The Musculoskeletal Tumor Society Clinical Practice Guideline on the Management of Metastatic Humeral Disease.

Management of Metastatic Humeral Disease is based on a systematic review of published studies surrounding the management of metastatic disease, multiple myeloma, and lymphoma limited to the humerus. This guideline contains seven action statements to assist orthopaedic surgeons, orthopaedic oncologists, physicians, and any other qualified healthcare professionals involved in the surgical management of metastatic disease of the humerus. It is also intended to serve as an information resource for decision makers, researchers, and developers of clinical practice guidelines. In addition to providing pragmatic practice recommendations, this guideline also highlights gaps in the literature and informs areas for future research and quality measure development. This guideline has been endorsed by the American Academy of Orthopaedic Surgeons.

AAOS Clinical Practice Guideline Summary: Treatment of Metastatic Carcinoma and Myeloma of the Femur.

The Musculoskeletal Tumor Society, in partnership with American Society of Clinical Oncology and American Society for Radiation Oncology, has developed a clinical practice guideline to assist providers with the care of patients with metastatic carcinoma and myeloma of the femur. The guideline was developed by an Expert Panel consisting of representatives of all three organizations by American Academy of Orthopaedic Surgeons (AAOS) methodologists using the AAOS standardized guideline development process. A systematic review of the available evidence was conducted, and the identified evidence was rated was rated for quality and potential for bias. Recommendations were developed based on this evidence in a standardized fashion. The guideline was approved by the guideline approval bodies of all three organizations. Thirteen recommendations were synthesized covering relevant subtopics such as imaging, use of bone-modifying agents, radiation therapy, and surgical reconstruction. The consensus of the expert panel was that bone-modifying agents may assist in reducing the incidence of femur fracture, regardless of tumor histology. The panel recommended the use of radiation therapy to decrease the rate of femur fractures for patients considered at increased risk. The panel recommended arthroplasty be considered to improve patient function and decrease the need of postoperative radiation therapy in patients with pathologic fractures in the femur.

Prevention and Treatment of Pathologic Femur Fractures: Evidence as of 2019.

This chapter is largely drawn from the recently published (2019) clinical practice guideline on the treatment of metastatic carcinoma and myeloma of the femur jointly produced by the Musculoskeletal Tumor Society, American Society for Radiation Oncology, and American Society of Clinical Oncology. Previous clinical practice guidelines on this topic broadly addressed the potential benefits of bone-targeted agents (eg, diphosphonates) on skeletal-related events, a broad term that encompasses pathologic fractures of any bone, need for surgery or radiation, and hypercalcemia. Guidelines on the use of palliative radiation therapy primarily focused on short-term pain control and long-term radiation-induced adverse effects. The starting goals of this guideline were twofold-focus on the femur, as fractures of the femur almost always require surgery and, when about the hip, dramatically alter patients' quality of life and, potentially, survival; and to address this topic in a multidisciplinary fashion that includes the insights of orthopaedic surgeons, along with radiation oncologists and medical oncologists. For many important clinical topics, there is a dearth of evidence, which will hopefully prompt researchers and funding agencies to help fill these evidentiary gaps.

Nanopatterning and Bioprinting in Orthopedic Surgery.

In part 1 of this article, the authors explore nanoscale modifications of the surfaces of biomaterials, which offer an exciting potential venue for the prevention of bacterial adhesion and growth. Despite advances in the design and manufacture of implants, infection remains an important and often devastating mode of failure. In part 2, additive technologies for tissue engineering, live cell printing (bioprinting), and tissue fabrication are briefly introduced. The similarities and differences between bioprinting and non-bio 3D-printing approaches and requirements are discussed, along with terminological definitions, current processes, requirements, and biomaterial and cell-type selection and sourcing.

Phenotypic and Genotypic Characterization and Treatment of a Cohort With Familial Tumoral Calcinosis/Hyperostosis-Hyperphosphatemia Syndrome.

Familial tumoral calcinosis (FTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is a rare disorder caused by mutations in the genes encoding fibroblast growth factor-23 (FGF23), N-acetylgalactosaminyltransferase 3 (GALNT3), or KLOTHO. The result is functional deficiency of, or resistance to, intact FGF23 (iFGF23), causing hyperphosphatemia, increased renal tubular reabsorption of phosphorus (TRP), elevated or inappropriately normal 1,25-dihydroxyvitamin D3 (1,25D), ectopic calcifications, and/or diaphyseal hyperostosis. Eight subjects with FTC/HHS were studied and treated. Clinical manifestations varied, even within families, ranging from asymptomatic to large, disabling calcifications. All subjects had hyperphosphatemia, increased TRP, and elevated or inappropriately normal 1,25D. C-terminal FGF23 was markedly elevated whereas iFGF23 was comparatively low, consistent with increased FGF23 cleavage. Radiographs ranged from diaphyseal hyperostosis to massive calcification. Two subjects with severe calcifications also had overwhelming systemic inflammation and elevated C-reactive protein (CRP). GALNT3 mutations were identified in seven subjects; no causative mutation was found in the eighth. Biopsies from four subjects showed ectopic calcification and chronic inflammation, with areas of heterotopic ossification observed in one subject. Treatment with low phosphate diet, phosphate binders, and phosphaturia-inducing therapies was prescribed with variable response. One subject experienced complete resolution of a calcific mass after 13 months of medical treatment. In the two subjects with systemic inflammation, interleukin-1 (IL-1) antagonists significantly decreased CRP levels with resolution of calcinosis cutis and perilesional inflammation in one subject and improvement of overall well-being in both subjects. This cohort expands the phenotype and genotype of FTC/HHS and demonstrates the range of clinical manifestations despite similar biochemical profiles and genetic mutations. Overwhelming systemic inflammation has not been described previously in FTC/HHS; the response to IL-1 antagonists suggests that anti-inflammatory drugs may be useful adjuvants. In addition, this is the first description of heterotopic ossification reported in FTC/HHS, possibly mediated by the adjacent inflammation. © 2016 American Society for Bone and Mineral Research.

Top five lesions that do not need referral to orthopedic oncology.

Patients with potential bone and soft tissue tumors can be challenging for orthopedic surgeons. Lesions that appear benign can still create anxiety for the clinician and patient. However, attention to a few key imaging and clinical findings is enough to correctly diagnose five of the most common bone and soft tissue lesions: lipoma, enchondroma, osteochondroma, nonossifying fibroma, and Paget disease. Accurate identification of these lesions should be within the scope of most orthopedic surgeons and, because most of these patients will not need surgical treatment, referral to orthopedic oncology will not typically be required.

Tumor localization and biochemical response to cure in tumor-induced osteomalacia.

Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with ¹¹¹Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and ¹8fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo-SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D3 (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.

Selective venous catheterization for the localization of phosphaturic mesenchymal tumors.

Tumor-induced osteomalacia (TIO) is characterized by renal phosphate wasting, hypophosphatemia, and aberrant vitamin D(3) metabolism and is caused by fibroblast growth factor 23 (FGF-23)-producing mesenchymal tumors, which are often difficult to locate. We investigated the utility of selective venous sampling in tumor localization. The primary endpoint was identification of the FGF-23 concentration ratio between the venous drainage of the tumor bed and the general circulation that was diagnostic of the location of an FGF-23-secreting tumor. Fourteen subjects underwent 15 sampling procedures after functional and anatomic imaging studies. Subjects fit into three imaging categories: no suspicious site, multiple sites, and single site (positive controls). FGF-23 levels were measured by ELISA. Suspicious tumors were resected for diagnosis, confirmation, and cure. In subjects with a positive venous sampling study and subsequent cure, a minimum ratio of 1.6 was diagnostic. In 7 of 14 subjects there was suggestive imaging, a diagnostic ratio, and an associated TIO tumor (true positive). Four of these required complicated resection procedures. In 4 of 14 subjects with no suspicious site on imaging studies, an FGF-23 diagnostic ratio was not detected (true negative). Biopsy or resection of a single lesion in 2 of 14 subjects with a diagnostic ratio failed to identify a TIO tumor (false positive). A diagnostic FGF-23 ratio was absent in 1 of 14 subjects whose tumor was a single highly suspicious lesion on imaging studies (false negative). These data yield a sensitivity of 0.87 [95% confidence interval (CI) 0.47-0.99] and a specificity of 0.71 (95% CI 0.29-0.96). Selective venous sampling for FGF-23 was particularly useful in subjects with multiple suspicious sites or an anatomically challenging planned resection but not in the absence of a suspicious lesion on imaging studies.