I've come across several instances in manga where the simple question of "で?" is used. What could it mean? I'm guessing it means something like "Is that so?," but I'm not sure.
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It's basically a shortening of それで何？, meaning something along the lines of 'and so...?' or 'then what?' It asks for either a continuation of the thought (especially in a story or something else temporally organised) or a conclusion (as in 'what you just said is setting something up, what is it?').
An abbreviation of 'それで何？'('Then what?' or 'So what?'). This phrase can be used to express both indifference or interest, in a conversation typically between close friends.
I think it does not translate to 'Is that so?'.
As the others says, it can be a short version of それで何. To know what else it can mean, though, remember that で, as a particle, is also used to give a reason for something, as in 何で. In response to something someone said, it's likely meant to be used the same way 'So' is to ask why they should give a flying flip about what they said.
(Tobacco is bad for you)
take a puff and blows it into the open air