Use of Cyclosporine in Uterine Transplantation

Uterine transplantation has been proposed as a possible solution to absolute uterine factor infertility untreatable by any other option. Since the first human attempt in 2000, various teams have tried to clarify which immunosuppressant would be most suitable for protecting the allogeneic uterine graft while posing a minimal risk to the fetus. Cyclosporine A (CsA) is an immunosuppressant widely used by transplant recipients. It is currently being tested as a potential immunosuppressant to be used during UTn. Its effect on the mother and fetus and its influence upon the graft during pregnancy have been of major concern. We review the role of CsA in UTn and its effect on pregnant transplant recipients and their offspring

Radiolabelling an 18F biologic via facile IEDDA “click” chemistry on the GE FASTLab™ platform

The use of biologics in positron emission tomography (PET) imaging is an important area of radiopharmaceutical development and new automated methods are required to facilitate their production. We report an automated radiosynthesis method to produce a radiolabelled biologic via facile inverse electron demand Diels-Alder (IEDDA) “click” chemistry on a single GE FASTLab™ cassette. We exemplified the method by producing a fluorine-18 radiolabelled interleukin-2 (IL2) radioconjugate from a trans-cyclooctene (TCO) modified IL2 precursor. The radioconjugate was produced using a fully automated radiosynthesis on a single FASTLab™ cassette in a radiochemical yield (RCY) of 19.8 ± 2.6% in 110 min (from start of synthesis); the molar activity was 132.3 ± 14.6 GBq/μmol. The in vitro uptake of [18F]TTCO-IL2 correlated with the differential receptor expression (CD25, CD122, CD132) in PC3, NK-92 and activated human PBMCs. The automated method may be adapted for the radiosynthesis of any TCO-modified protein via IEDDA chemistry

Immediate referral to colposcopy versus cytological surveillance for minor cervical cytological abnormalities in the absence of HPV test

A C K N O W L E D G E M E N T S The authors wish to acknowledge Jo Morrison for her clinical and editorial advice, Jane Hayes f or designing the search strategy and Gail Quinn, Clare Jess and Tracey Bishop for their contribution to the editorial process.This project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to the Cochrane Gynaecological, Neuro-oncology and Orphan Cancer Group. The views and opinions expressed therein are those of the authors andd o not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.Peer reviewedPublisher PD

Multispectral imaging of organ viability during uterine transplantation surgery in rabbits and sheep

Uterine transplantation surgery (UTx) has been proposed as a treatment for permanent absolute uterine factor infertility (AUFI) in the case of the congenital absence or surgical removal of the uterus. Successful surgical attachment of the organ and its associated vasculature is essential for the organ’s reperfusion and long-term viability. Spectral imaging techniques have demonstrated the potential for the measurement of hemodynamics in medical applications. These involve the measurement of reflectance spectra by acquiring images of the tissue in different wavebands. Measures of tissue constituents at each pixel can then be extracted from these spectra through modeling of the light–tissue interaction. A multispectral imaging (MSI) laparoscope was used in sheep and rabbit UTx models to study short- and long-term changes in oxygen saturation following surgery. The whole organ was imaged in the donor and recipient animals in parallel with point measurements from a pulse oximeter. Imaging results confirmed the re-establishment of adequate perfusion in the transplanted organ after surgery. Cornual oxygenation trends measured with MSI are consistent with pulse oximeter readings, showing decreased StO2 immediately after anastomosis of the blood vessels. Long-term results show recovery of StO2 to preoperative levels

Targeted desorption electrospray ionization mass spectrometry imaging for drug distribution, toxicity, and tissue classification studies

With increased use of mass spectrometry imaging (MSI) in support of pharmaceutical research and development, there are opportunities to develop analytical pipelines that incorporate exploratory high-performance analysis with higher capacity and faster targeted MSI. Therefore, to enable faster MSI data acquisition we present analyte-targeted desorption electrospray ionization–mass spectrometry imaging (DESI-MSI) utilizing a triple-quadrupole (TQ) mass analyzer. The evaluated platform configuration provided superior sensitivity compared to a conventional time-of-flight (TOF) mass analyzer and thus holds the potential to generate data applicable to pharmaceutical research and development. The platform was successfully operated with sampling rates up to 10 scans/s, comparing positively to the 1 scan/s commonly used on comparable DESI-TOF setups. The higher scan rate enabled investigation of the desorption/ionization processes of endogenous lipid species such as phosphatidylcholines and a co-administered cassette of four orally dosed drugs—erlotininb, moxifloxacin, olanzapine, and terfenadine. This was used to enable understanding of the impact of the desorption/ionization processes in order to optimize the operational parameters, resulting in improved compound coverage for olanzapine and the main olanzapine metabolite, hydroxy-olanzapine, in brain tissue sections compared to DESI-TOF analysis or matrix-assisted laser desorption/ionization (MALDI) platforms. The approach allowed reducing the amount of recorded information, thus reducing the size of datasets from up to 150 GB per experiment down to several hundred MB. The improved performance was demonstrated in case studies investigating the suitability of this approach for mapping drug distribution, spatially resolved profiling of drug-induced nephrotoxicity, and molecular–histological tissue classification of ovarian tumors specimens

Endometrial autotransplantation in rabbits: Potential for fertility restoration in severe Asherman's syndrome

[EN] Objective: Uterine transplantation is now considered a feasible treatment for women with absolute uterine factor infertility and has been successfully performed for a woman with Asherman's syndrome (AS). The endometrium is a clinically and histologically distinct entity from the surrounding myometrium. Endometrial transplantation (ETx) may offer a less invasive option, with less immunogenic impact, to restore fertility in women with severe AS. The objective of this study was to assess the feasibility of ETx by evaluating surgical and reproductive outcomes following endometrial autotransplantation in a rabbit model. Study design: A longitudinal study assessing surgical, biochemical, radiological, reproductive and histological outcomes following endometrial autotransplantation in ten New Zealand white rabbits. Results: Ten procedures were performed, including 8 endometrial auto-transplants (ETx) and 2 endometrial resections (ER), to control against endometrial regeneration. Eight procedures were successful, whereas two rabbits from the ETx group died intra-operatively. Three rabbits were euthanised at 48, 72 and 96 h post-operatively to assess gross and histological appearances. Two rabbits, one from the ETx group and one from the ER group, died four weeks and eight weeks post-operatively. Three rabbits subsequently underwent two cycles of in-vitro fertilization. The first cycle resulted in an implantation rate of 57% in the un-operated uteri. In two rabbits who underwent ETx, an implantation rate of 28.6% was seen. In the second cycle, an implantation rate of 61.9 % (13 implantations) was observed in the control uteri. In the two ETx females, an implantation rate of 14.3 % was seen. No pregnancies were seen in either cycle in the animals who underwent ER. Despite successful implantations in both cycles in the ETx rabbits, no livebirths were achieved. Following death or euthanasia there was gross and microscopic evidence of viable endometrium following ETx, but not following ER. Conclusion: This study has revealed, for the first time, the feasibility of ETx with gross and microscopic evidence of viable endometrium, and the demonstration of clinical pregnancies. Whilst further studies are essential, and the achievement of successful livebirths fundamental, ETx may offer a potential fertility restoring opportunity for women with severe, treatment refractory cases of AS.The study was funded by registered charity Womb Transplant UK (1138559).Jones, BP.; Vali, S.; Saso, S.; Garcia-Dominguez, X.; Chan, M.; Thum, M.; Ghaem-Maghami, S.... (2020). Endometrial autotransplantation in rabbits: Potential for fertility restoration in severe Asherman's syndrome. European Journal of Obstetrics & Gynecology and Reproductive Biology. 248:14-23. https://doi.org/10.1016/j.ejogrb.2020.03.011S1423248Asherman, J. G. (1950). TRAUMATIC INTRA-UTERINE ADHESIONS. BJOG: An International Journal of Obstetrics and Gynaecology, 57(6), 892-896. doi:10.1111/j.1471-0528.1950.tb06053.xHooker, A. B., de Leeuw, R., van de Ven, P. M., Bakkum, E. A., Thurkow, A. L., Vogel, N. E. A., … Huirne, J. A. F. (2017). Prevalence of intrauterine adhesions after the application of hyaluronic acid gel after dilatation and curettage in women with at least one previous curettage: short-term outcomes of a multicenter, prospective randomized controlled trial. Fertility and Sterility, 107(5), 1223-1231.e3. doi:10.1016/j.fertnstert.2017.02.113Wallach, E. E., Schenker, J. G., & Margalioth, E. J. (1982). Intrauterine adhesions: an updated appraisal. Fertility and Sterility, 37(5), 593-610. doi:10.1016/s0015-0282(16)46268-0Westendorp, I. C., Ankum, W. M., Mol, B. W., & Vonk, J. (1998). Prevalence of Asherman’s syndrome after secondary removal of placental remnants or a repeat curettage for incomplete abortion. Human Reproduction, 13(12), 3347-3350. doi:10.1093/humrep/13.12.3347Wallach, E., & Czernobilsky, B. (1978). Endometritis and Infertility. Fertility and Sterility, 30(2), 119-130. doi:10.1016/s0015-0282(16)43448-5Baradwan, S., Baradwan, A., & Al-Jaroudi, D. (2018). The association between menstrual cycle pattern and hysteroscopic march classification with endometrial thickness among infertile women with Asherman syndrome. Medicine, 97(27), e11314. doi:10.1097/md.0000000000011314Hooker, A. B., Lemmers, M., Thurkow, A. L., Heymans, M. W., Opmeer, B. C., Brolmann, H. A. M., … Huirne, J. A. F. (2013). Systematic review and meta-analysis of intrauterine adhesions after miscarriage: prevalence, risk factors and long-term reproductive outcome. Human Reproduction Update, 20(2), 262-278. doi:10.1093/humupd/dmt045Yu, D., Wong, Y.-M., Cheong, Y., Xia, E., & Li, T.-C. (2008). Asherman syndrome—one century later. Fertility and Sterility, 89(4), 759-779. doi:10.1016/j.fertnstert.2008.02.096Yamamoto, N., Takeuchi, R., Izuchi, D., Yuge, N., Miyazaki, M., Yasunaga, M., … Inoue, Y. (2013). Hysteroscopic adhesiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Reproductive Medicine and Biology, 12(4), 159-166. doi:10.1007/s12522-013-0149-xThomson, A. J. M., Abbott, J. A., Kingston, A., Lenart, M., & Vancaillie, T. G. (2007). Fluoroscopically guided synechiolysis for patients with Asherman’s syndrome: menstrual and fertility outcomes. Fertility and Sterility, 87(2), 405-410. doi:10.1016/j.fertnstert.2006.06.035Deans, R., & Abbott, J. (2010). Review of Intrauterine Adhesions. Journal of Minimally Invasive Gynecology, 17(5), 555-569. doi:10.1016/j.jmig.2010.04.016Song, D., Liu, Y., Xiao, Y., Li, T.-C., Zhou, F., & Xia, E. (2014). A Matched Cohort Study Comparing the Outcome of Intrauterine Adhesiolysis for Asherman’s Syndrome After Uterine Artery Embolization or Surgical Trauma. Journal of Minimally Invasive Gynecology, 21(6), 1022-1028. doi:10.1016/j.jmig.2014.04.015Panchal, S., Patel, H., & Nagori, C. (2011). Endometrial regeneration using autologous adult stem cells followed by conception by in vitro fertilization in a patient of severe Asherman′s syndrome. Journal of Human Reproductive Sciences, 4(1), 43. doi:10.4103/0974-1208.82360Singh, N., Mohanty, S., Seth, T., Shankar, M., Dharmendra, S., & Bhaskaran, S. (2014). Autologous stem cell transplantation in refractory Asherman′s syndrome: A novel cell based therapy. Journal of Human Reproductive Sciences, 7(2), 93. doi:10.4103/0974-1208.138864Tan, J., Li, P., Wang, Q., Li, Y., Li, X., Zhao, D., … Kong, L. (2016). Autologous menstrual blood-derived stromal cells transplantation for severe Asherman’s syndrome. Human Reproduction, 31(12), 2723-2729. doi:10.1093/humrep/dew235Santamaria, X., Cabanillas, S., Cervelló, I., Arbona, C., Raga, F., Ferro, J., … Simón, C. (2016). Autologous cell therapy with CD133+ bone marrow-derived stem cells for refractory Asherman’s syndrome and endometrial atrophy: a pilot cohort study. Human Reproduction, 31(5), 1087-1096. doi:10.1093/humrep/dew042Puntambekar, S., Telang, M., Kulkarni, P., Puntambekar, S., Jadhav, S., Panse, M., … Phadke, U. (2018). Laparoscopic-Assisted Uterus Retrieval From Live Organ Donors for Uterine Transplant: Our Experience of Two Patients. Journal of Minimally Invasive Gynecology, 25(4), 622-631. doi:10.1016/j.jmig.2018.01.009Saso, S., Haddad, J., Ellis, P., Lindsay, I., Sebire, N., McIndoe, A., … Smith, J. (2011). Placental site trophoblastic tumours and the concept of fertility preservation. BJOG: An International Journal of Obstetrics & Gynaecology, 119(3), 369-374. doi:10.1111/j.1471-0528.2011.03230.xViudes‐de‐Castro, M. P., Marco‐Jiménez, F., Más Pellicer, A., García‐Domínguez, X., Talaván, A. M., & Vicente, J. S. (2019). A single injection of corifollitropin alfa supplemented with human chorionic gonadotropin increases follicular recruitment and transferable embryos in the rabbit. Reproduction in Domestic Animals, 54(4), 696-701. doi:10.1111/rda.13411Garcia-Dominguez, X., Marco-Jimenez, F., Viudes-de-Castro, M. P., & Vicente, J. S. (2019). Minimally Invasive Embryo Transfer and Embryo Vitrification at the Optimal Embryo Stage in Rabbit Model. Journal of Visualized Experiments, (147). doi:10.3791/58055Esteves, P. J., Abrantes, J., Baldauf, H.-M., BenMohamed, L., Chen, Y., Christensen, N., … Mage, R. (2018). The wide utility of rabbits as models of human diseases. Experimental & Molecular Medicine, 50(5), 1-10. doi:10.1038/s12276-018-0094-1Graur, D., Duret, L., & Gouy, M. (1996). Phylogenetic position of the order Lagomorpha (rabbits, hares and allies). Nature, 379(6563), 333-335. doi:10.1038/379333a0Saso, S., Petts, G., David, A. L., Thum, M.-Y., Chatterjee, J., Vicente, J. S., … Smith, J. R. (2015). Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model. European Journal of Obstetrics & Gynecology and Reproductive Biology, 185, 164-169. doi:10.1016/j.ejogrb.2014.12.017Saso, S., Petts, G., Chatterjee, J., Thum, M.-Y., David, A. L., Corless, D., … Smith, J. R. (2014). Uterine allotransplantation in a rabbit model using aorto-caval anastomosis: a long-term viability study. European Journal of Obstetrics & Gynecology and Reproductive Biology, 182, 185-193. doi:10.1016/j.ejogrb.2014.09.029Ozsoy, M., Gonul, Y., Bal, A., Ozkececi, Z. T., Celep, R. B., Adali, F., … Tosun, M. (2015). Effect of IL-18 binding protein on hepatic ischemia-reperfusion injury induced by infrarenal aortic occlusion. Annals of Surgical Treatment and Research, 88(2), 92. doi:10.4174/astr.2015.88.2.92Hare, A., & Olah, K. (2005). Pregnancy following endometrial ablation: a review article. Journal of Obstetrics and Gynaecology, 25(2), 108-114. doi:10.1080/01443610500040745Johannesson, L., Enskog, A., Molne, J., Diaz-Garcia, C., Hanafy, A., Dahm-Kahler, P., … Brannstrom, M. (2012). Preclinical report on allogeneic uterus transplantation in non-human primates. Human Reproduction, 28(1), 189-198. doi:10.1093/humrep/des381Brännström, M., Johannesson, L., Dahm-Kähler, P., Enskog, A., Mölne, J., Kvarnström, N., … Olausson, M. (2014). First clinical uterus transplantation trial: a six-month report. Fertility and Sterility, 101(5), 1228-1236. doi:10.1016/j.fertnstert.2014.02.02

The surgical intelligent knife distinguishes normal, borderline and malignant gynaecological tissues using rapid evaporative ionisation mass spectrometry (REIMS)

Background Survival 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. Methods Aerosol 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. Results A 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). Conclusions The 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

Impact of Multiple COVID-19 Waves on Gynaecological Cancer Services in the UK

Funding: This research was funded by the British Gynaecological Cancer Society (EMSG1L5R) and Ovacome charity. It is supported by the National Cancer Research Institute Gynaecological Cancer Clinical Studies Group and the British Association of Gynaecological Pathologists. The funding bodies had no role in the study design, data collection, analysis, interpretation or writing of the report, or decision to submit for publication. The research team was independent of funders. Acknowledgments: The study is supported by researchers at the Barts Cancer Research United Kingdom Centre for Excellence, Queen Mary University of London (C16420/A18066). We are grateful for the endorsement and support from charities and patient support groups such as Ovacome, The Eve Appeal, Target Ovarian Cancer, Ovarian Cancer Action, Jo’s Cervical Cancer Trust, and GO Girls. We are grateful for the support received from the Royal College of Obstetricians and Gynaecologists, the National Cancer Research Institute Gynaecological Cancer Clinical Studies Group, and the British Association of Gynaecological Pathologists.Peer reviewedPublisher PD

British Gynaecological Cancer Society Recommendations for Evidence Based, Population Data Derived Quality Performance Indicators for Ovarian Cancer

Ovarian cancer survival in the UK lags behind comparable countries. Results from the ongoing National Ovarian Cancer Audit feasibility pilot (OCAFP) show that approximately 1 in 4 women with advanced ovarian cancer (Stage 2, 3, 4 and unstaged cancer) do not receive any anticancer treatment and only 51% in England receive international standard of care treatment, i.e., the combination of surgery and chemotherapy. The audit has also demonstrated wide variation in the percentage of women receiving anticancer treatment for advanced ovarian cancer, be it surgery or chemotherapy across the 19 geographical regions for organisation of cancer delivery (Cancer Alliances). Receipt of treatment also correlates with survival: 5 year Cancer survival varies from 28.6% to 49.6% across England. Here, we take a systems wide approach encompassing both diagnostic pathways and cancer treatment, derived from the whole cohort of women with ovarian cancer to set out recommendations and quality performance indicators (QPI). A multidisciplinary panel established by the British Gynaecological Cancer Society carefully identified QPI against criteria: metrics selected were those easily evaluable nationally using routinely available data and where there was a clear evidence base to support interventions. These QPI will be valuable to other taxpayer funded systems with national data collection mechanisms and are to our knowledge the only population level data derived standards in ovarian cancer. We also identify interventions for Best practice and Research recommendations

Targeting of Aberrant αvβ6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells.

Expression of the αvβ6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models. Highly selective targeting αvβ6 was achieved using a foot and mouth disease virus-derived A20 peptide, coupled to a fused CD28+CD3 endodomain. To achieve selective expansion of CAR T cells ex vivo, an IL-4-responsive fusion gene (4αβ) was co-expressed, which delivers a selective mitogenic signal to engineered T cells only. In vivo efficacy was demonstrated in mice with established ovarian, breast, and pancreatic tumor xenografts, all of which express αvβ6 at intermediate to high levels. SCID beige mice were used for these studies because they are susceptible to cytokine release syndrome, unlike more immune-compromised strains. Nonetheless, although the CAR also engages mouse αvβ6, mild and reversible toxicity was only observed when supra-therapeutic doses of CAR T cells were administered parenterally. These data support the clinical evaluation of αvβ6 re-targeted CAR T cell immunotherapy in solid tumors that express this integrin