Early, precise, and safe clinical evaluation of the pharmacodynamic effects of novel agents in the intact human tumor microenvironment.

Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.

Comparison of the biomechanical stability of transverse and oblique screw trajectories in retrograde intramedullary nailing of supracondylar femur fractures.

BACKGROUND: The goal was to determine the effect of addition of oblique trajectory distal interlock screws to a retrograde intramedullary femoral nail on implant stability (stiffness), cycles to failure and mode of failure. The hypothesis was that addition of oblique screws would increase implant stability and number of loading cycles to failure. METHODS: Eight matched pairs were tested; one femur implanted with a femoral nail with only transverse distal interlock screws and the other with transverse and oblique interlock screws. Axial compressive load was applied to the femoral head and the gluteal tendon was tensioned vertically to simulate standing or at 45° to the sagittal plane to simulate stair climbing. Loads were cycled to increasing amplitude until failure of fixation (10 mm displacement or 10° rotation). FINDINGS: In simulated standing, oblique screw specimen had greater sagittal bending (bowing) than transverse only specimen. Transverse (axial) plane motion was higher in simulated stair climbing in oblique screw specimen. Oblique screw specimen had higher sagittal plane translation at 600 N of load. At 300 N, oblique screw specimen had lower internal-external rotation than transverse only specimen. A larger number of cycles to failure were observed in four oblique screw of seven paired specimen. Failure (10 mm or 10 degrees of motion) was only achieved during simulated stair climbing. INTERPRETATION: Our hypothesis that adding oblique screws improves fixation was rejected. Activities of daily living other than standing may constitute a challenge to fracture fixation; fixation failure occurred at lower loads in simulated stair climbing than standing.

Impact of preoperative sarcopenia in patients undergoing sacral tumor resection.

INTRODUCTION: Sacral tumor resection is known for a high rate of complications. Sarcopenia has been found to be associated with wound complications; however, there is a paucity of data examining the impact of sarcopenia on the outcome of sacral tumor resection. METHODS: Forty-eight patients (31 primary sarcomas, 17 locally recurrent carcinomas) undergoing sacrectomy were reviewed. Central sarcopenia was assessed by measuring the psoas:lumbar vertebra index (PLVI), with the 50th percentile (0.97) used to determine which patients were high (>0.97) versus low (<0.97). RESULTS: Twenty-four (50%) patients had a high PLVI and 24 (50%) had a low PLVI (sarcopenic). There was no difference (p > 0.05) in the demographics of patients with or without sarcopenia. There was no difference in the incidence of postoperative wound complications (odds ratio [OR] = 1.0, p = 1.0) or deep infection (OR = 0.83, p = 1.0). Sarcopenia was not associated with death due to disease (hazard ratio [HR] = 2.04, p = 0.20) or metastatic disease (HR = 2.47, p = 0.17), but was associated with local recurrence (HR = 6.60, p = 0.01). CONCLUSIONS: Central sarcopenia was not predictive of wound complications or infection following sacral tumor resection. Sarcopenia was, however, an independent risk factor for local tumor recurrence following sacrectomy and should be considered when counseling patients on the outcome of sacrectomy.

Team Approach: Preoperative Management of Metabolic Conditions in Total Joint Replacement.

¼: Total joint arthroplasties (TJAs) of the knee and hip have been considered 2 of the most successful surgical procedures performed to date. ¼: Frailty is defined as increased vulnerability to adverse outcomes with physiologic stress. ¼: Preoperative optimization of frailty and metabolic bone conditions, including osteoporosis, vitamin D deficiency, and diabetes, through a multidisciplinary approach can help improve outcomes and minimize costs after TJA.

Custom total knee: understanding the indication and process.

Patient-specific total knee arthroplasty (TKA) is a copy of the bony knee morphology based on a pre-op computer tomography (CT). The images are segmented in 3D and software is utilized through a proprietary process to generate individual total knee implants to recreate the articulating surfaces. The distal condylar valgus angle of the prosthesis is matched anatomically to the distal femur and reversely matched on the tibia with a thicker lateral insert. The implant, a set of patient-specific jigs (PSJ), which are 3D printed in nylon, and a detailed surgical plan are sent to the hospital in one box. The system is available with one solid or two separated medial and lateral PE inserts. There is a cruciate retaining (CR) and posterior stabilized (PS) version available, including various insert thicknesses. The system allows the addition of two different cemented stem extensions if needed at the time of surgery.

The ACS-NSQIP surgical risk calculator is a poor predictor of postoperative complications in patients undergoing oncologic distal femoral replacement.

BACKGROUND: Distal femur replacement (DFR) has become a preferred reconstruction for tumors involving the femur but is associated with known complications. The ACS-NSQIP surgical risk calculator is an online tool developed to estimate postoperative complications in the first 30-days, however, has not been used in patients undergoing DFR. The purpose of this study was determining the utility of the ACS-NSQIP calculator to predict postoperative complications. METHODS: 56 (30 male, 26 female) patients who underwent DFR were analyzed using the CPT codes: 27,365 (Under Excision Procedures on the Femur and Knee Joint), 27,447 (Arthroplasty, knee, condyle and plateau), 27,486 (Revision of total knee arthroplasty, with or without allograft), 27,487 (Revision of total knee arthroplasty, with or without allograft) and 27,488 (Repair, Revision, and/or Reconstruction Procedures on the Femur [Thigh Region] and Knee Joint). The predicted rates of complications were compared to the observed rates. RESULTS: Complications were noted in 30 (54%) of patients. The predicted risk of complications based off the CPT codes were: 27,356 (14%); 27,447 (5%); 27,486 (7%); 27,487 (8%) and 27,488 (12%). Based on ROC curves, the use of the ACS-NSQIP score were poor predictors of complications (27356, AUC 0.54); (27447, AUC 0.45); (27486, AUC 0.45); (27487, AUC 0.46); (27488, AUC 0.46). CONCLUSIONS: Distal femur arthroplasty performed in the setting of oncologic orthopedics is a complex procedure in a "high risk" surgical group. The ACS-NSQIP does not adequately predict the incidence of complications in these patients and cannot be reliably used in the shared decision-making process.

Utility of the ACS-NSQIP surgical risk calculator in predicting postoperative complications in patients undergoing oncologic proximal femoral replacement.

INTRODUCTION: Proximal femur replacement (PFR) in the setting of tumor resection is associated with a high rate of postoperative complication. The online American College of Surgeons-National Surgical Quality Improvement Program (ACS-NSQIP) surgical risk calculator is approved by the Center of Medicare and Medicaid services to estimate 30-day postoperative complications. This study was to determine if the ACS-NSQIP can predict postoperative complications following PFR. METHODS: We reviewed 103 (61 male and 42 female) patients undergoing PFR using the Current Procedural Terminology (CPT) codes available in the calculator: 27125 (hemiarthroplasty), 27130 (total hip), 27132 (conversion to total hip), 27134 (revision total hip), 27137 (revision acetabulum), 27138 (revision femur), and 27365 (excision tumor hip). The predicted rates of complications were compared with the observed rates. RESULTS: Complications occurred in 54 (52%) of patients, with the predicted risk based on CPT codes: 27125 (21.5%); 27130 (7.8%); 27132 (16.6%), 27134 (17.8%), 27137 (14.4%), 274138 (22.7%), and 27365 (16.2%). The calculator was a poor predictor of complications (27125, area under the curve [AUC] 0.576); (27130, AUC 0.489); (27132, AUC 0.490); (27134, AUC 00.489); (27137, AUC 0.489); (27138, AUC 0.471); and (27365, AUC 0.538). CONCLUSION: Oncologic PFR is known for complications. The ACS-NSQIP does not adequately predict the incidence of complications, and therefore cannot reliably be used in their shared decision-making process preoperative.

Extremity Soft Tissue Sarcoma: Role of Local Control.

OPINION STATEMENT: For localized extremity soft tissue sarcoma (eSTS), treatment is individualized and each patient needs to be evaluated by a multidisciplinary team at a referral sarcoma center specialized in the care of sarcoma. For a majority of patients, treatment for eSTS involves limb-salvage surgery, with or without the addition of radiation therapy. Surgery should only be performed by surgeons specifically fellowship trained in the resection of eSTS. Surgery alone may be considered for small, low-grade, and superficial tumors as long a wide (≥ 2 cm) margin can be achieved. In cases where a less than wide negative margin can be achieved, radiation therapy should be utilized to facilitate a planned close margin resection to preserve critical structures (such as nerves, blood vessels, and bone) without a significant impact on oncologic outcomes. Soft tissue sarcomas are rare, and as such patients often present following an inadvertent excision. In these situations, we recommend preoperative radiation and wide tumor bed re-excision, as rates of residual tumor can be high in this scenario. While there is large amount of evidence to support the use of radiotherapy to enhance local tumor control, the evidence to support the use of chemotherapy to enhance local tumor control is lacking, and as such cannot be recommended for all patients.

Distal Nail Target and Alignment of Distal Tibia Fractures.

OBJECTIVES: To assess the relationship between the distal nail target and postoperative alignment for distal tibia fractures treated with intramedullary nailing. DESIGN: Retrospective cohort study. SETTING: A single level 1 trauma center. PATIENTS/PARTICIPANTS: One hundred thirty distal tibia fractures treated with intramedullary nailing over a 10-year period. MAIN OUTCOME MEASUREMENTS: Malalignment >5 degrees. RESULTS: Thirty-eight cases (29.2%) of malalignment >5 degrees included valgus (19 cases, 14.6%), procurvatum (13 cases, 10.0%), recurvatum (1 case, 0.8%), and combined valgus with procurvatum (5 cases, 3.8%). Medially directed nails demonstrated relative valgus (mean lateral distal tibia angle 86.4 vs. 89.4 degrees, P < 0.01) and more frequent coronal malalignment (24 of 78, 30.8% vs. 0 of 52, 0%, P < 0.01). Anteriorly directed nails demonstrated relative procurvatum (mean anterior distal tibia angle 82.8 vs. 80.9 degrees, P < 0.01) and more frequent sagittal malalignment (15 of 78, 19.2% vs. 3 of 52, 5.8%, P = 0.03). Malalignment was less common for nails targeting the central or slightly posterolateral plafond (0 of 30, 0% vs. 38 of 100, 38%), P < 0.01. Multivariate analysis demonstrated the distal nail target (P = 0.03), fracture within 5 cm of the plafond (P = 0.01), as well as night and weekend surgery (P = 0.03) were all independently associated with malalignment. CONCLUSIONS: Alignment of distal tibia fractures is sensitive to both injury and treatment factors. Nails should be targeted centrally or slightly posterolaterally to minimize malalignment. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The suitability of human adipose-derived stem cells for the engineering of ligament tissue.

Rupture of the anterior cruciate ligament (ACL) is the one of the most common sports-related injuries. With its poor healing capacity, surgical reconstruction using either autografts or allografts is currently required to restore function. However, serious complications are associated with graft reconstructions and the number of such reconstructions has steadily risen over the years, necessitating the search for an alternative approach to ACL repair. Such an approach may likely be tissue engineering. Recent engineering approaches using ligament-derived fibroblasts have been promising, but the slow growth rate of such fibroblasts in vitro may limit their practical application. More promising results are being achieved using bone marrow mesenchymal stem cells (MSCs). The adipose-derived stem cell (ASC) is often proposed as an alternative choice to the MSC and, as such, may be a suitable stem cell for ligament engineering. However, the use of ASCs in ligament engineering still remains relatively unexplored. Therefore, in this study, the potential use of human ASCs in ligament tissue engineering was initially explored by examining their ability to express several ligament markers under growth factor treatment. ASC populations treated for up to 4 weeks with TGFß1 or IGF1 did not show any significant and consistent upregulation in the expression of collagen types 1 and 3, tenascin C and scleraxis. While treatment with EGF or bFGF resulted in increased tenascin C expression, increased expression of collagens 1 and 3 were never observed. Therefore, simple in vitro treatment of human ASC populations with growth factors may not stimulate their ligament differentiative potential.