Alexander N. Fedenko

A Meta-Analysis of Osteosarcoma Outcomes in the Modern Medical Era

Four decades ago, specialized chemotherapy regimens turned osteosarcoma, once considered a uniformly fatal disease, into a disease in which a majority of patients survive. Though significant survival gains were made from the 1960s to the 1980s, further outcome improvements appear to have plateaued. This study aims to comprehensively review all significant, published data regarding osteosarcoma and outcome in the modern medical era in order to gauge treatment progress. Our results indicate that published survival improved dramatically from 1960s to 1980s and then leveled, or in some measures decreased. Recurrence rates decreased in the 1970s and then leveled. In contrast, published limb salvage rates have increased significantly every recent decade until the present. Though significant gains have been made in the past, no improvement in published osteosarcoma survival has been seen since 1980, highlighting the importance of a new strategy in the systemic management of this still very lethal condition.

The Role of Access of Joint Fluid to Bone in Periarticular Osteolysis: A Report of Four Cases*

In 1976, Harris et al. reported on four patients who had extensive, localized osteolysis after a total hip replacement14. This erosive or cavitary form of bone resorption has become a major problem that threatens the survival of otherwise successful total hip and knee replacements. Osteolysis has been associated with prosthetic arthroplasties since their introduction. Various etiologies of osteolysis have included infection5 and a foreign-body inflammatory reaction to particulate bone cement25, metal particles32,42, or polyethylene particles37. While there is substantial evidence that small particles and activated macrophages play an important role in osteolysis, the pathophysiology of this condition has been incompletely defined. The mechanism needs to account for osteolysis that occurs in the absence of a discernible periprosthetic particulate burden32, that develops around femoral endoprostheses inserted without cement27, and that occurs around metal-on-metal total hip replacements38,43. The lesions described in the present report are examples of a defined pathological entity know as osteoarthrotic cysts, or geodes3,35. This periarticular, cavitary form of bone resorption occurs in the absence of prosthetic implants. The findings presented here, combined with a review of the related pathology and pathophysiology, demonstrate that the most fundamental factor in the development of osteolysis in association with osteoarthrosis and total joint arthroplasty appears to be the access of joint fluid to bone. CASE 1. In 1990, radiographs of a seventy-four-year-old man demonstrated multiple cysts in the right femoral head (Fig. 1-A). Radiographs made in 1994 demonstrated dramatic enlargement of these cysts (Fig. 1-B). Pain gradually increased, and the patient had a total hip replacement. Examination of the femoral head revealed extensive full-thickness loss of articular cartilage and focal loss of subchondral bone; a thin fibrous membrane covered …

A Comparison of Fine-needle Aspiration, Core Biopsy, and Surgical Biopsy in the Diagnosis of Extremity Soft Tissue Masses

BackgroundBiopsy tissue can be obtained through a fine needle, a wider coring needle, or through an open surgical incision. Though much literature exists regarding the diagnostic yield of these techniques individually, none compare accuracy of diagnosis in the same mass.Questions/purposesWe asked how the diagnostic accuracy of fine-needle aspiration, core biopsy, and open surgical biopsy compare in regard to identifying malignancy, establishing the exact diagnosis, and guiding the appropriate treatment of soft tissue masses.Patients and MethodsWe prospectively studied 57 patients with palpable extremity soft tissue masses, performing fine-needle aspiration, followed by core biopsy, followed by surgical biopsy of the same mass.ResultsOpen surgical biopsy was 100% accurate on all accounts. With regard to determining malignancy, fine-needle aspiration and core biopsy had 79.17% and 79.2% sensitivity, 72.7% and 81.8% specificity, 67.9% and 76% positive predictive value, 82.8% and 84.4% negative predictive value, and an overall accuracy of 75.4% and 80.7%, respectively. In regard to determining exact diagnosis, fine-needle aspiration had a 33.3% accuracy and core biopsy had a 45.6% accuracy. With regard to eventual treatment, fine-needle aspiration was 38.6% accurate and core biopsy was 49.1% accurate.ConclusionsIn soft tissue mass diagnosis, core biopsy is more accurate than fine-needle aspiration on all accounts, and open biopsy is more accurate than both in determining malignancy, establishing the exact diagnosis, and the guiding appropriate treatment.Level of Evidence Level I, diagnostic study. See Guidelines for Authors for a complete description of levels of evidence.

Influence of cryosurgery on treatment outcome of low-grade chondrosarcoma

Successfully managing low-grade chondrosarcomas with margins considered less than wide would minimize the need for extensive reconstruction. We report our experience using cryotherapy as an adjuvant to treat patients with low-grade intracompartmental chondrosarcomas. Ten consecutive patients had intralesional resections including curettage, cryo-surgery, and polymethylmethacrylate application. Eight of these patients required prophylactic skeletal stabilization. We retrospectively reviewed the outcomes for tumor recurrence, disease progression, and complications. The Musculo-skeletal Tumor Society rating scale was used to evaluate functional outcome, and the mean score was 27 points (range, 25-30 points). The mean age of the patients was 54.4 years (range, 29-83 years), and the average followup was 38.5 months (range, 24-60 months). Patients were treated for lesions of the femur (n = 3), humerus (n = 3), scapula (n = 2), tibia (n = 1), and acetabulum (n = 1). There was no evidence of recurrence or metastases. At the latest followup, all patients were well, however, one patient had hardware loosening. In this small group of patients, intralesional resection with adjuvant cryoablation provided an alternative to more radical procedures for low-grade intracompartmental chondrosarcoma.Level of Evidence: Level IV Therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

First-Line Aldoxorubicin vs Doxorubicin in Metastatic or Locally Advanced Unresectable Soft-Tissue Sarcoma: A Phase 2b Randomized Clinical Trial

IMPORTANCE Standard therapy for advanced soft-tissue sarcoma has not changed substantially in decades, and patient prognosis remains poor. Aldoxorubicin, a novel albumin-binding prodrug of doxorubicin, showed clinical activity against advanced soft-tissue sarcoma in phase 1 studies. OBJECTIVE To evaluate efficacy and safety of aldoxorubicin vs doxorubicin in patients with advanced soft-tissue sarcoma. DESIGN, SETTING, AND PARTICIPANTS International, multicenter, phase 2b, open-label, randomized study at general community practices, private practices, or institutional practices. Between August 2012 and December 2013, 140 patients with previously untreated locally advanced, unresectable, or metastatic soft-tissue sarcoma were screened. INTERVENTIONS Randomization (2:1) to aldoxorubicin 350 mg/m2 (dose equivalent to doxorubicin 260 mg/m2) or doxorubicin 75 mg/m2, administered once every 3 weeks for up to 6 cycles. MAIN OUTCOMES AND MEASURES Primary end point was progression-free survival. Secondary end points were 6-month progression-free survival, overall survival, tumor response rate, and safety. All efficacy end points were evaluated by independent and local review. RESULTS A total of 126 patients were randomized, and 123 received aldoxorubicin (n = 83) or doxorubicin (n = 40). Median (range) patient age was 54.0 (21-77 years); 42 (34%) had leiomyosarcoma. By independent review, median progression-free survival was significantly improved (5.6 [95% CI, 3.0-8.1] vs 2.7 [95% CI, 1.6-4.3] months; P = .02) with aldoxorubicin compared with doxorubicin, as was the rate of 6-month progression-free survival (46% and 23%; P = .02). Median overall survival was 15.8 (95% CI, 13.0 to not available) months with aldoxorubicin and 14.3 (95% CI, 8.6-20.6) months with doxorubicin (P = .21). Overall tumor response rate (by Response Evaluation Criteria in Solid Tumors, version 1.1) by independent review was higher with aldoxorubicin than with doxorubicin (25% [20 patients, all partial response] vs 0%). Grade 3 or 4 neutropenia was more frequent with aldoxorubicin than with doxorubicin (24 [29%] vs 5 [12%]), but not grade 3 or 4 febrile neutropenia (12 [14%] vs 7 [18%]). No acute cardiotoxic effects were observed with either treatment, although left ventricular ejection fraction less than 50% occurred in 3 of 40 patients receiving doxorubicin. CONCLUSIONS AND RELEVANCE Single-agent aldoxorubicin therapy showed superior efficacy over doxorubicin by prolonging progression-free survival and improving rates of 6-month progression-free survival and tumor response. Aldoxorubicin therapy exhibited manageable adverse effects, without unexpected events, and without evidence of acute cardiotoxicity. Further investigation of aldoxorubicin therapy in advanced soft-tissue sarcoma is warranted. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01514188.

F-18 FDG PET and PET/CT evaluation of response to chemotherapy in bone and soft tissue sarcomas.

Objective: F-18 FDG PET has been used to grade sarcomas and assess response to therapy in advanced disease. Certain chemotherapy agents are thought to induce an inflammatory response in the tumor bed that can make interpretation of post-therapy FDG PET scans difficult. A review of our experience with PET in assessing therapy response in osseous and soft tissue sarcomas (OSTS) is presented. Methods: This is a retrospective study (January 1999 to December 2004) of 14 patients with histologic diagnosis of OSTS, who had 2 consecutive PET examinations for evaluation of chemotherapy response. The group included 8 men and 6 women, with age range of 18 to 56 years (average, 36 ± 14). Semiquantitative assessment of FDG uptake was performed by calculating maximum standard uptake value (SUVmax) before and after treatment. The response to therapy was assessed independently by tumor necrosis at post-therapy surgery and according to European Organization for Research and Treatment of Cancer (EORTC) criteria for PET. The follow-up PET examinations were performed at an interval of 28 to 166 days (average, 90 ± 45). All patients ended the ifosfamide regimen at 7 to 36 (average, 16 ± 9) days before the follow-up PET scans. Five of them received methotrexate, adriamycin, and/or cisplatin as well. Results: Based on the EORTC criteria alone, 3 patients (21.4%) had progression of disease (increase in SUVmax of 29%–69%; mean, 48% ± 20%), 5 patients (35.7%) had stable disease, and 6 patients (42.8%) had partial response (decrease in SUVmax of 27%–84%; mean, 62% ± 23%). Across all patients, the tumor necrosis postchemotherapy ranged from 5% to 100% (mean, 64% ± 34%). In 8 patients (57.1%) the tumor necrosis correlated with the SUVmax changes. However, for 3 patients, the SUVmax changes indicated partial response despite necrosis of fewer than 90% of the surgical specimens, whereas 3 patients with >90% tumor necrosis had SUVmax changes indicative of stable disease. Conclusion: The pathologically determined degree of necrosis postneoadjuvant chemotherapy was concordant with PET-assessed EORTC classification of response in 57.1% of the cases. However, a significant number of patients had discrepancies, which may be in part explained by chemotherapy-induced inflammation. The latter should be considered during post-therapy PET interpretation in OSTS.

Tumor necrosis has no prognostic value in neoadjuvant chemotherapy for soft tissue sarcoma

Neoadjuvant chemotherapy for treatment of soft tissue sarcomas is controversial, and the correlation between local recurrence and survival is unclear. Histologic necrosis is a well-documented predictor of survival in patients with malignant bone tumors; however, the association is unknown in patients with soft tissue sarcomas. We assessed the prognostic significance of tumor necrosis for treatment of soft tissue sarcomas. We retrospectively collected data from 82 patients who received neoadjuvant chemotherapy for treatment of soft tissue sarcomas of the extremities. Patients had wide resections if tumors were high-grade, deep to the investing fascia, and had clear margins. We quantified the amount of necrosis and analyzed the relationship with local recurrence and overall survival. At an average followup of 65 months (range, 24-154 months), the 5-year local recurrence rates for patients with less than 95% and 95% or greater necrosis were 20% and 33%, respectively. The overall 5-year survivorship rates for patients with less than 95% necrosis and 95% or greater necrosis were 82% and 78%, respectively. There was no difference in recurrencefree survival or overall patient survival based on the amount of histologic necrosis. Tissue necrosis from neoadjuvant chemotherapy does not seem to predict outcome in soft tissue sarcomas.Level of Evidence: Level IV, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.

A Rare Case of Periosteal Osteoblastoma Located in the Frontal Cranial Bone

Periosteal osteoblastoma is an extremely rare bone-forming neoplasm located on the surface of cortical bone. Of the fewer than 30 cases of periosteal osteoblastomas found in the literature, 2 have been reported to be located in cranial bone, and these have not been documented in detail with clinical history, radiographic findings, macroscopic features, and microscopic findings. Although the differential diagnoses of periosteal lesions include parosteal and periosteal osteosarcoma, periosteal chondroma and chondrosarcoma, osteochondroma, osteoid osteoma, periostitis ossificans, and myositis ossificans, an important differential diagnosis both radiologically and pathologically of such a lesion in the cranium is meningioma. We report an unusual case of periosteal osteoblastoma located in the frontal cranial bone that was radiologically consistent with a meningioma. The differential diagnosis of metaplastic meningioma with differentiation toward bone is discussed.

Immunohistochemical panel to differentiate endometrial stromal sarcoma, uterine leiomyosarcoma and leiomyoma: something old and something new

Aims To evaluate an immunohistochemical panel differentiating endometrial stromal sarcoma (ESS) from uterine leiomyosarcoma (ULMS) and leiomyoma (LM). Methods 94 cases (28 ESS, 41 ULMS, 25 LM) were retrieved and arrayed. 10 immunomarkers (estrogen receptor (ER), progesterone receptor (PR), CD10, smooth muscle actin, desmin, h-caldesmon, transgelin, GEM, ASC1, stathmin1) were used. A predictive model was constructed and examined by receiver operating characteristics curve analysis to determine area under the curve (AUC). Results The combination of ER+/PR+/CD10+/GEM−/h-caldesmon−/transgelin− can predict ESS versus ULMS with AUC predictive value of 0.872 (95% CI 0.784 to 0.961, p<0.0001). The combination of ER+/PR+/CD10+/h-caldesmon−/transgelin− can predict low grade (LG) ESS from ‘LG’ ULMS with AUC predictive value of 0.914 (95% CI 0.832 to 0.995, p<0.0001). Finally, ULMS and ESS, including the LGs, were more likely to be stathmin1+ than LM. Conclusions Due to the different clinical course and management, adding novel antibodies (GEM, transgelin) to the well established immunohistochemistry panel seemed to be useful in distinguishing ESS from ULMS and LG ESS from ‘LG’ ULMS. Finally, stathmin1 expression could be of value in differentiating LM from uterine sarcomas.

Lipoma arborescens of the biceps tendon sheath

Lipoma arborescens, described as lipomatous infiltration and distention of synovial villi resulting in a frond-like appearance, most frequently affects the suprapatellar recess of the knee. While there have been reports of this entity involving the upper extremity joints, bursa, and tendon sheaths, we present the first reported case of lipoma arborescens isolated to the biceps tendon sheath. We describe imaging and histologic findings with clinical correlation.