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Malignant intraosseous peripheral nerve sheath tumor is a very rare malignancy most commonly seen in patients with neurofibromatosis type 1. This tumor almost exclusively occurs in the maxillofacial region, with manifestation of this tumor in other regions of the skeleton infrequently reported. We describe a 23-year-old female with previously undiagnosed neurofibromatosis type 1 presenting with lower extremity weakness, paresthesias, and bowel/bladder symptoms. The patient had an aneurysmal lytic bone lesion centered in the upper sacrum with invasion of the L5 vertebral body. On MRI, the lesion was homogeneously isointense to muscle on T1, heterogeneously hyperintense to muscle on T2, and demonstrated homogeneously avid contrast enhancement. Multiple additional small lesions with similar imaging characteristics were identified in the paraspinal soft tissues. Low grade malignant peripheral nerve sheath tumor of the sacrum was diagnosed on biopsy. The patient was treated with sacral resection and radiation therapy for local disease control. Keywords: Malignant, Peripheral, Nerve, Sheath, Tumor, Neurofibromatosis

BackgroundAdoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a ‘cold’ tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS.Case presentationWe launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns.ConclusionWe describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion.Trial registration numbersNCT04177021,NCT01957709, andNCT03063632.

Introduction: Surgical navigation systems are increasingly used to aid resection and reconstruction of osseous malignancies. In the process of implementing image-based surgical navigation systems, there are numerous opportunities for error that may impact surgical outcome. This study aimed to examine modifiable sources of error in an idealized scenario, when using a bidirectional infrared surgical navigation system. Materials and Methods: Accuracy and precision were assessed using a computerized-numerical-controlled (CNC) machined grid with known distances between indentations while varying: 1) the distance from the grid to the navigation camera (range 150 to 247cm), 2) the distance from the grid to the patient tracker device (range 20 to 40cm), and 3) whether the minimum or maximum number of bidirectional infrared markers were actively functioning. For each scenario, distances between grid points were measured at 10-mm increments between 10 and 120mm, with twelve measurements made at each distance. The accuracy outcome was the root mean square (RMS) error between the navigation system distance and the actual grid distance. To assess precision, four indentations were recorded six times for each scenario while also varying the angle of the navigation system pointer. The outcome for precision testing was the standard deviation of the distance between each measured point to the mean three-dimensional coordinate of the six points for each cluster. Results: Univariate and multiple linear regression revealed that as the distance from the navigation camera to the grid increased, the RMS error increased (p Conclusion: In our model laboratory test environment, the infrared bidirectional navigation system was more accurate and precise when the distance from the navigation camera to the physical (working) space was minimized and all bidirectional markers were active. These findings may require alterations in operating room setup and software changes to improve the performance of this system.

Background:Many treatment options exist for unicameral bone cysts (UBC), without clear evidence of superiority. Meta-analyses have been limited by small numbers of patients in specific anatomic and treatment subgroups. The purpose of this study was to report the outcomes of injecting bone marrow aspirate and demineralized bone matrix (BMA/DBM) for the treatment of proximal humerus UBC.Methods:Fifty-one patients with proximal humerus lesions treated by BMA/DBM injection were retrospectively reviewed from a single academic medical center.Results:The mean number of injections performed per patient was 2.14 (range 1-5). Eleven patients underwent only one injection (22%), an additional 19 patients completed treatment after two injections (37%), four patients healed after three injections (8%), and one patient healed after four injections (2%). The cumulative success rate of serial BMA/DBM injections was 22% (11/51), 58% (30/51), 67% (34/51), and 69% (35/51). Eleven patients (22%) ultimately underwent open curettage and bone grafting, and five patients (10%) were treated with injection of calcium phosphate bone substitute.Conclusion:A BMA/DBM injection strategy avoided an open procedure in 78% of patients with a proximal humerus UBC. The majority of patients underwent at least 2 injection treatments.Level of Evidence:Level IV retrospective cohort study.

BACKGROUND The purpose of this study was to test the validity of a consumer-oriented activity monitor in adolescents and young adults undergoing limb salvage for primary bone malignancies. METHODS A cross-sectional population of participants with an average age of 16 (range 12 to 22) years produced 472 days of activity monitoring during 25 evaluations periods alongside patient-reported outcome measures. RESULTS Average daily steps ranged from 557 to 12,756 (mean=4711) and was moderately associated with the short-form (SF) 36 physical component subscale (r=0.46, P=0.04) as well as the SF6D health state utility measure (r=0.48, P=0.04), but not the SF36 mental component subscale (P=0.66) or Toronto extremity salvage score (P=0.07). Time from surgery was strongly correlated with average daily steps (r=0.7, P

Background:The most common modes of failure for megaprostheses are aseptic loosening followed by periprosthetic infection and stem fracture. Surgical technique for bone and implant exposure is controversial and may influence the success of revision and the need for additional future revisions. The purpose of this study was to evaluate the effectiveness of cortical fenestration for megaprosthesis revision, particularly for stem fracture.Methods:From 1985-2014, 196 adult and pediatric patients underwent limb salvage with a distal femoral or proximal tibial megaprosthesis (109 cemented, 87 pressfit). A retrospective chart review was performed to assess the rate of revision based on cemented or pressfit fixation and the use of a cortical window to extract the failed stem.Results:27% (29 of 109) of cemented and 18% (16 of 87) of pressfit implants were revised for stem failure. The reasons for revision in the cemented group were loosening (62%), infection (24%), and stem fracture (13%). In the pressfit group, the reasons were loosening (43%), infection (31%), stem fracture (6%), limb-length discrepancy (6%), malrotation (6%), and local recurrence (6%). A cortical window was used in 10 of 45 initial revisions (7 cemented, 3 pressfit) including all of the stem fractures, and in 2 of 15 subsequent re-revisions.Conclusion:Cortical fenestration is an effective, bone-preserving method of implant extraction, particularly for broken or cemented stems. It is associated with low rates of loosening and no increase in periprosthetic fractures.

Soft tissue sarcomas (STS) are rare solid tumors of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Guidelines for Soft Tissue Sarcoma (available at NCCN.org) provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as intra-abdominal/retroperitoneal STS, gastrointestinal stromal tumor, desmoid tumors, and rhabdomyosarcoma. This manuscript discusses guiding principles for the diagnosis and staging of STS and evidence for treatment modalities that include surgery, radiation, chemoradiation, chemotherapy, and targeted therapy.

BACKGROUND: The quantitative accuracy of MRI in predicting the intraosseous extent of primary sarcoma of bone has not been definitively confirmed, although MRI is widely accepted as an accurate tool to plan limb salvage resections. Because inaccuracies in MRI determination of tumor extent could affect the ability of a tumor surgeon to achieve negative margins and avoid local recurrence, we thought it important to assess the accuracy of MR-determined tumor extent to the actual extent observed pathologically from resected specimens in pediatric patients treated for primary sarcomas of bone. QUESTIONS/PURPOSES: (1) Does the quantitative pathologic bony margin correlate with that measured on preoperative MRI? (2) Are T1- or T2-weighted MRIs most accurate in determining a margin? (3) Is there a difference in predicting tumor extent between MRI obtained before or after neoadjuvant chemotherapy and which is most accurate? METHODS: We retrospectively studied a population of 211 potentially eligible patients who were treated with limb salvage surgery between August 1999 and July 2015 by a single surgeon at a single institution for primary sarcoma of bone. Of 131 patients (62%) with disease involving the femur or tibia, 107 (51%) were classified with Ewing’s sarcoma or osteosarcoma. Records were available for review in our online database for 79 eligible patients (37%). Twenty-six patients (12%) were excluded because of insufficient or unavailable clinical or pathology data and 17 patients (8%) were excluded as a result of inadequate or incomplete MR imaging, leaving 55 eligible participants (26%) in the final cohort. The length of the resected specimen was superimposed on preresection MRI sequences to compare the margin measured by MRI with the margin measured by histopathology. Arithmetic mean differences and Pearson r correlations were used to assess quantitative accuracy (size of the margin). RESULTS: All MR imaging types were positively associated with final histopathologic margin. T1-weighted MRI after neoadjuvant chemotherapy and final histopathologic margin had the strongest positive correlation of all MR imaging and time point comparisons (r = 0.846, p < 0.001). Mean differences existed between the normal marrow margin on T1-weighted MRI before neoadjuvant chemotherapy (t = 8.363; mean, 18.883 mm; 95% confidence interval [CI], 14.327-23.441; p < 0.001), T2-weighted MRI before neoadjuvant chemotherapy (t = 8.194; mean, 17.204 mm; 95% CI, 12.970-21.439; p < 0.001), T1-weighted after neoadjuvant chemotherapy (t = 10.808; mean, 22.178 mm; 95% CI, 18.042-26.313; p < 0.001), T2-weighted after neoadjuvant chemotherapy (t = 10.702; mean, 20.778 mm; 95% CI, 16.865-24.691; p < 0.001), and the final histopathologic margin. T1-weighted MRI after neoadjuvant chemotherapy compared with the final histopathologic margin had the smallest mean difference in MRI-measured versus histopathologic margin size (mean, 5.9 mm; SD = 4.5 mm). CONCLUSIONS: T1 MRI after neoadjuvant chemotherapy exhibited the strongest positive correlation and smallest mean difference compared with histopathologic margin. When planning surgical resections based on MRI obtained after neoadjuvant chemotherapy, for safety, one should account for a potential difference between the apparent margin of a tumor on an MRI and the actual pathologic margin of that tumor of up to 1 cm. LEVEL OF EVIDENCE: Level III, diagnostic study.

Gastrointestinal stromal tumors (GIST) are the most common soft tissue sarcoma of the gastrointestinal tract, resulting most commonly from KIT or platelet-derived growth factor receptor α (PDGFRα)-activating mutations. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma specific to the management of patients with GIST experiencing disease progression while on imatinib and/or sunitinib.

These NCCN Guidelines Insights highlight the important updates to the NCCN Guidelines for Soft Tissue Sarcoma (STS) specific to the role of radiation therapy in the management of patients with retroperitoneal/intra-abdominal STS. The guidelines have also included recommendations for genetic testing and counseling for patients with a clinical and/or family history of genetic cancer syndromes associated with a predisposition for the development of STS.

Giant cell tumor of bone is a locally aggressive lesion with a predilection for local recurrence, and in a small proportion of patients, metastatic disease can develop. Surgery is the mainstay of management for extremity-based lesions. For tumors located in challenging anatomical locations such as the sacrum and spine however, surgery may be associated with unacceptable functional morbidity. There are limited data regarding other treatment modalities such as radiation therapy, cytotoxic chemotherapy, interferon and bisphosphonates. Serial arterial embolization can be effective in some cases. Recent evidence has demonstrated denosumab to be a promising agent in the treatment of unresectable or metastatic disease.

Background: Despite a proposed lower incidence of aseptic loosening, uncemented distal femoral implants present challenges with the intra-operative assessment of the adequacy of stem fixation within the femoral canal. Our biomechanical study was intended to assess the adequacy of oncologic implant press-fit stem fixation within the reamed canal of the distal femur for the Stryker GMRS oncologic distal femoral implant. We hoped to answer the following: #1 Does the initial stem placement in the femoral canal using a standardized force (50 N) (i.e., “Scratch Fit”) predict the (adequacy)stability of the final stem placement (and implant fixation) within the femoral canal? #2 Is there a difference in the uncemented stem fixation and stability within the femur for different stem (Stryker GMRS) diameters (13, 14, and 15 mm) for the Stryker GMRS uncemented press-fit stems/(Stryker Global Orthopaedics) Methods: Femoral cadaveric specimens were thawed and cut at the distal end of the femur, at 13 cm from the distal joint line, to e represent a distal femoral tumor resection. Stryker GMRS uncemented stems were placed, after femoral reaming, into the distal femoral canal with firm, hand pressure applied via a customized, spring-based insertion tool positioned over the standard Stryker insertion tool and calibrated to apply a standard stem insertion force of 50 N (11.2 lbs). Initial stem placement, utilizing this method, resulted in a stem that was only partially implanted into the femur with a recorded distance (defined as “Scratch Fit”) between the stem collar and the cut surface of the femoral shaft. After completing final stem impaction into the femur, stem torsional testing was performed on a multi-axis biomechanical test frame with a 3-D Vicon motion-capture system with axial torsion applied to the stems with the proximal femur fixed to a potted base. Kinematics of both the implant and the distal femur were captured using the Vicon system which tracked reflective infrared targets at a 60 Hz sampling rate. The peak torsional moment at failure was compared to “Scratch Fit” metrics for each implant diameter to address the proposed research questions. Results: Scratch fit distances ranged from 7–46 mm with a mean of 29.1±12.7 mm. Peak torques ranged from 11.5 to 57.5 Nm with a mean of 33.6±17.0 Nm. Figure shows peak (max.) torque plotted against scratch fit for all stems/specimens with good correlation (r 2 =0.6404). When separated by stem diameters, figure shows strong correlations between peak torque and scratch fit. Conclusions: while there may be multiple metrics that affect uncemented stem implant placement and stability (i.e., femoral canal size, femoral reaming, and implant type/size (diameter), there appears to be some correlation between initial stem placement (i.e., “Scratch Fit”) after femoral reaming to implant torsional (rotational) stability; this correlation is stronger when controlled for stem diameter. This suggests that a greater initial “Scratch Fit” distance may provide improved press-fit stem fixation and may provide a better operative standard for making decisions regarding the fixation or stability of these implants.

Background: Our previous research investigated the ability of [F-18]fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging results to predict outcome in patients with sarcoma. Tumor uptake of FDG before and after neoadjuvant chemotherapy was predictive of patient outcome. With this background, a prospective clinical study was designed to assess whether tumor FDG uptake levels in the middle of neoadjuvant chemotherapy added additional prognostic information to pre-therapy imaging data. Methods: Sixty-five patients with either bone or soft-tissue sarcoma were treated with neoadjuvant-based chemotherapy according to the standard clinical practice for each tumor group. All patients had FDG PET studies before therapy, mid-therapy (after two cycles of chemotherapy), and before resection. Tumor FDG uptake (SUVmax, the maximum standardized uptake value) at each imaging time point, tumor type (bone or soft-tissue sarcoma), tumor size, and histopathologic grade were recorded for each patient. The time from the pre-therapy FDG PET study to events of local tumor recurrence, metastasis, or death were extracted from the clinical records for comparison with the imaging data. Univariate and multivariate analyses of the imaging and clinical data were performed. Results: Univariate and multivariate data analyses showed that the difference (measured as the percentage reduction) between the pre-therapy and mid-therapy maximum tumor uptake values added prognostic value to patient outcome predictions independently of other patient variables. Conclusions: The utility of a tumor pre-therapy FDG PET scan as a biomarker for the outcome of patients with sarcoma was strengthened by a mid-therapy scan to evaluate the interim treatment response. Level of Evidence: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence. Peer Review This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication. Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.

Background: Allograft reconstruction of oncologic resections involving the tibia can have unpredictable results. Prior studies have reported a high rate of complications and a long recovery period involving prolonged bracing, repeated procedures and extended periods of antibiotics. Methods: The case details of 30 tibial allografts (12 adults, 18 children; 20 intercalary, 7 hemicortical, 3 other) were reviewed retrospectively. Based on factors including function, pain, healing and infection, clinical outcomes were stratified into three categories: excellent, moderate, and poor. Results: The overall survival rate of the allografts was 66% at a mean follow-up of 42 mos (adults) and 63 mos (children). Healing for metaphyseal junctions was successful in 73% at a mean of 44 weeks and for diaphyseal junctions, 64% at 41 weeks. Intercalary allografts in adults (4 of 20) all became infected and none had excellent results. All hemicortical allografts were performed in adults and 6 of 7 had excellent results. Distal intercalary allografts in children (6 of 20) had either excellent or moderate results with no infections, but had 3 nonunions and 2 fractures. Proximal intercalary allografts in children (8 of 20) had 2 excellent results, but had 6 infections requiring a cement spacer. Five of the six spacers were ultimately revised to another allograft or an arthroplasty. Conclusion: For tibial allograft reconstruction, surgeons and patients should prepare for a prolonged treatment course that may include multiple complications and surgeries. Excellent or moderate results can be achieved eventually in most, but amputation may be necessary in 15-20% of cases.

Background: Synovial chondromatosis (SCh) can undergo malignant transformation. Pathologic diagnosis of secondary synovial chondrosarcoma (SChS) is challenging and misdiagnosis may result in over- or undertreatment. Method: A systematic review revealed 48 cases of SChS published in 27 reports since 1957. Data was collected to identify findings indicative of SChS and outcomes of treatment. Results: At median follow-up of 18 months, patients were reported as alive (10%), alive without disease (22%), alive with disease (15%), dead of disease (19%), dead of pulmonary embolism (4%), and unknown (29%). Initial diagnosis of SChS (grade: low/unknown 48%, intermediate/high 52%) was after biopsy in 58%, local resection in 29%, and amputation in 13%. Seventy-four percent of patients underwent 1.8 (mean) resections. Patients treated prior to 1992 were managed with amputation in 79% of cases compared to 48% after 1992. Symptoms were present for 72 mos prior to diagnosis of SChS. Synovial chondrosarcoma demonstrated symptom progression over several months (82%), rapid recurrence after complete resection (30%), and medullary canal invasion (43%). The SChS tumor dimensions were seldom quantified. Conclusion: Malignant degeneration of synovial chondromatosis is rare but can necessitate morbid surgery or result in death. Pathognomonic signs for SChS including intramedullary infiltration are present in the minority of cases. Progression of symptoms, quick local recurrence, and muscle infiltration are more suggestive of SChS. Periarticular cortical erosion, extra-capsular extension, and metaplastic chondroid features are non-specific. Although poorly documented for SChS, tumor size is a strong indicator of malignancy. Biopsy and partial resection are prone to diagnostic error. Surgical decisions are frequently based on size and clinical appearance and may be in conflict with pathologic diagnosis.

Objectives To evaluate ambulatory activity differences between youth with limb salvage procedures and typically developing youth (TDY) and assess differences in self-reported activity levels in the 2 groups, to provide a basis for physical activity assessment in patients who had undergone limb salvage surgery and treatment planning that incorporates regaining normal physical and daily living activities. Study design In this cohort comparison study, we compared ambulatory and self-reported activity levels in 20 youth (aged 11.7-20.8 years) who had undergone limb salvage surgery and a sex- and age-matched comparison cohort of 20 TDY. StepWatch activity monitor and Activity Scale for Kids data were used to answer these questions. Results Significant differences were found between the youth who had undergone limb salvage surgery and the TDY in total time active each day (43% vs 48%; P = .03), median total strides per day (4487 vs 7671; P = .001), and amount of time per day at high activity levels (20 minutes vs 47 minutes; P = .001). Self-reported overall physical activity, locomotion, and standing Activity Scale for Kids subscale scores were significantly lower in the youth undergoing limb salvage surgery compared with the TDY (summary score, 88.3 vs 97.7; P = .001). Conclusion Patients undergoing limb salvage surgery exhibit reduced physical activity compared with normal age-matched controls.

The major changes to the 2012 and 2011 NCCN Guidelines for Soft Tissue Sarcoma pertain to the management of patients with gastrointestinal stromal tumors (GISTs) and desmoid tumors (aggressive fibromatosis). Postoperative imatinib following complete resection for primary GIST with no preoperative imatinib is now included as a category 1 recommendation for patients with intermediate or high risk of recurrence. The panel also reaffirmed the recommendation for preoperative use of imatinib in patients with GISTs that are resectable with negative margins but associated with significant surgical morbidity. Observation was included as an option for patients with resectable desmoid tumors that are small and asymptomatic, not causing morbidity, pain, or functional limitation. Sorafenib is included as an option for systemic therapy for patients with desmoid tumors.

BACKGROUND: Myxoid/round cell liposarcoma (MRCL) is the second most common liposarcoma subtype, accounting for >33% of liposarcomas and approximately 10% of all soft tissue sarcomas. Although MRCL is a chemosensitive subtype, patients with metastatic disease have a poor outcome. NY-ESO-1 is a cancer-testis antigen (also known as cancer germ cell antigen) that has been successfully targeted in vaccine trials and in adoptive T-cell therapy trials for the treatment of several solid tumors. METHODS: The authors investigated the feasibility of targeting NY-ESO-1 in patients with MRCL by evaluating the prevalence of NY-ESO-1 expression in tumors using immunohistochemistry and quantitative reverse transcriptase-polymerase chain reaction analysis. NY-ESO-1–specific tumor recognition by NY-ESO-1–specific T-cells also was analyzed using a chromium release assay. RESULTS: A search of the University of Washington Sarcoma Tissue Bank identified paraffin-embedded tumor samples from 25 patients with MRCL. NY-ESO-1 expression was observed in every MRCL tumor assessed (100%); in 18 tumors (72%), staining was homogenous. In all but 2 tumors, staining was sufficiently robust (2þ) that such patients would be eligible for clinical trials of NY-ESO-1–directed therapy. By using NY-ESO-1 specific, CD8-positive T-cells, the in vitro sensitivity of myxoid liposarcoma cell lines to antigen-specific lysis was demonstrated. CONCLUSIONS: The current results establish NY-ESO-1 as an important target antigen for the treatment of patients with MRCL. Cancer 2012;118:4564-70. V C 2012 American Cancer Society.

Imaging has contributed to diagnosis and treatment decision making for patients with sarcomas, a highly heterogeneous tumor group. Derived from mesenchymal tissues, sarcomas occur in all parts of the body and in all patient age groups, with a highly variable histologic appearance and behavior. They are commonly separated into soft-tissue-derived and bone-derived groups; however, many exceptions to these classifications are seen clinically. Tumor size, cellular type and differentiation, and presence of necrosis are tumor features that can be used clinically to predict the risk of aggressive behavior. At present for soft-tissue sarcomas, the 5-y survival is approximately 60%, with substantially better survival for patients with bone tumors, particularly pediatric patients. Imaging with nuclear medicine techniques plays an important role in diagnosis, treatment planning, and follow-up. Conventional (99m)Tc-methylene diphosphonate bone scans, (201)Tl tumor imaging, and PET techniques have contributed to the care of sarcoma patients. Newer PET techniques with biologically specific imaging agents have also been evaluated to characterize sarcomas and contribute to risk stratification for poor outcome.

Background—Malnutrition is common at diagnosis and during treatment for sarcoma patients. Poor nutritional status is associated with increased risk of complications, particularly infections. We investigated the role of body mass index (BMI) on the incidence of surgical wound complications in patients with localized osteosarcoma treated on the Children's Oncology Group (COG) legacy trial, INT-0133. Procedure—Patients considered in this report had localized osteosarcoma, enrolled on COG trial INT-0133, remained on protocol therapy to have definitive surgery 6–16 weeks after study entry, and had adequate height, weight, and surgical complication data for analysis. By protocol design, definitive surgical resection was planned for 10 weeks after induction chemotherapy. Wound complications within 30 days after definitive surgery were considered post-operative. BMI was calculated at the start of neoadjuvant chemotherapy and expressed as age-and gender-adjusted percentile. The incidence of wound complications was evaluated by logistic regression or Fisher's exact test. Results—A total of 498 patients met criteria for analysis. Low BMI (≤10 th percentile) was seen in 73 (14.7%), middle BMI (11 th –94 th percentile) in 382 (76.7%), and high BMI (≥95 th percentile) in 43 (8.6%) patients. Wound infection or slough was seen in low BMI patients (OR=2.0, p=0.07) although the results did not reach statistical significance. Arterial thrombosis was more common in high BMI patients (OR=9.4, p=0.03). Conclusions—Abnormal BMI at the start of treatment for localized osteosarcoma is associated with increased risk of post-operative wound complications such as arterial thrombosis. Future studies should evaluate whether maintenance of age-appropriate BMI reduces the risk of surgical complications.

Multiple Osteochondromas (MO) is a disease of benign bony growths with a low incidence of malignant transformation. Secondary chondrosarcoma in children is rare even in children with MO. Making a diagnosis of malignancy in low-grade cartilage tumors is challenging and requires consideration of clinical, radiographic, and histopathological factors. We report two cases of skeletally immature patients with MO who presented with rapidly enlarging and radiographically aggressive lesions consistent with malignant transformation. Both underwent allograft reconstruction of the involved site with no signs of recurrence or metastatic disease at a minimum of four-year follow-up.

Leiomyosarcoma, a malignant neoplasm of smooth muscle, accounts for 7% of the sarcomas. Patients with leiomyosarcoma tumors have an average survival of 5 years. These tumors, which are derived from mesenchymal tissues, are difficult to diagnose, and treatment options remain controversial. The relatively rare incidence of this soft tissue sarcoma subtype has limited the number of patients available for studies and research. This study examines whether the imaging characteristics of positron emission tomography (PET) with radiolabeled fluorodeoxyglucose (FDG) provide a reliable, noninvasive means to predict tumor behavior in patients with leiomyosarcomas.[18F]-FDG-PET was performed on the tumors of participating patients before the neoadjuvant chemotherapy or resection, and a maximum tumor standard uptake value (SUVmax) was calculated.The SUVmax was correlated with tumor grade (P=0.001) and tumor size as greatest dimension (P=0.004). Analysis of these data indicated the potential effectiveness of FDG-PET imaging in predicting tumor grade.In leiomyosarcoma, the SUVmax from FDG-PET is a likely predictor of tumor behavior. The results of this study suggest that a large (by greatest dimension) intermediate grade tumor is expected to have the same predicted outcome as a high-grade tumor and should be treated in the same manner, as they share the same prognosis by definition of tumor grade. Improvements made in the clinical treatment of leiomyosarcomas by use of FDG-PET imaging data may lead to an increase in patient survival.

18F-FDG PET images of tumors often display highly heterogeneous spatial distribution of 18F-FDG–positive pixels. We proposed that this heterogeneity in 18F-FDG spatial distribution can be used to predict tumor biologic aggressiveness. This study presents data to support the hypothesis that a new heterogeneity-analysis algorithm applied to 18F-FDG PET images of tumors in patients is predictive of patient outcome. Methods:18F-FDG PET images from 238 patients with sarcoma were analyzed using a new algorithm for heterogeneity analysis in tumor 18F-FDG spatial distribution. Patient characteristics, tumor histology, and patient outcome were compared with image analysis results using univariate and multivariate analysis. Cox proportional hazards models were used to further analyze the significance of the data associations. Results: Statistical analyses show that heterogeneity analysis is a strong independent predictor of patient outcome. Conclusion: The new 18F-FDG PET tumor image heterogeneity analysis method is validated for the ability to predict patient outcome in a clinical population of patients with sarcoma. This method can be extended to other PET image datasets in which heterogeneity in tissue uptake of a radiotracer may predict patient outcome.

Pelvic Ewing sarcoma (ES) has poorer outcomes than extremity-based lesions and the method of local control is controversial.A retrospective review was performed of 40 primary pelvic or sacral ES treated by a single surgeon. All received modern chemotherapy and those that received radiation were treated with modern dosages.Fifty-five percent were disease-free at latest follow-up (median, 83.1 mos). Sixty-one percent had ≥ 99% necrosis, which was associated with 65% disease-free survival. Larger size (P = 0.016) and the absence of metastatic disease (P = 0.005) was predictive of survival. Eighty-three percent of relapsed patients were DOD. Half of patients who received surgery alone or RT alone have NED while 57% of those who received S/RT have NED. Complication rates were 69% (S/RT), 75% (surgery alone), 10% (RT alone). Functional outcomes were similar.Primary pelvic ES is localized at presentation in 50% and the absence of metastases is the strongest predictor for survival. Chemotherapy is key, but excellent histologic response is neither a guarantee nor a necessity for survival. More than one-third die despite an excellent histologic response and at least one-third with lung metastases survive. With chemotherapy, radiation, and surgery, reasonable control of disease can be achieved.Case-control or retrospective cohort study.

The effect of simulated early weight bearing on both micromotion and pullout strength of uncemented distal femoral stems was evaluated in this study. The effect of stem endosteal contact and bone quality on implant pullout strength was also analyzed. A randomized matched-pair study was performed using 8 bilateral pairs of fresh human cadaveric femoral specimens. Each specimen pair was dual-energy x-ray absorptiometry scanned, uniformly implanted, fluoroscopically imaged, and randomly assigned to the cycled or uncycled group. The cycled group received 5000 cycles of axial compressive loading (to 700 N) and the contralateral side was not cycled. Micromotion was monitored during cycling and compared with a failure threshold (150 µm), and all implants underwent direct axial distraction (pullout) testing. During cycling, minimal micromotion was observed with an asymptotic decrease in differential motion between the first and last 50 cycles. Both cycled and uncycled groups demonstrated no statistical difference in average pullout force (4888±2124 N vs 4367±1154 N; P =.43). The percentage of cortical contact for each implant was determined from panoramic fluoroscopy images using digital image analysis software. Contact area for the distal third of the stem showed the highest correlation with pullout force and with predicting pullout force. Bone quality did not correlate with pullout force ( r 2 =0.367) or stem contact area ( r 2 =0.394). In sum, press-fit uncemented femoral stems did not loosen or demonstrate decreased pullout strength with early weight bearing simulated by cyclical axial compressive loading. [ Orthopedics. 2015; 38(5):e417–e422.]

Limb salvage surgery is an effective procedure with a low risk of tumor recurrence. In an attempt to define the incidence of implant failure at 2, 5, and 10 years postoperatively, we retrospectively reviewed implant survival in a group (n = 105) of pediatric (18 years of age) and adult patients who were treated with distal femoral and/or proximal tibial implants for extremity tumors. Issues regarding the timing of failure, reason for failure, and whether pediatric patients had higher rates of failure were posed as secondary questions. The median followup was 57 months (1-235 months). Thirty-two (32/105, 31%) patients had 42 implant failures. The mean prosthesis Kaplan-Meier survivorship of the index group was 84% at 2 years, 73% at 5 years, and 59% at 10 years. Forty-seven percent of all failures occurred within 2 years postoperatively, and 69% occurred within 5 years postoperatively. Pediatric patients had a higher failure rate than adults (42% versus 24%). Aseptic loosening was the most common reason for failure (n = 18/32; 56%). The incidence of failure in tumor megaprostheses is similar to early published literature and the incidence of these failures is highest within the first 3 years.Therapeutic study, level IV.

Inflammatory leiomyosarcoma, a rare entity first described in 1995, has been characterized by smooth muscle differentiation, a near-haploid karyotype, and a surprisingly good prognosis. The morphology is similar to that of conventional leiomyosarcoma admixed with a chronic inflammatory infiltrate. Thus far, only 15 cases have been reported in the English language literature. We report the clinical and pathological features of 3 additional cases of inflammatory leiomyosarcoma. Two women (ages 64 and 25, respectively) and 1 man (age 32) presented with a thigh, ovary, and lung mass, respectively. Inflammatory symptoms, such as anorexia, fever, night sweats, abdominal pain, and diarrhea, coincided with the thigh and ovarian primaries. Immunohistochemical studies revealed diffuse positivity for desmin and poor expression for other smooth muscle and skeletal muscle markers (muscle-specific actin [0/3], α-smooth muscle actin 1/3 [focal], calponin [1/3], caldesmon [0/3], and myogenin [0/3]). CD68 was diffusely positive in both the histiocytes and spindle cell component in all cases. Ultrastructural evaluation of 1 case (lung primary) lacked definitive smooth muscle differentiation. Cytogenetic analysis in 1 of 2 cases that were karyotyped, identified a near-haploid karyotype, which has been reported in other cases of inflammatory leiomyosarcoma. The other case showed 2 clonal populations of cells with interstitial deletions of the short arm of chromosome 8 and the long arm of chromosome 9, respectively. The case without cytogenetic data was intimately associated with an ovarian mature teratoma. These data also suggest that inflammatory leiomyosarcoma may lack smooth muscle differentiation, characterized by diffuse immunoreactivity for desmin but lack of immunoreactivity for α-smooth muscle actin, calponin, and caldesmon. In addition, 2 of the 3 cases developed distant metastases to the lungs, which suggests that these lesions may have a worse prognosis than previously believed.

Purpose To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). Patients and Methods Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 × 2 factorial design. The primary end point for analysis was EFS. Results Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. Conclusion The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

Purpose Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. Patients and Methods One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. Results Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (≤ 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. Conclusion We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.

Positron emission tomography (PET) has become a powerful tool to evaluate various biological processes involving the musculoskeletal system. The positron-emitting radioisotopes commonly used in positron emission tomography in clinical practice (F-18, C-11, and O-15) can be incorporated into a number of physiologic tracers and substrates, with the synthesis of these radiopharmaceuticals taking place in association with a radioisotope-producing cyclotron. The ability of radiopharmaceuticals to function as indicators of specific physiologic processes provides an important measure of an aspect of a disease or repair that might not be apparent on the basis of structural changes alone. The use of positron emission tomography imaging and specific radiopharmaceuticals to measure biological activity of tissue quantitatively and to relate it to structure is unique in the diagnostic imaging process. Radioactive decay involves the emission of a positron (a positive electron) from a proton excess in a radioactive nucleus. The positron travels only a few millimeters in the tissue before colliding with a negative electron. This encounter results in the annihilation of both particles, with the creation of two gamma rays of 511 keV each, the energy equivalent of the two electron masses. These annihilation photons travel in 180° opposite directions from their source (Fig. 1). For positron emission tomography, positron detectors are lined up in a ring formation around the patient and they detect the pair of gamma rays resulting from the positron-electron annihilation. The paired detectors are located on opposite sides of the patient and register a count only if both detect a photon at precisely the same time, a coincidence event (Fig. 2). Computer-controlled image-manipulation techniques are used to reconstruct a cross-sectional image from the electronic information registered from the emission coming from the patient who received an injected radiopharmaceutical for the scan. Fig. 1 In the unstable atomic nucleus, a proton decays to …

The defining cytogenetic abnormality of Ewing's sarcoma is the presence of a balanced t(11;22) translocation expressing the EWS/FLI-1 chimeric fusion protein. The effect of EWS/FLI-1 appears to be dominant negative since over-expression of EWS does not overcome the sarcoma phenotype. Previous studies have shown that EWS/FLI-1 as well as related sarcoma fusion proteins are necessary and sufficient to induce transformation both in vitro and in vivo. In this study we report that synthetic small interfering RNA (siRNA) specifically suppresses EWS/FLI-1 fusion gene expression in SK-ES Ewing's sarcoma cells. Knockdown of the EWS/FLI-1 fusion protein is correlated with decreased cell proliferation and increased apoptosis. We demonstrate that Ewing's sarcoma tumors as well as Ewing's sarcoma cell lines predominantly express the CXCR4 chemokine receptor. Using an in vitro invasion assay, the SDF-1 ligand of CXCR4 was shown to be a potent stimulus of invasion by SK-ES cells. Knockdown of EWS/FLI-1 by RNA interference abrogates the invasiveness of SK-ES cells. These experiments suggest that targeted silencing of the EWS/FLI-1 fusion gene by siRNA represents a promising strategy to study the loss of EWS/FLI-1 protein in Ewing's sarcoma cells of otherwise identical genetic background.

Purpose: The aim of this study is to compare glucose metabolism and hypoxia in four different tumor types using positron emission tomography (PET). 18F-labeled fluorodeoxyglucose (FDG) evaluates energy metabolism, whereas the uptake of 18F-labeled fluoromisonidazole (FMISO) is proportional to tissue hypoxia. Although acute hypoxia results in accelerated glycolysis, cellular metabolism is slowed in chronic hypoxia, prompting us to look for discordance between FMISO and FDG uptake. Experimental Design: Forty-nine patients (26 with head and neck cancer, 11 with soft tissue sarcoma, 7 with breast cancer, and 5 with glioblastoma multiforme) who had both FMISO and FDG PET scans as part of research protocols through February 2003 were included in this study. The maximum standardized uptake value was used to depict FDG uptake, and hypoxic volume and maximum tissue:blood ratio were used to quantify hypoxia. Pixel-by-pixel correlation of radiotracer uptake was performed on coregistered images for each corresponding tumor plane. Results: Hypoxia was detected in all four patient groups. The mean correlation coefficients between FMISO and FDG uptake were 0.62 for head and neck cancer, 0.47 for breast cancer, 0.38 for glioblastoma multiforme, and 0.32 for soft tissue sarcoma. The correlation between the overall tumor maximum standardized uptake value for FDG and hypoxic volume was small (Spearman r = 0.24), with highly significant differences among the different tumor types (P < 0.005). Conclusions: Hypoxia is a general factor affecting glucose metabolism; however, some hypoxic tumors can have modest glucose metabolism, whereas some highly metabolic tumors are not hypoxic, showing discordance in tracer uptake that can be tumor type specific.

OBJECTIVE. In this article, we describe FDG uptake in schwannoma as measured on positron emission tomography (PET). FDG uptake is compared with tumor cellularity, tumor size, and tumor proliferation rate (Ki-67 index).CONCLUSION. Schwannomas generally have a high tumor-to-background ratio on FDG PET. Semiquantitative analysis with standardized uptake values (SUVs) reveals a wide variation in SUVs that can be explained by variations in the degree of cellularity. No correlation was found between FDG uptake and tumor size or tumor proliferation rate (Ki-67 index). Because these tumors often have a high level of FDG uptake, distinguishing schwannomas from malignant peripheral nerve sheath tumors before biopsy or surgery is not possible. Even in cases in which the maximum SUV or average SUV is greater than 6.0, schwannomas cannot be excluded. Therefore, schwannoma should be included in the differential diagnosis of peripheral nerve sheath tumors with low, intermediate, or high SUVs.

The aims of this study were to assess the potential of fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) for tumor grading in chondrosarcoma patients and to evaluate the role of standardized uptake value (SUV) as a parameter for prediction of patient outcome. FDG PET imaging was performed in 31 patients with chondrosarcoma prior to therapy. SUV was calculated for each tumor and correlated to tumor grade and size, and to patient outcome in terms of local relapse or metastatic disease with a mean follow-up period of 48 months. Chondrosarcomas were detectable in all patients. Tumor SUV was 3.38 +/- 1.61 for grade I (n = 15), 5.44 +/- 3.06 for grade II (n = 13), and 7.10 +/- 2.61 for grade III (n =3). Significant differences were found between patients with and without disease progression: SUV was 6.42 +/- 2.70 (n = 10) in patients developing recurrent or metastatic disease compared with 3.74 +/- 2.22 in patients without relapse (P = 0.015). Using a cut-off of 4 for SUV, sensitivity, specificity, and positive and negative predictive values for a relapse were 90%, 76%, 64%, and 94%, respectively. Combining tumor grade and SUV, these parameters improved to 90%, 95%, 90%, and 95%, respectively. Pretherapeutic tumor SUV obtained by FDG PET imaging was a useful parameter for tumor grading and prediction of outcome in chondrosarcoma patients. The combination of SUV and histopathologic tumor grade further improved prediction of outcome substantially, allowing identification of patients at high risk for local relapse or metastatic disease.

Background: Intercalary allografts are used for the reconstruction of major skeletal defects. Step-cuts help to provide rotational stability when intramedullary fixation is used. A modified step-cut is proposed to reduce rotation at the interface. This study compares the rotational stability of conventional and modified step-cuts. Methods: In Phase I, seven pairs of human cadaveric femora were divided into a conventional step-cut group (left femora) and a modified step-cut group (right femora). All femora were cut transversely at the mid-diaphysis. In the conventional group, a 1-cm step-cut was created in the exact midsagittal plane in both the proximal and distal segments. In the modified group, a 1-cm step-cut was created in the parasagittal plane, leaving 2 mm of additional bone on both the proximal and the distal fragment. Phase II was identical except that in the modified step-cut group only 1 mm of additional bone was left. Smooth femoral nails were then placed after standard reaming. Specimens were tested by fixing the proximal segment and applying ±2 N-m (17.7 in-lb) of torque to the distal segments with ten oscillation cycles. Maximum rotation was measured. The data were analyzed with the paired Student t test. Results: The average rotation in Phase I was 23.3° for the conventional step-cut group and 3.0° for the 2-mm modified step-cut group; the difference was significant (p < 0.001). Four femora sustained an incomplete fracture during nail insertion. The average rotation in Phase II was 20.6° for the conventional step-cut group and 0.5° for the 1-mm modified step-cut group without any fractures; the difference was significant (p < 0.001). Conclusions: Step-cut modification that leaves more bone in the sagittal plane provides rigid fixation and significantly more stability than the conventional step-cut technique. Clinical Relevance: Such a modification should facilitate osseous incorporation of an intercalary allograft while providing the benefits of intramedullary fixation. Excessive modification (>1 mm) can result in a fracture of the graft.

Hypoxia imparts resistance to radiotherapy and chemotherapy and also promotes a variety of changes in tumor biology through inducible promoters. The purpose of this study was to evaluate the use of positron emission tomography (PET) imaging with fluorine-18 fluoromisonidazole (FMISO) in soft tissue sarcomas (STS) as a measure of hypoxia and to compare the results with those obtained using [(18)F]fluorodeoxyglucose (FDG) and other known biologic correlates. FDG evaluates energy metabolism in tumors while FMISO uptake is proportional to tissue hypoxia. FMISO uptake was compared with FDG uptake. Vascular endothelial growth factor (VEGF) expression was also compared with FMISO uptake. Nineteen patients with STS underwent PET scanning with quantitative determination of FMISO and FDG uptake prior to therapy (neo-adjuvant chemotherapy or surgery alone). Ten patients receiving neo-adjuvant chemotherapy were also imaged after chemotherapy but prior to surgical resection. Standardized uptake value (SUV) was used to describe FDG uptake; regional tissue to blood ratio (or=1.2 was considered significant) was used for FMISO uptake. Significant hypoxia was found in 76% of tumors imaged prior to therapy. No correlation was identified between pretherapy hypoxic volume (HV) and tumor grade ( r=0.15) or tumor volume ( r=0.03). The correlation of HV with VEGF expression was 0.39. Individual tumors showed marked heterogeneity in regional VEGF expression. The mean pixel-by-pixel correlation between FMISO and FDG uptake was 0.49 (range 0.09-0.79) pretreatment and 0.32 (range -0.46-0.72) after treatment. Most tumors showed evidence of reduced uptake of both FMISO and FDG following chemotherapy. FMISO PET demonstrates areas of significant and heterogeneous hypoxia in soft tissue sarcomas. The significant discrepancy between FDG and FMISO uptake seen in this study indicates that regional hypoxia and glucose metabolism do not always correlate. Similarly, we did not find any relationship between the hypoxic volume and the tumor volume or VEGF expression. Identification of hypoxia and development of a more complete biologic profile of STS will serve to guide more rational, individualized cancer treatment approaches.

[(18)F]fluorodeoxyglucose positron emission tomography (FDG PET) is used to evaluate the metabolic activity of intermediate- to high-grade soft tissue sarcomas prior to the initiation of chemotherapy. FDG PET and MRI are repeated after chemotherapy to assess treatment response and to correlate this with the histologic response. This case report highlights discrepant results between the final histologic diagnosis (tumor response) and the percent change in maximum standard uptake variable (SUV(max)). Further investigation of the resected specimen identified the significant difference in tumor response assessment to be due to the heterogeneity of the tumor and heterogeneity in its response to treatment. FDG PET imaging has an important role in evaluating tumor metabolic activity and has played an increasingly important part in evaluating the response to neoadjuvant chemotherapy in sarcomas. Evaluating the heterogeneity of the tumor at baseline and after response to therapy can provide insight into prognosis and treatment planning.

71 Background: Soft tissue sarcomas (STS) are heterogeneous tumors which are morbid and lethal. G100 is under investigation in multiple clinical trials and contains a potent TLR4 agonist (oil-in-water emulsion of glucopyranosyl lipid A) that has been tested as vaccine adjuvant. We hypothesized IT G100 would induce robust local and potentially systemic anti-tumor immune response, leading to improved outcomes. Methods: 15 metastatic STS patients with superficial lesions were treated with weekly IT G100 for 8-12 wks; 12 patients received radiation (RT) for 2 wks to start, while 3 received IT G100 for 6 wks prior to RT. Biopsies and PBMC were collected pre and post treatment, and flow cytometry was performed on biopsies. TIL and PBMC were analyzed with TCR deep sequencing. PBMC were analyzed by single cell multiplex cytokine profiling. Results: No grade ≥ 3 toxicity was observed, and local tumor control was achieved in all evaluable tumors (14/14). Treated tumors tracked post-trial (mean 156 days) had persistent local control with 1 CR (7%), 1 PR (7%), and 11 SD (79%). In 3 patients with long term follow up, treated lesions remained controlled vs index lesions (-53% vs +31% at mean 235 days, p = 0.002). In all tumors after G100 alone, T cell infiltration increased. In P14, CD3 live cells in tumor rose from < 1% to 62%. PBMC clonality increased in 8/14 tested including P06, who had 4× increase in clonality and CR in the injected lesion; PBMC and TIL TCR overlap increased from 13.4% to 21.5%. P13 had a 2.3× rise in TIL clonality; the top clone (a CD4 T cell) expanded from 0.1% to 38% and expressed more TNFα than the rest (p < 0.0001). Single cell cytokine analysis of PBMC showed 7/13 (54%) increased in polyfunctionality (producing > 2 cytokines) in CD4 T cells; no consistent increase was seen in CD8 T cells. TNFα levels in pre-treatment monocytes correlated with PFS (R2= 0.5, p = 0.02). Conclusions: IT G100 is a viable agent for local control of metastatic STS lesions. With or without RT, G100 appears to cause CD4 T cell mediated local and systemic response. Combination of G100 with other immunomodulators could induce clinically significant systemic responses, as seen in follicular NHL treated with G100. Clinical trial information: NCT02180698.

PURPOSE: Dermatofibrosarcoma protuberans is caused by activation of the platelet-derived growth factor B (PDGFB) receptor, a transmembrane tyrosine kinase. We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate. PATIENTS AND METHODS: A patient with unresectable, metastatic dermatofibrosarcoma protuberans received imatinib mesylate (400 mg bid). Response to therapy was assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography, magnetic resonance imaging, and histopathologic and immunohistochemical evaluation. RESULTS: The patient was treated for 4 months with imatinib mesylate. The hypermetabolic uptake of FDG fell to background levels within 2 weeks of treatment, and the tumor volume shrank by over 75% during the 4 months of therapy, allowing for resection of the mass. There was no residual viable tumor in the resected specimen, indicating a complete histologic response to treatment with imatinib mesylate. CONCLUSION: Imatinib mesylate is highly active in dermatofibrosarcoma protuberans. The dramatic response seen in this patient demonstrates that inhibition of PDGFB receptor tyrosine kinase activity can significantly impact viability of at least one type of solid tumor.

BACKGROUND Response to neoadjuvant chemotherapy is a significant prognostic factor for osteosarcoma (OS) and the Ewing sarcoma family of tumors (ESFT). Conventional radiographic imaging does not discriminate between responding and nonresponding osseous tumors. [F-18]-fluorodeoxy-D-glucose (FDG) positron emission tomography (PET) is a noninvasive imaging modality that accurately predicts histopathologic response in patients with various malignancies. To describe the FDG PET imaging characteristics and to determine the correlation between FDG PET imaging and chemotherapy response in children with bone sarcomas, we reviewed our single institution experience. METHODS Thirty-three pediatric patients with OS or ESFT with osseous primary sites were evaluated by FDG PET. All patients received standard neoadjuvant chemotherapy. FDG PET standard uptake values before (SUV1) and after (SUV2) chemotherapy were analyzed and correlated with chemotherapy response assessed by histopathology in surgically excised tumors. Twenty-six patients had SUV1, SUV2, and surgical excision. RESULTS Although the mean SUV1 in children with OS or ESFT were similar (8.2. vs. 5.3, P = 0.13), mean SUV2 for OS patients was greater than the values for ESFT patients (3.3 vs. 1.5, P = 0.01). All ESFT patients and 28% of OS patients had a favorable histologic response to chemotherapy (≥ 90% necrosis). Combining ESFT and OS patients, both SUV2 and the ratio of SUV2 to SUV1 (SUV2:SUV1) were correlated with histologic response (P = 0.01 for both comparisons). CONCLUSION FDG PET evaluation of pediatric bone sarcomas demonstrated significant alteration in response to neoadjuvant chemotherapy. SUV2 and SUV2:SUV1 correlated with histopathologic assessment of response and potentially could be used as a noninvasive surrogate to predict response in patients. Cancer 2002;94:3277–84. © 2002 American Cancer Society. DOI 10.1002/cncr.10599

The impact of delayed adjuvant radiotherapy in patients treated by surgical resection for peripheral or torso soft tissue sarcoma has not been well characterized. We retrospectively examined this issue in an institutional patient cohort.One hundred two adult patients were treated at the University of Washington Medical Center between 1981 and 1998 with postoperative radiotherapy for cure of a newly diagnosed soft tissue sarcoma. Of this group, 58 patients had primary intermediate- or high-grade disease of the extremity or torso (50 extremity/8 torso). Tumor histology was predominantly malignant fibrohistiocytoma, synovial cell sarcoma, and leiomyosarcoma. The group was dichotomized according to time interval from definitive resection to the start of adjuvant radiation. Twenty-six patients had a short delay, defined as4 months, and 32 patients had a long delay ofor=4 months. Both groups were balanced with regard to site, size, margin status, and tumor depth; however, the long-delay group had a larger proportion of high histologic grade lesions and was treated more frequently with chemotherapy (31/32 [97%] for long-delay patients vs. 14/26 [54%] for short-delay patients). Median follow-up was 49.5 months (range: 7-113 months). Median follow-up for patients still alive was 54 months (range: 9-113 months). Survival outcomes were estimated by the Kaplan-Meier method.Overall local relapse-free survival at 5 years from the time of definitive resection was 74%. On univariate analysis, estimated 5-year local relapse-free survival was significantly improved in the short-delay group (88% vs. 62% for the long-delay group, p = 0.048 by log rank). Overall distant relapse-free survival, disease-free survival, and overall survival at 5 years were 77%, 68%, and 86%, respectively. These survival outcomes were statistically equivalent in both radiation delay groups. There was no evidence to suggest that delaying adjuvant systemic therapy for postoperative radiation negatively impacted distant relapse-free survival, disease-free survival, or overall survival. Patterns of failure analysis revealed that 11/12 disease failures in the long-delay group had a local component, with five patients presenting with solitary local recurrences. Severe chronic radiation-related soft tissue or peripheral nerve morbidity was infrequent (5/58 or 8.6%) and similar in both groups.Postoperative radiation delays of 4 months or greater were associated with inferior local disease control for intermediate- and high-grade soft tissue sarcomas of the extremity and torso. Our results suggest that timing postoperative radiation before postoperative chemotherapy may optimize local therapy for such patients without adversely affecting distant disease control, long-term morbidity, or overall survival. Prospective testing of this hypothesis is warranted.

One of the most important factors concerning the successful clinical outcome after transplantation of osteochondral allografts is the viability of the cartilage.The viability of cryopreserved cartilage is quite poor, 20–30% cell survival has been published. The purpose of this study was to develop a new storage method which improves the chondrocyte viability. The talus of cadaveric donors was used as a model tissue to compare human osteochondral allograft cartilage viability following cryopreservation with that remaining after prolonged refrigerated storage. Full-thickness cartilage punch biopsies had been cryopreserved, and tali were divided into two matched groups and stored in TCM for 60 days at +4 °C, either with or without regular medium replacement. The cartilage of each graft was biopsied and assayed for viability on every third day by the MTT reduction assay. During 4 °C storage, a recurring pattern of large fluctuations in apparent cartilage viability was observed in every stored graft, with or without medium replacement. These fluctuations did not appear in control specimens of either fresh or cryopreserved human skin that were assayed in parallel with the cartilage biopsies, so the viability fluctuation seems an intrinsic property of the cartilage in these conditions. Cartilage stored for 60 days at +4 °C showed significantly higher viability (35.2 ± 3.3 %) than fresh cartilage that had been cryopreserved (21.6 ± 1.8 %). This was true even when cryopreserved and thawed cartilage was subjected to a 3 day post thaw incubation under presumably favorable conditions (17.7 ± 1.6 %). These viability assay results, (reflective of intracellular metabolic activity), were corroborated by the fluorescent dye mixture SYTO-16 and propidium iodide. The data indicate that long-term stored refrigerated cartilage appears to retain a viability higher than that of cryopreserved cartilage for up to and perhaps beyond 60 days of storage. There was no viability index difference between the medium replaced and non-replaced groups. Although an exceptional result, in one individual case, more than 65% viable cells could be detected in the talar cartilage after 60 days storage at +4 °C.

The aim of this study was to adapt a reliable, reproducible and simple viability assay for cartilage and osteochondral studies. The previous assays (radioisotope uptake, assessment of matrix components, histological methods, oxygen consumption etc.) were complex, laborious, time consuming or suffer from difficulty of interpretation. MTT assay was chosen because it has been widely and successfully used in different cell and tissue studies, but has not been published on human solid articular cartilage. Fresh intact cartilage samples of human tali were tested to investigate the assay. The reliability of the MTT assay was also tested by an fluorescent dye combination. The MTT assay is based on the production of purple formazan pigment from methyltetrazolium salt by the mitochondrial enzymes of viable chondrocytes. The enzyme kinetics of the reaction was also investigated because it was unknown in the case of cartilage. The amount of pigment formed can be measured by spectrophotometry after extraction by methyl cellosolve. The color density is proportional to mitochondrial enzyme activity, reflecting the number of viable chondrocytes. The optimal reagent concentration, biopsy size, and incubation period were established. There is a linear relationship between the cartilage weight and the pigment production activity. A 9.8% nonspecific raction was observed in the negative controls. The enzyme kinetics of the reaction was also investigated. The MTT clevage up to 0.1% (w/v) follows the Michaelis kinetics. We calculated the Michaelis constant (2835 +/- 130 microM), the maximal velocity (36 +/- 3.2 x 10(-5)microMsec(-1)) and the velocity constant (1.27 +/- 0.2 x 10(-7)sec(-1)) of the reaction. The latter is a significant marker for each tissue type. The viability of cartilage was also assessed and calculated by a fluorescent dye combination comprising 1 microg/ml propidium iodide (PI) and 4 microM/ml SYTO-16 stains. The PI stains dead cells (red fluorescence), the SYTO-16 stains live cells (green fluorescence). The staining can be visualised simultaneously, and the live/dead ratio can be calculated by image analysis software from saved image files. The MTT assay is a simple, non-expensive, efficient, reliable, reproducible, sensitive viability test for cartilage studies. The MTT reduction assay and the staining method were corrobative.