LACC Trial: Final Analysis on Overall Survival Comparing Open Versus Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The aim of this study was to compare overall survival between open and minimally invasive radical hysterectomy with participants followed for 4.5 years. The primary objective was to evaluate whether minimally invasive surgery was noninferior in disease-free survival (DFS) to abdominal radical hysterectomy. Secondary outcomes included overall survival. Sample size was based on DFS of 90% at 4.5 years and 7.2% noninferiority margin for minimally invasive surgery. A total of 631 patients were enrolled: 319 assigned to minimally invasive and 312 to open surgery. Of these, 289 (90.6%) patients underwent minimally invasive surgery and 274 (87.8%) patients open surgery. At 4.5 years, DFS was 85.0% in the minimally invasive group and 96% in the open group (difference of -11.1; 95% CI, -15.8 to -6.3; P = .95 for noninferiority). Minimally invasive surgery was associated with lower rate of DFS compared with open surgery (hazard ratio [HR], 3.91 [95% CI, 2.02 to 7.58]; P < .001). Rate of overall survival at 4.5 years was 90.6% versus 96.2% for the minimally invasive and open surgery groups, respectively (HR for death of any cause = 2.71 [95% CI, 1.32 to 5.59]; P = .007). Given higher recurrence rate and worse overall survival with minimally invasive surgery, an open approach should be standard of care.

Cost-effectiveness of Accepting Kidneys From Deceased Donors With Common Cancers-A Modeling Study.

BACKGROUND: The disparity between the demand for and supply of kidney transplants has resulted in prolonged waiting times for patients with kidney failure. A potential approach to address this shortage is to consider kidneys from donors with a history of common cancers, such as breast, prostate, and colorectal cancers. METHODS: We used a patient-level Markov model to evaluate the outcomes of accepting kidneys from deceased donors with a perceived history of breast, prostate, or colorectal cancer characterized by minimal to intermediate transmission risk. Data from the Australian transplant registry were used in this analysis. The study compared the costs and quality-adjusted life years (QALYs) from the perspective of the Australian healthcare system between the proposed practice of accepting these donors and the conservative practice of declining them. The model simulated outcomes for 1500 individuals waitlisted for a deceased donor kidney transplant for a 25-y horizon. RESULTS: Under the proposed practice, when an additional 15 donors with minimal to intermediate cancer transmission risk were accepted, QALY gains ranged from 7.32 to 20.12. This translates to an approximate increase of 7 to 20 additional years of perfect health. The shift in practice also led to substantial cost savings, ranging between $1.06 and $2.3 million. CONCLUSIONS: The proposed practice of accepting kidneys from deceased donors with a history of common cancers with minimal to intermediate transmission risk offers a promising solution to bridge the gap between demand and supply. This approach likely results in QALY gains for recipients and significant cost savings for the health system.

Testosterone treatment, weight loss and health-related quality of life and psychosocial function in men: a two-year RCT.

OBJECTIVE: To determine the effect of testosterone vs placebo treatment on health-related quality of life (HR-QOL) and psychosocial function in men without pathologic hypogonadism in the context of a lifestyle intervention. DESIGN, SETTING, PARTICIPANTS: Secondary analysis of a 2-year, randomised controlled, testosterone therapy trial for prevention, or reversal of newly diagnosed, type 2 diabetes, enrolling men > 50 years at high risk for type 2 diabetes from six Australian centers. INTERVENTIONS: Injectable testosterone undecanoate or matching placebo on the background of a community-based lifestyle program. MAIN OUTCOMES: Self-reported measures of HR-QOL/psychosocial function. RESULTS: Of 1007 participants randomised into T4DM, 648 (64%) had complete data available for all HR-QOL/psychosocial function assessments at baseline and two years. Over 24 months, while most measures were not different between treatment arms, testosterone treatment, compared with placebo, improved subjective social status and sense of coherence. Baseline HR-QOL/psychosocial function measures did not predict the effect of testosterone treatment on glycemic outcomes, primary endpoints of T4DM. Irrespective of treatment allocation, larger decreases in body weight were associated with improved mental quality of life, mastery, and subjective social status. Men with better baseline physical function, greater sense of coherence, and less depressive symptoms experienced greater associated decreases in body weight, with similar effects on waist circumference. CONCLUSIONS: In this diabetes prevention trial, weight loss induced by a lifestyle intervention improved HR-QOL and psychosocial function in more domains than testosterone treatment. The magnitude of weight and waist circumference reduction were predicted by baseline physical function, depressive symptomology, and sense of coherence.

Sex Differences in Outcome and Prescribing Practice in ST-elevation MI Patients with Multivessel Disease and Incomplete Revascularisation.

Objective: To investigate the extent to which multivessel disease, incomplete revascularisation and prescribing differences contribute to sex-based outcome disparities in patients with ST-elevation MI (STEMI) and establish whether differences in cardiac death and MI (CDMI) rates persist at long-term follow-up. Methods and results: This observational study evaluates sex-based outcome differences (median follow-up 3.6 years; IQR [2.4-5.4]) in a consecutive cohort of patients (n=2,083) presenting with STEMI undergoing percutaneous coronary intervention). Of the studied patients 20.3% (423/2,083) were women and 38.3% (810/2,083) had multivessel disease (MVD). Incomplete revascularisation was common. The median residual SYNTAX score (rSS) was 5.0 (IQR [0-9]) in women and 5.0 (IQR [1-11]) in men (p=0.369), and in patients with MVD it was 9 (IQR [6-17]) in women and 10 (IQR [6-15]) in men (p=0.838). The primary endpoint CDMI occurred in 20.3% of women (86/423) and in 13.2% of men (219/1,660) (p=0.028). Differences persisted following multivariable risk adjustment: female sex was independently associated with CDMI (aHR 1.33; IQR [1.02-1.74]). Women with MVD had CDMI more often than all other groups (p<0.001 for all). Significant sex-based prescribing differences were evident: women were less likely to receive guideline-recommended potent P2Y12 inhibitors than men (31% versus 43%; p=0.012), and differences were particularly evident in patients with MVD (25% in women versus 45% in men, p=0.011). Conclusion: Sex-based differences in STEMI patient outcome persist at long-term follow-up. Poor outcomes were disproportionately found in women with MVD and those with rSS>8. Observed differences in P2Y12 prescribing practices may contribute to poor outcomes for women with MVD and incomplete revascularisation.

Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial.

OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant hand-grip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥95 cm, serum total testosterone ≤14 nmol/L (immunoassay), and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle programme and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2 years (OGTT ≥ 11.1 mmol/L and change in 2-h glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG, were performed. RESULTS: For type 2 diabetes at 2 years, the unadjusted OR for treatment was 0.53 (95% CI:.35-.79), which became 0.48 (95% CI:.30-.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; P < .001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.

Protocol for a Nested, Retrospective Study of the Australian Placental Transfusion Study Cohort.

Background Neonates, particularly if born preterm or with congenital anomalies, are among the pediatric patients most likely to need blood transfusion. However, they are also particularly vulnerable to adverse consequences of blood transfusion. Aiming to clamp the umbilical cord for at least a minute after birth is a simple safe procedure that is being increasingly adopted worldwide, although may be associated with increased rates of polycythemia and jaundice. It may also reduce the proportion of preterm babies who need a blood transfusion. The mechanisms for this are not fully understood. Potential mechanisms could include an increased volume of blood transfusion from the placenta to the baby after birth, and an overall reduction in the severity of illness in the first weeks after birth, which could lead to fewer blood tests and greater tolerance of anemia, or enhanced erythropoiesis. Objectives To investigate the mechanism behind the reduced need for blood transfusions after deferral of cord clamping. Methodology This protocol outlines the methods and data analysis plan for a study using nested retrospective data from a large randomized trial combined with additional data collected from patient medical and pathology records. The additional data items to be collected all relate to the receipt of transfusion and the factors that affect the risk for transfusion in preterm babies. The analysis will include all randomized babies from Australia and New Zealand for whom data are available. Causal mediation analysis is planned to estimate the effects of mediators on the relationship between the timing of cord clamping and the need for blood transfusion. The analysis is designed to discern whether initial severity of illness or the magnitude of placental transfusion mediates red blood cell transfusion dependence. Anticipated outcomes and dissemination We expect the study will identify potential strategies for reducing blood transfusions and associated negative outcomes in preterm infants. This will be relevant to researchers, clinicians, and parents. The results will be disseminated through publications, presentations, and inclusion in evidence-based guidelines.

Maternal diabetes independent of BMI is associated with altered accretion of adipose tissue in large for gestational age fetuses.

AIM: To analyse the effects of maternal diabetes mellitus (DM) and body mass Index (BMI) on central and peripheral fat accretion of large for gestational age (LGA) offspring. METHODS: This retrospective study included LGA fetuses (n = 595) with ultrasound scans at early (19.23 ± 0.68 weeks), mid (28.98 ± 1.62 weeks) and late (36.20 ± 1.59 weeks) stages of adipogenesis and measured abdominal (AFT) and mid-thigh (TFT) fat as surrogates for central and peripheral adiposity. Women were categorised according to BMI and DM status [pre-gestational (P-DM; n = 59), insulin managed (I-GDM; n = 132) and diet managed gestational diabetes (D-GDM; n = 29)]. Analysis of variance and linear regressions were applied. RESULTS: AFT and TFT did not differ significantly between BMI categories (normal, overweight and obese). In contrast, AFT was significantly higher in pregnancies affected by D-GDM compared to non-DM pregnancies from mid stage (0.44 mm difference, p = 0.002) and for all DM categories in late stage of adipogenesis (≥ 0.49 mm difference, p < 0.008). Late stage TFT accretion was higher than controls for P-DM and I-GDM but not for D-GDM (0.67 mm difference, p < 0.001; 0.49 mm difference, p = 0.001, 0.56 mm difference, p = 0.22 respectively). In comparison to the early non-DM group with an AFT to TFT ratio of 1.07, the I-GDM group ratio was 1.25 (p < 0.001), which normalised by 28 weeks becoming similar to control ratios. CONCLUSIONS: DM, independent of BMI, was associated with higher abdominal and mid-thigh fat accretion in fetuses. Use of insulin improved central to peripheral fat ratios in fetuses of GDM mothers.

An individual participant data meta-analysis of breast cancer detection and recall rates for digital breast tomosynthesis versus digital mammography population screening.

BACKGROUND: Although digital breast tomosynthesis (DBT) improves breast cancer screen-detection compared to digital mammography (DM), there is less evidence on comparative screening outcomes by age and breast density, and inconsistent evidence on its effect on recall rate. METHOD: We performed an individual participant data (IPD) meta-analysis from DBT screening studies (identified to November, 30 2019) that contributed to the study protocol. We estimated and compared cancer detection rate (CDR), recall rate, and positive predictive value (PPV) for recall for DBT and DM screening. Two-stage random-effects meta-analyses of detection outcomes adjusted for study and age, and were estimated in age and density subgroups. Screen-detected cancer characteristics were summarized descriptively within studies and screening-groups. RESULTS: Four prospective studies, from European population-based programs, contributed IPD for 66,451 DBT-screened participants and 170,764 DM-screened participants. Age-adjusted pooled CDR difference between DBT and DM was 25.49 of 10,000 (95% CI:6.73-44.25). There was suggestive evidence of a higher CDR for DBT compared to DM in the high-density (35.19 of 10,000; 95% CI:17.82-56.56) compared to low-density (17.4 of 10,000; 95% CI:7.62-27.18) group (P = .08). Pooled CDR difference between DBT and DM did not differ across age-groups (P = .71). Age-adjusted recall rate difference was 0.18% (95% CI:-0.80-1.17), indicating no difference between DBT and DM- this finding did not differ across age-groups (P = .96). Recall PPV was higher for DBT than DM with an estimated rate ratio of 1.31 (95% CI:1.07-1.61). DISCUSSION: DBT improved CDR compared to DM in all age and density groups. DBT also had higher recall PPV than DM, although further research is needed to explore the heterogeneity in recall rates across studies.

Distributional regression in clinical trials: treatment effects on parameters other than the mean.

BACKGROUND: The classical linear model is widely used in the analysis of clinical trials with continuous outcomes. However, required model assumptions are frequently not met, resulting in estimates of treatment effect that can be inefficient and biased. In addition, traditional models assess treatment effect only on the mean response, and not on other aspects of the response, such as the variance. Distributional regression modelling overcomes these limitations. The purpose of this paper is to demonstrate its usefulness for the analysis of clinical trials, and superior performance to that of traditional models. METHODS: Distributional regression models are demonstrated, and contrasted with normal linear models, on data from the LIPID randomized controlled trial, which compared the effects of pravastatin with placebo in patients with coronary heart disease. Systolic blood pressure (SBP) and the biomarker midregional pro-adrenomedullin (MR-proADM) were analysed. Treatment effect was estimated in models that used response distributions more appropriate than the normal (Box-Cox-t and Johnson's Su for MR-proADM and SBP, respectively), applied censoring below the detection limit of MR-proADM, estimated treatment effect on distributional parameters other than the mean, and included random effects for longitudinal observations. A simulation study was conducted to compare the performance of distributional regression models with normal linear regression, under conditions mimicking the LIPID study. The R package gamlss (Generalized Additive Models for Location, Scale and Shape), which implements maximum likelihood estimation for distributional regression modelling, was used throughout. RESULTS: In all cases the distributional regression models fit the data well, in contrast to poor fits obtained for traditional models; for MR-proADM a small but significant treatment effect on the mean was detected by the distributional regression model and not the normal model; and for SBP a beneficial treatment effect on the variance was demonstrated. In the simulation study distributional models strongly outperformed normal models when the response variable was non-normal and heterogeneous; and there was no disadvantage introduced by the use of distributional regression modelling when the response satisfied the normal linear model assumptions. CONCLUSIONS: Distributional regression models are a rich framework, largely untapped in the clinical trials world. We have demonstrated a sample of the capabilities of these models for the analysis of trials. If interest lies in accurate estimation of treatment effect on the mean, or other distributional features such as variance, the use of distributional regression modelling will yield superior estimates to traditional normal models, and is strongly recommended. TRIAL REGISTRATION: The LIPID trial was retrospectively registered on ANZCTR on 27/04/2016, registration number ACTRN12616000535471 .

Unpacking the behavioural components and delivery features of early childhood obesity prevention interventions in the TOPCHILD Collaboration: a systematic review and intervention coding protocol.

INTRODUCTION: Little is known about how early (eg, commencing antenatally or in the first 12 months after birth) obesity prevention interventions seek to change behaviour and which components are or are not effective. This study aims to (1) characterise early obesity prevention interventions in terms of target behaviours, delivery features and behaviour change techniques (BCTs), (2) explore similarities and differences in BCTs used to target behaviours and (3) explore effectiveness of intervention components in preventing childhood obesity. METHODS AND ANALYSIS: Annual comprehensive systematic searches will be performed in Epub Ahead of Print/MEDLINE, Embase, Cochrane (CENTRAL), CINAHL, PsycINFO, as well as clinical trial registries. Eligible randomised controlled trials of behavioural interventions to prevent childhood obesity commencing antenatally or in the first year after birth will be invited to join the Transforming Obesity in CHILDren Collaboration. Standard ontologies will be used to code target behaviours, delivery features and BCTs in both published and unpublished intervention materials provided by trialists. Narrative syntheses will be performed to summarise intervention components and compare applied BCTs by types of target behaviours. Exploratory analyses will be undertaken to assess effectiveness of intervention components. ETHICS AND DISSEMINATION: The study has been approved by The University of Sydney Human Research Ethics Committee (project no. 2020/273) and Flinders University Social and Behavioural Research Ethics Committee (project no. HREC CIA2133-1). The study's findings will be disseminated through peer-reviewed publications, conference presentations and targeted communication with key stakeholders. PROSPERO REGISTRATION NUMBER: CRD42020177408.

Transforming Obesity Prevention for CHILDren (TOPCHILD) Collaboration: protocol for a systematic review with individual participant data meta-analysis of behavioural interventions for the prevention of early childhood obesity.

INTRODUCTION: Behavioural interventions in early life appear to show some effect in reducing childhood overweight and obesity. However, uncertainty remains regarding their overall effectiveness, and whether effectiveness differs among key subgroups. These evidence gaps have prompted an increase in very early childhood obesity prevention trials worldwide. Combining the individual participant data (IPD) from these trials will enhance statistical power to determine overall effectiveness and enable examination of individual and trial-level subgroups. We present a protocol for a systematic review with IPD meta-analysis to evaluate the effectiveness of obesity prevention interventions commencing antenatally or in the first year after birth, and to explore whether there are differential effects among key subgroups. METHODS AND ANALYSIS: Systematic searches of Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsycInfo and trial registries for all ongoing and completed randomised controlled trials evaluating behavioural interventions for the prevention of early childhood obesity have been completed up to March 2021 and will be updated annually to include additional trials. Eligible trialists will be asked to share their IPD; if unavailable, aggregate data will be used where possible. An IPD meta-analysis and a nested prospective meta-analysis will be performed using methodologies recommended by the Cochrane Collaboration. The primary outcome will be body mass index z-score at age 24±6 months using WHO Growth Standards, and effect differences will be explored among prespecified individual and trial-level subgroups. Secondary outcomes include other child weight-related measures, infant feeding, dietary intake, physical activity, sedentary behaviours, sleep, parenting measures and adverse events. ETHICS AND DISSEMINATION: Approved by The University of Sydney Human Research Ethics Committee (2020/273) and Flinders University Social and Behavioural Research Ethics Committee (HREC CIA2133-1). Results will be relevant to clinicians, child health services, researchers, policy-makers and families, and will be disseminated via publications, presentations and media releases. PROSPERO REGISTRATION NUMBER: CRD42020177408.

A consensus-based core feature set for surgical complexity at laparoscopic hysterectomy.

BACKGROUND: There are no current standardized and accepted methods to characterize the surgical complexity of a laparoscopic hysterectomy. This leads to challenges when trying to understand the relationship between the patient and the surgical features and outcomes. The development of core feature sets for laparoscopic hysterectomy studies would enable future trials to measure the similar meaningful variables that can contribute to surgical complexity and outcomes. OBJECTIVE: The purpose of this study was to develop a core feature set for the surgical complexity of a laparoscopic hysterectomy. STUDY DESIGN: This was an international Delphi consensus study. A comprehensive literature review was conducted to identify the features that were reported in studies on laparoscopic hysterectomy complexity. All the features were presented for evaluation and prioritization to key experts in 3 rounds of online surveys. A priori consensus criteria were used to reach agreement on the final outcomes for inclusion in the core feature set. RESULTS: Experts represented North America, South America, Europe, Africa, Asia, and Oceania. Most of them had fellowship training in minimally invasive gynecologic surgery. Sixty-four potential features were entered into round 1. Experts reached a consensus on 7 features to be included in the core feature set. These features were grouped under the following domains: 1) patient features, 2) uterine features, and 3) nonuterine pelvic features. The patient features include obesity and other nonobesity comorbidities that alter or limit the ability of a surgeon to perform the basic or routine steps in a laparoscopic hysterectomy. The uterine features include the size and presence of fibroids. The nonuterine pelvic features include endometriosis, ovarian cysts, and adhesions (bladder-to-uterus, rectouterine pouch, and other adhesions). CONCLUSION: Using robust consensus science methods, an international consortium of experts has developed a core feature set that should be assessed and reported in all future studies that aim to assess the relationship between the patient features and surgical outcomes of laparoscopic hysterectomy.

Effects of delayed versus immediate umbilical cord clamping in reducing death or major disability at 2 years corrected age among very preterm infants (APTS): a multicentre, randomised clinical trial.

BACKGROUND: Very preterm infants are at increased risk of adverse outcomes in early childhood. We assessed whether delayed clamping of the umbilical cord reduces mortality or major disability at 2 years in the APTS Childhood Follow Up Study. METHODS: In this long-term follow-up analysis of the multicentre, randomised APTS trial in 25 centres in seven countries, infants (<30 weeks gestation) were randomly assigned before birth (1:1) to have clinicians aim to delay clamping for 60 s or more or clamp within 10 s of birth, both without cord milking. The primary outcome was death or major disability (cerebral palsy, severe visual loss, deafness requiring a hearing aid or cochlear implants, major language or speech problems, or cognitive delay) at 2 years corrected age, analysed in the intention-to-treat population. This trial is registered with the Australian and New Zealand Clinical Trials Registry (ACTRN12610000633088). FINDINGS: Between Oct 21, 2009, and Jan 6, 2017, consent was obtained for follow-up for 1531 infants, of whom 767 were randomly assigned to delayed clamping and 764 to immediate clamping. 384 (25%) of 1531 infants were multiple births, 862 (56%) infants were male, and 505 (33%) were born before 27 weeks gestation. 564 (74%) of 767 infants assigned to delayed clamping and 726 (96%) of 764 infants assigned to immediate clamping received treatment that fully adhered to the protocol. Death or major disability was determined in 1419 (93%) infants and occurred in 204 (29%) of 709 infants who were assigned to delayed clamping versus 240 (34%) of 710 assigned to immediate clamping, (relative risk [RR]) 0·83, 95% CI 0·72-0·95; p=0·010). 60 (8%) of 725 infants in the delayed clamping group and 81 (11%) of 720 infants in the immediate clamping group died by 2 years of age (RR 0·70, 95% CI 0·52-0·95); among those who survived, major disability at 2 years occurred in 23% (144/627) versus 26% (159/603) of infants, respectively (RR 0·88, 0·74-1·04). INTERPRETATION: Clamping the umbilical cord at least 60 s after birth reduced the risk of death or major disability at 2 years by 17%, reflecting a 30% reduction in relative mortality with no difference in major disability. FUNDING: Australian National Health and Medical Research Council.

Results of PD-L1 Analysis of Women Treated with Durvalumab in Advanced Endometrial Carcinoma (PHAEDRA).

Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.

Differential Levels of mRNAs in Normal B Lymphocytes, Monoclonal B Lymphocytosis and Chronic Lymphocytic Leukemia Cells from the Same Family Identify Susceptibility Genes.

INTRODUCTION: People with a family history of chronic lymphocytic leukemia (F-CLL) have an increased risk of monoclonal B lymphocytosis (F-MBL), which is found in up to 18% of first-degree relatives of patients compared to 5% of the total population. This may indicate that the presence of an F-MBL in the relative of a F-CLL patient is due to genetic susceptibility. In this study, we hypothesized that progressive changes in gene expression result in malignant transformation of B lymphocytes to F-MBL, and subsequent alterations in gene expression occur before overt F-CLL develops. The aim of this study of affected and unaffected individuals from a family with multiple CLL cases was to compare mRNA expression levels in control B-lymphocytes, pre-malignant F-MBL and malignant F-CLL cells. METHODS: To identify inherited changes in gene expression, a high-resolution DNA microarray was used to identify differentially abundant mRNAs in age-matched cases of F-MBL (n = 4), F-CLL (n = 2) and unaffected family relatives (F-Controls, n = 3) within one family. These were then compared to non-kindred controls (NK-Controls, n = 3) and sporadic CLL (S-CLL) cases (n = 6). RESULTS: Seven differentially abundant mRNAs were identified against similar genetic backgrounds of the family: GRASP and AC016745.3 were decreased in F-MBL and further decreased in F-CLL compared to F-Controls, whereas C11orf80 and METTL8 were progressively increased. PARP3 was increased in F-MBL compared to F-Controls but was decreased in F-CLL compared to F-MBL. Compared to F-Controls, levels of ROR1 and LEF1 were similarly increased in F-MBL and F-CLL. For six of the genes, there were no differences in mRNA levels between S-CLL and F-CLL; however PARP3 was higher in S-CLL. CONCLUSION: These results are consistent with the hypothesis that changes in expression of specific genes contribute to transformation from normal lymphocytes to MBL and CLL.

Association Between Premorbid Beta-Blocker Exposure and Sepsis Outcomes-The Beta-Blockers in European and Australian/American Septic Patients (BEAST) Study.

OBJECTIVES: To examine the effect of premorbid ß-blocker exposure on mortality and organ dysfunction in sepsis. DESIGN: Retrospective observational study. SETTING: ICUs in Australia, the Czech Republic, and the United States. PATIENTS: Total of 4,086 critical care patients above 18 years old with sepsis between January 2014 and December 2018. INTERVENTION: Premorbid beta-blocker exposure. MEASUREMENTS AND MAIN RESULTS: One thousand five hundred fifty-six patients (38%) with premorbid ß-blocker exposure were identified. Overall ICU mortality rate was 15.1%. In adjusted models, premorbid ß-blocker exposure was associated with decreased ICU (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97; p = 0.025) and hospital (adjusted odds ratio, 0.83; 95% CI, 0.71-0.99; p = 0.033) mortality. The risk reduction in ICU mortality of 16% was significant (hazard ratio, 0.84, 95% CI, 0.71-0.99; p = 0.037). In particular, exposure to noncardioselective ß-blocker before septic episode was associated with decreased mortality. Sequential Organ Failure Assessment score analysis showed that premorbid ß-blocker exposure had potential benefits in reducing respiratory and neurologic dysfunction. CONCLUSIONS: This study suggests that ß-blocker exposure prior to sepsis, especially to noncardioselective ß blockers, may be associated with better outcome. The findings suggest prospective evaluation of ß-blocker use in the management of sepsis.

Interval breast cancer rates for digital breast tomosynthesis versus digital mammography population screening: An individual participant data meta-analysis.

BACKGROUND: Digital breast tomosynthesis (DBT) improves breast cancer (BC) detection compared to mammography, however, it is unknown whether this reduces interval cancer rate (ICR) at follow-up. METHODS: Using individual participant data (IPD) from DBT screening studies (identified via periodic literature searches July 2016 to November 2019) we performed an IPD meta-analysis. We estimated ICR for DBT-screened participants and the difference in pooled ICR for DBT and mammography-only screening, and compared interval BC characteristics. Two-stage meta-analysis (study-specific estimation, pooled synthesis) of ICR included random-effects, adjusting for study and age, and was estimated in age and density subgroups. Comparative screening sensitivity was calculated using screen-detected and interval BC data. FINDINGS: Four prospective DBT studies, from European population-based programs, contributed IPD for 66,451 DBT-screened participants: age-adjusted pooled ICR was 13.17/10,000 (95%CI: 8.25-21.02). Pooled ICR was higher in the high-density (21.08/10,000; 95%CI: 6.71-66.27) than the low-density (8.63/10,000; 95%CI: 5.25-14.192) groups (P = 0.03) however estimates did not differ across age-groups (P = 0.32). Based on two studies that also provided data for 153,800 mammography screens (age-adjusted ICR 17.69/10,000; 95%CI: 13.22-23.66), DBT's pooled ICR was 16.83/10,000 (95%CI: 11.89-23.82). Comparative meta-analysis showed a non-significant difference in ICR (-0.44/10,000; 95%CI: -11.00-10.11) and non-significant difference in screening sensitivity (6.79%; 95%CI: -0.73-14.87%) between DBT and DM but a significant pooled difference in cancer detection rate of 33.49/10,000 (95%CI: 23.88-43.10). Distribution of interval BC prognostic characteristics did not differ between screening modalities except that those occurring in DBT-screened participants were significantly more likely to be negative for axillary-node metastases (P = 0.005). INTERPRETATION: Although heterogeneity in ICR estimates and few datasets limit recommendations, there was no difference between DBT and mammography in pooled ICR despite DBT increasing cancer detection.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

Effect of Testosterone Treatment on Bone Microarchitecture and Bone Mineral Density in Men: A 2-Year RCT.

CONTEXT: Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. OBJECTIVE: We aimed to determine the effect of testosterone treatment on bone microarchitecture using high resolution-peripheral quantitative computed tomography (HR-pQCT). METHODS: Men ≥ 50 years of age were recruited from 6 Australian centers and were randomized to receive injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. The primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (1 center). Secondary endpoints included other HR-pQCT parameters and bone remodeling markers. Areal BMD (aBMD) was measured by dual-energy x-ray absorptiometry (DXA) in 601 men (5 centers). Using a linear mixed model for repeated measures, the mean adjusted differences (95% CI) at 12 and 24 months between groups are reported as treatment effect. RESULTS: Over 24 months, testosterone treatment, versus placebo, increased tibial cortical vBMD, 9.33 mg hydroxyapatite (HA)/cm3) (3.96, 14.71), P < 0.001 or 3.1% (1.2, 5.0); radial cortical vBMD, 8.96 mg HA/cm3 (3.30, 14.62), P = 0.005 or 2.9% (1.0, 4.9); total tibial vBMD, 4.16 mg HA/cm3 (2.14, 6.19), P < 0.001 or 1.3% (0.6, 1.9); and total radial vBMD, 4.42 mg HA/cm3 (1.67, 7.16), P = 0.002 or 1.8% (0.4, 2.0). Testosterone also significantly increased cortical area and thickness at both sites. Effects on trabecular architecture were minor. Testosterone reduced bone remodeling markers CTX, -48.1 ng/L [-81.1, -15.1], P < 0.001 and P1NP, -6.8 µg/L[-10.9, -2.7], P < 0.001. Testosterone significantly increased aBMD at the lumbar spine, 0.04 g/cm2 (0.03, 0.05), P < 0.001 and the total hip, 0.01 g/cm2 (0.01, 0.02), P < 0.001. CONCLUSION: In men ≥ 50 years of age, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.