Window of opportunity with PD1 blockade before chemoradiotherapy for an advanced stage clear cell carcinoma of the cervix.

Clear cell carcinoma is a rare and very aggressive subset of cervical cancer, with poor outcome if diagnosed at advanced stage. There are few data available on the optimal management of this histotype, and treatment recommendations that include surgery and chemoradiotherapy, are essentially based on those for squamous cell carcinoma. Here we report the case of a young patient newly diagnosed with advanced stage (FIGO IIB) clear cell carcinoma of the uterine cervix who received a window of opportunity one injection of nivolumab followed by standard chemoradiotherapy. She showed a persistent complete remission after 28 months of follow-up, but developed hypothyroidism, as a consequence of immunotherapy, and required lifelong thyroid hormone replacement.

Knowledge of cytology results affects the performance of colposcopy: a crossover study.

OBJECTIVE: To determine whether knowledge of cytology affects the colposcopist's diagnostic accuracy in the identification of cervical intraepithelial neoplasia grade 2 and worse (≥ CIN2). METHOD: In this cross-over study, healthcare professionals interpreted colposcopy images from 80 patient cases with known histological diagnoses. For each case, 2 images taken with a colposcope were provided (native and after acetic acid application). Inclusion criteria consisted of women with a transformation zone type 1 or 2, who had both a cytological and histological diagnosis. Cases were distributed across two online surveys, one including and one omitting the cytology. A wash-out period of six weeks between surveys was implemented. Colposcopists were asked to give their diagnosis for each case as < CIN2 or ≥ CIN2 on both assessments. Statistical analysis was conducted to compare the two interpretations. RESULTS: Knowledge of cytology significantly improved the sensitivity when interpreting colposcopic images, from 51.1% [95%CI: 39.3 to 62.8] to 63.7% [95%CI: 52.1 to 73.9] and improved the specificity from 63.5% [95%CI: 52.3 to 73.5] to 76.6% [95%CI: 67.2 to 84.0]. Sensitivity was higher by 38.6% when a high-grade cytology (ASC-H, HSIL, AGC) was communicated compared to a low-grade cytology (inflammation, ASC-US, LSIL). Specificity was higher by 31% when a low-grade cytology was communicated compared to a high-grade. CONCLUSIONS: Our data suggests that knowledge of cytology increases sensitivity and specificity for diagnosis of ≥ CIN2 lesions at colposcopy. Association between cytology and histology may have contributed to the findings.

Factors influencing cervical cancer re-screening in a semi-rural health district of Cameroon: a cohort study.

BACKGROUND: Screening participation at recommended intervals is a crucial component of cervical cancer prevention effectiveness. However, little is known regarding the rate of re-screening in a Sub-Saharan context. This study aimed to estimate the re-screening rate of women in a semi-rural after an initial HPV-based screening and identify factors that influence adherence. METHODS: This cohort study at the Annex Regional Hospital of Dschang enrolled women screened for cervical cancer over 5 years ago and due for re-screening. Women who initially tested HPV-positive (n = 132) and a random sample of HPV-negative women (n = 220) participated in a telephone survey between October 2021 and March 2022 to assess re-screening participation and reasons. Sociodemographic factors were collected, and associations with rescreening were evaluated. RESULTS: A total of 352 participants aged under 50 years (mean age 37.4 years) were contacted, and 203 (58.0%) completed the survey. The proportion of women who complied with the screening recommendation was 34.0% (95% CI 27.5% - 40.5%), The weighted re-screening proportion was 28.4%. Age, marital status, education level, type of employment, and place of residence were not associated with the rate of re-screening. Main reported barriers to re-screening were lack of information (39.0%), forgetfulness (39.0%), and impression of being in good health (30.0%). Women who remembered the recommended screening interval were 2 to 3 times more likely to undergo re-screening (aOR (adjusted odds ratio) = 2.3 [1.2-4.4], p = 0.013). Human papilloma virus- positive status at the initial screening was also associated with the re-screening((aOR) (95% CI): 3.4 (1.8-6.5). CONCLUSION: Following an initial Human Papilloma Virus-based screening campaign in the West Region of Cameroon, one third of women adhered to re-screening within the recommended timeframe. Existing screening strategies would benefit from developing better information approaches to reinforce the importance of repeated cervical cancer screening.

Self-supervised learning-based cervical cytology for the triage of HPV-positive women in resource-limited settings and low-data regime.

Screening Papanicolaou test samples has proven to be highly effective in reducing cervical cancer-related mortality. However, the lack of trained cytopathologists hinders its widespread implementation in low-resource settings. Deep learning-assisted telecytology diagnosis emerges as an appealing alternative, but it requires the collection of large annotated training datasets, which is costly and time-consuming. In this paper, we demonstrate that the abundance of unlabeled images that can be extracted from Pap smear test whole slide images presents a fertile ground for self-supervised learning methods, yielding performance improvements compared to off-the-shelf pre-trained models for various downstream tasks. In particular, we propose Cervical Cell Copy-Pasting (C3P) as an effective augmentation method, which enables knowledge transfer from public and labeled single-cell datasets to unlabeled tiles. Not only does C3P outperforms naive transfer from single-cell images, but we also demonstrate its advantageous integration into multiple instance learning methods. Importantly, all our experiments are conducted on our introduced in-house dataset comprising liquid-based cytology Pap smear images obtained using low-cost technologies. This aligns with our long-term objective of deep learning-assisted telecytology for diagnosis in low-resource settings.

Assessment of women's sexual quality of life after benign adnexal surgery using vNOTES approach in comparison to conventional laparoscopy: protocol for a randomised controlled trial.

INTRODUCTION: Transvaginal natural orifice transluminal endoscopic surgery (vNOTES) has already proven its non-inferiority to conventional abdominal laparoscopy (CAL) for hysterectomy without conversion. The results in terms of efficacy and safety are promising. However, we note a lack of medical literature and no specific randomised controlled trial assessing women's sexual function after vNOTES for benign adnexal surgery. The aim of this RCT is to confirm the non-inferiority of the vNOTES approach for benign adnexal pathology compared with CAL on women's sexual function. Secondary outcomes will evaluate vNOTES's efficiency, morbidity and postoperative complications compared with CAL for benign adnexal surgery. The relationship between adnexal mass morcellation and the quality of the histological analysis will also be evaluated as secondary outcome. METHODS AND ANALYSIS: Women aged 18-70 years undergoing a benign adnexal surgery at the Geneva University Hospitals will be eligible and randomised with a 1:1 ratio to the CAL arm or the vNOTES arm, if inclusion criteria are met. Participants will complete the Female Sexual Function Index, the Couple Satisfaction Index-16 and a self-reported questionnaire on dyspareunia within 4 weeks prior to randomisation and at 3+6 months after surgery. General and clinical data will be collected when the patient is enrolled in the study, during hospitalisation and at 1 month postoperative to assess secondary outcomes.An absence of impairment on sexual function will be confirmed with a stability or an improvement of the evaluated scores in each group at 3 and 6 months postoperative compared with the preoperative scores. We expect to have no statistically significant difference in sexuality questionnaires scores between the two groups. ETHICS AND DISSEMINATION: Protocol of this study was validated by the Cantonal Research Ethics Commission of Geneva, Switzerland, on 9 August 2022. We aim to publish the study's results in peer-reviewed journals within 3 years. TRIAL REGISTRATION NUMBER: NCT05761275.

NANO-SBT-PEDF delivery system: A promising approach against ovarian cancer?

Pigment epithelium-derived factor (PEDF) is a secreted glycoprotein involved in various biological processes. Its expression declines during ovarian carcinogenesis where it could decrease macrophages polarization, inhibit angiogenesis and induce apoptosis. Altogether, PEDF represents an ideal anti-cancer agent against ovarian cancer. We previously proposed the non-viral Sleeping Beauty transposon (SBT) system to stably integrate the PEDF transgene into ovarian cancer cells. Here, we report the development of liposomes and lipid nanoparticles for SBT-PEDF gene therapy. We determined that the SBT-PEDF nanolipid delivery system was the best system to increase the expression of PEDF in ovarian cancer spheroids. We also developed an ex vivo model of ovarian tumors which allowed us to show that nanolipoplexe in combination to paclitaxel exhibits synergistic and effective anti-tumor efficacy on ovarian tumors. These findings demonstrate that lipid nanoparticle for SBT-PEDF gene therapy may be a promising therapeutic approach for ovarian cancer.

Exploring the potential impact of human papillomavirus on infertility and assisted reproductive technology outcomes.

Human papillomavirus (HPV) is a common sexually transmitted disease that has been linked to both cancer and reproductive health issues. While its impact on fertility and pregnancy success has been studied, there is still too little evidence about the influence of HPV on assisted reproductive technology (ART). Therefore, there exists a need for HPV testing in couples undergoing infertility treatments. Infertile men have been found to have a higher prevalence of seminal HPV infection, which can compromise sperm quality and reproductive function. As such, it could be important to investigate the correlation between HPV and ART outcomes in order to improve the quality of evidence. Understanding the potentially detrimental effects of HPV on ART outcomes may have promising important implications for the management of infertility. This minireview summarizes the so far limited developments in this area and highlights the major need for further well-designed studies to address this issue.

Case report Iatrogenic parasitic leiomyoma: the surgeon's invisible hand.

Uterine leiomyoma is the most common benign tumour of the uterus in women of reproductive age. When removed surgically, a mini-invasive procedure is preferentially used (laparoscopic or robotic) and the extraction of the specimen can be managed by power morcellation. In this consecutive case-series, we present three cases of parasitic leiomyoma that appeared following previous surgical management of leiomyoma using the technique of laparoscopic myomectomy with uncontained power morcellation. The time frame in between the initial surgery and the diagnosis of the parasitic leiomyoma was 5.7 years. All three patients were diagnosed with endometriosis: 2 cases prior to the initial surgery and 1 case after the initial surgery. One hypothesis could be that, due to pelvic inflammation, endometriosis is a risk factor for iatrogenic parasitic leiomyoma development in case of uncontained morcellation of leiomyoma during myomectomy.

Artificial Intelligence-Based Cervical Cancer Screening on Images Taken during Visual Inspection with Acetic Acid: A Systematic Review.

Visual inspection with acetic acid (VIA) is one of the methods recommended by the World Health Organization for cervical cancer screening. VIA is simple and low-cost; it, however, presents high subjectivity. We conducted a systematic literature search in PubMed, Google Scholar and Scopus to identify automated algorithms for classifying images taken during VIA as negative (healthy/benign) or precancerous/cancerous. Of the 2608 studies identified, 11 met the inclusion criteria. The algorithm with the highest accuracy in each study was selected, and some of its key features were analyzed. Data analysis and comparison between the algorithms were conducted, in terms of sensitivity and specificity, ranging from 0.22 to 0.93 and 0.67 to 0.95, respectively. The quality and risk of each study were assessed following the QUADAS-2 guidelines. Artificial intelligence-based cervical cancer screening algorithms have the potential to become a key tool for supporting cervical cancer screening, especially in settings where there is a lack of healthcare infrastructure and trained personnel. The presented studies, however, assess their algorithms using small datasets of highly selected images, not reflecting whole screened populations. Large-scale testing in real conditions is required to assess the feasibility of integrating those algorithms in clinical settings.

Telecytologic diagnosis of cervical smears for triage of self-sampled human papillomavirus-positive women in a resource-limited setting: concept development before implementation.

INTRODUCTION: Cytology is an option for triaging human papillomavirus (HPV)-positive women. The interpretation of cytologic slides requires expertise and financial resources that are not always available in resource-limited settings. A solution could be offered by manual preparation and digitization of slides on site for real-time remote cytologic diagnosis by specialists. In the present study, we evaluated the operational feasibility and cost of manual preparation and digitization of thin-layer slides and the diagnostic accuracy of screening with virtual microscopy. MATERIALS AND METHODS: Operational feasibility was evaluated on 30 cervical samples obtained during colposcopy. The simplicity of the process and cellularity and quality of digitized thin-layer slides were evaluated. The diagnostic accuracy of digital versus glass slides to detect cervical intraepithelial neoplasia grade 2 or worse was assessed using a cohort of 264 HPV-positive Cameroonian women aged 30 to 49 years. The histologic results served as the reference standard. RESULTS: Manual preparation was found to be feasible and economically viable. The quality characteristics of the digital slides were satisfactory, and the mean cellularity was 6078 squamous cells per slide. When using the atypical squamous cells of undetermined significance or worse threshold for positivity, the diagnostic performance of screening digital slides was not significantly different statistically compared with the same set of slides screened using a light microscope (P = 0.26). CONCLUSIONS: We have developed an innovative triage concept for HPV-positive women. A quality-ensured telecytologic diagnosis could be an effective solution in areas with a shortage of specialists, applying a same day "test-triage-treat" approach. Our results warrant further on-site clinical validation in a large prospective screening trial.

Transformation Zone Assessment Using Visual Inspection With Acetic Acid Before and After Thermal Ablation: Implications for Follow-Up.

PURPOSE: Thermal ablation (TA) has become the conventional method for treatment of precancerous cervical lesions in low-resource settings. After TA, both the squamocolumnar junction (SCJ) and the transformation zone (TZ) may be subject to change. Our aim was to evaluate SCJ and TZ variability after TA. METHODS: Study data were collected in a large prospective trial of a cervical cancer screening campaign in Cameroon. For each patient, two sets of cervical photos (native and with acetic acid) were taken before and 6-12 months after TA. The SCJ and TZ were evaluated independently by three observers according to the WHO nomenclature. When discordances were observed between the type of TZ and SCJ selected by each observer, a corrected TZ was established on the basis of the SCJ categorization. Interobserver agreement for TZ interpretation was evaluated using Cohen's kappa coefficient for agreement between two observers and Fleiss' kappa between three observers. RESULTS: Fifty consecutive participants were included in the analysis. Seventy-six percent were interpreted as TZ1-2, and 24% as TZ3 before TA. In 56% of cases, the entire SCJ could not be entirely visualized after TA, thus being recategorized as TZ3. Interobserver agreement was fair for diagnosis before TA (Kappa coefficient, 0.34; 95% CI, 0.27 to 0.45) and moderate for diagnosis after TA (Kappa coefficient, 0.40; 95% CI, 0.30 to 0.50). After TA, 36% progressed from TZ1-2 to TZ3, with a moderate interobserver agreement (Kappa coefficient, 0.44; 95% CI, 0.40 to 0.54). CONCLUSION: We observed a shift of the SCJ into the endocervical canal after TA. A significant proportion of participants had TZ 3 after treatment, raising the question of visual inspection with acetic acid's applicability as a first-line follow-up examination method after TA.

Inter- and intra-observer agreement in the assessment of the cervical transformation zone (TZ) by visual inspection with acetic acid (VIA) and its implications for a screen and treat approach: a reliability study.

BACKGROUND: In low-resource countries, interpretation of the transformation zone (TZ) using the classification of the International Federation for Cervical Pathology and Colposcopy (IFCPC), adopted by the World Health Organization, is critical for determining if visual inspection with acetic acid (VIA) screening and thermal ablation treatment are possible. We aim to assess inter- and intra-observer agreement in TZ interpretation. METHODS: We performed a prospective multi-observer reliability study. One hundred cervical digital images of Human papillomavirus positive women (30-49 years) were consecutively selected from a Cameroonian cervical cancer screening trial. Images of the native cervix and after VIA were obtained. The images were evaluated for the TZ type at two time points (rounds one and two) by five VIA experts from four countries (Côte d'Ivoire, Cameroon, Peru, and Zambia) according to the IFCPC classification (TZ1 = ectocervical fully visible; TZ2 = endocervical fully visible; TZ3 = not fully visible). Intra- and inter-observer agreement were measured by Fleiss' kappa. RESULTS: Overall, 37.0% of images were interpreted as TZ1, 36.4% as TZ2, and 26.6% as TZ3. Global inter-observer reliability indicated fair agreement in both rounds (kappa 0.313 and 0.288). The inter-observer agreement was moderate for TZ1 interpretation (0.460), slight for TZ2 (0.153), and fair for TZ3 (0.329). Intra-observer analysis showed fair agreement for two observers (0.356 and 0.345), moderate agreement for two other (0.562 and 0.549), and one with substantial agreement (0.728). CONCLUSION: Interpretation of the TZ using the IFCPC classification, adopted by the World Health Organization, is critical for determining if VIA screening and thermal ablation treatment are possible. However, the low inter- and intra-observer agreement suggest that the reliability of the referred classification is limited in the context of VIA. It's integration in treatment recommendations should be used with caution since TZ3 interpretation could lead to an important referral rate for further evaluation. Trial registration Cantonal Ethics Board of Geneva, Switzerland: N°2017-0110. Cameroonian National Ethics Committee for Human Health Research N°2018/07/1083/CE/CNERSH/SP.

Nab-PIPAC: a phase IB study protocol of intraperitoneal cisplatin and nab-paclitaxel administered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in the treatment of advanced malignancies confined to the peritoneal cavity.

INTRODUCTION: Intraperitoneal dissemination is a major problem resulting in very poor prognosis and a rapid marked deterioration in the quality of life of patients. Pressurised intraperitoneal aerosol chemotherapy (PIPAC) is an emergent laparoscopic procedure aiming to maximise local efficacy and to reduce systemic side effects. METHODS AND ANALYSIS: Nab-PIPAC, a bicentre open-label phase IB, aims to evaluate safety of nab-paclitaxel and cisplatin association using in patients with peritoneal carcinomatosis (PC) of gastric, pancreatic or ovarian origin as ≥1 prior line of systemic therapy. Using a 3+3 design, sequential intraperitoneal laparoscopic application of nab-paclitaxel (7.5, 15, 25, 37.5, 52.5 and 70 mg/m2) and cisplatin (10.5 mg/m2) through a nebuliser to a high-pressure injector at ambient temperature with a maximal upstream pressure of 300 psi. Treatment maintained for 30 min at a pressure of 12 mm Hg and repeated4-6 weeks intervals for three courses total.A total of 6-36 patients are expected, accrual is ongoing. Results are expected in 2024.The primary objective of Nab-PIPAC trial is to assess tolerability and safety of nab-paclitaxel and cisplatin combination administered intraperitoneally by PIPAC in patients with PC of gastric, pancreatic or ovarian origin. This study will determine maximum tolerated dose and provide pharmacokinetic data. ETHIC AND DISSEMINATION: Ethical approval was obtained from the ethical committees of Geneva and Vaud (CCER-2018-01327). The study findings will be published in an open-access, peer-reviewed journal and presented at relevant conferences and research meetings. TRIAL REGISTRATION NUMBER: NCT04000906.

Radiotherapy or Surgery of the Axilla After a Positive Sentinel Node in Breast Cancer: 10-Year Results of the Randomized Controlled EORTC 10981-22023 AMAROS Trial.

PURPOSE: The European Organisation for Research and Treatment of Cancer 10981-22023 AMAROS trial evaluated axillary lymph node dissection (ALND) versus axillary radiotherapy (ART) in patients with cT1-2, node-negative breast cancer and a positive sentinel node (SN) biopsy. At 5 years, both modalities showed excellent and comparable axillary control, with significantly less morbidity after ART. We now report the preplanned 10-year analysis of the axillary recurrence rate (ARR), overall survival (OS), and disease-free survival (DFS), and an updated 5-year analysis of morbidity and quality of life. METHODS: In this open-label multicenter phase III noninferiority trial, 4,806 patients underwent SN biopsy; 1,425 were node-positive and randomly assigned to either ALND (n = 744) or ART (n = 681). RESULTS: Per intention-to-treat analysis, 10-year ARR cumulative incidence was 0.93% (95% CI, 0.18 to 1.68; seven events) after ALND and 1.82% (95% CI, 0.74 to 2.94; 11 events) after ART (hazard ratio [HR], 1.71; 95% CI, 0.67 to 4.39). There were no differences in OS (HR, 1.17; 95% CI, 0.89 to 1.52) or DFS (HR, 1.19; 95% CI, 0.97 to 1.46). ALND was associated with a higher lymphedema rate in updated 5-year analyses (24.5% v 11.9%; P < .001). Quality-of-life scales did not differ by treatment through 5 years. Exploratory analysis showed a 10-year cumulative incidence of second primary cancers of 12.1% (95% CI, 9.6 to 14.9) after ART and 8.3% (95% CI, 6.3 to 10.7) after ALND. CONCLUSION: This 10-year analysis confirms a low ARR after both ART and ALND with no difference in OS, DFS, and locoregional control. Considering less arm morbidity, ART is preferred over ALND for patients with SN-positive cT1-2 breast cancer.

Utility of extended HPV genotyping for the triage of self-sampled HPV-positive women in a screen-and-treat strategy for cervical cancer prevention in Cameroon: a prospective study of diagnostic accuracy.

OBJECTIVE: To explore the utility of extended Human Papillomavirus (HPV) genotyping to detect cervical intraepithelial neoplasia grade 2 or more (CIN2+) in a 'screen-and-treat' strategy for HPV-positive women in low-resource settings. DESIGN: Prospective study of diagnostic accuracy. SETTING: The study took place in West Cameroon between September 2018 and March 2020. PARTICIPANTS: 2014 women were recruited. Asymptomatic, non-pregnant women aged 30-49 years without history of CIN treatment, anogenital cancer or hysterectomy were eligible. INTERVENTIONS: Participants performed self-sampling for HPV testing with GeneXpert followed by visual inspection with acetic acid and Lugol's iodine (VIA) triage before treatment if required. MAIN OUTCOME MEASURES: Liquid-based cytology, biopsies and endocervical brushing were performed in HPV-positive women as quality control. We assessed the detection rate of CIN2+ by HPV genotyping (two pools of genotypes obtained from the Xpert system, pool_1 (HPV 16, 18, 45) and pool_2 (HPV 16, 18, 45, 31, 33, 35, 52, 58)), VIA and cytology. RESULTS: 382 (18.2%) women were HPV-positive among which 11.5% (n=44) were CIN2+. Of those 44 participants, 41 were triaged positive by extended genotyping, versus 35 by VIA and 33 by cytology. Overall, triage positivity was of 68.4% for extended genotyping, 59.3% for VIA and 14.8% for cytology, with false positive rates of 83.4%, 84.1% and 37.7%, respectively. Extended genotyping had a higher sensitivity for CIN2+ detection (93.2%, CI: 81.3 to 98.6) than VIA (79.5%, CI: 64.7 to 90.2, p=0.034) and cytology (75.0%, CI: 59.7 to 86.8, p=0.005). No significant difference was observed in the overtreatment rate in triaged women by extended genotyping or VIA (9.9%, CI: 8.6 to 11.3, and 8.8%, CI: 7.7 to 10.1), with a ratio of 6.0 and 6.3 women treated per CIN2+ diagnosed. CONCLUSION: Triage of HPV-positive women with extended HPV genotyping improves CIN2+ detection compared with VIA with a minor loss of specificity and could be used to optimize the management of HPV-positive women. TRIAL REGISTRATION NUMBER: NCT03757299.

Harms and benefits of cervical cancer screening among non-attenders in Switzerland: The transition towards HPV-based screening.

Human papillomavirus (HPV) testing is replacing cytological screening for cervical cancer. Our aim was to assess the expected benefits and harms of different cervical screening strategies. This study is sub-analysis of a previous cost-effectiveness study with a target population of unscreened women without cervical cancer aged ≥ 25 years. A recursive decision-tree with one-year cycles was used to model the life-long natural HPV history. Markov cohort simulations were used to assess the expected outcomes from the model. The outcomes of three strategies were compared with the absence of screening: HPV-testing on self-collected vaginal samples (Self-HPV) followed by colposcopy (Self-HPV/colpo), Self-HPV and triage with cytology (Self-HPV/PAP), cytology and triage with HPV (PAP/HPV). All screening strategies resulted in reductions in cancer cases and deaths. Self-HPV strategies were associated with a lower cancer incidence and mortality life-long, not only when performed every 3 years but also when Self-HPV was performed every 5 years vs cytology every 3 years. The gain in life expectancy obtained was 82 days with Self-HPV/colpo, 81 days with Self-HPV/PAP and 75 days with PAP/HPV compared to no screening. The number of lifetime total visits was greater with PAP/HPV compared with the Self-HPV strategies (13.13 vs < 3). The number of conizations remained relatively stable with the change of screening frequency and strategy. Self-HPV may represent a reasonable balance of harms and benefits when performed every 5 years compared to cytology every 3 years. Self-HPV/PAP yielded the most efficient harm to benefit ratio when using colposcopy as a proxy for harms.

Linking unfolded protein response to ovarian cancer cell fusion.

BACKGROUND: Polyploid giant cancer cells (PGCCs) have been observed in epithelial ovarian tumors. They can resist antimitotic drugs, thus participating in tumor maintenance and recurrence. Although their origin remains unclear, PGCC formation seems to be enhanced by conditions that trigger the unfolded protein response (UPR) such as hypoxia or chemotherapeutic drugs like paclitaxel. Hypoxia has been shown to promote the formation of ovarian PGCCs by cell fusion. We thus hypothesized that the UPR could be involved in EOC cell fusion, possibly explaining the occurrence of PGCCs and the aggressiveness of EOC. METHODS: The UPR was induced in two ovarian cancer cell lines (SKOV3 and COV318). The UPR activation was assessed by Western blot and polyploidy indexes were calculated. Then, to confirm the implication of cell fusion in PGCC formation, two populations of SKOV3 cells were transfected with plasmids encoding for two distinct nuclear fluorescent proteins (GFP and mCherry) associated with different antibiotic resistance genes, and the two cell populations were mixed in co-culture. The co-culture was submitted to a double-antibiotic selection. The resulting cell population was characterized for its morphology, cyclicity, and proliferative and tumorigenic capacities, in addition to transcriptomic characterization. RESULTS: We demonstrated that cell fusion could be involved in the generation of ovarian PGCCs and this process was promoted by paclitaxel and the UPR activation. Double-antibiotic treatment of PGCCs led to the selection of a pure population of cells containing both GFP- and mCherry-positive nuclei. Interestingly, after 3 weeks of selection, we observed that these cells were no longer polynucleated but displayed a single nucleus positive for both fluorescent proteins, suggesting that genetic material mixing had occurred. These cells had reinitiated their normal cell cycles, acquired an increased invasive capacity, and could form ovarian tumors in ovo. CONCLUSIONS: The UPR activation increased the in vitro formation of PGCCs by cell fusion, with the newly generated cells further acquiring new properties. The UPR modulation in ovarian cancer patients could represent an interesting therapeutic strategy to avoid the formation of PGCCs and therefore limit cancer relapse and drug resistance.