Analysis of the Actions of RARγ Agonists on Growing Osteochondromas in a Mouse Model.

The actions of the retinoic acid nuclear receptor gamma (RARγ) agonist, palovarotene, on pre-existing osteochondromas were investigated using a mouse multiple osteochondroma model. This approach was based on the knowledge that patients often present to the clinic after realizing the existence of osteochondroma masses, and the findings from preclinical investigations are the effects of drugs on the initial formation of osteochondromas. Systemic administration of palovarotene, with increased doses (from 1.76 to 4.0 mg/kg) over time, fully inhibited tumor growth, keeping the tumor size (0.31 ± 0.049 mm3) similar to the initial size (0.27 ± 0.031 mm3, p = 0.66) while the control group tumor grew (1.03 ± 0.23 mm3, p = 0.023 to the drug-treated group). Nanoparticle (NP)-based local delivery of the RARγ agonist also inhibited the growth of osteochondromas at an early stage (Control: 0.52 ± 0.11 mm3; NP: 0.26 ± 0.10, p = 0.008). Transcriptome analysis revealed that the osteoarthritis pathway was activated in cultured chondrocytes treated with palovarotene (Z-score = 2.29), with the upregulation of matrix catabolic genes and the downregulation of matrix anabolic genes, consistent with the histology of palovarotene-treated osteochondromas. A reporter assay performed in cultured chondrocytes demonstrated that the Stat3 pathway, but not the Stat1/2 pathway, was stimulated by RARγ agonists. The activation of Stat3 by palovarotene was confirmed using immunoblotting and immunohistochemistry. These findings suggest that palovarotene treatment is effective against pre-existing osteochondromas and that the Stat3 pathway is involved in the antitumor actions of palovarotene.

Osteochondroma Pathogenesis: Mouse Models and Mechanistic Insights into Interactions with Retinoid Signaling.

Osteochondromas are cartilage-capped tumors that arise near growing physes and are the most common benign bone tumor in children. Osteochondromas can lead to skeletal deformity, pain, loss of motion, and neurovascular compression. Currently, surgery is the only available treatment for symptomatic osteochondromas. Osteochondroma mouse models have been developed to understand the pathology and the origin of osteochondromas and develop therapeutic drugs. Several cartilage regulatory pathways have been implicated in the development of osteochondromas, such as bone morphogenetic protein, hedgehog, and WNT/ß-catenin signaling. Retinoic acid receptor-γ is an important regulator of endochondral bone formation. Selective agonists for retinoic acid receptor-γ, such as palovarotene, have been investigated as drugs for inhibition of ectopic endochondral ossification, including osteochondromas. This review discusses the signaling pathways involved in osteochondroma pathogenesis and their possible interactions with the retinoid pathway.

Beyond the dermis-high-risk invasive squamous cell carcinoma: a retrospective review.

OBJECTIVE: Most cutaneous squamous cell carcinomas (cSCC) are low risk and can be treated with simple excision or ablation. High-risk cSCC require invasive treatment, including radical surgery. We present our experience in treating invasive cSCC of the pelvis and extremities. METHOD: A retrospective review of the data of patients with invasive cSCC, indicated for surgery between 2014 and 2018, from a single institution was carried out. RESULTS: A total of 19 patients (nine men, 10 women) were included in the study. Mean age was 62 years; mean tumour size was 8.6cm). Of the 19 patients, five patients with paraplegia with cSCC arising from hard-to-heal ulcers died of infection or bleeding after surgery or systemic therapy. Also, nine patients with localised cSCC underwent margin-negative resection with or without radiation; one patient experienced disease relapse. Of the participants, two patients with previous transplants and multifocal aggressive cSCC underwent numerous resections but succumbed to disease, and two patients who presented with locally recurrent disease after previous positive margin resection and radiation underwent re-resection but developed recurrent disease. CONCLUSIONS: Prognosis for invasive cSCC largely depends on clinical setting. Tumours arising from ulcers in patients with paraplegia have a poor prognosis regardless of treatment. Invasive cSCC in transplant patients are often multifocal and often recur. Debulking procedures are associated with local recurrence despite radiation. Patients presenting with localised disease have a favourable prognosis with wide resection, flap coverage and adjuvant therapy.

Increased Femoral Component Size Options Improves Manipulation Rate in Females and Knee Society Clinical Scores in Males.

INTRODUCTION: The gender-specific total knee arthroplasty (TKA) debate focuses on differences in distal femoral mediolateral to anteroposterior aspect ratio between males and females. However, randomized studies have been unable to demonstrate significant differences in outcomes utilizing gender-specific implants. No studies have examined the effect of intermediate femoral component sizes on outcome. We compared outcomes before and after intermediate sizing availability. MATERIALS AND METHODS: We identified 331 patients (413 knees) who underwent primary TKA between 2003 and 2004 with a single complete knee system. There were 121 males and 210 females. Three intermediate femoral sizes were added in March 2004 to the six initial options. Patients before March 2004 were assigned to group 1 (n=178), and after to group 2 (n=235). RESULTS: Follow-up averaged 8.5 years. Preoperative demographics and clinical scores were similar between groups. Knee Society (KS) clinical and functional scores improved in females in both groups, but there was no significant difference. Male patients in group 2 had a significant improvement in KS clinical scores compared to male patients in group 1 (group 1: 33.9, group 2: 41.1; p=0.01). Females in group 2 had significantly less need for manipulation, 1.9%, versus females in group 1, 8.7% (p=0.01). MUA rates were similar for men between groups. Overall, there were 19 revisions (4.6%) with no differences between groups or by genders. Once intermediate sizes were available, they were used in 48% of females and 13% of males. The average femoral component size for females in group 1 was 65 mm and decreased in group 2 to 62.5 mm. The average size of femoral components in males was 70 mm in both groups. CONCLUSIONS: Availability of intermediate size femoral component sizes was associated with a lower rate of manipulation in female patients. Greater KS clinical score improvement was observed in men after availability of additional femoral sizes.

The effect of surgery with radiation on pelvic Ewing sarcoma survival.

BACKGROUND: Pelvic Ewing sarcoma (ES) has poorer outcomes than extremity-based lesions and the method of local control is controversial. METHODS: A retrospective review was performed of 40 primary pelvic or sacral ES treated by a single surgeon. All received modern chemotherapy and those that received radiation were treated with modern dosages. RESULTS: Fifty-five percent were disease-free at latest follow-up (median, 83.1 mos). Sixty-one percent had ≥ 99% necrosis, which was associated with 65% disease-free survival. Larger size (P = 0.016) and the absence of metastatic disease (P = 0.005) was predictive of survival. Eighty-three percent of relapsed patients were DOD. Half of patients who received surgery alone or RT alone have NED while 57% of those who received S/RT have NED. Complication rates were 69% (S/RT), 75% (surgery alone), 10% (RT alone). Functional outcomes were similar. CONCLUSION: Primary pelvic ES is localized at presentation in 50% and the absence of metastases is the strongest predictor for survival. Chemotherapy is key, but excellent histologic response is neither a guarantee nor a necessity for survival. More than one-third die despite an excellent histologic response and at least one-third with lung metastases survive. With chemotherapy, radiation, and surgery, reasonable control of disease can be achieved. LEVEL OF EVIDENCE III: Case-control or retrospective cohort study.

Comparison of custom to standard TKA instrumentation with computed tomography.

PURPOSE: There is conflicting evidence whether custom instrumentation for total knee arthroplasty (TKA) improves component position compared to standard instrumentation. Studies have relied on long-limb radiographs limited to two-dimensional (2D) analysis and subjected to rotational inaccuracy. We used postoperative computed tomography (CT) to evaluate preoperative three-dimensional templating and CI to facilitate accurate and efficient implantation of TKA femoral and tibial components. METHODS: We prospectively evaluated a single-surgeon cohort of 78 TKA patients (51 custom, 27 standard) with postoperative CT scans using 3D reconstruction and contour-matching technology to preoperative imaging. Component alignment was measured in coronal, sagittal and axial planes. RESULTS: Preoperative templating for custom instrumentation was 87 and 79 % accurate for femoral and tibial component size. All custom components were within 1 size except for the tibial component in one patient (2 sizes). Tourniquet time was 5 min longer for custom (30 min) than standard (25 min). In no case was custom instrumentation aborted in favour of standard instrumentation nor was original alignment of custom instrumentation required to be adjusted intraoperatively. There were more outliers greater than 2° from intended alignment with standard instrumentation than custom for both components in all three planes. Custom instrumentation was more accurate in component position for tibial coronal alignment (custom: 1.5° ± 1.2°; standard: 3° ± 1.9°; p = 0.0001) and both tibial (custom: 1.4° ± 1.1°; standard: 16.9° ± 6.8°; p < 0.0001) and femoral (custom: 1.2° ± 0.9°; standard: 3.1° ± 2.1°; p < 0.0001) rotational alignment, and was similar to standard instrumentation in other measurements. CONCLUSIONS: When evaluated with CT, custom instrumentation performs similar or better to standard instrumentation in component alignment and accurately templates component size. Tourniquet time was mildly increased for custom compared to standard.

Prolonged prophylactic antibiotic use following megaprosthesis surgery may reduce periprosthetic infection.

Introduction: Megaprostheses provide a reconstructive option for patients with bone loss after musculoskeletal tumor resection. However, the postoperative surgical site infection (SSI) risk is significant. This study aims to evaluate outcomes of extended postoperative antibiotic regimens in patients after megaprosthesis surgery and gather insight into strategies to minimize SSI. Methods: This retrospective cohort study evaluated patients who underwent megaprosthesis surgery by a single surgeon at a single center from 2014 to 2022. Patient demographics, comorbidities, cancer treatment details, and antibiotic regimens were collected. Excluded were patients with less than 1 year of follow-up, active infection at time of surgery, non-healing wounds unrelated to SSI, and preoperative antibiotic regimens secondary to being immunocompromised. Measures of interest included the development of SSI within 1 year of surgery and development of antibiotic-related complications. Results: Included were 49 patients, with a mean age of 61.2 ± 2.0 years and a mean BMI of 29.4 ± 7.0. The mean drain duration was 6.5 days (standard deviation [SD], 6.9 days), and the mean intravenous antibiotic administration duration was 6.4 days (SD, 6.9 days). The median time to drain removal was five days, and the median time for intravenous antibiotic cessation was five days. The mean total antibiotic administration duration (intravenous and oral) was 25.4 days (SD, 13.4 days). Only 1 patient in the included cohort (2.04 %) developed an SSI requiring operative intervention. No other patient within the cohort experienced an antibiotic-related complication. Discussion: This study suggests that the site's current protocol for managing post-megaprosthesis antibiotic prophylaxis based on drain duration and incision healing status has resulted in a low rate of SSI and antibiotic-related complications. Further research is needed to validate these findings and gain additional insights into managing antibiotic prophylaxis after megaprosthesis surgery.

Genetic engineering of juvenile human chondrocytes improves scaffold-free mosaic neocartilage grafts.

BACKGROUND: Current cartilage transplantation techniques achieve suboptimal restoration and rely on patient donor cells or living grafts of chondrocytes. PURPOSE: We sought to enhance allogeneic grafts by testing mosaics of genetically engineered and naïve juvenile human chondrocytes (jCh). METHODS: We obtained specimens from three humans and performed three experiments (two in vitro, one in vivo). We compared neocartilage with and without (1) supplemented serum-free medium (chondrocyte differentiation medium [CDM]), (2) adenoviral BMP-2 (AdBMP-2) transduction, and (3) varying ratios (0.1-1) of transduced and naïve jCh. We compared (4) healing with mosaic grafts with naïve neocartilage or marrow stimulation in immunosuppressed rats. For each of 10 in vitro treatment groups, we had six replicates for each human, and for each of three in vivo treatment groups, we had four replicates for one human. We scored the histology with the semiquantitative Bern score. RESULTS: AdBMP-2 and naïve neocartilage growth in CDM were histologically superior (Bern score, 5.2 versus 3.7; 8.0 versus 1.8) and size (8.0 versus 6.1; 7.9 versus 2.2 mg) to standard medium. In CDM, AdBMP-2 decreased viability (76% versus 90%), but increased BMP-2 production (619 ng/mL versus 43 pg/mL). Ten percent and 25% AdBMP-2 transduction had Bern scores of 6.8 and 6.5 and viability of 84% and 83%, respectively. Twenty-five percent mosaic grafts provided better healing histologically than marrow stimulation or naive neocartilage. CONCLUSIONS: Low-level AdBMP-2 and CDM augment neocartilage parameters in vitro and vivo. CLINICAL RELEVANCE: Genetic augmentation of jCh and creation of mosaic neocartilage may improve graft viability and articular healing compared with naïve neocartilage.

Malignant Transformation in Ollier's Disease: A Novel Stem for a Tibial Megaprosthesis.

Ollier's disease is a rare syndrome characterized by multiple enchondromas with the potential for malignant transformation. The treatment for secondary chondrosarcoma is surgical resection, which can be a morbid procedure depending on the location and size of the tumor. We present a successful limb salvage in which the majority of the tibia was removed and replaced with a megaprosthesis. The complex reconstruction in this case required the use of a novel uncemented stem.

Improved accuracy of alignment with patient-specific positioning guides compared with manual instrumentation in TKA.

BACKGROUND: Coronal malalignment occurs frequently in TKA and may affect implant durability and knee function. Designed to improve alignment accuracy and precision, the patient-specific positioning guide is predicated on restoration of the overall mechanical axis and is a multifaceted new tool in achieving traditional goals of TKA. QUESTIONS/PURPOSES: We compared the effectiveness of patient-specific positioning guides to manual instrumentation with intramedullary femoral and extramedullary tibial guides in restoring the mechanical axis of the extremity and achieving neutral coronal alignment of the femoral and tibial components. METHODS: We retrospectively reviewed 569 TKAs performed with patient-specific positioning guides and 155 with manual instrumentation by two surgeons using postoperative long-leg radiographs. For all patients, we assessed the zone in which the overall mechanical axis passed through the knee, and for one surgeon's cases (105 patient-specific positioning guide, 55 manual instrumentation), we also measured the hip-knee-ankle angle and the individual component angles with respect to their mechanical axes. RESULTS: The overall mechanical axis passed through the central third of the knee more often with patient-specific positioning guides (88%) than with manual instrumentation (78%). The overall mean hip-knee-ankle angle for patient-specific positioning guides (180.6°) was similar to manual instrumentation (181.1°), but there were fewer ± 3° hip-knee-ankle angle outliers with patient-specific positioning guides (9%) than with manual instrumentation (22%). The overall mean tibial (89.9° versus 90.4°) and femoral (90.7° versus 91.3°) component angles were closer to neutral with patient-specific positioning guides than with manual instrumentation, but the rate of ± 2° outliers was similar for both the tibia (10% versus 7%) and femur (22% versus 18%). CONCLUSIONS: Patient-specific positioning guides can assist in achieving a neutral mechanical axis with reduction in outliers.

Salphage: Salvage Bacteriophage Therapy for Recalcitrant MRSA Prosthetic Joint Infection.

Prosthetic joint infections are a devastating complication of joint replacement surgery. Consequently, novel therapeutics are needed to thwart the significant morbidity and enormous financial ramifications that are associated with conventional treatments. One such promising adjuvant therapeutic is bacteriophage therapy given its antibiofilm activity and its ability to self-replicate. Herein we discuss the case of a 70-year-old female who had a recalcitrant MRSA prosthetic knee and femoral lateral plate infection who was successfully treated with adjuvant bacteriophage therapy. Moreover, this case discusses the importance of propagating bacteriophage therapeutics on bacteria that are devoid of toxins and the need to ensure bacteriophage activity to all bacterial morphologies. Overall, this case reinforces the potential benefit of using personalized bacteriophage therapy for recalcitrant prosthetic joint infections, but more translational research is needed to thereby devise effective, reproducible clinical trials.

Perivascular lymphocytic infiltration is not limited to metal-on-metal bearings.

BACKGROUND: Perivascular lymphocytic infiltration (PVLI) suggests an adaptive immune response. Metal hypersensitivity after THA is presumed associated with idiopathic pain and aseptic loosening, but its incidence and relationship to metallic wear leading to revision are unclear as are its presence and relevance in non-metal-on-metal arthroplasty. QUESTIONS/PURPOSES: We compared (1) incidence and severity of PVLI in failed hip metal-on-metal (MoM) to non-MoM implants and TKA; (2) PVLI in MoM and non-MoM hip arthroplasty based on reason for revision; and (3) PVLI grade to diffuse lymphocytic infiltration (DLI) and tissue reaction to metal particles. PATIENTS AND METHODS: We retrospectively examined incidence and severity of PVLI, DLI, and tissue reaction in periprosthetic tissue from 215 THA and 242 TKA revisions including 32 MoM hips. RESULTS: Perivascular lymphocytic infiltration was present in more TKAs (40%) than overall hip arthroplasties (24%) without difference in severity. Compared to non-MoM hips, MoM bearings were more commonly associated with PVLI (59% versus 18%) and demonstrated increased severity (41% versus 3% greater than mild). Histologically, PVLI correlated (r = 0.51) with DLI, but not tissue reaction. In THA, PVLI was most commonly associated with idiopathic pain (70%) and aseptic loosening (54%) in MoM, and infection in all hip revisions (53%). CONCLUSIONS: Perivascular lymphocytic infiltration is more extensive in revisions of MoM and in aseptic loosening, idiopathic pain, or infection but is also present in TKA, non-MoM, and different reasons for revision. It correlates with other signs of metal hypersensitivity, but not with histologic measures of metal particulate load. LEVEL OF EVIDENCE: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Femoroacetabular impingement: a common cause of hip pain in young adults.

OBJECTIVE: Femoroacetabular impingement (FAI) is a common cause of hip discomfort in young adults. Recently, a better understanding of the pathomechanics and morphologic abnormalities in the hip has implicated FAI as a possible factor in early osteoarthrosis. The clinical presentation, physical examination findings, and radiographic features are discussed in this article. DATA SOURCES: PubMed was searched using words and terms including femoacetabular impingement, hip osteoarthritis, hip arthroscopy, early osteoarthrosis, and hip dislocation. References of relevant studies were searched by hand. STUDY SELECTION: All studies directly involving the treatment of FAI were reviewed by 3 authors and selected for further analysis, including expert opinion and review articles. DATA SYNTHESIS: The quality of each study was assessed, and the results were summarized. CONCLUSIONS: Conservative measures, including physical therapy, restriction of activities, core strengthening, improvement of sensory-motor, and control and nonsteroidal anti-inflammatories are the mainstays of nonsurgical treatment. However, surgical management is often necessary to allow full return to activity with options including surgical dislocation of the hip, hip arthroscopy, periacetabular and rotational osteotomies, and combined hip arthroscopy with a limited open exposure. Although the literature is replete with short-term evidence to support surgical treatment, there are currently no long-term prospective data or natural history studies examining the implications of FAI and effects of early intervention.

Efficacy of treatment of trochanteric bursitis: a systematic review.

OBJECTIVE: Trochanteric bursitis (TB) is a self-limiting disorder in the majority of patients and typically responds to conservative measures. However, multiple courses of nonoperative treatment or surgical intervention may be necessary in refractory cases. The purpose of this systematic review was to evaluate the efficacy of the treatment of TB. DATA SOURCES: A literature search in the PubMed, MEDLINE, CINAHL, and ISI Web of Knowledge databases was performed for all English language studies up to April 2010. Terms combined in a Boolean search were greater trochanteric pain syndrome, trochanteric bursitis, trochanteric, bursitis, surgery, therapy, drug therapy, physical therapy, rehabilitation, injection, Z-plasty, Z-lengthening, aspiration, bursectomy, bursoscopy, osteotomy, and tendon repair. STUDY SELECTION: All studies directly involving the treatment of TB were reviewed by 2 authors and selected for further analysis. Expert opinion and review articles were excluded, as well as case series with fewer than 5 patients. Twenty-four articles were identified. According to the system described by Wright et al, 2 studies, each with multiple arms, qualified as level I evidence, 1 as level II, 1 as level III, and the rest as level IV. More than 950 cases were included. DATA EXTRACTION: The authors extracted data regarding the type of intervention, level of evidence, mean age of patients, patient gender, number of hips in the study, symptom duration before the study, mean number of injections before the study, prior hip surgeries, patient satisfaction, length of follow-up, baseline scores, and follow-up scores for the visual analog scale (VAS) and Harris Hip Scores (HHS). DATA SYNTHESIS: Symptom resolution and the ability to return to activity ranged from 49% to 100% with corticosteroid injection as the primary treatment modality with and without multimodal conservative therapy. Two comparative studies (levels II and III) found low-energy shock-wave therapy (SWT) to be superior to other nonoperative modalities. Multiple surgical options for persistent TB have been reported, including bursectomy (n = 2), longitudinal release of the iliotibial band (n = 2), proximal or distal Z-plasty (n = 4), osteotomy (n = 1), and repair of gluteus medius tears (n = 4). CONCLUSIONS: Efficacy among surgical techniques varied depending on the clinical outcome measure, but all were superior to corticosteroid therapy and physical therapy according to the VAS and HHS in both comparison studies and between studies. This systematic review found that traditional nonoperative treatment helped most patients, SWT was a good alternative, and surgery was effective in refractory cases.

Successful Treatment of a Recalcitrant Staphylococcus epidermidis Prosthetic Knee Infection with Intraoperative Bacteriophage Therapy.

Here, we present a case of a 79-year-old female with a recalcitrant Staphylococcal epidermidis prosthetic knee infection that was successfully treated with a single dose of adjuvant intra-articular bacteriophage therapy after debridement and implant retention surgery. The bacteriophage used in this case, PM448, is the first ɛ2 bacteriophage to be used in vivo. Currently the patient is without evidence of clinical recurrence and, interestingly, the patient had also suffered from debilitating aplastic anemia for over 2 years, which is recovering since receiving adjuvant bacteriophage therapy.

Potential Use of Adjuvant Bacteriophage Therapy With Debridement, Antibiotics, and Implant Retention Surgery to Treat Chronic Prosthetic Joint Infections.

The number of arthroplasties conducted annually continues to increase; however, approximately 1%-2% of all knee and hip arthroplasties will become infected. These prosthetic joint infections are costly, difficult to treat, and cause significant morbidity and mortality as a direct result of conventional surgical and medical managements. In this perspective, we discuss factors that make these infections arduous to treat as well as the potential use of adjuvant bacteriophage therapy with debridement, antibiotics, and implant retention surgery to cure these infections without removing the infected prosthesis. We also provide rationale as to why future clinical trials evaluating this novel therapeutic will need to be designed as noninferiority trials, and we compare this approach to 2-stage revision surgery. If bacteriophage therapy continues to show effectiveness, this could revolutionize the treatment of prosthetic joint infections and pioneer new treatments for similar infections.

Evolving techniques in foot and ankle amputation.

Multiple clinical pathways lead to lower extremity amputation, including trauma, dysvascular disease, congenital defects, and malignancy. However, the principles of successful amputation-careful preoperative planning, coordination of a multidisciplinary team, and good surgical technique-remain the same. Organized rehabilitation and properly selected prostheses are integral components of amputee care. In the civilian setting, amputation is usually performed as a planned therapy for an unsalvageable extremity, not as an emergency procedure. The partial loss of a lower limb often represents a major change in a person's life, but patients should be encouraged to approach amputation as the beginning of a new phase of life and not as the culmination of previous treatment failures.

Fine needle aspiration for clinical triage of extremity soft tissue masses.

BACKGROUND: Fine needle aspiration cytology (FNAC) is a rapid and low-morbid alternative to open biopsy or needle core biopsy for soft tissue masses. Numerous reports describe its use with metastatic or recurrent lesions, but FNAC is less accepted for primary lesions. QUESTIONS/PURPOSES: We wished (1) to estimate the sensitivity, specificity, and positive and negative predictive values of FNAC for diagnosing malignancy; (2) to estimate the accuracy of subtyping and grading. METHODS: We retrospectively examined the diagnostic accuracy and clinical effectiveness of office-based FNAC performed by a trained pathologist on 213 females and 219 males (mean age, 51.8 years) who presented with a palpable soft tissue mass to one musculoskeletal oncology clinic between 2002 and 2008. RESULTS: The FNAC was reported as benign in 62.0%, indeterminate in 8.1%, and malignant in 29.9%. A second technique, such as needle core biopsy or open biopsy, was performed for 24.8% of lesions before a definitive treatment plan was rendered. Final tissue confirmation by open biopsy or resection was available for 52.2% of benign FNAC and 78.3% of malignant FNAC. Sensitivity, specificity, and positive and negative predictive values for detecting malignancy with either histopathologic confirmation or clinical followup were 89.2%, 89.8%, 96.1%, and 98.1%. There were seven sampling and nine interpretation FNAC errors in determining the nature of the lesion. Subtyping and grading for malignant lesions were 77.2% and 95.2% accurate, respectively. CONCLUSIONS: FNAC is effective for initial triage and treatment selection at tertiary referral centers with close collaboration among the surgeon, pathologist, and radiologist. LEVEL OF EVIDENCE: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.