18F-Sodium fluoride PET-CT visualizes disease activity in chronic nonbacterial osteitis in adults.

Chronic nonbacterial osteitis (CNO) is a rare disease spectrum, which lacks biomarkers for disease activity. Sodium fluoride-18 positron emission tomography/computed tomography ([18F]NaF-PET/CT) is a sensitive imaging tool for bone diseases and yields quantitative data on bone turnover. We evaluated the capacities of [18F]NaF-PET/CT to provide structural and functional assessment in adult CNO. A coss-sectional study was performed including 43 adult patients with CNO and 16 controls (patients referred for suspected, but not diagnosed with CNO) who underwent [18F]NaF-PET/CT at our expert clinic. Structural features were compared between patients and controls, and maximal standardized uptake values (SUVmax [g/mL]) were calculated for bone lesions, soft tissue/joint lesions, and reference bone. SUVmax was correlated with clinical disease activity in patients. Structural assessment revealed manubrial and costal sclerosis/hyperostosis and calcification of the costoclavicular ligament as typical features associated with CNO. SUVmax of CNO lesions was higher compared with in-patient reference bone (mean paired difference: 11.4; 95% CI: 9.4-13.5; p < .001) and controls (mean difference: 12.4; 95%CI: 9.1-15.8; p < .001). The highest SUVmax values were found in soft tissue and joint areas such as the costoclavicular ligament and manubriosternal joint, and these correlated with erythrocyte sedimentation rate in patients (correlation coefficient: 0.546; p < .002). Our data suggest that [18F]NaF-PET/CT is a promising imaging tool for adult CNO, allowing for detailed structural evaluation of its typical bone, soft-tissue, and joint features. At the same time, [18F]NaF-PET/CT yields quantitative bone remodeling data that represent the pathologically increased bone turnover and the process of new bone formation. Further studies should investigate the application of quantified [18F]NaF uptake as a novel biomarker for disease activity in CNO, and its utility to steer clinical decision making.

Review of the role of bone-SPECT/CT in tarsal coalitions.

Tarsal coalition (TC) is a congenital abnormal connection (fibrous, cartilaginous, or osseous) between two or more bones in the hind and midfoot, mostly consisting of calcaneonavicular or talocalcaneal coalition, and is often asymptomatic. However, TCs may result in foot motion limitation and pain with or without flatfoot (pes planus), arising in adolescents and young adults. Appropriate imaging is needed to pinpoint foot pain in the (suspected) TC, starting with plain radiographs. Still, normal radiographs do not exclude TCs. Computed tomography (CT) and MRI are frequently used advanced imaging techniques. CT alone has known limited sensitivity in cartilaginous and fibrous TCs and correlation between CT abnormalities and pain may be challenging, as solely anatomical changes in TCs are often asymptomatic. MRI can depict soft tissue abnormalities in TC with high accuracy. Nonetheless, after the implantation of metallic osteosynthesis material, MRI is often limited due to image distortion, signal loss, and misregistration. Bone scintigraphy with [99mTc]Tc-diphosphonate single photon emission computed tomography/CT (bone-SPECT/CT) is a known sensitive tool to detect osteoblastic bone pathology. However, the literature concerning bone-SPECT/CT in TC patients is limited. This article reviews bone-SPECT/CT patterns in TCs, how it complements other imaging techniques and their relation to clinical complaints. Bone-SPECT/CT excels in accurate bone pathology characterization in TC, confidently excluding synchronous lesions elsewhere, and offering optimal insight into osseous structures and 3D-localization of bone metabolism for surgery planning. Furthermore, even with implanted osteosynthesis material, bone-SPECT/CT can pinpoint the culprit pain generator, where MRI is either contra-indicated or considerably hampered.

Regression of fibrous dysplasia in response to denosumab therapy: A report of two cases.

We present two patients with fibrous dysplasia who showed a decrease in lesional size and activity after denosumab therapy. Both patients also experienced a reduction in pain and bone turnover markers, which had not been accomplished during previous bisphosphonate therapy. These cases highlight the potential of denosumab to decrease lesional size in fibrous dysplasia. This finding has been reported in mice, but not in humans. Denosumab may be considered when bisphosphonates are not tolerated or not effective (enough), or in severe cases as neoadjuvant therapy to improve surgical possibilities and outcome. In addition, these results show that Na[18 F]F PET-CT is suitable for detecting change in each fibrous dysplasia lesion distinctively.

Denosumab Reduces Lesional Fluoride Skeletal Burden on Na[18F]F PET-CT in Patients With Fibrous Dysplasia/McCune-Albright Syndrome.

CONTEXT: The correlation between fibrous dysplasia/McCune-Albright syndrome (FD/MAS) skeletal disease burden on Na[18F]F positron emission tomography-computed tomography (PET-CT) and serum bone turnover markers (BTMs) was recently described. The effect of treatment on lesional fluoride burden in FD/MAS is unknown. OBJECTIVE: To investigate treatment response measurements in patients with FD/MAS who underwent Na[18F]F-PET-CT and treatment with antiresorptives. METHODS: Observational case series at an academic center of expertise for rare bone diseases. Fifteen consecutive patients were observed with FD/MAS with baseline and follow-up Na[18F]F-PET-CT parameters of healthy bone and FD lesions, BTMs, and pain scores at start of denosumab (n = 8) treatment and non-denosumab patients (n = 7). On Na[18F]F-PET-CT the volumetric measures of FD burden (fluoride tumor volume [FTV]) and "fraction affected skeleton" (FAS) represented the portion of the skeleton affected. This was correlated with BTMs and pain. RESULTS: Disease activity decreased significantly, with FTV 361 cm3 to 97 cm3 (P = .018) in denosumab-treated patients, but not in non-denosumab patients (P = .249). Serum P1NP and alkaline phosphatase (ALP) decreased significantly: 82 ng/mL vs 55 ng/mL (P = .023) and 119 IU/L vs 84 IU/L (P = .020), respectively. In denosumab-treated patients pain scores improved leading to pain medication reduction. This correlated with lesional uptake, but healthy bone activity did not change. BTMs and FTV correlated positively (P1NP r = 0.730, P < .001; and ALP r = 0.406, P = .006), as did change in BTMs and FTV: P1NP (P = 0.032) and ALP (P = 0.024). FAS strongly correlated with treatment-induced decrease in ALP (P = .027) and P1NP (P = .009). CONCLUSION: Na[18F]F-PET-CT captured treatment-induced lesional changes which correlated with BTMs and pain reduction. Therefore Na[18F]F-PET-CT can be used as an objective local parameter of response to denosumab treatment in FD/MAS.

Quantifying skeletal burden in fibrous dysplasia using sodium fluoride PET/CT.

PURPOSE: To quantify Na18F-PET/CT uptake in relation to clinical and biochemical parameters of fibrous dysplasia (FD) severity and healthy bone (HB) metabolism. Secondary aims: comparing normalization for volume of distribution and determining reproducibility of Na18F-PET/CT uptake parameters in HB and FD. Relating Na18F uptake to skeletal burden score (SBS), bisphosphonate therapy and pain measured by Brief Pain Inventory (BPI). METHODS: In a prospective cohort study (n = 20), Na18F-PET/CT parameters of HB and FD were assessed by two independent readers to determine the cutoff defining increased bone uptake, optimized normalization, and interobserver agreement (ICC) and were related to SBS, serum biomarkers, medication, and clinical parameters. RESULTS: Physiological bone standardized uptake value (SUV) was best normalized but displayed large interpatient variation (total range 4.1-13.7 g/mL), with very high interobserver agreement (ICC = 0.964). FD burden defined by patient-specific SUV cutoffs reached near-perfect agreement for SUVpeak (ICC = 0.994) and total lesion fluorination (TLF) (ICC = 0.999). TLF correlated weakly with SBS (R2 = 0.384, p = 0.047). TLF correlated positively with serum alkaline phosphatase (R2 = 0.571, p = 0.004) and procollagen type 1 N-terminal propeptide (R2 = 0.621, p = 0.002), SBS did not (p > 0.06). SBS and TLF both correlated with increased fibroblast growth factor-23 (R2 = 0.596, p = 0.007 and R2 = 0.541, p = 0.015, respectively). TLF was higher in use of bisphosphonates (p = 0.023), SBS was not. Average BPI scores correlated to increased FGF-23 (R2 = 0.535, p = 0.045), work-related BPI scores to higher SBS (R2 = 0.518, p = 0.024), higher TLF (R2 = 0.478, p = 0.036), and higher levels of FGF-23 (R2 = 0.567, p = 0.034). CONCLUSIONS: Individualized Na18F-PET/CT SUV cutoffs reproducibly discriminated HB from FD and were well-normalized. The strong relations of bone formation serum markers with Na18F-PET/CT FD burden measurements suggest clinical relevance over SBS as an adjunct instrument in FD patients. The correlation of both imaging modalities with increased work-related BPI scores also indicates clinical applicability. Moreover, SBS is known to remain stationary irrespective of use of medication, whereas TLF on Na18F-PET/CT was higher in baseline patients using bisphosphonates. This makes Na18F-PET/CT a promising tool to quantitatively measure treatment efficacy in FD.

Diagnostic performance of 18F-FDG PET/CT in patients with spinal infection: a systematic review and a bivariate meta-analysis.

PURPOSE: Diagnosis of spinal infection (SI) is challenging and usually requires multiple tests. We aimed to perform a systematic review and a bivariate meta-analysis on the diagnostic role of 18F-FDG PET/CT in patients with SI. METHODS: A comprehensive literature search of studies published through February 2019 in PubMed/MEDLINE and Cochrane library databases was carried out. Studies investigating the diagnostic performance of 18F-FDG PET/CT in patients with SI were eligible for inclusion in the qualitative analysis. For the quantitative analysis, pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR-) and diagnostic odds ratio (DOR) of 18F-FDG PET/CT in patients with suspected SI were calculated on a per examination-based analysis. Pooled data were presented with 95% confidence intervals (95% CI). RESULTS: Twenty-six articles (833 patients) using 18F-FDG PET/CT were eligible for the qualitative analysis. Twelve studies (396 patients) were selected for the meta-analysis. Overall, 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment. The bivariate meta-analysis on 18F-FDG PET/CT in patients with suspected SI provided the following results: sensitivity 94.8% (95% CI 88.9-97.6%) and specificity 91.4% (95% CI 78.2-96.9%). The pooled LR+, LR- and DOR were 4.7 (95% CI 2.9-7.7), 0.11 (95% CI 0.07-0.16) and 63.4 (95% CI 28.9-139), respectively. No significant heterogeneity or publication bias was found. CONCLUSION: 18F-FDG PET/CT demonstrated a very good diagnostic performance in patients with SI and can be used in patients in which MRI cannot be performed or is non-diagnostic or inconclusive. Several studies underlined the value of 18F-FDG PET/CT in assessing the response to treatment in patients with SI. Overall, larger multicentre and prospective studies and cost-effectiveness analyses are warranted.

Anaphylactic Reaction to Tc-99m Macrosalb.

A 49-year-old woman developed an anaphylactic reaction to Tc-99m macrosalb used for pulmonary scintigraphy. The patient received an intravenous injection of Tc-99m macrosalb 120 MBq, containing macroaggregates of human albumin 0.14 mg. Within 1 min she developed itching all over her body, an itching throat and dyspnoea. This was followed by urticaria and facial oedema. She was diagnosed with an anaphylactic shock. The patient received clemastine and prednisone, and fully recovered after release from the hospital. According to the Naranjo assessment algorithm, the relationship between the allergic reaction and the administration of Tc-99m macrosalb should be considered as 'probable'.

Bone SPECT/CT in Postoperative Spine.

Back pain is a common problem and the diagnosis and treatment depend on the clinical presentation, yet overlap between pain syndromes is common. Imaging of patients with chronic back pain in both pre- and postoperative scenarios include radiological, radionuclide, and hybrid techniques. In general, these techniques have their own advantages and limitations. The aim of surgery is to eliminate pathologic segmental motion and accompanying symptoms, especially pain. However, surgical procedures are not without complications and localizing the cause of the pain is often challenging. Radiobisphosphonate bone SPECT/CT is reported to be useful in evaluating benign orthopedic conditions and it often provides valuable information such as accurate localization and characterization of bone abnormalities. In this review, routinely used spinal surgical techniques and procedures are discussed, as well as the acute and delayed complications related to spinal surgery, the role of conventional imaging, and the potential uses of radionuclide bone SPECT/CT to diagnose pseudoarthrosis, cage subsidence, loosening and misalignment, hardware failure, and postoperative infection.

SPECT/CT in Postoperative Hand and Wrist Pain.

In this review we summarize the current evidence and experience regarding the performance of SPECT/CT in the evaluation of patients with postoperative painful wrist or hand. There is a wide range of operative wrist and hand interventions due to congenital, traumatic, degenerative, or inflammatory diseases. A significant number of patients suffer from pain after operative procedures. Several imaging modalities have been used to evaluate the reason for painful postoperative wrists like standard conventional x-rays, ultrasound, CT, MRI, or bone scintigraphy. In the last decade, bone SPECT/CT has offered a new approach in combining metabolic and morphologic cross-sectional information in patients with painful postoperative wrists and is increasingly used if standard imaging fails to identify the pain generator. SPECT/CT is less hampered by artifacts caused by metallic implants and shows more details of the cortical bone compared with MRI. MRI is generally superior regarding visualization of soft tissue structures like tendons, synovia, cartilage, muscles, and ligaments. SPECT/CT arthrography has been established to enable the assessment of cartilage and ligament tears.

SPECT/CT in Postoperative Painful Hip Arthroplasty.

Consecutive milestones in hip arthroplasty design and surgical technique have contributed to the successful and cost-effective intervention this procedure has become today in maintaining mobility and quality of life in patients with osteoarthritis, fracture, or other hip conditions. With the increasing prevalence of hip joint replacements, the need for improved diagnostic imaging tools to guide revision surgery has risen in parallel. Over the last few years, promising data have emerged on the potential role of bone SPECT/CT imaging in the assessment of patients with recurrent pain after arthroplasty. This review summarizes the trends in hip arthroplasty surgery (partial vs total arthroplasty; cemented vs cementless arthroplasty; resurfacing arthroplasty) and prosthesis design (bearing materials; stem designs) over the last decade. In particular, the impact on the biomechanics and interpretation of bone SPECT/CT findings is discussed, with emphasis on integrative reporting in the following frequently encountered conditions: lysis/aseptic loosening, septic loosening, heterotopic ossification, periprosthetic fracture, tendinopathies, and adverse local tissue reactions. Based on the available literature data, bone SPECT/CT is increasingly being used as second-line imaging modality when conventional investigations are nondiagnostic. Further outcome research is warranted to examine whether this technique could be used earlier in patient management.

SPECT/CT in Postoperative Foot and Ankle Pain.

Postoperative pain is a clinically relevant issue in orthopedic patients, affecting more than 40% 1 year after foot and ankle surgery. Because of the very complex anatomy with many different joints and several motion axes, clinical examination and conventional imaging are sometimes not sufficient to identify a local pain generator. Local uptake of bone-seeking radiopharmaceuticals is known to correlate accurately with sites of pain generating foci and, thus, bone scintigraphy has been an established method to evaluate these respective patients for many years. However, the specificity is rather low if only planar images are acquired. The development of SPECT and especially of hybrid SPECT and CT imaging has significantly enhanced the specificity of this technique. The combination of both functional and morphological imaging, ideally performed with a dedicated SPECT/CT system to minimize misregistration owing to motion artifacts and to enhance image quality by attenuation correction, allows an early and reliable detection of pathologic bone processes, even in patients where radiological imaging with MRI or CT is hampered by metal implants. In diabetic patients with a neuropathic Charcot osteoarthropathy, infection can be differentiated from inflammatory bone alterations (causing bone marrow edema) almost certainly using SPECT/CT with radiolabeled white blood cells and antigranulocyte antibodies, allowing an individual and precise treatment planning either in the initial course of the disease or even after surgery. This article reviews the most frequent clinical challenges in patients after foot and ankle surgery, including a description of the various surgical procedures, the different imaging options with their advantages and disadvantages, and aims to integrate bone SPECT/CT into the clinical diagnostic workup.

SPECT/CT in the Postoperative Painful Knee.

This review summarizes the role of SPECT/CT in patients with a painful postoperative knee and describes typical diagnostic criteria in these patients. Pain after knee surgery is common and is influenced by the underlying pathology, the type of surgery, and the patient. Knee joint-preserving surgery includes osteotomy, ligament reconstruction, meniscus surgery, and cartilage repair procedures, often used in combination. Knee arthroplasty procedures consist of unicondylar, patellofemoral, and primary or revision total knee prosthesis. In patients with pain after knee joint-preserving surgery, MRI remains the reference standard. After ligament reconstruction, CT can evaluate postoperative tunnel positioning, and bone SPECT/CT can contribute by assessing overloading or biodegradation problems. After meniscal or cartilage surgery, SPECT/CT can be particularly helpful to identify compartment overloading or nonhealing chondral or osteochondral lesions as cause of pain. SPECT/CT arthrography can assess cartilage damage at an early stage due to altered biomechanical forces. After corrective osteotomy of the knee, SPECT/CT can reveal complications such as overloading, nonunion, or patellofemoral problems. After arthroplasty, conventional radiographs lack both sensitivity to detect aseptic loosening and specificity in differentiating aseptic from infectious loosening. Secondly, hardware-induced artifacts still hamper CT and MRI, despite improving and increasingly available metal artifact reduction techniques. Bone scintigraphy is a proven useful adjunct to conventional radiography and MRI to reveal the pain generator and is less hampered by artifacts from metallic implants compared with CT and MRI. Nevertheless, the optimal imaging strategy in evaluating complications after knee arthroplasty is still a matter of debate. Although the evidence of the use of BS SPECT/CT is still limited, it is growing steadily. In particular, recent data on specific uptake patterns in tibial and femoral zones after total knee arthroplasty and the impact of integrating biomechanics into the assessment of SPECT/CT appear promising, but more research is needed.

PET in Benign Bone Marrow Disorders.

This review aims to describe the current status of benign bone marrow (BM) imaging using PET. BM imaging is important as the BM is not only involved in poiesis of different vital cell lines and can be affected by primary BM disorders, but it is also frequently affected by several extramedullary diseases. Indications for the use of PET in benign BM disorders are the detection of extramedullary hematopoiesis, evaluation of patients with a discrepancy between BM histology and clinical status, visualizing BM infarctions, location of the optimal site for BM biopsy, diagnosing and staging of other hematological BM disorders, evaluation of radiotherapy effect on BM, and evaluation of BM transplantation. The 3'-18F-fluoro-3'-deoxy-L-thymidine (FLT) and 2-18F-2-deoxy-D-glucose (FDG) are the current main PET tracers to image BM physiology and pathology. FLT is a DNA synthesis-related tracer that can be used effectively in primary BM disorders in both diagnosis and monitoring treatment response, for example, in aplastic anemia. In secondary benign BM disorders, FDG-PET reveals that the prevalence of BM involvement in several benign diseases is more common than thought before. Novel PET tracers, such as the proliferation marker 4DST and hypoxia markers FAZA, MISO, and ATSM, are promising to visualize (benign) BM pathology more specifically. PET/MRI using innovative MRI sequences is promising to improve BM imaging in the near future. Additional trials are recommended to evaluate possible clinical applications of these newer tracers and new applications of PET/MRI in daily practice. This should be followed by updated guidelines on the use of PET in benign BM diseases.

The clinical value of lymphatic micrometastases in patients with non-small cell lung cancer.

INTRODUCTION: In early stage non-small cell lung cancer (NSCLC), presence of lymphatic micrometastases and isolated tumor cells, primarily detected by immunohistochemistry, is suggested to be a prognostic factor. However, there is no consensus whether immunohistochemistry should be used routinely in lymph node assessment.The goal of our study was to determine whether recurrent disease is associated with the presence of lymphatic micrometastases and/or isolated tumor cells, at the time of the lung resection. METHODS: We retrospectively analyzed the prevalence of lymphatic micrometastases and/or isolated tumor cells in two groups of patients, who underwent a curative resection for early stage NSCLC. Group I had a follow-up of 5 years without recurrent disease. Group II consisted of a matched group of patients with recurrent disease. Patients were originally classified as having negative mediastinal lymph nodes.All lymph nodes obtained by mediastinoscopy and thoracotomy were re-examined by serial sectioning and immunohistochemistry. RESULTS: Micrometastases and/or isolated tumor cells were found in one of 16 patients in group I, which was significantly different from six of 16 patients in group II. (Fisher exact test, 4.6; p, 0.04; risk ratio, 2.4).Serial sectioning and immunohistochemistry did not change N-stage for the single patient in group I, in contrast to all six patients in group II. CONCLUSION: Presence of lymphatic micrometastases and/or isolated tumor cells is associated with distant recurrence in patients with early stage NSCLC. We recommend the routine use of serial sectioning and immunohistochemistry in lymph node assessment to improve the accuracy of staging.

PET and SPECT in osteomyelitis and prosthetic bone and joint infections: a systematic review.

OBJECTIVE: To review the literature on diagnostic accuracy and clinical value of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) for imaging of bone and joint infections. METHODS: The PubMed/MEDLINE and Embase (OvidSP) literature databases were systematically searched for publications on SPECT and PET on osteomyelitis and prosthetic bone and joint infections using specific guidelines with MeSH-terms, truncations, and completion using cross-references. RESULTS: In 44 original articles (15 for SPECT and 29 for (18)F-fluorodeoxyglucose [FDG]-PET) on osteomyelitis and prosthetic bone and joint infection, 1634 patients were included (580 patients SPECT, 1054 patients FDG-PET). Level of evidence (Oxford criteria) was 2-3b. For SPECT, the highest diagnostic accuracy of 95% for diagnosis of bone and joint infections is achieved with combined (111)In-WBC and (99m)Tc-sulfur colloid. Acceptable diagnostic accuracy was also obtained with (99m)Tc-WBC or (111)In-WBC combined with (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). FDG-PET is useful for diagnosis of osteomyelitis with a sensitivity and specificity generally over 95%. In patients with orthopedic implant infections, sensitivity varies widely from 28% to 91% and specificity from 9% to 97%. This variation in FDG-PET performance in orthopedic implant infections depends largely on the (use of different) criteria to diagnose infection. Determination of the best criteria is still a matter of debate. CONCLUSIONS: SPECT/computed tomography (CT) with (111)In-WBC combined with (99m)Tc-MDP or (99m)Tc-sulfur colloid seems to be the best imaging technique for diagnosis of bone and joint infections. FDG-PET is also useful for diagnosis of osteomyelitis with improved spatial resolution over SPECT imaging, allowing more accurate localization. Localization can be further improved by adding CT. Diagnosis of orthopedic implant infections with FDG-PET depends strongly on the localization of the implant and the criteria used to diagnose infection. Confirmation of well defined criteria to diagnose infection on FDG-PET in patients with metallic implants is thus of paramount importance for optimal diagnosis.

Pleural FDG Uptake More Than a Decade after Talc Pleurodesis.

Talc pleurodesis induces a strong local inflammatory reaction which can be detected by PET scan for years after the procedure. When patients undergo PET scanning in the workup of a suspected malignancy later in life, pleural FDG uptake may unnecessarily lead to an additional invasive diagnostic workup. We present two cases of positive pleural PET findings more than 10 years after talc pleurodesis, where we adopted a watchful waiting approach. Positive pleural PET findings as a result of prior talc pleurodesis should always be included in the differential diagnosis of pleural abnormalities.