Geoffrey B. Johnson

Receptor-Mediated Monitoring of Tissue Well-Being Via Detection of Soluble Heparan Sulfate by Toll-Like Receptor 4

Perturbations to the well-being of tissues in plants and invertebrates generate fragments of endogenous molecules that are recognized by innate immune receptors. Vertebrates have homologous receptors on specialized cells such as dendritic cells, but whether these receptors respond to fragments of endogenous molecules is not known. We tested the idea that Toll-like receptors on dendritic cells might recognize polysaccharide fragments of heparan sulfate proteoglycan. Dendritic cells were found to mature in response to heparan sulfate as measured by costimulatory protein expression, morphology, and T lymphocyte stimulation, but this maturation was absent when Toll-like receptor 4 was mutated or inhibited. These findings suggest that Toll-like receptors in vertebrates may monitor tissue well-being by recognizing fragments of endogenous macromolecules.

Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 4

Systemic inflammatory response syndrome (SIRS) is typically associated with trauma, surgery, or acute pancreatitis. SIRS resembles sepsis, triggered by exogenous macromolecules such as LPS acting on Toll-like receptors. What triggers SIRS in the absence of infection, however, is unknown. In this study, we report that a SIRS-like response can be induced in mice by administration of soluble heparan sulfate, a glycosaminoglycan associated with nucleated cells and extracellular matrices, and by elastase, which cleaves and releases heparan sulfate proteoglycans. The ability of heparan sulfate and elastase to induce SIRS depends on functional Toll-like receptor 4, because mutant mice lacking that receptor or its function do not respond. These results provide a molecular explanation for the initiation of SIRS.

Conditional signaling by Toll-like receptor 4

Signaling through Toll‐like receptor 4 (TLR4) is thought to initiate innate and adaptive immune responses. Signaling of TLR4 is usually studied using isolated cells, which are activated by subnanomolar concentrations of lipopolysaccharide (LPS). However, in normal tissues, cells bearing TLR4 reside in microenvironments containing large amounts of endogenous substances that can stimulate the receptor. We developed an in vitro model system using the human cell line HEK 293 and an in vivo model using mice that have normal or that lack TLR4 receptors to study how TLR4 functions in such microenvironments. Here we report that signaling through TLR4 is strongly inhibited by intact extracellular matrix and that inhibition is abrogated and endogenous agonist(s) are liberated when the matrix is degraded. Thus, release from inhibition rather than direct stimulation by agonists such as LPS is the critical first event by which TLR4 initiates immune responses.

Percutaneous Cryoablation of Musculoskeletal Oligometastatic Disease for Complete Remission

PURPOSE To assess the safety and effectiveness of percutaneous cryoablation to treat limited metastases to the musculoskeletal system, with the goal of complete disease remission. MATERIALS AND METHODS In a single-institution retrospective study of data from December 2003 to October 2011, 43 consecutive patients underwent initial cryoablation of limited (five or fewer) musculoskeletal metastases with the goal of complete disease remission (ie, no clinical or radiographic evidence of disease). Three patients were lost to follow-up. As a result, the present report describes 40 patients who underwent 40 cryoablation procedures to treat 52 tumors. RESULTS Local control was achieved in 45 of 52 tumors (87%; 95% confidence interval [CI], 75%-93%) at a median follow-up of 21 months (range, 4-62 mo). Thirteen of 19 treated bone metastases (68%) and 32 of 33 soft-tissue metastases (97%) showed local control (P = .007). One- and 2-year overall survival rates were 91% (95% CI, 75%-97%) and 84% (95% CI, 65%-93%), respectively. Median overall survival was 47 months (95% CI, 26-62 mo). One- and 2-year disease-free survival rates were 22% (95% CI, 11%-37%) and 7% (95% CI,<1% to 26%), respectively. Median disease-free survival was 7 months (95% CI, 5-10 mo). Two of 40 procedures (5%) were associated with major complications. CONCLUSIONS Percutaneous cryoablation is a safe and effective treatment to achieve local tumor control and short-term complete disease remission in patients with limited metastatic disease to the musculoskeletal system.

A genetic basis for the "Adonis" phenotype of low adiposity and strong bones.

Toll receptors in Drosophila contribute to host defense and establish the body plan. Mammalian homologues of Toll, the Toll‐like receptors (TLRs), are thought to function only in host defense. Here, we report that mice harboring mutations in TLR4 or in CD14, a co‐receptor for TLR4, have an “ideal” body plan consisting of increased bone mineral content, density, and size as well as decreased body fat. These mutant mice live long lives, have normal activity and fertility, and show no evidence of infection. Unlike many strains of caged wild‐type mice, they do not become obese. Although all mice continue to gain body fat, bone content, and overall weight, the difference in bone content and body fat between mutant and wild‐type mice increases with age. Thus, defects in TLR4/CD14 complex generate an “Adonis” phenotype, characterized by this ideal body type, and this function could potentially be exploited for the treatment of osteoporosis and obesity.

Multicenter Study of Planar Technetium 99m Pyrophosphate Cardiac Imaging: Predicting Survival for Patients With ATTR Cardiac Amyloidosis.

Importance Transthyretin cardiac amyloidosis (also known as ATTR cardiac amyloidosis) is an increasingly recognized cause of heart failure with preserved ejection fraction. In single-center studies, technetium 99m pyrophosphate (Tc 99m PYP) cardiac imaging noninvasively detects ATTR cardiac amyloidosis, but the accuracy of this technique in a multicenter study and the association of Tc 99m PYP myocardial uptake with survival are unknown. Objective To assess Tc 99m PYP cardiac imaging as a diagnostic tool for ATTR cardiac amyloidosis and its association with survival in a multicenter study. Design, Setting, and Participants Retrospective cohort study performed at 3 academic specialty centers for cardiac amyloidosis in the United States in which 229 participants were evaluated for cardiac amyloidosis and also underwent Tc 99m PYP cardiac imaging. The date of analysis and final confirmation from the statistician was May 4, 2016. Exposure Tc 99m PYP cardiac imaging for detection of ATTR cardiac amyloidosis. Main Outcomes and Measures Retention of Tc 99m PYP in the heart was assessed using both a semiquantitative visual score (range, 0 [no uptake] to 3 [uptake greater than bone]) and a quantitative heart to contralateral (H/CL) ratio. The H/CL ratio was calculated as total counts in a region of interest over the heart divided by background counts in an identical size region of interest over the contralateral chest. The outcome measured was time to death after Tc 99m PYP imaging. Results Tc 99m PYP imaging of 171 participants (121 with ATTR cardiac amyloidosis and 50 with non-ATTR cardiac amyloidosis [34 with AL amyloidosis and 16 with nonamyloid heart failure with preserved ejection fraction]; 86% male; median [IQR] age, 73 years [65-79 years]) demonstrated 91% sensitivity and 92% specificity for detecting ATTR cardiac amyloidosis with an area under the curve of 0.960 (95% CI, 0.930-0.981). Univariable and multivariable Cox proportional hazards regression analyses among participants with ATTR cardiac amyloidosis showed that an H/CL ratio of 1.6 or greater predicted worse survival (hazard ratio, 3.911 [95% CI, 1.155-13.247]; P = .03 for univariable analysis and 7.913 [95% CI, 1.679-37.296]; P = .01 for multivariable analysis). In Kaplan-Meier analysis over a 5-year follow-up period, survival was significantly worse if the H/CL ratio was 1.6 or greater rather than less than 1.6 (log-rank P = .02). Conclusions and Relevance In this multicenter study, Tc 99m PYP cardiac imaging conferred a high level of sensitivity and specificity for differentiation of patients with ATTR cardiac amyloidosis (irrespective of genotype) from patients with AL cardiac amyloidosis and patients with nonamyloid heart failure with preserved ejection fraction. An H/CL ratio of 1.6 or greater was associated with worse survival among patients with ATTR cardiac amyloidosis. Among patients for whom there is a high clinical suspicion of cardiac amyloidosis, Tc 99m PYP may be of diagnostic and prognostic importance.

Toll-like receptor-4 and allograft responses

Signaling through toll-like receptors (TLRs) is believed to be the critical first step in the activation of antigen presenting cells and the initiation of adaptive immune responses. Of these receptors, TLR-4 particularly recognizes endogenous agonists and may be important for allograft responses. We tested this concept using mice with defective function and structure of TLR-4 as recipients of grafts across major and minor histocompatibility barriers. The kinetics of rejection was the same in mutant mice and wild-type controls. Our results highlight an important difference between alloimmune and conventional immune responses.

Pitfalls and Artifacts

FDG PET is extremely useful in staging and restaging cancer, differentiating malignant from benign processes, and locating otherwise occult sites of malignancy. However, areas of real or apparent FDG activity do not always represent malignancy. In this chapter we will review the more common categories of pitfalls and artifacts and how they can be recognized and avoided. Pitfalls arise when real benign biologic processes result in imaging findings that mimic malignancy. Common pitfalls are seen with abnormal nonmalignant biologic processes, as well as normal physiologic and anatomic variation. Artifacts are imaging findings that arise in the process of patient preparation and imaging. Artifacts can mimic real biologic processes, or can negatively affect the interpretation of real biologic processes. Common artifacts result from errors related to attenuation correction, motion, truncation, glucose and insulin, FDG injection and uptake. When combining PET and CT imaging, some pitfalls and artifacts are avoided, while others may be newly created or multiplied.

The Added Value of 18F-FDG PET/CT for Evaluation of Patients with Esthesioneuroblastoma

The purpose of this study was to evaluate the clinical utility of 18F-FDG PET/CT in esthesioneuroblastoma staging and restaging and quantify the additional benefit of PET/CT to conventional imaging. Methods: A retrospective review was performed with institutional review board approval for patients with a diagnosis of esthesioneuroblastoma who underwent PET/CT from 2000 to 2010. PET/CT results were retrospectively reviewed by 2 radiologists who were unaware of the clinical and imaging data. Positive imaging findings were classified into 3 categories: local disease, cervical nodal spread, and distant metastasis. All conventional imaging performed in the 6 mo preceding PET/CT, and the medical records, were reviewed to determine the potential added value. Results: Twenty-eight patients (mean age, 52.3 ± 10 y; range, 23–81 y) were identified who underwent a total of 77 PET/CT examinations. Maximum standardized uptake value (SUVmax) was 8.68 ± 4.75 (range, 3.6–23.3) for the primary tumor and 8.57 ± 6.46 (range, 1.9–27.2) for the metastatic site. There was no clear association between primary tumor SUVmax and tumor grade (P = 0.30). Compared with conventional imaging, PET/CT changed disease stage or altered clinical management in 11 (39%) of 28 esthesioneuroblastoma patients. Of these, 10 (36%) of 28 were upstaged on the basis of their PET/CT studies. Cervical nodal metastases were found in 5 (18%) of 28, local recurrence in 2 (7%) of 28, cervical nodal and distant metastases in 2 (7%) of 28, and distant metastases in 1 (4%) of 28. One patient (4%) was downstaged after negative findings on PET/CT. Conclusion: PET/CT is a useful adjunct to conventional imaging in the initial staging and restaging of esthesioneuroblastoma by detecting nodal and distant metastatic disease not demonstrated by conventional imaging and identifying local recurrence hidden by treatment changes on conventional imaging.

Structural and Functional Imaging in Parkinsonian Syndromes

Movement disorders with parkinsonian features are common, and in recent years imaging has assumed a greater role in diagnosis and management. Thus, it is important that radiologists become familiar with the most common imaging patterns of parkinsonism, especially given the significant clinical overlap and diagnostic difficulty associated with these disorders. The authors review the most common magnetic resonance (MR) and molecular imaging patterns of idiopathic Parkinson disease and atypical parkinsonian syndromes. They also discuss the interpretation of clinically available molecular imaging studies, including assessment of cerebral metabolism with 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET), cortical amyloid deposition with carbon 11 ((11)C) Pittsburgh compound B and fluorine 18 ((18)F) florbetapir PET, and dopaminergic activity with iodine 123 ((123)I) ioflupane single photon emission computed tomography (SPECT). Although no single imaging test is diagnostic, a combination of tests may help narrow the differential diagnosis. Findings at (123)I ioflupane SPECT can confirm the loss of dopaminergic neurons in patients with parkinsonism and help distinguish these syndromes from treatable conditions, including essential tremor and drug-induced parkinsonism. FDG PET uptake can demonstrate patterns of neuronal dysfunction that are specific to a particular parkinsonian syndrome. Although MR imaging findings are typically nonspecific in parkinsonian syndromes, classic patterns of T2 signal change can be seen in multiple system atrophy and progressive supranuclear palsy. Finally, positive amyloid-binding PET findings can support the diagnosis of dementia with Lewy bodies. Combined with a thorough clinical evaluation, multimodality imaging information can afford accurate diagnosis, allow selection of appropriate therapy, and provide important prognostic information.