Controversies in orthopaedic oncology.

Chondrosarcoma is the second most common surgically treated primary bone sarcoma. Despite a large number of scientific papers in the literature, there is still significant controversy about diagnostics, treatment of the primary tumour, subtypes, and complications. Therefore, consensus on its day-to-day treatment decisions is needed. In January 2024, the Birmingham Orthopaedic Oncology Meeting (BOOM) attempted to gain global consensus from 300 delegates from over 50 countries. The meeting focused on these critical areas and aimed to generate consensus statements based on evidence amalgamation and expert opinion from diverse geographical regions. In parallel, periprosthetic joint infection (PJI) in oncological reconstructions poses unique challenges due to factors such as adjuvant treatments, large exposures, and the complexity of surgery. The meeting debated two-stage revisions, antibiotic prophylaxis, managing acute PJI in patients undergoing chemotherapy, and defining the best strategies for wound management and allograft reconstruction. The objectives of the meeting extended beyond resolving immediate controversies. It sought to foster global collaboration among specialists attending the meeting, and to encourage future research projects to address unsolved dilemmas. By highlighting areas of disagreement and promoting collaborative research endeavours, this initiative aims to enhance treatment standards and potentially improve outcomes for patients globally. This paper sets out some of the controversies and questions that were debated in the meeting.

Are our actions matching our words? A review of trainee ethnic and gender diversity in orthopaedic surgery.

Background: There is a lack of physician ethnic and gender diversity amongst surgical specialties. This study analyzes the literature that promotes diversity amongst surgical trainees. Specifically, this study sought to answer (i) how the number of publications regarding diversity in orthopaedic surgery compares to other surgical specialties, (ii) how the number of publications amongst all surgical subspecialties trends over time and (iii) which specific topics regarding diversity are discussed in the surgical literature. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used to query articles from PubMed, Web of Science, Embase and the Cumulative Index to Nursing and Allied Health Literature. Broad inclusion criteria for both ethnic and gender diversity of any surgical specialty were utilized. Results: Our query resulted 1429 publications, of which 408 duplicates were removed, and 701 were excluded on title and abstract screening, leaving 320 to be included. The highest number of related publications was in orthopaedic surgery (n = 73) followed by general surgery (n = 56). Out of 320 total articles, 260 (81.3 %) were published after 2015, and 56 of 73 (76.7 %) orthopaedic-specific articles were published after 2015. Conclusion: Orthopaedic surgery published the most about ethnic and gender diversity, however, still remains one of the least diverse surgical specialties. With the recent increase in publications on diversity in surgical training, close attention should be paid to ethnic and gender diversity amongst surgical trainees over the coming years. Should diversity remain stagnant, diversification efforts may need to be restructured to achieve a diverse surgeon workforce. Key message: Orthopaedic surgery is the surgical subspecialty that publishes the most about trainee ethnic and gender diversity followed by general surgery. With most of this literature being published over the last eight years, it is imperative to pay close attention to the ethnic and gender landscape of the surgeon workforce over the coming years.

Active surveillance of diffuse-type tenosynovial giant cell tumors: A retrospective, multicenter cohort study.

BACKGROUND: Diffuse-type tenosynovial giant cell tumor (D-TGCT) is a mono-articular, soft-tissue tumor. Although it can behave locally aggressively, D-TGCT is a non-malignant disease. This is the first study describing the natural course of D-TGCT and evaluating active surveillance as possible treatment strategy. METHODS: This retrospective, multicenter study included therapy naïve patients with D-TGCT from eight sarcoma centers worldwide between 2000 and 2019. Patients initially managed by active surveillance following their first consultation were eligible. Data regarding the radiological and clinical course and subsequent treatments were collected. RESULTS: Sixty-one patients with primary D-TGCT were initially managed by active surveillance. Fifty-nine patients had an MRI performed around first consultation: D-TGCT was located intra-articular in most patients (n = 56; 95 %) and extra-articular in 14 cases (24 %). At baseline, osteoarthritis was observed in 13 patients (22 %) on MRI. Most of the patients' reported symptoms: pain (n = 43; 70 %), swelling (n = 33; 54 %). Eight patients (13 %) were asymptomatic. Follow-up data were available for 58 patients; the median follow-up was 28 months. Twenty-one patients (36 %) had radiological progression after 21 months (median). Eight of 45 patients (18 %) without osteoarthritis at baseline developed osteoarthritis during follow-up. Thirty-seven patients (64 %) did not clinically deteriorate during follow-up. Finally, eighteen patients (31 %) required a subsequent treatment. CONCLUSION: Active surveillance can be considered adequate for selected therapy naïve D-TGCT patients. Although follow-up data was limited, almost two-thirds of the patients remained progression-free, and 69 % did not need treatment during the follow-up period. However, one-fifth of patients developed secondary osteoarthritis. Prospective studies on active surveillance are warranted.

The MOTION study: a randomized, phase III study of vimseltinib for the treatment of tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths and is caused by upregulation of the CSF1 gene. Vimseltinib is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit the CSF1 receptor. Here, we describe the rationale and design for the phase III MOTION trial (NCT05059262), which aims to evaluate the efficacy and safety of vimseltinib in participants with TGCT not amenable to surgical resection. In part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Tenosynovial giant cell tumor (or TGCT) is a rare, noncancerous tumor that grows in the soft tissue lining the spaces of joints and bursae (fluid-filled sacs that work to reduce friction in the joints). These tumors are linked to increased levels of a protein called CSF1. While this condition is typically treated with surgery, some patients may not be candidates for surgical removal of the tumor due to factors such as location or complexity of the tumor; therefore, drug treatments are needed to help these patients. Vimseltinib is an investigational oral drug specifically designed to inhibit the receptor to which the CSF1 protein binds. In this article, we describe the rationale and design for a phase III clinical trial that will test how well vimseltinib works in participants with TGCT who are not candidates for surgery. In the first part of the study, participants are randomly assigned to receive vimseltinib 30 mg twice weekly or a matching placebo (inactive substance) for up to 24 weeks. This first part is blinded, so participants will not know if they are receiving vimseltinib or the placebo. The second part of the study is a long-term treatment phase in which all participants will receive vimseltinib (unblinded). Clinical Trial Registration: NCT05059262 (ClinicalTrials.gov).

Prosthetic Limb Attachment via Electromagnetic Attraction through a Closed Skin Envelope.

OBJECTIVE: Current socket-based methods of prosthetic limb attachment are responsible for many of the dominant problems reported by persons with amputation. In this work, we introduce a new paradigm for attachment via electromagnetic attraction between a bone-anchored ferromagnetic implant and an external electromagnet. Our objective was to develop a design framework for electromagnetic attachment, and to evaluate this framework in the context of transfemoral amputation. METHODS: We first used inverse dynamics to calculate the forces required to suspend a knee-ankle-foot prosthesis during gait. We then conducted cadaveric dissections to inform implant geometry and design a surgical methodology for covering the implant. We also developed an in silico framework to investigate how electromagnet design affects system performance. Simulations were validated against benchtop testing of a custom-built electromagnet. RESULTS: The physical electromagnet matched simulations, with a root-mean-square percentage error of 4.2% between measured and predicted forces. Using this electromagnet, we estimate that suspension of a prosthesis during gait would require 33 W of average power. After 200 and 1000 steps of simulated walking, the temperature at the skin would increase 2.3℃ and 15.4℃ relative to ambient, respectively. CONCLUSION: Our design framework produced an implant and electromagnet that could feasibly suspend a knee-ankle-foot prosthesis during short walking bouts. Future work will focus on optimization of this system to reduce heating during longer bouts. SIGNIFICANCE: This work demonstrates the initial feasibility of an electromagnetic prosthetic attachment paradigm that has the potential to increase comfort and improve residual limb health for persons with amputation.

Thematic analysis of online discussion forums for soft tissue sarcomas.

BACKGROUND AND OBJECTIVES: As there is an increasing reliance on the internet for medical information, patients diagnosed with rare diseases have turned to online community forums to share information about their diagnoses. These forums help patients to gather and share information about their experience with disease. Additionally, these platforms enable patients to build unique connections based on their shared experiences. The objective of this study was to review shared posts in online community forums by individuals with soft tissue sarcomas to better understand commonly discussed themes. This information may improve the physicians' understanding of patients' concerns and feelings at the time of diagnosis and treatment. METHODS: We entered "sarcoma discussion forum" in search engines to identify internet discussion boards. Four major discussion forums were analyzed, and posts written between January 1, 2017 through May 1, 2022 addressing soft tissue sarcomas present in the upper and lower extremities were collected. Each post was analyzed by the two investigators in three steps (open coding, axial coding, and selective coding). RESULTS: A total of 506 posts were included in the final analysis. We used twenty-seven axial codes and four selective codes. Emotional Aspects/Connecting with Others was the most common theme (77 % of posts) followed by Information Support: Treatment (38 % of posts), Information Support: Diagnosis (24 % of posts) and Information Support: Recovery (21 % of posts). CONCLUSIONS: The most prevalent theme was centered on emotional aspects of these patients' journeys, highlighting the importance of providing resources to address emotional support for patients with soft tissue sarcoma and their families. LEVEL IV: Qualitative research study.

Approach to the Treatment of Expansile Metacarpal Aneurysmal Bone Cysts: A Report of Two Cases.

The two cases presented demonstrate the management of aneurysmal bone cysts of the metacarpal, which destroyed the normal bone architecture. Treatment of both cases included wide resection and metacarpal reconstruction with an intercalary fibular allograft. Denosumab use contrasts these two cases and is helpful in reestablishment of a cortical rim for fixation in the absence of a 1-cm margin proximally or distally to preserve the native carpometacarpal and metacarpophalangeal joints. Surgical resection and allograft reconstruction is a viable treatment for expansile metacarpal aneurysmal bone cysts, and neoadjuvant denosumab has utility in creating an ossified margin for fixation.

Monoclonal Antibody Disrupts Biofilm Structure and Restores Antibiotic Susceptibility in an Orthopedic Implant Infection Model.

Bacterial biofilms on orthopedic implants are resistant to the host immune response and to traditional systemic antibiotics. Novel therapies are needed to improve patient outcomes. TRL1068 is a human monoclonal antibody (mAb) against a biofilm anchoring protein. For assessment of this agent in an orthopedic implant infection model, efficacy was measured by reduction in bacterial burden of Staphylococcus aureus, the most common pathogen for prosthetic joint infections (PJI). Systemic treatment with the biofilm disrupting mAb TRL1068 in conjunction with vancomycin eradicated S. aureus from steel pins implanted in the spine for 26 of 27 mice, significantly more than for vancomycin alone. The mechanism of action was elucidated by two microscopy studies. First, TRL1068 was localized to biofilm using a fluorescent antibody tag. Second, a qualitative effect on biofilm structure was observed using scanning electron microscopy (SEM) to examine steel pins that had been treated in vivo. SEM images of implants retrieved from control mice showed abundant three-dimensional biofilms, whereas those from mice treated with TRL1068 did not. Clinical Significance: TRL1068 binds at high affinity to S. aureus biofilms, thereby disrupting the three-dimensional structure and significantly reducing implant CFUs in a well-characterized orthopedic model for which prior tested agents have shown only partial efficacy. TRL1068 represents a promising systemic treatment for orthopedic implant infection.

Arthroscopic debridement for acute hemorrhagic subacromial bursitis following COVID-19 vaccine administration: A case report.

The rapid rollout of vaccinations in response to the COVID-19 pandemic has led to their widespread distribution and administration throughout the world. The benefit of these vaccinations in preventing the spread of the disease and diminishing symptoms in patients who contract COVID-19 has been fervently studied and reported. While vaccinations remain an effective and generally safe method of limiting disease transmission and virus-related mortality, vaccine administration is not completely without risk. Shoulder injuries related to vaccine administration (SIRVA) have been described with previously available vaccines but have yet to be widely reported in the COVID-19 vaccination population. We present a case report of a young, high-functioning patient who presented with acute subacromial bursitis after COVID-19 vaccine administration due to improper vaccination technique. The patient was treated with arthroscopic shoulder surgery and had near immediate relief of shoulder symptoms.

The microbial profile of infected endoprosthetic reconstructions after wide excision for patients with musculoskeletal tumors: A call for pathogen-based practices.

BACKGROUND AND OBJECTIVES: Periprosthetic infection is a devastating complication following endoprosthetic reconstruction. This study utilized a large database of endoprostheses to describe the incidence, risk factors, and microbial profile of such infections to better catalogue and understand these catastrophic events. METHODS: A retrospective review of endoprosthetic reconstructions for an oncologic indication from January 1, 1981 to December 31, 2020 was performed. Demographic, oncologic, procedural and outcome data was analyzed. Multivariable logistic regression was used to identify potential risk factors for infection with significance defined as p < 0.05. RESULTS: Forty four out of 712 (6.2%) reconstructions resulted in infection at a mean time of 39.9 ± 44.5 months. Revision surgery (odds ratio [OR] 6.14, p < 0.001) or having a postoperative wound complication (OR 7.67, p < 0.001) were significantly associated with infection. Staphylococcus aureus and Staphylococcus epidermidis were the most commonly cultured organisms at a rate of 34.1% (15/44) and 22.7% (10/44), respectively. Ten infections resulted in amputation; five due to antimicrobial-resistant infections and three due to polymicrobial infections. CONCLUSION: Understanding the microbial profile of patients undergoing endoprosthetic reconstruction is paramount. This study demonstrates a relatively high rate of polymicrobial and antibiotic-resistant infections that portend worse outcomes, thus suggesting that pathogen-specific infectious practices may be warranted. LEVEL OF EVIDENCE: Retrospective cohort study, level III.

Multimodal management of tenosynovial giant cell tumors (TGCT) in the landscape of new druggable targets.

Tenosynovial giant cell tumor (TGCT) is a rare, benign, locally aggressive synovial based neoplastic process that can result in functional debilitation and end-stage arthrtitis. Although surgical resection is the primary treatment modality, novel systemic therapies are emerging as part of the multimodal armamentarium for patients with unresectable or complex disease burden. This review discusses the pathogenesis of TGCT, potential druggable targets and therapeutic approaches. It also evaluates the safety and efficacy of different systemic therapies.

Most Patients With Bone Sarcomas Seek Emotional Support and Information About Other Patients' Experiences: A Thematic Analysis.

BACKGROUND: Online discussion forums allow individuals who otherwise may be strangers to create a community where they can seek and share information. Patients with bone sarcomas and their support networks use discussion forums dedicated to cancer support. There is a paucity of published reports regarding the care experience of patients with bone sarcomas because studies on online discussion groups have primarily focused on some of the more common cancers, including breast and prostate cancer. Understanding commonly discussed themes among patients with bone sarcomas would allow treating physicians to have a better understanding of patient concerns when providing patient education and counseling. QUESTION/PURPOSE: We performed this study to review posts from bone sarcoma internet discussion boards to establish common themes related to the care experience of patients with sarcomas. METHODS: Online discussion forums were identified using the search term "sarcoma discussion forum." After identifying 12 websites, we excluded closed forum groups, websites with missing or invalid links to forums, and nonpublic forums, such as groups on Facebook. These websites include profiles and photos that are personal, and sufficient author anonymity could not be achieved for this study. Posts written between January 1, 2012, and May 1, 2022, posted on five discussion boards were reviewed and collected until we reached a point of data saturation in which we agreed that the collection of additional posts would not reveal new themes. Discussion threads were filtered to identify posts pertaining to the most common bone sarcomas: chondrosarcoma, Ewing sarcoma, and osteosarcoma. Grounded theory-the methodology of repeated analyses of qualitative data to identify recurring themes or concepts-was used to analyze posts. Caregiver posts were delineated from patient posts and categorized separately for subgroup analysis. Grounded theory, although a qualitative method, endeavors to integrate the strengths inherent in quantitative methods with qualitative approaches. Grounded theory categorizes words, language, and the meanings these imply and seeks to organize and reduce the data gathered into themes or essences, which, in turn, can be fed into descriptions, models, or theories. Our analysis used three reviews of text to assign and group codes based on repeating ideas or concepts. The first review (open coding) aims to assign codes based on the verbatim text included by the author to capture the specific thoughts and ideas of the post. The second review (axial coding) aims to consolidate the ideas of posts by applying broader concepts to each post. The third and final review (selective coding) aims to further consolidate the themes of each post by trying to embody the main message contained in a post. A total of 570 posts from 139 threads were collected and analyzed using grounded theory. Twenty-five axial codes and four selective codes were created. We defined data saturation by the absence of a new open code in the analysis of a block of 50 posts to ensure that signals of saturation were not accepted too early in the analysis. RESULTS: The four selective codes included emotional aspects or connecting with others, information support: diagnosis, information support: treatment, and information support: recovery. Of these four codes, emotional aspects and connecting with others was the most prevalent theme (78% [445 of 570] of posts) followed by information support: treatment (49% [282 of 570] of posts). Information support: diagnosis and information support: recovery were each captured in 15% of posts. CONCLUSION: Analysis of posts reveals that the two most common themes involve seeking out emotional support and information about the experiences of others with various treatment modalities. Although most of the posts we assessed contained experiential information and emotional support rather than directed medical advice, future studies should assess the accuracy of information shared among online sarcoma forums. CLINICAL RELEVANCE: Physicians caring for patients with sarcomas should not only address patient concerns related to medical care, but also provide emotional support directly and assist patients by providing resources to peer support outlets, including online discussion forums. Although we cannot ascertain the proportion of patients who use online sites given the anonymity of posts included, these findings suggest common experiential themes across patients with sarcomas outside their doctors' offices. It is important that providers be aware of reputable forums to provide as resources for their patients. The Musculoskeletal Tumor Society may further benefit from endorsing one or more of these forums and providing physician oversight to monitor misinformation.

Proximal Femur Replacements for an Oncologic Indication Offer a Durable Endoprosthetic Reconstruction Option: A 40-year Experience.

BACKGROUND: Proximal femur replacements (PFRs) are an effective surgical option to treat primary and metastatic tumors causing large bony defects in the proximal femur. Given the relative rarity of these indications, current studies on PFR for oncologic indications are generally limited by patient volume or relatively short-term follow-up. Because recent advances in systemic therapy have improved the prognosis of patients who undergo limb salvage surgery for musculoskeletal tumors, data on the long-term durability of endoprosthetic reconstructions have become increasingly important. QUESTIONS/PURPOSES: (1) How does the long-term survival of cemented bipolar PFRs compare with patient survival in patients who underwent PFR for benign, aggressive, and metastatic tumors? (2) What are common reasons for revisions of primary PFRs? (3) Which factors are associated with survival of primary PFRs? (4) What is the survivorship free from conversion of bipolar PFRs to THA? METHODS: Between January 1, 1980, and December 31, 2020, we treated 812 patients with an endoprosthetic reconstruction for an oncologic indication. All patients who underwent a primary PFR for an oncologic indication were included in this study. The study cohort consisted of 122 patients receiving a primary PFR. Eighteen patients did not reach a censored endpoint such as death, revision, or amputation within 2 years. Thirty-three patients died within 2 years of their surgery. Of the 122 patients with primary PFRs, 39 did not reach a censored endpoint and have not been seen within the past 5 years. However, the mean follow-up time for these patients was longer than 10 years. The Social Security Death Index was queried to identify any patients who may have died but might not have been captured by our database To allow for adequate follow-up, endoprosthetic reconstructions performed after December 31, 2020 were excluded. The mean age at the time of the index surgery was 48 ± 22 years. The mean follow-up time of surviving patients was 7 ± 8 years. All PFRs were performed using a bipolar hemiarthroplasty with a cemented stem, and all implants were considered comparable. Demographic, oncologic, procedural, and outcome data including prosthesis survival, patient survival, complication rates, and rates of conversion to THA were analyzed. Patient, prosthesis, and limb salvage survival rates were generated, with implant revision as the endpoint and death as a competing risk. Statistical significance was defined as p < 0.05. RESULTS: Generally, patients with benign or low-grade (Stage I) disease outlived their implants (100% patient survival through 30 years; p = 0.02), whereas the opposite was true in patients with high-grade, localized Stage II disease (64% patient survival at 5 years [95% CI 49% to 76%]; p = 0.001) or widespread Stage III metastatic disease (6.2% patient survival at 5 years [95% CI 0.5% to 24%]; p < 0.001). Primary PFR implant survival at 5, 10, 20, and 30 years was 97% (95% CI 90% to 99%), 81% (95% CI 67% to 90%), 69% (95% CI 46% to 84%), and 51% (95% CI 24% to 73%), respectively. Eight percent (10 of 122) of primary PFRs were revised for any reason. The most common causes of revision were aseptic loosening (3% [four of 122]), infection (3% [three of 122]), breakage of the implant (2% [two of 122]), and tumor progression (1% [one of 122]). Follow-up time was the only factor that was associated with revision of primary PFRs. Neither segment length nor stem length were associated with revision of primary. Six percent (seven of 122) of PFRs were converted to THA at a mean 15 ± 8 years from the index procedure. Survivorship free from conversion to THA (accounting for death as a competing risk) was 94% (95% CI 85% to 99%), 86% (95% CI 68% to 94%). and 77% (95% CI 51% to 91%) at 10, 20, and 30 years, respectively. CONCLUSION: Cemented bipolar PFRs for an oncologic indication are a relatively durable reconstruction technique. Given the relative longevity and efficacy of PFRs demonstrated in our study, especially in patients with high-grade or metastatic disease where implant survival until all-cause revision was longer than patient survival, surgeons should continue to seriously consider PFRs in appropriate patients. The relative rarity of these reconstructions limits the number of patients in this study as well as in current research; thus, further multi-institutional collaborations are needed to provide the most accurate prognostic data for our patients. LEVEL OF EVIDENCE: Level III, therapeutic study.

Risk Factors for All-Cause Early Reoperation Following Tumor Resection and Endoprosthetic Reconstruction: A Secondary Analysis from the PARITY Trial.

BACKGROUND: Oncologic resection and endoprosthetic reconstruction of lower-extremity musculoskeletal tumors are complex procedures fraught with multiple modes of failure. A robust assessment of factors contributing to early reoperation in this population has not been performed in a large prospective cohort. The aim of the present study was to assess risk factors for early reoperation in patients who underwent tumor excision and endoprosthetic reconstruction, with use of data from the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial. METHODS: Baseline characteristics were assessed, including age, sex, tumor type, tumor location, presence of a soft-tissue mass, diabetes, smoking status, chemotherapy use, and neutropenia. Operative factors were recorded, including operative time, topical antibiotics, silver-coated prosthetics, endoprosthetic fixation, extra-articular resection, length of bone resected, margins, tranexamic acid, postoperative antibiotics, negative-pressure wound therapy, and length of stay. Univariate analysis was utilized to explore the differences between patients who did and did not undergo reoperation within 1 year postoperatively, and a multivariate Cox proportional hazards regression model was utilized to explore the predictors of reoperation within 1 year. RESULTS: A total of 155 (25.7%) of 604 patients underwent ≥1 reoperation. In univariate analysis, tumor type (p < 0.001), presence of a soft-tissue mass (p = 0.045), operative time (p < 0.001), use of negative-pressure wound therapy (p = 0.010), and hospital length of stay (p < 0.001) were all significantly associated with reoperation. On multivariate assessment, tumor type (benign aggressive bone tumor versus primary bone malignancy; hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.04 to 0.63; p = 0.01), operative time (HR per hour, 1.15; 95% CI, 1.10 to 1.23; p < 0.001), and use of negative-pressure wound therapy (HR, 1.93; 95% CI, 1.30 to 2.90; p = 0.002) remained significant predictors of reoperation within 1 year. CONCLUSIONS: Independent variables associated with reoperation within 1 year in patients who underwent tumor resection and endoprosthetic reconstruction included tumor type (benign aggressive bone tumor versus primary bone malignancy), operative time, and use of negative-pressure wound therapy. These results will help to inform patients and surgeons regarding the risk of reoperation by diagnosis and reinforce operative time as a factor influencing reoperation. These results also support further investigation into the use of negative-pressure wound therapy at the time of surgery in this patient population. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Patient and Surgical Risk Factors for Surgical Site Infection in Lower-Extremity Oncological Endoprosthetic Reconstruction: A Secondary Analysis of the PARITY Trial Data.

BACKGROUND: The specific risk factors for surgical site infection (SSI) in orthopaedic oncology patients undergoing endoprosthetic reconstruction have not previously been evaluated in a large prospective cohort. In the current study, we aimed to define patient- and procedure-specific risk factors for SSI in patients who underwent surgical excision and endoprosthetic reconstruction for lower-extremity bone or soft-tissue tumors using the prospectively collected data of the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial. METHODS: PARITY was a multicenter, blinded, randomized controlled trial with a parallel 2-arm design that aimed to determine the effect of a long duration (5 days) versus short duration (24 hours) of postoperative prophylactic antibiotics on the rate of SSI in patients undergoing surgical excision and endoprosthetic reconstruction of the femur or tibia. In this secondary analysis of the PARITY data, a multivariate Cox proportional hazards regression model was constructed to explore predictors of SSI within 1 year postoperatively. RESULTS: A total of 96 (15.9%) of the 604 patients experienced an SSI. Of the 23 variables analyzed in the univariate analysis, 4 variables achieved significance: preoperative diagnosis, operative time, volume of muscle excised, and hospital length of stay (LOS). However, only hospital LOS was found to be independently predictive of SSI in the multivariate regression analysis (hazard ratio per day = 1.03; 95% confidence interval = 1.01 to 1.05; p < 0.001). An omnibus test of model coefficients demonstrated that the model showed significant improvement over the null model (χ2 = 78.04; p < 0.001). No multicollinearity was found. CONCLUSIONS: This secondary analysis of the PARITY study data found that the only independent risk factor for SSI on multivariate analysis was hospital LOS. It may therefore be reasonable for clinicians to consider streamlined discharge plans for orthopaedic oncology patients to potentially reduce the risk of SSI. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

Central Adjudication Committee and Clinical Site Investigator Agreement on Outcomes in the PARITY Trial: A Secondary Analysis of the PARITY Trial Data.

BACKGROUND: The detection of a surgical site infection (SSI) in patients with metal implants requires a high degree of clinical acumen. The inherent subjectivity of SSI diagnosis poses a challenge in the design of surgical trials because this subjectivity raises concern for outcome assessment bias. Central Adjudication Committees (CACs) are often utilized to minimize the variability in outcome assessment. Little research has been done to determine the reliability of outcome assessment in trials utilizing a CAC. In the present study, we determined the agreement between the study CAC and the clinical site investigators for the primary and secondary outcome assessments. METHODS: The Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial was a multicenter, blinded, parallel 2-arm, randomized controlled trial that aimed to determine the effect of a 5-day versus 1-day postoperative prophylactic antibiotic regimen on the rate of SSI in patients undergoing surgical excision of tumors in the femur or tibia. The blinded PARITY CAC adjudicated all primary and secondary outcomes identified during the 1-year study follow-up. In the present secondary analysis, the Cohen kappa statistic was utilized to determine the level of agreement. RESULTS: The primary outcome of SSI diagnosis demonstrated a substantial level of agreement between the CAC and the site investigators (0.699; 95% confidence interval [CI], 0.595 to 0.803]). Categorization of the SSI (i.e., superficial, deep, or organ space) showed moderate agreement (0.470; 95% CI, 0.382 to 0.558). Secondary outcomes such as the types of reoperations and the indication for reoperation typically showed substantial to almost perfect agreement, whereas antibiotic-related complications showed fair agreement (0.241; 95% CI, 0.000 to 0.474). CONCLUSIONS: Although there was a substantial level of agreement between the PARITY CAC and site investigators on the diagnosis of an SSI, as well as typically at least substantial agreement on the causes and types of reoperations, there was less agreement regarding the type of SSI and the occurrence of an antibiotic-related complication. Therefore, the CAC appears to have provided value when adjudicating the depth of infection and when determining the causality of medical complications associated with antibiotics. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.

The landscape of drug sensitivity and resistance in sarcoma.

Sarcomas are a family of rare malignancies composed of over 100 distinct histological subtypes. The rarity of sarcoma poses significant challenges in conducting clinical trials to identify effective therapies, to the point that many rarer subtypes of sarcoma do not have standard-of-care treatment. Even for established regimens, there can be substantial heterogeneity in responses. Overall, novel, personalized approaches for identifying effective treatments are needed to improve patient out-comes. Patient-derived tumor organoids (PDTOs) are clinically relevant models representative of the physiological behavior of tumors across an array of malignancies. Here, we use PDTOs as a tool to better understand the biology of individual tumors and characterize the landscape of drug resistance and sensitivity in sarcoma. We collected n=194 specimens from n=126 sarcoma patients, spanning 24 distinct subtypes. We characterized PDTOs established from over 120 biopsy, resection, and metastasectomy samples. We leveraged our organoid high-throughput drug screening pipeline to test the efficacy of chemotherapeutics, targeted agents, and combination therapies, with results available within a week from tissue collection. Sarcoma PDTOs showed patient-specific growth characteristics and subtype-specific histopathology. Organoid sensitivity correlated with diagnostic subtype, patient age at diagnosis, lesion type, prior treatment history, and disease trajectory for a subset of the compounds screened. We found 90 biological pathways that were implicated in response to treatment of bone and soft tissue sarcoma organoids. By comparing functional responses of organoids and genetic features of the tumors, we show how PDTO drug screening can provide an orthogonal set of information to facilitate optimal drug selection, avoid ineffective therapies, and mirror patient outcomes in sarcoma. In aggregate, we were able to identify at least one effective FDA-approved or NCCN-recommended regimen for 59% of the specimens tested, providing an estimate of the proportion of immediately actionable information identified through our pipeline. Highlights: Standardized organoid culture preserve unique sarcoma histopathological featuresDrug screening on patient-derived sarcoma organoids provides sensitivity information that correlates with clinical features and yields actionable information for treatment guidanceHigh-throughput screenings provide orthogonal information to genetic sequencingSarcoma organoid response to treatment correlates with patient response to therapyLarge scale, functional precision medicine programs for rare cancers are feasible within a single institution.

Orthopaedic infections: what have we learned?

Orthopaedic infections remain challenging complications to treat, with profound economic impact in addition to patient morbidity. The overall estimates of infection after orthopaedic surgery with internal devices has been estimated at 5%, with hospital costs eight times that of those without fracture-related infections and with significantly poorer functional and pain interference PROMIS scores. Orthopaedic infection interventions have been focused on prevention and treatment options. The creation of new modalities for orthopaedic infection treatment can benefit from the understanding of the temporal relationship between bacterial colonization and host-cell integration, a concept referred to as "the race for the surface." Regarding prevention, host modulation and antibiotic powder use have been explored as viable options to lower infection rates. Orthopaedic infection treatment has additionally continued to evolve, with PO antibiotics demonstrating equivalent efficacy to IV antibiotics for the treatment of orthopaedic infections in recent studies. In conclusion, orthopaedic infections remain difficult clinical dilemmas, although evolving prevention and treatment modalities continue to emerge.

Early identification of life-threatening soft-tissue infection using dynamic fluorescence imaging: first-in-kind clinical study of first-pass kinetics.

Necrotizing soft-tissue infections (NSTIs) are aggressive and deadly. Immediate surgical debridement is standard-of-care, but patients often present with non-specific symptoms, thereby delaying treatment. Because NSTIs cause microvascular thrombosis, we hypothesized that perfusion imaging using indocyanine green (ICG) would show diminished fluorescence signal in NSTI-affected tissues, particularly compared to non-necrotizing, superficial infections. Through a first-in-kind clinical study, we performed first-pass ICG fluorescence perfusion imaging of patients with suspected NSTIs. Early results support our hypothesis that ICG signal voids occur in NSTI-affected tissues and that dynamic contrast-enhanced fluorescence parameters reveal tissue kinetics that may be related to disease progression and extent.

The Role of Denosumab in the Treatment of Primary Tumors of Bone.

Many hand surgeons treat benign bone tumors without referral to orthopedic oncologists. However, there have been considerable advances in medical therapy for some of these tumors, with which hand surgeons may not be as familiar. This review focuses on the mechanism and uses of denosumab in the treatment of benign tumors of bone. Although the hand surgeon may not be directly prescribing this therapy, they are often the only physician treating the patient for these conditions. As such, awareness regarding the use of this therapy in reducing pain, decreasing tumor volume, and treatment of potential lung metastases is critical to those taking on these cases without the support of an orthopedic oncologist. This article aims to familiarize hand surgeons with denosumab to help promote knowledge of this therapeutic option and the potential role of this medication in the treatment of primary bone tumors in the hand.