoration in severe Asherman's syndrome, EUROPEAN JOURNAL OF OBSTETRICS & GYNECOLOGY AND REPRODUCTIVE BIOLOGY, Vol: 248, Pages: 14-23, ISSN: 0301-2115
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- Citations: 1
Tzafetas M, Mitra A, Paraskevaidi M, et al., 2020, The intelligent-Knife (i-Knife) and its intraoperative diagnostic advantage for the treatment of cervical disease, Proceedings of the National Academy of Sciences of USA, Vol: 117, Pages: 7338-7346, ISSN: 0027-8424
Clearance of surgical margins in cervical cancer prevents the need for adjuvant chemoradiation and allows fertility preservation. In this study, we determined the capacity of the rapid evaporative ionization mass spectrometry (REIMS), also known as intelligent knife (iKnife), to discriminate between healthy, preinvasive, and invasive cervical tissue. Cervical tissue samples were collected from women with healthy, human papilloma virus (HPV) ± cervical intraepithelial neoplasia (CIN), or cervical cancer. A handheld diathermy device generated surgical aerosol, which was transferred into a mass spectrometer for subsequent chemical analysis. Combination of principal component and linear discriminant analysis and least absolute shrinkage and selection operator was employed to study the spectral differences between groups. Significance of discriminatory m/z features was tested using univariate statistics and tandem MS performed to elucidate the structure of the significant peaks allowing separation of the two classes. We analyzed 87 samples (normal = 16, HPV ± CIN = 50, cancer = 21 patients). The iKnife discriminated with 100% accuracy normal (100%) vs. HPV ± CIN (100%) vs. cancer (100%) when compared to histology as the gold standard. When comparing normal vs. cancer samples, the accuracy was 100% with a sensitivity of 100% (95% CI 83.9 to 100) and specificity 100% (79.4 to 100). Univariate analysis revealed significant MS peaks in the cancer-to-normal separation belonging to various classes of complex lipids. The iKnife discriminates healthy from premalignant and invasive cervical lesions with high accuracy and can improve oncological outcomes and fertility preservation of women treated surgically for cervical cancer. Larger in vivo research cohorts are required to validate these findings.
Jones BP, Saso S, L'Heveder A, et al., 2020, The vaginal microbiome in uterine transplantation, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 127, Pages: 230-238, ISSN: 1470-0328
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- Citations: 14
L'Heveder A, Jones BP, Saso S, et al., 2019, Conservative management of uterine adenosarcoma: lessons learned from 20 years of follow-up, ARCHIVES OF GYNECOLOGY AND OBSTETRICS, Vol: 300, Pages: 1383-1389, ISSN: 0932-0067
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- Citations: 5
Marcus D, Savage A, Balog J, et al., 2019, ENDOMETRIAL CANCER: CAN THE IKNIFE DIAGNOSE ENDOMETRIAL CANCER?, Publisher: BMJ PUBLISHING GROUP, Pages: A100-A101, ISSN: 1048-891X
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- Citations: 5
Tzafetas M, Mitra A, Kalliala I, et al., 2019, THE IKNIFE AND ITS APPLICATION FOR THE TREATMENT OF CERVICAL ABNORMALITIES, Publisher: BMJ PUBLISHING GROUP, Pages: A589-A589, ISSN: 1048-891X
Tzafetas M, Mitra A, Lever S, et al., 2019, ONCOLOGICAL AND REPRODUCTIVE OUTCOMES AFTER FERTILITY-SPARING SURGERY IN WOMEN WITH CERVICAL CANCER: A SYSTEMATIC REVIEW AND META-ANALYSIS, Publisher: BMJ PUBLISHING GROUP, Pages: A76-A77, ISSN: 1048-891X
Crosbie EJ, Ryan NAJ, Arends MJ, et al., 2019, The Manchester International Consensus Group recommendations for the management of gynecological cancers in Lynch syndrome, Genetics in Medicine, Vol: 21, Pages: 2390-2400, ISSN: 1098-3600
PURPOSE: There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients. METHODS: Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice. RESULTS: Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer. CONCLUSION: This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.
Jones BP, Saso S, Bracewell-Milnes T, et al., 2019, Human uterine transplantation: a review of outcomes from the first 45 cases, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 126, Pages: 1310-1319, ISSN: 1470-0328
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- Citations: 97
Jones B, Saso S, Chan M, et al., 2019, Implementing uterine transplantation into multi-organ retrieval setting: specialist nurse in organ donation and intensive care nurse perspectives, Publisher: WILEY, Pages: 195-195, ISSN: 1470-0328
Jones B, Saso S, Chan M, et al., 2019, Uterine transplantation in the context of a multi-organ retrieval in the UK, Publisher: WILEY, Pages: 192-192, ISSN: 1470-0328
Memtsa M, Jurkovic D, Jauniaux ERM, et al., 2019, Diagnostic Biomarkers for Predicting Adverse Early Pregnancy Outcomes Scientific Impact Paper No. 58, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 126, Pages: E107-E113, ISSN: 1470-0328
Jones BP, Williams NJ, Saso S, et al., 2019, Uterine transplantation in transgender women, BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY, Vol: 126, Pages: 152-156, ISSN: 1470-0328
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- Citations: 47
Wahba J, Natoli M, Whilding LM, et al., 2018, Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer, Cancer Immunology, Immunotherapy, Vol: 67, Pages: 1753-1765, ISSN: 1432-0851
Epithelial ovarian cancer (EOC) is the most lethal of all gynecological malignancies in the UK. Recent evidence has shown that there is potential for immunotherapies to be successful in treating this cancer. We have previously shown the effective application of combinations of traditional chemotherapy and CAR (chimeric antigen receptor) T cell immunotherapy in in vitro and in vivo models of EOC. Platinum-based chemotherapy synergizes with ErbB-targeted CAR T cells (named T4), significantly reducing tumor burden in mice. Here, we show that paclitaxel synergizes with T4 as well, and look into the mechanisms behind the effectiveness of chemo-immunotherapy in our system. Impairment of caspase activity using pan-caspase inhibitor Z-VAD reveals this chemotherapy-induced apoptotic pathway as an essential factor in driving synergy. Mannose-6-phosphate receptor-mediated autophagy and the arrest of cell cycle in G2/M are also shown to be induced by chemotherapy and significantly contributing to the synergy. Increased expression of PD-1 on T4 CAR T cells occurred when these were in culture with ovarian tumor cells; on the other hand, EOC cell lines showed increased PD-L1 expression following chemotherapy treatment. These findings provided a rationale to look into testing PD-1 blockade in combination with paclitaxel and T4 immunotherapy. Combination of these three agents in mice resulted in significant reduction of tumor burden, compared to each treatment alone. In conclusion, the mechanism driving synergy in chemo-immunotherapy of EOC is multifactorial. A deeper understanding of such process is needed to better design combination therapies and carefully stratify patients.
Lathouras K, Saso S, Tzafetas M, et al., 2018, Genetic polymorphisms of matrix metalloproteinases 1-3 and their inhibitor are not associated with premature labor, FUTURE SCIENCE OA, Vol: 4, ISSN: 2056-5623
Saso S, Tziraki M, Clancy NT, et al., 2018, Use of Laser Speckle Contrast Analysis during pelvic surgery in a uterine transplantation model, Future Science OA, Vol: 4, Pages: FSO324-FSO324, ISSN: 2056-5623
Aim: Uterine transplantation (UTx) is proposed for treatment of uterine factor infertility. Our aim was to assess whether Endoscopic Laser Speckle Contrast Analysis (eLASCA) could evaluate pelvic blood flow at anastomotic sites required for sheep and rabbit UTx. Results/methodology: eLASCA detected blood flow in rabbit UTx #7 and #9. In sheep UTx #2, #3 and #5, the results allowed us to conclude that blood flow was present in the uterine graft following transplantation; and post-UTx, the animal had heart and respiratory rates, and oxygen saturation compatible with a normal hemodynamic status. Conclusion: These preliminary results establish the potential of Laser Speckle Contrast Analysis as noncontact and real-time tool for observation of spatially-resolved blood flow from which other parameters can be derived.
Natoli M, Karadimitris A, Ghaem-Maghami S, 2018, Immunomodulatory action of SGI-110 and combination with γd T cell immunotherapy in ovarian cancer, Annual Meeting of the American-Association-for-Cancer-Research (AACR), Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Brown R, Curry E, Zeller C, et al., 2018, Genes predisposed to DNA hypermethylation during acquired resistance to chemotherapy are identified in ovarian tumors by bivalent chromatin domains at initial diagnosis, Cancer Research, Vol: 78, Pages: 1383-1391, ISSN: 1538-7445
Bivalent chromatin domains containing both active H3K4me3 and repressive H3K27me3 histone marks define gene sets poised for expression or silencing in differentiating embryonic stem (ES) cells. In cancer cells, aberrantly poised genes may facilitate changes in transcriptional states after exposure to anticancer drugs. In this study, we used ChIP-seq to characterize genome-wide positioning of H3K4me3- and H3K27me3-associated chromatin in primary high-grade serous ovarian carcinomas and in normal ovarian surface and fallopian tube tissue. Gene sets with proximal bivalent marks defined in this manner were evaluated subsequently as signatures of systematic change in DNA methylation and gene expression, comparing pairs of tissue samples taken from patients at primary presentation and relapse following chemotherapy. We found that gene sets harboring bivalent chromatin domains at their promoters in tumor tissue, but not normal epithelia, overlapped with Polycomb-repressive complex target genes as well as transcriptionally silenced genes in normal ovarian and tubal stem cells. The bivalently marked genes we identified in tumors before chemotherapy displayed increased promoter CpG methylation and reduced gene expression at relapse after chemotherapy of ovarian cancer. Overall, our results support the hypothesis that preexisting histone modifications at genes in a poised chromatin state may lead to epigenetic silencing during acquired drug resistance.
Phelps DL, Balog J, Gildea LF, et al., 2018, The surgical intelligent knife distinguishes normal, borderline and malignant gynaecological tissues using rapid evaporative ionisation mass spectrometry (REIMS), British Journal of Cancer, Vol: 118, Pages: 1349-1358, ISSN: 0007-0920
BackgroundSurvival from ovarian cancer (OC) is improved with surgery, but surgery can be complex and tumour identification, especially for borderline ovarian tumours (BOT), is challenging. The Rapid Evaporative Ionisation Mass Spectrometric (REIMS) technique reports tissue histology in real-time by analysing aerosolised tissue during electrosurgical dissection.MethodsAerosol produced during diathermy of tissues was sampled with the REIMS interface. Histological diagnosis and mass spectra featuring complex lipid species populated a reference database on which principal component, linear discriminant and leave-one-patient-out cross-validation analyses were performed.ResultsA total of 198 patients provided 335 tissue samples, yielding 3384 spectra. Cross-validated OC classification vs separate normal tissues was high (97·4% sensitivity, 100% specificity). BOT were readily distinguishable from OC (sensitivity 90.5%, specificity 89.7%). Validation with fresh tissue lead to excellent OC detection (100% accuracy). Histological agreement between iKnife and histopathologist was very good (kappa 0.84, P < 0.001, z = 3.3). Five predominantly phosphatidic acid (PA(36:2)) and phosphatidyl-ethanolamine (PE(34:2)) lipid species were identified as being significantly more abundant in OC compared to normal tissue or BOT (P < 0.001, q < 0.001).ConclusionsThe REIMS iKnife distinguishes gynaecological tissues by analysing mass-spectrometry-derived lipidomes from tissue diathermy aerosols. Rapid intra-operative gynaecological tissue diagnosis may improve surgical care when histology is unknown, leading to personalised operations tailored to the individual.
Saso S, Clancy NT, Jones BP, et al., 2018, Use of biomedical photonics in gynecological surgery: a uterine transplantation model, Future Science OA, Vol: 4, Pages: FSO286-FSO286, ISSN: 2056-5623
Aim: Uterine transplantation (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility. The study aims were to compare pulse oximetry and multispectral imaging (MSI), for intraoperative tracking of uterine oxygen saturation in animal UTx models (rabbit and sheep). Results/methodology: Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Comparison of oxygen saturation values between the pre-UTx donor and post-UTx recipient, and pre-UTx and post-UTx recipient reveals a statistically significant decrease in saturation levels post-UTx. Conclusion: The use of MSI is the first case in gynecology and has demonstrated promise of possible future human use. MSI technique has advantages over pulse oximetry - it provides spatial information in a real-time, noncontact manner.
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