ABSTRACT
Over 80% of pancreatic ductal adenocarcinoma (PDA) patients are diagnosed with non-resectable late-stage disease that lacks effective neoadjuvant therapies. Stereotactic body radiation therapy (SBRT) has shown promise as an emerging neoadjuvant approach for treating PDA, and here, we report that its combination with local interleukin-12 (IL-12) microsphere (MS) immunotherapy results in marked tumor reduction and cures in multiple preclinical mouse models of PDA. Our findings demonstrate an increase of intratumoral interferon gamma (IFNγ) production following SBRT/IL-12 MS administration that initiates suppressor cell reprogramming and a subsequent increase in CD8 T cell activation. Furthermore, SBRT/IL-12 MS therapy results in the generation of systemic tumor immunity that is capable of eliminating established liver metastases, providing a rationale for follow-up studies in advanced metastatic disease.
Subject(s)
Interleukin-12/therapeutic use , Pancreatic Neoplasms/immunology , Pancreatic Neoplasms/therapy , Radiosurgery , Tumor Microenvironment/immunology , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Line, Tumor , Cellular Reprogramming , Humans , Immunity , Interferon-gamma/metabolism , Lymphocyte Activation/immunology , Mice, Inbred C57BL , Microspheres , Models, Biological , Myeloid Cells/pathology , Survival Analysis , Tumor Burden , Pancreatic NeoplasmsABSTRACT
Although radiotherapy (RT) is widely used to control tumor growth across many cancer types, there is a relatively high incidence of RT failure exhibited by tumor recurrence, therefore a clear need exists to achieve improved effectiveness of RT. The RT-elicited immune response largely impacts the efficacy of RT and includes immune cells that kill tumor cells, but also immunosuppressive cells, which dampen anti-tumor immunity. Using murine models in which syngeneic tumor cell lines (Colon38, Glioma261, Line1) are grown intramuscularly and treated with 15 Gy local RT, we assessed the effects of RT on both the systemic and intratumoral immune response. Here we demonstrate that RT stimulates increased production of two chemokines, CCL2 and CCL5, at the tumor site. Further, that this leads to increased CCR2+ CCR5+ monocytes in circulation and subsequently alters the intratumoral immune infiltrate favoring the largely immunosuppressive CCR2+ CCR5+ monocytes. Importantly, a CCR2/CCR5 antagonist administered daily (15 mg/kg subcutaneously) starting two days prior to RT reduces both circulating and intratumoral monocytes resulting in increased efficacy of RT in radioresponsive tumors. Overall, these data have important implications for the mechanism of RT and present a means to improve RT efficacy across many cancer types.
Subject(s)
Neoplasms, Experimental/radiotherapy , Receptors, CCR2/physiology , Receptors, CCR5/physiology , Animals , Cell Line, Tumor , Cell Movement , Female , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Monocytes/immunology , Neoplasms, Experimental/immunology , Receptors, CCR2/antagonists & inhibitorsABSTRACT
Despite advances in surgical techniques, 20% to 90% of rotator cuff (RTC) repairs fail. They tend to fail at the suture-tendon junction due to tension at the repair and gap formation prior to healing. This study evaluated the gap formation and ultimate tensile failure loads of a RTC repair with a decellularized human dermal allograft. Augmentation of a RTC repair with an extracellular matrix graft decreased gap formation and increased load to failure in a human RTC repair model.
Subject(s)
Acellular Dermis , Rotator Cuff/physiopathology , Tendon Injuries/surgery , Adult , Allografts , Biocompatible Materials , Biomechanical Phenomena , Cadaver , Extracellular Matrix , Female , Humans , Male , Middle Aged , Rotator Cuff/surgery , Rotator Cuff Injuries , Suture Anchors , Suture Techniques , Tendon Injuries/physiopathology , Wound HealingABSTRACT
Heterotopic ossification (HO) is a complication following total hip arthroplasty (THA) with traditional approaches. The direct anterior approach (DAA) has become a popular approach for THA; however, no study has evaluated HO formation following DAA THA. We examined the incidence of HO in a consecutive series of THA using the DAA in two separate hospitals. Standard preoperative radiographs were examined to determine the type of degenerative arthritis, and follow-up radiographs of at least 6 months after surgery were evaluated for the presence and classification of HO. The overall incidence of HO after DAA THA in this study was 98/236, or 41.5%, which falls within the reported range from recent studies involving more traditional approaches to the hip.
Subject(s)
Arthrography/methods , Arthroplasty, Replacement, Hip/adverse effects , Ossification, Heterotopic/etiology , Osteoarthritis/etiology , Adult , Age Distribution , Aged , Aged, 80 and over , Female , Follow-Up Studies , Hip Joint/diagnostic imaging , Hip Joint/surgery , Humans , Incidence , Male , Middle Aged , Ossification, Heterotopic/diagnostic imaging , Ossification, Heterotopic/epidemiology , Osteoarthritis/diagnostic imaging , Osteoarthritis/epidemiology , Retrospective Studies , Sex DistributionABSTRACT
Groin pain is often related to hip pathology. As a result, groin pain is a clinical complaint encountered by orthopaedic surgeons. Approximately one in four persons will develop symptomatic hip arthritis before age 85 years. Groin injuries account for approximately 1 in 20 athletic injuries, and groin pain accounts for 1 in 10 patient visits to sports medicine centers. Many athletes with chronic groin pain have multiple coexisting pathologies spanning several disciplines. In treating these patients, the orthopaedic surgeon must consider both musculoskeletal groin disorders and nonorthopaedic conditions that can present as groin pain. A comprehensive history and physical examination can guide the evaluation of groin pain.
