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The requirement of large-scale expensive cancer screening trials spanning decades creates considerable barriers to the development, commercialisation, and implementation of novel screening tests. One way to address these problems is to use surrogate endpoints for the ultimate endpoint of interest, cancer mortality, at an earlier timepoint. This Review aims to highlight the issues underlying the choice and use of surrogate endpoints for cancer screening trials, to propose criteria for when and how we might use such endpoints, and to suggest possible candidates. We present the current landscape and challenges, and discuss lessons and shortcomings from the therapeutic trial setting. It is hugely challenging to validate a surrogate endpoint, even with carefully designed clinical studies. Nevertheless, we consider whether there are candidates that might satisfy the requirements defined by research and regulatory bodies.
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Detección Precoz del Cáncer , Neoplasias , Humanos , Detección Precoz del Cáncer/métodos , Neoplasias/diagnóstico , Biomarcadores de Tumor/análisis , Ensayos Clínicos como Asunto , Proyectos de Investigación/normas , Biomarcadores/análisis , Determinación de Punto FinalRESUMEN
Analysis of cell-free DNA methylation (cfDNAme), alone or combined with CA125, could help to detect ovarian cancers earlier and may reduce mortality. We assessed cfDNAme in regions of ZNF154, C2CD4D and WNT6 via targeted bisulfite sequencing in diagnostic and early detection (preceding diagnosis) settings. Diagnostic samples were obtained via prospective blood collection in cell-free DNA tubes in a convenience series of patients with a pelvic mass. Early detection samples were matched case-control samples derived from the UK Familial Ovarian Cancer Screening Study (UKFOCSS). In the diagnostic set (ncases = 27, ncontrols = 41), the specificity of cfDNAme was 97.6% (95% CI: 87.1%-99.9%). High-risk cancers were detected with a sensitivity of 80% (56.3%-94.3%). Combination of cfDNAme and CA125 resulted in a sensitivity of 94.4% (72.7%-99.9%) for high-risk cancers. Despite technical issues in the early detection set (ncases = 29, ncontrols = 29), the specificity of cfDNAme was 100% (88.1%-100.0%). We detected 27.3% (6.0%-61.0%) of high-risk cases with relatively lower genomic DNA (gDNA) contamination. The sensitivity rose to 33.3% (7.5%-70.1%) in samples taken <1 year before diagnosis. We detected ovarian cancer in several patients up to 1 year before diagnosis despite technical limitations associated with archival samples (UKFOCSS). Combined cfDNAme and CA125 assessment may improve ovarian cancer screening in high-risk populations, but future large-scale prospective studies will be required to validate current findings.
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Metilación de ADN , Neoplasias Ováricas , Humanos , Femenino , Estudios de Casos y Controles , Estudios Prospectivos , Detección Precoz del Cáncer/métodos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Biomarcadores de Tumor/genética , Antígeno Ca-125 , Factores de Transcripción de Tipo Kruppel/genéticaRESUMEN
BACKGROUND: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes. METHODS: Cross-sectional associations were investigated between self-reported alcohol intake and serum or plasma concentrations of estradiol, estrone, progesterone (in premenopausal women only), testosterone, androstenedione, dehydroepiandrosterone sulfate, and sex hormone binding globulin (SHBG) in 45 431 premenopausal and 173 476 postmenopausal women. Multivariable linear regression was performed separately for UK Biobank, European Prospective Investigation into Cancer and Nutrition, and Endogenous Hormones and Breast Cancer Collaborative Group, and meta-analyzed the results. For testosterone and SHBG, we also conducted Mendelian randomization and colocalization using the ADH1B (alcohol dehydrogenase 1B) variant (rs1229984). RESULTS: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in premenopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal estradiol to 6.6% for postmenopausal dehydroepiandrosterone sulfate. There was an inverse association of alcohol with SHBG in postmenopausal women but a small positive association in premenopausal women. Two-sample randomization identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI, 0.6-7.6) and free testosterone (7.8%; 4.1-11.5), and an inverse association with SHBG (-8.1%; -11.3% to -4.9%). Colocalization suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (posterior probability for H4, 0.81 and 0.97, respectively). CONCLUSIONS: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.
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OBJECTIVE: To investigate psychological correlates in women referred with suspected ovarian cancer via the fast-track pathway, explore how anxiety and distress levels change at 12 months post-testing, and report cancer conversion rates by age and referral pathway. DESIGN: Single-arm prospective cohort study. SETTING: Multicentre. Secondary care including outpatient clinics and emergency admissions. POPULATION: A cohort of 2596 newly presenting symptomatic women with a raised CA125 level, abnormal imaging or both. METHODS: Women completed anxiety and distress questionnaires at recruitment and at 12 months for those who had not undergone surgery or a biopsy within 3 months of recruitment. MAIN OUTCOME MEASURES: Anxiety and distress levels measured using a six-item short form of the State-Trait Anxiety Inventory (STAI-6) and the Impact of Event Scale - Revised (IES-r) questionnaire. Ovarian cancer (OC) conversion rates by age, menopausal status and referral pathway. RESULTS: Overall, 1355/2596 (52.1%) and 1781/2596 (68.6%) experienced moderate-to-severe distress and anxiety, respectively, at recruitment. Younger age and emergency presentations had higher distress levels. The clinical category for anxiety and distress remained unchanged/worsened in 76% of respondents at 12 months, despite a non-cancer diagnosis. The OC rates by age were 1.6% (95% CI 0.5%-5.9%) for age <40 years and 10.9% (95% CI 8.7%-13.6%) for age ≥40 years. In women referred through fast-track pathways, 3.3% (95% CI 1.9%-5.7%) of pre- and 18.5% (95% CI 16.1%-21.0%) of postmenopausal women were diagnosed with OC. CONCLUSIONS: Women undergoing diagnostic testing display severe anxiety and distress. Younger women are especially vulnerable and should be targeted for support. Women under the age of 40 years have low conversion rates and we advocate reducing testing in this group to reduce the harms of testing.
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Ansiedad , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/psicología , Estudios Prospectivos , Persona de Mediana Edad , Ansiedad/etiología , Ansiedad/epidemiología , Adulto , Anciano , Encuestas y Cuestionarios , Derivación y Consulta/estadística & datos numéricos , Detección Precoz del Cáncer/psicología , Antígeno Ca-125/sangre , Distrés Psicológico , Estrés Psicológico/etiología , Estrés Psicológico/epidemiologíaRESUMEN
Ovarian cancer remains the most lethal gynaecological malignancy with 314 000 cases and 207 000 deaths annually worldwide. Ovarian cancer cases and deaths are predicted to increase in Australia by 42% and 55% respectively by 2040. Earlier detection and significant downstaging of ovarian cancer have been demonstrated with multimodal screening in the largest randomised controlled trial of ovarian cancer screening in women at average population risk. However, none of the randomised trials have demonstrated a mortality benefit. Therefore, ovarian cancer screening is not currently recommended in women at average population risk. More frequent surveillance for ovarian cancer every three to four months in women at high risk has shown good performance characteristics and significant downstaging, but there is no available information on a survival benefit. Population testing offers an emerging novel strategy to identify women at high risk who can benefit from ovarian cancer prevention. Novel multicancer early detection biomarker, longitudinal multiple marker strategies, and new biomarkers are being investigated and evaluated for ovarian cancer screening. Risk-reducing salpingo-oophorectomy (RRSO) decreases ovarian cancer incidence and mortality and is recommended for women at over a 4-5% lifetime risk of ovarian cancer. Pre-menopausal women without contraindications to hormone replacement therapy (HRT) undergoing RRSO should be offered HRT until 51 years of age to minimise the detrimental consequences of premature menopause. Currently risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) should only be offered to women at increased risk of ovarian cancer within the context of a research trial. Pre-menopausal early salpingectomy is associated with fewer menopausal symptoms and better sexual function than bilateral salpingo-oophorectomy. A Sectioning and Extensively Examining the Fimbria (SEE-FIM) protocol should be used for histopathological assessment in women at high risk of ovarian cancer who are undergoing surgical prevention. Opportunistic salpingectomy may be offered at routine gynaecological surgery to all women who have completed their family. Long term prospective opportunistic salpingectomy studies are needed to determine the effect size of ovarian cancer risk reduction and the impact on menopause.
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Detección Precoz del Cáncer , Neoplasias Ováricas , Femenino , Humanos , Estudios Prospectivos , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/prevención & control , Ovariectomía/efectos adversos , Ovariectomía/métodos , Salpingectomía/efectos adversos , Salpingectomía/métodosRESUMEN
OBJECTIVE: Symptom-triggered testing for ovarian cancer was introduced to the UK whereby symptomatic women undergo an ultrasound scan and serum CA125, and are referred to hospital within 2 weeks if these are abnormal. The potential value of symptom-triggered testing in the detection of early-stage disease or low tumor burden remains unclear in women with high grade serous ovarian cancer. In this descriptive study, we report on the International Federation of Gynecology and Obstetrics (FIGO) stage, disease distribution, and complete cytoreduction rates in women presenting via the fast-track pathway and who were diagnosed with high grade serous ovarian cancer. METHODS: We analyzed the dataset from Refining Ovarian Cancer Test accuracy Scores (ROCkeTS), a single-arm prospective diagnostic test accuracy study recruiting from 24 hospitals in the UK. The aim of ROCkeTS is to validate risk prediction models in symptomatic women. We undertook an opportunistic analysis for women recruited between June 2015 to July 2022 and who were diagnosed with high grade serous ovarian cancer via the fast-track pathway. Women presenting with symptoms suspicious for ovarian cancer receive a CA125 blood test and an ultrasound scan if the CA125 level is abnormal. If either of these is abnormal, women are referred to secondary care within 2 weeks. Histology details were available on all women who underwent surgery or biopsy within 3 months of recruitment. Women who did not undergo surgery or biopsy at 3 months were followed up for 12 months as per the national guidelines in the UK. In this descriptive study, we report on patient demographics (age and menopausal status), WHO performance status, FIGO stage at diagnosis, disease distribution (low/pelvic confined, moderate/extending to mid-abdomen, high/extending to upper abdomen) and complete cytoreduction rates in women who underwent surgery. RESULTS: Of 1741 participants recruited via the fast-track pathway, 119 (6.8%) were diagnosed with high grade serous ovarian cancer. The median age was 63 years (range 32-89). Of these, 112 (94.1%) patients had a performance status of 0 and 1, 30 (25.2%) were diagnosed with stages I/II, and the disease distribution was low-to-moderate in 77 (64.7%). Complete and optimal cytoreduction were achieved in 73 (61.3%) and 18 (15.1%). The extent of disease was low in 43 of 119 (36.1%), moderate in 34 of 119 (28.6%), high in 32 of 119 (26.9%), and not available in 10 of 119 (8.4%). Nearly two thirds, that is 78 of 119 (65.5%) women with high grade serous ovarian cancer, underwent primary debulking surgery, 36 of 119 (30.3%) received neoadjuvant chemotherapy followed by interval debulking surgery, and 5 of 119 (4.2%) women did not undergo surgery. CONCLUSION: Our results demonstrate that one in four women identified with high grade serous ovarian cancer through the fast-track pathway following symptom-triggered testing was diagnosed with early-stage disease. Symptom-triggered testing may help identify women with a low disease burden, potentially contributing to high complete cytoreduction rates.
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BACKGROUND: The health and well-being of the nursing workforce has received recent attention due to nurse attrition and the critical nurse shortages projected across the country. A nurse's well-being may impact patient outcomes. PURPOSE: The purpose of this scoping review was to assess the association between nurse well-being factors and specific patient outcomes. METHODS: The preferred reporting items for systematic reviews and meta-analyses (PRISMA) PRISMA Scoping Review protocol and 2020 reporting guidelines were utilized in this review. RESULTS: Staffing, environment, physical health, and mental health of nurses were correlated to specific adverse patient outcomes among the 97 articles included in the final review. The majority of the articles reported significant findings. CONCLUSIONS: Patient outcomes were reviewed as discrete events in the articles examined. With mixed results found on key patient outcomes, future research requires more in-depth investigation into the role nurse well-being has on patient outcomes.
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BACKGROUND: To evaluate outcomes of laparoscopic retroperitoneal para-aortic lymphadenectomy for stage 1b3-3b cervical cancer. METHODS: Pathology databases searched for all para-aortic lymphadenectomy cases 2005-2016. Descriptive statistics were used to analyse baseline characteristics, cox models for treatment affect after accounting for variables, and Kaplan Meier curves for survival (STATA v15). RESULTS: 191 patients had 1b3-3b cervical cancer of which 110 patients had Para-aortic lymphadenectomy. 8 (7.3%) patients stage 1b3, 82 (74.6%) stage 2b, and 20 (18.1%) stage 3b cervical cancer. Mean lymph node count 11.7 (SD7.6). The intra-operative and post-operative 30 day complication rates were 8.8% (CI: 4.3%, 15.7%) and 5.3% (CI: 1.9%, 11.2%) respectively.Para-aortic nodes were apparently positive on CT/MRI in 5/110 (5%) cases. Cancer was found in 10 (8.9%, CI: 4.3%, 15.7%) cases on histology, all received extended field radiotherapy. Only 2 were identified on pre-operative CT/MRI imaging. 3 of 10 suspected node-positive cases on CT/MRI had negative histology. Para-aortic lymphadenectomy led to alteration in staging and radiotherapy management in 8 (8%, CI: 3.7%, 14.6%) patients. Mean overall survival 42.81 months (SD = 31.79 months). Survival was significantly higher for women undergoing PAN (50.57 (SD 30.7) months) compared to those who didn't (31.27 (SD 32.5) months). CONCLUSION: Laparoscopic retroperitoneal para-aortic lymphadenectomy is an acceptable procedure which can guide treatment in women with locally advanced cervical cancer.
We evaluated outcomes for patients with stage 1b3-3b cervical cancer that had lymph nodes removed prior to planning their chemoradiotherapy. There were 3 groups patients that had their lymph nodes removed, those that did not and those that had their procedure abandoned so didn't have their lymph nodes removed. We looked at the lymph nodes down the microscope to see if they contained cancer and compared this to their pre-operative imaging. 8 patients had a change to their staging and treatment because they were found to have cancer in the lymph nodes. We found that the keyhole procedure to remove lymph nodes is an acceptable procedure which can guide treatment in women with locally advanced cervical cancer.
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Laparoscopía , Escisión del Ganglio Linfático , Estadificación de Neoplasias , Neoplasias del Cuello Uterino , Humanos , Femenino , Neoplasias del Cuello Uterino/cirugía , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/mortalidad , Escisión del Ganglio Linfático/métodos , Escisión del Ganglio Linfático/estadística & datos numéricos , Persona de Mediana Edad , Espacio Retroperitoneal , Laparoscopía/métodos , Laparoscopía/estadística & datos numéricos , Adulto , Resultado del Tratamiento , Estudios Retrospectivos , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Metástasis Linfática , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , AncianoRESUMEN
BACKGROUND: In UKCTOCS, there was a decrease in the diagnosis of advanced stage tubo-ovarian cancer but no reduction in deaths in the multimodal screening group compared with the no screening group. Therefore, we did exploratory analyses of patients with high-grade serous ovarian cancer to understand the reason for the discrepancy. METHODS: UKCTOCS was a 13-centre randomised controlled trial of screening postmenopausal women from the general population, aged 50-74 years, with intact ovaries. The trial management system randomly allocated (2:1:1) eligible participants (recruited from April 17, 2001, to Sept 29, 2005) in blocks of 32 using computer generated random numbers to no screening or annual screening (multimodal screening or ultrasound screening) until Dec 31, 2011. Follow-up was through national registries until June 30, 2020. An outcome review committee, masked to randomisation group, adjudicated on ovarian cancer diagnosis, histotype, stage, and cause of death. In this study, analyses were intention-to-screen comparisons of women with high-grade serous cancer at censorship (Dec 31, 2014) in multimodal screening versus no screening, using descriptive statistics for stage and treatment endpoints, and the Versatile test for survival from randomisation. This trial is registered with the ISRCTN Registry, 22488978, and ClinicalTrials.gov, NCT00058032. FINDINGS: 202â562 eligible women were recruited (50â625 multimodal screening; 50â623 ultrasound screening; 101â314 no screening). 259 (0·5%) of 50â625 participants in the multimodal screening group and 520 (0·5%) of 101â314 in the no screening group were diagnosed with high-grade serous cancer. In the multimodal screening group compared with the no screening group, fewer were diagnosed with advanced stage disease (195 [75%] of 259 vs 446 [86%] of 520; p=0·0003), more had primary surgery (158 [61%] vs 219 [42%]; p<0·0001), more had zero residual disease following debulking surgery (119 [46%] vs 157 [30%]; p<0·0001), and more received treatment including both surgery and chemotherapy (192 [74%] vs 331 [64%]; p=0·0032). There was no difference in the first-line combination chemotherapy rate (142 [55%] vs 293 [56%]; p=0·69). Median follow-up from randomisation of 779 women with high-grade serous cancer in the multimodal and no screening groups was 9·51 years (IQR 6·04-13·00). At censorship (June 30, 2020), survival from randomisation was longer in women with high-grade serous cancer in the multimodal screening group than in the no screening group with absolute difference in survival of 6·9% (95% CI 0·4-13·0; p=0·042) at 18 years (21% [95% CI 15·6-26·2] vs 14% [95% CI 10·5-17·4]). INTERPRETATION: To our knowledge, this is the first evidence that screening can detect high-grade serous cancer earlier and lead to improved short-term treatment outcomes compared with no screening. The potential survival benefit for women with high-grade serous cancer was small, most likely due to only modest gains in early detection and treatment improvement, and tumour biology. The cumulative results of the trial suggest that surrogate endpoints for disease-specific mortality should not currently be used in screening trials for ovarian cancer. FUNDING: National Institute for Health Research, Medical Research Council, Cancer Research UK, The Eve Appeal.
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Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Resultado del Tratamiento , Tamizaje Masivo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
OBJECTIVE: UKCTOCS provides an opportunity to explore symptoms in preclinical invasive epithelial ovarian cancer (iEOC). We report on symptoms in women with pre-clinical (screen-detected) cancers (PC) compared to clinically diagnosed (CD) cancers. METHODS: In UKCTOCS, 202638 postmenopausal women, aged 50-74 were randomly allocated (April 17, 2001-September 29, 2005) 2:1:1 to no screening or annual screening till Dec 31,2011, using a multimodal or ultrasound strategy. Follow-up was through national registries. An outcomes committee adjudicated on OC diagnosis, histotype, stage. Eligible women were those diagnosed with iEOC at primary censorship (Dec 31, 2014). Symptom details were extracted from trial clinical-assessment forms and medical records. Descriptive statistics were used to compare symptoms in PC versus CD women with early (I/II) and advanced (III/IV/unable to stage) stage high-grade-serous (HGSC) cancer. ISRCTN-22488978; ClinicalTrials.gov-NCT00058032. RESULTS: 1133 (286PC; 847CD) women developed iEOC. Median age (years) at diagnosis was earlier in PC compared to CD (66.8PC, 68.7CD, p = 0.0001) group. In the PC group, 48% (112/234; 90%, 660/730CD) reported symptoms when questioned. Half PC (50%, 13/26PC; 36%, 29/80CD; p = 0.213) women with symptomatic HGSC had >1symptom, with abdominal symptoms most common, both in early (62%, 16/26, PC; 53% 42/80, CD; p = 0.421) and advanced (57%, 49/86, PC; 74%, 431/580, CD; p = 0.001) stages. In symptomatic early-stage HGSC, compared to CD, PC women reported more gastrointestinal (change in bowel habits and dyspepsia) (35%, 9/26PC; 9%, 7/80CD; p = 0.001) and systemic (mostly lethargy/tiredness) (27%, 7/26PC; 9%, 7/80CD; p = 0.017) symptoms. CONCLUSIONS: Our findings, add to the growing evidence, that we should reconsider what constitutes alert symptoms for early tubo-ovarian cancer. We need a more nuanced complex of key symptoms which is then evaluated and refined in a prospective trial.
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Detección Precoz del Cáncer , Neoplasias Ováricas , Femenino , Humanos , Carcinoma Epitelial de Ovario/diagnóstico , Estudios Prospectivos , Neoplasias Ováricas/diagnóstico , Reino Unido/epidemiologíaRESUMEN
OBJECTIVE: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer, with low response rates to standard chemotherapy, and very poor survival for patients diagnosed at advanced stage. There is a limited understanding of the MOC immune landscape, and consequently whether immune checkpoint inhibitors could be considered for a subset of patients. METHODS: We performed multicolor immunohistochemistry (IHC) and immunofluorescence (IF) on tissue microarrays in a cohort of 126 MOC patients. Cell densities were calculated in the epithelial and stromal components for tumor-associated macrophages (CD68+/PD-L1+, CD68+/PD-L1-), T cells (CD3+/CD8-, CD3+/CD8+), putative T-regulatory cells (Tregs, FOXP3+), B cells (CD20+/CD79A+), plasma cells (CD20-/CD79a+), and PD-L1+ and PD-1+ cells, and compared these values with clinical factors. Univariate and multivariable Cox Proportional Hazards assessed overall survival. Unsupervised k-means clustering identified patient subsets with common patterns of immune cell infiltration. RESULTS: Mean densities of PD1+ cells, PD-L1- macrophages, CD4+ and CD8+ T cells, and FOXP3+ Tregs were higher in the stroma compared to the epithelium. Tumors from advanced (Stage III/IV) MOC had greater epithelial infiltration of PD-L1- macrophages, and fewer PD-L1+ macrophages compared with Stage I/II cancers (p = 0.004 and p = 0.014 respectively). Patients with high epithelial density of FOXP3+ cells, CD8+/FOXP3+ cells, or PD-L1- macrophages, had poorer survival, and high epithelial CD79a + plasma cells conferred better survival, all upon univariate analysis only. Clustering showed that most MOC (86%) had an immune depleted (cold) phenotype, with only a small proportion (11/76,14%) considered immune inflamed (hot) based on T cell and PD-L1 infiltrates. CONCLUSION: In summary, MOCs are mostly immunogenically 'cold', suggesting they may have limited response to current immunotherapies.
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Antígeno B7-H1 , Neoplasias Ováricas , Humanos , Femenino , Antígeno B7-H1/genética , Carcinoma Epitelial de Ovario/patología , Neoplasias Ováricas/tratamiento farmacológico , Linfocitos T CD8-positivos , Factores de Transcripción Forkhead/uso terapéutico , Linfocitos Infiltrantes de Tumor , Microambiente TumoralRESUMEN
Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.
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Neoplasias Ováricas , Salpingooforectomía , Femenino , Humanos , Adulto , Persona de Mediana Edad , Calidad de Vida , Consenso , Premenopausia , Neoplasias Ováricas/genética , Neoplasias Ováricas/prevención & control , Neoplasias Ováricas/cirugía , Ovariectomía , Predisposición Genética a la EnfermedadRESUMEN
BACKGROUND: Acceptance of the role of the fallopian tube in 'ovarian' carcinogenesis and the detrimental sequelae of surgical menopause in premenopausal women following risk-reducing salpingo-oophorectomy (RRSO) has resulted in risk-reducing early-salpingectomy with delayed oophorectomy (RRESDO) being proposed as an attractive alternative risk-reducing strategy in women who decline/delay oophorectomy. We present the results of a qualitative study evaluating the decision-making process among BRCA carriers considering prophylactic surgeries (RRSO/RRESDO) as part of the multicentre PROTECTOR trial (ISRCTN:25173360). METHODS: In-depth semistructured 1:1 interviews conducted using a predeveloped topic-guide (development informed by literature review and expert consultation) until informational saturation reached. Wording and sequencing of questions were left open with probes used to elicit additional information. All interviews were audio-recorded, transcribed verbatim, transcripts analysed using an inductive theoretical framework and data managed using NVIVO-v12. RESULTS: Informational saturation was reached following 24 interviews. Seven interconnected themes integral to surgical decision making were identified: fertility/menopause/cancer risk reduction/surgical choices/surgical complications/sequence of ovarian-and-breast prophylactic surgeries/support/satisfaction. Women for whom maximising ovarian cancer risk reduction was relatively more important than early menopause/quality-of-life preferred RRSO, whereas those more concerned about detrimental impact of menopause chose RRESDO. Women managed in specialist familial cancer clinic settings compared with non-specialist settings felt they received better quality care, improved hormone replacement therapy access and were more satisfied. CONCLUSION: Multiple contextual factors (medical, physical, psychological, social) influence timing of risk-reducing surgeries. RRESDO offers women delaying/declining premenopausal oophorectomy, particularly those concerned about menopausal effects, a degree of ovarian cancer risk reduction while avoiding early menopause. Care of high-risk women should be centralised to centres with specialist familial gynaecological cancer risk management services to provide a better-quality, streamlined, holistic multidisciplinary approach.
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Toma de Decisiones Clínicas , Genes BRCA1 , Genes BRCA2 , Neoplasias Ováricas/prevención & control , Procedimientos Quirúrgicos Profilácticos , Salpingectomía , Salpingooforectomía , Adulto , Estudios de Cohortes , Femenino , Heterocigoto , Humanos , Persona de Mediana Edad , Neoplasias Ováricas/genética , Ovariectomía , Premenopausia , Mastectomía Profiláctica , Conducta de Reducción del RiesgoRESUMEN
BACKGROUND: Epithelial tubo-ovarian cancer (EOC) has high mortality partly due to late diagnosis. Prevention is available but may be associated with adverse effects. A multifactorial risk model based on known genetic and epidemiological risk factors (RFs) for EOC can help identify women at higher risk who could benefit from targeted screening and prevention. METHODS: We developed a multifactorial EOC risk model for women of European ancestry incorporating the effects of pathogenic variants (PVs) in BRCA1, BRCA2, RAD51C, RAD51D and BRIP1, a Polygenic Risk Score (PRS) of arbitrary size, the effects of RFs and explicit family history (FH) using a synthetic model approach. The PRS, PV and RFs were assumed to act multiplicatively. RESULTS: Based on a currently available PRS for EOC that explains 5% of the EOC polygenic variance, the estimated lifetime risks under the multifactorial model in the general population vary from 0.5% to 4.6% for the first to 99th percentiles of the EOC risk distribution. The corresponding range for women with an affected first-degree relative is 1.9%-10.3%. Based on the combined risk distribution, 33% of RAD51D PV carriers are expected to have a lifetime EOC risk of less than 10%. RFs provided the widest distribution, followed by the PRS. In an independent partial model validation, absolute and relative 5-year risks were well calibrated in quintiles of predicted risk. CONCLUSION: This multifactorial risk model can facilitate stratification, in particular among women with FH of cancer and/or moderate-risk and high-risk PVs. The model is available via the CanRisk Tool (www.canrisk.org).
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Neoplasias de la Mama , Neoplasias Ováricas , Carcinoma Epitelial de Ovario/epidemiología , Carcinoma Epitelial de Ovario/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Herencia Multifactorial/genética , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Factores de RiesgoRESUMEN
BACKGROUND: Dissemination strategies to reach underserved and minority populations to promote screening for colorectal cancer (CRC) are key to reducing disparities. We conducted a study to examine a tailored messaging approach to navigate individuals from communities (i.e., lower income, less access to care, and underscreened) to clinics to receive CRC screening. We encountered several political, demographic, and secular trend issues that required reconsideration and redesign of implementation strategies. OBJECTIVES: Through study implementation from 2012 to 2017, changes in medical reimbursement and immigration policies-at the state level and later at the national level-affected healthcare delivery systems that had initially committed to supporting the study and our recruitment methods. Although our selected zip codes and sites had previously yielded high rates of CRC screening nonadherence, within a few years, these sites showed substantially higher screening adherence rates-yielding limited numbers of eligible participants. In addition, state immigration policy trends created mistrust and fear, leading to lower participation rates than anticipated. This report documents and provides valuable insights on how we and the community network developed creative strategies to overcome these challenges. METHODS: New relationships with community partners were extended to tap advisory board input to meet the challenges. Criteria for clinic participation widened from originally selected Federally Qualified Health Centers (FQHCs) to various nonprofit, hybrid, and privately insured reimbursement types. Recruitment site options were creatively redefined to reach community participants where they live, work, and receive services. RESULTS: Strategies that engage community members in identifying alternative healthcare delivery structures and that link recruitment efforts to community-based service organizations were found to be critical to recapturing community trust in the face of unfavorable political environments. Widening the type of clinic partners from FQHCs to stand-alone nonprofits and private clinics and identifying unusual types of recruitment sites provided alternative solutions for successful study implementation. DISCUSSION: In prevention-based studies that face unplanned system and political barriers to recruitment, embedding the study in the community may aid in reestablishing trust levels to improve engagement and recruitment of clinic partners and eligible participants.
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Neoplasias Colorrectales , Detección Precoz del Cáncer , Humanos , Detección Precoz del Cáncer/métodos , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/prevención & control , Instituciones de Atención AmbulatoriaRESUMEN
BACKGROUND: Despite the dramatic increase in opioid-related deaths in recent years, global access to treatment remains poor. A major barrier to people accessing Medication-assisted treatment of the opioid use disorder (MOUD) is the lack of providers who can prescribe and monitor MOUD. According to the World Drug Report, more young people are using drugs compared with previous generations and people in need of treatment cannot get it, women most of all. Nurse prescribers have the potential to enhance both access and treatment outcomes. Nurse prescribing practices do, however, vary greatly internationally. The aim of this scoping review is to explore nurse prescribing practices for MOUD globally with a view to informing equitable access and policies for people seeking MOUD. METHODS: This scoping review was informed by the preferred reporting items for systematic reviews and meta-analysis extension for scoping reviews (PRISMA-ScR). Electronic searches from 2010 to date were conducted on the following databases: PsycInfo, PubMed, Embase, and CINAHL. Only studies that met the eligibility criteria and described nurse prescribing policies and/or behaviours for MOUD were included. RESULTS: A total of 22 articles were included in the review which found several barriers and enablers to nurse prescribing of MOUD. Barriers included legislation constraints, lack of professional education and training and the presence of stigmatizing attitudes. Enablers included the presence of existing supportive services, prosocial messaging, and nurse prescriber autonomy. CONCLUSION: The safety and efficacy of nurse prescribing of MOUD is well established, and its expansion can provide a range of advantages to people who are dependent on opiates. This includes increasing access to treatment. Nurse prescribing of MOUD can increase the numbers of people in treatment from 'hard to reach' cohorts such as rural settings, or those with less financial means. It holds significant potential to reduce a wide range of harms and costs associated with high-risk opiate use. To reduce drug-related death and the global burden of harm to individuals, families, and communities, there is an urgent need to address the two key priorities of nurse prescriber legislation and education. Both of which are possible given political and educational commitment.
Asunto(s)
Trastornos Relacionados con Opioides , Adolescente , Femenino , Humanos , Analgésicos Opioides/uso terapéutico , Escolaridad , Trastornos Relacionados con Opioides/tratamiento farmacológico , PolíticasRESUMEN
BACKGROUND: The emphasis on digital technology and informatics in health care (digital health) has introduced innovative ways to deliver health care and engage populations in health research. However, inadequate attention to the development and implementation of digital health interventions can exacerbate health disparities. PURPOSE: We applied the transdisciplinary ConNECT Framework principles within the context of digital health, with an aim to describe strategies to achieve digital health equity. METHODS: We described the five ConNECT principles of (a) integrating context, (b) fostering a norm of inclusion, (c) ensuring equitable diffusion of innovations, (d) harnessing communication technology, and (e) prioritizing specialized training within the framework of achieving digital health equity. FINDINGS AND DISCUSSION: We describe proactive, actionable strategies for the systematic application of the ConNECT Framework principles to address digital health equity. Recommendations to reduce the digital health divide in nursing research and practice are also described.
Asunto(s)
Equidad en Salud , Humanos , Atención a la SaludRESUMEN
Native American young adults residing in urban communities are particularly vulnerable to substance use. After leaving high school, the pressures and stress of continuing education, finding employment, and the responsibilities related to family and tribal community obligations predispose these young adults to substance use. This study used a pre/post test design to evaluate a cultural-based Talking Circle intervention for the prevention of substance use among urban Native American young adults, ages 18-24. Three measures were used that included the Native-Reliance Questionnaire, the Indigenous-Global Assessment of Individual Needs (I-GAIN) Substance Use Scale, and the Patient Health Questionnaire (PHQ-9) measure for severity of depression. Findings revealed that participants demonstrated a higher sense of Native-Reliance, decrease in substance use, and a decrease in the PHQ-9 depressions scores from baseline to 6-month postintervention. These findings validate the importance of cultural-based interventions for the prevention of substance use among urban Native American young adults.
Asunto(s)
Indígenas Norteamericanos , Trastornos Relacionados con Sustancias , Humanos , Adulto Joven , Conducta Social , Trastornos Relacionados con Sustancias/prevención & control , Encuestas y CuestionariosRESUMEN
Starch synthesis is an elaborate process employing several isoforms of starch synthases (SSs), starch branching enzymes (SBEs) and debranching enzymes (DBEs). In cereals, some starch biosynthetic enzymes can form heteromeric complexes whose assembly is controlled by protein phosphorylation. Previous studies suggested that SSIIa forms a trimeric complex with SBEIIb, SSI, in which SBEIIb is phosphorylated. This study investigates the post-translational modification of SSIIa, and its interactions with SSI and SBEIIb in maize amyloplast stroma. SSIIa, immunopurified and shown to be free from other soluble starch synthases, was shown to be readily phosphorylated, affecting Vmax but with minor effects on substrate Kd and Km values, resulting in a 12-fold increase in activity compared with the dephosphorylated enzyme. This ATP-dependent stimulation of activity was associated with interaction with SBEIIb, suggesting that the availability of glucan branching limits SSIIa and is enhanced by physical interaction of the two enzymes. Immunoblotting of maize amyloplast extracts following non-denaturing polyacrylamide gel electrophoresis identified multiple bands of SSIIa, the electrophoretic mobilities of which were markedly altered by conditions that affected protein phosphorylation, including protein kinase inhibitors. Separation of heteromeric enzyme complexes by GPC, following alteration of protein phosphorylation states, indicated that such complexes are stable and may partition into larger and smaller complexes. The results suggest a dual role for protein phosphorylation in promoting association and dissociation of SSIIa-containing heteromeric enzyme complexes in the maize amyloplast stroma, providing new insights into the regulation of starch biosynthesis in plants.
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Endospermo/metabolismo , Proteínas de Plantas/metabolismo , Almidón Sintasa/metabolismo , Zea mays/metabolismo , Ensayo de Cambio de Movilidad Electroforética , Endospermo/enzimología , Glucanos/metabolismo , Inmunoprecipitación , Fosforilación , Proteínas de Plantas/aislamiento & purificación , Proteínas de Plantas/fisiología , Plastidios/metabolismo , Almidón/metabolismo , Almidón Sintasa/aislamiento & purificación , Almidón Sintasa/fisiología , Zea mays/enzimologíaRESUMEN
BACKGROUND: International Cancer Benchmarking Partnership Module 4 reports the first international comparison of ovarian cancer (OC) diagnosis routes and intervals (symptom onset to treatment start), which may inform previously reported variations in survival and stage. METHODS: Data were collated from 1110 newly diagnosed OC patients aged >40 surveyed between 2013 and 2015 across five countries (51-272 per jurisdiction), their primary-care physicians (PCPs) and cancer treatment specialists, supplement by treatment records or clinical databases. Diagnosis routes and time interval differences using quantile regression with reference to Denmark (largest survey response) were calculated. RESULTS: There were no significant jurisdictional differences in the proportion diagnosed with symptoms on the Goff Symptom Index (53%; P = 0.179) or National Institute for Health and Care Excellence NG12 guidelines (62%; P = 0.946). Though the main diagnosis route consistently involved primary-care presentation (63-86%; P = 0.068), onward urgent referral rates varied significantly (29-79%; P < 0.001). In most jurisdictions, diagnostic intervals were generally shorter and other intervals, in particular, treatment longer compared to Denmark. CONCLUSION: This study highlights key intervals in the diagnostic pathway where improvements could be made. It provides the opportunity to consider the systems and approaches across different jurisdictions that might allow for more timely ovarian cancer diagnosis and treatment.