Protocol for a mixed-method study to assess chronic cough in patients with renal cell carcinoma: the prevalence, impact on quality of life, trigger and potential clinical application of chronic cough as an early screening tool in patients with kidney cancer.

Introduction: Cough as a symptom of renal cell carcinoma (RCC) was first described by Creevy in 1935, and despite one (unpublished) study suggesting it may affect 31% of these patients, as well as cough being discussed in forums for patients with kidney cancer, few clinicians are aware of this association. The cough has been described as unusual in nature, resolving rapidly after treatment with nephrectomy/embolisation but returning if the tumour recurs.

Methods And Analysis: A prospective study using a questionnaire will identify the prevalence of cough in patients with suspected or confirmed RCC attending the Specialist Centre for Kidney Cancer (London, UK).

The anti-angiogenic tyrosine kinase inhibitor Pazopanib kills cancer cells and disrupts endothelial networks in biomimetic three-dimensional renal tumouroids.

Pazopanib is a tyrosine kinase inhibitor used to treat renal cell carcinoma. Few in vitro studies investigate its effects towards cancer cells or endothelial cells in the presence of cancer. We tested the effect of Pazopanib on renal cell carcinoma cells (CAKI-2,786-O) in two-dimensional and three-dimensional tumouroids made of dense extracellular matrix, treated in normoxia and hypoxia.

An overview of study designs.

The numbers of clinical trials have increased exponentially over the last decade, amplifying the pressure to select an appropriate study design to obtain reliable and valid evidence. The ability to find, critically appraise and use evidence to develop new interventions is fundamental to evidence-based medicine. Different study designs have their own advantages and disadvantages, and provide different evidentiary value.

Complex Open Pyeloplasty in a Pelvic Kidney.

A pelvic kidney occurs in between 1 in 2200 and 1 in 3000 people, due to failure of ascent during development. It is commonly asymptomatic and usually functions normally. Pelvic ureteral junction obstruction can either be congenital or acquired, and is characterized by intrinsic stenosis or extrinsic compression of the ureter at the junction with the pelvicalyceal renal system.

Evolution and oncological outcomes of a contemporary radical prostatectomy practice in a UK regional tertiary referral centre.

Objective: To investigate the clinical and pathological trends, over a 10-year period, in robot-assisted laparoscopic prostatectomy (RALP) in a UK regional tertiary referral centre.

Patients And Methods: In all, 1 500 consecutive patients underwent RALP between October 2005 and January 2015. Prospective data were collected on clinicopathological details at presentation as well as surgical outcomes and compared over time.

Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition.

Mutations of the tricarboxylic acid cycle enzyme fumarate hydratase cause hereditary leiomyomatosis and renal cell cancer. Fumarate hydratase-deficient renal cancers are highly aggressive and metastasize even when small, leading to a very poor clinical outcome. Fumarate, a small molecule metabolite that accumulates in fumarate hydratase-deficient cells, plays a key role in cell transformation, making it a bona fide oncometabolite.

Developmentally arrested structures preceding cerebellar tumors in von Hippel-Lindau disease.

There is increasing evidence that suggests that knockout of tumor-suppressor gene function causes developmental arrest and protraction of cellular differentiation. In the peripheral nervous system of patients with the tumor-suppressor gene disorder, von Hippel-Lindau disease, we have demonstrated developmentally arrested structural elements composed of hemangioblast progenitor cells. Some developmentally arrested structural elements progress to a frank tumor, hemangioblastoma.

Differentiation in neuroblastoma: diffusion-limited hypoxia induces neuro-endocrine secretory protein 55 and other markers of a chromaffin phenotype.

Background: Neuroblastoma is a childhood malignancy of sympathetic embryonal origin. A high potential for differentiation is a hallmark of neuroblastoma cells. We have previously presented data to suggest that in situ differentiation in tumors frequently proceeds along the chromaffin lineage and that decreased oxygen (hypoxia) plays a role in this.

Progression of epididymal maldevelopment into hamartoma-like neoplasia in VHL disease.

Inactivation of the von Hippel-Lindau (VHL) gene and activation of the hypoxia-inducible factor (HIF) in susceptible cells precedes formation of tumorlets and frank tumor in the epididymis of male VHL patients. We performed detailed histologic and molecular pathologic analysis of tumor-free epididymal tissues from VHL patients to obtain further insight into early epididymal tumorigenesis. Four epididymides from two VHL patients were serially sectioned to allow for three-dimensional visualization of morphologic changes.

Inhibition of hypoxia inducible factor hydroxylases protects against renal ischemia-reperfusion injury.

Acute renal failure resulting from hypoperfusion and hypoxia is a significant clinical problem. Hypoxia activates the heterodimeric transcription factor hypoxia inducible factor (HIF), leading to changes in gene expression that promote tissue adaptation and survival. To determine whether HIF may protect the kidney from ischemia-reperfusion injury, we subjected hif1a(+/-) and hif2a(+/-) mice to renal ischemia-reperfusion injury.

Expression of hypoxia-inducible factors in normal human lung development.

Pulmonary vascular development is essential for proper lung development, and its disturbance can lead to neonatal morbidity and mortality, as exemplified in congenital diaphragmatic hernia. Hypoxia-inducible factors (HIFs) appear to be key molecules in physiologic angiogenesis and in certain forms of lung pathology, such as bronchopulmonary dysplasia. Little is known about the qualitative and quantitative expression of HIFs in normal human fetal lung development.

New androgen receptor genomic targets show an interaction with the ETS1 transcription factor.

The androgen receptor (AR) initiates important developmental and oncogenic transcriptional pathways. The AR is known to bind as a homodimer to 15-base pair bipartite palindromic androgen-response elements; however, few direct AR gene targets are known. To identify AR promoter targets, we used chromatin immunoprecipitation with on-chip detection of genomic fragments.

Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein.

Growing evidence points to defects in the primary cilium as a critical mechanism underlying renal cyst development. Inactivation of the VHL gene is responsible for the autosomal dominant condition von Hippel-Lindau (VHL) disease and is implicated in most sporadic clear cell renal carcinomas. Manifestations of VHL disease include cysts in several organs, particularly in the kidney.

Regulation of E-cadherin expression by VHL and hypoxia-inducible factor.

Mutations in von Hippel-Lindau tumor suppressor gene (VHL) underlie the VHL hereditary cancer syndrome and also occur in most sporadic clear cell renal cell cancers (CCRCC). Currently, the mechanism(s) by which VHL loss of function promotes tumor development in the kidney are not fully elucidated. Here, we show that VHL inactivation in precancerous lesions in kidneys from patients with VHL disease correlates with marked down-regulation of the intercellular adhesion molecule E-cadherin.

Effects of VHL deficiency on endolymphatic duct and sac.

The von Hippel-Lindau (VHL) disease is caused by VHL germ line mutation. Inactivation of the wild-type copy of the VHL gene leads to up-regulation of hypoxic response and tumor formation within central nervous system (CNS), kidneys, pancreas, adrenal glands, epididymis, broad ligament, and the endolymphatic sac/petrous bone. Endolymphatic sac tumors (ELST) have been proposed to be derived from endolymphatic sac epithelium, but other possible structures of origin have been implicated.

Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma.

Defective function of the von Hippel-Lindau (VHL) tumor suppressor ablates proteolytic regulation of hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha), leading to constitutive activation of hypoxia pathways in renal cell carcinoma (RCC). Here we report a comparative analysis of the functions of HIF-1alpha and HIF-2alpha in RCC and non-RCC cells. We demonstrate common patterns of HIF-alpha isoform transcriptional selectivity in VHL-defective RCC that show consistent and striking differences from patterns in other cell types.