Can Periprosthetic Joint Infection of Tumor Prostheses Be Controlled With Debridement, Antibiotics, and Implant Retention?

BACKGROUND: Two-stage revision for periprosthetic joint infection (PJI) in patients who have undergone segmental replacement of the distal femur or proximal tibia after tumor resection can be associated with considerable morbidity, pain, and risk of complications because the procedure often results in removal of long, well-fixed stems from the diaphysis. A less-aggressive surgical approach, such as debridement, antibiotics, and implant retention (DAIR), may be attractive to patients and surgeons because of less morbidity, but the likelihood of eradicating infection in comparison to the traditional two-stage revision is not well established for oncology patients. Furthermore, the relative risk of subsequent amputation for DAIR versus two-stage revision has not been defined for this population. QUESTIONS/PURPOSES: (1) How does DAIR compare with two-stage revision in terms of infection control for patients with distal femoral or proximal tibial segmental modular endoprostheses? (2) Is DAIR as an initial procedure associated with an increased risk of amputation compared with two-stage revision for infection? METHODS: From the longitudinally maintained orthopaedic oncology surgical database at our institution, we identified 69 patients who had been treated for a clinical diagnosis of PJI at the knee between 1993 and 2015. We excluded 32% (22) of patients who did not meet at least one of the major criteria of the Musculoskeletal Infection Society (MSIS) for PJI, 3% (2) of patients who underwent immediate amputation, 3% (2) of patients who had a follow-up time of < 24 months, and 7% (5) of patients who did not have a primary tumor of the distal femur or proximal tibia. The study consisted of 38 patients, of whom eight underwent two-stage revision, 26 underwent DAIR, and four underwent extended DAIR (removal of all segmental components but with retention of stems and components fixed in bone) for their initial surgical procedure. To be considered free of infection, patients had to meet MSIS standards, including no positive cultures, drainage, or surgical debridement for a minimum of 2 years from the last operation. Factors associated with time-dependent risk of infection relapse, clearance, amputation, and patient survival were analyzed using Kaplan-Meier survivorship curves and the log-rank test to compare factors. Association of demographic and treatment factors was assessed using chi-square and Fisher exact tests. RESULTS: Continuous infection-free survival at 5 years was 16% (95% CI 2% to 29%) for patients undergoing DAIR compared with 75% (95% CI 45% to 100%) for patients undergoing two-stage revision (p = 0.006). The median (range) number of total surgical procedures was 3 per patient (1 to 10) for DAIR and 2 (2 to 5) for two-stage revision. Twenty-nine percent (11 of 38) of patients eventually underwent amputation. Survival without amputation was 69% (95% CI 51% to 86%) for DAIR compared with 88% (95% CI 65% to 100%) for two-stage revision at 5 years (p = 0.34). The cumulative proportion of patients achieving infection-free status (> 2 years continuously after last treatment) and limb preservation was 58% (95% CI 36% to 80%) for patients initially treated with DAIR versus 87% (95% CI 65% to 100%) for patients first treated with two-stage revision (p = 0.001). CONCLUSION: Infection control was better with two-stage revision than DAIR. The chance of eventual clearance of infection with limb preservation was better when two-stage revision was chosen as the initial treatment. However, the loss to follow-up in the two-stage revision group would likely make the true proportion of infection control lower than our estimate. Our experience would suggest that the process of infection eradication is a complex and difficult one. Most patients undergo multiple operations. Nearly one-third of patients eventually underwent amputation, and this was a serious risk for both groups. While we cannot strongly recommend one approach over the other based on our data, we would still consider the use of DAIR in patients who present with acute short duration of symptoms (< 3 weeks), no radiographic signs of erosion around fixed implants, and organisms other than Staphylococcus aureus. We would advocate the extended DAIR procedure with removal of all segmental or modular components, and we would caution patients that there is a high likelihood of needing further surgery. A prospective trial with strict adherence to indications may be needed to evaluate the relative merits of an extended DAIR procedure versus a two-stage revision. LEVEL OF EVIDENCE: Level III, therapeutic study.

Percutaneous Cementation for Improvement of Pain and Function for Osteolytic Pelvic Metastasis: A Systematic Review.

INTRODUCTION: Pelvic metastasis is a common presentation among patients presenting with skeletal metastasis. Image-guided percutaneous cementation of these lesions is becoming increasingly popular for the treatment of these lesions. The objective of this study was to conduct a systematic review that investigates clinical outcomes after percutaneous cementation for pelvic metastasis. METHODS: A systematic review was registered with International Prospective Register of Systematic Reviews and performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines using the PubMed, SCOPUS, and Ovid MEDLINE databases. All level I to IV clinical studies published in the English language investigating the clinical outcomes after percutaneous cementation for pelvic metastasis were included. RESULTS: Fourteen studies with 579 patients (278 men, 301 women) and 631 metastatic pelvic lesions were included in the study. The mean follow-up range was 0.7 to 26.4 months. Percutaneous cementation alone was performed in 441 patients (76.2%). Supplemental ablative procedures were performed in 77 patients (13.3%), and supplemental internal fixation using cannulated screws was performed in 107 patients (18.5%). Twelve studies with 430 patients (74.2%) reported pain-related and/or functional outcome scores, of which all studies reported overall clinically notable improvement at short-term follow-up. All studies reported periprocedural complications. Local cement leakage was the most common complication (162/631 lesions, 25.7%) followed by transient local pain (25/579 patients, 4.3%). There were no reported cases of major complications. Seven patients (1.2%) underwent re-intervention for persistent symptoms. CONCLUSIONS: Percutaneous cementation may be an effective method for treating pain and function related to pelvic metastasis. The most common complication was cement leakage surrounding the lesion. The rates of major complications were low, and most complications appeared minor and transient. Additional prospective studies are needed to further assess the efficacy of this procedure. LEVEL OF EVIDENCE: IV, systematic review of level I to IV therapeutic studies.

Bone mimetic environments support engineering, propagation, and analysis of therapeutic response of patient-derived cells, ex vivo and in vivo.

Bone metastases are the most common milestone in the lethal progression of prostate cancer and prominent in a substantial portion of renal malignancies. Interactions between cancer and bone host cells have emerged as drivers of both disease progression and therapeutic resistance. To best understand these central host-epithelial cell interactions, biologically relevant preclinical models are required. To achieve this goal, we here established and characterized tissue-engineered bone mimetic environments (BME) capable of supporting the growth of patient-derived xenograft (PDX) cells, ex vivo and in vivo. The BME consisted of a polycaprolactone (PCL) scaffold colonized by human mesenchymal stem cells (hMSCs) differentiated into osteoblasts. PDX-derived cells were isolated from bone metastatic prostate or renal tumors, engineered to express GFP or luciferase and seeded onto the BMEs. BMEs supported the growth and therapy response of PDX-derived cells, ex vivo. Additionally, BMEs survived after in vivo implantation and further sustained the growth of PDX-derived cells, their serial transplant, and their application to study the response to treatment. Taken together, this demonstrates the utility of BMEs in combination with patient-derived cells, both ex vivo and in vivo. STATEMENT OF SIGNIFICANCE: Our tissue-engineered BME supported the growth of patient-derived cells and proved useful to monitor the therapy response, both ex vivo and in vivo. This approach has the potential to enable co-clinical strategies to monitor bone metastatic tumor progression and therapy response, including identification and prioritization of new targets for patient treatment.

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression.

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

Unbiased metastatic niche-labeling identifies estrogen receptor-positive macrophages as a barrier of T cell infiltration during bone colonization.

Microenvironment niches determine cellular fates of metastatic cancer cells. However, robust and unbiased approaches to identify niche components and their molecular profiles are lacking. We established Sortase A-Based Microenvironment Niche Tagging (SAMENT), which selectively labels cells encountered by cancer cells during metastatic colonization. SAMENT was applied to multiple cancer models colonizing the same organ and the same cancer to different organs. Common metastatic niche features include macrophage enrichment and T cell depletion. Macrophage niches are phenotypically diverse between different organs. In bone, macrophages express the estrogen receptor alpha (ERα) and exhibit active ERα signaling in male and female hosts. Conditional knockout of Esr1 in macrophages significantly retarded bone colonization by allowing T cell infiltration. ERα expression was also discovered in human bone metastases of both genders. Collectively, we identified a unique population of ERα+ macrophages in the metastatic niche and functionally tied ERα signaling in macrophages to T cell exclusion during metastatic colonization. HIGHLIGHTS: SAMENT is a robust metastatic niche-labeling approach amenable to single-cell omics.Metastatic niches are typically enriched with macrophages and depleted of T cells.Direct interaction with cancer cells induces ERα expression in niche macrophages. Knockout of Esr1 in macrophages allows T cell infiltration and retards bone colonization.

A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

Advances in Virtual Cutting Guide and Stereotactic Navigation for Complex Tumor Resections of the Sacrum and Pelvis: Case Series with Short-Term Follow-Up.

Primary malignancies of the sacrum and pelvis are aggressive in nature, and achieving negative margins is essential for preventing recurrence and improving survival after en bloc resections. However, these are particularly challenging interventions due to the complex anatomy and proximity to vital structures. Using virtual cutting guides to perform navigated osteotomies may be a reliable method for safely obtaining negative margins in complex tumor resections of the sacrum and pelvis. This study details the technique and presents short-term outcomes. Patients who underwent an en bloc tumor resection of the sacrum and/or pelvis using virtual cutting guides with a minimum follow-up of two years were retrospectively analyzed and included in this study. Preoperative computer-assisted design (CAD) was used to design osteotomies in each case. Segmentation, delineating the tumor from normal tissue, was performed by the senior author using preoperative CT scans and MRI. Working with a team of biomedical engineers, virtual surgical planning was performed to create osteotomy lines on the preoperative CT and overlaid onto the intraoperative CT. The pre-planned osteotomy lines were visualized as "virtual cutting guides" providing real-time stereotactic navigation. A precision ultrasound-powered cutting tool was then integrated into the navigation system and used to perform the osteotomies in each case. Six patients (mean age 52.2 ± 17.7 years, 2 males, 4 females) were included in this study. Negative margins were achieved in all patients with no intraoperative complications. Mean follow-up was 38.0 ± 6.5 months (range, 24.8-42.2). Mean operative time was 1229 min (range, 522-2063). Mean length of stay (LOS) was 18.7 ± 14.5 days. There were no cases of 30-day readmissions, 30-day reoperations, or 2-year mortality. One patient was complicated by flap necrosis, which was successfully treated with irrigation and debridement and primary closure. One patient had local tumor recurrence at final follow-up and two patients are currently undergoing treatment for metastatic disease. Using virtual cutting guides to perform navigated osteotomies is a safe technique that can facilitate complex tumor resections of the sacrum and pelvis.