Vulvar High-Grade Squamous Intraepithelial Lesions Treated with Imiquimod: Can Persistence of Human Papillomavirus Predict Recurrence?

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.

Fertility-Sparing Approaches in Atypical Endometrial Hyperplasia and Endometrial Cancer Patients: Current Evidence and Future Directions.

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.

The effect of omitting axillary dissection and the impact of radiotherapy on patients with breast cancer sentinel node macrometastases: a cohort study following the ACOSOG Z0011 and AMAROS trials.

PURPOSE: To report the outcomes of implementing the ACOSOG Z0011 and AMAROS trials relevant to clinical practice, and to define target groups in whom to avoid or recommend axillary radiotherapy (ART). We also aimed to analyse the reduction in morbidity when axillary lymph node dissection (ALND) was omitted. METHODS: A retrospective cohort study of T1-T2 patients with macrometastases at sentinel lymph node (SLN) who were treated between 2011 and 2020. Breast surgery included either lumpectomy or mastectomy. Patients with ≤ 2 positive SLN were divided into two cohorts by whether they received ART or not. Survival outcomes and morbidity were analysed by Kaplan-Meyer curves and Cox-regression, respectively. RESULTS: 260 pN1a patients were included and ALND was avoided in 167 (64.2%). According the Z0011 results, 72 (43.1%) received no further ART; and based on AMAROS criteria 95 (56.9%) received ART. Median follow-up was 54 months. The 5-year overall survival was 96.8% in the non-RT cohort and 93.4% in the RT cohort (p = 0.19), while the respective 5-year disease-free survivals were 100% and 92.3% (p = 1.06). Lymphedema developed in 3.6% of patients after SLNB versus 43% after ALND (OR 20.25; 95%CI 8.13-50.43). Decreased upper-extremity range of motion appeared in 8.4% of patients after SLNB versus 31.2% after ALND (OR 4.95; 95%CI 2.45-9.98%). CONCLUSIONS: Our study confirms that omitting ALND is safe and has high survival rates in patients with T1-T2 tumours and ≤ 2 positive SLNs. Adding ART could be a treatment option for patients who present other risk factors. Avoiding ALND with or without ART was associated with significantly less arm morbidity.

Characterization of the Endometrial MSC Marker Ectonucleoside Triphosphate Diphosphohydrolase-2 (NTPDase2/CD39L1) in Low- and High-Grade Endometrial Carcinomas: Loss of Stromal Expression in the Invasive Phenotypes.

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.

Fertility-Sparing Treatment for Atypical Endometrial Hyperplasia and Endometrial Cancer: A Cochrane Systematic Review Protocol.

INTRODUCTION: Endometrial cancer is the fifth most common cancer in women and atypical endometrial hyperplasia is a precancerous lesion. Obesity is an important risk factor for endometrioid endometrial adenocarcinoma and endometrial hyperplasia. Progesterone is recommended as first-line treatment in endometrial cancer or atypical endometrial hyperplasia in women who wish to preserve fertility, but optimal treatment schedules have not been defined. Metformin or bariatric surgery may also be useful in these women. The effectiveness and safety of fertility-preserving treatments being used for women with atypical endometrial hyperplasia and stage IA grade 1 endometrial cancer is unclear. Therefore, the systematic review aims to determine this point. METHODS: We will search the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, trial registers, conference proceedings, abstracts, cooperative trial groups and reference lists. We will include randomised controlled trials (RCTs) that compare fertility-preserving therapy including orally administered progesterone versus a levonorgestrel-releasing intrauterine system (IUS), metformin, other pharmacological interventions or bariatric surgery, and any of these interventions with womb-removing surgery. Quasi-randomised trials, non-randomised trials and cohort studies will be included. Two review authors will independently assess study eligibility and risk of bias and extract data. The primary outcomes are complete pathologic response and live birth rate. Secondary outcomes include overall survival, progression-free survival, pregnancy rate, need for hysterectomy, adverse events, psychological symptoms and quality of life. PLANNED OUTCOMES: This review aims to clarify the effectiveness and risks of fertility-preserving treatments, including complete pathologic response rate, live birth rates, need for surgical treatment, adverse events, psychological symptoms and quality of life. The broad scope of the review includes the use of progesterone, metformin to reverse insulin resistance, and bariatric surgery or operative hysteroscopy. RESULTS: The results may help to determine the optimal fertility-sparing treatment in endometrial cancer and atypical endometrial hyperplasia. SYSTEMATIC REVIEW REGISTRATION: Prospero 2019 number CRD42019145991.

Predictive factors for omitting lymphadenectomy in patients with node-positive breast cancer treated with neo-adjuvant systemic therapy.

A pathologic complete response (pCR) in the axilla occurs in 30%-40% of patients with initially node-positive breast cancer after neo-adjuvant chemotherapy (NACT). Debate persists about whether to perform systematic axillary lymphadenectomy (ALND) in patients with initial node-positive disease and clinical complete response after NACT. We aimed to identify predictive factors of axillary pCR (ypN0) after NACT. This retrospective study analyzed data for all patients with initial biopsy-proven node-positive disease who underwent ALND after NACT between June 2008 and December 2016 at our institution. Clinical and pathologic features, recurrence and specific mortality rates were compared between patients who achieved an axillary pCR and those who did not (ypN0 vs ypN+, respectively). A total of 331 patients were included, of whom 128 (38.7%) became ypN0 after NACT. Among patients with >2 suspicious axillary lymph nodes before treatment, 54 (38%) achieved ypN0 status. The independent predictors of ypN0 were Ki-67 > 30 (OR 1.98; 95% CI, 1.146-3.381), HER2 positivity (OR 2.6; 95% CI, 1.354-5.108), nonluminal molecular-like subtype (OR 4.15; 95% CI, 2.068-5.108), and clinical complete response, defined as negative clinical and ultrasonographic findings (OR 2.8; 95% CI, 1.110-7.081). After a mean follow-up of 61 months, distant disease-free and overall survival rates were higher in patients with ypN0 disease (HR 4.14; 95% CI, 2.03-8.43) than ypN+ patients. Complete clinical response and the presence of nonluminal molecular-like subtypes independently predicted ypN0. Patients meeting these criteria might be suitable form omitting ALND and just performing targeted axillary procedures to patients meeting these criteria.

Impaired Expression of Ectonucleotidases in Ectopic and Eutopic Endometrial Tissue Is in Favor of ATP Accumulation in the Tissue Microenvironment in Endometriosis.

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.

Mejora coste efectiva en diagnóstico de cáncer endometrial con la incorporación del análisis molecular GynEC(R)-Dx / Cost-effective improvement in endometrial cancer diagnosis by the incorporation of molecular analysis

Objetivo: estimar el número de exploraciones evitables al comparar un algoritmo diagnóstico clásico de la metrorragia posmenopáusica (MPM) frente a un algoritmo que incorpore un test molecular como GynEC(R)-Dx. Material y métodos: estudio de cohortes, prospectivo y aleatorizado por centros realizado en mujeres que presentaron MPM. Las pacientes fueron aleatorizadas a seguir un algoritmo de estudio de MPM clásico vs GynEC(R)-Dx. Se registraron variables demográficas y se comparó el uso de recursos tales como biopsias, ecografías, histeroscopias y visitas entre ambos grupos. Adicionalmente se revalidó la sensibilidad (S), especificidad (E), valor predictivo positivo (VPP) y valor predictivo negativo (VPN) del test. Resultados: se incluyeron un total de 94 pacientes, 51 en grupo clásico y 43 en grupo GynEC(R)-Dx. En el grupo clásico se realizaron 95 exploraciones más respecto al grupo de GynEC(R)-Dx clasificadas en: 11 biopsias, 17 ecografías, 24 histeroscopias y 89 visitas. En el grupo GynEC(R)-Dx se realizaron 92 exploraciones innecesarias consideradas "fuera de protocolo". En la revalidación se observó una S 100%, E 92.5%, VPP 50%, VPN 100%. Conclusiones: la incorporación de un test molecular como GynEC(R)-DX para el estudio de la metrorragia posmenopáusica permite disminuir el número de exploraciones y visitas respecto a los algoritmos convencionales

Objective: The histopathology remains the gold standard to diagnose endometrial cancer (EC) from endometrial biopsy. Molecular tests have recently emerged as a useful tool to classify EC according to its prognosis. However, there is currently no published protocol that includes molecular diagnosis of postmenopausal women with abnormal uterine bleeding (AUB). We hypothesized that the incorporation of a molecular test in the management of postmenopausal women with AUB improves the cost-efectiveness of the diagnostic process. Material and methods: We present a prospective study performed in postmenopausal women who presented AUB between 2009-2014. Seven centers recruited the patients. Three of them follow the classical diagnosis algorithm (group 1) and four centers follow the one that incorporates a molecular test (Gynec(R)-Dx) performed on the remnants of aspirates (group 2). In group 2, when both the endometrial biopsy and the molecular test were negative, the consequent explorations were considered as "out of procotol". Clinical data, number of biopsies, ultrasounds, hysteroscopies and visits were compared between groups. In addition, the sensitivity (S), specificity (E), positive and negative predictive values (PPV and NPV) of the molecular test were calculated. Results: 94 patients were recruited. 51 vs 43 women were included in the classical and the molecular algorithm respectively. There were no differences in age, BMI, parity, use of tamoxifen or hormonal treatment. The detailed outcomes of explorations between classical vs molecular group are shown in Table 1. 324 vs 229 explorations were performed respectively (table 2). In the molecular group, 92 explorations were considered "out of protocol". The test validations showed a 100% S, 92.5% E, 50% PPV and 100% NPV. Conclusions: According to our results, the incorporation of a molecular test for the diagnosis of EC in postmenopausal women who complained with AUB reduces the number of explorations. Consequently, the molecular algorithm is more cost-effective than conventional algorithms

Analysis of the ectoenzymes ADA, ALP, ENPP1, and ENPP3, in the contents of ovarian endometriomas as candidate biomarkers 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.

The Shift From Sentinel Lymph Node Biopsy Performed Either Before or After Neoadjuvant Systemic Therapy in the Clinical Negative Nodes of Breast Cancer Patients. Results, and the Advantages and Disadvantages of Both Procedures.

BACKGROUND: In patients with breast cancer who are candidates for neoadjuvant therapy (NAT), the timing of when to perform sentinel lymph node biopsy (SLNB) remains under discussion. The aim of this study was to compare the advantages and disadvantages of SLNB performed before and after NAT. PATIENTS AND METHODS: One hundred seventy-two patients, T1c to T3 and N0 (clinically and according to ultrasound) candidates for NAT were included. We compared the outcomes of 2 groups: (1) 122 patients of whom SLNB was performed before NAT (pre-NAT) from December 2006 to April 2014; and (2) 50 patients with SLNB performed after NAT (post-NAT) from May 2014 to July 2016. RESULTS: Both groups were homogeneous in baseline patient characteristics. The SLNB was positive in 50 patients [41.7%] (33 macrometastases [66%] and 17 micrometastases [34%]) versus 6 patients [12%] (5 macrometastases [83.3%] and 1 micrometastases [16.7%]) in pre- and post-NAT groups, respectively. The lymphadenectomy was performed in 34 patients [28.3%] versus 4 patients [8%], with an odds ratio of 3.48 (95% confidence interval, 1.3-9.3). The recurrences in the pre-NAT group after a median follow-up of 62 months were 12 systemic, 2 local and systemic, and none axillary. In the post-NAT group were no recurrences after a median follow-up of 16 months. Finally, SLNB after NAT reduces the delay in starting NAT from 24 to 14 days (medians; P < .001) and the identification of the SLNB was in 122 patients [100%] versus 49 patients [98%]. CONCLUSION: SLNB performed after NAT significantly reduces the rate of lymphadenectomies without any increase in recurrences at early follow-up. Furthermore, it allows systemic treatment to be started earlier without interfering in the SLNB identification rate.