Quantitative liver function imaging and whole genome sequencing - Effective modalities for a new era in personalised decision-making for operable colorectal liver metastases?

Background: The optimal strategy for patients with colorectal liver metastases (CRLM) is unclear. The Precision1 prospective, observational trial assessed whether pre-operative functional imaging and whole genome sequencing (WGS), could enhance individualized decision-making.

Methods: Patients with CRLM considered for hepatectomy were recruited.

Effect of age, sex, breed and venipuncture site on platelet count and clumping in feline blood samples.

Objectives: To evaluate the associations between sex, age, breed and collection site on platelet count and platelet clumping in feline blood samples.

Methods: Cats presenting to a primary care feline hospital from January 2016 to January 2017 were recruited. Any cat undergoing blood collection for a complete blood count was eligible.

Oncolytic herpesvirus expressing PD-L1 BiTE for cancer therapy: exploiting tumor immune suppression as an opportunity for targeted immunotherapy.

Background: Programmed death-ligand 1 (PD-L1) is an important immune checkpoint protein that can be regarded as a pan-cancer antigen expressed by multiple different cell types within the tumor. While antagonizing PD-L1 is well known to relieve PD-1/PD-L1-mediated T cell suppression, here we have combined this approach with an immunotherapy strategy to target T cell cytotoxicity directly toward PD-L1-expressing cells. We developed a bi-specific T cell engager (BiTE) crosslinking PD-L1 and CD3ε and demonstrated targeted cytotoxicity using a clinically relevant patient-derived ascites model.

A Noninvasive Comparison Study between Human Gliomas with IDH1 and IDH2 Mutations by MR Spectroscopy.

The oncogenes that are expressed in gliomas reprogram particular pathways of glucose, amino acids, and fatty acid metabolism. Mutations in isocitrate dehydrogenase genes (IDH1/2) in diffuse gliomas are associated with abnormally high levels of 2-hydroxyglutarate (2-HG) levels. The aim of this study was to determine whether metabolic reprogramming associated with IDH mutant gliomas leads to additional ¹H MRS-detectable differences between IDH1 and IDH2 mutations, and to identify metabolites correlated with 2-HG.

A comparison of 2-hydroxyglutarate detection at 3 and 7 T with long-TE semi-LASER.

Abnormally high levels of the 'oncometabolite' 2-hydroxyglutarate (2-HG) occur in many grade II and III gliomas, and correlate with mutations in the genes of isocitrate dehydrogenase (IDH) isoforms. In vivo measurement of 2-HG in patients, using magnetic resonance spectroscopy (MRS), has largely been carried out at 3 T, yet signal overlap continues to pose a challenge for 2-HG detection. To combat this, several groups have proposed MRS methods at ultra-high field (≥7 T) where theoretical increases in signal-to-noise ratio and spectral resolution could improve 2-HG detection.

Recent advances in molecular pathology of craniopharyngioma.

Craniopharyngiomas are rare epithelial tumours arising along the path of the craniopharyngeal duct. Two major histological subtypes have been recognised, the papillary and the adamantinomatous. Craniopharyngiomas remain challenging tumours to manage and are associated with significant morbidities and mortality.

Prevalence of positive screening test for cognitive impairment among elderly urogynecologic patients.

Background: Impaired cognition has been correlated with adverse postoperative outcomes, such as an increased incidence of delirium, a longer length of hospital stay, and higher 6 month mortality. The incidence of cognitive impairment in the elderly is high. Per the Centers for Disease Control and Prevention, 1 in 8 adults aged 60 years and older deal with memory loss and confusion, and less than 20% inform their health care providers.

Improved localisation for 2-hydroxyglutarate detection at 3T using long-TE semi-LASER.

2-hydroxyglutarate (2-HG) has emerged as a biomarker of tumour cell IDH mutations that may enable the differential diagnosis of glioma patients. At 3 Tesla, detection of 2-HG with magnetic resonance spectroscopy is challenging because of metabolite signal overlap and a spectral pattern modulated by slice selection and chemical shift displacement. Using density matrix simulations and phantom experiments, an optimised semi-LASER scheme (TE = 110 ms) improves localisation of the 2-HG spin system considerably compared to an existing PRESS sequence.

Effects of hydroxyethyl starch 6 % (130/0.4) on blood loss during cesarean delivery: a propensity-matched analysis.

Background: Hydroxyethyl starch is commonly used in the obstetric patient population to prevent hypotension during cesarean delivery. Evidence suggests hetastarch is associated with a dysfunction in coagulation cascade. We hypothesized that hetastarch use to prevent spinal hypotension during cesarean delivery would be associated with an increase in blood loss when compared to crystalloid use.

Noninvasive Quantification of 2-Hydroxyglutarate in Human Gliomas with IDH1 and IDH2 Mutations.

Mutations in the isocitrate dehydrogenase genes (IDH1/2) occur often in diffuse gliomas, where they are associated with abnormal accumulation of the oncometabolite 2-hydroxyglutarate (2-HG). Monitoring 2-HG levels could provide prognostic information in this disease, but detection strategies that are noninvasive and sufficiently quantitative have yet to be developed. In this study, we address this need by presenting a proton magnetic resonance spectroscopy ((1)H-MRS) acquisition scheme that uses an ultrahigh magnetic field (≥ 7T) capable of noninvasively detecting 2-HG with quantitative measurements sufficient to differentiate mutant cytosolic IDH1 and mitochondrial IDH2 in human brain tumors.

The Wnt signalling cascade and the adherens junction complex in craniopharyngioma tumorigenesis.

Craniopharyngiomas are epithelial, sellar tumours with adamantinomatous (aCP) and papillary (pCP) subtypes. The aCP type usually occurs during childhood and pCP in middle-aged adults; aCPs often contain mutations in CTNNB1, encoding β-catenin, a component of the adherens junction and a mediator of Wnt signalling. No such mutational event has been associated with pCPs, where the BRAF gene appears to be more important.

Rathke's cleft cyst.

Rathke's cleft cysts are benign sellar and suprasellar lesions arising from epithelial remnants of Rathke's pouch with a peak incidence at 30-50 years of age. The majority are between 10 and 20mm in diameter and contain mucoid or gelatinous material encapsulated in a thin cyst wall of simple or pseudostratified cuboidal or columnar epithelium. Symptomatic cases are rare, but incidental lesions are found in 11% of unselected postmortem cases.

Sequence analysis of the catalytic subunit of PKA in somatotroph adenomas.

Objective: The pathogenetic mechanisms of sporadic somatotroph adenomas are not well understood, but derangements of the cAMP pathway have been implicated. Recent studies have identified L206R mutations in the alpha catalytic subunit of protein kinase A (PRKACA) in cortisol-producing adrenocortical adenomas and amplification of the beta catalytic subunit of protein kinase A PRKACB in acromegaly associated with Carney complex. Given that both adrenocortical adenomas and somatotroph adenomas are known to be reliant on the cAMP signalling pathway, we sought to determine the relevance of the L206R mutation in both PRKACA and PRKACB for the pathogenesis of sporadic somatotroph adenomas.

Granulation pattern, but not GSP or GHR mutation, is associated with clinical characteristics in somatostatin-naive patients with somatotroph adenomas.

Objective: Somatotroph adenomas causing acromegaly are histologically classified into densely granulated (DG) and sparsely granulated (SG) subtypes with different morphology, clinical characteristics and treatment outcomes. Granulation pattern has been reported to co-segregate with a recurrent mutation at codon 49 in growth hormone receptor (GHR) and GSP oncogene. This study examines response to the octreotide suppression test (OST) in relation to granulation pattern and mutation in GHR and GSP.

Pathology and pathogenesis of craniopharyngiomas.

Craniopharyngiomas are benign but locally invasive tumours of the sellar region that occur as two subtypes. The adamantinomatous type (aCP) occurs mainly during childhood while the papillary type (pCP) is found almost exclusively in adults. It is thought that aCPs arise from ectopic embryonic remnants of Rathke's pouch and these tumours share features with odontogenic tumours suggesting a common origin.

Imidazopurinones are markers of physiological genomic damage linked to DNA instability and glyoxalase 1-associated tumour multidrug resistance.

Glyoxal and methylglyoxal are reactive dicarbonyl metabolites formed and metabolized in physiological systems. Increased exposure to these dicarbonyls is linked to mutagenesis and cytotoxicity and enhanced dicarbonyl metabolism by overexpression of glyoxalase 1 is linked to tumour multidrug resistance in cancer chemotherapy. We report herein that glycation of DNA by glyoxal and methylglyoxal produces a quantitatively important class of nucleotide adduct in physiological systems-imidazopurinones.

Reversal of hyperglycemia-induced angiogenesis deficit of human endothelial cells by overexpression of glyoxalase 1 in vitro.

Dicarbonyl glycation of RGD and GFOGER sites in type IV collagen has been associated with decreased angiogenesis. In this study, we investigated whether overexpression of glyoxalase 1 to decrease dicarbonyl glycation would prevent the angiogenesis deficit induced by hyperglycemia in vitro. Transfection of human microvascular endothelial cells resulted in a four-fold increase in glyoxalase 1 activity compared with controls.