Longitudinal monitoring of circulating tumor DNA to detect relapse early and predict outcome in early breast cancer.

Purpose: Detection of molecular residual disease (MRD) allows for the identification of breast cancer patients at high-risk of recurrence, with the potential that early initiation of treatment at early stages of relapse could improve patient outcomes. The Invitae Personalized Cancer Monitoring™ assay (PCM) is a newly developed next-generation sequencing approach that utilizes up to 50 patient-specific, tumor-informed DNA variants, to detect circulating tumor DNA (ctDNA). The ability of the PCM assay to detect MRD before clinical relapse was evaluated.

Effects of dexmedetomidine on kidney and brain tissue microcirculation and histology in ovine cardiopulmonary bypass: a randomised controlled trial.

Cardiac surgery requiring cardiopulmonary bypass is associated with postoperative acute kidney injury and neurocognitive disorders, including delirium. Intra-operative inflammation and/or impaired tissue perfusion/oxygenation are thought to be contributors to these outcomes. It has been hypothesised that these problems may be ameliorated by the highly selective α -agonist, dexmedetomidine.

Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015).

Purpose: Ki67 assessed at diagnosis (Ki67) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki67) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki67) with recurrence-free survival. The aim was to define the association between Ki67 and after aromatase inhibitor (AI) exposure ∆Ki67 and Ki67 with key prognostic and biologic factors utilising data from the POETIC study.

Prevention of lymphoedema after axillary clearance by external compression sleeves PLACE randomised trial results. Effects of high BMI.

Unlabelled: Around 25% of women undergoing Axillary Clearance (ANC) develop lymphedema (LE). Intervention with a compression garment is recommended to prevent LE but no randomised evidence exists to support this strategy.

Methods: A randomised trial tested standard management versus application of graduated compression garments (20-24 mmHg) to affected arm, for 1 year.

Increased retinal drusen in IgA glomerulonephritis are further evidence for complement activation in disease pathogenesis.

Drusen are retinal deposits comprising cell debris, immune material and complement that are characteristic of macular degeneration but also found in glomerulonephritis. This was a pilot cross-sectional study to determine how often drusen occurred in IgA glomerulonephritis and their clinical significance. Study participants underwent non-mydriatic retinal photography, and their deidentified retinal images were examined for drusen by two trained graders, who compared central drusen counts, counts ≥ 10 and drusen size with those of matched controls.

Relationship between ER expression by IHC or mRNA with Ki67 response to aromatase inhibition: a POETIC study.

Background: In clinical practice, oestrogen receptor (ER) analysis is almost entirely by immunohistochemistry (IHC). ASCO/CAP recommends cut-offs of < 1% (negative) and 1-10% (low) cells positive. There is uncertainty whether patients with ER low tumours benefit from endocrine therapy.

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer.

Background: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks' presurgical AI treatment in ER+/HER2+ BCs.

Independent of Renox, NOX5 Promotes Renal Inflammation and Fibrosis in Diabetes by Activating ROS-Sensitive Pathways.

Excessive production of renal reactive oxygen species (ROS) plays a major role in diabetic kidney disease (DKD). Here, we provide key findings demonstrating the predominant pathological role of the pro-oxidant enzyme NADPH oxidase 5 (NOX5) in DKD, independent of the previously characterized NOX4 pathway. In patients with diabetes, we found increased expression of renal NOX5 in association with enhanced ROS formation and upregulation of ROS-sensitive factors early growth response 1 (EGR-1), protein kinase C-α (PKC-α), and a key metabolic gene involved in redox balance, thioredoxin-interacting protein (TXNIP).

Impact of the menstrual cycle on commercial prognostic gene signatures in oestrogen receptor-positive primary breast cancer.

Purpose: Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured.

Methods: Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle.

Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial.

Background: Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki67) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67). The POETIC trial aimed to test these two hypotheses.

Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer.

Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC.

Increases in arm volume predict lymphoedema and quality of life deficits after axillary surgery: a prospective cohort study.

Background: Lymphoedema develops after axillary clearance (ANC) in 25% of patients. This prospective, multi-centre study compared multi-frequency bioimpedance spectroscopy (BIS) with arm volume measurement to: (1) determine which test has better diagnostic accuracy, (2) identify factors predicting development of lymphoedema, and its effect on quality-of-life.

Methods: Participants (N = 1100) underwent measurements pre and post-ANC surgery for breast cancer.

Impact of aromatase inhibitor treatment on global gene expression and its association with antiproliferative response in ER+ breast cancer in postmenopausal patients.

Background: Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance.

Methods: Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (control n = 56) from the POETIC trial.

Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer.

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used.

Complement C5a Induces Renal Injury in Diabetic Kidney Disease by Disrupting Mitochondrial Metabolic Agility.

The sequelae of diabetes include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury associated with a disruption in mitochondrial metabolic agility, inflammation, and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes; conventional renoprotective agents did not therapeutically target this elevation.

Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer.

Importance: Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse.

Objective: To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer.

Three Dimensional Glomerular Reconstruction: A Novel Approach to Evaluate Renal Microanatomy in Diabetic Kidney Disease.

Mesangial metrics reflect glomerular filtration surface area in diabetes. The point-sampled intercept (PSI) method is the conventional method to calculate these parameters. However, this is time consuming and subject to underestimation.

Diagnostic application of kidney allograft-derived absolute cell-free DNA levels during transplant dysfunction.

Graft-derived cell-free DNA (donor-derived cell-free DNA) is an emerging marker of kidney allograft injury. Studies examining the clinical validity of this biomarker have previously used the graft fraction, or proportion of total cell-free DNA that is graft-derived. The present study evaluated the diagnostic validity of absolute measurements of graft-derived cell-free DNA, as well as calculated graft fraction, for the diagnosis of graft dysfunction.

Major Impact of Sampling Methodology on Gene Expression in Estrogen Receptor-Positive Breast Cancer.

To investigate the impact of sampling methodology on gene expression data from primary estrogen receptor-positive (ER+) breast cancer biopsies, global gene expression was measured in core-cut biopsies at baseline and surgery from patients randomly assigned to receive either two weeks of presurgical aromatase inhibitor (AI; n = 157) or no presurgical treatment (n = 56). Those genes most markedly altered in the AI group (eg, , , , ) were similarly altered in the no treatment group; some widely investigated genes that were apparently unaffected in the AI group (eg, ) were counter-altered in the control group, masking actual AI-dependent changes. In the absence of a control group, these artefactual changes would likely lead to the most affected genes being the erroneous focus of research.

Interobserver agreement for post mortem renal histopathology and diagnosis of acute tubular necrosis in critically ill patients.

Background: The renal histopathology of critically ill patients dying with acute kidney injury (AKI) in intensive care units of high income countries remains uncertain.

Methods: Retrospective observational assessment of interobserver agreement in the reporting of renal post mortem histopathology, and the ability of pathologists blinded to the clinical context to independently identify the presence of pre-mortem AKI from digital images of histological sections from 34 critically ill patients dying in teaching hospitals in Australia and Canada.

Results: We identified a heterogeneous cohort with a median age of 65 years (interquartile range [IQR], 56.