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Tenosynovial giant cell tumor (TGCT) is a neoplasm of the joint synovium that can have severe impacts on joint mobility, function, and quality of life. Traditionally, treatment modalities included partial or complete surgical synovectomy, radiotherapy (typically as an adjunct to surgery), and watchful monitoring (no medical or surgical intervention). However, these approaches have been met with varying degrees of success and high recurrence rates, as well as onerous complications and clinical sequelae. Pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, presents a promising molecular approach that targets a neoplastic driver of TGCT. While the introduction of pexidartinib allows clinicians to avoid the significant morbidity associated with traditional treatment options, there are also defined risks associated with pexidartinib treatment. Therefore, patient selection is critical in optimizing treatment modalities in TGCT. The purpose of this literature review is to identify the TGCT patient population that would derive maximal benefit with minimal risk from pexidartinib, and to determine the specific indications and contraindications for selecting pexidartinib over other therapeutic approaches. Specifically, this paper compares the efficacy and safety profile of pexidartinib across clinical and preclinical studies to that of surgery, radiotherapy, and watchful monitoring. Rates of improvement in joint mobility, pain, and recurrence-free survival across studies of pexidartinib have been encouraging. The most common adverse events are mild (hypopigmentation of the hair) or reversible (transient aminotransferase elevation). Severe or permanent adverse events (notably cholestatic hepatotoxicity) are rare. While the optimal treatment strategy remains highly dependent on a patient’s clinical circumstances and treatment goals, pexidartinib has surfaced as a promising therapeutic in cases where the morbidity of surgery or radiotherapy outweighs the benefits.

Supplemental material, sj-pdf-6-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-7-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-6-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-3-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-1-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-5-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-5-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-2-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-3-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-1-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-7-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-2-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-4-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

Supplemental material, sj-pdf-4-hpi-10.1177_11207000221130270 for Operative management of metastatic disease of the acetabulum: review of the literature and prevailing concepts by Alexander B Christ, Meredith K Bartelstein, Shachar Kenan, Koichi Ogura, Tomohiro Fujiwara, John H Healey and Nicola Fabbri in HIP International

BackgroundThe objective of this study was to report on the long-term effects of pexidartinib on tenosynovial giant cell tumor (TGCT).MethodsThis was a pooled analysis encompassing 3 pexidartinib-treated TGCT cohorts: 1) a phase 1 extension study (NCT01004861; 1000 mg/d; n = 39), 2) ENLIVEN patients randomized to pexidartinib (1000 mg/d for 2 weeks and then 800 mg/d; n = 61), and 3) ENLIVEN crossover patients (NCT02371369; 800 mg/d; n = 30). Eligible patients were 18 years old or older and had a histologically confirmed TGCT that was unresectable and symptomatic. Efficacy endpoints included the best overall response (complete or partial response) and the duration of response (DOR) by the Response Evaluation Criteria in Solid Tumors (RECIST) and the tumor volume score (TVS). The safety assessment included the frequency of treatment-emergent adverse events (TEAEs) and hepatic laboratory abnormalities (aminotransferase elevations and mixed/cholestatic hepatotoxicity). The data cutoff was May 31, 2019.ResultsOne hundred thirty patients with TGCT received pexidartinib (median treatment duration, 19 months; range, 1 to 76+ months); 54 (42%) remained on treatment at the end of the analysis (26 months after initial data cut of March 2017). The RECIST overall response rate (ORR) was 60%; the TVS ORR was 65%. The median times to response were 3.4 (RECIST) and 2.8 months (TVS), with 48 of the responding patients (62%) achieving a RECIST partial response by 6 months and with 72 (92%) doing so by 18 months. The median DOR was reached for TVS (46.8 months). Reported TEAEs were mostly low-grade, with hair color changes being most frequent (75%). Most liver abnormalities (92%) were aminotransferase elevations; 4 patients (3%) experienced mixed/cholestatic hepatotoxicity (all within the first 2 months of treatment), which was reversible in all cases (recovery spanned 1-7 months).ConclusionsThis study demonstrates the prolonged efficacy and tolerability of long-term pexidartinib treatment for TGCT.

PurposeThe role of chemotherapy (CT) and radiotherapy (RT) for management of extraskeletal osteosarcoma (ESOS) remains controversial. We examined disease outcomes for ESOS patients and investigated the association between CT/RT with recurrence and survival.Patients and methodsRetrospective review at 25 international sarcoma centers identified patients ≥18 years old treated for ESOS from 1971 to 2016. Patient/tumour characteristics, treatment, local/systemic recurrence, and survival data were collected. Kaplan-Meier survival and Cox proportional-hazards regression and cumulative incidence competing risks analysis were performed.Results370 patients with localized ESOS treated definitively with surgery presented with mainly deep tumours (n=294, 80%). 122 patients underwent surgical resection alone, 96 (26%) also received CT, 70 (19%) RT and 82 (22%) both adjuvants. Five-year survival for patients with localized ESOS was 56% (95% CI 51%-62%). Almost half of patients (n=173, 47%) developed recurrence: local 9% (35/370), distant 28% (102/370) or both 10% (36/370). Considering death as a competing event, there was no significant difference in cumulative incidence of local or systemic recurrence between patients who received CT, RT, both or neither (local p=0.50, systemic p=0.69). Multiple regression Cox analysis showed a significant association between RT and decreased local recurrence (HR 0.46 [95% CI 0.26-0.80], p=0.01).ConclusionAlthough the use of RT significantly decreased local recurrences, CT did not decrease the risk of systemic recurrence, and neither CT, nor RT nor both were associated with improved survival in patients with localized ESOS. Our results do not support the use of CT; however, adjuvant RT demonstrates benefit in patients with locally resectable ESOS.

BACKGROUND:We reviewed the disease control and complications of the treatment of sacrococcygeal chordoma from four tertiary cancer centers with emphasis on the effects of radiotherapy in surgically treated patients. METHODS:A total of 193 patients with primary sacrococcygeal chordoma from 1990 to 2015 were reviewed. There were 124 males, with a mean age of 59 ± 15 years and a mean follow-up of 7 ± 4 years. Eighty-nine patients received radiotherapy with a mean total dose of 61.8 ± 10.9 Gy. RESULTS:The 10-year disease-free and disease-specific survival was 58% and 72%, respectively. Radiation was not associated with local recurrence (hazard ratio [HR], 1.13; 95% confidence interval [CI], 0.59-2.17; P = 0.71), metastases (HR, 0.93; 95% CI, 0.45-1.91; P = 0.85) or disease-specific survival (HR, 0.96; 95% CI, 0.46-2.00; P = 0.91). Higher doses (≥70 Gy; HR, 0.52; 95% CI, 0.20-1.32; P = 0.17) may be associated with reduced local recurrence. Radiotherapy was associated with wound complications (HR, 2.76; 95% CI, 1.64-4.82;, P

Polymeric nanocarriers such as N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers deliver drugs to solid tumors and avoid the systemic toxicity of conventional chemotherapy. Because HPMA copolymers can target sites of inflammation and accumulate within innate immune cells, we hypothesized that HPMA copolymers could target tumor-associated macrophages (TAM) in both primary and metastatic tumor microenvironments. We verified this hypothesis, first in preliminary experiments with isolated bone marrow macrophage cultures in vitro and subsequently in a spontaneously metastatic murine breast cancer model generated from a well-established, cytogenetically characterized 4T1 breast cancer cell line. Using our standardized experimental conditions, we detected primary orthotopic tumor growth at 7 days and metastatic tumors at 28 days after orthotopic transplantation of 4T1 cells into the mammary fat pad. We investigated the uptake of HPMA copolymer conjugated with Alexa Fluor 647 and folic acid (P-Alexa647-FA) and HPMA copolymer conjugated with IRDye 800CW (P-IRDye), following their retroorbital injection into the primary and metastatic tumor-bearing mice. A significant uptake of P-IRDye was observed at all primary and metastatic tumor sites in these mice, and the P-Alexa647-FA signal was found specifically within CD11b+ TAMs costained with pan-macrophage marker CD68. These findings demonstrate, for the first time, a novel capacity of a P-Alexa647-FA conjugate to colocalize to CD11b+CD68+ TAMs in both primary and metastatic breast tumors. This underscores the potential of this HPMA nanocarrier to deliver functional therapeutics that specifically target tumor-promoting macrophage activation and/or polarization during tumor development. Mol Cancer Ther; 16(12); 2701-10. ©2017 AACR.

BackgroundPatients with failed distal femoral megaprostheses often have bone loss that limits reconstructive options and contributes to the high failure rate of revision surgery. The Compress(®) Compliant Pre-stress (CPS) implant can reconstruct the femur even when there is little remaining bone. It differs from traditional stemmed prostheses because it requires only 4 to 8 cm of residual bone for fixation. Given the poor long-term results of stemmed revision constructs, we sought to determine the failure rate and functional outcomes of the CPS implant in revision surgery.Questions/purposes(1) What is the cumulative incidence of mechanical and other types of implant failure when used to revise failed distal femoral arthroplasties placed after oncologic resection? (2) What complications are characteristic of this prosthesis? (3) What function do patients achieve after receiving this prosthesis?MethodsWe retrospectively reviewed 27 patients who experienced failure of a distal femoral prosthesis and were revised to a CPS implant from April 2000 to February 2013. Indications for use included a minimum 2.5 mm cortical thickness of the remaining proximal femur, no prior radiation, life expectancy > 10 years, and compliance with protected weightbearing for 3 months. The cumulative incidence of failure was calculated for both mechanical (loss of compression between the implant anchor plug and spindle) and other failure modes using a competing risk analysis. Failure was defined as removal of the CPS implant. Followup was a minimum of 2 years or until implant removal. Median followup for patients with successful revision arthroplasty was 90 months (range, 24-181 months). Functional outcomes were measured with the Musculoskeletal Tumor Society (MSTS) functional assessment score.ResultsThe cumulative incidence of mechanical failure was 11% (95% confidence interval [CI], 4%-33%) at both 5 and 10 years. These failures occurred early at a median of 5 months. The cumulative incidence of other failures was 18% (95% CI, 7%-45%) at 5 and 10 years, all of which were deep infection. Three patients required secondary operations for cortical insufficiency proximal to the anchor plug in bone not spanned by the CPS implant and unrelated to the prosthesis. Median MSTS score was 27 (range, 24-30).ConclusionsRevision distal femoral replacement arthroplasty after a failed megaprosthesis is often difficult as a result of a lack of adequate bone. Reconstruction with the CPS implant has an 11% failure rate at 10 years. Our results are promising and demonstrate the durable fixation provided by the CPS implant. Further studies to compare the CPS prosthesis and other reconstruction options with respect to survival and functional outcomes are warranted.Level of evidenceLevel IV, therapeutic study.

Single ray amputation after hand trauma or infection can result in good aesthetic and functional outcomes. The role of this procedure in the management of aggressive benign or malignant hand tumors has been described only in case reports and small case series. We retrospectively reviewed the records of all 25 patients who underwent single ray amputations at our center during a 10-year period; there were seven index, five middle, six ring, and seven small ray amputations performed. The minimum followup was 2 months (mean, 36 months; range, 2-120 months), with four patients having a followup of 1 year or less. No patients had local recurrences, although two patients had positive resection margins. One underwent repeat resection followed by radiotherapy. The other was treated with radiotherapy alone, as local tumor control would have required a hand amputation. Functional assessment based on the Musculoskeletal Tumor Society staging system showed an average of 27.5 (range, 21-30). Patients who underwent perioperative radiotherapy experienced a decrease in functional ability. Grip strength was an average of 66% (range, 38%-100%) of the contralateral side. Our study suggests single ray amputation for hand tumors has a low local recurrence rate and high functional scores. However, function can be compromised by radiotherapy and a decrease in grip strength by a mean of 34% is to be expected.Level IV, case series. See Guidelines for Authors for a complete description of levels of evidence.

BackgroundPatients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. The optimal choice of local control for overall and local disease control remains unclear.MethodsPatients with localized Ewing sarcoma of bone who were treated on 3 consecutive protocols with standard-dose, 5-drug chemotherapy every 3 weeks were included (n=465). Propensity scores were used to control for differences between local control groups by constructing multivariate models to assess the impact of local control type on clinical endpoints (event-free survival [EFS], overall survival, local failure, and distant failure) independent of differences in their propensity to receive each local control type.ResultsPatients who underwent surgery were younger (P=.02) and had more appendicular tumors (P

PurposeChemotherapy with alternating vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide cycles and primary tumor treatment with surgery and/or radiation therapy constitute the usual approach to localized Ewing sarcoma in North America. We tested whether chemotherapy intensification through interval compression could improve outcome.Patients and methodsThis was a prospective, randomized controlled trial for patients younger than 50 years old with newly diagnosed localized extradural Ewing sarcoma. Patients assigned to standard and intensified treatment were to begin chemotherapy cycles every 21 and 14 days, respectively, provided an absolute neutrophil count greater than 750×10(6)/L and a platelet count greater than 75×10(9)/L. Patients received vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1.2 g/m2) alternating with ifosfamide (9 g/m2) and etoposide (500 mg/m2) for 14 cycles, with filgrastim (5 mg/kg per day; maximum, 300 mg) between cycles. Primary tumor treatment (surgery, radiation, or both) was to begin at week 13 (after four cycles in the standard arm and six cycles in the intensified arm). The primary end point was event-free survival (EFS). The study is registered at ClinicalTrials.gov (identifier: NCT00006734).ResultsFive hundred eighty-seven patients were enrolled and randomly assigned, and 568 patients were eligible, with 284 patients in each regimen. For all cycles, the median cycle interval for standard treatment was 21 days (mean, 22.45 days); for intensified treatment, the median interval was 15 days (mean, 17.29 days). EFS at a median of 5 years was 65% in the standard arm and 73% in the intensified arm (P=.048). The toxicity of the regimens was similar.ConclusionFor localized Ewing sarcoma, chemotherapy administered every 2 weeks is more effective than chemotherapy administered every 3 weeks, with no increase in toxicity.

The hypothesis that microvesicle-mediated miRNA transfer converts noncancer stem cells into cancer stem cells (CSC) leading to therapy resistance remains poorly investigated. Here we provide direct evidence supporting this hypothesis, by demonstrating how microvesicles derived from cancer-associated fibroblasts (CAF) transfer miR-221 to promote hormonal therapy resistance (HTR) in models of luminal breast cancer. We determined that CAF-derived microvesicles horizontally transferred miR-221 to tumor cells and, in combination with hormone therapy, activated an ERlo/Notchhi feed-forward loop responsible for the generation of CD133hi CSCs. Importantly, microvesicles from patients with HTR metastatic disease expressed high levels of miR-221. We further determined that the IL6–pStat3 pathway promoted the biogenesis of onco-miR-221hi CAF microvesicles and established stromal CSC niches in experimental and patient-derived breast cancer models. Coinjection of patient-derived CAFs from bone metastases led to de novo HTR tumors, which was reversed with IL6R blockade. Finally, we generated patient-derived xenograft (PDX) models from patient-derived HTR bone metastases and analyzed tumor cells, stroma, and microvesicles. Murine and human CAFs were enriched in HTR tumors expressing high levels of CD133hi cells. Depletion of murine CAFs from PDX restored sensitivity to HT, with a concurrent reduction of CD133hi CSCs. Conversely, in models of CD133neg, HT-sensitive cancer cells, both murine and human CAFs promoted de novo HT resistance via the generation of CD133hi CSCs that expressed low levels of estrogen receptor alpha. Overall, our results illuminate how microvesicle-mediated horizontal transfer of genetic material from host stromal cells to cancer cells triggers the evolution of therapy-resistant metastases, with potentially broad implications for their control. Cancer Res; 77(8); 1927–41. ©2017 AACR.