Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth
. Presurgical window studies allow rapid
...assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin
using a robust window study design.
A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K-Akt-mTOR and insulin signaling pathways and obesity.
Eighty-eight women received metformin (
= 45) or placebo (
= 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0.57%; 95% CI, -7.57%-6.42%;
= 0.87). Metformin did not affect expression of markers of the PI3K-Akt-mTOR or insulin signaling pathways, and did not result in weight loss.
Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.
This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. ...TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P<0.001). Five-year recurrence-free survival was 93% and 95% for group 3 (POLE-mutant) and group 2 (microsatellite instable) vs 42% (group 1, p53-mutant) and 52% (group 4, NSMP; P<0.001). Targetable FBXW7 and FGFR2 mutations (6%), alterations in the PI3K-AKT pathway (60%) and hormone receptor positivity (45%) were frequently found. In conclusion, molecular analysis of high-risk endometrial cancer identifies four distinct prognostic subgroups, with potential therapeutic implications. High frequencies of targetable alterations were identified and may serve as targets for individualized treatment.
Screening with low-dose computed tomography reduces lung cancer (LC) mortality. Risk prediction models used for screening selection do not include genetic variables. Here, we investigated the ...performance of previously published polygenic risk scores (PRSs) for LC, considering their potential to improve screening selection.
We validated 9 PRSs in a high-risk case-control cohort, comprising genotype data from 652 surgical patients with LC and 550 cancer-free, high-risk (PLCOM2012 score ≥ 1.51%) participants of the Manchester Lung Health Check, a community-based LC screening program (n = 550). Discrimination (area under the curve AUC) between cases and controls was assessed for each PRS independently and alongside clinical risk factors.
Median age was 67 years, 53% were female, 46% were current smokers, and 76% were National Lung Screening Trial eligible. Median PLCOM2012 score among controls was 3.4%, 80% of cases were early stage. All PRSs significantly improved discrimination, AUC increased between +0.002 (P = .02) and +0.015 (P < .0001), compared with clinical risk factors alone. The best-performing PRS had an independent AUC of 0.59. Two novel loci, in the DAPK1 and MAGI2 genes, were significantly associated with LC risk.
PRSs may improve LC risk prediction and screening selection. Further research, particularly examining clinical utility and cost-effectiveness, is required.
Background
Surgical site infection (SSI) rates vary from 1% to 5% in the month following surgery. Due to the large number of surgical procedures conducted annually, the costs of these SSIs can be ...considerable in financial and social terms. Many interventions are used with the aim of reducing the risk of SSI in people undergoing surgery. These interventions can be broadly delivered at three stages: preoperatively, intraoperatively and postoperatively. The intraoperative interventions are largely focused on decontamination of skin using soap and antiseptics; the use of barriers to prevent movement of micro‐organisms into incisions; and optimising the patient's own bodily functions to promote best recovery. Both decontamination and barrier methods can be aimed at people undergoing surgery and operating staff. Other interventions focused on SSI prevention may be aimed at the surgical environment and include methods of theatre cleansing and approaches to managing theatre traffic.
Objectives
To present an overview of Cochrane Reviews of the effectiveness and safety of interventions, delivered during the intraoperative period, aimed at preventing SSIs in all populations undergoing surgery in an operating theatre.
Methods
Published Cochrane systematic reviews reporting the effectiveness of interventions delivered during the intraoperative period in terms of SSI prevention were eligible for inclusion in this overview. We also identified Cochrane protocols and title registrations for future inclusion into the overview. We searched the Cochrane Library on 01 July 2017. Two review authors independently screened search results and undertook data extraction and 'Risk of bias' and certainty assessment. We used the ROBIS (risk of bias in systematic reviews) tool to assess the quality of included reviews, and we used GRADE methods to assess the certainty of the evidence for each outcome. We summarised the characteristics of included reviews in the text and in additional tables.
Main results
We included 32 Cochrane Reviews in this overview: we judged 30 reviews as being at low risk of bias and two at unclear risk of bias. Thirteen reviews had not been updated in the past three years. Two reviews had no relevant data to extract. We extracted data from 30 reviews with 349 included trials, totaling 73,053 participants. Interventions assessed included gloving, use of disposable face masks, patient oxygenation protocols, use of skin antiseptics for hand washing and patient skin preparation, vaginal preparation, microbial sealants, methods of surgical incision, antibiotic prophylaxis and methods of skin closure. Overall, the GRADE certainty of evidence for outcomes was low or very low. Of the 77 comparisons providing evidence for the outcome of SSI, seven provided high‐ or moderate‐certainty evidence, 39 provided low‐certainty evidence and 31 very low‐certainty evidence. Of the nine comparisons that provided evidence for the outcome of mortality, five provided low‐certainty evidence and four very low‐certainty evidence.
There is high‐ or moderate‐certainty evidence for the following outcomes for these intraoperative interventions. (1) Prophylactic intravenous antibiotics administered before caesarean incision reduce SSI risk compared with administration after cord clamping (10 trials, 5041 participants; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.44 to 0.81; high‐certainty evidence ‐ assessed by review authors). (2) Preoperative antibiotics reduce SSI risk compared with placebo after breast cancer surgery (6 trials, 1708 participants; RR 0.74, 95% CI 0.56 to 0.98; high‐certainty evidence ‐ assessed by overview authors). (3) Antibiotic prophylaxis probably reduce SSI risk in caesarean sections compared with no antibiotics (82 relevant trials, 14,407 participants; RR 0.40, 95% CI 0.35 to 0.46; moderate‐certainty evidence; downgraded once for risk of bias ‐ assessed by review authors). (4) Antibiotic prophylaxis probably reduces SSI risk for hernia repair compared with placebo or no treatment (17 trials, 7843 participants; RR 0.67, 95% CI 0.54 to 0.84; moderate‐certainty evidence; downgraded once for risk of bias ‐ assessed by overview authors); (5) There is currently no clear difference in the risk of SSI between iodine‐impregnated adhesive drapes compared with no adhesive drapes (2 trials, 1113 participants; RR 1.03, 95% CI 0.66 to 1.60; moderate‐certainty evidence; downgraded once for imprecision ‐ assessed by review authors); (6) There is currently no clear difference in SSI risk between short‐term compared with long‐term duration antibiotics in colorectal surgery (7 trials; 1484 participants; RR 1.05 95% CI 0.78 to 1.40; moderate‐certainty evidence; downgraded once for imprecision ‐ assessed by overview authors). There was only one comparison showing negative effects associated with the intervention: adhesive drapes increase the risk of SSI compared with no drapes (5 trials; 3082 participants; RR 1.23, 95% CI 1.02 to 1.48; high‐certainty evidence ‐ rated by review authors).
Authors' conclusions
This overview provides the most up‐to‐date evidence on use of intraoperative treatments for the prevention of SSIs from all currently published Cochrane Reviews. There is evidence that some interventions are useful in reducing SSI risk for people undergoing surgery, such as antibiotic prophylaxis for caesarean section and hernia repair, and also the timing of prophylactic intravenous antibiotics administered before caesarean incision. Also, there is evidence that adhesive drapes increase SSI risk. Evidence for the many other treatment choices is largely of low or very low certainty and no quality‐of‐life or cost‐effectiveness data were reported. Future trials should elucidate the relative effects of some treatments. These studies should focus on increasing participant numbers, using robust methodology and being of sufficient duration to adequately assess SSI. Assessment of other outcomes such as mortality might also be investigated as part of non‐experimental prospective follow‐up of people with SSI of different severity, so the risk of death for different subgroups can be better understood.
Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to ...benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n = 89, 68%), followed by null (n = 12, 9%) and cytoplasmic (n = 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n = 22/27; p < 0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC).
Abstract
Background
Cervical cancer remains an important global public health concern. Understanding the factors contributing to a decline in screening uptake in high-income countries is fundamental ...to improving screening rates. We aimed to identify general practice and patient characteristics related to cervical screening coverage in England between 2013 and 2022.
Methods
We analyzed a panel of 59 271 General Practice (GP)-years from 7881 GP practices. We applied correlated random effects regression to examine the association between cervical screening uptake and a rich set of GP practice workforce, size, quality and patient characteristics.
Results
Our results show a decline in overall screening rates from 2013/14 to 2021/22 from 77% to 72%. We find GP workforce and list size characteristics are strongly related to screening rates. An increase in 1 FTE Nurse per 1000 patients is related to a 1.94 percentage point increase in cervical screening rates. GP practices located in more deprived areas have lower screening rates.
Conclusions
GP workforce and patient characteristics need to be considered by decision-makers to increase screening rates. The implementation of self-sampling screening methods could help address some of the current barriers to screening, including lack of healthcare staff and facilities.
Endometrial cancer is the most common malignancy of the female genital tract and its incidence is rising in parallel with the mounting prevalence of obesity. Early diagnosis has great potential to ...improve outcomes as treatment can be curative, especially for early stage disease. Current tests and procedures for diagnosis are limited by insufficient accuracy in some and unacceptable levels of invasiveness and discomfort in others. There has, therefore, been a growing interest in the search for sensitive and specific biomarkers for endometrial cancer detection based on non-invasive sampling methodologies. Urine, the prototype non-invasive sample, is attractive for biomarker discovery as it is easily accessible and can be collected repeatedly and in quantity. Identification of urinary biomarkers for endometrial cancer detection relies on the excretion of systemic biomarkers by the kidneys or urinary contamination by biomarkers shed from the uterus. In this review, we present the current standing of the search for endometrial cancer urinary biomarkers based on cytology, genomic, transcriptomic, proteomic, and metabolomic platforms. We summarize the biomarker candidates and highlight the challenges inherent in urinary biomarker discovery. We review the various technologies with promise for biomarker detection and assess these novel approaches for endometrial cancer biomarker research.
Type 2 diabetes mellitus (T2DM) is an established risk factor for endometrial cancer but its impact on endometrial cancer survival outcomes is unclear. The aim of this study was to investigate ...whether pre-existing T2DM impacts survival outcomes in endometrial cancer.
Women diagnosed with endometrial cancer were recruited to a single centre prospective cohort study. Relevant sociodemographic and clinico-pathological data were recorded at baseline. T2DM status was based on clinical and biochemical assessment, verified by general practitioner records and analysed in relation to overall, cancer-specific and recurrence-free survival using Kaplan-Meier estimation and multivariable Cox-regression.
In total, 533 women with median age and BMI of 66 years (Interquartile range (IQR), 56, 73) and 32kg/m
(IQR 26, 39) respectively, were included in the analysis. The majority had low-grade (67.3%), early-stage (85.1% stage I/II), endometrial cancer of endometrioid histological phenotype (74.7%). A total of 107 (20.1%) had pre-existing T2DM. Women with T2DM had a two-fold increase in overall mortality (adjusted HR 2.07, 95%CI 1.21-3.55, p=0.008), cancer-specific mortality (adjusted HR 2.15, 95% CI 1.05-4.39, p=0.035) and recurrence rates (adjusted HR 2.22, 95% CI 1.08-4.56, p=0.030), compared to those without, in multivariable analyses.
T2DM confers an increased risk of death in endometrial cancer patients. Well-designed longitudinal studies with large sample sizes are now needed to confirm these findings.
Ovarian cancers are hallmarked by chromosomal instability. New therapies deliver improved patient outcomes in relevant phenotypes, however therapy resistance and poor long-term survival signal ...requirements for better patient preselection. An impaired DNA damage response (DDR) is a major chemosensitivity determinant. Comprising five pathways, DDR redundancy is complex and rarely studied alongside chemoresistance influence from mitochondrial dysfunction. We developed functional assays to monitor DDR and mitochondrial states and trialled this suite on patient explants.
We profiled DDR and mitochondrial signatures in cultures from 16 primary-setting ovarian cancer patients receiving platinum chemotherapy. Explant signature relationships to patient progression-free (PFS) and overall survival (OS) were assessed by multiple statistical and machine-learning methods.
DR dysregulation was wide-ranging. Defective HR (HRD) and NHEJ were near-mutually exclusive. HRD patients (44%) had increased SSB abrogation. HR competence was associated with perturbed mitochondria (78% vs 57% HRD) while every relapse patient harboured dysfunctional mitochondria. DDR signatures classified explant platinum cytotoxicity and mitochondrial dysregulation. Importantly, explant signatures classified patient PFS and OS.
Whilst individual pathway scores are mechanistically insufficient to describe resistance, holistic DDR and mitochondrial states accurately predict patient survival. Our assay suite demonstrates promise for translational chemosensitivity prediction.
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