Evading the host response:Staphylococcus“hiding”in cortical bone canalicular system causes increased bacterial burden

Extremity reconstruction surgery is increasingly performed rather than amputation for patients with large-segment pathologic bone loss.Debate persists as to the optimal void filler for this“limb salvage”surgery,whether metal or allograft bone.Clinicians focus on optimizing important functional gains for patients,and the risk of devastating implant infection has been thought to be similar regardless of implant material.Recent insights into infection pathophysiology are challenging this equipoise,however,with both basic science data suggesting a novel mechanism of infection of Staphylococcus aureus(the most common infecting agent)into the host lacunar–canaliculi network,and also clinical data revealing a higher rate of infection of allograft over metal.The current translational study was therefore developed to bridge the gap between these insights in a longitudinal murine model of infection of allograft bone and metal.Real-time Staphylococci infection characteristics were quantified in cortical bone vs metal,and both microarchitecture of host implant and presence of host immune response were assessed.An orders-of-magnitude higher bacterial burden was established in cortical allograft bone over both metal and cancellous bone.The establishment of immune-evading microabscesses was confirmed in both cortical allograft haversian canal and the submicron canaliculi network in an additional model of mouse femur bone infection.These study results reveal a mechanism by which Staphylococci evasion of host immunity is possible,contributing to elevated risks of infection in cortical bone.The presence of this local infection reservoir imparts massive clinical implications that may alter the current paradigm of osteomyelitis and bulk allograft infection treatment.

Patient-derived orthotopic xenograft models for cancer of unknown primary precisely distinguish chemotherapy,and tumor-targeting S.typhimurium A1-R is superior to first-line chemotherapy

Cancer of unknown primary(CUP)is a recalcitrant disease with poor prognosis because it lacks standard first-line therapy.CUP consists of diverse malignancy groups,making personalized precision therapy essential.The present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft(PDOX)model.This paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of S.typhimurium A1-R with first-line chemotherapy using the CUP PDOX model.The present study is the first to use a CUP PDOX model,which was able to precisely distinguish the chemotherapeutic course.We found that a carboplatinum(CAR)-based regimen was effective for this CUP patient.We also demonstrated that S.typhimurium A1-R was more effective against the CUP tumor than first-line chemotherapy.Our results indicate that S.typhimurium A1-R has clinical potential for CUP,a resistant disease that requires effective therapy.