Primary cervical lymphoma is a rare entity of cervical malignancy. The diagnostic pitfalls arise from the non-specific clinical presentation and poor sensitivity of cervical cytology in detecting the disease. Here, we present a case of extra-nodal marginal zone cervical lymphoma in a postmenopausal nulliparous woman. The patient underwent colposcopy due to an abnormal cervical smear and was found to have a large cervical lesion in keeping with high-grade cervical intraepithelial neoplasia (CIN). Cervical conisation was performed, and a low-grade B-cell lymphoma confined to the cervix was found underneath the surface CIN. As there was no established treatment for this uncommon disease, multidisciplinary involvement was required for optimal management and follow-up of the patient. The prognosis is generally favourable in comparison to the common cervical malignancies.

High risk human papillomaviruses (hrHPV) infect mucosal epithelia and are the causative agents of cervical cancer. Prophylactic vaccines protect against disease caused by several, but not all hrHPV types. Furthermore, prophylactic vaccines are not widely available to populations with the greatest disease burden and have no therapeutic effect in previously infected individuals. Therapeutic vaccines that enhance host immunity in individuals with persistent hrHPV infections represents a promising strategy to support cervical cancer control. However, efficacy of a therapeutic vaccine depends not only on antigen selection and delivery system, but also on the route of immunisation. Because cervical intraepithelial lesions are confined to the genital mucosa, an effective therapeutic vaccine may need to elicit immune effector cells at the site of disease. Here we study the effect of immunisation route on vaccine immunogenicity using previously described ChAdOx1- and MVA-vectored hrHPV therapeutic vaccines encoding a multigenotype insert. In addition, we used GFP-expressing viral-vectored vaccines to monitor vaccine uptake in the cervix by real-time in vivo imaging. Among all regimens tested, the intramuscular prime-intranasal boost induced the highest magnitude of E6-specific CD8+ T cells in both the spleen and cervicovaginal compartment, and also generated the greatest frequency of cervicovaginal CD8+ TRM cells.

Cervical perforation by coil threads is an uncommon complication. Predisposing factors may include prior cervical interventions, hypoestrogenic atrophy, thread material, and duration of use. Awareness is essential when evaluating abnormal bleeding or atypical thread presentation despite radiologically correct placement.

BACKGROUND:The clearance of high-risk oncogenic human papillomaviruses (hrHPV) and related cervical lesions is associated with the development of a robust T-cell response. Therapeutic vaccination that induces HPV antigen-specific T cells is a promising approach. METHOD:A 2-vector dosing strategy using Chimpanzee Adenovirus Oxford 1-HPV and Modified Vaccinia virus Ankara-HPV, both encoding the same multiantigen HPV cassette was given on a 0/28-day schedule to participants with persistent cervical hrHPV and a history of low-grade cervical lesions. An open-label lead-in was followed by a randomized, blinded, placebo-controlled main phase. The primary endpoint was the safety of the different dose regimens; secondary endpoints included immunogenicity, and clearance of hrHPV and associated lesions at 12 months. Nine participants were enrolled in the lead-in and 99 were randomized 67:32 to 5 active dose arms or placebo, respectively. RESULTS:The regimens were well-tolerated with no grade 3-related treatment emergent adverse events or serious adverse reactions. All dosing regimens generated antigen-specific CD4+ and CD8+ T-cell responses. There was no difference in hrHPV clearance between the pooled active groups and placebo (20/64 [31.3%] versus 10/30 [33.3%]; P > .99), nor in lesion clearance. A trend toward higher hrHPV clearance (60%) was observed with the highest Chimpanzee Adenovirus Oxford 1-HPV doses. No association between the peripheral immune response and clearance was demonstrated. CONCLUSIONS:A heterologous, multiantigenic HPV 2-component immunotherapy regimen was well-tolerated and immunogenic but did not result in a statistically significant clearance of either hrHPV or the associated cervical lesions in women with persistent high-risk HPV infections. TRIAL REGISTRATION:EudraCT 2019-001890-98; NCT04607850.

Cervical decidual reaction in pregnancy is a common finding. In rare cases, these changes can mimic the appearance of invasive cervical cancers.We are presenting a case of a pregnant woman with a large cervical mass. Whilst magnetic resonance imaging (MRI) supported a diagnosis of cervical cancer, cervical tissue biopsies showed decidual reaction and no invasion. Cervical appearance postpartum reverted back to normal. Importantly, cervical biopsies were obtained in a fully equipped theatre attended by multiple specialities in case of life-threatening haemorrhage during pregnancy.

Endometriosis is a chronic inflammatory condition characterised by the presence of endometrium-like tissue outside the uterus. Despite its high prevalence and recent advances in molecular science, many aspects of endometriosis and its pathophysiology are still poorly understood. Previously, in vitro and in vivo modelling have been instrumental in establishing our current understanding of endometriosis. As the field of molecular science and the advance towards personalised medicine is ever increasing, more sophisticated models are continually being developed. These hold great potential to provide more intricate knowledge of the underlying pathophysiology and facilitate investigations into potential future approaches to diagnosis and treatment. This review provides an overview of different in vitro and in vivo models of endometriosis that are pertinent to establishing our current understanding. Moreover, we discuss new cross-cutting approaches to endometriosis modelling, such as the use of microfluidic cultures and 3D printing, which have the potential to shape the future of endometriosis research.

The complex and dynamic cellular composition of the human endometrium remains poorly understood. Previous endometrial single-cell atlases profiled few donors and lacked consensus in defining cell types. We introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas (313,527 cells) combining published and new endometrial single-cell transcriptomics datasets of 63 women with and without endometriosis. HECA assigns consensus and identifies previously unreported cell types, mapped in situ using spatial transcriptomics and validated using a new independent single-nuclei dataset (312,246 nuclei, 63 donors). In the functionalis, we identify intricate stromal-epithelial cell coordination via transforming growth factor beta (TGFβ) signaling. In the basalis, we define signaling between fibroblasts and an epithelial population expressing progenitor markers. Integration of HECA with large-scale endometriosis genome-wide association study data pinpoints decidualized stromal cells and macrophages as most likely dysregulated in endometriosis. The HECA is a valuable resource for studying endometrial physiology and disorders, and for guiding microphysiological in vitro systems development.

Graphical abstract Abstract Immunological dysregulation plays a fundamental role in the inflammatory aspects of endometriosis. Circulating blood leukocytes, one of the most abundant immune cell populations in the human body, have been shown diagnostic significance in some diseases. Nevertheless, the association between peripheral blood leukocyte counts and endometriosis remains unexplored to date. We analyzed two targeted study cohorts: a tertiary center cohort (Endometriosis at Oxford University (ENDOX) Study: 325 cases/177 controls) and a large-scale population study (UK Biobank (UKBB): 1537 cases/6331 controls). In both datasets, peripheral venous blood sample results were retrieved, and counts of leukocyte subpopulations, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils, were analyzed. Logistic regression models were used to investigate the association of leukocyte subtype alterations with endometriosis status, adjusting for confounding factors. We demonstrate that a higher blood basophil level is associated with increased odds of endometriosis. This association was first discovered in the ENDOX cohort (basophils >0.04 × 109/L: OR 1.65 (95% CI: 1.06–2.57), Ptrend = 0.025) and replicated in the UKBB dataset (basophils >0.04 × 109/L: OR 1.26 (95% CI: 1.09–1.45), Ptrend = 0.001). Notably, women with basophil counts in the upper tercile had significantly increased odds of having stage III/IV endometriosis (ENDOX study: OR = 2.30, 95% CI (1.25–4.22), Ptrend = 0.007; UKBB study (OR = 1.40, 95% CI (1.07–1.85), Ptrend = 0.015). None of the other leukocyte subtypes showed an association. Our findings suggest an association between inflammatory responses and the pathogenesis of endometriosis; future studies are warranted to investigate whether the association is causal. Lay summary Endometriosis is a long-term disease affecting approximately 10% of women during their fertile age. It happens when the tissue similar to the lining of the womb grows in other parts of the body, commonly causing pelvic pain and subfertility. Most diagnostic tests for endometriosis are neither accurate nor reliable, leading to a long wait before a correct diagnosis. Looking for changes in blood cell counts could guide doctors for further testing to confirm diagnosis. Our study shows that a higher number of basophils, a specialized type of white cells, commonly measured in a simple blood test, are positively linked with a higher likelihood of endometriosis. The link becomes stronger in severe endometriosis cases. Although we are showing a robust link, whether this can be used to find endometriosis sooner needs to be tested in future studies.

INTRODUCTION:Vulval cancer is a rare gynaecological malignancy. In this study, we present a tertiary centre case analysis to examine the recurrence patterns and survival outcomes of vulval squamous cell carcinoma (SCC). METHODS:This is a retrospective cohort study of women who received treatment at Oxford University Hospitals between February 2010 and July 2022 for primary vulval SCC. RESULTS:We included 98 cases. The median age at diagnosis was 68 years. Human Papillomavirus (HPV) infection and lichen sclerosis were observed in 21 and 50 cases, respectively. Surgical excision was the primary treatment. Recurrence within 2 years was more common with advanced stage (p = 0.047, RR = 2.26) and extracapsular lymph node spread (p = 0.013, RR = 2.88). Local recurrence was not associated with a specific cut-off value for tumour-free margin. Poor survival outcomes were observed with higher grade (p = 0.01), advanced FIGO stage (p < 0.001), HPV-independent cancer (p = 0.048), lymph node involvement (p < 0.001, HR = 7.14), extracapsular spread (p < 0.001, HR = 7.93), lymphovascular space invasion (p = 0.002, HR = 3.17), tumour diameter wider than 23 mm (p = 0.029, HR = 2.53) and depth of invasion more than 6 mm (p = 0.006, HR = 3.62). Perineural invasion is associated with shorter disease-free survival. Five-year cancer-specific survival rates for stages I, III, and IV were 90.2%, 40.8%, and 14.3%, respectively. CONCLUSION:

Large loop excision of the transformation zone is an extremely common procedure routinely carried out in a gynaecology or colposcopy outpatient setting under local anaesthetic. Here, we present a rare case resulting in emergency hysterectomy. A healthy para 3, who had been diagnosed with microscopic cancer of the cervix, attended colposcopy for repeat excision. The colposcopy revealed a normal cervix, and diathermy loop excision was performed. During the procedure, heavy bleeding from the anterior cutting edge was noted. Despite the best attempts to manage the haemorrhage conservatively in outpatients, the bleeding persisted, and the patient was transferred to theatres. Examination under anaesthesia revealed an injury to the descending branch of the uterine artery, and emergency hysterectomy was performed. Immediate recognition of an extremely rare complication, fast decision-making and a cross-disciplinary approach led to a satisfactory outcome.

The human endometrium, the inner lining of the uterus, exhibits complex, dynamic changes throughout the menstrual cycle in response to ovarian hormones. Aberrant response of endometrial cells to hormones is associated with multiple disorders, including endometriosis. Previous single-cell studies of the endometrium profiled a limited number of donors and lacked consensus in defining cell types and states. Here, we introduce the Human Endometrial Cell Atlas (HECA), a high-resolution single-cell reference atlas, combining published and newly generated single-cell transcriptomics datasets of endometrial biopsies of women with and without endometriosis. The HECA assigned consensus cell types and states, and uncovered novel ones, which we mapped in situ using spatial transcriptomics. We quantified how coordinated interactions between cell states in space and time contribute to endometrial regeneration and differentiation. In the continuously changing functionalis layer, we identified an intricate coordination of TGFβ signalling between stromal and epithelial cells, likely crucial for cell differentiation. In the basalis layer, we defined signalling between fibroblasts and a new epithelial cell population expressing epithelial stem/progenitor markers, suggesting their role in endometrial regeneration. Additionally, integrating the HECA single-cell data with genome-wide association study data and comparing endometrial samples from women with and without endometriosis, we pinpointed subsets of decidualised stromal cells and macrophages as the most dysregulated cell states in endometriosis. Overall, the HECA is an invaluable resource for studying endometrial physiology, investigating endometrial disorders, and guiding the creation of endometrial microphysiological in vitro systems.

Current immunotherapeutic approaches for human papillomavirus (HPV)-driven cervical cancer target the viral oncogenes E6 and E7. We report viral canonical and alternative reading frame (ARF)-derived sequences presented on cervical tumor cells, including antigens encoded by the conserved viral gene E1. We confirm immunogenicity of the identified viral peptides in HPV-positive women, and women with cervical intraepithelial neoplasia. We observe consistent transcription of the E1, E6, and E7 genes in 10 primary cervical tumor resections from the four most common high-risk HPV subtypes (HPV16, 18, 31, and 45), suggesting the suitability of E1 as therapeutic target. We finally confirm HLA presentation of canonical peptides derived from E6 and E7, and ARF-derived viral peptides from a reverse-strand transcript spanning the HPV E1 and E2 genes in primary human cervical tumor tissue. Our results extend currently known viral immunotherapeutic targets in cervical cancer and highlight E1 as an important cervical cancer antigen.

Despite an efficacious prophylactic human papillomavirus (HPV) vaccine there is still a considerable global burden of HPV-related disease. Therapeutic vaccines that could prevent cancers in at-risk women are urgently needed. Most candidate therapeutic vaccines have focused on two high-risk (hr) HPV genotypes, 16 and 18, and two viral targets, E6 and E7, which may limit global coverage and efficacy. We designed the synthetic gene '5GHPV3' by selecting conserved regions from each of the six early proteins and generating consensus sequences to represent five hrHPV genotypes. 5GHPV3 was delivered by plasmid DNA, chimpanzee adenovirus (ChAdOx1) and modified vaccinia Ankara (MVA) vectors in prime-boost regimens to mice. ChAdOx1-5GHPV3 / MVA-5GHPV3 induced higher magnitude and more durable HPV-specific T cell responses than other regimens. Vaccine-induced T cells were polyfunctional and persisted at high frequencies for at least six weeks. Importantly, HPV-specific effector CD8 + T cells were detected in the cervix following systemic administration of ChAdOx1-5GHPV3 / MVA-5GHPV3 and increased in frequency over time, indicating continued trafficking of T cells to the cervix. Finally, T cells specific for 5GHPV3 encoded antigens were detected by IFN-γ Elispot in women with current or past hrHPV infections, confirming the presence of epitopes relevant to natural immune control.

Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.

High-risk human papillomavirus (HPV) infection is known to be a necessary factor for cervical and anogenital malignancies. Cervical cancers account for over a quarter of a million deaths annually. Despite the availability of prophylactic vaccines, HPV infections remain extremely common worldwide. Furthermore, these vaccines are ineffective at clearing pre-existing infections and associated preinvasive lesions. As cervical dysplasia can regress spontaneously, a therapeutic HPV vaccine that boosts host immunity could have a significant impact on the morbidity and mortality associated with HPV. Therapeutic vaccines differ from prophylactic vaccines in that they are aimed at generating cell-mediated immunity rather than neutralising antibodies. This review will cover various therapeutic vaccine strategies in development for the treatment of HPV-associated lesions and cancers.