HPV self-sampling among cervical cancer screening users in Spain: A randomized clinical trial of on-site training to increase the acceptability.

A randomized clinical trial was conducted to compare the impact of two different instructions on vaginal self-sampling in its acceptability and willingness for future screening rounds among women attending cervical cancer screening (CCS). From November 2018 to May 2021, women aged 30-65 living in Spain attending CCS were randomized 1:1 in two arms. In the "On-site training arm (TRA)", women took a self-sample at the primary health care centre following provider's instructions. In the "No on-site training arm (NO-TRA)" women only received instructions to take self-sample at home. All women had to return a new sample collected at home one month after the baseline visit and an acceptability questionnaire. The proportion of self-samples returned, and acceptability was computed by the study arm. A total of 1158 women underwent randomization, 579 women per arm. At follow-up, women in TRA were more likely to return the home sample than women in the NO-TRA (82.4% and 75.5% respectively; p = 0.005). Over 87% of all participants favoured home-based self-sampling approach for future CCS, similar by arm. Over 80% of women in both arms chose to collect and return the self-sample at a health centre or pharmacy. Home-based self-sampling was a highly accepted strategy for CCS in Spain. Trying it first with prior on-site training at the health centre significantly increased the sample's return suggesting that a provider's supervision raised confidence and adherence. It is an option to consider when moving to self-sampling in established CCS. Preferred delivery sites most likely contextual. Registration on ClinicalTrials.gov: NCT05314907.

Prevalence and genotype distribution of cervical human papilomavirus infection in the pre-vaccination era: a population-based study in the Canary Islands.

OBJECTIVE: National Spanish studies show that prevalence of cervical human papillomavirus (HPV) infection in the female population is increasingly frequent, with an overall estimate of 14% in women aged 18-65 years. The objective of this study is to know the prevalence and distribution of HPV types in the female population of the Canary Islands prior to the introduction of HPV vaccines and to investigate the associated clinical and sociodemographic factors. METHODS: Based on the Primary Health Care database, a sample of adult women (aged 18-65 years) of Gran Canaria (GC) and Tenerife (TF) stratified into nine age groups was carried out between 2002 and 2007. Women were contacted by postal letter and telephone call and were visited in their primary care centre. A clinical-epidemiological survey was completed and cervical samples were taken for cytological study and HPV detection. HPV prevalence and its 95% CI were estimated, and multivariate analyses were performed using logistic regression to identify factors associated with the infection. RESULTS: 6010 women participated in the study, 3847 from GC and 2163 from TF. The overall prevalence of HPV infection was 13.6% (CI 12.8%-14.5%) and 11.1% (CI 10.3%-11.9%) for high-risk types. The most frequent HPV type was 16 followed by types 51, 53, 31, 42 and 59. HPV types included in the nonavalent vaccine were detected in 54.1% of infected women. Factors associated with an increased risk of infection were: young ages (18-29 years), the number of sexual partners throughout life, not being married, being a smoker, and having had previous cervical lesions or genital warts. CONCLUSIONS: It is confirmed that prevalence of HPV infection in the female population of the Canary Islands is high, but similar to that of Spain, HPV 16 being the most frequent genotype. The determinants of infection are consistent with those of other populations.

Management of endometrial cancer in patients aged 80 years and older: Identifying patients who may benefit from a curative treatment.

OBJECTIVE: The goal of this study was to evaluate the demographic characteristics, pathology, treatment, prognostic factors and survival rates in elderly patients with endometrial cancer, and to compare their results with those of younger ones, in order to define the specific characteristics of this malignancy in this population. STUDY DESIGN: Retrospective analysis of all endometrial cancer patients managed at the University Hospital of the Canary Islands (Spain) between 1990 and 2016. Survival curves were calculated by using the Kaplan-Meier method and compared with the log-rank test. Logistic regression analysis was used to assess the independent effect of different variables on cancer-specific survival. Statistical significance was considered for p < 0.05. RESULTS: The study included 1799 endometrial cancer patients; 170 of them (9.4%) were 80 years old or older. Elderly patients received less surgery (68.2% vs. 92.4%), lymphadenectomy (10.3% vs. 26.2%) and adjuvant treatment (37.1% vs. 51.2%) than younger ones, and presented higher probability of receiving palliative treatment (27.6% vs. 4%). Endometrioid tumors were more frequently diagnosed in younger patients (78.8% vs. 62.9%), while type 2-endometrial cancer was more frequently diagnosed in elderly ones (37.1% vs. 21.2%). Cancer-specific survival in older patients was significantly poorer than in younger ones, with a mean of 61.4 months (95%CI 51.7-71.1) versus 226 months (95%CI 218.9-233.1), respectively. In a multivariate analysis: age, FIGO stage, histology, tumor differentiation and adjuvant treatment were independently associated with survival. CONCLUSION: Although endometrial cancer is more aggressive in older patients, they are less likely to receive optimal treatment, which negatively affects their survival. Specific guidelines for the management of this population, including a comprehensive geriatric assessment, should be developed to improve their prognosis.

Should the Presence of Metastatic Para-Aortic Lymph Nodes in Locally Advanced Cervical Cancer Lead to More Aggressive Treatment Strategies?

STUDY OBJECTIVE: To evaluate risk factors in patients with locally advanced cervical cancer (LACC) undergoing pretherapeutic laparoscopic para-aortic lymphadenectomy (LPL) as well as the progression-free and overall survival rates specifically in the subgroup of patients with metastatic para-aortic lymph nodes (PLNs). DESIGN: Retrospective study conducted on demographic data, pathologic and surgical findings, complications, and disease status recorded for LACC patients undergoing LPL during the period 2009 to 2015. SETTING: Department of Gynecologic Oncology of the Complejo Hospitalario Universitario Insular-Materno Infantil, Canary Islands, Spain (Canadian Task Force Classification II-3). PATIENTS: Women with LACC undergoing pretherapeutic LPL. All patients were treated with definitive chemoradiotherapy after surgery, and those with metastatic PLN received extended lumboaortic radiation therapy. INTERVENTIONS: Survival analysis was performed with the Kaplan-Meier method. Statistical significance was considered for p <.05. MEASUREMENTS AND MAIN RESULTS: The study included 139 patients. The median age was 48 years (range, 28-73). The most frequent histologic type was squamous cell carcinoma (77%), and the most frequent 2009 FIGO stage was IIB (48.2%). LPL identified metastatic PLN in 18.7% of patients (n = 26). The mean overall survival for the whole population, after 23 months of follow-up, was 68.2 months (95% CI, 63-73.4). For patients without para-aortic metastases, the mean survival time was 76.9 months (95% CI, 70.3-80.4), whereas for patients with positive PLNs the median survival time was 21 months (95% CI, 6.1-35.9; p <.0001). A logistic regression analysis revealed that the presence of metastatic PLNs and tumor size (>5 cm) were both independent risk factors for poor survival (OR, 117.5; 95% CI, 11.6-990.2; p <.0001, and OR, 21.5; 95% CI, 2-230.3; p = .01, respectively). CONCLUSION: LACC patients with metastatic PLNs had a poor prognosis and low survival rate. We postulate that this finding could be accounted for by the presence of hidden systemic disease and high recurrence rate after therapy. Efforts should be made to improve available therapeutic strategies for this particular subgroup of patients.

Identification of Defensive Performance Factors in the 2010 FIFA World Cup South Africa.

The aim of this study was to determine the efficacy of defensive play in elite football, to identify variables associated with the direct recovery of ball possession, and to propose a model for predicting the success of defensive transitions. We analyzed 804 transitions in the final stages of the Fedération Internationale Football Association (FIFA) World Cup 2010, and investigated the following variables using univariate, bivariate, and multivariate analyses: duration of defensive transition, possession loss zone, position of players at the start and end of the defensive transitions, defensive organization, general defensive approach, time of the match, position of defense, zone in which the offensive transition ends, match status, and outcome of the defensive transition. We found that the defensive transitions started most frequently in the middle offensive zone (48.9%), with an organized defense set-up (98.8%), and were unsuccessful on 57.2% of occasions. The bivariate analysis showed that the variable most strongly associated with direct recovery of the possession of the ball (p = 0.018) is the area in which the ball is lost, and the multivariate analysis showed that the duration of the defensive transition can be used as a performance indicator, with transitions lasting between 0 and 15 s associated with a higher likelihood of directly recovering the ball. This work has allowed us to identify a pattern of tactical-strategic behavior with major probabilities of success in the defensive transitions. These results will be able to be used by coaches to improve the performance of their teams in this type of situation in the game.

Bariatric Surgery: Does It Play a Role in Fertility-Preserving Treatment Among Obese Young Women With Endometrial Cancer?

We present the case of a 17-year-old nulliparous woman with a history of obesity (body mass index 36.2 kg/m(2)), type 2 diabetes, and polycystic ovary syndrome, who was diagnosed with grade 1 endometrioid adenocarcinoma without radiological evidence of myometrial invasion or metastatic disease. After failure of a fertility-preserving treatment with a levonorgestrel-releasing intrauterine device, bariatric surgery was proposed to treat the obesity and improve control of her type 2 diabetes in an attempt to increase the chances of obtaining response to local treatment. Nine months after laparoscopic sleeve gastrectomy and 18 months after insertion of the intrauterine device, the patient reached normal body weight (body mass index 20.3 kg/m(2)) and showed complete response to treatment. As far as we know, this is the first published case of an adolescent obese patient treated with bariatric surgery concomitantly with fertility-preserving management of endometrial cancer. We propose that bariatric surgery may play a role as an adjuvant therapy in fertility-preserving treatment of endometrial cancer with local progestin, in which it could enhance remission rates and reduce recurrence.

Time trends of human papillomavirus types in invasive cervical cancer, from 1940 to 2007.

Contribution over time of human papillomavirus (HPV) types in human cancers has been poorly documented. Such data is fundamental to measure current HPV vaccines impact in the years to come. We estimated the HPV type-specific distribution in a large international series of invasive cervical cancer (ICC) over 70 years prior to vaccination. Paraffin embedded ICC cases diagnosed between 1940 and 2007 were retrieved from eleven countries in Central-South America, Asia and Europe. Included countries reported to have low-medium cervical cancer screening uptake. Information on age at and year of diagnosis was collected from medical records. After histological confirmation, HPV DNA detection was performed by SPF-10/DEIA/LiPA25 (version1). Logistic regression models were used for estimating the adjusted relative contributions (RC) of HPV16 and of HPV18 over time. Among 4,771 HPV DNA positive ICC cases, HPV16 and HPV18 were the two most common HPVs in all the decades with no statistically significant variations of their adjusted-RC from 1940-59 to 2000-07 (HPV16-from 61.5 to 62.1%, and HPV18-from 6.9 to 7.2%). As well, the RC of other HPV types did not varied over time. In the stratified analysis by histology, HPV16 adjusted-RC significantly increased across decades in adenocarcinomas. Regarding age, cases associated to either HPV16, 18 or 45 were younger than those with other HPV types in all the evaluated decades. The observed stability on the HPV type distribution predicts a high and stable impact of HPV vaccination in reducing the cervical cancer burden in future vaccinated generations.

The nuclear receptor LXRα controls the functional specialization of splenic macrophages.

Macrophages are professional phagocytic cells that orchestrate innate immune responses and have considerable phenotypic diversity at different anatomical locations. However, the mechanisms that control the heterogeneity of tissue macrophages are not well characterized. Here we found that the nuclear receptor LXRα was essential for the differentiation of macrophages in the marginal zone (MZ) of the spleen. LXR-deficient mice were defective in the generation of MZ and metallophilic macrophages, which resulted in abnormal responses to blood-borne antigens. Myeloid-specific expression of LXRα or adoptive transfer of wild-type monocytes restored the MZ microenvironment in LXRα-deficient mice. Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets.

The hMSH2(M688R) Lynch syndrome mutation may function as a dominant negative.

The hMSH2(M688R) mismatch repair (MMR) gene mutation has been found in five large families from Tenerife, Spain, suggesting it is a Lynch syndrome or hereditary non-polyposis colorectal cancer (LS/HNPCC) founder mutation. In addition to classical LS/HNPCC tumors, these families present with a high incidence of central nervous system (CNS) tumors normally associated with Turcot or constitutional mismatch repair deficiency (CMMR-D) syndromes. Turcot and CMMR-D mutations may be biallelic, knocking out both copies of the MMR gene. The hMSH2(M688R) mutation is located in the ATP hydrolysis (ATPase) domain. We show that the hMSH2(M688R)-hMSH6 heterodimer binds to mismatched nucleotides but lacks normal ATP functions and inhibits MMR in vitro when mixed with the wild-type (WT) heterodimer. Another alteration that has been associated with LS/HNPCC, hMSH2(M688I)-hMSH6, displays no identifiable differences with the WT heterodimer. Interestingly, some extracolonic tumors from hMSH2(M688R) carriers may express hMSH2-hMSH6, yet display microsatellite instability (MSI). The functional analysis along with variability in tumor expression and the high incidence of CNS tumors suggests that hMSH2(M688R) may act as a dominant negative in some tissues, while the hMSH2(M688I) is most likely a benign polymorphism.

Laparoscopic extraperitoneal para-aortic lymphadenectomy in the staging of locally advanced cervical cancer: is it a feasible procedure at a peripheral center?

OBJECTIVE: The study's aim was to evaluate the feasibility of laparoscopic extraperitoneal para-aortic lymphadenectomy at a peripheral center for the staging of patients with locally advanced cervical cancer (LACC). METHODS: From March 2009 to January 2011, 30 patients with LACC underwent laparoscopic extraperitoneal para-aortic lymphadenectomy. All patients were treated with definitive radiotherapy tailored according to the staging results. Data on demographics, pathologic findings, surgery, complications, and disease status at follow-up are presented. RESULTS: Patients' mean age was 47.6 years (range, 28-67 years). The mean body mass index was 26.3 (range, 19.1-35.6). Mean operative time was 118.7 minutes (range, 77-195 minutes) with an average of 14.2 lymph nodes removed (range, 5-34). Intraoperative complications were a lumbar artery injury and a bowel injury. No postoperative complications occurred. Mean postoperative hospital stay was 1.9 days (range, 1-6 days). Pathological examination revealed that 26.7% (8/30) of patients had metastatic disease in para-aortic lymph nodes. Two patients with disease at the para-aortic level died 5 and 12 months after diagnosis; both of them developed pulmonary and hepatic metastases. The rest of the patients were free of disease, after completion of the treatment, during a mean follow-up time of 15.6 months (range, 5-27 months). CONCLUSIONS: Laparoscopic extraperitoneal aortic lymphadenectomy is a feasible procedure, even at peripheral centers, that is useful to identify patients with LACC and para-aortic disease and to tailor their treatment. Gynecologic oncologists are encouraged to learn this procedure and offer it to their patients.

Human papillomavirus genotype distribution in cervical cancer cases in Spain. Implications for prevention.

OBJECTIVE: Human papillomavirus (HPV) genotype distribution in invasive cervical cancer (ICC) is critical to guide the introduction and to assess the impact of HPV prophylactic vaccines. This study aims to provide specific information for Spain. METHODS: 1043 histological confirmed ICC cases diagnosed from 1940 to 2007 from six Spanish regions were assembled. HPV DNA detection was performed by SPF(10) broad-spectrum PCR followed by deoxyribonucleic acid enzyme immunoassay and genotyping by reverse hybridization line probe assay (LiPA(25)) (version 1). RESULTS: Of 1043 ICC cases, 904 were HPV DNA positive (adjusted prevalence: 89.1%). The eight most common types, in decreasing order, were HPV 16, 18, 33, 31, 45, 35, 52 and 56, accounting for more than 90% of cases. HPV 16 and 18 contributed to 72.4% of all HPV positive ICC cases. In cervical adenocarcinomas, this contribution increased up to 94%. HPV 16 and 18 relative contributions showed a stable pattern over the 60 year study period. HPV 45, 18 and 16-positive ICC cases presented at younger ages than cases with other HPV types (adjusted mean age: 43.8, 45.2, 52.6 and 57.7 years, respectively). CONCLUSIONS: HPV 16 and 18 accounted together for a 72.4% of positive cases, with no statistically significant changes in their relative contributions over the last decades. In 94% of cervical adenocarcinomas we identified at least one of the two HPV types included in the current vaccines (HPV 16/18). Results suggest a major impact of HPV vaccines on reduction of ICC burden in Spain in the HPV vaccinated cohorts.

Serous and mucinous borderline ovarian tumors: are there real differences between these two entities?

OBJECTIVE: To evaluate the clinical outcome and pathological features of patients with borderline ovarian tumors (BOT) with special emphasis on serous and mucinous histology. STUDY DESIGN: Medical and anatomopathological records were reviewed in the Gynecological Oncology Department of the Canarian University Hospital between 1990 and 2005. Survival rates were analyzed by using the Kaplan-Meier technique. RESULTS: The study included 163 patients. Serous tumors corresponded to 68 cases and mucinous tumors to 91 cases. Eighty-nine percent of patients were at FIGO stage I, 1.2% at stage II and 9.8% at stage III. Serous histology was significantly related to the presence of peritoneal implants (22.4% vs 3.6%; p=0.001), positive peritoneal cytology (35.7% vs 8.5%; p=0.001) and bilaterality (27.9% vs 1.1%, p<0.0001). Event-free survival (EFS) rates at 2, 5 and 10 years were 96.7%, 92.7% and 90.5%, respectively, with a mean survival time of 183 months (CI 95% 172-193). Thirteen recurrence cases were found (7.9%) with a mean time to recurrence of 39.6 months (range 4-140). Overall survival (OS) rates at 2, 5 and 10 years were 100%, 96.4% and 93.6%, respectively, with a mean time of 189 months (CI 95% 179-198). Mucinous BOT were associated with significantly lower OS rates than serous BOT (10 years OS: 88.5% vs 98.2%; p=0.01). CONCLUSIONS: Serous tumors present more unfavorable anatomopathological characteristics but are associated with better prognosis than mucinous tumors. If mucinous BOT diagnosis is retained physicians should be aware that their aggressive potential is not negligible.

Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR.

Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis. The transcriptional pathways that allow macrophages to sense and respond to apoptotic cells are poorly defined. We found that liver X receptor (LXR) signaling was important for both apoptotic cell clearance and the maintenance of immune tolerance. Apoptotic cell engulfment activated LXR and thereby induced the expression of Mer, a receptor tyrosine kinase critical for phagocytosis. LXR-deficient macrophages exhibited a selective defect in phagocytosis of apoptotic cells and an aberrant proinflammatory response to them. As a consequence of these defects, mice lacking LXRs manifested a breakdown in self-tolerance and developed autoantibodies and autoimmune glomerulonephritis. Treatment with an LXR agonist ameliorated disease progression in a mouse model of lupus-like autoimmunity. Thus, activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.

Clinicopathologic analysis of uterine sarcomas from a single institution in the Canary Islands.

OBJECTIVE: To evaluate the clinicopathologic data and prognostic factors for patients with uterine sarcomas treated at a single institution, with special emphasis on malignant mixed müllerian tumors (MMMT). METHODS: Medical and anatomic pathology records were reviewed. Survival rates were analyzed using the Kaplan-Meier method. RESULTS: The study included 89 patients: 48.4% with MMMT; 22.4% with leiomyosarcomas; 20.2% with endometrial stromal sarcomas; and 9% with adenosarcomas. FIGO stages I, II, III, and IV were identified in 57.3%, 9.0%, 22.5%, and 7.8% of patients respectively. Event-free survival rates after 2, 5, and 10 years were 70%, 61%, and 55% respectively, with a median time of 90 months (95% CI, 41-140 months). Overall survival rates after 2, 5, and 10 years were 50%, 45%, and 39% respectively, with a median time of 43 months (95% CI, 3-83 months). Multivariate analysis showed that stage, histology, tumor size, and parity had an independent influence on overall survival. CONCLUSIONS: MMMT are the most aggressive tumors and their behavior strongly resembles that of high-grade endometrial adenocarcinoma. Prognostic factors affecting survival were stage, histology, tumor size, and parity.

Successful term delivery following conservative management for villoglandular papillary adenocarcinoma of the uterine cervix: A case report.

BACKGROUND: Villoglandular papillary adenocarcinoma (VPA) is a rare subtype of adenocarcinoma of the uterine cervix. A conservative surgical approach is considered feasible. Only three cases of VPA and pregnancy have been reported. CASE: A 34-year-old asymptomatic woman was diagnosed of a well-differentiated VPA without extracervical spread of the disease. A cold knife conization was performed. Five years later, the patient became pregnant. The pregnancy developed without complications and was finished with a caesarean delivery, due to nonreassuring fetal status. A healthy child was born. Last control 8 years later showed no evidence of disease. CONCLUSIONS: A successful pregnancy can be completed in patients with VPA without lymph-vascular invasion treated in a conservative way. This management is particularly desirable in young women to preserve reproductive capability.

Differential gene expression profile in endometrioid and nonendometrioid endometrial carcinoma: STK15 is frequently overexpressed and amplified in nonendometrioid carcinomas.

Endometrial carcinoma (EC) comprises at least two types of cancer: endometrioid carcinomas (EECs) are estrogen-related tumors, which are frequently euploid and have a good prognosis. Nonendometrioid carcinomas (NEECs; serous and clear cell forms) are not estrogen related, are frequently aneuploid, and are clinically aggressive. We used cDNA microarrays containing 6386 different genes to analyze gene expression profiles in 24 EECs and 11 NEECs to identify differentially expressed genes that could help us to understand differences in the biology and clinical outcome between histotypes. After supervised analysis of the microarray data, there was at least a 2-fold difference in expression between EEC and NEEC in 66 genes. The 31 genes up-regulated in EECs included genes known to be hormonally regulated during the menstrual cycle and to be important in endometrial homeostasis, such as MGB2, LTF, END1, and MMP11, supporting the notion that EEC is a hormone-related neoplasm. Conversely, of the 35 genes overexpressed in NEECs, three genes, STK15, BUB1, and CCNB2, are involved in the regulation of the mitotic spindle checkpoint. Because STK15 amplification/overexpression is associated with aneuploidy and an aggressive phenotype in other human tumors, we used fluorescence in situ hybridization to investigate whether STK15 amplification occurred in ECs. We found that STK15 was amplified in 55.5% of NEECs but not in any EECs (P