Spatial Atlas for Mapping Vascular Microcalcification Using 18F-NaF PET/CT: Application in Hyperphosphatemic Familial Tumoral Calcinosis.

BACKGROUND: Vascular calcification causes significant morbidity and occurs frequently in diseases of calcium/phosphate imbalance. Radiolabeled sodium fluoride positron emission tomography/computed tomography has emerged as a sensitive and specific method for detecting and quantifying active microcalcifications. We developed a novel technique to quantify and map total vasculature microcalcification to a common space, allowing simultaneous assessment of global disease burden and precise tracking of site-specific microcalcifications across time and individuals. METHODS: To develop this technique, 4 patients with hyperphosphatemic familial tumoral calcinosis, a monogenic disorder of FGF23 (fibroblast growth factor-23) deficiency with a high prevalence of vascular calcification, underwent radiolabeled sodium fluoride positron emission tomography/computed tomography imaging. One patient received serial imaging 1 year after treatment with an IL-1 (interleukin-1) antagonist. A radiolabeled sodium fluoride-based microcalcification score, as well as calcification volume, was computed at all perpendicular slices, which were then mapped onto a standardized vascular atlas. Segment-wise mCSmean and mCSmax were computed to compare microcalcification score levels at predefined vascular segments within subjects. RESULTS: Patients with hyperphosphatemic familial tumoral calcinosis had notable peaks in microcalcification score near the aortic bifurcation and distal femoral arteries, compared with a control subject who had uniform distribution of vascular radiolabeled sodium fluoride uptake. This technique also identified microcalcification in a 17-year-old patient, who had no computed tomography-defined calcification. This technique could not only detect a decrease in microcalcification score throughout the patient treated with an IL-1 antagonist but it also identified anatomic areas that had increased responsiveness while there was no change in computed tomography-defined macrocalcification after treatment. CONCLUSIONS: This technique affords the ability to visualize spatial patterns of the active microcalcification process in the peripheral vasculature. Further, this technique affords the ability to track microcalcifications at precise locations not only across time but also across subjects. This technique is readily adaptable to other diseases of vascular calcification and may represent a significant advance in the field of vascular biology.

Long-term outcome of (neo)adjuvant zoledronic acid therapy in locally advanced breast cancer.

PURPOSE: The role of zoledronic acid (ZOL), a bone-targeted bisphosphonate, in the treatment of patients with breast cancer remains an active area of study. Here, we report the long-term outcomes of a randomized placebo-controlled phase II clinical trial in which ZOL treatment was added to neoadjuvant chemotherapy in women with locally advanced breast cancer. METHODS: 120 women with clinical stage II-III (≥ T2 and/or ≥ N1) newly diagnosed breast cancer were randomized to receive either 4 mg intravenous ZOL every 3 weeks for 1 year (17 total doses) beginning with the first dose of neoadjuvant chemotherapy, or chemotherapy alone. Clinical endpoints included time to recurrence (TTR), time to bone recurrence (TTBR), time to non-bone recurrence (TTNBR), breast cancer survival (BCS) and overall survival (OS). RESULTS: With a median follow-up interval of 14.4 years, there were no significant differences in any of the clinical endpoints studied between the control and ZOL groups in the overall study population. However, ER+/HER2- patients younger than age 45 who were treated with ZOL had significantly worse TTR and TTNBR with a trend towards worse TTBR, BCS and OS (TTR: P = 0.024, HR 6.05 [1.26-29.1]; TTNBR: P = 0.026, HR 6.94 [1.26-38.1]; TTBR: P = 0.054, HR 6.01 [0.97-37.1]; BCS: P = 0.138, HR 4.43 [0.62-31.7]; OS: P = 0.138, HR 4.43 [0.62-31.7]). These differences were not seen in older ER+/HER2- patients or triple-negative patients of any age. CONCLUSION: Addition of ZOL to neoadjuvant therapy did not significantly affect clinical outcomes in the overall study population but was associated with increased extra-skeletal recurrence and a trend towards worse survival in ER+/HER2- patients younger than age 45. These findings suggest caution when using zoledronic acid in young, premenopausal women with locally advanced breast cancer and warrant further investigation. Clinical Trial Registration Number NCT00242203, Date of Registration: 10/17/2005.

Structural and Molecular Imaging-based Characterization of Soft Tissue and Vascular Calcification in Hyperphosphatemic Familial Tumoral Calcinosis.

Hyperphosphatemic Familial Tumoral Calcinosis (HFTC) is a rare disorder caused by deficient FGF23 signaling and resultant ectopic calcification. In this study, we systematically characterized and quantified macro- and micro-calcification in an HFTC cohort using computed tomography (CT) and 18F-sodium fluoride positron emission tomography/CT (18F-NaF PET/CT). Fourier-transform infrared (FTIR) spectroscopy was performed on four phenotypically different calcifications from a patient with HFTC, showing the dominant component to be hydroxyapatite. Eleven patients with HFTC were studied with CT and/or 18F-NaF PET/CT. Qualitative review was done to describe the spectrum of imaging findings on both modalities. CT-based measures of volume (e.g., total calcific burden and lesion volume) and density (Hounsfield units) were quantified and compared to PET-based measures of metabolic activity (e.g., mean standardized uptake values). Microcalcification scores (mCSs) were calculated for the vasculature of six patients using 18F-NaF PET/CT and visualized on a standardized vascular atlas. Ectopic calcifications were present in 82% of patients, predominantly near joints and the distal extremities. Considerable heterogeneity was observed in total calcific burden per patient (823.0 ± 670.1 cm3, n = 9) and lesion volume (282.5 ± 414.8 cm3, n = 27). The largest lesions were found at the hips and shoulders. 18F-NaF PET offered the ability to differentiate active vs. quiescent calcifications. Calcifications were also noted in multiple anatomic locations, including brain parenchyma (50%). Vascular calcification was seen in the distal aorta, carotid, and coronaries in 50%, 70%, 73%, and 50%, respectively. 18F-NaF-avid, but CT-negative calcification was seen in a 17-year-old patient, implicating early onset vascular calcification. This first systematic assessment of calcifications in a cohort of patients with HFTC has identified the early onset, prevalence, and extent of macro- and micro-calcification. It supports 18F-NaF PET/CT as a clinical tool for distinguishing between active and inactive calcification, informing disease progression, and quantification of ectopic and vascular disease burden.

Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare disorder in which patients develop sometimes large debilitating calcifications of soft tissues and blood vessels. It is caused by deficient fibroblast growth factor-23 that leads to high phosphate levels, which contributes to the calcifications. The calcifications and manifestations of this disorder have not been well characterized. We determined the mineral composition of the calcifications to be hydroxyapatite. Capitalizing on the fact fluoride can be integrated into hydroxyapatite, we used radiolabeled sodium fluoride positron emission tomography/computed tomography scans (18F-NaF PET/CT) to characterize and quantify the calcifications in 11 patients. 82% of the patients had calcifications, with the largest located at the hips and shoulders. Micro-calcifications were found in the blood vessels of most patients, including children. The technique also enabled us to differentiate between active versus stable calcifications. This first systematic assessment of calcifications in patients with HFTC showed the utility of 18F-NaF PET/CT as a tool to identify and quantify calcifications, as well as distinguish between active and stable calcifications. This approach will inform disease progression and may prove useful for measuring response to treatment.

Emerging Role of 18F-NaF PET/Computed Tomographic Imaging in Osteoporosis: A Potential Upgrade to the Osteoporosis Toolbox.

Osteoporosis is a metabolic bone disorder that leads to a decline in bone microarchitecture, predisposing individuals to catastrophic fractures. The current standard of care relies on detecting bone structural change; however, these methods largely miss the complex biologic forces that drive these structural changes and response to treatment. This review introduces sodium fluoride (18F-NaF) positron emission tomography/computed tomography (PET/CT) as a powerful tool to quantify bone metabolism. Here, we discuss the methods of 18F-NaF PET/CT, with a special focus on dynamic scans to quantify parameters relevant to bone health, and how these markers are relevant to osteoporosis.

Applications of Artificial Intelligence in 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography:: Current State and Future Directions.

This review discusses the current state of artificial intelligence (AI) in 18F-NaF-PET/CT imaging and the potential applications to come in diagnosis, prognostication, and improvement of care in patients with bone diseases, with emphasis on the role of AI algorithms in CT bone segmentation, relying on their prevalence in medical imaging and utility in the extraction of spatial information in combined PET/CT studies.

Artificial Intelligence in Lymphoma PET Imaging:: A Scoping Review (Current Trends and Future Directions).

Malignant lymphomas are a family of heterogenous disorders caused by clonal proliferation of lymphocytes. 18F-FDG-PET has proven to provide essential information for accurate quantification of disease burden, treatment response evaluation, and prognostication. However, manual delineation of hypermetabolic lesions is often a time-consuming and impractical task. Applications of artificial intelligence (AI) may provide solutions to overcome this challenge. Beyond segmentation and detection of lesions, AI could enhance tumor characterization and heterogeneity quantification, as well as treatment response prediction and recurrence risk stratification. In this scoping review, we have systematically mapped and discussed the current applications of AI (such as detection, classification, segmentation as well as the prediction and prognostication) in lymphoma PET.

Artificial Intelligence in Vascular-PET:: Translational and Clinical Applications.

Positron emission tomography (PET) offers an incredible wealth of diverse research applications in vascular disease, providing a depth of molecular, functional, structural, and spatial information. Despite this, vascular PET imaging has not yet assumed the same clinical use as vascular ultrasound, CT, and MR imaging which provides information about late-onset, structural tissue changes. The current clinical utility of PET relies heavily on visual inspection and suboptimal parameters such as SUVmax; emerging applications have begun to harness the tool of whole-body PET to better understand the disease. Even still, without automation, this is a time-consuming and variable process. This review summarizes PET applications in vascular disorders, highlights emerging AI methods, and discusses the unlocked potential of AI in the clinical space.

Quantitative Craniofacial Analysis and Generation of Human Induced Pluripotent Stem Cells for Muenke Syndrome: A Case Report.

In this case report, we focus on Muenke syndrome (MS), a disease caused by the p.Pro250Arg variant in fibroblast growth factor receptor 3 (FGFR3) and characterized by uni- or bilateral coronal suture synostosis, macrocephaly without craniosynostosis, dysmorphic craniofacial features, and dental malocclusion. The clinical findings of MS are further complicated by variable expression of phenotypic traits and incomplete penetrance. As such, unraveling the mechanisms behind MS will require a comprehensive and systematic way of phenotyping patients to precisely identify the impact of the mutation variant on craniofacial development. To establish this framework, we quantitatively delineated the craniofacial phenotype of an individual with MS and compared this to his unaffected parents using three-dimensional cephalometric analysis of cone beam computed tomography scans and geometric morphometric analysis, in addition to an extensive clinical evaluation. Secondly, given the utility of human induced pluripotent stem cells (hiPSCs) as a patient-specific investigative tool, we also generated the first hiPSCs derived from a family trio, the proband and his unaffected parents as controls, with detailed characterization of all cell lines. This report provides a starting point for evaluating the mechanistic underpinning of the craniofacial development in MS with the goal of linking specific clinical manifestations to molecular insights gained from hiPSC-based disease modeling.