Rural residence and health-related quality of life in a sample of Spain perimenopausal women.

BACKGROUND: The prevalence and severity of perimenopausal symptoms are typically associated with multiple factors, including demographic characteristics. The sociodemographic characteristics of women living in rural areas differ from those residing in urban areas, and it has been suggested that these differences could potentially influence the prevalence of symptoms experienced during perimenopause. OBJECTIVES: To evaluate if perimenopausal women living in Spanish rural areas have a higher prevalence of perimenopausal symptoms and assess their influence on health-related quality of life. METHODS: A cross-sectional study was conducted in a sample of 270 perimenopausal women residing in rural and urban areas. The participants completed the Cervantes Scale Short Version and Beck Depression Inventory 2. RESULTS: Perimenopausal women in rural areas reported a higher incidence of perimenopausal symptoms and a lower perception of health-related quality of life compared to those in urban areas, as evidenced by higher scores on the total Cervantes Scale Short Version scale (33.2 (±16.2) vs. 26.4 (±18.1), p = .001). No differences in the Beck Depression Inventory 2 score were detected. CONCLUSIONS: Perimenopausal women residing in rural areas of Spain reported a higher prevalence of perimenopausal symptoms and experienced a poorer Health-Related Quality of Life compared to those living in urban areas of Spain.

Prognostic factors in patients with uterine sarcoma: the SARCUT study.

OBJECTIVE: Uterine sarcomas are a rare and heterogeneous group of malignancies that include different histological sub-types. The aim of this study was to identify and evaluate the impact of the different prognostic factors on overall survival and disease-free survival of patients with uterine sarcoma. METHODS: This international multicenter retrospective study included 683 patients diagnosed with uterine sarcoma at 46 different institutions between January 2001 and December 2007. RESULTS: The 5-year overall survival for leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma, and adenosarcoma was 65.3%, 78.3%, 52.4%, and 89.5%, respectively, and the 5-year disease-free survival was 54.3%, 68.1%, 40.3%, and 85.3%, respectively. The 10-year overall survival for leiomyosarcoma, endometrial stromal sarcoma, undifferentiated sarcoma and adenosarcoma was 52.6%, 64.8%, 52.4%, and 79.5%, respectively, and the 10-year disease-free survival was 44.7%, 53.3%, 40.3%, and 77.5%, respectively. The most significant factor associated with overall survival in all types of sarcoma except for adenosarcoma was the presence of residual disease after primary treatment. In adenosarcoma, disease stage at diagnosis was the most important factor (hazard ratio 17.7; 95% CI 2.86 to 109.93). CONCLUSION: Incomplete cytoreduction, tumor persistence, advanced stage, extra-uterine and tumor margin involvement, and the presence of necrosis were relevant prognostic factors significantly affecting overall survival in uterine sarcoma. The presence of lymph vascular space involvement and administration of adjuvant chemotherapy were significantly associated with a higher risk of relapse.

SUCCOR quality: validation of ESGO quality indicators for surgical treatment of cervical cancer.

OBJECTIVE: To evaluate whether compliance with European Society of Gynaecological Oncology (ESGO) surgery quality indicators impacts disease-free survival in patients undergoing radical hysterectomy for cervical cancer. METHODS: In this retrospective cohort study, 15 ESGO quality indicators were assessed in the SUCCOR database (patients who underwent radical hysterectomy for International Federation of Gynecology and Obstetrics (FIGO) stage 2009 IB1, FIGO 2018 IB1, and IB2 cervical cancer between January 2013 and December 2014), and the final score ranged between 0 and 16 points. Centers with more than 13 points were classified as high-quality indicator compliance centers. We constructed a weighted cohort using inverse probability weighting to adjust for the variables. We compared disease-free survival and overall survival using Cox proportional hazards regression analysis in the weighted cohort. RESULTS: A total of 838 patients were included in the study. The mean number of quality indicators compliance in this cohort was 13.6 (SD 1.45). A total of 479 (57.2%) patients were operated on at high compliance centers and 359 (42.8%) patients at low compliance centers. High compliance centers performed more open surgeries (58.4% vs 36.7%, p<0.01). Women who were operated on at centers with high compliance with quality indicators had a significantly lower risk of relapse (HR=0.39; 95% CI 0.25 to 0.61; p<0.001). The association was reduced, but remained significant, after further adjustment for conization, surgical approach, and use of manipulator surgery (HR=0.48; 95% CI 0.30 to 0.75; p=0.001) and adjustment for adjuvant therapy (HR=0.47; 95% CI 0.30 to 0.74; p=0.001). Risk of death from disease was significantly lower in women operated on at centers with high adherence to quality indicators (HR=0.43; 95% CI 0.19 to 0.97; p=0.041). However, the association was not significant after adjustment for conization, surgical approach, use of manipulator surgery, and adjuvant therapy. CONCLUSIONS: Patients with early cervical cancer who underwent radical hysterectomy in centers with high compliance with ESGO quality indicators had a lower risk of recurrence and death.

Clinical relevance of high-intermediate risk endometrial cancer according to European risk classification.

OBJECTIVE: Risk models in endometrial cancer define prognosis and indicate adjuvant therapy. One of the currently used classifications was designed in 2016 in collaboration with the European Society of Medical Oncology (ESMO), the European Society of Gynecologic Oncology (ESGO), and the European Society of Radiotherapy (ESTRO). A high-intermediate risk group was introduced within the intermediate risk group. The purpose of this study was to evaluate the clinical relevance of this subclassification. METHODS: A multicenter retrospective study was carried out at five international tertiary institutions. Patients diagnosed with intermediate risk endometrial cancer on the basis of definitive pathology findings were included. Patients were stratified into intermediate and high-intermediate risk groups. Incidence of nodal metastases, and disease free and overall survival were compared between the two risk groups in univariate and multivariate analysis. RESULTS: 477 patients were included: 325 (68%) patients were identified as intermediate and 152 (32%) as high-intermediate endometrial cancer patients. Nodal metastases were found in 18 patients (11.8%) in the high-intermediate risk endometrial cancer group and 16 patients (4.9%) in the intermediate risk group. Lymphovascular space invasion was found to be a strong predictive factor of lymph node involvement. High-intermediate risk was found to be an independent factor of disease free survival (hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00 to 3.08; p=0.050) and overall survival (HR 1.99; 95% CI 1.10 to 3.60; p=0.022) in the multivariate analysis. CONCLUSIONS: The study validates the clinical significance of the intermediate risk endometrial cancer subclassification. Prognosis for high-intermediate risk endometrial cancer was significantly poorer. The prevalence of lymph node metastases was higher in this group of patients.

Vascular Endothelial Growth Factor (VEGF) Polymorphisms and Serum VEGF Levels in Women With Epithelial Ovarian Cancer, Benign Tumors, and Healthy Ovaries.

OBJECTIVE: This study analyzed the relation of 5 single-nucleotide polymorphisms (SNPs) in the VEGF (vascular endothelial growth factor) gene in patients with epithelial ovarian cancer (EOC), compared with patients carrying benign tumors or healthy ovaries. We studied serum VEGF levels and the relation with SNPs and association between VEGF SNPs and haplotypes with progression-free survival (PFS) in patients with cancer. METHODS: The genotyping of VEGF gene polymorphisms (-2578 C/A, -1154 G/A, -460 T/C, +405 G/C, +936 C/T) was performed in DNA isolated from blood samples of 100 women. The different genotypes were evaluated by quantitative real-time polymerase chain reaction. Vascular endothelial growth factor protein concentration was assessed in serum using solid-phase sandwich enzyme-linked immunosorbent assay. RESULTS: We found statistically significant differences in the distribution of VEGF genotypes among the 3 groups of patients: -2578 C/A between those with EOC and healthy ovary (P = 0.04), -460 T/C between those with EOC and healthy ovary (P = 0.03), and -460 T/C between those with benign tumors and healthy ovary (P = 0.02). Vascular endothelial growth factor serum levels were analyzed in patients with EOC. Higher levels were found in patients with clear cell carcinoma compared with those with serous, mucinous, or endometrioid tumors (P < 0.05). No clear association was observed between VEGF SNPs and serum VEGF levels. There was no significant correlation between VEGF SNPs and PFS. In haplotype analysis, CGTCT and CGTGT showed worse prognosis without reaching the statistical significance. CGCGC and AGTGC haplotypes had statistically significant differences among patients with EOC, benign tumors, and healthy ovaries (Ps = 0.046 and 0.041, respectively). CONCLUSIONS: The distribution of VEGF genotypes was different in patients with EOC, compared with those with benign tumors or women with healthy ovaries. Vascular endothelial growth factor serum levels were higher in patients with clear cell carcinoma. No correlation was found with improved PFS, but CGTCT and CGTGT haplotypes showed worse prognosis.

Value of colposcopy with dynamic spectral imaging in the detection and evolution of high-grade cervical lesions.

OBJECTIVE: To analyze the performance of colposcopy assisted with dynamic spectral imaging (CC-DSI) compared to conventional colposcopy (CC) in diagnosing cervical intraepithelial neoplasia 2+ (CIN2+). METHODS: In total, 973 consecutive women were referred for colposcopy between 2012 and 2016 and were examined simultaneously by CC and CC-DSI; 877 were eligible. Comparisons between CC and CC-DSI were performed against the histological diagnosis performed by either punch biopsy or loop electrosurgical excision procedure (LEEP). RESULTS: In final histology, 494 women had no CIN, 250 had CIN1 and 133 had CIN2+. The sensitivity to identify women with CIN2+ was significantly higher for CC-DSI compared to CC for the entire group and in the subgroup of 675 women referred with ASCUS or LSIL. In women with HPV16/18 infections, the sensitivity of CC increased with the addition of DSI from 53% to 79% (p < 0.001). Using a multivariant Cox regression model, CC-DSI was an independent factor for progression of the cervical lesions (HR: 2.29, 95% CI 1.07-4.90). Other predictive factors were the number of sexual partners (HR: 1.05, 95% CI: 1.01-1.09) and anal intercourse (HR: 2.45, 95% CI 1.23-5.02). CONCLUSION: CC-DSI improves the ability to detect cervical lesions compared to CC and could help predict their potential to progress.

Risk Factors Associated with CIN2+ in Spanish Patients with L-SIL/ASCUS Cytology Collected from a Madrid Hospital.

The management of patients with L-SIL/ASCUS cytology is controversial and not clearly standardized. OBJECTIVE: To analyze the risk factors associated with H-SIL/CIN2+ in a cohort of patients with ASCUS or L-SIL in a Pap smear. METHODS: Between 2012 and 2022, 1259 eligible women with ASCUS/L-SIL were referred for colposcopy. The risk factors associated with H-SIL/CIN2+ were analyzed. The colposcopic study, conventional or assisted with dynamic spectral imaging (DSI), was performed in all cases. Guided biopsies were performed in cases of abnormal examination or random biopsies when no lesions were found. A LEEP was performed in H-SIL/CIN2+ results or persistent LSIL/CIN. RESULTS: A normal or metaplastic specimen was found in 750 women (63.2%), LSIL/CIN1 in 346 (29.1%), and H-SIL/CIN2+ in 92 (7.7%). The presence of HR-HPV (OR = 2.1; IC 95% = 1.4-3.2), smoking habits (OR = 2.2; IC 95% = 1.4-3.5), and the performance of DSI combined with colposcopy (OR = 0.6; IC 95% = 0.37-0.83) were the factors associated with the detection of H-SIL/CIN2+. A summative effect of HR-HPV and smoking habit (OR = 2.9; IC 95% = 1.7-5.0) was observed in the detection of H-SIL/CIN2+. In multivariate analysis, the presence of HPV 16/18 was the unique independent factor associated with H-SIL/CIN2+. CONCLUSION: In women carrying an ASCUS/LSIL in the Pap smear, the unique independent factor predictive of H-SIL/CIN2+ is the presence of the HPV 16/18 genotype. Smoking women carrying ASCUS/LSIL with HR-HPV should be targeted for stricter follow-up to avoid an unsuspected H-SIL/CIN2+.

Effectiveness of Prophylactic Human Papillomavirus Vaccine in the Prevention of Recurrence in Women Conized for HSIL/CIN 2-3: The VENUS Study.

Background: Recent data have shown that the human papillomavirus (HPV) vaccine could impact on a decrease in high-grade cervical intraepithelial lesions (HSIL) in women who have undergone surgical treatment. This study aimed to evaluate the efficacy of human papilloma virus (HPV) vaccination against persistent/recurrent disease in patients undergoing conization for high-grade squamous intraepithelial lesion/cervical intraepithelial neoplasia-grade 2-3 (HSIL/CIN 2-3). Methods: From January 2009 to March 2019, 563 patients with HSIL/CIN 2-3 underwent conization. The population was divided into two groups according to vaccination status: vaccinated-group (V-Group) and non-vaccinated-group (NV-Group). Bivalent or quadrivalent vaccines were administered indiscriminately. A follow-up was scheduled every 6-12 months according to clinical guidelines. The mean follow-up was 29.6 vs. 36.5 months in the V-group and NV-group, respectively. Results: 277 (49.2%) women were vaccinated, while 286 (50.8%) were not. Overall, persistent/recurrent HSIL/CIN 2-3 was presented by 12/277 (4.3%) women in the V-Group and 28/286 (9.8%) in the NV-Group (HR: 0.43, 95% Confidence interval 0.22-0.84, p = 0.014). Vaccination was associated with a 57% reduction in HSIL persistence/recurrence after treatment. When no disease was present in the first 6-month follow-up visit, persistence/recurrence rates were very low in both groups: 1.1% in the V-Group vs. 1.5% in the NV-Group (p > 0.05). The factor associated with a high-risk of HSIL persistence/recurrence was the presentation of a positive co-test in the first control after treatment (p < 0.001). Conclusions: Our results corroborate the benefit of HPV vaccination in woman treated for HSIL/CIN 2-3, showing a reduction of persistent/recurrent HSIL/CIN 2-3.

Quadrivalent Human Papillomavirus Vaccine Effectiveness after 12 Years in Madrid (Spain).

A fully government-funded human papillomavirus (HPV) vaccination program started in 2007 in Spain (only 11-14-year-old girls). The first of those vaccinated cohorts, with the quadrivalent vaccine (Gardasil), turned 25 years old in 2018, the age at which cervical cancer screening begins in Spain. The current study could provide the first evidence about the effectiveness of the quadrivalent vaccine against HPV in Spain and the influence of age of vaccination. The present ambispective cohort study, which was conducted on 790 women aged 25 and 26 years old, compares the rate of HPV prevalence and cytologic anomaly according to the vaccination status. The overall infection rate was 40.09% (vaccinated group) vs. 40.6% (non-vaccinated group). There was a significant reduction in the prevalence of HPV 6 (0% vs. 1.3%) and 16 (2.4% vs. 6.1%), and in the prevalence of cytological abnormalities linked to HPV16: Atypical Squamous Cells of Undetermined Significance (ASCUS) (2.04% vs. 14%), Low-grade Squamous Intraepithelial Lesions (LSIL) (2.94% vs. 18.7%) and High-grade Squamous Intraepithelial Lesion (HSIL) (0% vs. 40%), in the vaccinated group vs. the non-vaccinated group. Only one case of HPV11 and two cases of HPV18 were detected. The vaccine effectively reduces the prevalence of vaccine genotypes and cytological anomalies linked to these genotypes.

HE4 tumor marker as a predictive factor for lymphatic metastasis in endometrial cancer.

Endometrial cancer is the most common genital cancer in high-resource countries. Treatment is essentially surgical, but the role of lymphadenectomy in the treatment of low-stage and low-grade tumors has not been defined. Although no tumor factors have been validated for use as preoperative prognostic markers of endometrial cancer at yet, human epididymis protein 4 (HE4) has received much interest as a potential diagnostic and prognostic tumor marker. Since 2008, several studies have explored its utility in the management of endometrial cancer: HE4 may be a useful preoperative prognostic marker because it is associated with lymphatic metastasis and other unfavorable factors in endometrial cancer. In addition, some studies have explored a HE4 cutoff value to classify patients according to lymph node involvement. HE4 might be beneficial as a serum marker that helps clinicians in the decision-making algorithm for treatment of endometrial cancer, enabling them to perform individualized operations and decrease the adverse effects of unnecessary surgery.

Thromboprophylaxis in gynecologic cancer surgery: Is extended prophylaxis with low molecular weight heparin justified?

OBJECTIVE: Evidence on the optimal duration of thromboprophylaxis with low molecular weight heparin after gynecologic cancer surgery is scarce and the benefits of extended prophylaxis have not been validated specifically in these patients. The aim of this study is to assess the efficacy and safety of postoperative venous thromboembolism (VTE) prophylaxis with enoxaparin 40 mg for 28 days, as recommended by international guidelines, compared to 7 days in patients undergoing surgery for gynecologic cancer. STUDY DESIGN: Prospective cohort study compared to a historic cohort of women who underwent surgery for gynecologic cancer in our center between 2004 and 2014. Pre- and postoperative screening with a routine duplex scan was done in the prospective cohort. Comparative analysis of comorbidity, surgical technique and incidence of VTE, as well as prognostic factors of events and mortality. RESULTS: N:571 patients (28 days: 207, 7 days: 364). No significant differences were identified between groups in regard to the factors related to VTE in our series. There were no differences in VTE incidence between groups after one month (1.9% vs 1.4%; p = 0.729), 90 days (2.4% vs 2.5%; p > 0.99) or during follow-up (Breslow p = 0.156). No deaths due to VTE at 90 days were recorded. Only one case of asymptomatic DVT was identified in the screening with duplex. The incidence of postoperative bleeding was similar in both groups (0.5% vs 2.2%; p = 0.166). The presence of a history of VTE was the only independent risk factor for VTE after one month (OR 14.31 CI 95% 2.67-76.87; p = 0.002) and 90 days (OR 8.27 CI 95% 1.65-41.45; p = 0.010). No differences were identified regarding age, other comorbidities, type of tumor, stage, surgical approach, reintervention or adjuvant therapy in the multivariate analysis. CONCLUSION: Extended prophylaxis for 28 days with enoxaparin did not improve the rates of VTE following gynecologic oncological surgery in our series compared to the 7-day therapy, although neither was this extended duration associated with adverse events or mortality.

[Overexpression and prognostic value of p53 and HER2/neu proteins in benign ovarian tissue and in ovarian cancer]. / Grado de expresión y valor pronóstico de las proteínas p53 y HER2/neu en el tejido ovárico benigno y en el cáncer de ovario.

BACKGROUND AND OBJECTIVE: To investigate the prognostic value of p53 and HER2/neu overexpression in epithelial ovarian cancer (EOC). PATIENTS AND METHOD: p53 and HER2/neu immunostaining were performed in 198 tissue samples, 124 EOC, 44 benign ovarian tumors and 30 normal ovaries. Nuclear p53 and membranous HER2/neu immunostaining were evaluated. RESULTS: Neither p53 nor HER2/neu overexpression was seen in the benign ovarian tumors. HER2/neu immunostaining was observed in one normal ovary. P53 overexpression was found in 25% EOC and was related with advanced stage, endometrioid, clear cell and undifferentiated types, grade G3, and sub-optimal surgery. HER2/neu immunostaining was observed in 24.2% and it was associated with advanced stage, clear cell and undifferentiated types, and suboptimal surgery. Both, p53 and HER2/neu overexpression decreased overall and progression-free survival, but in the multivariant analysis, only HER2/neu overexpression was an independent prognostic factor of overall survival (RR = 2.8; 95% confidence interval [CI], 1.2-5.6) and recurrence (RR = 2.8; 95% CI, 1.1-7.1). Simultaneous p53 and HER2/neu overexpression made the prognosis worse (p < 0.01). CONCLUSIONS: HER2/neu overexpression (but not p53 overexpression) is a major prognostic factor in EOC.

[Third generation selective estrogen receptor modulators benefits beyond bone: effects on breast]. / Beneficios extraóseos de los moduladores selectivos del receptor estrogénico de tercera generación: efectos sobre la mama.

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. Thus, ospemifen, arzoxifene, lasofoxifene and bazedoxifene (BZA) appeared as third-generation SERMs. Among all them, only BZA reached the stage of clinical use. BZA has been shown to have an anti-estrogen effect in experimental studies, but not a protective effect on clinical breast cancer in pivotal clinical trials (301 and extensions). However, in these studies comparing BZA versus RLX and placebo, RLX has not shown the expected preventive effect on breast cancer. This lack of effect can be the consequence of the size and characteristics of BZA's studies in a population with low incidence of breast cancer.

[Third generation selective estrogen receptor modulators: benefits beyond bone. II, endometrial action]. / Beneficio extraóseo de los moduladores selectivos del receptor estrogénico de tercera generación: II, acción en el endometrio.

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or third-generation SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450mg of CEE.

Beneficios extraóseos de los moduladores selectivos del receptor estrogénico de tercera generación: efectos sobre la mama / Third generation selective estrogen receptor modulators benefits beyond bone: effects on breast

Los selective estrogen receptor modulators (SERM, «moduladores selectivos del receptor estrogénico») son sustancias con efecto estrogénico/antiestrogénico que actúan de forma distinta según el tejido y su composición. Desde el descubrimiento de que tamoxifeno y raloxifeno (RLX) presentaban un efecto preventivo del cáncer mamario, se ha emprendido la búsqueda del SERM ideal. Así, aparecieron ospemifeno, arzoxifeno, lasofoxifeno y bazedoxifeno (BZA) como SERM de tercera generación. De todos ellos, tan solo BZA ha alcanzado la etapa de utilización clínica. Se dispone de datos experimentales y clínicos sobre ca´ncer de mama tanto para RLX como para BZA. RLX disminuye significativamente la incidencia de cáncer de mama con receptores estrogénicos positivos en mujeres osteoporóticas posmenopaúsicas. BZA ha demostrado actuar como un antagonista de los estrógenos en estudios experimentales, pero no un efecto protector del cáncer de mama en sus estudios de referencia (301 y extensiones). Sin embargo, en estos estudios que comparan BZA frente a RLX y placebo, RLX tampoco ha demostrado la acción preventiva del cáncer de mama esperada. Es posible que la explicación resida en que estos datos reflejen un efecto estadístico motivado porque los estudios con BZA se han diseñado en una población con baja incidencia de carcinoma mamario (AU)

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. Thus, ospemifen, arzoxifene, lasofoxifene and bazedoxifene (BZA) appeared as third-generation SERMs. Among all them, only BZA reached the stage of clinical use. BZA has been shown to have an anti-estrogen effect in experimental studies, but not a protective effect on clinical breast cancer in pivotal clinical trials (301 and extensions). However, in these studies comparing BZA versus RLX and placebo, RLX has not shown the expected preventive effect on breast cancer. This lack of effect can be the consequence of the size and characteristics of BZA’s studies in a population with low incidence of breast cancer (AU)

Beneficio extraóseo de los moduladores selectivos del receptor estrogénico de tercera generación: II, acción en el endometrio / Third generation selective estrogen receptor modulators: benefits beyond bone. II, endometrial action

Los selective estrogen receptor modulators (SERM, «moduladores selectivos del receptor estrogénico») son moléculas que se vinculan a los receptores de estrógenos ejerciendo un efecto estrogénico o antiestrogénico, según su estructura y el tipo de tejido. Desde el descubrimiento del efecto preventivo en cáncer de mama del tamoxifeno y el raloxifeno (RLX), el SERM ideal sería el que indujera efectos estrogénicos a nivel óseo o en el sistema nervioso central y antiestrogénicos en la mama y el endometrio. Sin embargo, uno de los inconvenientes más importantes para la consolidación de tamoxifeno ha sido su relación con la aparición de cáncer de endometrio. Por ello, se inicia la búsqueda de una molécula con efectos neutros o protectores a este nivel. Así aparecieron ospemifeno, arzoxifeno, lasofoxifeno (LFX) y bazedoxifeno (BZA) como SERM de tercera generación. De todos ellos, tan solo BZA ha alcanzado la etapa de utilización clínica. Los datos experimentales y clínicos tanto para RLX como para los SERM de tercera generación de los que se dispone de información (BZA y LFX) muestran neutralidad o incluso antagonismo frente a los estrógenos a nivel endometrial. El BZA ha demostrado un comportamiento equivalente al vehículo en distintas condiciones experimentales y actúa como un antagonista de los estrógenos en diseños en los que se coadministran estradiol o estrógenos equinos conjugados (EEC). En los estudios de referencia a 7 años se detectaron diferencias significativas en la incidencia de adenocarcinoma de endometrio a favor de BZA comparado con placebo. En un ensayo clínico para valorar en mujeres posmenopaúsicas el efecto de la combinación de EEC y BZA sobre la sintomatología, se comprobó la capacidad de dosis de BZA de 20 mg o superiores para evitar la presentación de hiperplasia inducida por 0,625 o 0,450 de EEC (AU)

The selective estrogen receptor modulators (SERMs) are substances with estrogenic/anti-estrogen effect that act differently depending on the tissue and composition. Since the discovery that tamoxifen and raloxifene (RLX) had a breast cancer preventive effect, the search for the perfect SERM has been the goal. The evidence that tamoxifen significantly increased the risk of endometrial cancer as compared to placebo made this tissue the center of interest in developing new SERMs. Thus, ospemifen, arzoxifene, lasofoxifene (LFX) and bazedoxifene (BZA) appeared as third-generation SERMs but only BZA reached the stage of clinical use. Both experimental and clinical data available on the effects of RLX or thirdgeneration SERMs reaching clinical stage (LFX and BZA) show either neutrality or anti-estrogenic effects at endometrial level. BZA has shown to be equivalent to vehicle in several experimental conditions and acts as anti-estrogen in models were estrogens (conjugated equine estrogens [CEE] or E2) were co-administered. In a 7 years pivotal study the incidence of endometrial adenocarcinoma has been significantly lower in the BZA than in the placebo group. Moreover, in a clinical trial to evaluate the ability of a combination of BZA and CEE to prevent hot flushes in symptomatic postmenopausal women, doses of 20 mg or higher of BZA have significantly decreased the risk of presenting endometrial hyperplasia when co-administered with either 0.650 or 0.450 mg of CEE (AU)

La inmunosupresión es un factor mayor de riesgo en la recidiva de las lesiones del tracto genital inferior asociadas al virus del papiloma humano / Immunosuppression is a major prognostic factor in recurrence of human papillomavirus-associated lesions of the lower genital track

Objetivo: Analizar las características de las lesiones preneoplásicas del tracto genital inferior (TGI) y los factores asociados a su recidiva. Material y métodos: Se estudió a 376 mujeres tratadas de algún tipo de neoplasia intraepitelial del TGI, en la década de los 90. Las lesiones se agruparon en cervicales y vulvares, y estas en lesiones de alto (CIN II-III o VIN) y de bajo grado (CIN I o atipia vulvar por virus del papiloma humano [AV-VPH]). El tratamiento de las CIN se realizó con asa diatérmica y para las lesiones vulvares fue la resección con bisturí frío y/o láser CO2.ResultadosLa edad media de las mujeres fue 32 años. La multicentricidad fue identificada en el 57% de las CIN y en el 87% de las lesiones vulvares. Un 10% de las mujeres en ambos grupos presentó algún tipo de inmunosupresión. Se identificó VPH de riesgo alto en el 25% de los casos. Con un seguimiento medio de 21 meses, la recidiva global de la CIN fue del 17% y la acumulada a 5 años del 47%. En las lesiones vulvares fue del 15 y el 54%, respectivamente. En ambos grupos lesionales la recidiva apareció en los primeros 3 años en más del 90% de los casos y se asoció a la inmunosupresión y el genotipo viral de riesgo alto, aunque el único factor de riesgo independiente en el análisis multivariante fue la inmunosupresión. Ninguna paciente progresó a cáncer invasor. Conclusiones: La inmunosupresión es el factor riesgo predictivo más importante de recurrencia. Las conductas orientadas a estimular la inmunidad podrían ser eficaces en prevención de la recurrencia de la enfermedad por el VPH (AU)

Objective: To analyze the characteristics of preneoplastic lesions of the lower genital tract (LGT) and the factors associated with their recurrence. Material and methods: A total of 376 women treated for some type of intraepithelial neoplasm of the LGT between 1990 and 1999 were studied. The lesions were classified into cervical intraepithelial neoplasms (CIN) and vulvar intraepithelial neoplasms (VIN) and were further classified into high-grade lesions (CIN 2-3 or VIN) and low-grade lesions (CIN 1 or human papillomavirus vulvar atypia [HPV-VA]). Treatment of cervical lesions consisted of CO2 laser and / or loop electrosurgical excision while that of vulvar lesions consisted of cold-knife local excision and / or CO2 laser. Results: The mean age of women was 32 years. Multicentric disease was found in 57% of CIN lesions and in 87% of vulvar lesions. Ten percent of women in both groups had some type of immunosuppression. High-risk HPV was identified in 25% of patients. With a mean follow-up of 21 months, the overall CIN recurrence was 17% and accumulated recurrence rate at 5 years was 47%. In vulvar lesions, these values were 15% and 54%, respectively. In both groups, more than 90% of recurrences occurred in the first 3 years, and relapse was associated with immunosuppression and high-risk viral genotype. In multivariate analysis, the only independent risk factor was immunosuppression. None of the lesions progressed to invasive cancer. Conclusions: The most important risk factor predictive of recurrence is immunosuppression. Measures to stimulate immunity could be effective in preventing HPV-related disease (AU)

Grado de expresión y valor pronóstico de las proteínas p53 y HER2/neu en el tejido ovárico benigno y en el cáncer de ovario / Overexpression and prognostic value of p53 and HER2/neu proteins in benign ovarian tissue and in ovarian cancer

Fundamento y objetivo: Determinar la expresión de las proteínas p53 y HER2/neu en el tejido ovárico y analizar su valor pronóstico en el cáncer de ovario. Pacientes y método: Se estudió a un total de 198 pacientes, 124 con cáncer epitelial de ovario (CEO), 44 con tumores benignos y 30 con ovarios normales. Se midió la expresión nuclear de p53 y en membrana de HER2/neu mediante técnicas inmunohistoquímicas. Resultados: No se observó sobreexpresión de p53 o HER2/neu en los tumores benignos de ovario. Sólo hubo sobreexpresión de HER2/neu en un ovario normal. El 25% de los casos de CEO mostró sobreexpresión de p53 y ésta se relacionó con los estadios avanzados, con los tipos histológicos endometrioides, de células claras e indiferenciados, con el grado G3 y con la citorreducción subóptima. El 24,2% de los CEO sobreexpresó HER2/neu y se relacionó con los tumores en estadio avanzado, con los tipos histológicos de células claras e indiferenciado y con una citorreducción subóptima. Tanto la sobreexpresión de p53 como la de HER2/neu se asociaron a una reducción de la supervivencia global y libre de enfermedad de las pacientes con CEO; sin embargo, en el estudio multivariable sólo la sobreexpresión de HER2/neu fue un factor independiente predictivo de menor supervivencia, tanto global (riesgo relativo [RR] = 2,8; intervalo de confianza [IC] del 95%, 1,2-5,6) como libre de enfermedad (RR = 2,8; IC del 95%, 1,1-7,1). La sobreexpresión conjunta de ambas proteínas empeoró aún más el pronóstico de estas pacientes (p < 0,01). Conclusiones: La sobreexpresión de HER2/neu es un factor pronóstico importante en el CEO, no así la sobreexpresión de p53

Background and objetive: To investigate the prognostic value of p53 and HER2/neu overexpression in epithelial ovarian cancer (EOC). Patients and method: p53 and HER2/neu immunostaining were performed in 198 tissue samples, 124 EOC, 44 benign ovarian tumors and 30 normal ovaries. Nuclear p53 and membranous HER2/neu immunostaining were evaluated. Results: Neither p53 nor HER2/neu overexpression was seen in the benign ovarian tumors. HER2/neu immunostaining was observed in one normal ovary. P53 overexpression was found in 25% EOC and was related with advanced stage, endometrioid, clear cell and undifferentiated types, grade G3, and sub-optimal surgery. HER2/neu immunostaining was observed in 24.2% and it was associated with advanced stage, clear cell and undifferentiated types, and suboptimal surgery. Both, p53 and HER2/neu overexpression decreased overall and progression-free survival, but in the multivariant analysis, only HER2/neu overexpression was an independent prognostic factor of overall survival (RR = 2.8; 95% confidence interval [CI], 1.2-5.6) and recurrence (RR = 2.8; 95% CI, 1.1-7.1). Simultaneous p53 and HER2/neu overexpression made the prognosis worse (p < 0.01). Conclusions: HER2/neu overexpression (but not p53 overexpression) is a major prognostic factor in EOC