Francis J. Hornicek

Percutaneous radiofrequency coagulation of osteoid osteoma compared with operative treatment.

Osteoid osteoma, a benign bone tumor, has traditionally been treated with operative excision. A recently developed method for percutaneous ablation of the tumor has been proposed as an alternative to operative treatment. The relative outcomes of the two approaches to treatment have not previously been compared, to our knowledge. The rates of recurrence and of persistent symptoms were compared in a consecutive series of eighty-seven patients who were managed with operative excision and thirty-eight patients who were managed with percutaneous ablation with radiofrequency. Patients who had a spinal lesion were excluded. The minimum duration of follow-up was two years. There was a recurrence, defined as the need for subsequent intervention, after operative treatment in six (9 per cent) of sixty-eight patients who had been managed for a primary lesion and in two of nineteen who had been managed for a recurrent lesion. The average length of the hospital stay was 4.7 days for the patients who had a primary lesion and 5.1 days for those who had a recurrent lesion. There was a recurrence after percutaneous treatment in four (12 per cent) of thirty-three patients who had been managed for a primary lesion and in none of five who had been managed for a recurrent lesion. The average length of the hospital stay was 0.2 day for these thirty-eight patients. With the numbers available, we could detect no significant difference between the two treatments with regard to the rate of recurrence. The rate of persistent symptoms (that is, symptoms that did not necessitate additional treatment) was greater than the rate of recurrence. According to responses to a questionnaire, eight (30 per cent) of twenty-seven patients had persistent symptoms after operative treatment and six (23 per cent) of twenty-six patients had persistent symptoms after percutaneous treatment with radiofrequency. Two patients had complications after operative excision, necessitating a total of five additional operations. There were no complications associated with the percutaneous method. The results of the present study suggest that percutaneous ablation with radiofrequency is essentially equivalent to operative excision for the treatment of an osteoid osteoma in an extremity. The percutaneous method is preferred for the treatment of extraspinal osteoid osteoma because it generally does not necessitate hospitalization, it has not been associated with complications, and it is associated with a rapid convalescence.

Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors

The presence of growth-induced solid stresses in tumors has been suspected for some time, but these stresses were largely estimated using mathematical models. Solid stresses can deform the surrounding tissues and compress intratumoral lymphatic and blood vessels. Compression of lymphatic vessels elevates interstitial fluid pressure, whereas compression of blood vessels reduces blood flow. Reduced blood flow, in turn, leads to hypoxia, which promotes tumor progression, immunosuppression, inflammation, invasion, and metastasis and lowers the efficacy of chemo-, radio-, and immunotherapies. Thus, strategies designed to alleviate solid stress have the potential to improve cancer treatment. However, a lack of methods for measuring solid stress has hindered the development of solid stress-alleviating drugs. Here, we present a simple technique to estimate the growth-induced solid stress accumulated within animal and human tumors, and we show that this stress can be reduced by depleting cancer cells, fibroblasts, collagen, and/or hyaluronan, resulting in improved tumor perfusion. Furthermore, we show that therapeutic depletion of carcinoma-associated fibroblasts with an inhibitor of the sonic hedgehog pathway reduces solid stress, decompresses blood and lymphatic vessels, and increases perfusion. In addition to providing insights into the mechanopathology of tumors, our approach can serve as a rapid screen for stress-reducing and perfusion-enhancing drugs.

Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas

PURPOSE Treatment of extremity soft-tissue sarcomas yields excellent local control, but distant failure is common with large, high-grade tumors. A regimen of preoperative chemotherapy consisting of mesna, adriamycin, ifosfamide, and dacarbazine (MAID) interdigitated with radiotherapy followed by resection and postoperative chemotherapy with or without radiotherapy was designed to improve treatment outcome. We report the mature outcome data on 48 treated patients and compare them with the data of an historical matched control patient population. METHODS AND MATERIALS Adult patients with high-grade extremity soft-tissue sarcomas >or=8 cm were treated with three cycles of preoperative chemotherapy combined with 44 Gy of radiotherapy followed by surgery. Three cycles of postoperative MAID were planned. For patients with positive surgical margins, 16 Gy was delivered postoperatively. RESULTS All 48 patients (M0) received the MAID protocol treatment, and their outcome was superior to that of the historical control patients. The 5-year actuarial local control, freedom from distant metastasis, disease-free survival, and overall survival rate was 92% and 86% (p = 0.1155), 75% and 44% (p = 0.0016), 70% and 42% (p = 0.0002), and 87% and 58% (p = 0.0003) for the MAID and control patient groups, respectively. Acute hematologic toxicity in the MAID group included febrile neutropenia in 12 patients (25%). Wound healing complications occurred in 14 (29%) of 48 MAID patients. One MAID patient developed late fatal myelodysplasia. CONCLUSION After aggressive chemoradiation and surgery, these patients showed a significant reduction in distant metastases, with a highly significant gain in disease-free and overall survival compared with a historical control group. On the basis of this experience, the Radiation Therapy Oncology Group conducted a multi-institutional trial.

Factors affecting nonunion of the allograft-host junction.

Nonunion of allograft-host junction after bone transplantation is not uncommon, and its treatment frequently is problematic. To improve the understanding of these nonunions, a retrospective review was performed of 163 nonunions in 945 patients who underwent allograft transplantation (17.3%) for various benign and malignant tumors at the authors’ institution between 1974 and 1997. Of these 945 patients, 558 did not receive adjuvant therapy. Chemotherapy was administered to 354 patients and only 33 patients received radiation therapy alone. Seventy-one patients had radiation treatment and chemotherapy. Of the 163 patients who had nonunion develop at the allograft-host junction, there were 269 reoperations performed on the involved extremity. In 108 patients, treatment was successful resulting in union of the allograft-host junction. Forty-nine patients did not respond to multiple surgical treatment attempts. The greater the number of surgical procedures, the worse the outcome. The rate of nonunions increased to 27% for the patients who received chemotherapy as compared with 11% for the patients who did not receive chemotherapy. The order of allografts from highest rate of nonunion to lowest was as follows: alloarthrodesis, intercalary, osteoarticular, and alloprosthesis. Infection and fracture rates were higher in the patients with nonunions as compared with the patients without nonunions.

A spatially and temporally restricted mouse model of soft tissue sarcoma

Soft tissue sarcomas are mesenchymal tumors that are fatal in approximately one-third of patients. To explore mechanisms of sarcoma pathogenesis, we have generated a mouse model of soft tissue sarcoma. Intramuscular delivery of an adenovirus expressing Cre recombinase in mice with conditional mutations in Kras and Trp53 was sufficient to initiate high-grade sarcomas with myofibroblastic differentiation. Like human sarcomas, these tumors show a predilection for lung rather than lymph node metastasis. Using this model, we showed that a prototype handheld imaging device can identify residual tumor during intraoperative molecular imaging. Deletion of the Ink4a-Arf locus (Cdkn2a), but not Bak1 and Bax, could substitute for mutation of Trp53 in this model. Deletion of Bak1 and Bax, however, was able to substitute for mutation of Trp53 in the development of sinonasal adenocarcinoma. Therefore, the intrinsic pathway of apoptosis seems sufficient to mediate p53 tumor suppression in an epithelial cancer, but not in this model of soft tissue sarcoma.

Failure Mode Classification for Tumor Endoprostheses: Retrospective Review of Five Institutions and a Literature Review

BACKGROUND Massive endoprostheses provide orthopaedic oncologists with many reconstructive options after tumor resection, although failure rates are high. Because the number of these procedures is limited, failure of these devices has not been studied or classified adequately. This investigation is a multicenter review of the use of segmental endoprostheses with a focus on the modes, frequency, and timing of failure. METHODS Retrospective reviews of the operative databases of five institutions identified 2174 skeletally mature patients who received a large endoprosthesis for tumor resection. Patients who had failure of the endoprosthesis were identified, and the etiology and timing of failure were noted. Similar failures were tabulated and classified on the basis of the risk of amputation and urgency of treatment. Statistical analysis was performed to identify dependent relationships among mode of failure, anatomic location, and failure timing. A literature review was performed, and similar analyses were done for these data. RESULTS Five hundred and thirty-four failures were identified. Five modes of failure were identified and classified: soft-tissue failures (Type 1), aseptic loosening (Type 2), structural failures (Type 3), infection (Type 4), and tumor progression (Type 5). The most common mode of failure in this series was infection; in the literature, it was aseptic loosening. Statistical dependence was found between anatomic location and mode of failure and between mode of failure and time to failure. Significant differences were found in the incidence of failure mode Types 1, 2, 3, and 4 when polyaxial and uniaxial joints were compared. Significant dependence was also found between failure mode and anatomic location in the literature data. CONCLUSIONS There are five primary modes of endoprosthetic failure, and their relative incidences are significantly different and dependent on anatomic location. Mode of failure and time to failure also show a significant dependence. Because of these relationships, cumulative reporting of segmental failures should be avoided because anatomy-specific trends will be missed. Endoprosthetic design improvements should address failure modes specific to the anatomic location.

Treatment and Outcome of 82 Patients with Angiosarcoma

BackgroundAngiosarcomas are an uncommon type of malignancy that are generally thought to behave usually in a locally aggressive fashion; they often metastasize to distant sites.MethodsPatients with a diagnosis of angiosarcoma treated at our institution between 1980 and 2006 were analyzed for patient demographics, tumor characteristics, multimodality treatment, and outcomes.ResultsA total of 82 patients were divided into those with primary and advanced disease. Overall, the median age was 65 (range, 22–91) years, and 44% of patients were women. Median size of tumors was 3.8 cm, and 76% of tumors were intermediate or high grade. Tumors were located throughout the body: 32 cutaneous, 22 deep soft tissues or organs, 10 radiation or lymphedema field, 8 bone, and 7 nonirradiated breast. Of 46 patients with primary disease, all patients underwent surgical resection, 67% received radiotherapy, and 27% received chemotherapy. Five-year disease-specific survival was 60%, and negative prognostic factors included intermediate or high grade, and tumors arising in a radiated or lymphedema field. Of 36 patients with advanced disease, 36% underwent a palliative operation, 78% received radiation, and 58% received chemotherapy. Median survival was just 7.3 months, and cutaneous tumors predicted a better prognosis compared with other sites.ConclusionsPrimary angiosarcomas treated with aggressive surgical resection and the addition of radiation for close margins or worrisome pathologic features can result in long-term survival in most patients. The role of adjuvant chemotherapy is unclear. Patients with advanced disease have a poor prognosis, but there can be dramatic responses to chemotherapy in a minority of patients.

Accuracy of CT-guided biopsies in 359 patients with musculoskeletal lesions.

Abstract. The study was undertaken to assess the diagnostic accuracy and clinical usefulness of computed tomography (CT)-guided biopsies and fine needle aspirates of musculoskeletal lesions. The analysis compared the accuracy according to anatomical location, size, type of lesion, and histology. On the basis of the information obtained by reviewing the report of the CT biopsy and comparing it with the final diagnosis for 359 cases, the overall accuracy was determined to be 71%. The accuracy for 101 fine needle aspirations was 63% and for 258 CT-guided core biopsies was 74%. It is of note that the biopsies of 81 pelvic lesions had higher rates of diagnostic accuracy (81%) than those of 278 non-pelvic sites (68%), and especially 94 lesions of the spine (61%). The lowest success rates occurred in 26 patients with infectious diseases (50%). We conclude that these procedures remain the logical and safe choice for diagnostic studies of patients with lesions of the musculoskeletal system.

Phase II Study of High-Dose Photon/Proton Radiotherapy in the Management of Spine Sarcomas

PURPOSE Radiotherapy (XRT) for spine sarcomas is constrained by spinal cord, nerve, and viscera tolerance. Negative surgical margins are uncommon; hence, doses of >or=66 Gy are recommended. A Phase II clinical trial evaluated high-dose photon/proton XRT for spine sarcomas. METHODS AND MATERIALS Eligible patients had nonmetastatic, thoracic, lumbar, and/or sacral spine/paraspinal sarcomas. Treatment included pre- and/or postoperative photon/proton XRT with or without radical resection; patients with osteosarcoma and Ewings sarcoma received chemotherapy. Shrinking fields delivered 50.4 cobalt Gray equivalent (Gy RBE) to subclinical disease, 70.2 Gy RBE to microscopic disease in the tumor bed, and 77.4 Gy RBE to gross disease at 1.8 Gy RBE qd. Doses were reduced for radiosensitive histologies, concurrent chemoradiation, or when diabetes or autoimmune disease present. Spinal cord dose was limited to 63/54 Gy RBE to surface/center. Intraoperative boost doses of 7.5 to 10 Gy could be given by dural plaque. RESULTS A total of 50 patients (29 chordoma, 14 chondrosarcoma, 7 other) underwent gross total (n = 25) or subtotal (n = 12) resection or biopsy (n = 13). With 48 month median follow-up, 5-year actuarial local control, recurrence-free survival, and overall survival are: 78%, 63%, and 87% respectively. Two of 36 (5.6%) patients treated for primary versus 7/14 (50%) for recurrent tumor developed local recurrence (p < 0.001). Five patients developed late radiation-associated complications; no myelopathy developed but three sacral neuropathies appeared after 77.12 to 77.4 Gy RBE. CONCLUSIONS Local control with this treatment is high in patients radiated at the time of primary presentation. Spinal cord dose constraints appear to be safe. Sacral nerves receiving 77.12-77.4 Gy RBE are at risk for late toxicity.

MicroRNA-199a-3p Is Downregulated in Human Osteosarcoma and Regulates Cell Proliferation and Migration

microRNAs (miRNA, miR) play an important role in cancer cell growth and migration; however, the potential roles of miRNAs in osteosarcoma remain largely uncharacterized. By applying a miRNA microarray platform and unsupervised hierarchical clustering analysis, we found that several miRNAs have altered expression levels in osteosarcoma cell lines and tumor tissues when compared with normal human osteoblasts. Three miRNAs, miR-199a-3p, miR-127-3p, and miR-376c, were significantly decreased in osteosarcoma cell lines, whereas miR-151-3p and miR-191 were increased in osteosarcoma cell lines in comparison with osteoblasts. Transfection of precursor miR-199a-3p into osteosarcoma cell lines significantly decreased cell growth and migration, thus indicating that the inhibition effect is associated with an increase in the G1-phase and a decrease of the S-phase cell population. In addition, we observed decreased mTOR and Stat3 expression in miR-199a-3p transfected cells. This study provides new insights for miRNAs in osteosarcoma and suggests that miR-199a-3p may play a functional role in osteosarcoma cell growth and proliferation. Restoring miR-199a-3ps function may provide therapeutic benefits in osteosarcoma. Mol Cancer Ther; 10(8); 1337–45. ©2011 AACR.