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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

Soft tissue sarcoma (STS) of the extremities is typically treated with limb-sparing surgery and radiation therapy; with this treatment approach, high local control rates can be achieved. However, postradiation bone fractures, fractures occurring in the prior radiation field with minimal or no trauma, are a serious late complication that occurs in 2–22% of patients who receive surgery and radiation for STS. Multiple risk factors for sustaining a postradiation fracture exist, including high radiation dose, female sex, periosteal stripping, older age, femur location, and chemotherapy administration. The treatment of these pathological fractures can be difficult, with complications including delayed union, nonunion, and infection posing particular challenges. Here, we review the mechanisms, risk factors, and treatment challenges associated with postradiation fractures in STS patients.

The complexity of pelvic anatomy and the extent of tumor growth makes treatment of patients with primary bone sarcomas in the pelvis difficult in terms of local control. Before the 1970s, most tumors in the bony pelvis were surgically treated with hindquarter amputation. Currently, improved techniques for clinical staging, adjuvant treatments, evolutions in metallurgy, and development of new surgical techniques make limb-salvage surgery and reconstruction possible alternatives to hemipelvectomy and resection-arthrodesis. The advantages of amputation over resections at the pelvis are a lower incidence of complications, a limited area at risk for recurrence, and a faster recovery time compared with all but the most limited pelvic resections. The disadvantages, especially after periacetabular resections, are leg-length discrepancy and impaired hip and gait function. The indication for limb salvage is the ability to obtain wide margins without compromising survival and function. Although having to resect the sciatic nerve to obtain adequate margins does not always mean that an amputation should be performed, the combination of a major pelvic resection and the functional consequences of sciatic nerve resection results in an extremity usually not worth saving; loss of femoral nerve function does not result in a significant gait disturbance, especially if the hemipelvis is stable. Reconstruction options after major pelvic resections have also evolved, but they remain difficult, especially when the acetabulum is involved.

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.

The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133hi/ERlo cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133hi/ERlo/IL6hi cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133hi/ERlo/OXPHOSlo. These cells exit metabolic dormancy via an IL6-driven feed-forward ERlo-IL6hi-Notchhi loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133hi CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy., ER+ breast cancer patients treated with endocrine therapies often acquire resistance and develop metastasis. In this study, the authors demonstrate that endocrine therapies can promote the self-renewal of CD133hi/ERlo drug resistant cells with metastatic potential driven through the IL6-Notch3 axis activation.

The mechanisms of metastatic progression from hormonal therapy (HT)-induced tumour dormancy to hormonal therapy resistance is largely unknown in luminal breast cancer. Analysis of clinical specimens revealed the enrichment of CD133hi/ERlo cancer cells in primary tumours following neo-adjuvant endocrine therapy and in HT refractory metastatic disease. We developed spontaneous experimental models of metastatic luminal breast cancer and determined that endocrine therapy can promote the generation of HT- resistant, self-renewing CD133hi/ERlo/IL6hicells. Dual pharmacological inhibition of IL6R-IL6 (tocilizumab) and ER (HT) abrogated the establishment of CD133hi/ERlo/IL6hi cancer stem cells (CSCs), restoring endocrine sensitivity to hormone-refractory metastatic disease, in both experimental and patient-derived endocrine-resistant bone metastasis. Hormonal therapy, initially abrogated oxidative phosphorylation (OXPHOS) generating dormant (self-renewal deficient-CD133hi/ERlo/OXPHOSlo) cancer cells, These cells exited metabolic dormancy via an IL6 driven feed-forward ERlo-IL6hi-Notchhi loop, activating OXPHOS, in the absence of ER activity. Importantly, the inhibition of IL6R/IL6-Notch pathways switched the self-renewal of CD133hi CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy. Citation Format: Pasquale Sansone, Ceccarelli Claudio, Marjan Berishaj, Qing Chang, Rajasekhar Vinagolu, Fabiana Perna, Robert Bowman, Michele Vidone, Laura Daly, Jennifer Nnoli, Donatella Santini, Taffurelli Mario, Natalie Shih, Michael Feldman, Jun James Mao, Christopher Colameco, Jinbo Chen, Angela DeMichele, Nicola Fabbri, John Healey, Monica Cricca, Giuseppe Gasparre, David Lyden, Massimiliano Bonafe, Jacqueline F. Bromberg. Self-renewal of CD133hi cells by IL6/Notch3 signaling regulates endocrine resistance in metastatic breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-236.

Aims and backgroundInformation is scarce on systemic treatment of pelvic osteosarcoma because most chemotherapy protocols for osteosarcoma include patients with extremity tumors and aged up to 30–40 years.MethodsData on patients ResultsForty patients between 11 and 36 years were included. The most frequent histological subtype was osteoblastic followed by chondroblastic (37.5%). Complete surgical remission was achieved in 65% of patients. Eighteen patients had MAP/standard-dose ifosfamide, 22 MAP/high-dose ifosfamide. Primary chemotherapy was given to 25 patients and 6 (24%) of them had a good histological response. Median follow-up was 32 months (range, 4–134). Five-year overall survival was 27.5%: 33% in localized and 0 in metastatic patients (P = 0.02); 45% in patients with complete surgical remission and 0 for patients without complete surgical remission (P = 0.001). Local recurrence rate was 46%. In patients with complete surgical remission, 5-year overall survival was 32% with MAP/standard-dose ifosfamide and 59% with MAP/high-dose ifosfamide regimen (P = 0.3).ConclusionsLocal control is the major issue in the treatment of pelvic osteosarcoma. Poor pathological response and high incidence of chondroblastic variant indicate different characteristics between pelvic and extremity osteosarcoma. Chemotherapy with MAP and high-dose ifosfamide might be beneficial in patients with pelvic osteosarcoma and warrants further investigation.