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The objective of this study was to evaluate the relationship between the excision type and the persistence/recurrence of CIN2-3. A total of 227 women with CIN2-3 who were treated with LLETZ were evaluated. The types of excision according to the IFCPC 2011, volume, cone dimensions, margins of resection, post-cone high-risk human papillomavirus (HR-HPV) status, and viral load were studied. The time to recurrence was assessed using Kaplan-Meier curves. Persistent/recurrent CIN2-3 was found in 12 cases (5.2%). Type 1 excision was performed in 107 patients, with 7 recurrences (6.5%); type 2 excision in 74 patients, with 4 recurrences (5.4%); and type 3 excision in 46 patients, with 1 recurrence (2.1%). The percentage of clear margins in type 1 excisions was 44.9%, that in type 2 excisions was 59.5%, and that in type 3 excisions was 69.6% ( p = 0.008). Type 1 excision was associated with 28.5% post-LLETZ HR-HPV positivity, that in type 2 reached 20.6%, and that in type 3 reached 11.4%; this difference was non-significant ( p = 0.24). (4) Conclusions: Type 3 excision was associated with a larger proportion of clear margins and lower post-cone HR-HPV positivity, with a lower incidence of the persistence/recurrence of CIN2-3.

Human Papillomavirus (HPV) prophylactic vaccination has proven effective in preventing new infections, but it does not treat existing HPV infections or associated diseases. Hence, there is still an important reservoir of HPV in adults, as vaccination programs are mainly focused on young women. The primary objective of this non-randomized, open-label trial is to evaluate if a 3-dose regimen of Gardasil-9 in HPV16/18-positive women could reduce the infective capacity of their body fluids. We aim to assess if vaccine-induced antibodies could neutralize virions present in the mucosa, thus preventing the release of infective particles and HPV transmission to sexual partners. As our main endpoint, the E1^E4-HaCaT model will be used to assess the infectivity rate of cervical, anal and oral samples, obtained from women before and after vaccination. HPV DNA positivity, virion production, seroconversion, and the presence of antibodies in the exudates, will be evaluated to attribute infectivity reduction to vaccination. Our study will recruit two different cohorts (RIFT-HPV1 and RIFT-HPV2) of non-vaccinated adult women. RIFT-HPV1 will include subjects with an HPV16/18 positive cervical test and no apparent cervical lesions or cervical lesions eligible for conservative treatment. RIFT-HPV2 will include subjects with an HPV16/18 positive anal test and no apparent anal lesions or anal lesions eligible for conservative treatment, as well as women with an HPV16/18 positive cervical test and HPV-associated vulvar lesions. Subjects complying with inclusion criteria for both cohorts will be recruited to the main cohort, RIFT-HPV1. Three doses of Gardasil-9 will be administered intramuscularly at visit 1 (0 months), visit 2 (2 months) and visit 3 (6 months). Even though prophylactic HPV vaccines would not eliminate a pre-existing infection, our results will determine if HPV vaccination could be considered as a new complementary strategy to prevent HPV-associated diseases by reducing viral spread. Trial registration: https://clinicaltrials.gov/ct2/show/NCT05334706., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: The Cancer Epidemiology Research Program from Catalan Institute of Oncology (ICO-IDIBELL) has received sponsorship/grants and free reagents from MSD, Roche, GSK, IDT, Hologic and Seegene, as well as structural funds from CIBERESP and the Government of Catalonia. None of these entities had any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript, nor alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 López-Codony et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Vulvar high-grade squamous intraepithelial lesion (vulvar HSIL) or vulvar intraepithelial neoplasia (VIN) is a premalignant condition that can progress to carcinoma. Imiquimod is a topical drug with high effectiveness and low morbidity. We aimed (1) to assess the long-term response to imiquimod in a cohort of patients with vulvar HSIL and (2) and to analyze the role of HPV determined in pre- and post-imiquimod treatment biopsies in the persistence or recurrence of vulvar HSIL. Design: Retrospective study between 2011 and 2022. Setting : Referrals from the primary care area of Baix Llobregat treated in the gynecology department of a university hospital in Barcelona, Spain. Population : 20 women with vulvar HSIL treated with imiquimod. Methods: The inclusion criteria were vulvar HSIL, vulvar HPV determination by pre- and post-treatment biopsy, acceptance of medical treatment, at least one follow-up and 4 weeks of treatment. Main outcome measures : Histological diagnosis of vulvar HSIL with pre- and post-imiquimod HPV determination. Response to treatment (complete, partial, no response, recurrence). Results: After imiquimod, 10 (50%) and 6 (30%) cases had complete and partial responses, respectively. Another 4 cases (20%) did not respond. Before treatment, 19 (95%) cases were positive for vulvar HPV (16 cases had HPV type 16). After treatment, 10 cases (50%) were positive for HPV (8 cases with HPV type 16): 2 cases (20%) with a complete response, 5 cases (83.3%) with a partial response and 3 cases (75%) with no response. Eight of the 10 HPV-negative cases (80%) post-treatment showed a complete response. HPV type 16 was present in 16 cases (84.2%) pre-treatment and in 8 cases (80%) post-treatment. Ten patients underwent additional treatments following a partial response, no response or recurrence. The 2 HIV and 3 immunosuppressed patients treated with imiquimod showed a partial response and required additional treatment. All these patients were HPV-positive pre- and post-treatment (100%). Response to imiquimod was associated with post-treatment vulvar HPV positivity ( p = 0.03). The median time to a complete response in HPV-negative cases was 4.7 months versus 11.5 months in HPV-positive cases post-imiquimod treatment. Recurrence of vulvar HSIL was observed in 7 patients (35%), with a median time to recurrence of 19.7 months (range 3.2-32.7). Recurrence was experienced in 10% of cases with a complete response, in 4/6 (66.6%) cases with a partial response, and in 2/4 (50%) women with no response. Four of the 7 recurrent cases (57%) were infected with HIV or immunosuppressed. Six (85%) of the recurrent cases were HPV-positive post-treatment (all were HPV type 16). Four (30.7%) of the non-recurrent cases were HPV-positive post-treatment with imiquimod ( p = 0.05), two of which were HPV type 16 (50%). Conclusions: Imiquimod effectively treats vulvar HSIL. Cases with a complete response showed less HPV positivity post-treatment than partial or non-response cases. Recurrences were more frequent in those with a partial or no response to imiquimod, and in immunosuppressed patients. In recurrent cases, 85% were HPV-positive post-treatment, while 30.7% of non-recurrent cases were HPV-positive. HPV positivity in the post-treatment biopsy suggests the need for stricter follow-up of patients.

Endometrial cancer (EC) is the fourth most common cancer in women in developed countries. Although it is usually diagnosed in postmenopausal women, its incidence has increased in young women, as well in recent decades, with an estimated rate of 4% in those under 40 years of age. Factors involved in this increase, particularly in resource-rich countries, include delayed childbearing and the rise in obesity. The new molecular classification of EC should help to personalize treatment, through appropriate candidate selection. With the currently available evidence, the use of oral progestin either alone or in combination with other drugs such as metformin, levonorgestrel-releasing intrauterine devices and hysteroscopic resection, seems to be feasible and safe in women with early-stage EC limited to the endometrium. However, there is a lack of high-quality evidence of the efficacy and safety of conservative management in EC. Randomized clinical trials in younger women and obese patients are currently underway.

Introduction: The Objective was to investigate the incidence of lymphedema after breast cancer treatment and to analyze the risk factors involved in a tertiary level hospital., Methods: Prospective longitudinal observational study over 3 years post-breast surgery. 232 patients undergoing surgery for breast cancer at our institution between September 2013 and February 2018. Sentinel lymph node biopsy (SLNB) or axillary lymphadenectomy (ALND) were mandatory in this cohort. In total, 201 patients met the inclusion criteria and had a median follow-up of 31 months (range, 1-54 months). Lymphedema was diagnosed by circumferential measurements and truncated cone calculations. Patients and tumor characteristics, shoulder range of motion limitation and local and systemic therapies were analyzed as possible risk factors for lymphedema., Results: Most cases of lymphedema appeared in the first 2 years. 13.9% of patients developed lymphedema: 31% after ALND and 4.6% after SLNB (p < 0.01), and 46.7% after mastectomy and 11.3% after breast-conserving surgery (p < 0.01). The lymphedema rate increased when axillary radiotherapy (RT) was added to radical surgery: 4.3% for SLNB alone, 6.7% for SLNB + RT, 17.6% for ALND alone, and 35.2% for ALND + RT (p < 0.01). In the multivariate analysis, the only risk factors associated with the development of lymphedema were ALND and mastectomy, which had hazard ratios (95% confidence intervals) of 7.28 (2.92-18.16) and 3.9 (1.60-9.49) respectively., Conclusions: The main risk factors for lymphedema were the more radical surgeries (ALND and mastectomy). The risk associated with these procedures appeared to be worsened by the addition of axillary radiotherapy. A follow-up protocol in patients with ALND lasting at least two years, in which special attention is paid to these risk factors, is necessary to guarantee a comprehensive control of lymphedema that provides early detection and treatment.

Ectonucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) has been described in human non-pathological endometrium in both epithelial and stromal components without changes along the cycle. It was identified as a stromal marker of basalis. In the present study, we aimed to evaluate NTPDase2 distribution, using immunolabeling and in situ enzyme activity approaches, in endometrial carcinoma (EC) at different tumor grades. NTPDase2 was present in tumor epithelial EC cells, as in the non-pathological endometria, but the expression underwent changes in subcellular distribution and also tended to decrease with the tumor grade. In stroma, NTPDase2 was identified exclusively at the tumor-myometrial junction but this expression was lost in tumors of invasive phenotype. We have also identified in EC samples the presence of the perivascular population of endometrial mesenchymal stem cells (eMSCs) positive for sushi domain containing 2 (SUSD2) and for NTPDase2, already described in non-tumoral endometrium. Our results point to NTPDase2 as a histopathological marker of tumor invasion in EC, with diagnostic relevance especially in cases of EC coexisting with other endometrial disorders, such as adenomyosis, which occasionally hampers the assessment of tumor invasion parameters.

Objective: To assess the long-term risk factors predicting residual/recurrent cervical intraepithelial neoplasia (CIN 2-3) and time to recurrence after large loop excision of the transformation zone (LLETZ)., Design: Retrospective study., Setting: Colposcopy clinic., Population: 242 women with CIN 2-3 treated between 1996 and 2006 and followed up until June 2016., Methods: Age, margins, and high-risk human papillomavirus (HR-HPV) were estimated using Cox proportional hazard and unconditional logistic regression models. The cumulative probability of treatment failure was estimated by Kaplan-Meier analysis., Main Outcome Measure: Histologically confirmed CIN 2-3, HR-HPV, margins, age., Results: CIN 2-3 was associated with HR-HPV (HR = 30.5, 95% confidence interval [CI] = 3.80-246.20), age >35 years (HR = 5.53, 95% CI = 1.22-25.13), and margins (HR = 7.31, 95% CI = 1.60-33.44). HR-HPV showed a sensitivity of 88.8% and a specificity of 80%. Ecto + /endocervical + (16.7%), uncertain (19.4%) and ecto - /endocervical + margins (9.1%) showed a higher risk of recurrence (odds ratio [OR] = 13.20, 95% CI = 1.02-170.96; OR = 15.84, 95% CI = 3.02-83.01; and OR = 6.60, 95% CI = 0.88-49.53, respectively). Women with involved margins and/or who were HR-HPV positive had more treatment failure than those who were HR-HPV negative or had clear margins (P-log-rank <0.001)., Conclusions: HR-HPV and margins seem essential for stratifying post-LLETZ risk, and enable personalised management. Given that clear margins present a lower risk, a large excision may be indicated in older women to reduce the risk., Tweetable Abstract: After LLETZ for CIN 2-3, recurrences appear more often in women with positive HR-HPV and involved margins and aged over 35., (© 2019 Royal College of Obstetricians and Gynaecologists.)

Endometriosis is a prevalent disease defined by the presence of endometrial tissue outside the uterus. Adenosine triphosphate (ATP), as a proinflammatory molecule, promotes and helps maintain the inflammatory state of endometriosis. Moreover, ATP has a direct influence on the two main symptoms of endometriosis: infertility and pain. Purinergic signaling, the group of biological responses to extracellular nucleotides such as ATP and nucleosides such as adenosine, is involved in the biology of reproduction and is impaired in pathologies with an inflammatory component such as endometriosis. We have previously demonstrated that ectonucleotidases, the enzymes regulating extracellular ATP levels, are active in non-pathological endometria, with hormone-dependent changes in expression throughout the cycle. In the present study we have focused on the expression of ectonucleotidases by means of immunohistochemistry and in situ activity in eutopic and ectopic endometrial tissue of women with endometriosis, and we compared the results with endometria of women without the disease. We have demonstrated that the axis CD39-CD73 is altered in endometriosis, with loss of CD39 and CD73 expression in deep infiltrating endometriosis, the most severe, and most recurring, endometriosis subtype. Our results indicate that this altered expression of ectonucleotidases in endometriosis boosts ATP accumulation in the tissue microenvironment. An important finding is the identification of the nucleotide pyrophophatase/phosphodiesterase 3 (NPP3) as a new histopathological marker of the disease since we have demonstrated its expression in the stroma only in endometriosis, in both eutopic and ectopic tissue. Therefore, targeting the proteins directly involved in ATP breakdown could be an appropriate approach to consider in the treatment of endometriosis.

Problem: The diagnosis of endometriosis, a prevalent chronic disease with a strong inflammatory component, is usually delayed due to the lack of noninvasive diagnostic tests. Purinergic signaling, a key cell pathway, is altered in many inflammatory disorders. The aim of the present work was to evaluate the levels of adenosine deaminase (ADA), alkaline phosphatase (ALP), ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and ENPP3, elements of purinergic signaling, as biomarker candidates for endometriosis., Method of Study: A case-control comparative study was conducted to determine ADA, ALP, ENPP1 and ENPP3 levels in echo-guided aspirated fluids of endometriomas (case group) and simple ovarian cysts (control group) using the ELISA technique., Results: Adenosine deaminase, ALP, ENPP1, and ENPP3 were present and quantifiable in the contents of endometriomas and simple cysts. There were significant differences in ADA and ENPP1 levels in endometriomas in comparison with simple cysts (2787 U/L and 103.9 ng/mL more in endometriomas, for ADA and ENPP1, respectively). Comparisons of ALP and ENPP3 levels between the two groups did not reveal significant differences., Conclusion: The ectoenzymes ADA and ENPP1 are biomarker candidates for endometriosis., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

MDA-MB-231 is a breast cancer cell line which possesses large quantities of epidermal growth factor (EGF) receptors and specific high-affinity transforming growth factor-beta1 (TGF-beta1) receptors. We have established that these cells secrete constitutively measurable levels of EGF and TGF-beta1 in conditioned medium. The constitutive secretion of EGF decreased over time in culture (42 h), while the constitutive secretion of TGF-beta1 remained constant. TGF-beta1 secretion in EGF-treated cells was lower than in controls (P < 0.0001), but EGF concentrations were not modified after TGF-beta1 supplement. We postulate that in MDA-MB-231 cell line there is a dual regulation between both growth factors.

The human cell line MDA-MB-231 is a prototype for the study of hormone-independent breast cancer. Modification of cell growth behaviour has been observed after treating these cells with growth factors. EGF is a typical stimulatory growth factor for many cell types, whereas transforming growth factor beta(1)(TGF-beta(1)) acts with inhibitory character. Here we observed cell growth inhibition after EGF as well as after TGF-beta(1)treatments. Nevertheless, in the 42-h experiments, EGF-treated cultures grew before (18 hours) respect to the TGF-beta(1)and E(2)-treated cultures (24 h), and in the 11-day experiments, EGF-treated cultures started growing (7 days) after TGF-beta(1)-treated cultures (5 days). Estradiol inhibited the proliferation of these cells only after several days of treatment., (Copyright 1998 Academic Press.)

Results of epidermal growth factor (EGF) receptor in human breast tumours show large variations, mainly due to the lack of standardization of the assays. Our EGF receptor values are higher than those reported previously which may be due to the use of the hydroxyapatite to separate bound and non-bound ligand in a radioligand assay. We found EGF receptors in 58% (103/178) of the tumours (EGF receptor levels: 3 to 625 fmol/mg of membrane protein, mean = 33.3, median = 17.4), with a median Kd of 0.642 nmol/l. There was an inverse correlation between EGF receptors and estrogen receptors (r = -0.215, p = 0.00002, Kendall correlation). There was a difference between EGF receptor content in grade II (mean = 16.9) and grade III tumours (mean = 59.3) (p = 0.027), but not between histopathological types and lymph node status. The relevance of EGF receptor largely depends on the reliability of its determination. The standardized EORTC methodology is a reproducible alternative which will expand EGF receptor determination and permit comparability of data between laboratories.

Background: The aim of this study was to determine whether the induction of progesterone receptors (PR) for estrogen receptors (ER) in variable in breast cancer, whether it differs among pre and post menopausal women and whether the ER/PR quotient may be an index of tumoral biology., Methods: The ER and PR content was determined by enzyme immunoassay in 814 breast tumors and the ER/PR quotient was calculated in the ER+PR+ tumors (n = 395)., Results: ER/PR values < 1 were more frequent in premenopausal women (66%) than in post menopausal women (38%). No influence was observed with regard to age., Conclusions: The highest ER/PR values were found in post menopausal women indicating decreased estrogen receptor transcriptional activity in this subgroup contrary to that found in premenopausal women.

Objective: To study the changes in bound and unbound cytosolic estrogen receptor (ER) and progesterone receptor (PR) in fibroid and myometrium after treatment with gonadotropin-releasing hormone agonists (GnRH-a)., Design: Prospective randomized study., Setting: A tertiary institutional hospital., Patients: Thirty premenopausal women with normal regular menstrual cycles and uterine fibroids., Interventions: Patients were randomized to receive buserelin acetate for 3 months (n = 20) or no treatment (n = 10) before hysterectomy., Main Outcome Measures: Bound and unbound ER and PR., Results: In nontreated women, values of unbound ER and PR in fibroid were higher than in myometrium. There were no differences in total receptors. The total and unbound ER in myometrium was higher in treated than in nontreated women. There were no differences in fibroid., Conclusions: The higher content of unbound hormone receptors in fibroid correlates with an exacerbation of the hormone dependence of this tissue compared with myometrium. The increase of total and unbound ER in myometrium after treatment suggests a higher level of synthesis or a lower level of degradation of receptors in this tissue.