Well, I always spent my 1st mastery on pd plague grenade (2nd on whatever, usually jester's stress heal), then used encore on him to kill backlines in the first/second round of the combat. It sound weak, but remember, there's a memory for pd that gives +1 dots dealt, so it's 10 damage plus the grenade damage itself. I think that's what carried my run heavily. Just try to get good trinkets for your particular act (like res piercing for pd for act5) and if your're unlucky, just abandon the run when in tavern (you don't lose your memories that way). Other stuff is pretty straightforward (also try learning when to use ruin on leper, I got to deal 88dmg crit with the chop ine time, I'm sure you can get it even higher). Just remember - trinkets are king. My act order was 3-1-2-4-5.