[PSMA PET, an important addition in prostate cancer diagnostics]. / PSMA-PET: aanwinst voor de prostaatkankerdiagnostiek.

PSMA PET/CT is a diagnostic technique for patients with prostate cancer. It makes use of a radioligand that specifically binds to 'prostate specific membrane antigen' (PSMA), expressed by the prostate cancer cells. PSMA PET has proven to be highly effective in prostate cancer diagnostics in both primary staging and re-staging. PSMA PET/CT has a much higher accuracy than traditional CT and skeletal scintigraphy for the detection of metastases, allowing metastases to be detected in an earlier stage. The clinical relevance of the improved detection is now under investigation. Staging with PSMA PET/CT sometimes leads to avoiding surgery because distant metastases are found that were not detected with conventional imaging. In the Netherlands, PSMA PET/CT is now indicated both in primary prostate cancer diagnostics for the detection of metastases and for the detection of biochemical recurrence after prostatectomy or after radiotherapy.

Aporte de la centellografía con trazadores tecneciados fosfatados al diagnóstico de amiloidosis cardíaca / Contribution of scintigraphy with technetium phosphated tracers to the diagnosis of cardiac amyloidosis / Contribuição da cintilografia com traçadores fosfatados com tecnécio para o diagnóstico de amiloidose cardíaca

Las amiloidosis son enfermedades causadas por el depósito patológico extracelular de un material proteico fibrilar e insoluble denominado amiloide, que puede estar vinculado a cadenas livianas (AL) o transtirretina (TTR). La amiloidosis cardíaca provoca una cardiomiopatía restrictiva de carácter progresivo caracterizada por falla cardíaca con función sistólica relativamente preservada, que se asocia a elevada mortalidad. Aunque el diagnóstico definitivo tradicionalmente se basa en la biopsia endomiocárdica, los avances en imagenología han mejorado su abordaje y la reciente introducción de terapias especificas permiten augurar cambios significativos en el pronóstico. El tratamiento difiere según el tipo de amiloide involucrado y su resultado depende de la instauración precoz de este, por lo cual resulta esencial un diagnóstico preciso y temprano. El centellograma cardíaco con fosfatos marcados (99mTc-PYP u otros), ampliamente disponible y de relativo bajo costo, se considera en la actualidad como una "biopsia molecular no invasiva" para el diagnóstico de la amiloidosis tipo ATTR, que debe ser usado en conjunto con la investigación de proteínas monoclonales en pacientes con sospecha clínica de la enfermedad.

Amyloidoses are diseases caused by the extracellular deposition of a fibrillar and insoluble protein material called amyloid, which can be linked either to light chains (AL) or transthyretin (TTR). Cardiac amyloidosis causes a progressive restrictive cardiomyopathy characterized by heart failure with relatively preserved systolic function, which is associated with high mortality. Although a definitive diagnosis is traditionally based on endomyocardial biopsy, advances in cardiac imaging have improved its approach, and the recent introduction of specific therapies predicts significant changes in prognosis. Since treatment differs according to the type of amyloid involved and the results depend on a prompt implementation, an accurate and early diagnosis is essential. Cardiac scintigraphy with labeled phosphates (99mTc-PYP or others), widely available and relatively inexpensive, is currently considered a "noninvasive molecular biopsy" for the diagnosis of ATTR type amyloidosis, which should be used in conjunction with investigation of monoclonal proteins in patients with clinical suspicion of the disease.

As amiloidoses são doenças causadas pela deposição patológica extracelular de um material proteico fibrilar e insolúvel, denominado amiloide, que pode estar ligado a cadeias leves (AL) ou transtirretina (TTR). A amiloidose cardíaca causa cardiomiopatia restritiva progressiva caracterizada por insuficiência cardíaca com função sistólica relativamente preservada, que está associada a alta mortalidade. Embora o diagnóstico definitivo seja tradicionalmente baseado na biópsia endomiocárdica, os avanços nos exames de imagem aprimoraram sua abordagem e a recente introdução de terapias específicas pode predizer mudanças significativas no prognóstico. O tratamento varia de acordo com o tipo de amiloide envolvida e seu resultado depende do início precoce, por isso um diagnóstico preciso e precoce é essencial. A cintilografia cardíaca com fosfatos marcados (99mTc-PYP ou outros), amplamente disponível e relativamente econômico, é atualmente considerada uma "biópsia molecular não invasiva" para o diagnóstico de amiloidose do tipo ATTR, que deve ser usada em conjunto com a investigação de proteínas monoclonais em pacientes com suspeita clínica da doença.

Enhanced quantitative method for the diagnosis of grade 1 cardiac amyloidosis in 99mTc-DPD scintigraphy.

The lack of a standardized cut-off value in the quantitative method and an inter-observer disagreement in the evaluation of the semiquantitative score in 99mTc-DPD scintigraphy leaves several patients with cardiac amyloidosis (CA) undiagnosed (grade 1 and H/CL: 1-1.49). This study aims to increase diagnostic productivity of 99mTc-DPD scintigraphy in CA. This is a retrospective study of 170 patients with suspicion of CA. A total of 81 (47.6%) were classified as transthyretin CA (TTR-CA) and 9 (5.3%) as light-chain CA (LC-CA) applying the visual score. An enhanced quantitative method and cut-off point were attempted to reclassify inconclusive patients and reduce inter-observer variability. Applying the proposed quantitative method, of the 19 patients with grade 1 uptake, 2 became grade 0 (none-CA), 2 were reclassified as grade 3 (TTR-CA), and 2 were regrouped as grade 2 (1 TTR-CA and 1 LC-CA). Adjusting the quantitative method's cut-off value to 1.3, four patients previously inconclusive were reclassified as TTR-CA, the diagnosis was confirmed in 3 and rejected in 1. When a 1.3 threshold is compared to 1.5, the sensitivity increases to 94% without reducing its specificity. The quantitative method improves the visual interpretation, reclassifying doubtful cases. The optimization of the cut-off value from 1.5 to 1.3 reclassifies a higher percentage of patients as TTR-CA with a higher sensitivity without reducing its specificity.

Implications of physics, chemistry and biology for dosimetry calculations using theranostic pairs.

Theranostics is an emerging paradigm that combines imaging and therapy in order to personalize patient treatment. In nuclear medicine, this is achieved by using radiopharmaceuticals that target identical molecular targets for both imaging (using emitted gamma rays) and radiopharmaceutical therapy (using emitted beta, alpha or Auger-electron particles) for the treatment of various diseases, such as cancer. If the therapeutic radiopharmaceutical cannot be imaged quantitatively, a "theranostic pair" imaging surrogate can be used to predict the absorbed radiation doses from the therapeutic radiopharmaceutical. However, theranostic dosimetry assumes that the pharmacokinetics and biodistributions of both radiopharmaceuticals in the pair are identical or very similar, an assumption that still requires further validation for many theranostic pairs. In this review, we consider both same-element and different-element theranostic pairs and attempt to determine if factors exist which may cause inaccurate dose extrapolations in theranostic dosimetry, either intrinsic (e.g. chemical differences) or extrinsic (e.g. injecting different amounts of each radiopharmaceutical) to the radiopharmaceuticals. We discuss the basis behind theranostic dosimetry and present common theranostic pairs and their therapeutic applications in oncology. We investigate general factors that could create alterations in the behavior of the radiopharmaceuticals or the quantitative accuracy of imaging them. Finally, we attempt to determine if there is evidence showing some specific pairs as suitable for theranostic dosimetry. We show that there are a variety of intrinsic and extrinsic factors which can significantly alter the behavior among pairs of radiopharmaceuticals, even if they belong to the same chemical element. More research is needed to determine the impact of these factors on theranostic dosimetry estimates and on patient outcomes, and how to correctly account for them.

99m Tc-labeled antibiotics for infection diagnosis: Mechanism, action, and progress.

Discovery of penicillin marked a turning point in the history of infection therapy which also led to the emergence of bacterial resistance. It is now 100 years to fight with ever-muted variants of pathogens by developing more and more antibiotics. Since 1987 to todate, no successful class of antibiotic was introduced; this three decade period is known as "the discovery void" period. While, the clinically approved antibiotics are gradually dying in front of bacterial resistance due to which bacterial infections are appearing leading cause of death and disability. Nuclear medicine imaging technique is the strongest modality to diagnose and follow-up of deep-seated and complicated infections. However, the selection of radiolabeled antimicrobial agents plays critical role in gaining sensitivity and specificity of the imaging results. This review comprises of two main sections; first section explains antibiotic targets, and second section explains the imaging efficacy of 99m Tc-labeled antimicrobial agents against bacterial infection along with the emphasis on progress and update of 99m Tc-labeled antibiotics as infection imaging probes. The review, in conclusion, could be an acceleration for radiopharmaceutical chemists for designing and developing 99m Tc-labeled antimicrobial agents to improve infection imaging quality.

Quantitative assessment of dry mouth in scrub typhus using salivary scintigraphy.

Scrub typhus is an acute febrile illness caused by the intracellular pathogen Orientia tsutsugamushi. The clinical features include fever, myalgia, lymphadenopathy, and dry mouth. However, no studies have assessed the symptom of dry mouth in patients with scrub typhus. We investigated the pattern of salivary scintigraphy during the acute febrile state and compared it with any changes after treatment. Fourteen patients underwent both pre- and post-treatment salivary scintigraphy. Imaging analysis was conducted using radioactivity in the oral cavity, parotid glands, and submandibular glands. During the acute phase, the radioactivity in the oral cavity markedly decreased, while that in the parotid and submandibular glands was preserved. After treatment, radioactivity in the oral cavity showed a significant increase at 20-min, 40-min, and after wash-out. The ejection fraction (%) of the parotid glands also increased after treatment. In contrast, the radioactivity levels of the parotid and submandibular glands were not statistically different after treatment. Salivary scintigraphy indicated that insufficient saliva excretion from the salivary glands into the oral cavity was one reason for the dry mouth reported by patients with scrub typhus. In the future, salivary scintigraphy imaging could contribute to the evaluation of dry mouth in patients with scrub typhus.

Effect of 26 Weeks of Liraglutide Treatment on Coronary Artery Inflammation in Type 2 Diabetes Quantified by [64Cu]Cu-DOTATATE PET/CT: Results from the LIRAFLAME Trial.

Background: Quantification of coronary artery inflammation and atherosclerosis remains a challenge in high-risk individuals. In this study we sought to investigate if the glucagon like peptide-1 receptor agonist liraglutide has a direct anti-inflammatory effect in the coronary arteries using positron emission tomography (PET) with a radioactive tracer targeting activated macrophages in the vessel-wall. Methods: Thirty randomly selected participants with type 2 diabetes from the placebo-controlled trial LIRAFLAME were enrolled in this sub-study. Participants were, prior to enrollment in this sub-study, randomized to either treatment with daily liraglutide (n=15) or placebo (n=15). Both groups underwent a combined [64Cu]Cu-DOTATATE positron emission tomography and computed tomography scan of the heart at baseline and after 26 weeks of treatment. Coronary artery uptake of [64Cu]Cu-DOTATATE were measured as maximum standardized uptake values (SUVmax); and means of the maximum values (mSUVmax), both values were calculated at the level of each participant and each individual coronary-segment. Results: SUVmax and mSUVmax values decreased significantly in the liraglutide group both at the participant level (SUVmax: p=0.013; mSUVmax: p=0.004) and at the coronary-segment level (SUVmax: p=0.001; mSUVmax: p<0.0001). No change was observed in the placebo group neither at the participant level (SUVmax: p=0.69; mSUVmax: p=0.67) or at the coronary-segment level (SUVmax: p=0.49; mSUVmax: p=0.30). When comparing the mean change in uptake values between the two groups at both the participant level (SUVmax: p=0.076; mSUVmax: p=0.077) and the coronary segment level (SUVmax: p=0.13; mSUVmax: p=0.11) a borderline significant difference was observed. Baseline SUVmax [64Cu]Cu-DOTATATE uptake values showed a weak positive correlation with the inflammatory biomarker high-sensitivity c-reactive protein (τ =0.26, p=0.045). Conclusion: Liraglutide treatment for 26-weeks caused a significant reduction in [64Cu]Cu-DOTATATE uptake in the coronary arteries whereas this was not seen in the placebo treated group. In addition, [64Cu]Cu-DOTATATE PET/CT as a marker of coronary inflammation correlated with the systemic inflammation marker hs-CRP.

Growth trends analysis of unilateral condylar hyperplasia followed up with planar scintigraphy: Retrospective overview of 249 cases.

ABSTRACT: The current research aimed to retrospectively investigate the trends of the growth of condylar hyperplasia with serial planar scintigraphs.Patients of unilateral condylar hyperplasia with at least one follow-up planar scintigraph were retrospectively included in the study. Patients' age, gender at the initial scan, durations of following scans, and ratios between condylar activities were recorded.The study retrospectively included 111 patients of unilateral condylar hyperplasia. Patients were divided into 3 groups (progressive, relatively stable, regressive) according to ratio variation between initial and last scans. There were 23 (21%) patients fell into the progressive group, 40 (36%) patients into the relatively stable group, and 48 (43%) patients into the regressive group. More female patients were in the progressive group than those in the other groups (P < .01). There were no significant differences among the 3 groups in terms of age or durations of follow-up (P > .05). There were no strong relations between ratio differences and ages. However, a weak relation seems to exist in the regressive group with r = -0.240, (P = .10).Our investigation showed that more than a half of patients with condylar hyperplasia remain constantly or progressively active growth in patients in the follow-up scans. Roughly less than a half of patients showed regressive trends toward normal growth. Patients' age seemly does not play a role in the growth trend pattern, although there are no optimum follow-up periods, regularly follow-up scans are needed to determine the growth status of condylar hyperplasia.

Reappraisal of bone scintigraphy as a new tool for the evaluation of disease activity in patients with rheumatoid arthritis.

We aimed to compare the reliability of bone scintigraphy (BS) and fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-derived parameters in the detection of active arthritis in 28-joint areas and evaluate the reliability of joint counts between BS and clinical assessment in patients with rheumatoid arthritis (RA). We enrolled 106 patients (67 in the development group and 39 in the validation groups) with active RA who underwent BS, 18F-FDG PET/computed tomography (CT), and clinical evaluation of disease activity. We compared the results of BS-derived joint assessment with those of PET-derived and clinical joint assessments. Subsequently we developed a disease activity score (DAS) using BS-positive joints and validated it in an independent group. The number of BS-positive joints in 28-joint areas significantly correlated with the swollen /tender joint counts (SJC/TJC) and PET-derived joint counts. A BS uptake score of 2 (strong positive) was significantly more sensitive compared with a BS uptake score of 1 (weak positive) in detecting a PET-positive joint among the 28-joints. After conducting multivariate analyses including erythrocyte sediment rate (ESR) and patient global assessment (PGA) in addition to BS-derived parameters, BS/DAS was obtained as follows: 0.056 × number of BS-positive joints in 28 joints + 0.012 × ESR + 0.030 × PGA. A significant correlation between BS/DAS and DAS28-ESR was confirmed in the validation group. Strong positive uptake of BS is sensitive and reproducible for the detection of active joints, and can complement the clinical assessment of disease activity in RA.

Comparison of liver scintigraphy and the liver-spleen contrast in Gd-EOB-DTPA-enhanced MRI on liver function tests.

The liver-spleen contrast (LSC) using hepatobiliary-phase images could replace the receptor index (LHL15) in liver scintigraphy; however, few comparative studies exist. This study aimed to verify the convertibility from LSC into LHL15. In 136 patients, the LSC, not at 20 min, but at 60 min after injecting gadolinium-ethoxybenzyl-diethylenetriaminepentaacetic acid was compared with the LHL15, albumin-bilirubin (ALBI) score, and the related laboratory parameters. The LHL15 was also compared with their biochemical tests. The correlation coefficients of LSC with LHL15, ALBI score, total bilirubin, and albumin were 0.740, -0.624, -0.606, and 0.523 (P < 0.00001), respectively. The correlation coefficients of LHL15 with ALBI score, total bilirubin, and albumin were -0.647, -0.553, and 0.569 (P < 0.00001), respectively. The linear regression equation on the estimated LHL15 (eLHL15) from LSC was eLHL15 = 0.460 · LSC + 0.727 (P < 0.00001) and the coefficient of determination was 0.548. Regarding a contingency table using imaging-based clinical stage classification, the degree of agreement between eLHL15 and LHL15 was 65.4%, and Cramer's V was 0.568 (P < 0.00001). Therefore, although the LSC may be influenced by high total bilirubin, the eLHL15 can replace the LSC as an index to evaluate liver function.

Clinical utility of quantitative analysis of bone scintigraphy in detecting clinically active joint and high disease activity in patients with rheumatoid arthritis.

BACKGROUND: The purpose of this study was to investigate the efficiency of quantitative parameters of bone scintigraphy in detecting clinically active joint and high disease activity in patients with rheumatoid arthritis. METHODS: We retrospectively enrolled 65 patients with rheumatoid arthritis who underwent bone scintigraphy for diagnostic work-up. Quantitative analysis of bone scintigraphy images was conducted using an in-house software, and joint uptake ratio of 28 joints was measured for the calculation of the disease activity score of 28 joints using erythrocyte sedimentation rate (DAS28-ESR). The relationship between joint uptake ratio and clinical findings and the efficiency of joint uptake ratio in detecting clinically active joint and high disease activity were assessed. RESULTS: Clinically active joint (tender and/or swollen joints) showed significantly higher joint uptake ratio than did other non-affected joints (p < 0.05). The sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of joint uptake ratio for identifying clinically active joint were 78.7%, 52.0%, 32.9%, and 89.1%, respectively, and those of the summed joint uptake ratio for detecting high disease activity were 92.9%, 66.8%, 43.3%, and 97.1%, respectively; the joint uptake ratio showed high detection ability, especially for active joints of the elbow, wrist, and metacarpo-phalangeal joint areas. The summed joint uptake ratio of 28 joints showed a significantly strong positive correlation with DAS28-ESR (p < 0.001; correlation coefficient, 0.725). CONCLUSION: Quantitative parameters of bone scintigraphy showed high sensitivity and NPV for detecting clinically active joint and high disease activity in patients with rheumatoid arthritis.

Diagnosis of bone metastases in breast cancer: Lesion-based sensitivity of dual-time-point FDG-PET/CT compared to low-dose CT and bone scintigraphy.

We compared lesion-based sensitivity of dual-time-point FDG-PET/CT, bone scintigraphy (BS), and low-dose CT (LDCT) for detection of various types of bone metastases in patients with metastatic breast cancer. Prospectively, we included 18 patients with recurrent breast cancer who underwent dual-time-point FDG-PET/CT with LDCT and BS within a median time interval of three days. A total of 488 bone lesions were detected on any of the modalities and were categorized by the LDCT into osteolytic, osteosclerotic, mixed morphologic, and CT-negative lesions. Lesion-based sensitivity was 98.2% (95.4-99.3) and 98.8% (96.8-99.5) for early and delayed FDG-PET/CT, respectively, compared with 79.9% (51.1-93.8) for LDCT, 76.0% (36.3-94.6) for BS, and 98.6% (95.4-99.6) for the combined BS+LDCT. BS detected only 51.2% of osteolytic lesions which was significantly lower than other metastatic types. SUVs were significantly higher for all lesion types on delayed scans than on early scans (P<0.0001). Osteolytic and mixed-type lesions had higher SUVs than osteosclerotic and CT-negative metastases at both time-points. FDG-PET/CT had significantly higher lesion-based sensitivity than LDCT and BS, while a combination of the two yielded sensitivity comparable to that of FDG-PET/CT. Therefore, FDG-PET/CT could be considered as a sensitive one-stop-shop in case of clinical suspicion of bone metastases in breast cancer patients.

Review: Radionuclide Molecular Imaging Targeting HER2 in Breast Cancer with a Focus on Molecular Probes into Clinical Trials and Small Peptides.

As the most frequently occurring cancer worldwide, breast cancer (BC) is the leading cause of cancer-related death in women. The overexpression of HER2 (human epidermal growth factor receptor 2) is found in about 15% of BC patients, and it is often associated with a poor prognosis due to the effect on cell proliferation, migration, invasion, and survival. As a result of the heterogeneity of BC, molecular imaging with HER2 probes can non-invasively, in real time, and quantitatively reflect the expression status of HER2 in tumors. This will provide a new approach for patients to choose treatment options and monitor treatment response. Furthermore, radionuclide molecular imaging has the potential of repetitive measurements, and it can help solve the problem of heterogeneous expression and conversion of HER2 status during disease progression or treatment. Different imaging probes of targeting proteins, such as monoclonal antibodies, antibody fragments, nanobodies, and affibodies, are currently in preclinical and clinical development. Moreover, in recent years, HER2-specific peptides have been widely developed for molecular imaging techniques for HER2-positive cancers. This article summarized different types of molecular probes targeting HER2 used in current clinical applications and the developmental trend of some HER2-specific peptides.

Does postoperative quantitative bone scintigraphy reflect outcomes following medial open-wedge high tibial osteotomy?

PURPOSE: The present study evaluated changes in bone tracer uptake (BTU) after medial open-wedge high tibial osteotomy (MOWHTO) and determined whether postoperative BTU correlates with clinical symptoms, radiologic parameters, or cartilage regeneration following MOWHTO. METHODS: A total of 210 knees underwent MOWHTO for medial compartmental osteoarthritis (OA) were enrolled in this study. Mean follow-up period was 42.7 months. We assessed BTU for the medial compartment of the knee before MOWHTO and at the time of plate removal. Radiologic parameters included Kellgren-Lawrence (K-L) grade and Hip-Knee-Ankle angle (HKAA). Clinical evaluation included American Knee Society (AKS) score and cartilage status was graded at the time of MOWHTO and second-look arthroscopy according to the International Cartilage Repair Society (ICRS) grading system and articular cartilage regeneration stage. Statistical analysis performed to assess the relationships among postoperative BTU of the medial compartment, radiologic parameters, arthroscopic changes and clinical outcomes. RESULTS: BTU of medial femoral condyle and tibial plateau were significantly decreased at 2 years after MOWHTO (p<0.001). AKS scores and arthroscopic cartilage status were also significantly improved following MOWHTO. BMI and postoperative HKAA showed significant correlations with postoperative changes of BTU in uni- and multi-variable analysis. Meanwhile, postoperative changes of BTU did not show significant correlation with clinical outcomes or cartilage regeneration following MOWHTO. CONCLUSION: Lower BMI and postoperative valgus alignment were significant predictor for postoperative BTU decrease of the medial compartment following MOWHTO. However, postoperative changes of BTU did not reflect cartilage regeneration or clinical outcomes until the midterm follow-up.