The Binding of Isaac: Rebirth

I thought runs using seeds didn't count for items?

Oh, meh, I guess that makes sense.

Just had my first encounter with the Dark Room. The boss (Mega Satan? The Lamb) isn't all that difficult but all the rooms before it knocked me down to 2 red hearts so I ended up dying when he was down to about 25% HP, unfortunately. I would say normal Satan is much more difficult. Also had my first experience as Guppy earlier. Having no cap on flies between rooms is incredible.

Cleared the Dark Room my second time around with an easy-mode build of Ipecac + Spirit of the Night + Dark Bum on a tanky Maggy.

 Spoiler

Mega Satan appears to be a boss you unlock after you beat The Lamb. A door appears at the starting room in the Dark Room and you need some sort of special key in order to open it and fight Mega Satan. I'm not sure how you obtain this key yet but after beating The Lamb I got an unlock that said "The Angels await" or something like that.