Chemotherapy influences the pseudocapsule composition in soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas are a heterogeneous group of malignant tumors. Standard treatment for soft tissue sarcoma of the extremity is surgical excision and adjuvant therapy; however, the role of neoadjuvant chemotherapy is controversial. QUESTIONS/PURPOSES: We sought to (1) define the histologic characteristics of the pseudocapsule in soft tissue sarcomas; (2) compare the appearance of this structure in chemotherapy-treated versus untreated soft tissue sarcomas; and (3) evaluate the effect of chemotherapy on the presence and viability of tumor cells at the host-sarcoma interface. METHODS: Twenty-eight patients with biopsy-proven, deep, high-grade extremity soft tissue sarcomas greater than 5 cm (AJCC stage III) treated with chemotherapy and surgical excision were compared histologically with 47 matched control subjects treated with surgery alone. RESULTS: A pseudocapsule was identifiable in the majority of tumors and consisted of two identifiable layers, each with specific histological characteristics suggesting the biologic processes occurring in these layers are different. The pseudocapsule was more frequently observed in the group treated with chemotherapy and it was more frequently continuous, thicker, and better developed in this group. Chemotherapy decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CONCLUSIONS: Neoadjuvant chemotherapy contributed to the development of a pseudocapsule and decreased the number of tumors with malignant cells identified within and beyond the pseudocapsule. CLINICAL RELEVANCE: These findings may provide a histological explanation for the clinical effect of chemotherapy in soft tissue sarcoma. LEVEL OF EVIDENCE: Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Multifocal Desmoid-Type Fibromatosis: Case Series and Potential Relationship to Neuronal Spread.

Multifocal desmoid-type fibromatosis (DTF) is very rare and usually regional. We report three cases that initially appeared to be multifocal, but subsequent detailed imaging revealed unsuspected tracking along nerves in two cases. This neural spread is reminiscent of neuromuscular choristoma (NMC), a rare developmental lesion in which mature skeletal muscle cells, or rarely smooth muscle cells, infiltrate and enlarge peripheral nerves. NMC is frequently associated with DTF. These two cases suggest that DTF spread along nerves and appeared as distinct multifocal lesions while actually being contiguous. The third case was felt to represent true multifocal tumor development, possibly due to tumor seeding at the time of chest surgery. The relationship of DTF to NMC is discussed.

Pilot study of vascular health in survivors of osteosarcoma.

BACKGROUND: Cardiovascular-related toxicities have been reported among survivors of osteosarcoma. METHODS: Fasting blood samples from 24 osteosarcoma survivors were analyzed for high-sensitivity C-reactive protein (hsCRP), triglycerides, total cholesterol, high-density lipoprotein (HDL), apolipoprotein-ß, lipoprotein (a), fibrinogen, circulating endothelial cells (CECs), and surface expression of vascular cell adhesion molecule-1 (VCAM-1). Values were compared to subjects in the natural history Coronary Artery Risk Development in Young Adults (CARDIA) cohort study except for CECs and VCAM-1 expression, which were compared to controls studied at the University of Minnesota Lillehei clinical trials unit. PROCEDURE: Survivors (54.2% male), median age 18 years (9-32) at diagnosis, 36.5 years (20-56) at evaluation were treated with a variety of chemotherapeutic exposures, all but one were exposed to doxorubicin (median dose 450 mg/m(2) ; range: 90-645 mg/m(2)), 14 (58.3%) received cisplatin, and 3 (12.5%) were exposed to carboplatin. Two survivors (8.3%) received radiation therapy for disease relapse. Compared to CARDIA subjects, mean hsCRP (3.0 mg/L ± 2.0 vs. 1.6 ± 2.3), triglycerides (151 mg/dl ± 81.7 vs. 95.4 ± 101.3), lipoprotein (a) (34.9 mg/dl ± 17.7 vs. 13.8 ± 22.0), and fibrinogen (315.0 mg/dl ± 49.3 vs. 252.4 ± 61.7) were significantly elevated. The number of CECs (0.47 cells/ml ± 2.5 vs. 0.92 ± 2.5) did not differ while surface expression of VCAM-1 (86.4% ± 34.0 vs. 42.1 ± 33.8) was significantly elevated compared to controls. CONCLUSIONS: Among survivors of osteosarcoma, assessed a median of 14 years from diagnosis, there is evidence of vascular inflammation, dyslipidemia, and early atherogenesis.

Molecular mechanisms of cancer pain.

Pain is the most disruptive influence on the quality of life of cancer patients. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of cancer pain is poorly understood. New insights into these mechanisms are now arising from animal models, and have the potential to fundamentally change the way that cancer pain is controlled.

Multiple malignant tumors in a patient with familial chordoma, a case report.

BACKGROUND: Chordoma is a rare bone tumor that is typically resistant to chemotherapy and is associated with genetic abnormalities of the T-box transcription factor T (TBXT) gene, which encodes the transcription factor brachyury. Brachyury is felt to be a major contributor to the development of chordomas. CASE PRESENTATION: We describe a 67-year-old woman who developed an undifferentiated pleomorphic sarcoma in her thigh. Despite treatment with standard chemotherapy regimens, she had a rapidly progressive course of disease with pulmonary metastases and passed away 8 months from diagnosis with pulmonary complications. Her medical history was remarkable in that she had a spheno-occipital chordoma at age 39 and later developed multiple other tumors throughout her life including Hodgkin lymphoma and squamous cell carcinoma and basal cell carcinoma of the skin. She had a family history of chordoma and her family underwent extensive genetic study in the past and were found to have a duplication of the TBXT gene. CONCLUSIONS: Brachyury has been found to associate with tumor progression, treatment resistance, and metastasis in various epithelial cancers, and it might play roles in tumorigenesis and aggressiveness in this patient with multiple rare tumors and germ line duplication of the TBXT gene. Targeting this molecule may be useful for some malignancies.

A suspicious vulvar mass diagnosed as a subpubic cartilaginous cyst.

BACKGROUND: Subpubic cartilaginous cysts were initially described in 1996 with few reports to date. CASE: We describe a 62-year-old woman with a history of breast cancer who presented with a painful, fixed, vulvar mass. MRI revealed an 18 x 10 x 12 mm3 mass extending from the anterior portion of the symphysis pubis without bony involvement. Excision was performed. Histologically, the mass consisted of fibrocartilage with extensive degenerative changes, compatible with a subpubic cartilaginous cyst. Over 24 months later, there has been no recurrence. CONCLUSION: Subpubic cartilaginous cyst is a rare, benign lesion occurring on the vulva and should be considered in the differential diagnosis of a painful, superior vulvar mass.

Local irradiation in combination with bevacizumab enhances radiation control of bone destruction and cancer-induced pain in a model of bone metastases.

Skeletal metastases are a major source of morbidity for cancer patients. The purpose of this study was to evaluate the effects of megavoltage irradiation and antiangiogenic therapy on metastatic bone cancer. A tumor xenograft model was prepared in C3H/Scid mice using 4T1 murine breast carcinoma cells. Twenty-eight mice bearing tumors were treated with either bevacizumab (15 mg/kg), local megavoltage irradiation (30 Gy in 1 fraction), combination of bevacizumab and local megavoltage irradiation or physiologic saline solution (control group). Tumor area, bone destruction, tumor microvessel density, pain-associated behaviors and expression of substance P were assessed. Combined modality treatment reduced the frequency of pain-associated behaviors, decreased levels of nociceptive protein expression in the spinal cord, maintained cortical integrity and decreased the density of microvessels as compared to single modality treatments. We conclude that concurrent antiangiogenic therapy and localized radiotherapy for the treatment of bone metastases warrants further evaluation in human clinical trials.

Osteoclasts direct bystander killing of bone cancer.

Primary and metastatic bone cancers are difficult to eradicate and novel approaches are needed to improve treatment and extend life. As bone cancer grows, osteoclasts, the principal bone-resorbing cells of the body, are recruited to and activated at sites of cancer. In this investigation, we determined if osteoclast lineage cells could function as a cell-based gene delivery system to bone cancers. We used the cytosine deaminase (CD) 5-fluorocytosine (5-FC) enzyme/prodrug system and studied bone marrow and bones from transgenic mice expressing a novel CD gene regulated by the osteoclast tartrate-resistant acid phosphatase (TRAP) gene promoter (Tg/NCD). DsRed2-labeled 2472 sarcoma cells were placed in Tg/NCD osteoclastogenic cultures and treated with 5-FC. 5-FC treatment resulted in profound bystander killing (90%; P < 0.05). The effect of 5-FC treatment on osteoclast lineage cells was most dramatic when administered at the beginning of the 7-day cultures, suggesting that mature osteoclasts are less sensitive to 5-FC. Evaluation of osteoclast-directed bystander killing in vivo revealed dramatic killing of bone cancer with only a modest effect on osteoclast number. Specifically, 5-FC treatment of tumor-bearing Tg/NCD mice or Tg/NCD bone marrow transplanted C3H mice (Tg/NCD-C3H) resulted in 92% and 44% reductions in tumor area, respectively (P < 0.05). Eight of ten 5-FC-treated Tg/NCD mice had complete bone tumor killing and five of six 5-FC-treated Tg/NCD-C3H mice had reduced tumor compared with controls. In addition, Tg/NCD osteoclasts were resistant to 5-FC treatment in vivo, a very important feature, as it identifies osteoclasts as an ideal CD gene delivery system.

Biology of bone cancer pain.

Bone cancer pain is a devastating manifestation of metastatic cancer. Unfortunately, current therapies can be ineffective, and when they are effective, the duration of the patient's survival typically exceeds the duration of pain relief. New, mechanistically based therapies are desperately needed. Study of experimental animal models has provided insight into the mechanisms that drive bone cancer pain and provides an opportunity for developing targeted therapies. Mechanisms that drive bone cancer pain include tumor-directed osteoclast-mediated osteolysis, tumor cells themselves, tumor-induced nerve injury, stimulation of transient receptor potential vanilloid type 1 ion channel, endothelin A, and host cell production of nerve growth factor. Current and future therapies include external beam radiation, osteoclast-targeted inhibiting agents, anti-inflammatory drugs, transient receptor potential vanilloid type 1 antagonists, and antibody therapies that target nerve growth factor or tumor angiogenesis. It is likely that a combination of these therapies will be superior to any one therapy alone.

Novel cytosine deaminase fusion gene enhances the effect of radiation on breast cancer in bone by reducing tumor burden, osteolysis, and skeletal fracture.

BACKGROUND: Painful breast carcinoma metastases in bone are a common manifestation of malignant disease. Eradication of these tumors can be evasive, and as a result, skeletal morbidity increases with disease progression. EXPERIMENTAL DESIGN: The treatment potential of cytosine deaminase (CD) gene therapy combined with radiation treatment was evaluated in vitro and in vivo using a 4T1 murine breast carcinoma model. 4T1 carcinoma cells were transduced with a fusion gene encoding the extracellular and transmembrane domains of the human nerve growth factor receptor and the cytoplasmic portion of the yeast CD gene (NGFR-CD(y)). RESULTS AND CONCLUSIONS: CD-expressing tumor cells (4TCD(y)) were highly sensitive to treatment by 5-fluorocytosine prodrug (P < 0.0001). 5-Fluorocytosine treatment of 4TCD(y), but not 4T1 cells, enhanced the effects of radiation in vitro (P < 0.0001). 5-Fluorocytosine prodrug treatment also increased the therapeutic potential of radiation in vivo. Mice with 4TCD(y) intrafemoral tumors showed increased effectiveness of radiation based on improved reductions in tumor size, reductions in tumorigenic osteolysis, and a decrease in skeletal fractures (P < 0.01).

Advances in treating metastatic bone cancer: summary statement for the First Cambridge Conference.

The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Leadership, Communication, and Negotiation Across a Diverse Workforce*: An AOA Critical Issues Symposium.

The current workforce in the United States is rapidly changing and is increasingly inclusive of individuals from a broad range of ages, ethnicities, and cultural backgrounds. Engaging and leading a diverse workforce creates great opportunities for innovation and adaptation in our evolving medical economic and clinical care delivery environment. For optimal engagement of employees and partners, orthopaedic surgeons must develop the necessary skills for executing change inside complex organizations and across teams composed of a variety of providers and skilled workers. Important skills include leadership, effective communication, and negotiation within an ever-changing employee milieu. Understanding generalizable differences between age-based generations can increase the effectiveness of one's strategies to execute change and increase organizational performance. One of the greatest impediments to effective communication and negotiations that all leaders face is unconscious bias. For leaders, even the tiniest unconscious biases have an outsized impact. Common domains that harbor unconscious bias include sex, race, and ethnicity. Addressing unconscious bias begins with developing awareness and then deploying various tactics that might include equity in compensation, promotion, and "being heard." Effective negotiation skills also are essential to lead a diverse workforce and develop a successful organization. The most basic goal in any negotiation should be to establish a relationship (or deepen an existing relationship) while seeking an agreement that provides win-win opportunities for all parties. To effectively achieve a win-win scenario, leaders must recognize and address their tendency to interpret others' behaviors, values, and beliefs through the lens of their own beliefs and experiences. Finally, and fortunately, there is a set of leader attributes that transcends the generational differences and diversity that is encountered in the workplace. These attributes include integrity, credibility, effective listening, having a vision of your destination, fairness, humility, and caring.

Osteoclasts direct bystander killing of cancer cells in vitro.

Cytosine deaminase (CD) catalyzes the deamination of 5-fluorocytosine (5FC) to produce the highly toxic chemotherapeutic agent 5-fluorouracil (5FU). A unique feature of the CD/5FC enzyme/prodrug system is its ability to kill adjacent cells via bystander killing. Bystander killing of cancer cells can be mediated by non-cancerous accessory cells transduced with the CD gene; one type of non-cancerous accessory cell found in primary bone cancer and breast cancer metastases to bone is the osteoclast. This manuscript determines if osteoclast precursor cells, transduced with the CD gene, can function as a gene delivery system capable of killing cancer cells. An osteoclast precursor cell line (RAW 264.7, RAW) and authentic bone marrow-derived osteoclast precursor cells were transduced with a retroviral vector containing the cytosine deaminase fusion gene (NCD) composed of the human nerve growth factor receptor and CD genes. RAW cells and bone marrow-derived osteoclast precursor cells transduced with NCD expressed NCD protein and converted 5FC to 5FU. Treatment of NCD-transduced osteoclast precursor cells with the 5FC prodrug resulted in significant killing in vitro. NCD-transduced osteoclasts were co-cultured with either DsRed2-labeled sarcoma cells (2472-DSR) or green fluorescent protein (GFP)-labeled breast cancer cells (GFP-4T1). Treatment of the NCD osteoclast/tumor cell co-cultures with 5FC resulted in bystander killing of 2472-DSR cells (P < 0.006) and GFP-4T1 cells (P < 0.004). These findings demonstrate that NCD-transduced osteoclasts can promote killing of cancer cells and introduce the exciting possibility for developing osteoclast-mediated, CD-based treatment of primary bone cancers and breast cancer metastases to bone.

Direct and bystander killing of sarcomas by novel cytosine deaminase fusion gene.

Soft tissue and bone sarcomas of the extremities can be difficult to eradicate, and standard treatment may require limb amputation. New therapies to decrease tumor size could improve the effectiveness of treatment and decrease the frequency of limb amputation. Cytosine deaminase (CD)-based gene therapy has been shown to be effective in decreasing growth of solid tumors when animals with CD-expressing tumor cells are treated with 5 fluorocytosine (5FC), an inert prodrug that is converted to 5-fluorouracil (5FU) by CD. In this investigation, we used a novel CD-containing fusion gene to determine whether CD-based gene therapy affected soft tissue or bone sarcomas. The novel fusion gene (NGFR-CD) encodes for a protein with extracellular and transmembrane domains of human nerve growth factor receptor (NGFR) and cytoplasmic CD. Murine 2472 (2) sarcoma cells were transduced with fusion genes containing either the bacterial (NGFR-(b)CD) or yeast (NGFR-(y)CD) CD gene. 5FC treatment killed NGFR-(b)CD- and NGFR-(y)CD-transduced sarcoma cells in vitro through direct and bystander effects (P < 0.01). In contrast, 5FC treatment of mice with s.c. 2NGFR-(b)CD or 2NGFR-(y)CD tumors affected only 2NGFR-(y)CD tumors. 5FC had no effect on growth of NGFR-(b)CD tumors but caused significant decrease in the size of 2NGFR-(y)CD tumors (51 +/- 60 versus 938 +/- 767 mm(3), treated versus control, P < 0.01). Evaluation of bystander killing in vivo revealed significant tumor killing, with a 5-fold reduction in s.c. tumor volume evident in saline versus 5FC-treated mice when tumors were comprised of 90% 2472 cells and 10% 2NGFR-(y)CD selected for fluorescence-activated cell sorting (P < 0.01). Bone sarcomas were eliminated in 9 of 10 5FC-treated mice, compared with 11.8 +/- 6.0 mm(2) in saline-treated mice (P < 0.002). In addition, 5FC treatment of bone sarcomas caused a significant reduction in cancer-induced bone destruction (P < 0.002) and resulted in a reduction in the number of osteoclasts. Finally, 5FC treatment had no effect on animal weight or survival, whereas doses of 5FU providing equivalent tumor reduction as 5FC resulted in treatment-associated deaths and significant weight loss (P < 0.001).

Management of Unplanned Excision for Soft-Tissue Sarcoma With Preoperative Radiotherapy Followed by Definitive Resection.

BACKGROUND AND OBJECTIVES: The purpose of this study was to review the outcomes after preoperative radiotherapy and definitive surgery for patients who initially had inadvertent excision for sarcoma. MATERIALS AND METHODS: Treatment records of 44 consecutive patients, who initially underwent unplanned excision of soft-tissue sarcoma between January 2004 and January 2012, were reviewed. All patients had clinically localized disease before treatment and received preoperative external-beam radiotherapy followed by definitive oncologic surgery at our institution. RESULTS: The median follow-up was 36 months. Residual tumor after preoperative radiotherapy and wound bed excision was identified in 39% (17/44) of the cases. Kaplan-Meier estimates for 5-year local control, recurrence-free survival, and overall survival are 95% (95% confidence interval [CI], 80-99), 86% (95% CI, 69-94), and 94% (95% CI, 79-99) respectively. Perioperative morbidity occurred in 25% of patients (11/44.) All patients with perioperative wound complications had lower extremity sarcomas. CONCLUSIONS: Optimal management for unplanned excision of soft-tissue sarcoma is unknown. Our institution has adopted the approach of preoperative radiotherapy, followed by definitive surgery. In our series of 44 patients, local control was excellent at 95%, with perioperative complications seen only in patients with lower extremity sarcomas, suggesting that this is a reasonable approach to manage inadvertently resected sarcoma.

Limb salvage and amputation in survivors of pediatric lower-extremity bone tumors: what are the long-term implications?

The past four decades have seen tremendous progress in the treatment of pediatric and adolescent cancers. As a consequence, there are increasing numbers of adult childhood cancer survivors. This has prompted investigation into the long-term consequences of cancer treatments. One group that merits special study is the survivors of lower-extremity bone tumors. Their function and quality of life may depend in part on both the surgery and the age at which it was performed. Comparisons between studies are difficult because small numbers of patients and the use of varying research designs and methods have limited research in this area. The purpose of this article is to review the major surgical approaches to lower-limb bone tumors and their impact on pediatric patients. The results show that survival is equivalent between amputation and limb salvage. Complications occur more frequently in limb salvage. The long-term outcomes of those undergoing amputation and limb salvage have not been found to be substantially different in regard to quality of life. In conclusion, prospective long-term follow-up of pediatric patients with lower-limb tumors is needed to (1) determine in a uniform manner the long-term complications, quality of life, and functionality of this population and describe differences within this patient population based on age at diagnosis and surgical procedure, (2) identify areas of concern that are amenable to intervention, and (3) provide clinicians and future patients a better understanding of the surgical options.

Radiation treatment decreases bone cancer pain through direct effect on tumor cells.

The most used treatment for bone cancer pain is radiation; however, the mechanism responsible for analgesia after irradiation is unknown. The mechanistic influence of a single, localized 10-, 20- or 30-Gy dose of radiation on painful behaviors, osteolysis, histopathology and osteoclast number was evaluated in mice with painful femoral sarcomas. Dramatic reductions in pain behaviors (P < 0.05) and osteolysis (P < 0.0001) were seen in mice irradiated with 20 and 30 Gy. Irradiation reduced the tumor area by more than 75% (P < 0.05) but did not affect osteoclast frequency per mm2 tumor. Treatment with 20 Gy prior to tumor injection had no effect on tumor growth or pain behaviors, suggesting that radiation reduces osteolysis and pain through direct tumor effects. To demonstrate that tumor elimination was responsible for reduction in osteolysis and pain, sarcoma cells containing the suicide gene cytosine deaminase (CD) were inoculated into femora. After onset of bone cancer pain, mice were treated with the prodrug 5-fluorocytosine (5-FC). 5-FC treatment significantly reduced both osteolysis (P < 0.0005) and bone cancer pain (P < 0.05). The findings in this study demonstrate that one mechanism through which radiation decreases bone cancer pain is by direct effects on tumor cells.

Efficacy of systemic morphine suggests a fundamental difference in the mechanisms that generate bone cancer vs inflammatory pain.

Pain is the cancer related event that is most disruptive to the cancer patient's quality of life. Although bone cancer pain is one of the most severe and common of the chronic pains that accompany breast, prostate and lung cancers, relatively little is known about the mechanisms that generate and maintain this pain. Recently, we developed a mouse model of bone cancer pain and 16 days following tumor implantation into the intramedullary space of the femur, significant bone destruction and bone cancer pain-related behaviors were observed. A critical question is how closely this model mirrors human bone cancer pain. In the present study we show that, as in humans, pain-related behaviors are diminished by systemic morphine administration in a dose dependent fashion that is naloxone-reversible. Humans suffering from bone cancer pain generally require significantly higher doses of morphine as compared to individuals with inflammatory pain and in the mouse model, the doses of morphine required to block bone cancer pain-related behaviors were ten times that required to block peak inflammatory pain behaviors of comparable magnitude induced by hindpaw injection of complete Freund's adjuvant (CFA) (1-3mg/kg). As these animals were treated acutely, there was not time for morphine tolerance to develop and the rightward shift in analgesic efficacy observed in bone cancer pain vs. inflammatory pain suggests a fundamental difference in the underlying mechanisms that generate bone cancer vs. inflammatory pain. These results indicate that this model may be useful in defining drug therapies that are targeted for complex bone cancer pain syndromes.

Lentivirus transduction of human osteoclast precursor cells and differentiation into functional osteoclasts.

Gene transfer into stem cells has been an ongoing priority as a treatment for genetic disease and cancer for more than two decades. Methods described herein, form the basis for providing the cell source to determine if osteoclast precursor cells (OcP) can be used as therapeutic gene delivery systems in vivo. Osteoclasts and tumor associated macrophages or OcP, support survival, tumor progression and osteolysis in bone cancers. Two sources of precursor cells are compared: CD14+ cells, the standard OcP, found abundantly in peripheral blood and CD34+ cells, hematopoietic stem cells that are rare, but which can be expanded into OcP. Our findings characterize cell yield at each step of the transduction process and thus provide essential data for planning future in vivo experiments. In addition we demonstrate that essential functions of OcP are preserved following lentiviral transduction. Specifically, neither the transduction method nor the lentiviral transduction influence the OcP's ability to form osteoclasts, express the marker gene, EGFP, or resorb bone. Finally, we conclude that CD34+ cells yield significantly more transduced cells and form functionally superior osteoclasts in vitro. This study represents a step towards considering human gene therapy for bone cancer by demonstrating successful transduction of human OcP for use as cellular delivery vehicles to sites of bone cancer.

Response of imatinib-resistant extra-abdominal aggressive fibromatosis to sunitinib: case report and review of the literature on response to tyrosine kinase inhibitors.

PURPOSE: Aggressive fibromatosis (AF) is usually a slowly growing locally invasive tumor, but may exhibit a much more aggressive phenotype. The role of chemotherapy in AF is not well defined, but can be useful in some cases. We examined the response of a case to both imatinib and sunitinib. METHODS: We report a case of an aggressive multicentric extra-abdominal AF that was responsive to sunitinib, but resistant to imatinib. RESULTS: A 23-year-old woman developed painful multifocal AF of both legs and gluteal muscles that progressed after surgery and treatment with methotrexate/vinblastine and pegylated-liposomal doxorubicin. She received six cycles of ifosfamide/etoposide (IMV), and obtained a good response with elimination of pain. After 5 months, she developed progression and again received six cycles of IMV, with cessation of symptoms. After 13 months, tumors recurred. Although the AF was symptomatic and progressing, she was hesitant to receive chemotherapy and began treatment with sunitinib 50 mg/day for 28 days of a 42-day cycle. At 4 months, she could walk on her heels without pain. After 13 months of sunitinib, therapy was changed to imatinib 400 mg/day; after 7 days she noticed increasing pain in the AF lesions and decreased knee flexibility. Imatinib was continued, but after 2 months of imatinib, she could only walk a few steps due to pain. Sunitinib was reinstituted at 37.5 mg/day and symptoms improved within 1.5 weeks, with a marked reduction of symptoms at 1 month. She was doing well with a normal activity level, 32 months after initially beginning sunitinib. CONCLUSIONS: We conclude that sunitinib may be useful in some cases of AF.