Survivorship, complications, and outcomes following distal femoral replacement for neoplastic indications.

Background: Distal femoral replacements (DFRs) are excellent treatment options for limb salvage procedures in patients who have bone loss secondary to neoplasm. Multiple studies report adequate survivorship and complication rates following DFR implantation, primarily for non-neoplastic indications. However, current literature regarding neoplasm-specific reports is often limited by sample size, survivorship, and patient reported outcome measurements. Therefore, we sought to examine patients who received a DFR for a neoplastic indication at multiple tertiary academic centers. Specific outcomes analyzed included: (1) revision-free survival, (2) medical/surgical complications, and (3) Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR). Methods: All patients who underwent a DFR for a neoplastic indication were retrospectively reviewed. A total of 29 knees were included for various neoplastic indications. Outcomes of interest included: post-operative thromboses, pneumonia, dislocations, periprosthetic joint infections (PJIs), aseptic loosening, osteolysis, emergency department visits, inpatient readmissions, and revision surgeries. Patient-reported outcome measure (PROM) collected included: Knee Injury and Osteoarthritis Outcome Score for Joint Replacement (KOOS JR). Results: Revision-free survivorship was 72.4 % at 23 months with radiographic follow-up. PJI was the most common post-operative complication, affecting 3 knees (10.3 %). The mean number of emergency department visits and inpatient readmissions averaged less than one per patient (0.63 and 0.41, respectively). KOOS JR scores improved markedly among from baseline to final follow-up (44.1-57.8). Conclusion: The use of DFR led to satisfactory medium-term clinical outcomes with an acceptable complication rate for this challenging group of patients. The marked improvement in patient satisfaction for this patient population gives a promising outlook for patients who will undergo this procedure in the future and can guide patient-provider regarding surgical expectations.

Use of a Cannulated, Percutaneous Expandable Reamer for Physeal Sparing Excision of a Femoral Head Chondroblastoma.

The treatment of chondroblastoma in the epiphysis of the femoral head in skeletally immature individuals is challenging and often requires surgical hip dislocation. We present a unique method of percutaneous use of an expandable reamer (X-REAM, Wright Medical) to treat a chondroblastoma of the femoral head in a 9-year-old boy without requiring surgical hip dislocation. The described technique provides access to the tumor in the proximal femoral epiphysis and local tumor control. However, the approach involves placing a cannula through the epiphyseal plate, resulting in partial premature epiphyseal closure. At 5 years after surgery, the patient has an asymptomatic leg-length discrepancy and radiographic evidence of premature physeal closure, but no restrictions on activity or evidence of local recurrence. A percutaneous expandable reamer can be used to treat chondroblastoma of the femoral head while avoiding surgical hip dislocation.

National evaluation of patterns and predictors of underuse of multimodal therapy for high-risk extremity soft tissue sarcoma.

BACKGROUND: Treatment of high-risk extremity soft tissue sarcomas remains widely varied. Despite growing support for a multimodal approach for treatment of these rare and aggressive neoplasms, its dissemination remains underused. This national study aimed to evaluate variations in treatment patterns and uncover factors predictive of underuse of multimodal therapy in high-risk extremity soft tissue sarcomas. METHODS: The 2010 to 2015 National Cancer Database was used to evaluate trends in 3 common treatment patterns: surgery alone, surgery + adjuvant therapy, and neoadjuvant therapy + surgery. Demographic-, sarcoma-, hospital-, and treatment-level factors of 6,725 surgically treated patients with stage II or III intermediate- to high-grade extremity soft tissue sarcomas were evaluated by types of treatment modality. Stepwise multivariable logistic regression was performed to identify factors predictive of each treatment modality. RESULTS: When compared to surgery alone (34.6%) and adjuvant therapy (41.2%), use of neoadjuvant therapy + surgery for high-risk extremity soft tissue sarcomas remained low (25.3%). However, time trend analysis demonstrated that neoadjuvant therapy + surgery has significantly increased by 7% per year, whereas surgery alone decreased by 4% every year (P < .05 for both). Factors predictive of surgery alone were older age, nonprivate insurance, increasing travel distance, and multimorbidity (P < .05). Conversely, factors associated with neoadjuvant therapy + surgery were private insurance, higher education, and care at academic or high-volume institutions (for all, P < .05). Tumor-related factors predictive for neoadjuvant therapy + surgery included size <5 cm and higher-grade tumors (P < .05). CONCLUSION: Adoption of multimodality therapy for high-risk extremity soft tissue sarcomas remains low and gradual in the United States. Dissemination of multimodality therapy will require attention to access and hospital factors to maximize these therapies for high-risk extremity soft tissue sarcomas.

The Effect of Modern Antiretroviral Therapy on Complication Rates After Total Hip Arthroplasty.

BACKGROUND: Antiretroviral therapy (ART) remains the cornerstone of decreasing morbidity and mortality in patients with human immunodeficiency virus (HIV), but additional information on its impact on total hip arthroplasty (THA) complication rates is needed to mitigate risks postoperatively. Therefore, we sought to examine patients with HIV who were and were not taking ART compared with a cohort without HIV in the setting of primary THA with respect to the following outcomes: length of stay, readmissions, and postoperative infection. METHODS: A retrospective database review was performed with PearlDiver for patients who underwent THA from 2010 to 2019 (n = 729,101). Patients with HIV who were and were not taking ART were then identified and were matched with patients without HIV at a 1:1:1 ratio based on age, sex, Charlson Comorbidity Index, diabetes, obesity, and tobacco use, resulting in 601 patients in each cohort. Length of stay, 30-day readmissions, and complications at 90 days and 1 year were analyzed. Continuous outcomes were measured via Student t tests, and categorical outcomes were measured via chi-square analyses. RESULTS: Patients with HIV who were and were not taking ART were found to have similar lengths of stay compared with patients without HIV (range, 4.1 to 4.3 days). Readmission rates were slightly higher in patients with HIV who were taking ART at 4.2% (odds ratio [OR], 1.96 [95% confidence interval (CI), 0.99 to 3.87]) and patients with HIV who were not taking ART at 3.5% (OR, 1.63 [95% CI, 0.81 to 3.30]) compared with patients without HIV at 2.1%. Periprosthetic joint infection rates at 1 year were slightly higher among patients with HIV who were not taking ART at 5.3% (OR, 1.41 [95% CI, 0.82 to 2.45]) compared with patients with HIV who were taking ART at 4.2% (OR, 1.09 [95% CI, 0.61 to 1.94]) and patients without HIV at 3.8%. CONCLUSIONS: Patients with HIV who are and are not taking ART are approaching normalization to the general population in the setting of THA. It is important to note that, although complications may have been mitigated by modern therapy, extreme care should be taken while clinically evaluating these patients prior to the surgical procedure given the complexity of their clinical status. The findings of this study underscore the utility of ART and patient optimization to reduce risk in this patient population. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Current Biopsy Methods for Primary Musculoskeletal Lymphoma: A Retrospective Multicenter Review.

Primary musculoskeletal lymphoma often requires multiple biopsies for tissue confirmation. This challenge is understood by specialists but has not been specifically quantified. One-hundred-eighteen biopsies performed in 100 cases of primary musculoskeletal lymphoma was performed. Demographics, tumor location and the method and performer of biopsy were recorded. Pearson chi-square and analysis of variance (ANOVA) statistics were used to compare rates of diagnostic yield, time to diagnosis and the presence of crush artifact based on method of biopsy, imaging, performer and tumor location. Diagnostic yield of initial biopsy is 82%. Open biopsy is associated with a higher yield compared to percutaneous techniques (p = 0.005). Biopsies performed by the treating surgeon had a higher yield compared to other practitioners (p = 0.035). Musculoskeletal lymphomas are a greater diagnostic challenge compared to other lesions. A higher index of suspicion and more aggressive sampling procedure may be necessary to establish this diagnosis. (Journal of Surgical Orthopaedic Advances 29(3):149-153, 2020).

Marjolin's Tumor Complicating Chronic Periprosthetic Infection of a Total Knee Arthroplasty.

Marjolin's tumor is a term used to describe a malignancy developing in the setting of a chronic wound, infection, or other tissue subject to chronic inflammatory changes. These malignancies usually present after many years of chronicity, and can range from lower grade basal cell carcinomas to high-grade sarcomas. We present the case of a squamous cell carcinoma that developed within a chronic periprosthetic infection of a total knee arthroplasty of 7 years duration. The intra-articular location, association with an orthopaedic implant, and brief latency period are all unique features of this case.

CT-based Structural Rigidity Analysis Is More Accurate Than Mirels Scoring for Fracture Prediction in Metastatic Femoral Lesions.

BACKGROUND: Controversy continues regarding the appropriate assessment of fracture risk in long bone lesions affected by disseminated malignancy. QUESTIONS/PURPOSES: The purpose of this ongoing Musculoskeletal Tumor Society-sponsored, multi-institutional prospective cross-sectional clinical study is to compare CT-based structural rigidity analysis (CTRA) with physician-derived Mirels scoring for predicting pathologic fracture in femoral bone lesions. We hypothesized CTRA would be superior to Mirels in predicting fracture risk within the first year based on (1) sensitivity, specificity, positive predictive value, and negative predictive value; (2) receiver operator characteristic (ROC) analysis; and (3) fracture prediction after controlling for potential confounding variables such as age and lesion size. METHODS: Consented patients with femoral metastatic lesions were assigned Mirels scores by the individual enrolling orthopaedic oncologist based on plain radiographs and then underwent CT scans of both femurs with a phantom of known density. The CTRA was then performed. Between 2004 and 2008, six study centers performed CTRA on 125 patients. The general indications for this test were femoral metastatic lesions potentially at risk of fracture. The enrolling physician was allowed the choice of prophylactic stabilization or nonsurgical treatment, and the local treating oncology team along with the patient made this decision. Of those 125 patients, 78 (62%) did not undergo prophylactic stabilization and had followup sufficient for inclusion, which was fracture through the lesion within 12 months of CTRA, death within 12 months of CTRA, or 12-month survival after CTRA without fracture, whereas 15 (12%) were lost to followup and could not be studied here. The mean patient age was 61 years (SD, 14 years). There were 46 women. Sixty-four of the lesions were located in the proximal femur, 13 were in the diaphysis, and four were distal. Osteolytic lesions prevailed (48 lesions) over mixed (31 lesions) and osteoblastic (15 lesions). The most common primary cancers were breast (25 lesions), lung (14 lesions), and myeloma (11 lesions). CTRA was compared with Mirels based on sensitivity/specificity analysis, ROC, and fracture prediction by multivariate analysis. For the CTRA, reduction greater than 35% in axial, bending, or torsional rigidities at the lesion was considered at risk for fracture, whereas a Mirels score of 9 or above, as suggested in the original manuscript, was used as the definition of impending fracture. RESULTS: CTRA provided higher sensitivity (100% versus 66.7%), specificity (60.6% versus 47.9%), positive predictive value (17.6% versus 9.8%), and negative predictive value (100% versus 94.4%) compared with the classic Mirels definition of impending fracture (≥ 9), although there was considerable overlap in the confidence intervals. ROC curve analysis found CTRA to be better than the Mirels score regardless of what Mirels score cutoff was used. After controlling for potential confounding variables including age, lesion size, and Mirels scores, multivariable logistic regression indicated that CTRA was a better predictor of fracture (likelihood ratio test = 10.49, p < 0.001). CONCLUSIONS: CT-based structural rigidity analysis is better than Mirels score in predicting femoral impending pathologic fracture. CTRA appears to provide a substantial advance in the accuracy of predicting pathological femur fracture over currently used clinical and radiographic criteria. LEVEL OF EVIDENCE: Level III, diagnostic study.

Treatment Planning and Fracture Prediction in Patients with Skeletal Metastasis with CT-Based Rigidity Analysis.

PURPOSE: Pathologic fractures could be prevented if reliable methods of fracture risk assessment were available. A multicenter prospective study was conducted to identify significant predictors of physicians' treatment plan for skeletal metastasis based on clinical fracture risk assessments and the proposed CT-based Rigidity Analysis (CTRA). EXPERIMENTAL DESIGN: Orthopedic oncologists selected a treatment plan for 124 patients with 149 metastatic lesions based on the Mirels method. Then, CTRA was performed, and the results were provided to the physicians, who were asked to reassess their treatment plan. The pre- and post-CTRA treatment plans were compared to identify cases in which the treatment plan was changed based on the CTRA report. Patients were followed for a 4-month period to establish the incidence of pathologic fractures. RESULTS: Pain, lesion type, and lesion size were significant predictors of the pre-CTRA plan. After providing the CTRA results, physicians changed their plan for 36 patients. CTRA results, pain, and primary source of metastasis were significant predictors of the post-CTRA plan. Follow-up of patients who did not undergo fixation resulted in 7 fractures; CTRA predicted these fractures with 100% sensitivity and 90% specificity, whereas the Mirels method was 71% sensitive and 50% specific. CONCLUSIONS: Lesion type and size and pain level influenced the physicians' plans for the management of metastatic lesions. Physicians' treatment plans and fracture risk predictions were significantly influenced by the availability of CTRA results. Due to its high sensitivity and specificity, CTRA could potentially be used as a screening method for pathologic fractures.

Standardization of rehabilitation after limb salvage surgery for sarcomas improves patients' outcome.

BACKGROUND AND OBJECTIVE: The purpose of this study is to establish a standardized postoperative rehabilitation protocol following limb salvage surgery (LSS) in patients with primary bone sarcoma in five major anatomical locations: distal femur, proximal tibia, proximal and total femur, humerus and shoulder girdle and pelvic resections. SETTING AND DESIGN: Retrospective study. PATIENTS AND METHODS: All LSSs were performed by an orthopedic oncology surgeon, and rehabilitation of all patients was based on a devised standardized rehabilitation protocol. Patient outcomes were measured using the modified Musculoskeletal Tumor Society-International Symposium on the Limb Salvage (MSTS-ISOLS) scoring system. RESULTS: A total of 59 patients received LSS in the above mentioned locations; endoprostheses were used in 49, bone allograft in five, while no replacements were made in five patients. At a mean follow-up of 24 months, the mean modified MSTS-ISOLS score for all patients was 87% (95% CI; 0.85-0.89). The highest scores were encountered for patients with distal femur replacement: 93% (95% CI; 0.91-0.95). Seven patients had interruption of more than six weeks in their rehabilitation and had a mean score of 71% (95% CI; 0.64-0.82). CONCLUSION: The proposed rehabilitation protocol is a comprehensive, organized and applicable guideline to be used after performing LSS at the above mentioned anatomical locations. The use of standardized rehabilitation protocol resulted in improved patient functional outcome.

Potential for functional redundancy in EGF and TGFalpha signaling in desmoid cells: a cDNA microarray analysis.

Genes that replace or duplicate the function of other genes are considered functionally redundant. In this cDNA microarray study, using an Agilent microarray platform and GeneSifter analysis software, we evaluated (1) the degree of downstream transcriptional redundancy and (2) the level of genetic uniqueness apparent in desmoid tumor cells stimulated in vitro for 3 h or for 24 h with 100 ng/ml of exogenous recombinant human EGF (rhEGF) or with recombinant human transforming growth factor alpha (rhTGFalpha). Our intent was to identify genes costimulated, or genes unique to, desmoid cells stimulated in vitro with rhEGF and rhTGFalpha. This experimental approach demonstrated a 55% transcriptional redundancy in the number of desmoid genes significantly upregulated or downregulated following 3 h of stimulation with rhEGF or with rhTGFalpha, and a 65% transcriptional redundancy following 24 h of growth factor stimulation. Approximately 150 genes costimulated by rhEGF and rhTGFalpha were identified. This study suggests that EGF and TGFalpha retain some level of functional redundancy, possibly resulting from their divergence from a common ancestral gene.

FAP-associated desmoid invasiveness correlates with in vitro resistance to doxorubicin.

Desmoid tumors are locally invasive myofibroblastic lesions that arise predominantly in the abdominal wall or shoulder girdle and are prone to aggressive local recurrences without metastases. We hypothesized the intrinsic invasiveness and drug resistance displayed by cells derived from a familial adenomatous polyposis (FAP)-associated desmoid tumor would surpass the response shown by cells derived from sporadic desmoid tumors. In vitro cell motility and expression of motility-associated genes were quantified using Boyden Chambers and Enzyme-Linked ImmunoSorbent Assays, respectively. Doxorubicin resistance was quantified by Trypan Blue dye exclusion. cDNA microarrays identified genes responsive to doxorubicin. FAP-associated tumor cells were significantly more invasive and refractory to doxorubicin than were cells extracted from sporadic tumors. Pro-MMP1 protein predominated over MMP3 in FAP-associated cell culture supernatants, while MMP3 was the dominant antigen in sporadic tumor cell supernatants. Three genes associated with apoptosis were identified by microarray, two prosurvival genes overexpressed in FAP-associated cell cultures (NTN1, TNFRSF10C) and one proapoptosis gene overexpressed in sporadic tumor cell cultures (FOXL2).

Desmoid cell motility is induced in vitro by rhEGF.

Desmoid tumors are benign but locally invasive myofibroblastic lesions that arise predominantly in the abdominal wall or shoulder and are prone to aggressive local recurrences. A perceived association between desmoid activity and the expression of growth factors during pregnancy or following trauma suggests a cause-and-effect relationship between growth factor stimulation and desmoid invasiveness. We used Boyden Chambers to quantify cell motility in order to determine the effect of growth factor stimulation on desmoid cell migration. Desmoid cell cultures were treated under serum-free conditions with epidermal growth factor (rhEGF) or transforming growth factor alpha (rhTGFalpha). Additional cell cultures were pretreated under serum-free conditions with the EGF receptor (EGFR) inhibitor AG1478, alone or in combination with the TGFbeta1 receptor inhibitor SB431542, and then stimulated with growth factor prior to being assayed for cell motility. The experiments demonstrated a direct dose-dependent relationship between rhEGF stimulation and desmoid motility. In contrast, rhTGFalpha was less effective at inducing cell migration. rhEGF-induced cell migration could be diminished, but not reduced to control levels, by inhibiting EGFR. When EGF and TGFbeta1 receptors were inhibited simultaneously, the level of rhEGF-induced cell migration was reduced significantly beyond the level of cell migration generated by inhibition of EGFR alone.

Fas death pathway in sarcomas correlates with epidermal growth factor transcription.

Modulation of apoptosis may influence sarcoma pathogenesis and/or aggressiveness. The Fas death pathway, mediated by FasL or TGFbeta, is one of two apoptotic pathways. Recent studies report that EGF can modulate TGFbeta and/or FasL expression/activity; thus, EGF has the potential to influence activation of the Fas pathway. EGF is not always detectable in mesenchymal tumors; therefore, we hypothesized EGF would define which Fas ligand predominates. We assayed 57 surgically removed human sarcomas for 10 genes involved in the Fas pathway. Skeletal muscle biopsies from eight patients served as controls. Sample transcripts were detected by real-time RT-PCR. We attempted to identify relevant predictor variables. The 57 sarcomas were segregated into two categories defined by EGF mRNA content: (1) 23 tumors with EGF concentrations that approximated muscle EGF transcript levels (high-EGF tumors); and (2) 34 tumors that either lacked EGF mRNA, or whose mRNA levels were very low and frequently undetected by PCR (low-EGF tumors). TGFbeta1 expression best predicted Fas transcript concentrations in the 34 low-EGF sarcomas, while FasL predicted Fas mRNA levels in the remaining 23 high-EGF sarcomas. The results suggest ligand activity in the Fas death pathway correlates with EGF transcription in sarcomas.