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Appendix A. Calculation of Structural Rigidity

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. Clin Cancer Res; 21(11); 2514–9. ©2015 AACR.

Mesenchymal stromal cells (MSCs) are a key component of the bone marrow (BM) niche, providing essential support required for maintenance of hematopoietic stem cells. To advance our understanding of physiological functions of p53 and Mdm2 in BM-MSCs, we developed traceable conditional mouse models targeting Mdm2 and/or Trp53 in vivo. We demonstrate that Mdm2 is essential for the emergence, maintenance and hematopoietic support of BM-MSCs. Mdm2 haploinsufficiency in BM-MSCs resulted in genotoxic stress–associated thrombocytopenia, suggesting a functional role for Mdm2 in hematopoiesis. In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected BM against hematopoietic toxicity from a murine Mdm2i, DS-5272. The transcriptional changes were associated with dysregulation of glycolysis, gluconeogenesis, and Hif-1α in BM-MSCs. Our results reveal a physiologic function of Mdm2 in BM-MSC, identify a previously unknown role of p53 pathway in BM-MSC–mediated support in AML and expand our understanding of the mechanism of hematopoietic toxicity of MDM2is.

Purpose: There is still no standard nonsurgical regimen for conventional chondrosarcoma (CHS). We aimed to identify whether any CHSs have a favored microenvironment for immunotherapy via multidimensional evaluation of the immunologic characteristics of this tumor. Experimental Design: We obtained 98 newly-diagnosed CHS fresh tumors from several institutions and performed comprehensive analysis of data from CyTOF, whole-exome sequencing, and flow cytometry in 22 cases. Clinical data from immunotherapy responders and nonresponders were compared to explore possible biomarkers of immunotherapy response. Mechanism studies were conducted to interpret the biomarker phenotype. Results: Based on the integrated data of single-cell CyTOF and flow cytometry, the CHS immune-microenvironment phenotypes were classified into three groups: subtype I, the “granulocytic–myeloid-derived suppressor cell (G-MDSC) dominant” cluster, with high number of HLA-DR− CD14− myeloid cells; subtype II, the “immune exhausted” cluster, with high exhausted T-cell and dendritic-cell infiltration; and subtype III, the “immune desert” cluster, with few immune cells. Immune cell–rich subtypes (subtype I and II) were characterized by IDH mutation, pathologic high grade, and peritumoral edema, while subtype I cases were exclusively featured by myxoid transformation. In clinical practice involving 12 individuals who received PD-1 antibody immunotherapy, all of the 3 cases with controlled diseases were retrospectively classified as subtype II. In mechanism, IDH mutation significantly elevated chemokine levels and immune-cell infiltration in immune-inactivated tumors. Conclusions: This study is the first to provide immune characterization of CHS, representing a major step to precise immunotherapy against this malignancy. Immunotherapy is promising for the “immune exhausted” subtype of patients with CHS.

The standard preoperative radiotherapy regimen of 50 Gy delivered in 25 fractions for 5 weeks for soft tissue sarcomas results in excellent local control, with major wound complications occurring in approximately 35% of patients. We aimed to investigate the safety of a moderately hypofractionated, shorter regimen of radiotherapy, which could be more convenient for patients.This single-centre, open-label, single-arm, phase 2 trial (HYPORT-STS) was done at a single tertiary cancer care centre (MD Anderson Cancer Center, Houston, TX, USA). We administered preoperative radiotherapy to a dose of 42·75 Gy in 15 fractions of 2·85 Gy/day for 3 weeks (five fractions per week) to adults (aged ≥18 years) with non-metastatic soft tissue sarcomas of the extremities or superficial trunk and an Eastern Cooperative Oncology Group performance status of 0-3. The primary endpoint was a major wound complication occurring within 120 days of surgery. Major wound complications were defined as those requiring a secondary operation, or operations, under general or regional anaesthesia for wound treatment; readmission to the hospital for wound care; invasive procedures for wound care; deep wound packing to an area of wound measuring at least 2 cm in length; prolonged dressing changes; repeat surgery for revision of a split thickness skin graft; or wet dressings for longer than 4 weeks. We analysed our primary outcome and safety in all patients who enrolled. We monitored safety using a Bayesian, one-arm, time-to-event stopping rule simulator comparing the rate of major wound complications at 120 days post-surgery among study participants with the historical rate of 35%. This trial is registered with ClinicalTrials.gov, NCT03819985, recruitment is complete, and follow-up continues.Between Dec 18, 2018, and Jan 6, 2021, we assessed 157 patients for eligibility, of whom 120 were enrolled and received hypofractionated preoperative radiotherapy. At no time did the stopping rule computation indicate that the trial should be stopped early for lack of safety. Median postoperative follow-up was 24 months (IQR 17-30). Of 120 patients, 37 (31%, 95% CI 24-40) developed a major wound complication at a median time of 37 days (IQR 25-59) after surgery. No patient had acute radiation toxicity (during radiotherapy or within 4 weeks of the radiotherapy end date) of grade 3 or worse (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) or an on-treatment serious adverse event. Four (3%) of 115 patients had late radiation toxicity (≥6 months post-surgery) of at least grade 3 (CTCAE or Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme): femur fractures (n=2), lymphoedema (n=1), and skin ulceration (n=1). There were no treatment-related deaths.Moderately hypofractionated preoperative radiotherapy delivered to patients with soft tissue sarcomas was safe and could therefore be a more convenient alternative to conventionally fractionated radiotherapy. Patients can be counselled about these results and potentially offered this regimen, particularly if it facilitates care at a sarcoma specialty centre. Results on long-term oncological, late toxicity, and functional outcomes are awaited.The National Cancer Institute.

BACKGROUND Locally advanced malignancies of the upper torso and shoulder girdle (UT-SG) necessitate extensive resection and complex reconstruction. Due to the infrequent nature of these operations, a global reconstructive algorithm has not been defined. METHODS A retrospective review of all patients who received reconstructive surgery following malignant tumor extirpation in the UT-SG from 2008 to 2018 at the University of Texas MD Anderson Cancer Center. Factors predicting the need for flap reconstruction and risk for postoperative complications were evaluated. RESULTS In total, 252 procedures met inclusion criteria. The most common pathology was sarcoma (76%) and 52% were primary tumors. The median defect area was 112 cm2 (range 4-1350 cm2 ). Reconstructive techniques included pedicled flaps (46%), local tissue rearrangement (38%), and free flaps (16%). On univariate analysis, the probability of needing a free flap increased 39% when the defect size increased by 100 cm2 . The strongest independent predictors of requiring a free flap were major vessel exposure (adjusted odds ratio [OR] = 4.92, 95% confidence interval [CI], 1.36-17.84, P = .015) and major peripheral nerve exposure (adjusted OR = 3.2, 95% CI, 1.1-9.2, P = .031). CONCLUSION Despite the aggressive nature of their malignancies, patients requiring an UT-SG resection demonstrate high survival rates and therefore demand a durable reconstruction. Exposed critical structures and defect size were predictive of free tissue transfer.

Purpose The role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the association between CT/RT with recurrence and survival. Patients and methods Retrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan–Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed. Results 370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n = 294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%–62%). Almost half of patients (n = 173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p = 0.50, systemic p = 0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 [95% CI 0.26–0.80], p = 0.01). Conclusion Although the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS.

Purpose To characterize local relapse after surgical fixation and postoperative radiotherapy (RT) for multiple myeloma (MM) with cortical involvement of long bones. Patients and Methods We retrospectively identified patients with MM involving cortical long bones treated with surgical fixation followed by postoperative RT at our institution. Local failures, defined as radiographic recurrence along the surgical hardware, were documented, and potential associations of independent variables (RT dose, fractionation, and extent of hardware coverage) with local failure were assessed by univariate Cox regression. Results We identified 33 patients with 40 treated sites with a median follow-up of 25.7 months; 68% of treatments were for pathologic fracture, and 32% were for impending fracture. The most common dose and fractionation were 20 to 25 Gy in 8 to 12 fractions. On average, 76% of the surgical hardware was covered by the postoperative RT field (median, 80%; range, 28%-100%). Local failure was observed in 5 cases (12.5%), 2 within the RT field and 3 out of field. None of the relapses resulted in hardware failure, and 2 were retreated with RT. The extent of hardware coverage predicted disease relapse along the hardware (hazard ratio = 6.44; 95% confidence interval, 1.09-37.97; P = .04); however, total RT dose, biologically effective dose, and number of fractions did not. Conclusion After internal fixation of long bones with MM, full hardware coverage with the RT field could reduce the risk, though small, of disease developing in the future in the proximate hardware. Postoperative RT doses of 20 to 25 Gy in 8 to 10 fractions can achieve excellent local control.

Open biopsy of bone is the diagnostic benchmark for the diagnosis of skeletal lesions. Intraoperative pathology consultation with frozen section analysis is commonly performed to confirm adequacy of lesional tissue and guide intraoperative decision making. The purpose of this study was to determine the accuracy and clinical utility of intraoperative frozen section during open bone biopsy.A retrospective review of 485 open biopsies of osseous lesions from 474 patients between 1997 and 2014 was performed. Pathology reports, operative notes, and prebiopsy imaging were assessed to determine the accuracy rates of frozen section analysis compared with final pathology. Pearson chi-squared and Fisher exact tests were performed to compare the accuracy and clinical utility rates based on soft-tissue extension, previous biopsy, lesional consistency, disease, and location.Overall diagnostic yield of open bone biopsy was 95.3%. Frozen section analysis was accurate in 54.2%, equivocal positive in 21.2%, equivocal negative in 21.0%, and incorrect in 3.5% of cases. Previous nondiagnostic biopsy and the type of disease were found to have statistically significant effects on the accuracy of frozen section analysis.Frozen section analysis was diagnostic in approximately one half of open biopsy cases. Additional information in equivocal positive results suggests that frozen section analysis is helpful for intraoperative decision making (clinical utility) in 75.4% of cases.Retrospective review level IV.

OBJECTIVES Synovial sarcomas (SS) arising in distal extremities are rare and have been studied using mostly case reports and small series. We aimed to evaluate clinical presentation and survival outcomes for patients with hand or foot SS. MATERIALS AND METHODS We conducted a retrospective review of 84 patients diagnosed with primary hand (n=20) and foot (n=64) SS between 1979 and 2019. Progression-free survival (PFS), overall survival (OS), local recurrence-free survival and metastasis-free survival were estimated using the Kaplan-Meier method and log-rank test. Cox-proportional hazards regression was used to estimate the hazard ratios. RESULTS Of 84 patients, 63 (75%) presented with localized disease with 36 years median age at diagnosis (range: 4 to 76) and 21 (25%) with metastasis with 30 years median age at diagnosis (range: 15 to 64). Among patients presenting with localized disease, (1) 5 years-PFS, OS, local recurrence-free survival, and metastasis-free survival rates were 82%, 88%, 100%, and 86%, respectively. (2) Tumor size

The mechanisms by which tumors metastasize to bone are complex. Upon the successful establishment of metastatic deposits in the skeleton, detection of the disease becomes essential for therapeutic planning. The roles of CT, skeletal scintigraphy, SPECT/CT, MRI, PET/CT and PET/MRI will be reviewed. Therapeutic response criteria specifically designed to evaluate bone metastases (MD Anderson/MDA criteria) can guide image interpretation. Knowledge of therapeutic strategies such as systemic therapy with bisphosphonates or radiopharmaceuticals, radiation therapy, surgery, and percutaneous interventions such as vertebroplasty and radiofrequency ablation can help the radiologist produce reports that will provide maximum benefit to clinicians and patients.

BackgroundPeriprosthetic infection is a major cause of failure after segmental endoprosthetic reconstruction. The purpose of this study is to determine whether certain aspects of drain output affect infection risk, particularly the 30 mL/day criterion for removal.MethodsTwo hundred and ninety-five patients underwent segmental bone resection and lower limb endoprosthetic reconstruction at one institution. Data on surgical drain management and occurrence of infection were obtained from a retrospective review of patients’ charts and radiographs. Univariate and multivariate Cox regression analyses were performed to identify factors associated with infection.ResultsThirty-one of 295 patients (10.5%) developed infection at a median time of 13 months (range 1–108 months).Staphylococcus aureuswas the most common organism and was responsible for the majority of cases developing within 1 year of surgery. Mean output at the time of drain removal was 72 mL/day. Ten of 88 patients (11.3%) with ≤ 30 mL/day drainage and 21 of 207 patients (10.1%) with > 30 mL/day drainage developed infection (p= 0.84). In multivariate analysis, independent predictive factors for infection included sarcoma diagnosis (HR 4.13, 95% CI 1.4–12.2,p= 0.01) and preoperative chemotherapy (HR 3.29, 95% CI 1.1–9.6,p= 0.03).ConclusionWaiting until drain output is < 30 mL/day before drain removal is not associated with decreased risk of infection for segmental endoprostheses of the lower limb after tumor resection. Sarcoma diagnosis and preoperative chemotherapy were independent predictors of infection.

Aside from a characteristic SS18–SSX translocation identified in almost all cases, no genetic anomalies have been reliably isolated yet to drive the pathogenesis of synovial sarcoma. In the following review, we explore the structural units of wild-type SS18 and SSX, particularly as they relate to the transcriptional alterations and cellular pathway changes imposed by SS18–SSX. Native SS18 and SSX contribute recognizable domains to the SS18–SSX chimeric proteins, which inflict transcriptional and epigenetic changes through selective protein interactions involving the SWI/SNF and Polycomb chromatin remodeling complexes. Multiple oncogenic and developmental pathways become altered, collectively reprogramming the cellular origin of synovial sarcoma and promoting its malignant transformation. Synovial sarcoma is characterized by complex epigenetic and signaling landscapes. Identifying the operational pathways and concomitant genetic changes induced by SS18–SSX fusions could help develop tailored therapeutic strategies to ultimately improve disease control and patient survivorship.

Background. Clear cell chondrosarcoma (CCC) represents less than 6% of all chondrosarcomas, and thus, our understanding of this rare entity is limited. Analyzing clinical characteristics and treatment patterns, thus increasing our knowledge, may improve treatment strategy. We review our institutional experience with 15 patients, including one case with dedifferentiation. Methods. A retrospective review was conducted in CCC patients treated at our institution from 1996 to 2015, with at least 2-year follow-up. Descriptive statistics and Kaplan–Meier survival analyses were performed. Results. Of 19 patients identified, 15 patients had at least 2-year follow-up and were included. The median age at diagnosis was 43 years. 80% were male. The most common presenting signs were pain (12 patients; 80%) and fracture (2 patients; 13.3%). The most common site was proximal femur (8 patients; 53%). All patients had MSTS Stage I disease. Primary treatment included wide resection in 10 patients (67%) and intralesional or marginal resection in 5 patients (33%). Three patients died of disease during the study period, 1 with dedifferentiation of recurrent CCC. The median time to death from disease was 15.3 years (95% CI: (14.2; NA)). The median time to either recurrence or death was 7.73 years for patients who had intralesional/marginal resection and 16.44 years for patients with wide resection (HR (wide vs. intralesional/marginal) = 0.21, 95% CI: (0.04; 1.18), p = 0.053 ). The median time to recurrence or death was significantly shorter for patients not initially treated at a sarcoma center ( p = 0.01 ). Conclusions. CCC is a rare entity, and our understanding of it is still evolving. We observed a higher recurrence rate for intralesional or marginal resection, and wide resection alone remains the mainstay of treatment. Better outcomes were observed in patients initially treated by trained musculoskeletal oncologists. Due to the propensity of CCC to recur decades after initial resection, lifelong surveillance is recommended.

BACKGROUND : Bone metastasis is common in renal cell carcinoma (RCC), and the lesions are mainly osteolytic. The mechanism of bone destruction in RCC bone metastasis is unknown. METHODS : We used a direct intrafemur injection of mice with bone-derived 786-O RCC cells (Bo-786) as an in vivo model to study if inhibition of osteoblast differentiation is involved in osteolytic bone lesions in RCC bone metastasis. RESULTS : We showed that bone-derived Bo-786 cells induced osteolytic bone lesions in the femur of mice. We examined the effect of conditioned medium of Bo-786 cells (Bo-786 CM) on both primary mouse osteoblasts and MC3T3-E1 preosteoblasts and found that Bo-786 CM inhibited osteoblast differentiation. Secretome analysis of Bo-786 CM revealed that BIGH3 (Beta ig h3 protein), also known as TGFBI (transforming growth factor beta-induced protein), is highly expressed. We generated recombinant BIGH3 and found that BIGH3 inhibited osteoblast differentiation in vitro . In addition, CM from Bo-786 BIGH3 knockdown cells (786-BIGH3 KD) reduced the inhibition of osteoblast differentiation compared to CM from vector control. Intrafemural injection of mice with 786-BIGH3 KD cells showed a reduction in osteolytic bone lesions compared to vector control. Immunohistochemical staining of 18 bone metastasis specimens from human RCC showed strong BIGH3 expression in 11/18 (61%) and moderate BIGH3 expression in 7/18 (39%) of the specimens. CONCLUSIONS: These results suggest that suppression of osteoblast differentiation by BIGH3 is one of the mechanisms that enhance osteolytic lesions in RCC bone metastasis, and raise the possibilty that treatments that increase bone formation may improve therapy outcomes.

Osteofibrous dysplasia is an indolent benign fibro-osseous tumor, while adamantinoma is a locally aggressive biphasic malignancy with epithelial and fibro-osseous components. Predominantly arising in the tibial diaphysis of children and young adults, both tumors are resistant to chemotherapy and radiation. Wide surgical resection is regarded as the mainstay of therapy for adamantinoma, and limb-salvage reconstructive procedures can achieve good functional outcomes, albeit with non-negligible rates of complications. This review discusses emerging advances in the pathogenesis, histogenesis, and diagnosis of these entities and presents advantages and limitations of the most common surgical techniques used for their management.

Objective We evaluated our experience treating patients with localized extraskeletal myxoid chondrosarcomas (EMCs) to evaluate outcomes and relapse rates in order to better inform treatment decisions for these rare soft tissue sarcomas. Materials and methods We reviewed the records of 41 consecutive patients with localized EMC treated at our institution from 1990 to 2016. Most patients (n=33, 80%) received combined modality therapy with surgery and radiation therapy, whereas only 8 (20%) underwent surgery alone. The Kaplan-Meier method was used to estimate rates of overall survival, disease-specific survival, local control (LC), and distant metastatic-free survival (DMFS). Results Median follow-up time was 94 months (range, 8 to 316). The 10-year LC, DMFS, disease-specific survival, and overall survival rates were 90%, 69%, 85%, and 66%, respectively. There were 5 patients (12%) with local relapse at a median time of 75 months (range, 13 to 176). On univariate analysis, the only significant factor associated with poorer LC was the use of surgery alone (10 y LC, 63% vs. 100% for combined modality therapy, P=0.004), which remained the only factor also significant on the multivariable analysis (P=0.02; hazard ratio [HR], 12.7; 95% confidence interval [CI], 1.4-115.3). In total, 13 patients (32%) developed distant metastatic at a median time of 28 months (range, 3 to 154). Interestingly, local recurrence was the only factor associated with poorer DMFS on multivariate analysis (P=0.04; HR, 3.9; 95% CI, 1.1-14.7). Conclusions For patients with EMC, surgery alone was associated with a higher risk of local recurrence. Therefore, we recommend optimal local therapeutic strategies upfront with both surgery and radiation therapy to reduce the risk of local and ultimately distant recurrence.

BACKGROUND AND OBJECTIVES Local recurrence in Ewing sarcoma (ES) is associated with poor prognosis. The purpose of the study is to determine what factors affect overall survival after local recurrence and whether wide excision constitutes appropriate treatment. METHODS From 1992 to 2017, 26 patients were treated for local recurrence of ES. Sixteen patients presented with local recurrence only while 10 had metastasis. The median follow-up was 23 months (range, 3-255 months). Overall survival was assessed with Kaplan-Meier analysis. RESULTS At the last follow-up, seven of 26 (27%) patients were alive. Overall survival after local recurrence was 28% at 5 years. Later onset of local recurrence (P = .041), surgical treatment (P

Consensus is lacking as to the optimal radiotherapy dose and fractionation schedule for treating bone metastases.To assess the relative efficacy of high-dose, single-fraction stereotactic body radiotherapy (SBRT) vs standard multifraction radiotherapy (MFRT) for alleviation of pain in patients with mostly nonspine bone metastases.This prospective, randomized, single-institution phase 2 noninferiority trial conducted at a tertiary cancer care center enrolled 160 patients with radiologically confirmed painful bone metastases from September 19, 2014, through June 19, 2018. Patients were randomly assigned in a 1:1 ratio to receive either single-fraction SBRT (12 Gy for ≥4-cm lesions or 16 Gy for4-cm lesions) or MFRT to 30 Gy in 10 fractions.The primary end point was pain response, defined by international consensus criteria as a combination of pain score and analgesic use (daily morphine-equivalent dose). Pain failure (ie, lack of response) was defined as worsening pain score (≥2 points on a 0-to-10 scale), an increase in morphine-equivalent opioid dose of 50% or more, reirradiation, or pathologic fracture. We hypothesized that SBRT was noninferior to MFRT.In this phase 2 noninferiority trial of 96 men and 64 women (mean [SD] age, 62.4 [10.4] years), 81 patients received SBRT and 79 received MFRT. Among evaluable patients who received treatment per protocol, the single-fraction group had more pain responders than the MFRT group (complete response + partial response) at 2 weeks (34 of 55 [62%] vs 19 of 52 [36%]) (P = .01), 3 months (31 of 43 [72%] vs 17 of 35 [49%]) (P = .03), and 9 months (17 of 22 [77%] vs 12 of 26 [46%]) (P = .03). No differences were found in treatment-related toxic effects or quality-of-life scores after SBRT vs MFRT; local control rates at 1 and 2 years were higher in patients receiving single-fraction SBRT.Delivering high-dose, single-fraction SBRT seems to be an effective treatment option for patients with painful bone metastases. Among evaluable patients, SBRT had higher rates of pain response (complete response + partial response) than did MFRT and thus should be considered for patients expected to have relatively long survival.ClinicalTrials.gov identifier: NCT02163226.

BACKGROUND The prognosis of early stage synovial sarcomas is not well-defined since long-term follow-up is lacking in most studies. The optimal use of surgery, radiation, and chemotherapy needs to be clarified for this group. METHODS From 1994 to 2012, 63 patients were treated for localized synovial sarcoma with T1 (

An athletic and otherwise healthy 17-year-old girl presented to her pediatrician with a 2-year history of mild intermittent left groin and medial thigh pain of insidious onset and no history of trauma. She was 3-years postmenarche when her symptoms began. The patient described the pain as a ‘‘muscle-type ache’’ that occurred after playing soccer or cheerleading. Plain radiographs of the pelvis showed a bone lesion in the left inferior pubic ramus (Fig. 1A), after which a CT scan of the pelvis was obtained, and an orthopaedic oncology referral was made. On presentation to our clinic, the patient reported no pain at the time of the visit, but rather she stated that the aching pain occurred only with activity, and generally persisted for 24 to 48 hours. She denied any fevers, chills, or other constitutional symptoms. Physical examination showed a well-appearing 17-yearold adolescent girl in no apparent distress. She was afebrile and vital signs were within normal limits. She ambulated without a limp. Her examination was unremarkable except for mild pain in the region of the left ischial tuberosity with resisted knee flexion. There was no tenderness to deep palpation in that area. Otherwise she had full painless ROM of her hip and knee, with full strength and normal sensation throughout her left lower extremity. Serum laboratory tests were normal including the white blood cell count, erythrocyte sedimentation rate, and C-reactive protein.

The patellar height can influence extensor mechanism and the knee function. Thus, during knee arthroplasty, the surgeon seeks to maintain the correct patellar height. However, it is more difficult to define and maintain the correct patella height in megaprosthesis reconstructions after tumor resections. The objective of this study was to evaluate patellar height after distal femur endoprosthesis reconstruction and its association to knee function.This retrospective analysis included 108 patients who underwent distal femur resections and endoprosthesis reconstruction. The minimum follow-up was 1 year or until the patients underwent patellar resurfacing or endoprosthesis revision. Patellar height was calculated using Insall-Salvati ratio (ISR) and Insall-Salvati patellar tendon insertion ratio (PTR) at 2 different times: postoperatively and at the final follow-up. The postoperative ratio was calculated using the best postoperative radiograph taken at least 1 month after the procedure. The final measures were based on the radiograph available at the last follow-up consultation. The ISR and PTR were associated to anterior knee pain (AKP), range of motion (ROM), and extension lag (EXL).The average follow-up was 4.5years. The mean postoperative ISR was 1.02, and the mean ISR at final follow-up was 0.95 (P.0001). The mean postoperative PTR was 1.45, and the mean PTR at final follow-up was 1.40 (P=.016). There was no association between patellar height and AKP, ROM, and EXL. Patellar height decreases significantly after distal femur resections but does not affect AKP, ROM, and EXL.

The purpose of this study is to demonstrate the surgical technique and to show the results of percutaneous cementoplasty (PC) for acetabular metastases using lateral approach under regional anesthesia. Forty-two cases underwent PC for acetabular metastases. The PC was performed using spinal anesthesia, lateral approach and fluoroscopic guidance. We assessed visual analogue scale (VAS) and revised musculoskeletal tumor society (MSTS) rating system and maximum standardized uptake value (SUVmax) of the acetabular lesion using F-18-FDG PET/CT before and after the PC. The mean injected volume of polymethylmethacrylamide to the pelvis was 21±11.8 ml. The mean of regional VAS (6.2±1.1 vs. 3.1±2.7, p0.001), MSTS (10.3±3.9 vs. 18.3±3.2, p0.001) and local SUVmax (8.6±5.2 vs. 5.7±3.6 , p = 0.012) on PET/CT showed significant reductions after surgery. Twenty-three patients (55%) died of disease at mean 11.8±4.8 months after surgery. PC using lateral approach and regional anesthesia could be a simple and safe surgical method for relieving pain and maintaining skeletal stability against acetabular metastasis.

Background:For transfemoral amputations, the residual femoral length is critically important to prosthetic function. The aim of this report is to describe a novel method of extending femoral length and to assess its stability over time.Case Description and Methods:A 57-year-old woman with recurrent parosteal osteosarcoma was treated with above-knee amputation. A portion of the distal femoral endoprosthesis, which included uncemented fixation with a Compress® stem, was retained in an effort to extend the short femoral remnant and maximize stump length.Findings:At 3 years follow-up, the Compress stem remained well-fixed, and there was no soft tissue breakdown over the implant. The patient ambulated with a prosthetic limb and no external support.Outcomes and Conclusion:To the best of our knowledge, this is the first report of using the Compress device as a means to maintain stable fixation and extend residual femoral length following above-knee amputation.Clinical relevanceExtension of residual bone length i...

BACKGROUND: Although cephalomedullary nail fixation is often used for metastatic peritrochanteric lesions of the femur, there is concern regarding the durability of the implant in comparison to endoprosthetic reconstruction. Previous studies have reported the proportion of patients who undergo reoperation for loss of stability, but the adequacy of the construct has not been critically evaluated in a competing risk analysis that incorporates death of the patient in the calculation. QUESTIONS/PURPOSES: (1) What is the cumulative incidence of reoperation of cephalomedullary nails with death as a competing risk for metastatic lesions of the proximal femur? (2) What is the survival of patients with metastases to the proximal femur after cephalomedullary nailing? (3) What clinical factors are associated with implant stability in these patients? METHODS: Between 1990 and 2009, 11 surgeons at one center treated 217 patients with cephalomedullary nails for metastatic proximal femoral lesions. This represented 40% (217 of 544) of the patients undergoing surgery for metastases in this location during the study period. In general, we used cephalomedullary nails when there was normal bone in the femoral head, no fracture in the neck, and a moderate-sized lesion; we favored bipolar hemiarthroplasty for femoral neck fractures and disease affecting the femoral head; finally, we used proximal femoral endoprosthetic replacement for large lesions with severe bone destruction. A retrospective study was conducted of 199 patients with cephalomedullary nails for peritrochanteric metastases from 1990 to 2009. Pathologic fracture, defined as a breach in cortex with a clear fracture line either with or without displacement, was present in 61 patients. The most common primary cancers were breast (42 of 199 patients [21%]), lung (37 of 199 patients [18%]), and renal cell (34 of 199 patients [17%]). A competing risk analysis was performed to describe the cumulative incidence of implant revision. Patient overall survival was assessed by Kaplan-Meier survivorship. A univariate analysis was performed to determine whether there was an association between revision surgery and various patient factors, including tumor histology, pathologic fracture, cementation, and radiation. RESULTS: Loss of implant stability necessitating revision surgery occurred in 19 of 199 patients (10%). In a competing risk analysis with death of the patient as the competing event, the cumulative incidence of revision surgery was 5% (95% confidence interval [CI], 3%-9%) at 12 months and 9% (95% CI, 5%-13%) at 5 years. Using Kaplan-Meier analysis, the overall patient survival was 31% (95% CI, 25%-37%) at 12 months and 5% (95% CI, 3%-9%) at 60 months. Patients with lung cancer had the shortest overall survival of 11% (95% CI, 1%-21%) at 12 months, and patients with multiple myeloma had the longest overall survival of 71% (95% CI, 49%-94%) at 12 months (p < 0.001). Duration of patient survival beyond the median 7 months was the only factor associated with a greater likelihood of revision surgery. Factors not associated with revision included tumor histology, pathologic fracture, closed versus open nailing, cementation, gender, age, and postoperative radiation. CONCLUSIONS: The competing risk analysis demonstrates a relatively low cumulative incidence of reoperation and suggests that cephalomedullary nailing is reasonable for patients with moderate-sized proximal femoral metastasis not affecting the femoral head. For the large majority of patients, the construct achieves the goal of stabilizing the femur for the duration of the patient’s life. Longer patient survival was associated with greater risk of revision surgery, but no particular tumor histology was found to have a greater cumulative incidence of reoperation. Future work with a larger number of patients and stricter surgical indications may be needed to corroborate these findings. LEVEL OF EVIDENCE: Level III, therapeutic study.

Standard treatment of localized soft tissue sarcoma should include surgical resection, which can be performed alone or in combination with perioperative radiotherapy and/or chemotherapy. The purpose of surgical intervention is to excise the tumor completely and to prevent disease relapse. Surgeons should remove the tumor with a sufficiently wide margin of the surrounding normal tissue; however, it is also necessary to pay attention to maximizing postoperative physical function. In order to balance the two competing goals, surgeons have been working to establish better methods for determining surgical margins and better guidelines for achieving adequate margins. At the present time, limb-sparing surgery is the mainstay of surgical treatment for soft tissue sarcomas of the extremities. In this article, we review the fundamentals of surgical margins as they pertain to soft tissue sarcomas and make recommendations for surgical treatment based upon current literature.

Background Insufficiency of the rotator cuff is a major problem after resections of proximal humeral tumors and can limit shoulder motion despite preservation of the deltoid muscle and axillary nerve. Allograft-prosthetic composite reconstruction offers one method to reattach the rotator cuff tendons and has been successful in small studies with short followup. However, data are lacking with regard to implant durability, changes in Musculoskeletal Tumor Society (MSTS) scores over time, and delayed complications with extended followup. Questions/purposes (1) What is the cumulative incidence of allograft-prosthetic composite revision surgery 5 years after the procedure? (2) What are the early- and intermediate-term MSTS scores of allograft-prosthetic composite reconstruction of the shoulder? (3) What are the complications of allograft-prosthetic composite reconstruction? Methods Twenty-one patients underwent allograft-prosthetic composite reconstruction after tumor resection of the proximal humerus between 2000 and 2015. Six patients who were lost to followup were not included. All patients had malignant or aggressive benign tumors that could be treated with a wide intraarticular approach preserving the deltoid muscle, axillary nerve, and glenoid. Cumulative incidence of implant revision was calculated with death of the patient as a competing risk. Minimum followup was 24 months (with the exception of one patient who died at 22 months), and median followup was 97 months (range, 20-198 months). The upper extremity MSTS score was used to assess function. Various complications were identified from radiographs and charts. Results The cumulative risk of implant revision was 10.1% at 5 years (95% confidence interval [CI], 1.6%-28.0%). Mean MSTS scores were 86% (± SD 9%) at 1 year and 78% (± SD 13%) at 5 years (mean difference ± SD 9% ± 14%, p = 0.015). Mean active forward elevation was 101° (± SD 33°) at 1 year and 92° (± SD 34°) at 5 years (mean difference ± SD 8° ± 36°, p = 0.41). Notable adverse events included progressive radiographic superior subluxation > 1 cm after 12 months followup (12 of 21 patients), delayed union > 12 months (10 of 21 patients), resorption of the greater tuberosity (nine of 21 patients), and aseptic loosening (three of 21 patients). Conclusions At intermediate 5-year followup, allograft-prosthetic composite reconstruction of the proximal humerus has an acceptable overall MSTS score and a low incidence of implant revision, but loss of patients to followup and exclusion from the study likely make the results seem better than they actually are. The MSTS score deteriorates between 1 and 5 years. Decreased active forward elevation is not likely to be the sole reason for worsening MSTS scores. A variety of delayed complications including delayed union, resorption of the greater tuberosity, and superior subluxation occurs frequently and may contribute to overall scores. Future studies that compare allograft-prosthetic composites against other forms of reconstruction should attempt to control for possible selection bias and have sufficiently long followup to detect the deterioration of MSTS scores that occur with time. Level of evidence Level IV, therapeutic study.

Objective Pathologic or osteoporotic femoral neck fractures usually treated with joint replacement surgery rather than joint-preserving surgery because multiple screw fixation has a high risk for fixation failure and nonunion as well as the need for a postoperative protection period. However, joint-preserving surgery might be preferable in high-risk patients with short life expectancy due to advanced disease. Recently introduced hollow-perforated screws are devices for achieving percutaneous fixation by simultaneous injection to the weak bone area through its multiple side holes. We report our experience of surgical treatment of femoral neck fractures by controlled bone cement injection into the femoral head and neck through a modified hollow-perforated screw in patients with advanced cancer. Methods We modified the hollow perforated screw with variable placing of screw-side holes as fracture patterns. Polymethylmethacrylate (PMMA) bone cement was injected through the screw holes to control its injection into the selective areas of the femoral head and neck while avoiding the fracture sites. One or two of these were fixed percutaneously in 12 patients who have Garden stage I or II femoral neck fractures in the advanced state of advanced cancer. Seven patients had pathologic fracture by metastatic cancer, but 5 had osteoporotic fractures. Results Eleven patients died a mean of 4.1 months after surgery and 1 patient lived with ability to walk for 48 months. Sixteen modified hollow perforated-screws and 16 standard cannulated screws were used for fixation. The mean volume of cement injection was 13.8 ml. The complication developed in 4 patients: cement leakage to the hip joint in 2 patients, subtrochanteric fracture in 1 patient (5 months after surgery) and fixation failure in 1 patients (2 months after surgery). Nine patients could walk with or without a walking aid, and all others also could return to the prefracture-ambulation state with effective pain relief on the third postoperative day. Conclusion This current surgical method could be useful in patients with short life expectancy because of quick pain relief, early return to ambulation, simple operative procedures and short hospital stay. The modified hollow perforated screw which has a diversity of side hole locations for the regulation of bone cement injection into the planned area seems useful for selective femoral neck fractures.

BACKGROUND This study was performed to determine the maximum tolerated dose (MTD) of gemcitabine given concurrently with preoperative, fixed-dose external-beam radiation therapy (EBRT) for patients with resectable, high-risk extremity and trunk soft tissue sarcoma (STS). METHODS Gemcitabine was administered on days 1, 8, 22, 29, 43, and 50 with EBRT (50 Gy in 25 fractions over 5 weeks). The gemcitabine MTD was determined with a toxicity severity weight method (TSWM) incorporating 6 toxicity types. The TSWM is a Bayesian procedure that choses each cohort's dose to have a posterior mean total toxicity burden closest to a predetermined clinician-defined target. Clinicopathologic and outcome data were also collected. RESULTS Thirty-six patients completed the study. According to the TSWM, the gemcitabine MTD was 700 mg/m2. At this dose level, 4 patients (24%) experienced grade 4 toxicity; no toxicity-related deaths occurred. All tumors were resected with microscopically negative margins. Pathologic responses of >90% tumor necrosis were achieved in 17 patients (47%); 14 (39%) had complete responses. With a median follow-up of 6.2 years, the 5-year locoregional recurrence–free survival, distant metastasis–free survival, and overall survival rates were 85%, 80%, and 86%, respectively. CONCLUSIONS The TSWM combines data from qualitatively different toxicities and can be used to determine the MTD for a drug given as part of a multimodality treatment. Neoadjuvant gemcitabine plus radiation therapy is feasible and safe in patients with high-risk extremity and trunk STS. Major pathologic responses can be achieved, and after complete resection, long-term clinical outcomes are encouraging. Cancer 2015 © 2015 American Cancer Society.

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. Clin Cancer Res; 21(11); 2514–9. ©2015 AACR.