Transcriptome analysis of adenomyosis eutopic endometrium reveals molecular mechanisms involved in adenomyosis-related implantation failure and pregnancy disorders.

BACKGROUND: Women with adenomyosis are characterized by having defective decidualization, impaired endometrial receptivity and/or embryo-maternal communication, and implantation failure. However, the molecular mechanisms underlying adenomyosis-related infertility remain unknown, mainly because of the restricted accessibility and the difficult preservation of endometrial tissue in vitro. We have recently shown that adenomyosis patient-derived endometrial organoids, maintain disease-specific features while differentiated into mid-secretory and gestational endometrial phase, overcoming these research barriers and providing a robust platform to study adenomyosis pathogenesis and the associated molecular dysregulation related to implantation and pregnancy disorders. For this reason, we aim to characterize the dysregulated mechanisms in the mid-secretory and gestational endometrium of patients with adenomyosis by RNA-sequencing. METHODS: Endometrial organoids were derived from endometrial biopsies collected in the proliferative phase of women with adenomyosis (ADENO) or healthy oocyte donors (CONTROL) (n = 15/group) and differentiated into mid-secretory (-SECorg) and gestational (-GESTorg) phases in vitro. Following RNA-sequencing, the significantly differentially expressed genes (DEGs) (FDR < 0.05) were identified and selected for subsequent functional enrichment analysis and QIAGEN Ingenuity Pathway Analysis (IPA). Statistical differences in gene expression were evaluated with the Student's t-test or Wilcoxon test. RESULTS: We identified 1,430 DEGs in ADENO-SECorg and 1,999 DEGs in ADENO-GESTorg. In ADENO-SECorg, upregulated genes included OLFM1, FXYD5, and RUNX2, which are involved in impaired endometrial receptivity and implantation failure, while downregulated genes included RRM2, SOSTDC1, and CHAC2 implicated in recurrent implantation failure. In ADENO-GESTorg, upregulated CXCL14 and CYP24A1 and downregulated PGR were related to pregnancy loss. IPA predicted a significant inhibition of ID1 signaling, histamine degradation, and activation of HMGB1 and Senescence pathways, which are related to implantation failure. Alternatively, IPA predicted an inhibition of D-myo-inositol biosynthesis and VEGF signaling, and upregulation of Rho pathway, which are related to pregnancy loss and preeclampsia. CONCLUSIONS: Identifying dysregulated molecular mechanisms in mid-secretory and gestational endometrium of adenomyosis women contributes to the understanding of adenomyosis-related implantation failure and/or pregnancy disorders revealing potential therapeutic targets. Following experimental validation of our transcriptomic and in silico findings, our differentiated adenomyosis patient-derived organoids have the potential to provide a reliable platform for drug discovery, development, and personalized drug screening for affected patients.

Structural Similarities, in Relation with the Cross-Reactivity, of Hymenoptera Allergenic Dipeptidyl Peptidases IV-An Overall Comparison Including a New Dipeptidyl Peptidase IV Sequence from Vespa velutina.

(1) Background: Dipeptidyl Peptidases IV (DPPIVs), present in many organisms, are minor components in the venoms of Hymenoptera, where they have been identified as cross-reactive allergenic molecules. Considering that the structure of homologous DPPIVs is well characterized, we aimed to explain which regions have higher similarity among these proteins and present a comparison among them, including a new Vespa velutina DPPIV sequence. Moreover, two cases of sensitization to DPPIVs in wasp- and honeybee-sensitized patients are presented. (2) Methods: Proteomic analyses have been performed on the venom of the Asian hornet Vespa velutina to demonstrate the sequence of its DPPIV (allergen named Vesp v 3, with sequence accession number P0DRB8, and with the proteomic data available via ProteomeXchange with the identifier PXD046030). A comparison performed through their alignments and analysis of the three-dimensional structure showed a region with higher similarity among Hymenoptera DPPIVs. Additionally, ImmunoCAP™ determinations (including specific inhibition experiments), as well as IgE immunoblotting, are performed to demonstrate the allergenicity of Api m 5 and Ves v 3. (3) Results and Conclusions: The data presented demonstrate that the similarities among Hymenoptera DPPIVs are most likely localized at the C-terminal region of these enzymes. In addition, a higher similarity of the Vespa/Vespula DPPIVs is shown. The clinical cases analyzed demonstrated the allergenicity of Api m 5 and Ves v 3 in the sera of the allergic patients, as well as the presence of this minor component in the preparations used in venom immunotherapy.

Association of blood cadmium and lead levels with self-reported reproductive lifespan and pregnancy loss: The national health and nutrition examination survey 1999-2018.

Cadmium and lead are known to interfere with the endocrine function. Thus, hormonally regulated processes such as menarche, menopause and pregnancy are likely influenced by chronic exposure to these metals. In US post-menopausal women, who already completed their reproductive lifespan, we evaluated the association between blood cadmium and lead levels with self-reported reproductive lifespan and personal history of pregnancy loss. We selected 5317 post-menopausal women participating in the National Health and Nutrition Examination Survey (NHANES), 1999-2018. Blood cadmium and lead levels were measured by inductively coupled plasma mass spectrometry. Reproductive lifespan was defined as the number of years between self-reported age at menarche and menopause. Personal history of pregnancy loss was defined as number of self-reported pregnancy losses out of the self-reported number of pregnancies. The fully adjusted mean difference in reproductive lifespan (95% confidence interval [CI]) comparing the 80th to the 20th percentiles of blood cadmium and lead distributions was, respectively, 0.50 (0.10, 0.91) and 0.72 (0.41, 1.03) years. Ever smoker showed stronger association of blood lead with reproductive lifespan. For self-reported pregnancy loss, the corresponding fully adjusted relative prevalence (95% CI) was 1.10 (0.93, 1.31) for cadmium and 1.10 (1.00, 1.21) for lead, and remained similar after additional adjustment for reproductive lifespan. In never smokers, the relative prevalence was 1.07 (1.04, 1.11) and 1.16 (1.05, 1.28) for blood cadmium and lead, respectively. These findings suggest that blood cadmium and lead exposures increase reproductive lifespan and prevalence of pregnancy loss in the general population. Additional studies are needed to improve the understanding of mechanisms and prevention potential of metals-related pregnancy outcomes.

Medroxyprogesterone acetate: an alternative to GnRH-antagonist in oocyte vitrification for social fertility preservation and preimplantation genetic testing for aneuploidy.

RESEARCH QUESTION: Can medroxyprogesterone acetate (MPA) be used as a pituitary suppressor instead of a gonadotrophin releasing hormone (GnRH) antagonist during ovarian stimulation in elective fertility preservation and preimplantation genetic testing for aneuploidy (PGT-A) cycles? DESIGN: A multicentre, retrospective, observational, cohort study conducted in 11 IVIRMA centres affiliated to private universities. Of a total of 1652 cycles of social fertility preservation, 267 patients were stimulated using a progestin-primed ovarian stimulation protocol (PPOS), and 1385 patients received a GnRH antagonist. In the PGT-A cycles, 5661 treatments were analysed: 635 patients received MPA and 5026 patients received GnRH antagonist. A further 66 fertility preservation and 1299 PGT-A cycles were cancelled. All cycles took place between June 2019 and December 2021. RESULTS: In the social fertility preservation cycles, the number of mature oocytes vitrified in MPA was similar to the number of those treated with an antagonist, a trend that was seen regardless of age (≤35 or >35 years). In the PGT-A cycles, no differences were found in number of metaphase II, two pronuclei, number of biopsied embryos (4.4 ± 3.1 versus 4.5 ± 3.1), rate of euploidy (57.9% versus 56.4%) or ongoing pregnancy rate (50.4% versus 47.1%, P = 0.119) between the group receiving MPA versus a GnRH antagonist, whereas the clinical miscarriage rate was higher in the antagonist group (10.4% versus 14.8%, P = 0.019). CONCLUSIONS: Administration of PPOS yields similar results to GnRH antagonists in oocytes retrieved, rate of euploid embryos and clinical outcome. Hence, PPOS can be recommended for ovarian stimulation in social fertility preservation and PGT-A cycles, as it allows greater patient comfort.

Extracellular vesicles secreted by adenomyosis endometrial organoids contain miRNAs involved in embryo implantation and pregnancy.

RESEARCH QUESTION: Do extracellular vesicles secreted by the endometrium of women with adenomyosis contain miRNAs involved in adenomyosis-related infertility? DESIGN: A descriptive study using organoids from eutopic endometrium of women with adenomyosis (n = 4) generated and differentiated to secretory and gestational phases, in which miRNA cargo from extracellular vesicles secreted by these differentiated organoids in each phase was analysed by next-generation sequencing. miRNAs in secretory-extracellular vesicles and gestational-extracellular vesicles were selected based on the counts per million. miRNAs target genes in each phase were obtained from miRNet and gene ontology was used for enrichment analysis. RESULTS: miRNA sequencing identified 80 miRNAs in secretory-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-24-3p, hsa-miR-26a-5p, hsa-miR-92a-3p, hsa-miR-92b-3p, hsa-miR-200c-3p and hsa-miR-423a-5p, related to adenomyosis pathogenesis and implantation failure. Further, 60 miRNAs were identified in gestational-phase extracellular vesicles, including hsa-miR-21-5p, hsa-miR-26a-5p, hsa-miR-30a-5p, hsa-miR-30c-5p, hsa-miR-222-3p and hsa-miR-423a-5p were associated with preeclampsia and miscarriage. Among the target genes of these miRNAs, PTEN, MDM4, PLAGL2 and CELF1, whose downregulation (P = 0.0003, P < 0.0001, P = 0.0002 and P = 0.0003, respectively) contributes to adenomyosis pathogenesis, and impaired early embryo development, leading to implantation failure and miscarriage, are highlihghted. Further, functional enrichment analyses of the target genes revealed their involvement in cell differentiation, proliferation, apoptosis, cell cycle regulation and response to extracellular stimuli. CONCLUSIONS: Eutopic endometrium in secretory and gestational phase from women with adenomyosis releases extracellular vesicles containing miRNAs involved in adenomyosis progression, impaired embryo implantation and pregnancy complications.

COVID-19 Incidence and Mortality in Patients Operated on for Breast Cancer. Comparison with the General Population.

BACKGROUND: Breast Cancer (BC) remains the most diagnosed malignancy and the most common cause of cancer-related mortality in women worldwide. Covid-19 mortality in BC patients has been linked to comorbid conditions rather than to cancer treatment itself, although this was not confirmed by a meta-analysis. Also, during Covid-19 outbreaks, a great deal of health care resources is reassigned to critical Covid-19 patients. PATIENTS AND METHODS: During 5 consecutive trimesters (from 1/12/2020 to 31/3/2021) 2511 BC patients older than 20 years from our institution were surveyed. 1043 of them had received a Covid test and these made our study group, which was conveniently compared with the Covid-19 tested background feminine Catalan population. RESULTS: 13.1% of our patients presented with a positive Covid-19 test, whereas confirmed COVID-19 infection amounted to 7.1% of the feminine Catalan tested population. The COVID-19-specific mortality rate was 11.7% (16/137) in the study group, which compares with a 4.7% rate for the overall population. Most deaths occurred in patients over 70. CONCLUSION: Three clinical factors were significantly associated with Covid-19 mortality in BC, namely lack of hormone therapy, distant metastases, and BC dwelling in nursing homes. BC patients are at a higher risk of Covid-19 infection and mortality in comparison with the reference group without BC.

Long-Term Risk of Breast Cancer after Diagnosis of Benign Breast Disease by Screening Mammography.

Assessing the long-term risk of breast cancer after diagnosis of benign breast disease by mammography is of utmost importance to design personalised screening strategies. We analysed individual-level data from 778,306 women aged 50-69 years with at least one mammographic screening participation in any of ten breast cancer screening centers in Spain from 1996 to 2015, and followed-up until 2017. We used Poisson regression to compare the rates of incident breast cancer among women with and without benign breast disease. During a median follow-up of 7.6 years, 11,708 (1.5%) women had an incident of breast cancer and 17,827 (2.3%) had a benign breast disease. The risk of breast cancer was 1.77 times higher among women with benign breast disease than among those without (95% CI: 1.61 to 1.95). The relative risk increased to 1.99 among women followed for less than four years, and remained elevated for two decades, with relative risk 1.96 (95% CI: 1.32 to 2.92) for those followed from 12 to 20 years. Benign breast disease is a long-term risk factor for breast cancer. Women with benign breast disease could benefit from closer surveillance and personalized screening strategies.

Diagnostic Performance of a Fecal Immunochemical Test-Based Colorectal Cancer Screening Program According to Ambient Temperature and Humidity.

Exposure of the fecal immunochemical test (FIT) to different ambient temperatures and humidity is unavoidable in population-based screening programs in Southern European countries, and it could lead to a decrease in target colorectal lesions. The objective was to evaluate the effect of ambient temperature and humidity on the FIT sensitivity in a population-based screening program for colorectal cancer (CRC) using an ecological design. The retrospective cohort included individuals aged 50−69 years who participated in CRC screening (Barcelona) from 2010−2015, and were followed until 2017 to identify interval CRCs. The positivity rate, and detection rates for advanced polyps and CRC were compared according to ambient temperature, humidity, and quarters of the year. A positive FIT was defined as the detection of ≥20 µg Hb/g in feces. The monthly ambient temperature and humidity were recorded on the day that the FIT was performed. In total, 92,273 FIT results from 53,860 participants were analyzed. The FIT positivity rate was lower at >24 °C than at ≤24 °C (p = 0.005) but was not affected by humidity. The temperature's impact on positivity did not lead to a decrease in the FIT detection rate for advanced neoplasia or the interval cancer detection rate in a program where the samples were refrigerated until the analysis and screening invitations were discontinued in July and August.

Mammographic features of benign breast lesions and risk of subsequent breast cancer in women attending breast cancer screening.

OBJECTIVES: To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings. METHODS: We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves. RESULTS: Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12). CONCLUSION: BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses. KEY POINTS: • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses.

Differences in breast cancer-risk factors between screen-detected and non-screen-detected cases (MCC-Spain study).

PURPOSE: The variation in breast cancer (BC)-risk factor associations between screen-detected (SD) and non-screen-detected (NSD) tumors has been poorly studied, despite the interest of this aspect in risk assessment and prevention. This study analyzes the differences in breast cancer-risk factor associations according to detection method and tumor phenotype in Spanish women aged between 50 and 69. METHODS: We examined 900 BC cases and 896 controls aged between 50 and 69, recruited in the multicase-control MCC-Spain study. With regard to the cases, 460 were detected by screening mammography, whereas 144 were diagnosed by other means. By tumor phenotype, 591 were HR+, 153 were HER2+, and 58 were TN. Lifestyle, reproductive factors, family history of BC, and tumor characteristics were analyzed. Logistic regression models were used to compare cases vs. controls and SD vs. NSD cases. Multinomial regression models (controls used as a reference) were adjusted for case analysis according to phenotype and detection method. RESULTS: TN was associated with a lower risk of SD BC (OR 0.30 IC 0.10-0.89), as were intermediate (OR 0.18 IC 0.07-0.44) and advanced stages at diagnosis (OR 0.11 IC 0.03-0.34). Nulliparity in postmenopausal women and age at menopause were related to an increased risk of SD BC (OR 1.60 IC 1.08-2.36; OR 1.48 IC 1.09-2.00, respectively). Nulliparity in postmenopausal women was associated with a higher risk of HR+ (OR 1.66 IC 1.15-2.40). Age at menopause was related to a greater risk of HR+ (OR 1.60 IC 1.22-2.11) and HER2+ (OR 1.59 IC 1.03-2.45) tumors. CONCLUSION: Reproductive risk factors are associated with SD BC, as are HR+ tumors. Differences in BC-risk factor associations according to detection method may be related to prevailing phenotypes among categories.

Short-term impact of the COVID-19 pandemic on a population-based screening program for colorectal cancer in Catalonia (Spain).

The COVID-19 pandemic caused the suspension at all levels of the Catalan FIT-based CRC screening program on March 12, 2020. Screening invitations to FIT were resumed on September 1, 2020. We aimed to assess the short-term impact of the pandemic and describe strategies implemented to minimize harm by the disruption of the FIT-based CRC screening in the Metropolitan Area of Barcelona. We analyzed participation rate, colonoscopy adherence, time intervals to colonoscopy, detection rates, and advanced-stage cancers in 2019 and 2020. To identify perceived distress levels during the suspension of the screening we conducted a phone interview. As a result of the suspension, 43% of the individuals due for screening did not receive their invitation by December 31, 2020. A percent decrease of 5.1% in participation and of 8.9% in colonoscopy adherence among invitees between January-March was observed, with a recovery to 2019 levels when the screening activities were restarted. The time interval between a positive test to colonoscopy was longer in 2020 than in 2019. A decrease in advanced neoplasia rate and an increase in later stages of CRC were also observed. Individuals with a positive test did not report higher levels of perceived distress compared to those with a negative test. Although the disruption of screening had a temporary impact on participation and colonoscopy adherence, timing delay continues and a large backlog in the invitation of the target population remains. Thus, it is critical to implement strategies to minimize the long-term effects.

Health and economic impact at a population level of both primary and secondary preventive lung cancer interventions: A model-based cost-effectiveness analysis.

OBJECTIVES: Robust economic evaluations are needed to identify efficient strategies for lung cancer prevention that combine brief and intensive smoking cessation intervention programmes with screening using low-dose computed tomography (LDCT) at different ages, frequencies, and coverages. We aimed to assess the cost-effectiveness of smoking cessation approaches combined with lung cancer screening in the European context at a population level from a societal perspective. MATERIALS AND METHODS: A microsimulation model that describes the natural history of lung cancer and incorporates several prevention strategies was developed. Discounted lifetime QALYs and costs at a rate of 3% were used to calculate incremental cost-effectiveness ratios, defined as additional costs in 2017 Euros per QALY gained. RESULTS: Smoking cessation interventions reduce the incidence of lung cancer by 8%-46% and are consistently more effective and cost-effective when starting at younger ages. Screening reduces lung cancer mortality by 1%-24% and is generally less effective and more costly than smoking cessation interventions. The most cost-effective strategy would be to implement intensive smoking cessation interventions at ages 35, 40 and 45, combined with screening every three years between the ages of 55 and 65. CONCLUSIONS: Combining smoking cessation interventions with LDCT screening is a very attractive prevention strategy that substantially diminishes the burden of lung cancer. These combined prevention strategies, especially when providing several intensive interventions for smoking cessation at early ages, are more cost-effective than both approaches separately and allow for a more intensified LDCT without losing efficiency.

Factors associated with serum IgM concentrations: a general adult population study.

BACKGROUND AND AIM: To investigate the influence of common factors on serum immunoglobulin M (IgM) concentrations in adults, and clinical associations with high and low values. METHODS: We measured serum IgM levels using immunonephelometry in a random sample of 1510 individuals (aged 18-91 years, 44.7% male). We obtained data defining metabolic syndrome from all participants, defined atopy by skin prick tests to aeroallergens, and assessed lifestyle factors by questionnaire. RESULTS: Women showed higher IgM concentrations than men; 95 (6.3%, mostly male) individuals showed low (<0.40 g/L) IgM values, and 64 (4.2%, mostly female) showed high (>2.30 g/L) IgM values. Individuals with abnormal IgM concentrations had no history of opportunistic infections nor a different atopy prevalence. Serum IgM concentrations decreased with age, and obesity was negatively associated with IgM concentrations. Alcohol consumption, smoking, physical activity, and metabolic syndrome had no significant influence in the multivariate analyses. CONCLUSIONS: Many adults in the general population show abnormally high or low IgM concentrations with no evidence of immunodeficiency-associated diseases. Sex and age should be considered when defining reference IgM concentrations.

Positive impact of a faecal-based screening programme on colorectal cancer mortality risk.

INTRODUCTION: The effectiveness of colorectal cancer (CRC) screening programs is directly related to participation and the number of interval CRCs. The objective was to analyse specific-mortality in a cohort of individuals invited to a CRC screening program according to type of CRC diagnosis (screen-detected cancers, interval cancers, and cancers among the non-uptake group). MATERIAL AND METHODS: Retrospective cohort that included invitees aged 50-69 years of a CRC screening program (target population of 85,000 people) in Catalonia (Spain) from 2000-2015 with mortality follow-up until 2020. A screen-detected CRC was a cancer diagnosed after a positive faecal occult blood test (guaiac or immunochemical); an interval cancer was a cancer diagnosed after a negative test result and before the next invitation to the program (≤24 months); a non-uptake cancer was a cancer in subjects who declined screening. RESULTS: A total of 624 people were diagnosed with CRC (n = 265 screen-detected, n = 103 interval cancers, n = 256 non-uptake). In the multivariate analysis, we observed a 74% increase in mortality rate in the group with interval CRC compared to screen-detected CRC adjusted for age, sex, location and stage (HR: 1.74%, 95% CI:1.08-2.82, P = 0.02). These differences were found even when we restricted for advanced-cancers participants. In the stratified analysis for type of faecal occult blood test, a lower mortality rate was only observed among FIT screen-detected CRCs. CONCLUSION: CRC screening with the FIT was associated with a significant reduction in CRC mortality.

Medroxyprogesterone acetate is a useful alternative to a gonadotropin-releasing hormone antagonist in oocyte donation: a randomized, controlled trial.

OBJECTIVE: To compare ovarian response and reproductive outcomes in oocyte donors undergoing pituitary suppression with medroxyprogesterone acetate (MPA) versus those undergoing conventional treatment with a gonadotropin-releasing hormone (GnRH) antagonist. DESIGN: A prospective, randomized, controlled trial of cycles was conducted from October 2017 to June 2019 to evaluate ovarian response in terms of the number of oocytes. The reproductive outcomes of the recipients were retrospectively analyzed later. SETTING: A university-affiliated private in vitro fertilization center. PATIENT(S): We randomly divided 318 donors into 2 groups in a 1:1 ratio. The oocytes obtained were assigned to 364 recipients. One hundred sixty-one donors were treated with a daily dose of 10 mg of MPA administered orally from the beginning of ovarian stimulation (OS), and 156 were treated with a GnRH antagonist (initiated once the leading follicle reached a diameter of 13 mm). Transvaginal ultrasound was performed, and serum estradiol, luteinizing hormone, and progesterone levels were recorded during monitoring. The following additional parameters were analyzed: endocrine profile (in follicular fluid), number of metaphase II oocytes, and pregnancy outcome. INTERVENTION(S): The donors included in the study group were stimulated using recombinant follicle-stimulating hormone and MPA at 10 mg/day, simultaneously begun on cycle day 2 or 3. Ovulation was induced using a GnRH agonist when dominant follicles matured. A short protocol with ganirelix at 0.25 mg/day was used for the control group. Oocytes were assigned to the recipients, followed by routine in vitro fertilization procedures in which 1 embryo was usually transferred. MAIN OUTCOME MEASURE(S): The primary outcome measure was the numbers of oocytes and metaphase II oocytes retrieved. The secondary outcomes were the incidence of premature luteinizing hormone surge, serum and follicular fluid hormone profiles, and clinical pregnancy outcomes in the recipient group. RESULT(S): The number of oocytes retrieved was 21.4 ± 11.7 in the MPA group and 21.2 ± 9.2 in the antagonist group (mean difference 0.14; 95% confidence interval -2.233, 2.517). The total dose of recombinant follicle-stimulating hormone, duration of OS, and endocrine profiles of the serum and follicular fluids were comparable in the 2 groups. No early ovulation was observed in either group. No statistically significant differences with respect to implantation rate (68.1% in the MPA group vs. 62% in the antagonist group), clinical pregnancy rate (64.5% in the MPA group vs. 57.8 in the antagonist group), ongoing pregnancy rate (55.4% in the MPA group vs. 48.5% in the antagonist group), live birth rate (55.1% in the MPA group vs. 48.5% in the antagonist group), or cumulative live birth rate (73.8% in the MPA group vs. 70.7% in the antagonist group) were observed between the groups. CONCLUSION(S): The administration of MPA resulted in oocyte retrieval rates, endocrine profiles, viable embryo numbers, and pregnancy outcomes similar to those achieved with the GnRH antagonist. Therefore, MPA can be recommended for OS in oocyte donation because it permits a more patient-friendly approach. CLINICAL TRIAL REGISTRATION NUMBER: NCT03300960.

Text messaging as a tool to improve cancer screening programs (M-TICS Study): A randomized controlled trial protocol.

BACKGROUND: Short message service (SMS) based interventions are widely used in healthcare and have shown promising results to improve cancer screening programs. However, more research is still needed to implement SMS in the screening process. We present a study protocol to assess the impact on health and economics of three targeted SMS-based interventions in population-based cancer screening programs. METHODS/DESIGN: The M-TICs study is a randomized controlled trial with a formal process evaluation. Participants aged 50-69 years identified as eligible from the colorectal cancer (CRC) and breast cancer (BC) screening program of the Catalan Institute of Oncology (Catalonia, Spain) will be randomly assigned to receive standard invitation procedure (control group) or SMS-based intervention to promote participation. Two interventions will be conducted in the CRC screening program: 1) Screening invitation reminder: Those who do not participate in the CRC screening within 6 weeks of invite will receive a reminder (SMS or letter); 2) Reminder to complete and return fecal immunochemical test (FIT) kit: SMS reminder versus no intervention to individuals who have picked up a FIT kit at the pharmacy and they have not returned it after 14 days. The third intervention will be performed in the BC screening program. Women who had been screened previously will receive an SMS invitation or a letter invitation to participate in the screening. As a primary objective we will assess the impact on participation for each intervention. The secondary objectives will be to analyze the cost-effectiveness of the interventions and to assess participants' perceptions. EXPECTED RESULTS: The results from this randomized controlled trial will provide important empirical evidence for the use of mobile phone technology as a tool for improving population-based cancer screening programs. These results may influence the cancer screening invitation procedure in future routine practice. TRIAL REGISTRATION: Registry: NCT04343950 (04/09/2020); clinicaltrials.gov.

Role of community pharmacies in a population-based colorectal cancer screening program.

In Catalonia (Spain), population-based colorectal cancer (CRC) screening offers biennial fecal occult blood testing to men and women aged 50-69 years old. The program is organized in screening hubs, most of which use a pharmacy-based model to distribute and collect fecal immunochemical test (FIT) kits The comprehensive evaluation of CRC screening programs, which include the role and implications of pharmacy involvement, is essential to ensure program quality and identify areas for further improvement. The present study aimed to assess the adherence of community pharmacies to the CRC screening program and to analyze data on FIT kit distribution and collection in the Metropolitan area of Barcelona (Catalonia, Spain). Time to FIT completion was assessed by Kaplan-Meier estimation, and with the log-rank test. A Cox regression model was used to adjust for other variables associated with the completion of FIT such as sex, age, deprivation score index and previous screening behavior. Overall, 82.4% of pharmacies adhered with CRC screening program. Out of 82,902 FIT kits distributed to screening invitees 77,524 completed FIT kits were returned to pharmacies (93.5%) with a participation of 39.8% among the 193,766 invitees. From those who completed a FIT, the median time to return the kit was 3 days. FIT completion time was significantly lower among women, older age, high deprivation score index and previous CRC screening (p < 0.005). Our findings highlight the large involvement of community pharmacists with CRC screening program as well as a high quality in the process of FIT distribution and collection.

Breast density, benign breast disease, and risk of breast cancer over time.

OBJECTIVES: Assessing the combined effect of mammographic density and benign breast disease is of utmost importance to design personalized screening strategies. METHODS: We analyzed individual-level data from 294,943 women aged 50-69 years with at least one mammographic screening participation in any of four areas of the Spanish Breast Cancer Screening Program from 1995 to 2015, and followed up until 2017. We used partly conditional Cox models to assess the association between benign breast disease, breast density, and the risk of breast cancer. RESULTS: During a median follow-up of 8.0 years, 3697 (1.25%) women had a breast cancer diagnosis and 5941 (2.01%) had a benign breast disease. More than half of screened women had scattered fibroglandular density (55.0%). The risk of breast cancer independently increased with the presence of benign breast disease and with the increase in breast density (p for interaction = 0.84). Women with benign breast disease and extremely dense breasts had a threefold elevated risk of breast cancer compared with those with scattered fibroglandular density and without benign breast disease (hazard ratio [HR] = 3.07; 95%CI = 2.01-4.68). Heterogeneous density and benign breast disease was associated with nearly a 2.5 elevated risk (HR = 2.48; 95%CI = 1.66-3.70). Those with extremely dense breast without a benign breast disease had a 2.27 increased risk (95%CI = 2.07-2.49). CONCLUSIONS: Women with benign breast disease had an elevated risk for over 15 years independently of their breast density category. Women with benign breast disease and dense breasts are at high risk for future breast cancer. KEY POINTS: • Benign breast disease and breast density were independently associated with breast cancer. • Women with benign breast disease had an elevated risk for up to 15 years independently of their mammographic density category.

Risk of breast cancer two years after a benign biopsy depends on the mammographic feature prompting recall.

OBJECTIVE: We aimed to explore whether the type of mammographic feature prompting a false-positive recall (FPR) during mammography screening influences the risk and timing of breast cancer diagnosis, particularly if assessed with invasive procedures. STUDY DESIGN: We included information on women screened and recalled for further assessment in Spain between 1994 and 2015, with follow-up until 2017, categorizing FPRs by the assessment (noninvasive or invasive) and mammographic feature prompting the recall. MAIN OUTCOME MEASURES: Breast cancer rates in the first two years after FPR (first period) and after two years (second period). RESULTS: The study included 99,825 women with FPRs. In both periods, the breast cancer rate was higher in the invasive assessment group than in the noninvasive group (first period 12 ‰ vs 1.9 ‰, p < 0.001; second period 4.4‰ vs 3.1‰, p < 0.001). During the first period, the invasive assessment group showed diverse breast cancer rates for each type of mammographic feature, with a higher rate for asymmetric density (31.9‰). When the second period was compared with the first, the breast cancer rate decreased in the invasive assessment group (from 12‰ to 4.4‰, p < 0.001) and increased in the noninvasive assessment group (from 1.9‰ to 3.1‰, p < 0.001). CONCLUSION: In the context of mammography screening, the risk of breast cancer diagnosis during the first two years after FPR was particularly high for women undergoing invasive assessment; importantly, the risk was modified by type of mammographic feature prompting the recall. This information could help to individualize follow-up after exclusion of malignancy.

6-Year Risk of Developing Lung Cancer in Spain: Analysis by Autonomous Communities.

INTRODUCTION: Lung cancer screening with low-dose computed tomography (LDCT) has been proposed as a strategy to reduce lung cancer mortality. Since LDCT has side effects there is a need to carefully select the target population for screening programmes. Because in Spain health competences are transferred to the seventeen Autonomous Communities (ACs), the present paper aims to identify individuals at high risk of developing lung cancer in the different ACs. METHODS: We used the 2011-2012 data of the Spanish National Interview Health Survey (n=21,006) to estimate the proportion of individuals at high risk of developing lung cancer using a 6-year prediction model (PLCOm2012). This proportion was then extrapolated into absolute figures for the Spanish population, using the population census data of 2018 from the National Institute of Statistics. RESULTS: The proportion of individuals aged 50-74 with a risk of lung cancer ≥2% was 9.5% (15.9% in men, 3.5% in women). This proportion ranged from 6.6% in Región de Murcia to 12.7% in Andalucía and 13.0% in Extremadura. When extrapolated to the Spanish population, it was estimated that a total of 1,341,483 individuals may have a 6-year risk of lung cancer ≥2%. CONCLUSIONS: The present study is the first one that evaluated the number of individuals at high risk of developing lung cancer in the different Spanish ACs using a prediction model and selecting people with a 6-year risk ≥2%. Further studies should assess the cost and effectiveness associated to the implementation of a lung cancer screening programme to such population.