Hum, good question.
I not sure about a solution because in the blog I'm doing I'm just using one category for each post. I prefer to use tags for multiple keywords.
In post-per-cat last version you can already include and exclude categories by their ID and filter out parent categories, so that's already a help.
The wordpress version I'm using (2.7.1) has no way to say, for each post, which is the most relevant category. If this was possible then it could be used as a way to filter post listing in the sidebar: you could choose to list posts for all the categories in currently displayed post or just posts from the most relevant category of the currently displayed post.
Creating post-per-cat options for each post seems a bit too much of a trouble.
So the most straight forward solution would be to list posts in all the categories the currently displayed post belongs to.
Well, I'll try to give it a bit more thought.