Propofol Induced Hyperkalemia and Its Management in End Stage Renal Disease Patients.

Propofol related infusion syndrome (PRIS) is a rare, but extremely dangerous complication of propofol administration. Unexplained anion-gap metabolic acidosis, rhabdomyolysis, hyperkalemia, acute kidney injury, elevated liver enzymes, and potentially fatal cardiac arrhythmias are characteristic of PRIS. Risk factors for the develop- ment of PRIS include dose and duration of propofol infusion, severe illness, and concomitant administration of catecholamine and glucocorticoids. PRIS causing hyperkalemia is a well-known clinical entity. Although the development of PRIS depends on the duration and total amount of drug infused, repeated boluses of propofol, commonly used for rapid sequence intubation and conscious sedation, can potentially precipitate fatal hyperkalemia. This is of particular concern in advanced chronic kidney disease (CKD) and end stage renal disease (ESRD) patients. We report a case of a propofol induced hyperkalemia causing near fatal cardiac arrhythmia in a dialysis dependent ESRD patient. We report successful revival from cardiac arrest by intensive calcium regimen and hemodialysis. This case highlights underrecognized problem of propofol-induced hy- perkalemia, which can be of particular concerns in advanced CKD and ESRD.

Expression of PAFR as part of a prosurvival response to chemotherapy: a novel target for combination therapy in melanoma.

Melanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cells in vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas.

Platelet-activating factor receptor (PAF-R)-dependent pathways control tumour growth and tumour response to chemotherapy.

BACKGROUND: Phagocytosis of apoptotic cells by macrophages induces a suppressor phenotype. Previous data from our group suggested that this occurs via Platelet-activating factor receptor (PAF-R)-mediated pathways. In the present study, we investigated the impact of apoptotic cell inoculation or induction by a chemotherapeutic agent (dacarbazine, DTIC) on tumour growth, microenvironmental parameters and survival, and the effect of treatment with a PAF-R antagonist (WEB2170). These studies were performed in murine tumours: Ehrlich Ascitis Tumour (EAT) and B16F10 melanoma. METHODS: Tumour growth was assessed by direct counting of EAT cells in the ascitis or by measuring the volume of the solid tumour. Parameters of the tumour microenvironment, such as the frequency of cells expressing cyclo-oxygenase-2 (COX-2), caspase-3 and galectin-3, and microvascular density, were determined by immunohistochemistry. Levels of vascular endothelium growth factor (VEGF) and prostaglandin E2 (PGE2) were determined by ELISA, and levels of nitric oxide (NO) by Griess reaction. PAF-R expression was analysed by immunohistochemistry and flow cytometry. RESULTS: Inoculation of apoptotic cells before EAT implantation stimulated tumour growth. This effect was reversed by in vivo pre-treatment with WEB2170. This treatment also reduced tumour growth and modified the microenvironment by reducing PGE2, VEGF and NO production. In B16F10 melanoma, WEB2170 alone or in association with DTIC significantly reduced tumour volume. Survival of the tumour-bearing mice was not affected by WEB2170 treatment but was significantly improved by the combination of DTIC with WEB2170. Tumour microenvironment elements were among the targets of the combination therapy since the relative frequency of COX-2 and galectin-3 positive cells and the microvascular density within the tumour mass were significantly reduced by treatment with WEB2170 or DTIC alone or in combination. Antibodies to PAF-R stained the cells from inside the tumour, but not the tumour cells grown in vitro. At the tissue level, a few cells (probably macrophages) stained positively with antibodies to PAF-R. CONCLUSIONS: We suggest that PAF-R-dependent pathways are activated during experimental tumour growth, modifying the microenvironment and the phenotype of the tumour macrophages in such a way as to favour tumour growth. Combination therapy with a PAF-R antagonist and a chemotherapeutic drug may represent a new and promising strategy for the treatment of some tumours.

Câncer e o microambiente tumoral / Cancer and the tumor microenvironment

Antes tido como um conjunto de células alteradas em proliferação, hoje o cânceré mais bem entendido como um microambiente, em que as interações entre os elementos celulares e moleculares que o compõem são determinantes na progressão tumoral. Como resultado, a compreensão do evento neoplásico ganha complexidade crescente. A dinâmica das células tumorais passa a ser avaliada como parte de um verdadeiro tecido tumoral, sujeita a condições de vascularização, de oxigenação, de pressão intersticial e de necrose tecidual, que influenciam na cinética tumoral. Estão sendo identificados novos componentes deste nicho tumoral e as suas respectivas atuações. Entre esses integrantes, encontram-se os elementos da imunidade, cuja modulação tem sido demonstrada por uma série de pesquisas aqui revisadas, tanto no sentido da vigilância imunológica, como pressão seletiva negativa, quanto nofavorecimento da progressão tumoral. Esta revisão analisará a neoplasia do ponto de vista de um microambiente tumoral, focando na participação imunológica e na cinética tumoral, expondo as principais idéias e descobertas que criaram e estão aperfeiçoando o conceito de câncer.

Formerly referred to as a group of altered cells in proliferation, today cancer is better understood as a microenvironment, in which the interactions between the cellular andmolecular elements are determinative in tumor progression. As a result, the comprehension of a neoplasic event gains increasing complexity. The dynamics of the tumor cells are nowanalyzed as part of a true tumoral tissue, subject to conditions of vascularization, oxygenation, interstitial pressure and tissue necrosis, which influence tumor kinetics. New components of this tumoral niche and their respective actions are being identified. Among these constituentsare the elements of the immune system which, as a series of experiments have shown, are involved in the aspect of immunosurveillance, as negative selective pressure, as well as inmechanisms of tumor progression. This review will analyze neoplasia as a tumor microenvironment, focusing on immunological participation and on tumor kinetics, and exposing the mainideas and discoveries that created and are improving the concept of cancer.