Combination therapies in clinical trials for renal cell carcinoma: how could they impact future treatments?

Introduction: Pharmacological combinations using immune checkpoint inhibition (ICI), tyrosine kinase inhibition (TKIs), and mammalian target of rapamycin inhibitors (mTOR) have improved survival in metastatic clear cell renal cell cancer (mccRCC). Despite improvements in survival, complete durable responses are rare.

Areas Covered: Molecular pathways involved in mccRCC and drugs targets are highlighted.

Inherited salt-losing tubulopathies are associated with immunodeficiency due to impaired IL-17 responses.

Increased extracellular sodium activates Th17 cells, which provide protection from bacterial and fungal infections. Whilst high salt diets have been shown to worsen autoimmune disease, the immunological consequences of clinical salt depletion are unknown. Here, we investigate immunity in patients with inherited salt-losing tubulopathies (SLT).

Approaches to screening for hyperglycaemia in pregnant women during and after the COVID-19 pandemic.

Aim: To evaluate the diagnostic and prognostic performance of alternative diagnostic strategies to oral glucose tolerance tests, including random plasma glucose, fasting plasma glucose and HbA , during the COVID-19 pandemic.

Methods: Retrospective service data (Cambridge, UK; 17 736 consecutive singleton pregnancies, 2004-2008; 826 consecutive gestational diabetes pregnancies, 2014-2019) and 361 women with ≥1 gestational diabetes risk factor (OPHELIA prospective observational study, UK) were included. Pregnancy outcomes included gestational diabetes (National Institute of Health and Clinical Excellence or International Association of Diabetes and Pregnancy Study Groups criteria), diabetes in pregnancy (WHO criteria), Caesarean section, large-for-gestational age infant, neonatal hypoglycaemia and neonatal intensive care unit admission.

Hydrogen Gas Does Not Ameliorate Renal Ischemia Reperfusion Injury in a Preclinical Model.

In renal transplantation, ischemia reperfusion injury impairs early graft function and can reduce long term graft survival. Hydrogen has antioxidant and anti-inflammatory properties that can reduce the effects of ischemic injury. The aim of this study was to examine the effects of hydrogen gas administered during reperfusion in a preclinical model of kidney ischemia reperfusion injury.

Plateau Waves of Intracranial Pressure and Partial Pressure of Cerebral Oxygen.

This study investigates 55 intracranial pressure (ICP) plateau waves recorded in 20 patients after severe traumatic brain injury (TBI) with a focus on a moving correlation coefficient between mean arterial pressure (ABP) and ICP, called PRx, which serves as a marker of cerebrovascular reactivity, and a moving correlation coefficient between ABP and cerebral partial pressure of oxygen (pbtO2), called ORx, which serves as a marker for cerebral oxygen reactivity. ICP and ICPamplitude increased significantly during the plateau waves, whereas CPP and pbtO2 decreased significantly. ABP, ABP amplitude, and heart rate remained unchanged.

Stimulation of incretin secreting cells.

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon like peptide-1 (GLP-1) are secreted from enteroendocrine cells in the gut and regulate physiological and homeostatic functions related to glucose control, metabolism and food intake. This review provides a systematic summary of the molecular mechanisms underlying secretion from incretin cells, and an understanding of how they sense and interact with lumen and vascular factors and the enteric nervous system through transporters and G-protein coupled receptors (GPCRs) present on their surface to ultimately culminate in hormone release. Some of the molecules described below such as sodium coupled glucose transporter 1 (SGLT1), G-protein coupled receptor (GPR) 119 and GPR40 are targets of novel therapeutics designed to enhance endogenous gut hormone release.

The effect of bariatric surgery on gastrointestinal and pancreatic peptide hormones.

Bariatric surgery for obesity has proved to be an extremely effective method of promoting long-term weight reduction with additional beneficial metabolic effects, such as improved glucose tolerance and remission of type 2 diabetes. A range of bariatric procedures are in common use, including gastric banding, sleeve gastrectomy and the Roux-en-Y gastric bypass. Although the mechanisms underlying the efficacy of bariatric surgery are unclear, gastrointestinal and pancreatic peptides are thought to play an important role.

Performance of a computerised visual acuity measurement device in subjects with age-related macular degeneration: comparison with gold standard ETDRS chart measurements.

Purpose: The aim of the study was to compare the performance of two different COMPlog computerised, single letter scoring, visual acuity (VA) measurements against gold standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart measurements in patients with age-related macular degeneration (AMD). One computerised algorithm presented five and the other presented three letters per line; both computerised algorithms utilised half, rather than the full-letter width spacing standard on ETDRS charts that might induce crowding, fixation problems, increased test-retest variability (TRV), and bias.

Methods: Fifty patients with AMD (mean age 83 years) underwent timed test and retest VA measurements using ETDRS charts and COMPlog five (C5) and three (C3) letters per line computerised VA measurement algorithms.

Endocannabinoids and striatal function: implications for addiction-related behaviours.

Since the identification and cloning of the major cannabinoid receptor expressed in the brain almost 25 years ago research has highlighted the potential of drugs that target the endocannabinoid system for treating addiction. The endocannabinoids, anandamide and 2-arachidonoyl glycerol, are lipid-derived metabolites found in abundance in the basal ganglia and other brain areas innervated by the mesocorticolimbic dopamine systems. Cannabinoid CB1 receptor antagonists/inverse agonists reduce reinstatement of responding for cocaine, alcohol and opiates in rodents.

Role of ATP binding and hydrolysis in the gating of the cystic fibrosis transmembrane conductance regulator.

The CFTR gene is unique within the ATP-binding cassette (ABC) protein family, predominantly of transporters, by coding a chloride channel. The gating mechanism of ABC proteins has been characterized by the ATP Switch model in terms cycles of dimer formation and dissociation linked to ATP binding and hydrolysis, respectively. It would be of interest to assess the extent that Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), a functional channel, fits the ATP Switch model for ABC transporters.

Clinical impact of computed tomography-based image-guided brachytherapy for cervix cancer using the tandem-ring applicator - the Addenbrooke's experience.

Aims: We report our initial 3-year experience of chemoradiotherapy for cervical cancer with computed tomography-based image-guided high dose rate (HDR) brachytherapy using the tandem-ring applicator.

Materials And Methods: Twenty-eight patients were treated between February 2005 and December 2007. All patients received initial external beam radiotherapy (EBRT) followed by HDR brachytherapy (planned dose 21 Gy to point A in three fractions over 8 days).

The introduction of single best answer questions as a test of knowledge in the final examination for the fellowship of the Royal College of Radiologists in Clinical Oncology.

Aims: The single best answer (SBA) format of multiple choice questions (MCQ) is recognised to be better suited to the assessment of the higher levels of knowledge essential for clinical practice, such as data interpretation, problem solving and decision making, than traditional true/false MCQ. In autumn 2006, the Royal College of Radiologists (RCR) introduced SBA questions as its sole written test of knowledge for the Final Fellowship Examination in Clinical Oncology (Final FRCR Examination). This article reviews the application of SBA questions to clinical oncology and analyses the first year's experience of the new examination format.

Testing for association on the X chromosome.

The problem of testing for genotype-phenotype association with loci on the X chromosome in mixed-sex samples has received surprisingly little attention. A simple test can be constructed by counting alleles, with males contributing a single allele and females 2. This approach does assume not only Hardy-Weinberg equilibrium in the population from which the study subjects are sampled but also, perhaps, an unrealistic alternative hypothesis.

Orthotopic liver transplantation for subacute hepatic failure following partial treatment of isoniazid-resistant tuberculosis.

The management of patients with pre-existing tuberculosis (TB) undergoing liver transplantation is challenging. Cautious immunosuppression is required to prevent reactivation of disease, and second-line anti-tuberculous treatment may be necessary to prevent graft hepatotoxicity. Furthermore, liver transplantation in the context of isoniazid-resistant TB has seldom been reported.

Reduction of radiotherapy-induced late complications in early breast cancer: the role of intensity-modulated radiation therapy and partial breast irradiation. Part II--Radiotherapy strategies to reduce radiation-induced late effects.

Radiotherapy after conservation surgery has been proven to decrease local relapse and death from breast cancer, and is now firmly established in the management of early breast carcinoma. Currently, the challenge is to optimise the therapeutic ratio by minimising treatment-related morbidity, while maintaining or improving local control and survival. The second part of this review examines the role of two approaches: intensity-modulated radiation therapy (IMRT) and partial breast irradiation, as means of improving the therapeutic ratio.

Acute toxicity of chemo-radiotherapy for cervical cancer: the Addenbrooke's experience.

Aims: An audit of acute treatment-related toxicity during chemo-radiotherapy for cervical cancer was carried out to assess its tolerance outside research settings.

Materials And Methods: Between May 1999 and April 2003, 74 patients with carcinoma of the cervix were treated with radical radiotherapy given concurrently with weekly cisplatin chemotherapy. Fifty-nine (79.

Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study.

Background: Renal involvement is frequently present in antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis and is an important cause of end-stage renal failure (ESRF).

Methods: This retrospective, multicenter, sequential cohort study reports presenting features and outcome of 246 new patients diagnosed in London, UK, between 1995 and 2000.

Results: Diagnostic subgroups were microscopic polyangiitis, 120 patients (49%); Wegener's granulomatosis (WG), 82 patients (33%); renal-limited vasculitis, 33 patients (13.

An evidence-based approach to the treatment of prostatitis: is it possible?

The classification of prostatitis has been re-evaluated, and the National Institutes of Health (NIH) has defined the separate groups more thoroughly. Furthermore, the development of the NIH chronic prostatitis symptom index (CPSI) has allowed the symptoms to be measured and the effect of interventions calculated. A search of the literature finds that the quality of treatment trials in prostatitis is poor and the level of evidence for many of the existing strategies is lacking; there is a total absence of any meta-analyses of randomized controlled trials (level 1a).

Abdominal wall hernias: a cross-sectional pictorial review.

The classification of abdominal wall hernias is often made difficult by confusing eponymous and anatomic nomenclature. In this article, we review the anatomy that defines the various types of hernias. The specific cross-sectional radiologic features required to correctly identify each type are then emphasized.

A randomized, controlled trial of the efficacy of a communication course for first time hearing aid users.

Many centres include a communication course as part of their auditory rehabilitation. These usually take the form of a small group and include discussion of the effects of hearing loss, use of the hearing aid, hearing tactics and lip reading. To investigate the efficacy of such a rehabilitation programme a randomized, controlled trial of a communication course was undertaken.