Ovarian Cancer Prevention and Screening Menon, Usha; Karpinskyj, Chloe; Gentry-Maharaj, Aleksandra
Obstetrics and gynecology (New York. 1953)
131, Številka:
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There has been much progress in ovarian cancer screening and prevention in recent years. Improved tools that combine genetic and epidemiologic factors to predict an individualʼs ovarian cancer risk ...are set to become available for tailoring preventive and screening approaches. The increasing evidence on tubal origins of a proportion of ovarian cancer has paved the way to use of opportunistic bilateral salpingectomy at tubal ligation and hysterectomy in the general population. Clinical trials are in progress to estimate the long-term effects on endocrine function. In women at high risk, risk reducing salpingo-oophorectomy remains the standard of care with the current focus on management of resulting noncancer outcomes, especially sexual dysfunction in younger women. This has led to evaluation of early bilateral salpingectomy and delayed oophorectomy in this population. Meanwhile, modeling suggests that BRCA mutation carriers should consider using the oral contraceptive pill for chemoprevention. In the general population, the largest ovarian cancer screening trial to date, the UK Collaborative Trial of Ovarian Cancer Screening reported a stage shift with annual multimodal screening using the longitudinal CA 125 Risk of Ovarian Cancer Algorithm but not with annual transvaginal ultrasound screening. There was no definitive mortality reduction with either screening strategy compared with no screening. Further follow-up until December 2018 in now underway. Stage shift and higher rates of optimal cytoreduction were also reported during 3- to 4-monthly multimodal screening in the United Kingdom and U.S. high-risk screening trials. Although all agree that there is not yet evidence to support general population screening, recommendations for high-risk screening vary between countries. A key finding from the screening trials has been the better performance of longitudinal algorithms compared with a single cutoff for CA 125. A major focus of ovarian cancer biomarker discovery work has been tumor DNA markers in both plasma and novel specimens such as cervical cytology samples.
Ovarian cancer screening: Current status and future directions Nash, Zachary; Menon, Usha
Baillière's best practice & research. Clinical obstetrics & gynaecology/Baillière's best practice and research in clinical obstetrics and gynaecology,
20/May , Letnik:
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Ovarian cancer is the third most common gynaecological malignancy and the most lethal worldwide. Most patients are diagnosed with advanced disease which carries significant mortality. Improvements in ...treatment have only resulted in modest increases in survival. This has driven efforts to reduce mortality through screening. Multimodal ovarian cancer screening using a longitudinal CA125 algorithm has resulted in diagnosis at an earlier stage, both in average and high risk women in two large UK trials. However, no randomised controlled trial has demonstrated a definitive mortality benefit. Extended follow up is underway in the largest trial to date, UKCTOCS, to explore the delayed reduction in mortality that was noted. Meanwhile, screening is not currently recommended in the general population Some countries offer surveillance of high risk women. Novel screening modalities and longitudinal biomarker algorithms offer potential improvements to future screening strategies as does the development of better risk stratification tools.
•Screening for ovarian cancer is not currently recommended for the general population.•Extended follow up of the largest trial to date, the UKCTOCS, aims to confirm delayed mortality benefit.•Novel biomarkers and screening strategies have the potential to improve screening further.
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.
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.
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.
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.
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.
The cost-effectiveness of population-based panel testing for high- and moderate-penetrance ovarian cancer (OC)/breast cancer (BC) gene mutations is unknown. We evaluate the cost-effectiveness of ...population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutation testing compared with clinical criteria/family history (FH) testing in unselected general population women.
A decision-analytic model comparing lifetime costs and effects of criteria/FH-based BRCA1/BRCA2 testing is compared with BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing in those fulfilling clinical criteria/strong FH of cancer (≥10% BRCA1/BRCA2 probability) and all women age 30 years or older. Analyses are presented for UK and US populations. Identified carriers undergo risk-reducing salpingo-oophorectomy. BRCA1/BRCA2/PALB2 carriers can opt for magnetic resonance imaging/mammography, chemoprevention, or risk-reducing mastectomy. One-way and probabilistic sensitivity analysis (PSA) enabled model uncertainty evaluation. Outcomes include OC, BC, and additional heart disease deaths. Quality-adjusted life-years (QALYs), OC incidence, BC incidence, and incremental cost-effectiveness ratio (ICER) were calculated. The time horizon is lifetime and perspective is payer.
Compared with clinical criteria/FH-based BRCA1/BRCA2 testing, clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is cost-effective (ICER = £7629.65/QALY or $49 282.19/QALY; 0.04 days' life-expectancy gained). Population-based testing for BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 mutations is the most cost-effective strategy compared with current policy: ICER = £21 599.96/QALY or $54 769.78/QALY (9.34 or 7.57 days' life-expectancy gained). At £30 000/QALY and $100 000/QALY willingness-to-pay thresholds, population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 panel testing is the preferred strategy in 83.7% and 92.7% of PSA simulations; criteria/FH-based panel testing is preferred in 16.2% and 5.8% of simulations, respectively. Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing can prevent 1.86%/1.91% of BC and 3.2%/4.88% of OC in UK/US women: 657/655 OC cases and 2420/2386 BC cases prevented per million.
Population-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than any clinical criteria/FH-based strategy. Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD51D/BRIP1/PALB2 testing is more cost-effective than BRCA1/BRCA2 testing alone.
SUMMARY
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.
Significance Statement
There is increasing evidence for the role of heteromeric enzyme complexes (HECs) during starch biosynthesis in cereal endosperms. This study demonstrates the effects of protein phosphorylation on starch synthase IIa (SSIIa) activity and the formation of SSIIa‐containing HECs. Protein phosphorylation is shown to have multiple effects, modulating the enzyme’s catalytic activity and the balance between high‐molecular‐weight and low‐molecular‐weight complexes, and monomers.
Ovarian cancer has a poor survival rate due to late diagnosis and improved methods are needed for its early detection. Our primary objective was to identify and incorporate additional biomarkers into ...longitudinal models to improve on the performance of CA125 as a first-line screening test for ovarian cancer.
This case-control study nested within UKCTOCS used 490 serial serum samples from 49 women later diagnosed with ovarian cancer and 31 control women who were cancer-free. Proteomics-based biomarker discovery was carried out using pooled samples and selected candidates, including those from the literature, assayed in all serial samples. Multimarker longitudinal models were derived and tested against CA125 for early detection of ovarian cancer.
The best performing models, incorporating CA125, HE4, CHI3L1, PEBP4 and/or AGR2, provided 85.7% sensitivity at 95.4% specificity up to 1 year before diagnosis, significantly improving on CA125 alone. For Type II cases (mostly high-grade serous), models achieved 95.5% sensitivity at 95.4% specificity. Predictive values were elevated earlier than CA125, showing the potential of models to improve lead time.
We have identified candidate biomarkers and tested longitudinal multimarker models that significantly improve on CA125 for early detection of ovarian cancer. These models now warrant independent validation.
There are no internationally agreed upon clinical guidelines as to which women with gynecological cancer would benefit from Lynch syndrome screening or how best to manage the risk of gynecological ...cancer in women with Lynch syndrome. The Manchester International Consensus Group was convened in April 2017 to address this unmet need. The aim of the Group was to develop clear and comprehensive clinical guidance regarding the management of the gynecological sequelae of Lynch syndrome based on existing evidence and expert opinion from medical professionals and patients.
Stakeholders from Europe and North America worked together over a two-day workshop to achieve consensus on best practice.
Guidance was developed in four key areas: (1) whether women with gynecological cancer should be screened for Lynch syndrome and (2) how this should be done, (3) whether there was a role for gynecological surveillance in women at risk of Lynch syndrome, and (4) what preventive measures should be recommended for women with Lynch syndrome to reduce their risk of gynecological cancer.
This document provides comprehensive clinical guidance that can be referenced by both patients and clinicians so that women with Lynch syndrome can expect and receive appropriate standards of care.
Achievement of diabetes care goals is suboptimal globally. Diabetes-focused quality improvement (QI) is effective but remains untested in South Asia.
To compare the effect of a multicomponent QI ...strategy versus usual care on cardiometabolic profiles in patients with poorly controlled diabetes.
Parallel, open-label, pragmatic randomized, controlled trial. (ClinicalTrials.gov: NCT01212328).
Diabetes clinics in India and Pakistan.
1146 patients (575 in the intervention group and 571 in the usual care group) with type 2 diabetes and poor cardiometabolic profiles (glycated hemoglobin HbA1c level ≥8% plus systolic blood pressure BP ≥140 mm Hg and/or low-density lipoprotein cholesterol LDLc level ≥130 mg/dL).
Multicomponent QI strategy comprising nonphysician care coordinators and decision-support electronic health records.
Proportions achieving HbA1c level less than 7% plus BP less than 130/80 mm Hg and/or LDLc level less than 100 mg/dL (primary outcome); mean risk factor reductions, health-related quality of life (HRQL), and treatment satisfaction (secondary outcomes).
Baseline characteristics were similar between groups. Median diabetes duration was 7.0 years; 6.8% and 39.4% of participants had preexisting cardiovascular and microvascular disease, respectively; mean HbA1c level was 9.9%; mean BP was 143.3/81.7 mm Hg; and mean LDLc level was 122.4 mg/dL. Over a median of 28 months, a greater percentage of intervention participants achieved the primary outcome (18.2% vs. 8.1%; relative risk, 2.24 95% CI, 1.71 to 2.92). Compared with usual care, intervention participants achieved larger reductions in HbA1c level (-0.50% CI, -0.69% to -0.32%), systolic BP (-4.04 mm Hg CI, -5.85 to -2.22 mm Hg), diastolic BP (-2.03 mm Hg CI, -3.00 to -1.05 mm Hg), and LDLc level (-7.86 mg/dL CI, -10.90 to -4.81 mg/dL) and reported higher HRQL and treatment satisfaction.
Findings were confined to urban specialist diabetes clinics.
Multicomponent QI improves achievement of diabetes care goals, even in resource-challenged clinics.
National Heart, Lung, and Blood Institute and UnitedHealth Group.
The
tumor-suppressor gene is mutated in >95% of high-grade serous ovarian cancers. Detecting an autologous antibody response to TP53 that might improve early detection.
An immunoassay was developed ...to measure TP53 autoantibody in sera from 378 cases of invasive epithelial ovarian cancer and 944 age-matched healthy controls from the United States, Australia, and the United Kingdom. Serial preclinical samples from cases and controls were also assayed from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).
Using a cutoff value of 78 U/mL to achieve a specificity of 97.4%, TP53 autoantibody was elevated in 30% of 50 cases from MD Anderson, 21.3% of 108 cases from the Australian Ovarian Cancer Study, and 21% of 220 cases from the UKCTOCS. Among 164 cases with rising CA125 detected with the UKCTOCS risk of ovarian cancer algorithm (ROCA), 20.7% had elevated TP53 autoantibody. In cases missed by the ROCA, 16% of cases had elevated TP53 autoantibody. Of the 34 ovarian cancer cases detected with the ROCA, TP53 autoantibody titers were elevated 11.0 months before CA125. In the 9 cases missed by the ROCA, TP53 autoantibody was elevated 22.9 months before cancer diagnosis. Similar sensitivity was obtained using assays with specific mutant and wild-type TP53.
TP53 autoantibody levels provide a biomarker with clinically significant lead time over elevation of CA125 or an elevated ROCA value. Quantitative assessment of autoantibodies in combination with CA125 holds promise for earlier detection of invasive epithelial ovarian cancer.
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Background The present study was designed to evaluate the metabolic profile, cardiovascular risk factors and quality of life in children with congenital adrenal hyperplasia (CAH) and compare it with ...age- and sex-matched controls. Methods Fifty-two patients aged 3-21 years with classic CAH due to 21-hydroxylase deficiency were included in the study. Metabolic profiling was done for 36 cases and compared with 28 healthy age- and sex-matched controls. Quality of life was assessed in all 52 children and their parents using a validated Pediatric Quality of Life Inventory (PedsQL) questionnaire and was compared with normative data from the same population. Results The median age was 12 years with 14 (27%) males and 38 (73%) females. Out of the total 52 patients, 35 (67%) had salt wasting and 17 (33%) had simple virilising CAH. The median height standard deviation score (SDS) of cases was similar to that of controls (-0.72 vs. -0.64, p = 0.57) and 81% of females had normal pubertal status indicating a good control of the disease. Weight SDS, body mass index (BMI) SDS, mean diastolic blood pressure and insulin resistance were significantly higher in cases when compared to controls (0.31 vs. -0.3; 0.96 vs. 0.17; 67.8 ± 10.49 vs. 61 ± 8.49 and 2.1 vs. 0.95, respectively). The quality of life was significantly reduced in all domains as per parents' perspective, whereas the children reported reduced quality of social and school functioning. There was no significant correlation between quality of life and metabolic parameters. Conclusions Children with CAH despite a reasonably good control of the disease have a higher cardiovascular risk and reduced quality of life when compared to healthy controls.
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