The role of whole brain radiation therapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based clinical practice guideline

QUESTION: Should patients with newly-diagnosed metastatic brain tumors undergo open surgical resection versus whole brain radiation therapy (WBRT) and/or other treatment modalities such as radiosurgery, and in what clinical settings? TARGET POPULATION: These recommendations apply to adults with a newly diagnosed single brain metastasis amenable to surgical resection. RECOMMENDATIONS: Surgical resection plus WBRT versus surgical resection alone Level 1 Surgical resection followed by WBRT represents a superior treatment modality, in terms of improving tumor control at the original site of the metastasis and in the brain overall, when compared to surgical resection alone. Surgical resection plus WBRT versus SRS + or - WBRT Level 2 Surgical resection plus WBRT, versus stereotactic radiosurgery (SRS) plus WBRT, both represent effective treatment strategies, resulting in relatively equal survival rates. SRS has not been assessed from an evidence-based standpoint for larger lesions (\u3e3 cm) or for those causing significant mass effect (\u3e1 cm midline shift). Level 3 Underpowered class I evidence along with the preponderance of conflicting class II evidence suggests that SRS alone may provide equivalent functional and survival outcomes compared with resection + WBRT for patients with single brain metastases, so long as ready detection of distant site failure and salvage SRS are possible. Note The following question is fully addressed in the WBRT guideline paper within this series by Gaspar et al. Given that the recommendation resulting from the systematic review of the literature on this topic is also highly relevant to the discussion of the role of surgical resection in the management of brain metastases, this recommendation has been included below

The inotropic effect of cardioactive glycosides in ventricular myocytes requires Na+–Ca2+ exchanger function

Glycoside-induced cardiac inotropy has traditionally been attributed to direct Na+–K+-ATPase inhibition, causing increased intracellular [Na+] and consequent Ca2+ gain via the Na+–Ca2+ exchanger (NCX). However, recent studies suggested alternative mechanisms of glycoside-induced inotropy: (1) direct activation of sarcoplasmic reticulum Ca2+ release channels (ryanodine receptors; RyRs); (2) increased Ca2+ selectivity of Na+ channels (slip-mode conductance); and (3) other signal transduction pathways. None of these proposed mechanisms requires NCX or an altered [Na+] gradient. Here we tested the ability of ouabain (OUA, 3 μm), digoxin (DIG, 20 μm) or acetylstrophanthidin (ACS, 4 μm) to alter Ca2+ transients in completely Na+-free conditions in intact ferret and cat ventricular myocytes. We also tested whether OUA directly activates RyRs in permeabilized cat myocytes (measuring Ca2+ sparks by confocal microscopy). In intact ferret myocytes (stimulated at 0.2 Hz), DIG and ACS enhanced Ca2+ transients and cell shortening during twitches, as expected. However, prior depletion of [Na+]i (in Na+-free, Ca2+-free solution) and in Na+-free solution (replaced by Li+) the inotropic effects of DIG and ACS were completely prevented. In voltage-clamped cat myocytes, OUA increased Ca2+ transients by 48 ± 4% but OUA had no effect in Na+-depleted cells (replaced by N-methyl-d-glucamine). In permeabilized cat myocytes, OUA did not change Ca2+ spark frequency, amplitude or spatial spread (although spark duration was slightly prolonged). We conclude that the acute inotropic effects of DIG, ACS and OUA (and the effects on RyRs) depend on the presence of Na+ and a functional NCX in ferret and cat myocytes (rather than alternate Na+-independent mechanisms)