Relationship of Thermostability and Binding Affinity in Metal-binding WW-Domain Minireceptors.

The design of metallo-miniproteins advances our understanding of the structural and functional roles of metals in proteins. We recently designed a metal-binding WW domain, WW-CA-Nle, which displays three histidine residues on its surface for coordination of divalent metals Ni(II), Zn(II) and Cu(II). However, WW-CA-Nle is a molten globule in the apo state and thus showed only moderate binding affinities with Kd values in the µM regime. In this report, we hypothesize that improved thermal stability of the apo state of the metal binding WW-domain scaffold should lead to improved preorganization of the metal-binding site and consequently to higher metal-binding affinities. By redesigning WW-CA-Nle, we obtained WW-CA variants, WW-CA-min and WW-CA-ANG, which were fully folded in the apo states and displayed moderate to excellent thermostabilities in the apo and holo states. We were able to show that the improved thermal stabilities led to improved metal binding, which was reflected in Kd values that were at least one order of magnitude lower compared to WW-CA-Nle. EPR spectroscopy and ITC measurements revealed a better defined and predisposed metal binding site in WW-CA-ANG.

Does Wound VAC Temporization Offer Patient-Reported Outcomes Similar to Single-Stage Excision Reconstruction After Myxofibrosarcoma Resection?

BACKGROUND: Vacuum-assisted closure (VAC) temporization is a promising technique to achieve local control in aggressive soft tissue sarcomas. Despite its previously reported efficacy, adoption of VAC temporization remains limited, primarily due to the scarce literature on patient-reported outcomes (PROs) supporting its efficacy. This study compared the postoperative PROs after VAC temporization or single-stage (SS) excision and reconstruction for patients undergoing surgical resection for myxofibrosarcoma management. METHODS: A retrospective analysis of myxofibrosarcoma patients who underwent surgical resections at our institution from 2016 to 2022 was performed. Postoperative PROs collected prospectively for those treated with VAC temporization or SS excision/reconstruction were compared using a visual analog scale (VAS) for pain and three Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaires: Global Health Short-Form Mental (SF Mental), Global Health Short-Form Physical (SF Physical), and Physical Function Short-Form 10a (SF 10a). Absolute and differential (postoperative minus preoperative) scores at the 1-month, 3-month, 6-month, 1-year, and 2-year time points were compared. RESULTS: The analysis included 79 patients (47 treated with VAC temporization and 32 treated with SS excision/reconstruction). All outcomes were similar between the groups except for physical function 1 year after surgery, in which the differential PROMIS SF 10a scores were higher in the SS group (p = 0.001). All the remaining absolute and differential PROMIS and VAS pain scores were similar between the groups at all time points. Postoperative complications did not differ between the groups. CONCLUSION: The PROs for physical and mental health, physical function, and pain were similar between the myxofibrosarcoma patients who had VAC temporization and those who had SS excision/reconstruction after surgical resection.

Risk factors for local recurrence of upper extremity desmoid tumors.

INTRODUCTION: Upper extremity (UE) desmoid tumors are locally aggressive neoplasms with high recurrence rates. Our study sought to analyze the demographics and treatment strategies of UE desmoid tumors and identify risk factors for recurrence. MATERIALS AND METHODS: A retrospective review of 52 patients with histologically confirmed UE desmoid tumors treated at our institution between 1990 and 2015 was conducted. Survival was assessed using the Kaplan-Meier method and the Cox proportional hazards model was used for risk factor analysis. RESULTS: For the entire cohort, median age was 40 (29-47) years, 75% were female, and 48% had local recurrence. The median tumor size was 45 (15-111) cm3 on imaging. Twenty-two patients had a previous resection. The most common treatments were surgery alone (50%) and surgery with adjuvant radiotherapy (21%). Tumor size ≥5 cm and tumor volume ≥40 cm3 on imaging were associated with increased recurrence (p = 0.006 and p = 0.005, respectively). Age and sex were not associated with local recurrence. Patients with a tumor size ≥5 cm were 2.6 times more likely to present with recurrence. At the 10-year mark, a lower local recurrence-free survival was seen in patients with tumors ≥5 cm (72.2% vs. 36.3%, p = 0.042) or ≥40 cm3 (67.2% vs. 32.7%, p = 0.034). CONCLUSION: In our study, only tumor dimensions appeared to modify recurrence risk.

Prediction of 5-year survival in soft tissue leiomyosarcoma using a machine learning model algorithm.

BACKGROUND AND OBJECTIVES: Leiomyosarcoma (LMS) is associated with one of the poorest overall survivals among soft tissue sarcomas. We sought to develop and externally validate a model for 5-year survival prediction in patients with appendicular or truncal LMS using machine learning algorithms. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used for development and internal validation of the models; external validation was assessed using our institutional database. Five machine learning algorithms were developed and then tested on our institutional database. Area under the receiver operating characteristic curve (AUC) and Brier score were used to assess model performance. RESULTS: A total of 2209 patients from the SEER database and 81 patients from our tertiary institution were included. All models had excellent calibration with AUC 0.84-0.85 and Brier score 0.15-0.16. After assessing the performance indicators according to the TRIPOD model, we found that the Elastic-Net Penalized Logistic Regression outperformed other models. The AUCs of the institutional data were 0.83 (imputed) and 0.85 (complete-case analysis) with a Brier score of 0.16. CONCLUSION: Our study successfully developed five machine learning algorithms to assess 5-year survival in patients with LMS. The Elastic-Net Penalized Logistic Regression retained performance upon external validation with an AUC of 0.85 and Brier score of 0.15.

Wound vacuum-assisted closure temporization after tumor resection of soft tissue sarcomas-A cost analysis in a propensity-score matched population.

BACKGROUND: Vacuum-assisted closure (VAC) temporization is a technique associated with high local control rates used in myxofibrosarcoma. We sought to compare the costs and postoperative outcomes of VAC temporization and single-stage (SS) excision/reconstruction. METHODS: We conducted a retrospective analysis of patients with myxofibrosarcoma surgically treated at our institution between 2000 and 2022. Variables of interest included total, direct, and indirect costs for initial episode of care, 90 days and 1 year after initial admission, and postoperative outcomes. Costs were compared between the VAC temporization and SS groups. RESULTS: After matching, 13 patients in the SS group and 23 in the VAC group were analyzed. We found no difference in median and mean total inpatient costs, between the VAC temporization and SS group. While total 90-day and 1-year costs were higher in the VAC group compared to the SS group, mean costs were similar. There were no differences in postoperative complications between groups. A subanalysis of the entire cohort (n = 139) revealed lower local recurrence and overall death rates in the VAC temporization group. CONCLUSION: VAC temporization had similar inpatient costs and postoperative outcomes to SS excision/reconstruction. While median 90-day and 1-year costs were higher in the VAC group, mean costs did not differ.

Phosphaturic mesenchymal tumor: management and outcomes of ten patients treated at a single institution.

BACKGROUND: Phosphaturic mesenchymal tumor (PMT) is a rare tumor that causes tumor-induced osteomalacia. Patients present with non-specific symptoms secondary to renal phosphate wasting and decreased bone mineralization. We sought to assess: (1) What are the common presenting features, laboratory and imaging findings, histologic findings of phosphaturic mesenchymal tumors? (2) What are the available treatment strategies for phosphaturic mesenchymal tumors and their long-term outcomes in terms of local recurrence and symptom control after treatment? METHODS: We retrospectively identified patients with a histologic diagnosis of PMT located in the axial or appendicular skeleton, or surrounding soft tissues. A total of 10 patients were finally included in our study. RESULTS: Median tumor size was 1.9 cm (range, 1.1 to 6.1) and median time from symptom onset to diagnosis was 3 years (range, 0.5 to 15 years). All patients but one presented with hypophosphatemia (median 1.9 mg/dL, range 1.2 to 3.2). Pre-operative FGF-23 was elevated in all cases (median 423.5 RU/mL, range 235 to 8950). Six patients underwent surgical resection, three were treated percutaneously (radiofrequency ablation or cryoablation), and one refused treatment. Only one patient developed local recurrence and no patients developed metastatic disease. At last follow-up, nine patients showed no evidence of disease and one was alive with disease. CONCLUSION: Phosphaturic mesenchymal tumor is a rare tumor presenting with non-specific symptoms. Surgery is the standard treatment when negative margins can be achieved without significant morbidity. In patients with small tumors in surgically-inaccessible areas, radiofrequency ablation or cryoablation can be performed successfully.

Complications and Functional Outcomes after Reconstruction of the Proximal Humerus with Allograft-Prosthetic Composite - A Systematic Review of the Literature.

INTRODUCTION: Allograft prosthetic composite (APC) reconstruction is performed after resection of proximal humerus tumors or failure of arthroplasty implants. There is limited literature on the postoperative outcomes of this technique. We sought to assess implant survival, failure rates, and postoperative functional outcomes after APC reconstruction of the proximal humerus. METHODS: A systematic review of the PubMed and Embase databases was conducted. The study was registered on PROSPERO (ID: 448663). The STROBE checklist was used for quality assessment. Implant failure was determined using the Henderson classification for biological reconstruction. Functional outcome was primarily assessed using the Musculoskeletal Tumor Society (MSTS) score at last follow-up. RESULTS: Twenty-five studies with a total of 488 patients were included. Mean follow-up in reporting studies ranged from 2.5 to 10 years. Five-year revision-free survival for implants ranged from 41 to 92%. Overall implant failure rate ranged from 9 to 54%, and reoperation rate ranged from 0 to 55%. Graft-host non-union (type 2) was the most common mode of failure, with rates ranging from 0 to 75%. The mean MSTS scores at last follow-up ranged from 57 to 90% across studies. A trend towards better functional outcomes was seen in patients having an APC with a reverse total shoulder arthroplasty (rTSA) compared with those with hemiarthroplasty (HA). CONCLUSIONS: APCs show promise in proximal shoulder reconstruction, with heterogenous functional outcomes that are non-inferior to other reconstruction techniques. Graft host non-union is a common mode of failure and remains a concern in this type of prosthesis. Future studies should compare rTSA-APCs and rTSA endoprostheses while controlling for potential confounders.

Reconstruction of the elbow with distal humerus endoprosthetic replacement after tumor resection: a systematic review of the literature and institutional case series.

BACKGROUND: Distal humerus replacement (DHR) is a modular endoprosthesis mainly used for bone reconstruction after resection of primary or metastatic bone lesions. Studies on DHR failure rates and postoperative functional outcomes are scarce. We sought to assess implant survival, modes of failure, and functional outcomes in patients undergoing DHR for oncologic indications. METHODS: A systematic review of the PubMed and Embase databases was performed. PRISMA guidelines were followed for this manuscript. Our study was registered on PROSPERO (457,260). Quality appraisal of included studies was conducted using the STROBE checklist. Prosthetic failure was assessed using the Henderson classification for megaprosthetic failures. We additionally performed a retrospective review of patients treated with a DHR for oncologic indications at a large tertiary care academic center. Weighted means were calculated to pool data. RESULTS: Eleven studies with a total of 162 patients met the inclusion criteria. Mean follow-up was 3.7 years (range, 1.66-8 years). Henderson type 2 failures (aseptic loosening) were the most common mode of failure, occurring in 12% of cases (range, 0%-33%). Five-year implant survival was 72% (range, 49%-93.7%). Mean postoperative Musculoskeletal Tumor Society (MSTS) score was 81.1 (range, 74-84.3). In our institutional case series, 2 out of 5 patients had DHR revision for periprosthetic fracture and aseptic loosening at 16 and 27 months after surgery, respectively. CONCLUSIONS: Distal humerus replacement is a successful reconstruction strategy for tumors of the distal humerus, with high implant survival and good to excellent functional outcomes.

Debridement, Antibiotics, and Implant Retention (DAIR) Plus Offers Similar Periprosthetic Joint Infection Treatment Success Rates to Two-Stage Revision in Oncologic Megaprosthesis.

BACKGROUND: Prosthetic joint infections (PJIs) after megaprosthesis implantation are associated with high rates of treatment failure and amputation. Our study analyzed PJI treatment success rates by surgical strategy and assessed risks of reinfection and amputation. METHODS: We retrospectively analyzed the outcomes of patients diagnosed with PJI after undergoing megaprosthesis implantation for oncologic indications. The 2011 Musculoskeletal Infection Society criteria were used to define PJI. Reinfection, reoperation, and amputation for PJI recurrence were assessed. A total of 67 patients with megaprosthesis PJIs were included. There were fourteen patients who were treated with debridement, antibiotics, and implant retention (DAIR), 31 with DAIR plus (DAIR with modular component exchange and stem retention), and 21 with two-stage revisions. Kaplan-Meier estimates were used for survival analyses and Cox proportional hazards for risk factor analyses. RESULTS: The two-year reinfection-free survival was 25% for DAIR and 60% for DAIR plus or two-stage revision (P = .049). The five-year amputation-free survival was 84% for DAIR plus or two-stage revision, and 48% for DAIR (P = .13). Reinfection-free, reoperation-free, and amputation-free survival were similar between DAIR plus and two-stage revision at the 2- and 5-year marks. Body mass index ≥30 (hazard ratio [HR] = 2.65) and chronic kidney disease (HR = 11.53) were risk factors for reinfection. Treatment with DAIR plus or two-stage revision (HR = 0.44) was a protective factor against reinfection. CONCLUSIONS: A DAIR was associated with high rates of treatment failure and higher amputation rates than DAIR plus or 2-stage surgery. A DAIR plus was not inferior to 2-stage revision clearing a PJI and might be performed in patients who cannot withstand two-stage revision surgery.

Reverse Fragility Index: Comparing Revision Rates Between Direct Anterior and Other Approaches in Total Hip Arthroplasty. A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Despite increasing adoption of the direct anterior (DA) approach in total hip arthroplasty (THA), uncertainty persists regarding its outcomes beyond the 1-year mark in comparison to other approaches. We used the reverse fragility index (RFI) to evaluate the robustness of reported findings in the literature. METHODS: We conducted a systematic review of randomized controlled trials (RCTs) comparing implant revision rates between DA and other approaches in THA, defined as all those different from DA. Our primary outcome was the RFI, which gauges the number of events needed for a nonsignificant result to become significant, in the revision rate between DA and other approaches. We also calculated the reverse fragility quotient by dividing the RFI by each study's sample size. Median values and interquartile ranges (IQRs) were displayed. RESULTS: A total of 10 RCTs with a total of 971 patients were included. The median RFI was 5 (IQR, 4 to 5), indicating the study's results would be statistically significant if the outcomes of 5 patients in 1 treatment arm were reversed. The median reverse fragility quotient was 0.049 (IQR, 0.04 to 0.057), indicating that a change of outcome in 4.9% of patients would render the revision rate significant. The median number of patients lost to follow-up was 4 (IQR, 0 to 7). Of the 10 RCTs, 6 had more patients lost to follow-up than their respective RFI values. CONCLUSIONS: Notable fragility was evidenced in most studies comparing DA to other approaches for THA. Surgeons should not solely rely on the P value to determine clinical significance and instead use multiple metrics. LEVEL OF EVIDENCE: II.

Candida spondylodiscitis: a systematic review and meta-analysis of seventy two studies.

OBJECTIVES: Knowledge of Candida spondylodiscitis is limited to case reports and smaller case series. Controversy remains on the most effective diagnostical and therapeutical steps once Candida is suspected. This systematic review summarized all cases of Candida spondylodiscitis reported to date concerning baseline demographics, symptoms, treatment, and prognostic factors. METHODS: A PRISMA-based search of PubMed, Web of Science, Embase, Scopus, and OVID Medline was performed from database inception to November 30, 2022. Reported cases of Candida spondylodiscitis were included regardless of Candida strain or spinal levels involved. Based on these criteria, 656 studies were analyzed and 72 included for analysis. Kaplan-Meier curves, Fisher's exact, and Wilcoxon's rank sum tests were performed. RESULTS: In total, 89 patients (67% males) treated for Candida spondylodiscitis were included. Median age was 61 years, 23% were immunocompromised, and 15% IV drug users. Median length of antifungal treatment was six months, and fluconazole (68%) most commonly used. Thirteen percent underwent debridement, 34% discectomy with and 21% without additional instrumentation. Median follow-up was 12 months. The two year survivorship free of death was 80%. The two year survivorship free of revision was 94%. Younger age (p = 0.042) and longer length of antifungal treatment (p = 0.061) were predictive of survival. CONCLUSION: Most patients affected by Candida spondylodiscitis were males in their sixties, with one in four being immunocompromised. While one in five patients died within two years of diagnosis, younger age and prolonged antifungal treatment might play a protective role.

Risk factors for 30-day soft tissue complications after pelvic sarcoma surgery: A National Surgical Quality Improvement Program study.

INTRODUCTION: Soft tissue (ST) complications after resection of bone and ST sarcomas of the pelvis occur more frequently than in appendicular tumors. We sought to identify risk factors for complications within 30 days of surgery. METHODS: The National Surgical Quality Improvement Program database was used for this study. Patients with sarcomas of bone and ST of the pelvis were retrieved using Current Procedural Terminology and International Classification of Diseases codes. Outcomes assessed were ST complications, overall complication rates, 30-day reoperation, and mortality. RESULTS: A total of 770 patients with pelvic bone and ST sarcoma were included. The ST complication rate was 12.6%, including 4.9% superficial and 4.7% deep surgical site infections. Higher ST complication rates were seen in patients >30 years, with partially dependent health status, hematocrit <30%, bone tumors, tumor >5 cm, amputation procedures, and longer operative times. ST complication rates were 1.5 and 3 times higher in pelvic sarcoma surgeries than in the lower and upper extremities, respectively. Age >30 years (odds ratio [OR] = 5.07), hematocrit <30% (OR = 1.84), operative time 1-3 h (OR = 2.97), and >3 h (OR = 4.89) were risk factors for ST complications. CONCLUSION: One in nine patients with pelvic sarcoma surgery will develop ST complications within 30 days. Risk factors for ST complications were age >30, hematocrit <30%, and longer operative time.

Giant cell-rich osteosarcoma: A match pair analysis of 11 new cases and literature review of 56 patients.

BACKGROUND: Limited remains known on giant cell-rich osteosarcoma (GCRO) with current studies being case reports or smaller series. This investigation compared GCRO and conventional osteoblastic osteosarcoma (OOS) with regard to demographics and survival. METHODS: An institutional tumor registry was used to identify 11 patients (six males) treated for GCRO. Mean age was 43 years. Staging showed American Joint Committee on Cancer (AJCC) stages IIA in four and IIB in seven patients. Mean follow-up was 14 years. Study initiatives were: (1) Comparison of demographics between GCRO and 167 OOS from our institutional registry, (2) Differences in survival between GCRO and 33 OOS case controls (based on sex and AJCC stage), as well as 10 OOS using an age-based propensity match, and (3) Summary of all GCRO cases reported in the literature. RESULTS: (1) Sex (p = 0.53), grading (p = 0.56), AJCC stage (p = 0.42), and chemotherapeutic response rate (p = 0.67) did not differ between groups. Age was significantly increased in GCRO (p = 0.001). (2) Case-control and propensity-matched groups revealed no difference in disease-free survival, local recurrence, and distant disease-free survival at 2 years (p > 0.05). (3) Mean age of 56 patients (50% males) reported in the literature was 26 years. After merging with our 11 cases, the 2-year disease-free survival was 66%. CONCLUSIONS: GCRO remains a rare disease with high short-term mortality. Although affecting older patients more than conventional osteosarcoma, GCRO should not be viewed as a predictor of survival compared to OOS.

Prognostic and predictive factors in undifferentiated pleomorphic sarcoma: A long-term study from a large tertiary care urban center.

BACKGROUND AND OBJECTIVES: Undifferentiated pleomorphic sarcoma (UPS) is an aggressive type of soft tissue sarcoma (STS) with high rates of metastatic disease and local recurrence. We sought to identify risk factors for local recurrence, metastasis, and overall death, and assess their impact on overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS). METHODS: A total of 386 cases of UPS treated at our institution from 1980 to 2020 were included. Cox proportional hazards regression was used to identifying risk factors for death, local recurrence, and/or metastasis. Using the Kaplan-Meier method, we assessed OS, LRFS, and MFS. RESULTS: Sixty-six (17%) and 121 (30%) patients with UPS developed local recurrence or metastasis, respectively. Lymph node (LN) involvement was present in 13.5% of patients. The most affected organ in patients with metastatic disease was the lungs (76.9%). Age ≥ 60 (hazard ratio [HR] = 2.42) and size ≥7 cm (HR = 1.52) were some of the significant risk factors for overall death. LN involvement was an important risk factor for both LR (HR = 2.79) and distant metastasis (HR = 5.73). CONCLUSIONS: UPS displays high rates of metastatic disease and local recurrence. Using a tumor size cutoff value of 7 cm yields superior prognostic value than the standard STS T-score thresholds. Lymphovascular invasion is an important risk factor for the development of metastasis.

Are Pathologic Fractures in Patients With Osteosarcoma Associated With Worse Survival Outcomes? A Systematic Review and Meta-analysis.

BACKGROUND: Pathologic fractures occur in 5% to 10% of patients with osteosarcoma, and prior studies have suggested they are prognostically important. However, because they represent an uncommon event in the setting of an already rare disease, most studies fail to reach conclusive findings, and there is no agreement about how best to treat pathologic fractures. QUESTIONS/PURPOSES: (1) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer overall survivorship? (2) Is the occurrence of a pathologic fracture in patients with osteosarcoma associated with poorer local recurrence-free survival or metastasis-free survival? (3) Is the surgical approach (amputation or limb salvage) associated with differences in local recurrence rates in patients with osteosarcoma with pathologic fractures? METHODS: This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Our study was registered in PROSPERO (ID: 380459). A search of the PubMed and Embase databases resulted in 625 and 747 titles, respectively. After application of the inclusion and exclusion criteria, 21 articles were finally included. Quality assessment of all studies was performed using the Newcastle-Ottawa Quality Assessment Scale. The Risk of Bias In Non-Randomized Studies of Interventions tool was used in the 11 articles that evaluated the effect of an intervention (amputation or limb salvage) on local recurrence rates. The relative risk (RR) was calculated to compare outcomes in patients with osteosarcoma with pathologic fractures and those without. Heterogeneity among studies was calculated using the I 2 statistic. The pooled RR was calculated using the fixed-effects or random-effects model depending on study heterogeneity. The fragility index and the ratio between the fragility index and the total number of participants for each outcome was additionally calculated to assess the robustness of our results. A total of 7604 patients with osteosarcoma, 12% of whom (885) had pathologic fractures, were included in our analysis. RESULTS: Pathologic fractures in patients with osteosarcoma were associated with lower 3-year (RR 1.53 [95% CI 1.29 to 1.82]; p < 0.001) and 5-year overall survival (RR 1.27 [95% CI 1.16 to 1.40]; p < 0.001). No difference in recurrence rates was found between patients with osteosarcoma with pathologic fractures and those without (RR 1.22 [95% CI 0.91 to 1.64]; p = 0.18). However, having a pathologic fracture was associated with an increased risk of developing metastasis (RR 1.33 [95% CI 1.08 to 1.63]; p = 0.01). Treatment with limb salvage surgery was not associated with a higher rate of local recurrence (RR 1.58 [95% CI 0.88 to 2.85]; p = 0.13). CONCLUSION: In light of these findings, surgeons should be aware that after appropriate case selection, patients with osteosarcoma and pathologic fractures undergoing limb salvage surgery may have similar rates of local recurrence to those undergoing amputation. Therefore, a pathologic fracture may no longer be an absolute contraindication for limb salvage surgery. Future studies adjusting for potential confounders such as tumor size, tumor location, and response to neoadjuvant therapy would provide further insight into the effect of pathologic fractures on our assessed outcomes. LEVEL OF EVIDENCE: Level III, therapeutic study.

High Rates of Treatment Failure and Amputation in Modular Endoprosthesis Prosthetic Joint Infections Caused by Fungal Infections With Candida.

BACKGROUND: Fungal prosthetic joint infections (PJIs) are rare yet severe events associated with high rates of recurrent infection. Although bacterial PJIs associated with megaprostheses are known to be associated with higher rates of recurrence and amputation, little is known about fungal PJIs near megaprostheses. QUESTIONS/PURPOSES: In patients with fungal megaprosthesis PJIs from one institutional registry, We asked: (1) what were the most common microorganisms isolated? (2) What were the reoperation-, revision-, and amputation-free survival rates 1 and 2 years after surgery? METHODS: We conducted a retrospective analysis of megaprostheses in our institutional database. Between 2000 and 2022, 86 patients with a diagnosis of PJI after megaprosthesis implantation were surgically treated at our institution. We considered patients with microbiological cultures that were positive for fungal organisms and who had a minimum follow-up of 2 years from the initial treatment for PJI. Ten patients with fungal megaprosthesis PJIs were included. Although four patients had a follow-up shorter than 2 years, all reached one of the study endpoints at that earlier interval, and therefore were included. All included patients were treated between 2016 and 2022, and the diagnosis of PJI was made in accordance with the 2011 Musculoskeletal Infection Society criteria. Patients were treated with either debridement, antibiotics, and implant retention (DAIR), DAIR-plus (debridement, antibiotics, modular implant component exchange, and stem retention), or one-stage or two-stage revision. In general, DAIR was used for acute PJIs, while DAIR-plus was performed in patients with chronic PJIs who were deemed medically unfit to endure the high morbidity associated with removal of the stems. In cases of prior unsuccessful DAIR-plus or patients with fewer comorbidities, one-stage or two-stage revision was the main treatment approach. The median age at diagnosis was 67 years (range 32 to 84 years), 5 of 10 patients were female, and the median BMI was 31 kg/m2 (range 20 to 43 kg/m2). The median follow-up was 26 months (range 1 to 54 months). A Kaplan-Meier survival analysis was performed to calculate reoperation-, revision-, and amputation-free survival at 1 and 2 years from the index surgery for PJI. RESULTS: The two most common organisms were Candida albicans (5 of 10 patients) and C.parapsilosis (3 of 10). Six of 10 patients had coinfection with a bacterial organism. One-year reoperation-free and revision-free survival were 35% (95% CI 9% to 64%) and 42% (95% CI 11% to 71%), respectively. Two-year reoperation-free and revision-free survival were 12% (95% CI 1% to 40%) and 14% (95% CI 1% to 46%), respectively. Amputation-free survival was 74% (95% CI 30% to 93%) at the 1-year interval and 40% at the 2-year interval (95% CI 7% to 73%). At the final follow-up interval, four patients had undergone amputations and four were being administered chronic antifungal suppression. CONCLUSION: Megaprosthesis fungal PJIs are rare but devastating. Arthroplasty surgeons should consider treatment efficacy, which appears to be low across surgical strategies, and the patient's capacity to withstand it. A lower decision threshold for performing amputation may be considered in patients who require rapid infection control to initiate immunosuppressive treatments. Future studies should aim to compare the surgical and clinical outcomes of fungal PJIs with those of other etiologies while controlling for potential variables. Efforts should be made to establish multi-institutional collaborations to achieve larger study samples. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Treatment and Outcomes of Fungal Prosthetic Joint Infections: A Systematic Review of 225 Cases.

BACKGROUND: Fungal prosthetic joint infections (PJIs) after a total joint arthroplasty are a rare, yet severe, occurrence not often reported in the literature. Unlike in bacterial PJIs, no clear consensus exists on fungal PJI optimal management. METHODS: A systematic review was performed using the PubMed and Embase databases. Manuscripts were assessed for inclusion and exclusion criteria. The Strengthening the Reporting of Observational Studies in Epidemiology checklist was applied for quality assessment. Individual demographic, clinical, and treatment information was retrieved from included manuscripts. RESULTS: Seventy one patients who had a PJI of the hip and 126 of the knee were included. Infection recurrence occurred in 29.6% and 18.3% of patients with hip or knee PJI, respectively. Patients who had knee PJIs recurrence had a significantly higher Charlson Comorbidity Index (CCI). For knee PJIs, infection recurrence was more common in patients with Candida albicans (CA) PJIs (P = .022). Two-stage exchange arthroplasty was the most common procedure in both joints. Multivariate analysis found that CCI ≥ 3 was associated with an 18.5-fold increase in the risk of knee PJI recurrence (Odds ratio [OR] = 18.57). Additional risk factors for recurrence in the knee included CA etiology (OR = 3.56) and C-reactive protein at presentation ≥ 6 (OR = 6.54). Compared to debridement, antibiotics, and implant retention, 2-stage procedure was a protective factor for PJI recurrence in the knee (OR = 0.18). No risk factors were found in patients who had hip PJIs. CONCLUSION: Treatment of fungal PJIs varies widely, but 2-stage revision is the most common. Risk factors for knee fungal PJI recurrence include elevated CCI, infection by CA, and high C-reactive protein at presentation.

Postoperative Outcomes of Total Femur Replacement in Oncologic and Nononcologic Patients: A Systematic Review of the Literature.

BACKGROUND: Total femur replacement (TFR) is used for primary reconstruction after extensive tumor resection or as a revision surgery due to prosthetic failure. Studies on TFR rates of failure and functional outcomes are scarce. The purpose of our study was to compare the modes of failure, amputation rates, and functional outcomes after TFR between oncologic and nononcologic patients. METHODS: We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were for this manuscript. Our study was registered on PROSPERO (413582). Quality assessment of all studies was performed using Strengthening the Reporting of Observational Studies in Epidemiology checklist. Endoprosthesis failure was assessed using the Henderson classification and functional outcomes using the Musculoskeletal Tumor Society score. Weighted means and standard deviations were calculated. RESULTS: Overall failure rate was similar between groups. Henderson type 4 failures were more common within the nononcologic group, while the others were more frequently found in the oncologic group. Overall amputation rate was higher in the oncologic group mainly due to type 5 failure. Amputations occurred mainly after type 4 and type 5 failures. Functional outcome was better within the oncologic group (70.5 versus 61.7, respectively; P < .001). CONCLUSIONS: Total femoral replacement in the oncologic and nononcologic group is associated with a high rate of failure (31% and 32.5%, respectively). Overall amputation rate was higher in the oncologic group mainly due to type 5 failure. Functional outcome was better within the oncologic group. LEVEL OF EVIDENCE: Level III.

Gram negative periprosthetic hip infection: nearly 25% same pathogen infection persistence at a mean of 2 years.

PURPOSE: While gram negative (GN) periprosthetic joint infections (PJI) have previously been described as difficult to treat pathogens with high rates of reinfection, limited investigations have addressed midterm outcomes and risk of infection persistence by the same pathogen. This study analyzed (1) baseline demographics, treatment strategy, and midterm outcomes of GN PJIs, as well as (2) differences in reinfection and relapse rates compared to gram positive (GP) PJIs. METHODS: We identified 29 patients that were revised for 30 GN PJIs of total hip arthroplasties (THAs) between 2010 and 2020 using a university-based hip registry. Mean age was 77 years, 63% were females (19), and mean BMI was 27 kg/m2. Major causative pathogens included Escherichia coli (12), Klebsiella pneumoniae (5), Pseudomonas aeruginosa (5), and Enterobacter cloacae complex (5). Mean follow-up was 3.5 years. Study outcomes included (1) Kaplan-Meier survivorship analyses of all 30 GN PJIs, and (2) comparison of 18 two-stage exchanges for GN PJIs and 104 two-stage exchanges for GP PJIs, performed during the time from 2013 to 2017. RESULTS: (1) The 5-year survivorship free of recurrent PJI was 69%, and there were 7 recurrent PJIs at a mean of 2 years. There were 2 further suprafascial wound infections, resulting in a 61% survivorship free of any infection at 5-years. At a mean of 2 years, there were 7 patients with reinfection by the same GN pathogen (6 PJIs, one wound infection) as at index revision (23%). (2) Following two-stage exchange, the 5-year survivorship free of recurrent PJI (GN: 74%; GP: 91%; p = 0.072), any infection (GN: 61%; GP: 91%; p = 0.001), and reinfection by the same pathogen was significantly lower among GN PJIs (GN: 73%; GP: 98%; p < 0.001). CONCLUSIONS: Patients revised for GN PJIs are at increased risk of reinfection as opposed to GP infections. Affected patients must be counseled on the exceptionally high risk of infection persistence with one in four developing relapses. LEVEL OF EVIDENCE: Therapeutic Level III.

Corynebacterium periprosthetic joint infection: a systematic review of 52 cases at 2.5 years follow-up.

INTRODUCTION: While large progress has been achieved in identifying and treating the most common pathogens involved in periprosthetic joint infections (PJI), there remains limited knowledge on atypical pathogens such as Corynebacterium. For that reason, we analyzed infection and diagnostical characteristics, as well as treatment outcome in Corynebacterium PJI. METHODS: A systematic review was performed based on a structured PubMed and Cochrane Library analysis using the PRISMA algorithm. The search was performed by 2 independent reviewers, and articles from 1960 to 2022 considered eligible for inclusion. Out of 370 search results, 12 studies were included for study synthesis. RESULTS: In total, 52 cases of Corynebacterium PJI were identified (31 knees, 16 hips, 4 elbows, 1 shoulder). Mean age was 65 years, with 53% females, and a mean Charlson Comorbidity Index of 3.9. The most common species was Corynebacterium striatum in 37 cases (71%). Most patients were treated with two-stage exchange (40%), isolated irrigation and debridement (21%), and resection arthroplasty (19%). Mean duration of antibiotic treatment was 8.5 weeks. At a mean follow-up of 2.5 years, there were 18 reinfections (33%), and 39% were for Corynebacterium. Initial infection by Corynebacterium striatum species was predictive of reoperation (p = 0.035) and reinfection (p = 0.07). CONCLUSION: Corynebacterium PJI affects multimorbid and elderly patients, with one in three developing a reinfection at short term. Importantly, the relative majority of reinfections was for persistent Corynebacterium PJI.