Cumulative burden of late, major surgical intervention in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study (CCSS) cohort.

BACKGROUND: Multimodal cancer therapy places childhood cancer survivors at increased risk for chronic health conditions, subsequent malignancies, and premature mortality as they age. We aimed to estimate the cumulative burden of late (>5 years from cancer diagnosis), major surgical interventions among childhood cancer survivors, compared with their siblings, and to examine associations between specific childhood cancer treatments and the burden of late surgical interventions. METHODS: We analysed data from the Childhood Cancer Survivor Study (CCSS), a retrospective cohort study with longitudinal prospective follow-up of 5-year survivors of childhood cancer (diagnosed before age 21 years) treated at 31 institutions in the USA, with a comparison group of nearest-age siblings of survivors selected by simple random sampling. The primary outcome was any self-reported late, major surgical intervention (defined as any anaesthesia-requiring operation) occurring 5 years or more after the primary cancer diagnosis. The cumulative burden was assessed with mean cumulative counts (MCC) of late, major surgical interventions. Piecewise exponential regression models with calculation of adjusted rate ratios (RRs) evaluated associations between treatment exposures and late, major surgical interventions. FINDINGS: Between Jan 1, 1970, and Dec 31, 1999, 25 656 survivors were diagnosed (13 721 male, 11 935 female; median follow-up 21·8 years [IQR 16·5-28·4]; median age at diagnosis 6·1 years [3·0-12·4]); 5045 nearest-age siblings were also included as a comparison group. Survivors underwent 28 202 late, major surgical interventions and siblings underwent 4110 late, major surgical interventions. The 35-year MCC of a late, major surgical intervention was 206·7 per 100 survivors (95% CI 202·7-210·8) and 128·9 per 100 siblings (123·0-134·7). The likelihood of a late, major surgical intervention was higher in survivors versus siblings (adjusted RR 1·8, 95% CI 1·7-1·9) and in female versus male survivors (1·4; 1·4-1·5). Survivors diagnosed in the 1990s (adjusted RR 1·4, 95% CI 1·3-1·5) had an increased likelihood of late surgery compared with those diagnosed in the 1970s. Survivors received late interventions more frequently than siblings in most anatomical regions or organ systems, including CNS (adjusted RR 16·9, 95% CI 9·4-30·4), endocrine (6·7, 5·2-8·7), cardiovascular (6·6, 5·2-8·3), respiratory (5·3, 3·4-8·2), spine (2·4, 1·8-3·2), breast (2·1, 1·7-2·6), renal or urinary (2·0, 1·5-2·6), musculoskeletal (1·5, 1·4-1·7), gastrointestinal (1·4, 1·3-1·6), and head and neck (1·2, 1·1-1·4) interventions. Survivors of Hodgkin lymphoma (35-year MCC 333·3 [95% CI 320·1-346·6] per 100 survivors), Ewing sarcoma (322·9 [294·5-351·3] per 100 survivors), and osteosarcoma (269·6 [250·1-289·2] per 100 survivors) had the highest cumulative burdens of late, major surgical interventions. Locoregional surgery or radiotherapy cancer treatment were associated with undergoing late surgical intervention in the same body region or organ system. INTERPRETATION: Childhood cancer survivors have a significant burden of late, major surgical interventions, a late effect that has previously been poorly quantified. Survivors would benefit from regular health-care evaluations aiming to anticipate impending surgical issues and to intervene early in the disease course when feasible. FUNDING: US National Institutes of Health, US National Cancer Institute, American Lebanese Syrian Associated Charities, and St Jude Children's Research Hospital.

Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates.

BACKGROUND: Bisphosphonates are effective in reducing hip and osteoporotic fractures. However, concerns about atypical femur fractures have contributed to substantially decreased bisphosphonate use, and the incidence of hip fractures may be increasing. Important uncertainties remain regarding the association between atypical femur fractures and bisphosphonates and other risk factors. METHODS: We studied women 50 years of age or older who were receiving bisphosphonates and who were enrolled in the Kaiser Permanente Southern California health care system; women were followed from January 1, 2007, to November 30, 2017. The primary outcome was atypical femur fracture. Data on risk factors, including bisphosphonate use, were obtained from electronic health records. Fractures were radiographically adjudicated. Multivariable Cox models were used. The risk-benefit profile was modeled for 1 to 10 years of bisphosphonate use to compare associated atypical fractures with other fractures prevented. RESULTS: Among 196,129 women, 277 atypical femur fractures occurred. After multivariable adjustment, the risk of atypical fracture increased with longer duration of bisphosphonate use: the hazard ratio as compared with less than 3 months increased from 8.86 (95% confidence interval [CI], 2.79 to 28.20) for 3 years to less than 5 years to 43.51 (95% CI, 13.70 to 138.15) for 8 years or more. Other risk factors included race (hazard ratio for Asians vs. Whites, 4.84; 95% CI, 3.57 to 6.56), height, weight, and glucocorticoid use. Bisphosphonate discontinuation was associated with a rapid decrease in the risk of atypical fracture. Decreases in the risk of osteoporotic and hip fractures during 1 to 10 years of bisphosphonate use far outweighed the increased risk of atypical fracture among Whites but less so among Asians. After 3 years, 149 hip fractures were prevented and 2 bisphosphonate-associated atypical fractures occurred in Whites, as compared with 91 and 8, respectively, in Asians. CONCLUSIONS: The risk of atypical femur fracture increased with longer duration of bisphosphonate use and rapidly decreased after bisphosphonate discontinuation. Asians had a higher risk than Whites. The absolute risk of atypical femur fracture remained very low as compared with reductions in the risk of hip and other fractures with bisphosphonate treatment. (Funded by Kaiser Permanente and others.).

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.

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.

What Is the Long-term Survivorship of Primary and Revision Cemented Distal Femoral Replacements for Limb Salvage of Patients With Sarcoma?

BACKGROUND: Cemented endoprosthetic reconstruction after resection of primary bone sarcomas has been in common use for decades. Although multiple studies have reported the survivorship of primary endoprostheses, implant survivorship after revision surgery is less well established. Given that earlier advances in systemic therapy improved survival of patients with sarcoma, the usage of revision endoprostheses can be expected to increase and, as such, understanding revision implant survivorship will help to inform patient and surgeon expectations. Additionally, as new implants are developed that allow alternative reconstruction options, a normative dataset establishing accurate expectations for revision cemented endoprostheses is a critical benchmark by which to measure progress. QUESTIONS/PURPOSES: (1) What is the implant survivorship free of all-cause revision for primary and revision cemented distal femoral replacements (DFRs) used in the treatment of malignant or benign tumors? (2) What are the most common indications for revision of primary and revision DFRs in an oncology population with mean follow-up of more than 10 years? (3) How does the indication for revision of a primary DFR affect the subsequent risk for and type of revision DFR complication? (4) What patient, tumor, or implant characteristics are associated with improved survivorship free of revision in cemented DFRs used in patients treated initially for primary malignant or benign tumors? METHODS: This was a retrospective, comparative study using our institution's longitudinally-maintained database of 806 cemented endoprostheses starting in 1980 and assessed through December 31, 2018. In all, 365 DFRs were inserted during this time, but 14% (51 of 365) were placed for nonprimary bone tumors and 1% (5 of 365) were cementless reconstructions, leaving 309 cemented DFRs. Seventy-one percent (218 of 309) were primary implants and 29 percent (91 of 309) were revision implants (used to revise a prior DFR in all patients). During this time period, our strong bias was to use cemented stems and, thus, nearly all of our patients had cemented stems. Six percent (13 of 218) of primary DFRs were implanted more than 2 years before the study end; however, they lacked 2 years of follow-up data and, thus, were considered lost to follow-up, leaving 205 implants in the primary DFR analysis group. Only the first revision after primary DFR revision surgery was included in the revision cohort analysis. Thirty-two percent (29 of 91) of revision DFRs were second or more revision patients and were excluded, leaving 62 implants in the revision analysis group. Most patients in both groups were men (57% [117 of 205] for primary and 71% [44 of 62] for revision) who had been diagnosed with osteosarcoma (75% [153 of 205] and 73% [45 of 62] for primary and revision, respectively). The primary cohort had mean age of 26 ± 16 years with a mean follow-up of 136 ± 122 months, and the revision cohort had mean age of 31 ± 13 years (p = 0.02) with 141 ± 101 months of follow-up. Study endpoints included all-cause implant revision and cause-specific revision for soft tissue complications, aseptic loosening, structural complications (defined as periprosthetic or implant fracture), infection, or tumor progression. Planned surgery for implant lengthening procedures was excluded. Implant survivorship free from all-cause revision was calculated using a competing risk (cumulative incidence) estimator with death as a competing risk. A log-rank test using chi-square analysis was used to evaluate the differences in implant survivorship between primary DFRs and first revisions. The cause-specific incidences of implant revision were tabulated for primary and revision DFRs. Cox regression analysis investigated the odds of subsequent all-cause revision surgery for revision cemented DFRs based on the primary implant complication. A binary logistic regression analysis using age, gender, indication for revision, tumor type, infection, perioperative chemotherapy, and radiation was performed to identify factors associated with a second DFR reoperation. Relative effect sizes are reported as ORs. RESULTS: The revision DFR cohort had a shorter mean survival to all-cause revision than the primary cohort (mean 10 years [95% CI 7 to 12] versus 18 years [95% CI 15 to 20]; p < 0.001). The most common complications necessitating revision for revision implants were periprosthetic or implant fracture in 37% (23 of 62) and aseptic loosening in 15% (9 of 62), and the type of primary implant complication was not associated with risk of subsequent all-cause revision surgery for revision implants. Stem diameter less than 15 mm was associated with repeat all-cause revision in cemented revision DFRs after controlling for resection length, stem length, implant fabrication (custom or modular), and presence of a porous collar (OR 4 [95% CI 1 to 17]; p = 0.03). No other parameters that we explored, including patient age, gender, chemoradiation history, or primary tumor diagnosis, were associated with repeat revision surgery. CONCLUSION: Understanding modifiable factors that can improve revision DFR survival is critical to achieving long-term limb salvage for patients with tumors around the knee. Our data suggest that utilizing implants with the largest possible stems-or at a minimum increasing the stem size over the primary implant-is important to revision cemented DFR survivorship and is an important part of our revision practice. Improving revision implants' resistance to aseptic loosening through designs that resist torsion (a common mode of cemented fixation failure)-such as with the use of custom cross-pin fabrication-may be one method to improve survivorship. Another will be improved implant metallurgy that is resistant to fatigue fracture. Next steps may include understanding the optimal ratio of femoral diaphyseal width to implant diameter in patients where anatomic constraints preclude the insertion of cemented stems 15 mm or more in diameter. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Is High-dose Radiation Therapy Associated With Early Revision Due to Aseptic Loosening in Patients With a Sarcoma of the Lower Extremities Reconstructed With a Cemented Endoprosthesis?

BACKGROUND: The durability of endoprostheses after limb salvage surgery is influenced by surgical factors (resection length, implant location, and residual bone quality), implant design (modular versus custom design, rotating versus fixed hinge, coating, collars, and the use of cross pins), and host factors (patient's immune status, activity levels, and age). In general, radiation therapy increases the risk of fractures, infection, delayed wound healing, and impaired osseointegration. Several studies have shown exposure to radiation to be associated with higher endoprosthesis revision rates and higher periprosthetic infection rates, but results are inconsistent. Although radiation therapy is not routinely used in the treatment of many bone sarcomas in current practice, it is still used in high doses after resection and prosthetic reconstruction in patients who have Ewing sarcoma with close or positive margins and in patients with soft tissue sarcoma. It is also used in varying doses after prosthetic reconstruction in patients with myeloma or bone metastasis after resection of periarticular destructive tumors. These patients may be at an increased risk of complications due to their radiation exposure, but this is a difficult question to study given the rarity of these diagnoses and poor overall survival of these patients. We therefore leveraged a large, longitudinally collected, 40-year endoprosthesis database that included patients who received radiation to the extremity for many bone and soft tissue sarcomas to investigate the association between preoperative or postoperative radiation therapy and endoprosthesis survival. QUESTIONS/PURPOSES: (1) Is receiving preoperative or postoperative radiation therapy in low or high doses for the treatment of bone or soft tissue malignancy of the lower extremities associated with decreased implant survivorship free from amputation or revision due to any cause? (2) Is receiving preoperative or postoperative radiation therapy in low or high doses for the treatment of bone or soft tissue malignancy of the lower extremities associated with decreased implant survivorship free from revision specifically due to aseptic loosening? (3) Is receiving preoperative or postoperative radiation therapy for the treatment of Ewing sarcoma of the femur specifically associated with decreased implant survivorship free from revision specifically due to aseptic loosening? METHODS: This was a retrospective, comparative study using our institution's database of 822 endoprostheses. Between 1980 and 2019, we treated 541 patients with primary cemented endoprostheses of the extremities. Of those patients, 8% (45 of 541) were excluded due to unknown radiation status, 3% (17 of 541) because of prior failed allograft, 15% (83 of 541) due to metastatic disease from a carcinoma, 1% (6 of 541) due to a nononcologic diagnosis, 4% (20 of 541) due to benign tumor diagnosis, 16% (87 of 541) due to upper extremity tumor location, 9% (49 of 541) due to not receiving chemotherapy, and 3% (14 of 541) due to expandable prostheses. Of the remaining 220 patients, 6% (13) were considered missing because they did not have 2 years of follow-up and did not reach a study endpoint. No patients had surgery within the last 2 years of the study end date. In all, 207 patients met inclusion criteria and were eligible for analysis. Patients who had received radiation to the lower extremities at any point in their treatment course were included in the radiation group and were compared with patients who did not receive radiation. For patients where radiation dose was available, the radiation group was subdivided into a low-dose (≤ 3000 cGy) and high-dose (> 3000 cGy) group. Revision surgery was defined as any surgery necessitating removal or replacement of the tibial or femoral stem. The complications necessitating revision or amputation were poor wound healing, aseptic loosening, implant breakage, deep infection, and tumor progression. The primary outcome of interest was implant survival free from revision or amputation due to any cause. The secondary outcome of interest was implant survival free from revision or amputation specifically due to aseptic loosening. The Kaplan-Meier survivorship curves were generated with implant survival free from revision or amputation as the endpoint and patient death as a competing risk. A log-rank test was used to identify differences in survivorship between the patients who received radiation and those who did not. Multivariate regression was used to identify factors associated with decreased implant survival. An odds ratio was used to determine relative effect size among the factors associated with decreased implant survival. RESULTS: The mean implant survival time for patients who did not receive radiation was 18.3 years (95% confidence interval [CI] 15.4 to 21.3) whereas the mean implant survival time for patients who received low- and high-dose radiation were 19.1 years (95% CI 14.5 to 23.7; p = 0.59) and 13.8 years (95% CI 8.2 to 19.5; p = 0.65), respectively. The mean implant survival free from revision for aseptic loosening for patients who did not receive radiation was 27.1 years (95% CI 24.1 to 30.1) whereas the mean implant survival for patients who received low- and high-dose radiation were 24.1 years (95% CI 19.1 to 29.1; p = 0.34) and 16.4 years (95% CI 10.6 to 22.2; p = 0.01), respectively. Patients who received high-dose radiation had decreased 5-year implant survivorship free from amputation or revision due to aseptic loosening (73% [95% CI 44% to 89%]) compared with patients who did not receive radiation (95% [95% CI 90% to 99%]; p = 0.01). For patients treated for Ewing sarcoma of the femur, the 5-year implant survival free from amputation or revision due to aseptic loosening for patients who did not receive radiation (100% [95% CI 100% to 100%]) was no different compared with patients who received radiation (71% [95% CI 35% to 90%]; p = 0.56). CONCLUSION: The results of this study may apply to scenarios where radiation is used, such as Ewing sarcoma with positive margins or local recurrence and after prosthetic reconstruction in patients with myeloma or bone metastasis after resection of periarticular destructive tumors. Surgeons may consider closer monitoring for early clinical and radiographic signs of aseptic loosening in patients who received high-dose radiation. These patients may also benefit from constructs that have increased resistance to aseptic loosening such as cross-pin or side plate fixation. The association between radiation and aseptic loosening should be further studied with larger studies with homogeneity in tumor diagnosis and prosthesis. The dose-dependent relationship between radiation and bone-related complications may also benefit from controlled, laboratory-based biomechanical studies. LEVEL OF EVIDENCE: Level III, therapeutic study.

What Are Risk Factors for and Outcomes of Late Amputation After Treatment for Lower Extremity Sarcoma: A Childhood Cancer Survivor Study Report.

BACKGROUND: Although pediatric lower extremity sarcoma once was routinely treated with amputation, multiagent chemotherapy as well as the evolution of tumor resection and reconstruction techniques have enabled the wide adoption of limb salvage surgery (LSS). Even though infection and tumor recurrence are established risk factors for early amputation (< 5 years) after LSS, the frequency of and factors associated with late amputation (≥ 5 years from diagnosis) in children with sarcomas are not known. Additionally, the resulting psychosocial and physical outcomes of these patients compared with those treated with primary amputation or LSS that was not complicated by subsequent amputation are not well studied. Studying these outcomes is critical to enhancing the quality of life of patients with sarcomas. QUESTIONS/PURPOSES: (1) How have treatments changed over time in patients with lower extremity sarcoma who are included in the Childhood Cancer Survivor Study (CCSS), and did primary treatment with amputation or LSS affect overall survival at 25 years among patients who had survived at least 5 years from diagnosis? (2) What is the cumulative incidence of amputation after LSS for patients diagnosed with pediatric lower extremity sarcomas 25 years after diagnosis? (3) What are the factors associated with time to late amputation (≥ 5 years after diagnosis) in patients initially treated with LSS for lower extremity sarcomas in the CCSS? (4) What are the comparative social, physical, and emotional health-related quality of life (HRQOL) outcomes among patients with sarcoma treated with primary amputation, LSS without amputation, or LSS complicated by late amputation, as assessed by CCSS follow-up questionnaires, the SF-36, and the Brief Symptom Inventory-18 at 20 years after cancer diagnosis? METHODS: The CCSS is a long-term follow-up study that began in 1994 and is coordinated through St. Jude Children's Research Hospital. It is a retrospective study with longitudinal follow-up of more than 38,000 participants treated for childhood cancer when younger than 21 years at one of 31 collaborating institutions between 1970 and 1999 in the United States and Canada. Participants were eligible for enrollment in the CCSS after they had survived 5 years from diagnosis. Within the CCSS cohort, we included participants who had a diagnosis of lower extremity sarcoma treated with primary amputation (547 patients with a mean age at diagnosis of 13 ± 4 years) or primary LSS (510 patients with a mean age 14 ± 4 years). The LSS cohort was subdivided into LSS without amputation, defined as primary LSS without amputation at the time of latest follow-up; LSS with early amputation, defined as LSS complicated by amputation occurring less than 5 years from diagnosis; or LSS with late amputation, defined as primary LSS in study patients who subsequently underwent amputation 5 years or more from cancer diagnosis. The cumulative incidence of late amputation after primary LSS was estimated. Cox proportional hazards regression with time-varying covariates identified factors associated with late amputation. Modified Poisson regression models were used to compare psychosocial, physical, and HRQOL outcomes among patients treated with primary amputation, LSS without amputation, or LSS complicated by late amputation using validated surveys. RESULTS: More study participants were treated with LSS than with primary amputation in more recent decades. The overall survival at 25 years in this population who survived 5 years from diagnosis was not different between those treated with primary amputation (87% [95% confidence interval [CI] 82% to 91%]) compared with LSS (88% [95% CI 85% to 91%]; p = 0.31). The cumulative incidence of amputation at 25 years after cancer diagnosis and primary LSS was 18% (95% CI 14% to 21%). With the numbers available, the cumulative incidence of late amputation was not different among study patients treated in the 1970s (27% [95% CI 15% to 38%]) versus the 1980s and 1990s (19% [95% CI 13% to 25%] and 15% [95% CI 10% to 19%], respectively; p = 0.15). After controlling for gender, medical and surgical treatment variables, cancer recurrence, and chronic health conditions, gender (hazard ratio [HR] 2.02 [95% CI 1.07 to 3.82]; p = 0.03) and history of prosthetic joint reconstruction (HR 2.58 [95% CI 1.37 to 4.84]; p = 0.003) were associated with an increased likelihood of late amputation. Study patients treated with a primary amputation (relative risk [RR] 2.04 [95% CI 1.15 to 3.64]) and LSS complicated by late amputation (relative risk [RR] 3.85 [95% CI 1.66 to 8.92]) were more likely to be unemployed or unable to attend school than patients treated with LSS without amputation to date. The CCSS cohort treated with primary amputation and those with LSS complicated by late amputation reported worse physical health scores than those without amputation to date, although mental and emotional health outcomes did not differ between the groups. CONCLUSION: There is a substantial risk of late amputation after LSS, and both primary and late amputation status are associated with decreased physical HRQOL outcomes. Children treated for sarcoma who survive into adulthood after primary amputation and those who undergo late amputation after LSS may benefit from interventions focused on improving physical function and reaching educational and employment milestones. Efforts to improve the physical function of people who have undergone amputation either through prosthetic design or integration into the residuum should be supported. Understanding factors associated with late amputation in the setting of more modern surgical approaches and implants will help surgeons more effectively manage patient expectations and adjust practice to mitigate these risks over the life of the patient. LEVEL OF EVIDENCE: Level III, therapeutic study.

A prospective real-world study of the diffuse-type tenosynovial giant cell tumor patient journey: A 2-year observational analysis.

BACKGROUND AND OBJECTIVES: Diffuse-tenosynovial giant cell tumor (D-TGCT) is a rare, locally aggressive, typically benign neoplasm affecting mainly large joints, representing a wide clinical spectrum. We provide a picture of the treatment journey of D-TGCT patients as a 2-year observational follow-up. METHODS: The TGCT Observational Platform Project registry was a multinational, multicenter, prospective observational study at tertiary sarcoma centers spanning seven European countries and two US sites. Histologically confirmed D-TGCT patients were categorized as either those who remained on initial treatment strategy (determined at baseline visit) or those who changed treatment strategy with specific changes documented (e.g., systemic treatment to surgery) at the 1-year and/or 2-year follow-up visits. RESULTS: A total of 176 patients were assessed, mean diagnosis age was 38.4 (SD ± 14.6) years; most patients had a knee tumor (120/176, 68.2%). For the 2-year observation period, most patients (75.5%) remained on the baseline treatment strategy throughout, 54/79 patients (68.4%) remained no treatment, 30/45 patients (66.7%) remained systemic treatment, 39/39 patients (100%) remained surgery. Those who changed treatment strategy utilized multimodal treatment options. CONCLUSIONS: This is the first prospectively collected analysis to describe D-TGCT patient treatments over an extended follow-up and demonstrates the need for multidisciplinary teams to determine an optimal treatment strategy.

Metaphyseal Stem Tip Location is a Risk Factor for Aseptic Loosening of Cemented Distal Femoral Replacements.

BACKGROUND: The objective of this study was to describe the incidence of aseptic loosening (AL) of cemented stem distal femoral replacements (DFR) and to identify modifiable risk factors for its development. METHODS: A retrospective review was performed of 245 consecutive primary, cemented stem DFRs implanted at a single institution over a 40-year period. The primary outcome was revision surgery for AL. A multivariate analysis was performed to identify risk factors for AL. Radiographs were reviewed to identify stem tip location, which was defined as diaphyseal or metaphyseal. Implant survival to AL was compared using Kaplan-Meier analysis. RESULTS: AL and structural failure were the most common causes of implant failure (incidence 11.8%, 29/245). Younger age (P = .002), male sex (P = .01), longer resection length (P = .04), and nonmodular implants (P = .002) were all significantly associated with AL. After 1:1 matching, stem tip location in metaphyseal bone was independently associated with AL (P = .04). 36% (9/25) of implants that loosened had a stem tip located in the metaphysis vs only 8% (2/25) of implants that did not fail. 30-year survival to AL was lower for implants with a metaphyseal stem tip than implants with a diaphyseal stem tip (22.7% vs 47.6%; P = .11). CONCLUSION: A stem tip location in metaphyseal bone is associated with diminished survival to AL. When templating before DFR, stem tip location can assist in identifying high-risk reconstructions that may benefit from alternative or supplemental fixation techniques to prevent the development of AL.

Cranial Nerve Palsies: A Rare, Long-Term Complication of Radiotherapy for Nasopharyngeal Carcinoma.

UNLABELLED: Cranial nerves (CN) are believed to be relatively resistant to radiotherapy (RT); however, there have been case reports of cranial nerve palsy (CNP) following RT. We present a case of a gentleman with cranial nerve palsy of CN V and VII after RT for nasopharyngeal carcinoma (NPC). CASE PRESENTATION: A 54-year-old male presented to our clinic with masticatory difficulty, facial hypoesthesia, and dysphagia. In 1998, he was treated with external beam RT for NPC. He underwent sural nerve grafting, anastomosing his functioning hypoglossal nerve to the buccal branch of the facial nerve in an end-to-side fashion, and direct implantation of a nerve graft from the spinal accessory to the masseter muscle. He unfortunately was unable to regain masticatory function postoperatively. CONCLUSION: Cranial nerve palsies are severely debilitating to patients and difficult to treat. Radiation-induced CNP is important to consider in the differential diagnosis in patients previously treated for NPC.

Three-dimensional virtual surgery accuracy for free fibula mandibular reconstruction: planned versus actual results.

PURPOSE: Virtual surgical planning (VSP) can promote efficiency, but the ability to transfer the proposed plan to the actual result has not been adequately studied. The purpose of this study was to morphometrically compare the virtually preplanned scenario with the postoperative 3-dimensional (3D) anatomic result. MATERIALS AND METHODS: A retrospective review of 10 patients who underwent mandibular reconstruction using a free fibula flap and VSP were evaluated. Pre- and postoperative Digital Imaging and Communications in Medicine files were imported into Mimics 10.01 software (Materialise, Leuven, Belgium) for surgical planning. Preoperative VSP and 1-week postoperative computed tomographic (CT) scans were evaluated to assess surgical accuracy using VSP. The pre- and postoperative morphometric measurements were compared using the Student t test. RESULTS: Twenty CT scans from 10 patients (mean age, 56.9±20.2 yr) who underwent partial mandibular resection were analyzed. The dimensions of the fibula segments after osteotomy showed no difference from the preoperative VSP (mean difference in fibula height, 1.2 mm; mean difference in width, 0.9 mm; mean difference in length, 1.3 mm). The postoperative anterior and posterior mandibular angles differed from the VSP by 12.4° and -12.5°, respectively. The condylar distance and inclination showed a discrepancy of only 1.7 mm and 4.6°, respectively, between VSP and postoperative CT scans. CONCLUSIONS: VSP confers reproducible precision and accuracy for free fibular mandibular reconstruction. The benefit was most striking for large reconstructions requiring multiple fibular segments. Future directions include assessing the use of external registration devices to enhance surgical accuracy and to follow patients longitudinally to monitor the long-term benefit of VSP.

Surgically assisted maxillary expansion imparts three-dimensional nasal change.

PURPOSE: The impact of surgically assisted maxillary expansion (SAME) on facial soft tissue structures has not been adequately studied using 3-dimensional (3D) objective analysis. The purpose of this study was to analyze nasolabial soft tissue after SAME using 3D photographic technology. MATERIALS AND METHODS: This was a retrospective cohort study of patients undergoing SAME in which pre- and postexpansion 3D photographs (3D VECTRA Photosystem, Canfield, Fairfield, NJ) were analyzed. Nasolabial anthropometric measurements were performed using the 3D postprocessing software (Mirror). A follow-up period of at least 6 months was required for final evaluation. Two observers verified the landmarks on each dataset before measuring. Statistical analysis involved the paired t test, the Simes correction for multiple comparisons, and repeated measures analysis of covariance (ANCOVA) to control for age, gender, and the time lag between pre- and postoperative assessments. RESULTS: Twelve patients (24 photogrammetric datasets) were included. The male-to-female ratio was 0.5 (mean age, 17.3 yr). Nasal changes after SAME showed significant increases (P < .05) in alar width (from 33.1 to 34.5 mm), sill width (from 9.2 to 9.7 mm), and columella projection (from 94.1 to 95.1 mm) after the Simes correction. ANCOVA showed a significant increase in alar base width. Distinct changes in nostril shape and dimension were found, but lacked statistical significance. CONCLUSION: Three-dimensional analysis shows widening of the alar width and alar base width after SAME. The magnitude of nasal change parallels that of expansion at the piriform aperture.

Wound healing complications with intraoperative brachytherapy for head and neck cancer: a unique form of radiation injury.

BACKGROUND: Intraoperative brachytherapy (IOBT) to the tumor bed coupled with surgery has been shown to increase survival and to improve locoregional disease control after head and neck tumor extirpation. Flap reconstruction attempts to restore patient anatomy, while also covering the radioactive implants. The purpose of this study was to better characterize the wound healing complications experienced by patients undergoing reconstruction in the setting of IOBT after tumor ablation, as well as to identify risk factors predicting complications and the need for reoperation. METHODS: A retrospective chart review of patients receiving IOBT for head and neck cancer at Yale-New Haven Hospital between 2005 and 2013 was conducted. Patient, tumor, treatment, and reconstructive details were recorded. The number and type of flap complications, as well as instances in which patients had to be taken back to the operating room, were documented. Bivariate and multivariate logistic regressions were performed to identify risk factors associated with the occurrence of 1 or more flap complications, as well as the need for reoperation. RESULTS: Ninety-three patients aged 31 to 93 years (mean, 64 ± 12 years) who underwent IOBT with flap reconstruction were included in the study. Of these, 94% had a prior history of radiation (external beam or previous IOBT). Overall, 48 (51.6%) patients experienced at least 1 flap complication, the most common of which was flap dehiscence (32% of patients). Thirty-two patients (34% of the cohort) had to be taken back to the operating room at least once for flap debridement or a revision procedure. On multivariate analysis, only the placement of mandibular hardware during flap reconstruction was significantly associated with the risk of developing any type of flap complication (odds ratio, 3.7; P = 0.009) or with subsequent return to the operating room (odds ratio, 3.9; P = 0.012). CONCLUSIONS: This study, the largest of its kind, demonstrated a very high complication rate for flaps used to cover brachytherapy implants in this patient cohort. However, many of the patient complications could be managed nonoperatively. Avoiding the use of mandibular hardware with IOBT suggests a method of reducing complications with reconstruction.

Hip Preservation and Capanna Reconstruction for Pediatric Proximal Femur Ewing Sarcoma: A Report of 2 Cases.

CASE: This is a first report describing preservation of the femoral head by transcervical resection of proximal femoral Ewing sarcoma in 2 pediatric patients. A unique Capanna reconstruction supported joint salvage. At 1 year, Pediatric Outcomes Data Collection Instrument and Pediatric Toronto Extremity Salvage Score outcomes were excellent. Surveillance magnetic resonance imaging was without evidence of recurrence or impaired perfusion to the femoral head. CONCLUSION: We demonstrate the feasibility of hip joint preservation and maintenance of femoral head viability after transcervical resection of pediatric proximal femur bone sarcomas while preserving the medial circumflex femoral artery. This technique may be a preferred option over joint sacrifice and endoprosthetic replacement in young patients when tumor margins permit.

Management of Segmental Tibial Bone Defects With the Magnetic Motorized Intramedullary Transport Nail: A Case Series.

SUMMARY: Critical-sized bone defects in the tibia can arise as sequelae of trauma, infection, tumor, or the treatment of congenital limb deficiencies. Treatment of these defects often requires bone transport, which has traditionally been accomplished using circular external fixators. The development of a bone transport nail facilitated tibia reconstruction through distraction osteogenesis using an all-internal device, thus avoiding the complications associated with chronic external fixation. Given the rarity of these cases, few studies have been published on the reconstruction outcomes using this implant. We sought to investigate the bone healing indices (including regenerate consolidation and time to docking site union) associated with the use of a magnetically controlled all-internal bone transport nail for the reconstruction of 4 patients treated for posttraumatic tibial bone loss. Perioperative and device-related complications are also reported.

Treatment of Angular Deformity and Limb Length Discrepancy With a Retrograde Femur Magnetic Intramedullary Nail: A Fixator-assisted, Blocking Screw Technique.

BACKGROUND: Fixator-assisted nailing techniques that incorporate magnetic internal lengthening nails (MILNs) permit acute deformity correction and then gradual limb lengthening without needing postoperative external fixators. PURPOSES: We sought to investigate the safety and accuracy of a fixator-assisted, blocking screw technique using retrograde MILNs for the correction of LLD and limb malalignment. METHODS: Forty-one patients (13 patients with genu varum and 28 patients with genu valgum) with LLD treated with fixator-assisted, blocking screw retrograde MILN reconstruction were included. Preoperative LLD, mechanical axis deviation, and joint orientation angles were compared with values at the end of treatment, and bone healing indices were calculated. Perioperative complications were tracked. RESULTS: Preoperatively, the mean mechanical lateral distal femoral angle of the varus cohort was 98 ± 12°, whereas the mean lateral distal femoral angle of the valgus cohort was 82±4°. Both cohorts had an average 3-cm LLD. 99% of the planned limb lengthening was achieved. Final LDFAs were 91 ± 6° and 89 ± 4° in the varus and valgus cohorts, respectively, and the limb mechanical axis angles were normalized. 10 patients underwent a total of 21 returns to the operating room. Most commonly, this involved percutaneous injection of bone marrow aspirate concentrate to bone regenerate exhibiting delayed union (6 patients). CONCLUSIONS: The use of a retrograde MILN with a fixator-assisted, blocking screw technique is an effective means of acute deformity correction and gradual limb lengthening through minimal incisions. The accuracy of deformity correction relies on intraoperative execution of the appropriate nail start site, osteotomy location, and placement of blocking screws.

One-Stage Synovectomies Result in Improved Short-Term Outcomes Compared to Two-Stage Synovectomies of Diffuse-Type Tenosynovial Giant Cell Tumor (D-TGCT) of the Knee: A Multicenter, Retrospective, Cohort Study.

Diffuse-type tenosynovial giant cell tumors' (D-TGCTs) intra- and extra-articular expansion about the knee often necessitates an anterior and posterior surgical approach to facilitate an extensive synovectomy. There is no consensus on whether two-sided synovectomies should be performed in one or two stages. This retrospective study included 191 D-TGCT patients from nine sarcoma centers worldwide to compare the postoperative short-term outcomes between both treatments. Secondary outcomes were rates of radiological progression and subsequent treatments. Between 2000 and 2020, 117 patients underwent one-stage and 74 patients underwent two-stage synovectomies. The maximum range of motion achieved within one year postoperatively was similar (flexion 123-120°, p = 0.109; extension 0°, p = 0.093). Patients undergoing two-stage synovectomies stayed longer in the hospital (6 vs. 4 days, p < 0.0001). Complications occurred more often after two-stage synovectomies, although this was not statistically different (36% vs. 24%, p = 0.095). Patients treated with two-stage synovectomies exhibited more radiological progression and required subsequent treatments more often than patients treated with one-stage synovectomies (52% vs. 37%, p = 0.036) (54% vs. 34%, p = 0.007). In conclusion, D-TGCT of the knee requiring two-side synovectomies should be treated by one-stage synovectomies if feasible, since patients achieve a similar range of motion, do not have more complications, but stay for a shorter time in the hospital.

Complementary Effects of Surgery and Pexidartinib in the Management of Patients with Complex Diffuse-Tenosynovial Giant Cell Tumor.

Tenosynovial giant cell tumor (TGCT) is a rare neoplasm of the joint synovium that has a wide clinical spectrum including pain and stiffness in the affected joint, joint swelling, periarticular erosions, and cartilage loss, which can severely impact quality of life. The mainstay treatment for TGCT has been surgery involving partial or total synovectomy using arthroscopic or open techniques. However, surgical resection alone is associated with high recurrence rates, particularly in diffuse-TGCT (D-TGCT) cases. The 3 cases presented here summarize a combination approach (surgery+pexidartinib [tyrosine kinase inhibitor]) in patients with previously unresectable or inoperable D-TGCT. Case 1-Hip. A 29-year-old male was treated with pexidartinib prior to surgery, resulting in tumor reduction. A left total hip arthroplasty (THA) was then performed with a lack of recurrence in 12 months postoperative, and the patient currently on pexidartinib treatment. Case 2-Foot. A 35-year-old female, nearly a decade following a left foot mass resection, was treated with pexidartinib following disease recurrence. A decrease in soft tissue lesions at the midfoot and decreased marrow enhancement at the first metatarsal head were seen within 4-5 months of pexidartinib treatment; the patient is currently on pexidartinib (400 mg/day) with improved symptom control. Case 3-Knee. A 55-year-old male patient received pexidartinib pre- and postoperatively. A reduction in swelling and the size of the popliteal cyst was significant and maintained, with the synovial disease growing when pexidartinib was discontinued. Surgery and adjuvant therapy eliminated the disease as of the last follow-up visit (11 months postoperative). These cases provide a unique perspective based on tumor location, type/timing of treatment strategy, and patient outcomes. Optimal treatment strategies for this debilitating disease may entail utilizing a combination approach (surgery+systemic treatment) to reduce surgical morbidity and the risk of postoperative disease recurrence.

Survival of Patients With Primary Osseous Malignancies of the Mobile Spine Is Associated With Access to "Standard Treatment" Protocols.

INTRODUCTION: Malignancies of the mobile spine carry high morbidity and mortality. This study sought to examine factors associated with receipt of "standard" treatment and survival for patients with primary mobile spine tumors in the California Cancer Registry (CCR). METHODS: The CCR (1988 to 2016) data were obtained for patients with primary tumors of the mobile spine and at least 1-year follow-up. Sacrum/pelvis tumors were excluded. Age at diagnosis, sex, race, neighborhood socioeconomic status, insurance, Charlson Comorbidity Index, histologic diagnosis, stage at diagnosis, and treatment at a National Cancer Institute-designated Cancer Center (NCICC) were collected. Multivariate analyses were done to identify factors associated with all-cause mortality and receipt of "standard" treatment. RESULTS: Four hundred eighty-four patients (64% White, 56% low neighborhood socioeconomic status, and 36% privately insured) were included. Chordoma (37%) was the most common diagnosis. Only 16% had metastatic disease at presentation. Only 29% received treatment at an NCICC. Lower age, Charlson Comorbidity Index, less extensive stage of disease, and private insurance were associated with lower all-cause mortality (all P < 0.05). Medicaid/public insurance (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.13 to 2.41) and Medicare (HR, 1.80; 95% CI, 1.25 to 2.59) were associated with higher mortality compared with private insurance. Patients who received no known treatment (HR, 2.41; CI, 1.51 to 3.84) or treatment other than the "standard" (HR, 1.45; CI, 1.11 to 1.91) had higher mortality compared with those who received the standard protocols. A critical predictor of receiving the standard treatment protocol was being treated at an NCICC. If patients did not receive care at such institutions, they received optimal treatment only 40% of the time (HR, 0.5; P = 0.004). CONCLUSIONS: Receipt of defined "standard treatment" protocols was associated with care received at an NCICC and lower all-cause mortality in patients with primary osseous malignancies of the mobile spine. Patients with public insurance are vulnerable to worse outcomes, regardless of age, disease burden, or receipt of standard treatment. LEVEL OF EVIDENCE: III.