His most well-known work is in breast cancer, where with Veronesi and others at IEO he developed techniques for sentinel lymph node biopsy (SLNB) and radioguided occult lesion localisation (ROLL).

Experience with ROLL and radionuclide therapy with the avidin–biotin pre-targeting system in brain tumours led to intra-operative avidination for radionuclide therapy (IART) in breast cancer. Here, the surgeon injects avidin during surgery and then next day the patient receives radiolabelled biotin that goes to correct location in the breast. Paganelli reported this as capable of controlling recurrence as effectively as external beam radiotherapy.