Giant cell tumor of bone is a benign albeit aggressive tumor commonly affecting the bones of the knee. Patients with these tumors present with pain, swelling, and inability to bear weight on the involved extremity. These destructive tumors typically arise in the metaphyseal region of the long bones in individuals in the second, third, and fourth generations of life. Histologically, the multinucleated giant cells are the hallmark of the lesion, easily recognized on histological review, which recently have become therapeutic targets for medical management of the disease. For decades, surgical management has been the primary treatment for giant cell tumor of the bone. Some tumors can be treated with excision and filling of the osseous void with bone cement or allograft. This is an effective treatment option with a low to moderate risk of local recurrence while preserving limb function. For more destructive tumors, wide excision and reconstruction with prosthetic, structural allograft or combined allograft prosthetic components are utilized. Advances in medical management of the disease have also demonstrated promise as an effective treatment; however, its use has usually been limited to the treatment of metastatic disease, recurrent disease or when advanced local disease would require surgical treatment felt to be overly morbid.

Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine Interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients, and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER− primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA-MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET–derived full length IL-8(1–77) had significantly higher potency than the non-osteolytic MDA-MB-231-derived IL-8(6–77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7 days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28 days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer.

III.

Background: Orthopaedic surgery has generally lagged behind other surgical subspecialties with respect to racial and ethnic diversity in its U.S. residency programs. Efforts have been made to increase the number of underrepresented minorities (URMs) applying to orthopaedic surgery residencies; however, the impact on diversity at the residency program level is unknown. The purpose of this study was to determine whether orthopaedic surgery residency programs have become more racially diverse over time. Methods: The Graduate Medical Education Track database was queried for individual racial/ethnic identification of orthopaedic surgery residents in U.S. Accreditation Council for Graduate Medical Education (ACGME)-accredited programs for 15 consecutive years (2002-2003 through 2016-2017). The number of URMs in each residency program during each academic year was recorded. The number of programs per year with no URMs, 1 URM, 2 URMs, and >2 URMs was recorded, and the change over time was assessed. Results: The number of programs per year with >1 URM resident decreased over time, from 61 programs in 2002 to 53 programs in 2016, with the trough being 31 programs in 2010 (p < 0.0001). The number of programs per year without any URM residents increased over the period of study, from 40 programs in 2002 to 60 programs in 2016, with the peak being 76 programs in 2011 (p < 0.0001). Conclusions: The number of residency programs with >1 URM resident has decreased significantly over time, suggesting that diversity at the program level is limited. Program-level diversity should be further examined as a potential barrier to the recruitment of URMs to orthopaedics. Difficulty attracting URM residents to certain programs may have the unintended consequence of effectively limiting potential positions for these candidates, which can decrease the odds of minority students matching into orthopaedics and, therefore, perpetuate the cycle of lack of diversity in our field. Orthopaedic surgery in the United States lags behind other specialties with respect to racial and ethnic diversity among both residents and academic faculty 1-3. Minorities have been underrepresented in orthopaedics relative to the number of medical students who are underrepresented minorities (URMs) 1,4. In 2006, African Americans and Hispanics/Latinos represented 13.8% of medical school graduates but only 7.8% of orthopaedic surgery residents and 4.9% of orthopaedic surgery faculty 1. Previously, it has been demonstrated that the proportion of minority residents in orthopaedics did not significantly increase over time, with African Americans, Hispanics, and Native Americans constituting 8.8% of orthopaedic residents in 1995 and 9.1% of residents in 2010 2. Disclosure: The authors indicated that no external funding was received for any aspect of this work. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked "yes" to indicate that the author had a relevant financial relat...

In the context of breast cancer, the importance of the skeleton in the regulation of primary tumour development and as a site for subsequent metastasis is well characterized. Our understanding of the contributions made by the host bone and bone marrow cells increasingly demonstrates the extent of the interaction between tumour cells and normal host cells. As a result, the need to develop and utilize therapies that can impede the growth and/or function of tumour cells while sparing normal host bone and bone marrow cells is immense and expanding. The need for these new treatments is, however, superimposed on the orthopaedic management of patients’ quality of life, where pain control and continued locomotion are paramount. Indeed, the majority of the anticancer therapies used to date often result in direct or indirect damage to bone. Thus, although the bone microenvironment regulates tumour cell growth in bone, cells within the bone marrow niche also mediate many of the orthopaedic consequences of tumour progression as well as resistance to the antitumour effects of existing therapies. In this Review, we highlight the effects of existing cancer treatments on bone and the bone marrow microenvironment as well as the mechanisms mediating these effects and the current utility of modern orthopaedic interventions.